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Stanley J. Dudrick
a d e m e c u V a d e m e c u m
Table of contents
1. Clinical Implications
of Carbohydrate, Proteins,
Lipids, Vitamins and Trace
Elements in Nutrition Support
2. Current Nutrient Substrates
3. Biochemistry of Amino Acids:
Clinical Implications
4. Acute Phase Proteins
in Critically Ill Patients
5. Arginine Metabolism
in Critical Care and Sepsis
6. Wound Healing and the Role
of Nutrient Substrates
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LANDES
B I OS C I E NC E
I SBN 1- 57059- 595- X
LANDES
B I OS C I E NC E
The Biology and Practice
of Current Nutritional
Support
2nd edition
7. Protein Metabolism in Liver
and Intestine During Sepsis:
Mediators, Molecular Regulation,
and Clinical Implications
8. Biochemical Assessment and
Monitoring of Nutritional Status
9. Optimizing Drug Therapy
and Enteral Nutrition: Detecting
Drug-Nutrient Interactions
10. Techniques and Monitoring
of Total Parenteral Nutrition
11. Radiologic Assessment
of Nutritional and Metabolic
Status
12. Enteral Nutrition: Indications,
Monitoring and Complications
(excerpt)
Rifat Latifi, M.D.
Department of Surgery
University of Arizona
Tucson, Arizona, U.S.A.
Stanley J. Dudrick, M.D.
Yale University School of Medicine
St. Marys Hospital/Yale Affiliate
Waterbury, Connecticut, U.S.A.
The Biology and Practice
of Current Nutritional Support
2nd Edition
GEORGETOWN, TEXAS
U.S.A.
v a d e m e c u m
L A N D E S
B I O S C I E N C E
VADEMECUM
The Biology and Practice of Current Nutritional Support, 2nd Edition
LANDES BIOSCIENCE
Georgetown, Texas U.S.A.
Copyright 2003 Landes Bioscience
All rights reserved.
No part of this book may be reproduced or transmitted in any form or by any
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ISBN: 1-57059-595-X
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Dedication
Jonathan Evans Rhoads, M.D.
1907-2002
Dedicated to the surgeon of the century, whose extraordinary personal at-
tributes and countless professional, educational and scientific contributions
serve as the quintessential model that has greatly influenced and inspired the
editors and will continue to endure for future generations.
Rifat Latifi, M.D. and Stanley J. Dudrick, M.D.
Contents
Foreword ....................................................................... xvii
1. Clinical Implications of Carbohydrate, Proteins,
Lipids, Vitamins and Trace Elements
in Nutrition Support ......................................................... 1
Larry H. Bernstein
Overview .................................................................................................... 1
Stress Hypermetabolism and the Nutritionally-Dependent
Adaptive Dichotomy .............................................................................. 2
Energy Requirements of Injured Man ......................................................... 3
Nutritional Requirements ........................................................................... 6
Clinical vs. Laboratory Information ............................................................ 8
Information Model ................................................................................... 10
Length of Stay (LOS) ................................................................................ 11
Improving Correction of Malnutrition...................................................... 11
Nutrition Support Monitoring .................................................................. 12
Quality Management ................................................................................ 13
2. Current Nutrient Substrates ............................................ 17
Wendy Swails Bollinger, Timothy J. Babineau
and George L. Blackburn
Introduction ............................................................................................. 17
Hepatic Disease and Stress: Branched-Chain Amino Acid
Enriched Diets ..................................................................................... 17
Arginine .................................................................................................... 24
Glutamine ................................................................................................ 27
Nucleotides ............................................................................................... 33
Lipids ....................................................................................................... 35
Conclusion ............................................................................................... 43
3. Biochemistry of Amino Acids:
Clinical Implications....................................................... 52
Rifat Latifi, Khawaja Aizimuddin
Introduction ............................................................................................. 52
Structure of Amino Acid and Proteins ....................................................... 52
Amino Acid and Protein Synthesis ............................................................ 53
Post-Synthetic Modification...................................................................... 54
Protein Function ....................................................................................... 54
Classification of Amino Acids ................................................................... 55
Amino Acids in Critical Illness and Injury ................................................ 58
Amino Acids in Circulation ...................................................................... 59
Digestion of Amino Acids ......................................................................... 59
Absorption of Amino Acids ....................................................................... 60
Biochemical Transformation of Amino Acids ............................................ 61
4. Acute Phase Proteins in Critically Ill Patients ................. 63
Khawaja Azimuddin, Rifat Latifi and Rao R. Ivatury
Role of the Acute Phase Response ............................................................. 63
Physiology ................................................................................................ 63
Sequence of Events During Acute Phase Response .................................... 65
Modulation of the Acute Phase Response .................................................. 65
The Acute Phase Proteins .......................................................................... 65
Albumin ................................................................................................... 66
Prealbumin ............................................................................................... 67
Retinol-Binding Protein ............................................................................ 67
Transferrin ................................................................................................ 67
C-Reactive Protein .................................................................................... 67
Ceruloplasmin .......................................................................................... 68
Fibrinogen ................................................................................................ 68
Complement ............................................................................................. 68
Amyloid.................................................................................................... 68
Alpha 1 Acid Glycoprotein ....................................................................... 68
Alpha-1 Protease Inhibitor ........................................................................ 68
Monitoring Nutrition in the Critically Ill Patient ...................................... 69
5. Arginine Metabolism in Critical Care and Sepsis ............ 72
Rima I. Kandalaft, V. Bruce Grossie, Jr.
Pathways of Arginine and Ornithine Metabolism...................................... 72
Fate of Exogenous Arginine ...................................................................... 80
Nitric Oxide in Critical Care .................................................................... 81
Conclusion ............................................................................................... 83
6. Wound Healing and the Role of Nutrient Substrates ...... 88
David A. Lanning, Rifat Latifi
Basic Principles of Wound Healing ........................................................... 88
Malnutrition and Wound Healing ............................................................ 89
Nutritional Supplementation and Wound Healing ................................... 91
Specific Nutrients, Vitamins, and Trace Elements ..................................... 92
Conclusion ............................................................................................... 98
7. Protein Metabolism in Liver and Intestine
During Sepsis: Mediators, Molecular Regulation,
and Clinical Implications .............................................. 103
Timothy A. Pritts, Eric Hungness and Per-Olof Hasselgren
Introduction ........................................................................................... 103
Liver ....................................................................................................... 103
Intestine .................................................................................................. 113
8. Biochemical Assessment and Monitoring
of Nutritional Status ..................................................... 126
Robert S. DeChicco, Laura E. Matarese, Douglas Seidner and Ezra Steiger
The Incidence of Malnutrition ............................................................... 126
Methods of Nutrition Assessment ........................................................... 126
9. Optimizing Drug Therapy and Enteral Nutrition:
Detecting Drug-Nutrient Interactions .......................... 145
Marcia L. Brackbill, Gretchen M. Brophy
Introduction ........................................................................................... 145
Avoiding Tube Occlusions ...................................................................... 145
Pharmacokinetic Interactions .................................................................. 148
Pharmacodynamic Interactions ............................................................... 150
Influence of Tube Placement on Drug Efficacy ....................................... 151
Optimizing Tolerance to Enteral Nutrition and Drug Therapy ............... 152
Summary ................................................................................................ 153
10. Techniques and Monitoring of Total
Parenteral Nutrition...................................................... 158
Renee Piazza-Barnett, Laura E. Matarese, Douglas L. Seidner
and Ezra Steiger
Introduction ........................................................................................... 158
Macronutrients ....................................................................................... 158
Micronutrients/Additives ........................................................................ 159
Access/Delivery ....................................................................................... 162
Monitoring Parameters ........................................................................... 163
Complications of Parenteral Nutrition Therapy ...................................... 165
Cycling Total Parenteral Nutrition .......................................................... 177
Conclusion ............................................................................................. 177
11. Radiologic Assessment of Nutritional
and Metabolic Status ..................................................... 181
Diane R. Horowitz, Rifat Latifi
Introduction ........................................................................................... 181
Ultrasound Use in Assessing Body Composition ..................................... 181
Conclusion ............................................................................................. 190
12. Enteral Nutrition: Indications, Monitoring
and Complications ........................................................ 192
Gayle Minard
Introduction ........................................................................................... 192
Indications .............................................................................................. 192
Contraindications ................................................................................... 194
Monitoring ............................................................................................. 194
Complications ........................................................................................ 195
Conclusion ............................................................................................. 198
13. Enteral Access: Open, Endoscopic
& Laparoscopic Techniques .......................................... 199
Keith Zuccala, John M. Porter
Gastrostomy ........................................................................................... 199
Jejunostomy ............................................................................................ 203
Conclusion ............................................................................................. 206
14. Total Parenteral Nutrition: Current Concepts
and Indications ............................................................. 208
Rifat Latifi, Stanley J. Dudrick
Introduction ........................................................................................... 208
General Indications for Use of TPN........................................................ 209
Specific Indications for Total Parenteral Nutrition .................................. 210
Short Bowel Syndrome ........................................................................... 210
Enterocutaneous Fistula .......................................................................... 211
Inflammatory Bowel Disease ................................................................... 212
Liver Failure ............................................................................................ 212
Acute Pancreatitis .................................................................................... 214
Cancer and TPN: To Feed or Not to Feed? ............................................. 215
15. Intestinal Adaptation: New Insights .............................. 219
Jon S. Thompson
Introduction ........................................................................................... 219
Structural Changes .................................................................................. 219
Functional Adaptation ............................................................................ 220
Summary ................................................................................................ 230
Systemic Factors ...................................................................................... 230
Clinical Implications ............................................................................... 235
16. Intestinal Regeneration and Nutrition .......................... 250
Jon S. Thompson, Shailendra K. Saxena and John G. Sharp
Introduction ........................................................................................... 250
Mechanism ............................................................................................. 250
Clinical Implications ............................................................................... 253
17. Nutritional and Metabolic Management
of Short Bowel Syndrome ............................................. 261
Stanley J. Dudrick, Frizan Abdullah and Rifat Latifi
Introduction ........................................................................................... 261
Pathophysiology ...................................................................................... 263
Nutritional and Metabolic Management ................................................. 265
Immediate Postoperative Period .............................................................. 265
Bowel Adaptation Period ........................................................................ 268
Long-Term Management Period ............................................................. 270
Growth Hormone, Glutamine, and Hormone Modified Diet ................. 270
Surgical Considerations ........................................................................... 271
18. Pharmacologic Aspects of Short Bowel Syndrome ........ 275
Patricia Pecora Fulco, Donald F. Kirby
Physiologic Considerations ..................................................................... 275
Site Specific Contributions ..................................................................... 276
Adaptation .............................................................................................. 278
Intravenous Access in SBS Patients ......................................................... 278
Conclusion ............................................................................................. 296
19. Nutritional Support in Inflammatory Bowel Disease.... 306
John H. Seashore, Melissa F. Perkal
Introduction ........................................................................................... 306
Malnutrition in Inflammatory Bowel Disease ......................................... 306
Nutritional Support in Inflammatory Bowel Disease............................... 309
Summary ................................................................................................ 314
20. Nutrition Support of Acute Pancreatitis........................ 320
Rifat Latifi, Stanley J. Dudrick
Introduction ........................................................................................... 320
Pathophysiology of Acute Pancreatitis ..................................................... 320
Alcohol and Biliary Disease ..................................................................... 322
Oxygen-Derived Free Radicals ................................................................ 322
Pancreatic Ischemia in Experimental Acute Pancreatitis .......................... 323
Metabolic Changes and Other Complications
in Acute Pancreatitis ........................................................................... 323
Biochemical Abnormalities ..................................................................... 325
Lung Injury ............................................................................................ 326
Nutritional Management in Acute Pancreatitis ....................................... 326
The Effects Of Nutrient Substrates ......................................................... 327
Inhibition of Pancreatic Secretion ........................................................... 328
Rationale for TPN in Acute Pancreatitis ................................................. 329
Dextrose and Amino Acids ..................................................................... 329
Lipids ..................................................................................................... 330
Administration and Monitoring of TPN................................................. 330
21. Nutritional Management of Chronic Pancreatitis:
Current Concepts .......................................................... 334
Rifat Latifi, Paul G. Perch and Stanley J. Dudrick
Introduction ........................................................................................... 334
Etiologic and Risk Factors of Chronic Pancreatitis .................................. 335
Nutritional Deficiencies in Chronic Pancreatitis ..................................... 335
Pancreatic Diabetes ................................................................................. 336
Diagnosis of Malabsorption in Chronic Pancreatitis ................................ 336
Principles of Clinical Management of Chronic Pancreatitis ..................... 337
Enteral Feeding ....................................................................................... 338
Total Parenteral Nutrition ....................................................................... 339
Nutrient Substrates in Chronic Pancreatitis ............................................ 339
Enzyme Treatment of Exocrine Pancreatic Insufficiency .......................... 340
The Role of Exogenous Pancreatic Enzymes in Pain Management .......... 341
The Effect of Exogenous Enzymes in Gastrointestinal Hormones ........... 342
Conclusion ............................................................................................. 342
22. Nutritional Support in Liver Failure
and Liver Transplantation ............................................. 346
Rifat Latifi
Introduction ........................................................................................... 346
Malnutrition in Patients with Chronic Liver Disease .............................. 347
Hepatic Encephalopathy ......................................................................... 347
Amino Acids in Hepatic Encephalopathy ................................................ 349
Nutritional Assessment ........................................................................... 350
Peritransplant Nutrition: Support ........................................................... 352
Metabolic Changes ................................................................................. 353
Nutrition Status of Donors ..................................................................... 353
How to Feed Liver Transplant Patients .................................................... 354
Conclusion ............................................................................................. 356
23. Nutritional Support in Renal Transplantation .............. 360
Susan T. Crowley, Richard Formica and Antonio Cayco
Introduction ........................................................................................... 360
Protein Malnutrition and Nitrogen Balance ............................................ 360
Dyslipidemia .......................................................................................... 362
Vitamin Supplementation....................................................................... 364
Bone Metabolism.................................................................................... 365
Summary ................................................................................................ 366
24. Biology of Nutrition Support
in the Critically Ill Patient ............................................ 369
Rifat Latifi, Selman Uranes
Introduction ........................................................................................... 369
Protein and Nitrogen Metabolism in Critically Ill Patients ...................... 370
Amino Acid Metabolism......................................................................... 370
Branched-Chain Amino Acids (BCAA) ................................................... 372
Nucleotides and Nucleic Acids in Nutritional Support ............................ 372
Omega 3-Fatty Acids .............................................................................. 375
Growth Hormone ................................................................................... 375
Immune-Enhancing Enteral Nutrition: Clinical Evidence ....................... 376
Summary ................................................................................................ 378
Selected References ................................................................................. 379
25. Nutrition Support in Patients with Pulmonary
Failure and ARDS ......................................................... 384
Vanessa Fuchs, A.K. Malhotra and Rifat Latifi
Malnutrition and Lung Functions ........................................................... 384
Anatomy of Respiratory Failure .............................................................. 384
Acute Respiratory Distress Syndrome (ARDS) ........................................ 385
Nutritional Assessment ........................................................................... 387
Molecular Basis Nutritional Management ............................................... 389
Summary ................................................................................................ 392
26. Nutritional Support for the Burned Patient .................. 395
G.J.P Williams, Michael J. Muller and David N. Herndon
Introduction ........................................................................................... 395
Hypermetabolism in Burns ..................................................................... 395
Physiologic Responses to Burn Injury ..................................................... 397
Nutritional Support ................................................................................ 399
Hormonal Manipulation of Burn Hypermetabolism............................... 406
Summary ................................................................................................ 409
27. Nutritional Support after Small Bowel
Transplantation ............................................................. 418
S. Janes, S.V. Beath
Introduction ........................................................................................... 418
Recovery from Ischemia and Preservation ............................................... 419
Weaning off Parenteral Nutrition ............................................................ 420
Establishment of Normal Diet ................................................................ 424
Monitoring ............................................................................................. 424
Complications after Intestinal Transplant and Implications
for Nutritional Support ...................................................................... 425
Conclusion ............................................................................................. 426
28. Nutritional Support in Patients with Head
and Neck Cancer ........................................................... 430
Matthew E. Cohen, Rosemarie L. Fisher
Introduction ........................................................................................... 430
Risk Factors for Malnutrition.................................................................. 430
Malnutrition and Clinical Outcome ....................................................... 432
Surgery, Nutritional Support and Clinical Outcome ............................... 434
Radiotherapy, Nutritional Support and Clinical Outcome ...................... 439
Chemotherapy, Nutritional Support and Clinical Outcome .................... 440
Enteral Nutrition Delivery ...................................................................... 441
Surgical Gastrostomy or Jejunostomy...................................................... 444
Conclusion ............................................................................................. 445
29. Nutritional Support in Patients with Gastrointestinal,
Pancreatic and Liver Cancer .......................................... 449
Matthew E. Cohen
Esophageal Cancer .................................................................................. 453
Gastric Cancer ........................................................................................ 455
Colon Cancer ......................................................................................... 456
Pancreatic Cancer ................................................................................... 459
Liver Cancer ........................................................................................... 460
Cost Effectiveness ................................................................................... 463
Conclusion ............................................................................................. 464
30. The Treatment of Obesity ............................................. 473
Souheil Abou-Assi, Rifat Latifi and Stephen J.D. OKeefe
Epidemiology.......................................................................................... 473
Measurements of Obesity ........................................................................ 473
Health Risks Associated with Obesity ..................................................... 474
Can Obesity and Its Co-Morbid Diseases Be Reversed? .......................... 475
Summary of Interventions, and Results of Randomized
Controlled Trials ................................................................................ 475
Bariatric Surgery ..................................................................................... 481
Current Operations ................................................................................ 481
Nutritional Complications Following Bariatric Surgery........................... 484
Index ............................................................................. 489
Editors
Rifat Latifi, M.D.
Associate Professor of Clinical Surgery
Department of Surgery
University of Arizona
Tucson, Arizona, U.S.A.
Chapters 3, 6, 11, 17, 20, 24, 25, 30
Stanley J. Dudrick, M.D.
Professor of Surgery
Yale University School of Medicine
St. Marys Hospital/Yale Affiliate
Waterbury, Connecticut, U.S.A.
Chapters 14, 17, 20, 21
Frizan Abdullah
Department of Surgery
Yale University
New Haven, Connecticut, U.S.A.
Chapter 17
Souheil Abou-Assi
Section of Nutrition
Division of Gastroenterology
Department of Internal Medicine
Richmond, Virginia, U.S.A.
Chapter 30
Khawaja Azimuddin
University of New Mexico
Espanola Hospital
Espanola, New Mexico, U.S.A.
Chapters 3, 4
Timothy J. Babineau
Minimally Invasive Surgery
Boston Medical Center
Boston University School
of Medicine
Boston, Massachusetts, U.S.A.
Chapter 2
S. V. Beath
The Birmingham Children's
Hospital and
University of Birmingham
Birmingham, U.K.
Chapter 27
Larry H. Bernstein
Yale University Pathology
Bridgeport, Connecticut, U.S.A.
Chapter 1
George L. Blackburn
Division of Nutrition
Beth Israel Deaconess Medical
Center
Harvard Medical School
Boston, Massachusetts, U.S.A.
Chapter 2
Wendy Swails Bollinger
Department of Health Matters
Pennsylvania State University
University Park, Pennsylvania, U.S.A.
Chapter 2
Contributors
Marcia Brackbill
Department of Pharmacy
Shenandoah University
Winchester, Virginia, U.S.A.
Chapter 9
Gretchen M. Brophy
Department of Pharmacy
and Neurosurgery
Virginia Commonwealth University
Medical College of Virginia
Richmond, Virginia, U.S.A.
Chapter 9
Antonio Cayco
Section of Nephrology
Yale University School of Medicine
New Haven, Connecticut, U.S.A.
Chapter 23
Matthew E. Cohen
Section of Digestive Diseases
Yale University School of Medicine
New Haven, Connecticut, U.S.A.
Chapters 28, 29
Susan T. Crowley
Section of Nephrology
Yale University School of Medicine
New Haven, Conneticut, U.S.A.
Chapter 23
John M. Daly
Department of Surgery
Weill Medical College of Cornell
University
New York, New York, U.S.A.
Forward
Robert S. Dechicco
The Cleveland Clinic Foundation
Cleveland, Ohio, U.S.A.
Chapter 8
Rosemarie L. Fisher
Section of Digestive Diseases
Yale University School of Medicine
New Haven, Connecticut, U.S.A.
Chapter 28
Richard Formica
Section of Nephrology
Yale University School of Medicine
New Haven, Conneticut, U.S.A.
Chapter 23
Vanessa Fuchs
Hospital General de Mxico
The American British Cowdray
Medical Center
Mxico DF, Mexico
Chapter 25
Bruce Grossie
Department of Nutrition and Food
Sciences
Texas Woman's University
Denton, Texas, U.S.A.
Chapter 5
Per-Olof Hasselgren
Department of Surgery
Beth Israel Medical Center
Harvard Medical School
Boston, Massachusetts, U.S.A.
Chapter 7
David N. Herndon
Galveston Shriners Hospital
Blocker Burn Unit
Galveston, Texas, U.S.A.
Chapter 26
Diane R. Horowitz
Radiologist
Private Practice
Orlando, Florida, U.S.A.
Chapter 11
Eric Hungnness
Department of Surgery
University of Cincinnati
Cincinnati, Ohio, U.S.A.
Chapter 7
Rao R. Ivatury
Virginia Commonwealth University
Department of Surgery
Medical College of Virginia
Hospitals and Physicians
Richmond, Virginia, U.S.A.
Chapter 4
S. Janes
The Birmingham Children's
Hospital and
University of Birmingham
Birmingham, U.K.
Chapter 27
Rima I. Kandalaft
Department of Nutrition and Food
Sciences
Texas Woman's University
Denton, Texas, U.S.A.
Chapter 5
Donald F. Kirby
Section of Nutrition
Medical College of Virginia
Hospitals
Richmond, Virginia, U.S.A.
Chapter 18
David A. Lanning
Childrens Hospital of Michigan
Wayne State University
Detroit, Michigan, U.S.A.
Chapter 6
A. K. Malhotra
Virginia Commonwealth University
Department of Surgery
Medical College of Virginia
Hospitals and Physicians
Richmond, Virginia, U.S.A.
Chapter 25
Laura E. Matarese
The Cleveland Clinic Foundation
Cleveland, Ohio, U.S.A.
Chapters 8, 10
Gayle Minard
Department of Surgery
The University of Tennessee
Memphis, Tennessee, U.S.A.
Chapter 12
Michael M. J. Muller
Department of Surgery
South Auckland Burn Service
Middlemore Hospital
Otahuhu, Auckland, New Zealand
Chapter 26
Stephen J. D. O'Keefe
Section of Nutrition
Division of Gastroenterology
Department of Internal Medicine
Richmond, Virginia, U.S.A.
Chapter 30
Patricia Pecora Fulco
Medical College of Virginia Hospitals
Virginia Commonwealth University
Richmond, Virginia, U.S.A.
Chapter 18
Paul G. Perch
Department of Surgery
Virginia Commonwealth University
Medical College of Virginia
Hospitals and Physicans
Richmond, Virginia, U.S.A.
Chapter 21
Melissa F. Perkal
Department of Surgery
Yale University School of Medicine
New Haven, Connecticut, U.S.A.
Chapter 19
Renee Piazza-Barnett
The Cleveland Clinic Foundation
Cleveland, Ohio, U.S.A.
Chapter 10
John M. Porter
Department of Surgery
University of Arizonia
Tucson, Arizona
Chapter 13
Timothy A. Pritts
Department of Surgery
University of Cincinnati
Cincinnati, Ohio, U.S.A.
Chapter 7
Shailendra K. Sazena
Department of Surgery
University of Nebraska Medical
Center
Omaha, Nebraska, U.S.A.
Chapters 15, 16
John H. Seashore
Yale University School of Medicine
New Haven, Connecticut, U.S.A.
Chapter 19
Douglas L Seidner
The Cleveland Clinic Foundation
Cleveland, Ohio, U.S.A.
Chapters 8, 10
Ezra Steiger
Cleveland Clinic Hospital
Cleveland, Ohio, U.S.A.
Chapter 8
John G. Sharp
Department of Anatomy
University of Nebraska Medical
Center
Surgical Services at the Omaha VA
Medical Center
Omaha, Nebraska, U.S.A.
Chapters 15, 16
Jon S. Thompson
Department of Surgery
University of Nebraska Medical
Center
Omaha, Nebraska, U.S.A.
Chapter 15, 16
Selman Uranues
Department of Surgery
AustriaGraz University
Graz, Austria
Chapter 24
G.J.P. Williams
Clinical Burns Fellow
Shriners Burns Hospital
Galveston, Texas, U.S.A.
Chapter 26
Abdulmasih Zarif
St. Mary's Hospital
Waterberry, Connecticut, U.S.A.
Chapter 17
Keith Zuccala
Danbury Hospital
Danbury, Connecticut, U.S.A.
Chapter 13
Foreword
It has been over 35 years since Dudrick et al described the growth of
beagle puppies fed intravenously demonstrating normal weight gain and
normal growth compared to their orally fed counterparts. This major achieve-
ment is worthy of all the accolades that have been heaped on Drs. Dudrick,
Rhoades and Vars for this work done at the University of Pennsylvania.
These studies demonstrated for the very first time that one could grow an
animal from a young age by administration of all nutrients by vein. This
study in animals was followed shortly thereafter in 1967 by the birth of a
young child with intestinal atresia. She was treated for well over a year with
intravenous nutrition demonstrating normal growth. Studies such as these
were replicated in a whole variety of clinical situations such as trauma, can-
cer, inflammatory bowel disease, radiation enteritis, G-I fistula and poor
wound healing.
Major achievements by Dr. Dudrick were not only to initiate a new therapy
and bring it from the laboratory to the clinical bedside but also to refine the
technique such that it could be applied with low morbidity. The develop-
ment of nutrition support teams and the development of the American So-
ciety of Parenteral and Enteral Nutrition were created by the concept of
teaching proper nutritional support throughout the world. Teams of doc-
tors, nurses, dietitians and pharmacists as well as others came together in
hospitals to administer parenteral and enteral nutrition. Utilization of teams
minimized complications and maximized effectiveness.
The decade of the 1970s was marked by the ever-increasing use of
parenteral nutrition demonstrating its metabolic efficacy in terms of weight
gain, serum protein metabolism, wound healing and improvement in out-
come. Prospective randomized trials were then begun and carried through
into the 1980s evaluating the use of parenteral nutrition compared with
other modalities in situations of cancer treatment.
The use of crystalline amino acids replaced protein hydrolysates. Fat emul-
sions were refined and brought into general use. Multi-vitamin preparations
were better defined along with micronutrient requirements. These studies
were painstaking occurring in both animal models and in humans, but they
were necessary as new nutrient administration techniques gave rise to vita-
min and mineral deficiencies. Early recognition of these problems led to
their solution.
The decades of the 1980s and 1990s demonstrated efficacy of certain
specific amino acids that would provide either metabolic fuels such as
glutamine for the intestinal track and for muscle as well as specific amino
acids such as arginine that might enhance immune effector cell function.
Omega-3 fatty acids, use of RNA and use of specific vitamins and minerals
were demonstrated to enhance immunological cell function. We entered an
age of nutrient pharmacology as noted by Dr. J. Wesley Alexander. Prospec-
tive randomized trials of enteral and parenteral nutrition were carried out in
elective surgery patients as well as critically ill patients in the intensive care
unit. These studies focused not only on clinical outcome measures but also
focused on cost efficiencies. Again, use of nutritional support teams in hos-
pitals minimized morbidity using nutritional support.
Drs. Latifi and Dudrick have superbly put this text, The Biology and
Practice of Current Nutrition Support, together. The chapters vary from
methods of assessing and monitoring nutritional status to those of the use of
intravenous and enteral nutritional support. Practical chapters define
laparoscopic placement of feeding tubes as well as the use of a variety of nutri-
tional substrates, which can be administered in different clinical scenarios.
Of particular importance, is the chapter on nutritional metabolic man-
agement of the short bowel syndrome. Dr. Dudrick was the first to propose
the use of long-term intravenous nutritional support for patients with short
gut syndrome and defined quite well the metabolic needs of these patients.
Many were kept alive for long periods of time by their intestinal tract to adapt
and finally giving way to combinations of enteral and parenteral nutrition.
There is no question that the discovery, implementation and utilization of
total parenteral nutritional support have made enormous benefits to our
patients; saving lives and improving clinical outcome. The recent death of
Dr. Jonathan E. Rhoads, former Chairman of the Department of Surgery at
the University of Pennsylvania and mentor to Dr. Stanley J. Dudrick exem-
plifies the value of an inquisitive mind and the strength of working in part-
nership with many others to achieve beneficial outcomes.
John M. Daly, M.D.
Lewis Atterbury Stimson Professor
Chairman, Department of Surgery
Weill Medical College of Cornell University
Surgeon-in-Chief
New York Presbyterian Hospital-Weill Cornell Center
CHAPTER 1
CHAPTER 1
Clinical Implications of Carbohydrate,
Proteins, Lipids, Vitamins and Trace
Elements in Nutrition Support
Larry H. Bernstein
Overview
Malnutrition occurs in 30-50% of hospitalized patients admitted to acute care
hospitals.
1
Patients who are malnourished or are at malnutrition risk usually have
risk factors or disease co-morbidities, any and all of which, unattended, may ad-
versely affect the outcomes of the surgical patient. Severe malnutrition is usually
easily recognized merely by extreme or significant weight loss, loss of strength, and
loss of function. Identifying severe malnutrition in a timely manner, then, should
lead to appropriate intervention.
1,2
Nevertheless, that is not always the case, and
malnutrition of moderate degree is often unnoticed at the time of admission. It is
especially important for surgeons to be aware of the risk of malnutrition, particu-
larly in the geriatric patient, because of the very strong association between malnu-
trition and postoperative complications.
3,4
Malnutrition occurs with co-morbidities
and is a significant co-morbidity. The surgeon also has to be concerned with the
effects of the metabolic requirements for acute injury independent of and interact-
ing with a malnourished state.
The Malnutrition Risk
The problem of unrecognized patient risk is tied to our conception and defini-
tion of the malnutrition risk. Increasingly, the risk of malnutrition is viewed in
terms of unexpected complications, such as, pneumonia, urinary infection, sepsis,
systemic inflammatory response syndrome (SIRS), which lends itself to expression
in statistical terms. That has not always been the case.
Definitions of Malnutrition
We traditionally make a distinction between marasmus, or chronic inanition
and kwashiorkor. Marasmus is starvation with loss of fat stores and skeletal muscle,
but sparing of circulating transport proteins produced by the liver. Kwashiorkor is
defined by the decrease in circulating plasma proteins. These concepts fit neatly into
measurement criteria using anthropometrics and the laboratory, but they dont em-
body the dynamic changes of the critically-ill patient. We refine our concept of the
high risk surgical patient, in particular, by reviewing the metabolic response to stress
injury.
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
2
The Biology and Practice of Current Nutritional Support
1
Imperative for Nutritional Intervention
The identification of geriatric surgical patients at high risk for malnutrition and
initiating their timely nutritional support is a critical standard of care issue used by
the Joint Commission for Accreditation of Healthcare Organizations. This can be
achieved by a systematized program for identifying patients who might need either
nutritional supplements or aggressive nutritional support. The program has to iden-
tify chronic losses and an acute stress state by both clinical and laboratory charac-
teristics and allow for timely correction of deficits.
5,6
Stress Hypermetabolism and the Nutritionally-Dependent
Adaptive Dichotomy
Stress Injury
Stress injury is described in three stages: the ebb phase, the catabolic flow phase,
and the anabolic flow phase.
7,8
The ebb phase is dominated by circulatory changes
that requires fluid resuscitation over a period of 8-24 hours. The catabolic flow
phase is dominated by catabolism with initial liver glycogenolysis over the first 24
hours concomitant with skeletal muscle proteolysis to provide gluconeogenic sub-
strates, and lipolysis to provide fatty acid fuel for energy after enzyme induction.
This phase lasts for three to 10 days, but may be extended. The anabolic flow phase
emerges as metabolism shifts to synthetic activities and reparative processes.
Cytokine and Hormonal Events
It is essential to control the hormonal and metabolic balances in these phases for
the metabolic management of the stressed patient. The catabolic flow phase is driven
by cytokine mediators released by lymphocytes and macrophages in the cellular
immune reaction, dominated by interleukin-6 (IL-6).
9
The release of these media-
tors is proportionate to the amount of the injury. The release of cytokines is linked
to upregulation of hormonal and humoral events.
9
The hormonal events include
the release of glucagon and catecholamines, thyroid hormone, growth hormone,
and cortisol, and their effectshyperglycemia, metabolic rate, release of free fatty
acids and associated ketosis, insulin growth factor 1 (IGF1), and negative nitrogen
balance from gluconeogenesis.
Catabolic Reactions
The principal action of glucagon is on the conversion of hepatic glycogen to
glucose, thereby, raising the plasma glucose level. Thyroid hormone (T
4
) has an
effect on target organs through the free hormone (FT
4
). The catabolic effect of
growth hormone on lipid metabolism is reciprocal to an anabolic effect through
IGF1. An adrenal cortisol secretory response opposes the action of insulin and
promotes a diabetogenic response. Hypercortisolemia results in muscle proteolysis.
Amino acids, especially branch chains amino acids from skeletal muscle, provide
the gluconeogenic precursors through alanine. These hormones are released by the
stress response and drive the metabolic pathways necessary for the use of carbohy-
drate and fatty acid fuels, and necessary to support the repair of damaged tissue.
The humoral events include the changes in and interactions between serum pro-
teins in the inflammatory response. The systemic effects of fever, tachycardia, in-
creased energy expenditure, muscle weakness and wasting are associated with the
elevations of acute phase reactants (APRs) (C-reactive protein, tumor necrosis
factor-alpha, alpha-1 acid glycoprotein) and hormonal changes.
7,8
3
Clinical Implications of Nutrition Elements
1
Suppressed Syntheses
The stress response immediately suppresses synthetic activity by the liver,
9
an
organ that has a sole synthetic function with NADP dominated pathways. The se-
rum cholesterol decreases as does the production of essential transport proteins,
such as, albumin, transferrin, cortisol-binding globulin (CBG), thyroxine-binding
globulin (TBG), transthyretin or thyroxine-binding prealbumin (TTR), insulin
growth-factor 1 (IGF1).
9
While the transport proteins decline abruptly by as much
as 40%, the synthesis of APRs is unaffected. Their essentially controlling and adap-
tive role they exert through their binding to and effects on active ligands.
Nutritionally-Dependent Adaptive Dichotomy (NDAD)
The above relationship, under the influence of cytokines, Ingenbleek refers to as
the nutritionally-dependent adaptive dichotomy (NDAD).
9
One has to also con-
sider that this adaptive relationship in stress injury is affected by protein malnutri-
tion prior to the injurious state. Why? Because the basal level of binding proteins is
set low and the adaptive response is blunted.
Free Ligands and the Adaptive State
The metabolic effect of stress injury in the catabolic phase increases the flow of
fuel substrates for energy using processes by its effect on the liver. The decrease in
CBG, TBG, TTR and RBP increases the hypermetabolic effect. The free hormone
hypothesis states that hormonal effect on target tissue is a result of the free hormone.
The adrenal gland is releasing increased cortisol which has an amplified effect with
its binding to a lower plasma concentration of CBG. The liver is the repository for
extrathyroidal T
4
. The extrathyroidal T
4
is released with a decreased circulating TBG
and TTR.
9
The result is an increased thyroidal activity measured by an increased
free T
4
(FT
4
). This is actually what is referred to as the sick euthyroid syndrome. The
TSH is not affected or slightly decreased, but not in the hyperthyroid range. Vita-
min A is stored in the liver, and it is transported in the circulation in a complex with
TTR and RBP. The vitamin A and RBP are dependent on the level of TTR.
Effect of Stress Injury on Liver Syntheses
The metabolic effect of stress injury on the liver is coupled with the reciprocal
effect of GSH.
9
The decreased synthesis of GSH dependent IGF1 occurs with a
high level of GSH. The IGF1 promotes anabolism and protein retention. The result
is an increase of lipid utilization with a breakdown of lean body mass to support
gluconeogenesis. The IGF1 is bound to IGF1 binding protein-3 (IGFBP-3), which
is unaffected by stress. The decreased level of IGF1, which has a short halflife of 8
hours, results in a decrease in the free and active protein, supporting the increased
catabolism.
Energy Requirements of Injured Man
Proteolysis and Nitrogen Loss
The hypermetabolism as it affects protein metabolism is measured by the break-
down of skeletal muscle and the oxidation of amino acids through alanine to
alpha-ketoglutarate in the Krebs cycle.
7,8
This results in the release of the amino
group and the production of urea nitrogen through the urea cycle. The somatic
protein loss is also associated with the release of 3-methyl histidine, an amino acid
specific for skeletal muscle that is excreted into the urine with urea nitrogen.
4
The Biology and Practice of Current Nutritional Support
1
Cuthbertson described the catabolic loss of nitrogen that cccurs with severe
injury and is associated with skeletal muscle wasting, loss of strength, and attrib-
uted to extensive breakdown of muscle.
7,8
The increased rate of metabolism in stress
injury is measured by the rate of protein oxidation and by the rate of CO
2
produc-
tion. The rate of protein oxidation is measured by the rate of nitrogen appearance
in the urine. There is normally 4 grams of unmeasured nitrogen to be accounted for
in 24 hours, so the total nitrogen is calculated from urinary urea nitrogen by adding
4 grams, assuming that the nonurea nitrogen is negligible.
Nitrogen Loss and Gluconeogenesis
The rate of gluconeogenesis is decreased in normal man, a nitrogen sparing
effect, when 6-10 grams of carbohydrate is provided. The rate of gluconeogenesis is
not increased in starvation as the body economy relies on lipolysis and fatty acid
fuels associated with ketogenesis. These patients have a normal or decreased urinary
nitrogen. The rate of gluconeogenesis is accelerated during the acute catabolic state,
even when glucose is provided. This is unabated, though, by providing exogenous
glucose.
10
The loss of nitrogen with trauma or sepsis is related to the extent of the
injury.
7,8
Nitrogen balance studies measure nitrogen equilibrium, which is the net
loss or gain of protein from the body.
11
The nitrogen loss after severe injury is
proportional to the severity and extent of trauma, and it tapers off in days. Indeed,
the nitrogen loss is greatest with severe trauma and delayed refeeding. The net ac-
cretion of body protein in the reparative phase is slow in the post-injury phase and
has been measured by Hill and associates using whole body neutron activation
analysis.
12
Anabolism with refeeding occurs at a constant rate of 3 gm of nitrogen
(20 gm protein) per 70 kg body weight per day, but muscle activity is required for
rebuilding the loss.
12
Stress Metabolism of Carbohydrate and Fat
Stress injury results in alterations in carbohydrate and fat utilization. Adipose
tissue is converted to fatty acids and glycerol as described above. Fatty acids are
oxidized by non glucose-dependent tissues. The glycerol is and unoxidized ketones
are used as a glucose fuel. As the concentration of plasma glucose rises in severe
injury, the hyperglycemia is related to crude muscle losses with increased urinary
nitrogen loss. The site of injury is supported by the breakdown of whole body
protein to support the immune response. This is not associated with a lack of insu-
lin, but with increased activities of counterregulatory hormones opposing the insu-
lin action.
9
Fat is not utilized as the primary fuel in the extensively injured extremity
because of the shift to glycolytic metabolism in the injured tissue associated with
increased production of lactate.
7-9
A significant amount of glucose production by
the liver is from lactate and pytuvate as the wound metabolizes glucose.
Measuring Energy Expenditure
Indirect calorimetry and tracer techniques are used to study substrate oxidation
in vivo.
10,13,14
The latter requires blood sampling and is only used in the research
setting. CO
2
production is used to measure substrate oxidation and energy expen-
diture by indirect calorimetry from measurement of respiratory gas exchange rates.
The method assumes the CO
2
expired is proportional to the rate of respiration.
The assumption depends on the O
2
disappearing from the inspired air being used
exclusively for biological oxidations so that all the CO
2
expired is derived from
5
Clinical Implications of Nutrition Elements
1
combustion of substrates. It is also assumed that all of the nonprotein nitrogen
excreted into the urine is derived only from the oxidation of free amino acids, which
is 16% of the nitrogen content. Indirect calorimetry measures the net loss of sub-
strate by oxidation, regardless of cycling that may occur along the way. The method
of indirect calorimetry and the Fick principle both measure the oxygen consump-
tion (VO
2
) and the carbon dioxide production (VCO
2
). Indirect calorimetry mea-
sures the oxygen consumption (VO
2
) and the transpulmonary O
2
gradient from the
respiratory gas exchange. Fick proposed to measure the VO
2
and VCO
2
from gas
exchange and the transpulmonary O
2
and CO
2
gradient by heart catheterization. In
this idealized model, the O
2
input and CO
2
output is measured, and the cardiac
output (CO) provides the flow rate. The result is:
VO
2
= CO (arterial O
2
mixed venous O
2
)
VCO
2
= CO (arterial CO
2
mixed venous CO
2
)
Assuming that ambient air is the only source for O
2
and the only sink for meta-
bolic CO
2
, the VO
2
and the VCO
2
are measured from the fractional concentrations
of O
2
and CO
2
concentrations in the inspired (FI) and the expired (FE) air flows.
The calculation is:
VO
2
= (FIO
2
FEO
2
)Ve
VCO
2
= (FICO
2
FECO
2
)Ve, where Ve is the ventilatory rate.
The only significant difference between these is that the measures of VCO
2
are
12% lower and less accurate with Fick than with indirect calorimetry.
13
Energy of Fuels
The respiratory quotient (RQ), defined as VCO
2
/VO
2
, is the measure of
efficiency of respiration.
10
The calorimetric RQ is between 0.69 and 1.00. The en-
ergy expenditure being measured by the VO
2
, a value of less than 1.0 is incomplete
combustion. RQ is important for calculating the nutritional requirements in pro-
viding assisted nutritional support. The RQ for fat is 0.7, whereas the RQ for carbo-
hydrate is 1.0. We have to weigh the advantage of the administration of fat versus
carbohydrate energy sources. Fat has an advantage over carbohydrate because it is a
dense calorie source and it is efficiently oxidized based on its low RQ. The effect of
excessive carbohydrate calories is excessive CO
2
production, which drives a hyperp-
nea, detrimental to the pulmonary compromized patient. Lipid has a rate of admin-
istration that is rate limited by its clearance. Excessive fat administration is
immunosuppressive.
Harris-Benedict Equation
The use of indirect calorimetry is limited in most clinical settings, except for
intensive care units, because of cost requirements for the technology and for the
staffing. The Harris-Benedict equation is most commonly used to calculate the esti-
mated calorie and protein needs with reasonable agreement with actual needs.
Males BEE = 66.47 + 13.75 W + 5.0 H6.76 A
Females BEE = 655.10 + 9.56 W + 1.85 H4.68 A, where W is weight in
kg, H is height in cm and A is age in years.
Consideration must be given to existing energy needs that go beyond basal or
resting needs. This basic estimate of energy needs (BEE/REE) is often increased to
reflect the energy required for physical activity and any anticipated hypermetabolic
response to injury or illness.
BEE x (activity factor) x (injury factory) = TEE (total energy expenditure)
6
The Biology and Practice of Current Nutritional Support
1
Nutritional Requirements
Energy Requirements Under Stress
The calorie and protein requirements for stressed patients are shown in Table
1.1. For normal energy needs 100-150 g of CHO must be furnished daily. Glucose
oxidation under normal conditions is at approximately 2-4 mg/kg/min, and in
severe stress is only slightly greater at 3-5 mg/kg/min. Catabolism of peripheral
muscle and lipolysis release carbohydrate and lipid substrates in severe stress (14).
An excess of 400-500 g of glucose per day is not used. However, administration of
carbohydrate as a sole energy source has a calorigenic effect, increasing the utiliza-
tion of fuel by about 20% over REE. Protein sparing by glucose is abrogated by
severe stress.
Protein Requirements
Protein is required for growth, maintenance and repair of tissue. 6.25 grams of
protein has one gram of nitrogen. Nitrogen balance occurs when protein synthesis
and breakdown are in equilibrium. Dietary protein contains 20 common amino
acids of which nine are essential. The recommended dietary allowance of protein
for an adult (non pregnant or lactating) is 0.8 g/kg/day. In the catabolic phase of
acute stress or trauma, protein requirements are increased at 1.5 to 2.0 g/kg/day or
more for wound repair, or to replace protein lost in drainage of exudate. The provi-
sion of adequate calories and protein is mandatory.
Fat Requirements
35% of diet intake as fat is required for energy and for essential fatty acids.
EFAD occurs at a ratio of 0.4 or greater. Linolenic acid deficiency is characterized
by: growth retardation, scaly dermatitis, and alteration of the normal triene:tetrene
ratio. Linoleic acid is derived from linoleic and may be derived exogenously. Oils as
corn, soy and safflower contain 50-70% of their fat as linolenic. Linoleic acid is a
precursor of arachidonic acid, which is needed for prostaglandin and thromboxane
synthesis. Most lipid emulsions presently available are composed for the most part
of long chain triglycerides (LCT). Complications from use of LCTs include com-
promised immune function, hyperlipidemia, impaired alveolar diffusion capacity,
and reduced function of the reticulo-endothelial system.
Minerals and Trace Elements
The macronutrients, water and electrolytes constitute the major part of nutri-
ent intake, regardless of the route of administration. The major mineralscalcium,
phosphorus, and magnesium, and electrolytessodium, potassium and chloride
must be provided. They are essential for neuromuscular, cardiac, endocrine and
skeletal function. Potassium is the main intracellular cation and it is in equilibrium
with sodium, divalent cations, and anions. Its intracellular concentration is 140
mmol/L. The total body potassium is 71 mmol/kg. The total body potassium is
depleted in malnourished surgical patients, and it is disproportionately reduced
compared with nitrogen. It is increased with short term TPN without increasing
the total body nitrogen, but long term feeding also increases nitrogen.
11
It is impor-
tant to keep in mind the following:
1. glucose infusions increase the need for K
+
;
2. there is a retention of 3 meq K
+
per gm of nitrogen;
7
Clinical Implications of Nutrition Elements
1
3. infusion of about 80-120 meq K
+
per day is required to replenish stores in
patients receiving TPN.
The most important divalent cation is magnesium, important for membrane,
mitochondrial, and nuclear metabolic functions. The extracellular magnesium ac-
counts for only 3% of the total body magnesium. Magnesium becomes depleted
with protein-energy malnutrition, and it has to be increased to about 15 mmol per
day to improve nitrogen balance. Phosphate is the main intracellular anion. It is
critical for buffering systems, energy linked nucleotide reactions, membrane func-
tion, oxygen transfer systems, and neuromuscular function. The majority of phos-
phorus is in bone matrix with calcium. The serum phosphorus falls rapidly during
TPN, and it is extremely sensitive to the administration of glucose and insulin and
less sensitive to use of a mixed substrate. As with magnesium and potassium, phos-
phorus promotes nitrogen retention. The importance of monitoring for adequate
blood levels of magnesium and phosphate is covered later.
Vitamins
Beyond maintenance requirements, little of a definitive nature is known regard-
ing the needs for vitamins and minerals in critical illness or injury, except for the
nutrients involved in wound repair, as Vit A, Vit C and Zinc.
11
The most important
trace elements for our consideration include iron, zinc, chromium, copper, manga-
nese, iodide, selenium and molybdenum, and cobalt. These are required for meta-
bolic function and their deficiency is associated with specific biochemical change
and functional abnormality that is relieved by giving these nutrients. Of these, co-
balt is associated with vitamin B
12
. These are absorbed in bound and elemental
forms, and they circulate as protein-bound complexes or ligands that are not in free
equilibrium with tissue stores. These are usually incorporated as cofactors of en-
zymes or proteins in tissue. In relationship to this dissociation of plasma level and
tissue stores, the plasma concentration is not a measure the total body stores. For
example, zinc plasma concentration is normal in the hypercatabolic state as zinc is
being lost and the patient is in negative zinc balance. The plasma zinc is maintained
by a net outflow from tissue stores. A positive zinc balance occurs with provision of
nutritional support as there is a net inflow of zinc into tissue with anabolism, and
the plasma level falls unless exogenous zinc is given. Vitamins are active in minute
quantities and have to be provided in any regimen of TPN to avoid deficiency.
Patients with steatorrhea, short bowel, and pancreatic insufficiency require increased
fat soluble vitamins, including 10,000-30,000 IU per day of vitamin A. Patients
with chronic liver disease will have reduced vitamin A stores. Those receiving TPN
may need 3300 IU per day.
Table 1.1. Calorie and protein needs in stress
Stress Clinical Setting CHO% NPC:N Stress
0 Simple starvation 28 150:1 1.0
1 Elective Surgery 32 100:1 1.5
2 Polytrauma 40 100:1 2.0
3 Sepsis 50 180:1 2.5
8
The Biology and Practice of Current Nutritional Support
1
Clinical vs. Laboratory Information
Clinical and Functional Status
The importance of clinical indicators is correlation with functional status and
identification of prior co-morbidities, i.e., cancer, sepsis, major surgical procedure,
prolonged vomiting or diarrhea, fistula, inability to take in or utilize nutrients.
15
These are associated with depletion from hypo- and/or hypermetabolism. Clinical
indicators are excellent categorical criteria for risk assessment, but they can by them-
selves, contribute to over- and underutilization (malutilization) of nutritional sup-
port. Table 1.2 lists clinical risk factors for malnutrition.
Laboratory Evaluation
Laboratory indicators are objective and may be used for measuring calorie and
protein needs, for identifying serious clinical risk of malnutrition, for documenting
agreement between clinical criteria and actual deficits, for documenting anabolic
response from nutrient repletion, and for assessing prognosis.
5,6
These are shown in
Table 1.3. The finding that the laboratory is no better than subjective global assess-
ment is expected concordance between two types of observations. The sensitivity
and onespecificity of a test is actually fitted to a receiver-operator characteristic
curve to remove, as much as possible, the effect of decision value selection, but it is
affected by the choice of the dependent variable that is used to define the outcome.
We have to put into context additional value provided by the laboratory. Agree-
ment between SGA and severe losses for at least two laboratory measures confirms
correlation between clinical and laboratory tests. On the other hand, there are unique
patient (sub)groups (syndromic classes) that have incongruously depressed serum
proteins either because of early protein depletion or repletion that may or may not
agree with clinical assessment.
16
Redundant Laboratory Abnormals
Syndromic classes is treated in the information-based definition of decision-values
proposed by Spiekerman, Rudolph and Bernstein.
16
A simple example of this con-
cept is the observation that a patient has an albumin of 2.7 g/dl AND and lympho-
cyte count of 1,080. In a more formal way, one takes the tests and scales them for
intervals, assigning values in the assigned ranges from 1 to k. The test combinations
form pattern classes, which group into the malnourished and nonmalnourished
groups with frequencies related to risk. The existence of three groups (non-disease,
moderate, severe) requires a multivalued logic with at two decision-values for a
laboratory test. In the absence of a gold standard test to use as a supervisory vari-
able, it would be possible to determine the correct assignment of laboratory data to
each group only if sufficient variables are used to form a classification.
Tests to Monitor
Test selection has a basis in pathophysiology. Hypermetabolism increases pro-
teolysis and gluconeogenesis with loss of muscle mass and amino acid oxidation
resulting in urinary loss of nitrogen as 3-methyl histidine, creatinine, and urea.
Nitrogen loss is a primary measure of stress. The greatest nitrogen losses in trauma
occur in the first few days, at a time when total urinary nitrogen reflects the cata-
bolic phase more accurately than urinary urea nitrogen.
9
Clinical Implications of Nutrition Elements
1
Liver transport proteins are characterized by different rates of production and
degradation, and short halflife is a useful characteristic for following catabolism and
anabolic response. The acute phase proteins, C-reactive protein (CRP) and alpha-1
antitrypsin are elevated with the inflammatory response (ceruloplasmin and trans-
ferrin are also) even when other proteins are severely depressed. CRP is a particularly
good indicator of bacterial infection. CRP and TNF- are increased associated with
the cytokine mediated response, particularly interleukin-6.
Table 1.4 is a comparison of the plasma proteins that are used to assess protein
energy malnutrition (PEM). The phenomenon of protein depletion is referred to as
an inverted acute phase response. Serum albumin, with a halflife of 21 days, is in-
sensitive for measuring anabolism, and its volume distribution makes it a popula-
tion rather than an individual measure of nutrition. It is unsuitable for the dynamic
evaluation of nutritional repletion. Albumin increases by only 0.2 g/dl a week with
aggressive nutrition support. Transferrin, with a halflife of 8 days, is somewhat bet-
ter than albumin, but it is affected by iron balance. Table 1.5 shows the features of
an ideal nutritional marker.
Rapid Turnover Proteins
Proteins with short halflifes less than 2 days, such as transthyretin (prealbumin,
thyroxine-binding prealbumin, TBPA, TTR), are needed to measure the anabolic
response. TTR increases at an expected rate of 1 g/dl a day, or doubles in a week
with nutrition support.
5,16
It may be halved after a week to 10 days NPO. It may be
elevated by corticosteroid therapy after a few days. Retinol-binding protein (RBP),
which has a half-life of 36 hours, circulates bound with vitamin A to TTR in a 1:1:1
molar ratio. The complex is elevated in patients with renal failure on dialysis and
RBP is excreted in the urine. RBP and TTR are both measured easily by nephelom-
etry. Insulin growth-factor 1 (IGF1) or somatomedin C is the best measure of ana-
bolic response because it has the insulin effect without the lipolytic effect of growth
hormone. It is bound to the IGFBP3 receptor and it is difficult to measure because
of an extraction and long incubation time. The method has been improved by an
automated column methodology (Nichols). Arguments have been made for mea-
suring fibronectin, which may have a role in wound healing. Fibronectin is de-
creased in burn patients and appears to be a predictor of sepsis. The most easily
measured of this class of tests is TTR. A TTR of less than 8.5 mg/dl is a critical
Table 1.2. Clinical risk factors
inadequate nutrient intake for 5 days or more
recent unexplained weight loss
surgery or disease of the gastrointestinal tract
unwillingness or inability to eat or eat enough
Table 1.3. Laboratory risk factors
Total lymphocyte count < 1200/mm
2
Pre-Albumin < 11 mg/dl
Transferrin < 150 mg/dl
Albumin < 3.0 g/dl
10
The Biology and Practice of Current Nutritional Support
1
finding for a burn patient because the patient cant hold a graft. A TTR of less than
5 mg/dl is severe protein depletion. A case study illustrates its advantage.
Case Example
An 88-year old woman with lower GI bleeding associated with perforated di-
verticulitis had a surgical resection and proximal diverting colostomy with a some-
what complicated recovery. She was maintained on PPN initially and changed to
central TPN day 13 when she had an obstruction that resolved by day 20 after the
small bowel was decompressed.
Postoperative Day
Test 1 13 16 26 Reference range
ALB, g/L 27 25 25 27 35-55
TTR, mg/L 72 121 160 205 160-350
Information Model
Getting the Most Out of Information
I previously referred to the concept of syndromic classes.
16,17
Even though it is a
formal idea that is measurable, it is not important for surgeons to feel a deficiency
of knowledge with unfamiliarity with this. The truth of the matter is that you use it
often in practice. Clinical decisions are made by observing data from laboratory
and clinical findings together.
The evaluation of nutritional status is somewhat refined by an information model.
The model is derived from the fundamental theory of communication, which uses
Table 1.5. Features of an ideal marker
Identify clinically significant depletion
Reflects severity of deficits
Indicator of current status and change in status
Sensitive to decline
Sensitive to improvement
Minimal interference
Table 1.4. Plasma protein used in nutrition assessment
Albumin: limited value for detecting acute changes in nutritional status.
3.0-3.5 g/dl Mild depletion
2.5-2.9 g/dl Moderate depletion
2.4 or less Severe depletion
Transferrin: half-life of 8 days
Affected by iron metabolism
TTR: half-life is 1.9 days
Early predictor of protein malnutrition
Measures response to nutritional support
A serum TTR < 11 mg/dl is protein malnutrition
TTR decreases at a rate of 0.8 to 1.5 mg/dl per day, depending on the level of stress with no
oral feeding. It doubles in a week with nutritional support.
11
Clinical Implications of Nutrition Elements
1
redundancy to minimize the effects of noise in message transmission. We use an
information model for medical decision-making by treating disease as a symptom
complex that is a coded-message (each coded-message is a syndromic class). The
message transmission can be interpreted from the redundant information (correla-
tion) in the message. Regression is the most common approach to continuous data.
It is a smoothing function and carries a risk of loosing information. It does not
reveal the structure of the data. There are approaches that learn and classify data
(clinical and laboratory) based on analysis of the information content of the data,
such as, recursive partitioning and amalgamation, Rypkas truth table comprehen-
sion,
17
Rudolphs group-based reference,
16
and neural networks. These are based on
classification matrices that are formed by similarities and differences of features that
define data sets. Normal-reference is defined by Rudolph and Bernstein
18
as the set
having no information. That is a departure from distance from the center.
Length of Stay (LOS)
Association between Malnutrition and Length of Hospital Stay
Clinical and laboratory indicators of nutritional status are associated with excess
LOS.
19
The best predictor of nutritional class is a combination of tests.
20
Use of the
chemistry profile can take into account the information in: albumin, total protein,
cholesterol. TTR (prealbumin, transthyretin, thyroxine-binding prealbumin), with
its short halflife (1.9 days), is sensitive to changes in nutrititional status and is an
indication of severity of deficits. It is not affected by hydration status in the way that
albumin is. Serum TTR can be combined with the chemistry panel. These tests may
be scored and used to predict LOS. Although the information model can be used to
examine the relationship between malnutrition and LOS, it can be used to examine
the effects of an implementation program, which includes early feeding, but may
include other measures. In this case LOS becomes an outcome variable and inter-
ventions become inputs.
Improving Correction of Malnutrition
Identify Malnutrition Risk and Intervene
The ability to identify malnourished patients and to implement early interven-
tion has implications for continuous quality improvement.
1
Using laboratory as well
as clinical indicators of malnutrition should allow identification of all patients at
risk within 24 hours of admission. Laboratory tests can be triggered by admission
criteria, such as weight loss, decreased food intake, or medical condition, or they can
be added to a standard admission profile. Advanced age over 65 years or serum
albumin concentration below 3.2 g/dl can be used as automatic criteria for obtain-
ing TTR.
Monitoring Effectiveness of Feeding
The greatest value of TTR is its measure of current nutritional status.
5,6,21
Thereby,
it allows determination of adequacy of feeding, and it should reduce the discharge of
wasted patients who are at risk of readmission. Its physiological range is 16-35 mg/
dl. Serious malnutrition is reflected by a serum concentration < 11 mg/dl, severe at
< 7 mg/dl. It increases at a rate of 1 mg/dl per day with adequate nutritional sup-
port. A TTR concentration of less than 11 mg/dl after a week of nutrition support
or a daily increase of less than 0.5 mg/dl is a reasonable indication that the feeding is
12
The Biology and Practice of Current Nutritional Support
1
inadequate or that the patient is unresponsive. Serum TTR concentration is a prog-
nostic indicator.
Clinical Processes Incorporating Transthyretin (Prealbumin)
A profile including TTR can be incorporated into a clinical practice guideline
implemented through a critical pathway. Although TTR acts as an acute phase
reactant, it can be used to establish a baseline for nutritional support. Urinary ni-
trogen excretion is often used to assess the amount of protein deficit prior to feed-
ing. Failure to increase TTR is an indication of inability to provide adequate nutrients
by method of feeding. Systematic identification of patients at risk, appropriate tim-
ing and mode of feeding, and monitoring effectiveness are essential elements for
such a guideline.
Nutrition Support Monitoring
TTR a Measure of NDAD
We have seen how the use of a short halflife protein, such as TTR can be used
alone, or in combination with serum albumin and clinical indicators for identify-
ing serious risk. TTR is a measure of the NDAD, so the decrease in TTR is associ-
ated with changes in CRP, TNF
alpha
, RBP and IGF1.
9
In some patients who have
recieved high dose corticosteroids, the TTR is elevated, but it is possible to trend
patients as they receive nutritional support. In these patients it might be argued
that urinary nitrogen excretion is done weekly.
Nitrogen Loss
Nitrogen balance is daily intake of nitrogen minus the excretion. The intake
represents nutritional nitrogen and the excretion consists of measured urinary ni-
trogen plus a factor for unmeasured gastrointestinal and cutaneous losses, usually 2
to 4 grams. Nitrogen balance is calculated as:
N intake(urinary N + change BUN + 4)
change in BUN (g) = (0.6 weight) (SUNfSUNi),
where i and f are the initial and final values in the measurement period, SUN is
serum urea nitrogen (g/l), and weight is body weight in kilograms. A positive bal-
ance indicates an anabolic state with an overall gain in body protein for the day. A
negative nitrogen balance indicates a catabolic state with a net loss of protein. Uri-
nary nitrogen excretion may rise to 30-50 g/day with severe stress, which is the
equivalent of 1 to 1.5 kg of lean body mass.
Overfeeding and Monitors
We have already considered the consequence of lipids versus carbohydrate as an
energy source. The effects of excess carbohydrate are hyperglycemia and on driving
pCO
2
production with CO
2
retention. Carbohydrate also leads to fatty liver. This
necessitates the close monitoring of pCO
2
measurement for patients on nutritional
support and less frequent evaluation of liver function, such as the alkaline phos-
phatase. Table 1.6 lists the complications of overfeeding. The electrolytes have to be
monitored because of losses from fluid loss. The fluid associated electrolyte losses
are listed in Table 1.7.
We have to add to the complications the serious effect of hypophosphatemia.
Hypophosphatemia and hypokalemia can both occur as a result of the refeeding
syndrome. They have to be watched as closely as the pCO
2
, the glucose, and the
13
Clinical Implications of Nutrition Elements
1
TTR. The K
+
, Mg
2+
and H
2
PO
3
2-
are intracellular cations and anion, respectively.
They move into the cell and out of the circulation with refeeding. They are critical
for excitation-contraction coupling, and failure to monitor these can result in sud-
den death. In the case of magnesium, the serum level is not an accurate measure of
the total body load. A patient with tetany may have low calcium concentration, but
if the calcium fails to resolve this, than administration of magnesium is the best test.
Table 1.8 lists the requirements for monitoring phosphate levels. The lowering of
serum phosphorus levels leads to a decrease in ATP and other phosphorylated com-
pounds in the tissues and blood. When the serum level falls to 1.0 mg/dl or lower,
leukocyte dysfunction and a potential for sepsis occurs. In addition, reduced nucle-
otide production due to hypophosphatemia can result in hemolytic anemia, neuro-
muscular dysfunction, myocardial depression and respiratory failure. Adequate
treatment of the severely malnourished patient requires adequate nutritional sup-
port with careful monitoring. Repletion must be initiated slowly while monitoring
serum phosphorus, along with serum electrolytes, glucose, and magnesium levels.
Quality Management
Excess LOS variation is a global outcome variable. It is dependent on extended
period after surgery without oral intake (Meguids IONIP), initial condition, unex-
pected complication (wound site infection, pneumonia), and malnutrition. The ef-
fect of nutritional status is independent and interacts with the other factors. The
laboratory tests predict outcome by forming severity classes. Mozes et al
22
recently
classified surgical and nonsurgical major diagnostic categories into groups homoge-
neous with respect to LOS from seven laboratory values (wbc, Na, K, CO
2
, BUN,
HCT, ALB) for 73,117 admissions at UCSF and Stanford. Studies have shown that
Hb, cholesterol
23
and insulin-like growth factor 1 (IGF1)
24
are predictors of mortal-
ity. Nutritional markers are important tests in any analysis.
Quality Management has to focus on medical outcomes of alternative strategies,
i.e., feeding, not feeding, delayed intervention, and the costs of interventions. Policy
considerations are the organizational purview of a Nutrition Committee and the
Nutrition Support Team. The cost of data collection can be significant. The cost of
prevention, with an effect on under- and over-utilization, can be less than the cost of
failure to develop a system. The use of the laboratory has a low cost in supporting a
system of quality management.
The information model has been used to determine optimum decision-values
for tests, and has been used to examine the relationship between tests, malnutrition
and LOS. It can be used to examine differences in the effects of interventions. Not
all interventions can be assumed to be equivalent. Preoperative feeding for five days
before a major procedure assumes utilization costs that have a different significance
for marginally than severely at risk patients. Perioperative interventions, intrave-
nous and enteral, are uniquely identified input variables. In addition to the assign-
ment of treatment effects, it is necessary to identify the initial pretreatment condition
as distinguished from the treatment effects. Therefore, laboratory data need to be
adequate to examine post-treatment status. These can be described in the form of a
truth table with each defining variable as a column and each patient as a row.
It is important to recognize that a quality improvement model for nutritional
interventions has to take into account the expectations of costs to do nothing, the
expected costs of alternative interventions, and the costs reduced by failure avoid-
ance. Traditional cost accounting models are not adequate for the complexity
of the issues.
14
The Biology and Practice of Current Nutritional Support
1
The ability to identify malnourished patients and to implement early interven-
tion has implications for continous quality improvement (1). Using laboratory as
well as clinical indicators of malnutrition should allow identification of all patients
at risk within 24 hours of admission. Laboratory tests can be triggered by admis-
sion criteria, such as weight loss, decreased food intake, or medical condition, or
they can be in a standard admission profile.
Transthyretin (prealbumin, thyroxine-binding prealbumin, TBPA, TTR) is a
transport protein with a short halflife (1.9 days) that is sensitive to changes in
nutrititional status and is an indication of severity of deficits. It allows determina-
tion of adequacy of feeding, and it should reduce the discharge of wasted patients
who are at risk of readmission. It has a physiological range of 16-35 mg/dl. Serious
Table 1.6. Problems of overfeeding
excess CO
2
production
fat deposition
hyperglycemia
pulmonary edema
worsening of existing congestive heart failure
hepatic complications
Table 1.7. Etiology of common electrolyte deficiencies
Electrolyte Cause of Deficiency
Sodium Loss of skin, GI tract, lungs or kidney
Kidneydiuretic use, renal damage, adrenal insuffic
Potassium Starvation, loss from skin, bile, lower GI tract or fistula.
Renal: diuretics, alkalosis, Amphotericin
Bicarbonate Diarrhea, pancreas or small bowel loss, renal tubular acidosis,
mineralcorticoid deficiency
Chloride Diuretics, gastric loss, intestinal loss, secretory loss, renal
reabsorption due to drug therapy-carbenicillin, sulfate, phosphate
Magnesium starvation, intestinal loss, malabsorption, diarrhea, laxative abuse,
diuretics, cyclosporin
Phosphorus starvation, alkalosis, glucose administration, diabetic keto
acidosis, GI tract losses, aluminum containing antacids.
Table 1.8. Clinical conditions for which phosphorus levels should
be monitored during treatment
Refeeding phase for the malnourished patient
Alcohol withdrawal and nutritional support
Insulin therapy with diabetic keto-acidosis
Phosphate binding antacid therapy
Recovery diuretic phase after severe burns
Severe respiratory alkalosis
15
Clinical Implications of Nutrition Elements
1
malnutrition is reflected by a serum concentration < 11 mg/dl, severe at < 7 mg/dl.
It increases at a rate of 1 mg/dl per day with adequate nutritional support. The table
of ranges shows the effect of nutrition support on TBPA. Moderately malnourished
patients with low ALB have increased TBPA with nutrition support.
A profile including TTR can be incorporated into a clinical practice guideline
implemented through a critical pathway. Although TTR acts as a acute phase reac-
tant, it can be used to establish a baseline for nutritional support. Urinary nitrogen
excretion is often used to assess the amount of protein deficit prior to feeding. Fail-
ure to increase TTR is an indication of inability to provide adequate nutrients by
method of feeding. Systematic identification of patients at risk, appropriate timing
and mode of feeding, and monitoring effectiveness are essential elements for such a
guideline.
Selected References
1. Brugler L, DiPrinzio MJ, Bernstein L. The five-year evolution of a malnutrition
treatment program in a community hospital. J Qual Imp. 1999; 25:191-206.
2. Bernstein LH, Shaw-Stiffel TA, Schorow M et al. Financial implications of malnu-
trition. In: Labbe R, ed. Clinics in laboratory medicine. Nutition support. Vol 13.
Philadelphia: Saunders, June 1993:491-506.
3. Meguid MM, Mughal MM, Meguid V et al. Risk-benefit analysis of malnutrition
and preoperative nutrition support: a review. Nutr Int 1987; 3:25-34.
4. Meguid MM, Campos ACL, Meguid V et al. IONIP: a criterion of surgical out-
come and patient selection for preoperative nutritional support. Br J Clin Pract
1988; 42(suppl 63):8-14.
5. Bernstein LH, Leukhardt-Fairfield CJ, Pleban W et al. Usefulness of data on albu-
min and prealbumin concentrations in determining effectiveness of nutritional
support. Clin Chem 1989; 35:271-274.
6. Bernstein LH. Utilizing laboratory parameters to monitor effectiveness of nutri-
tional support. Nutr Int 1994; 10:58-60.
7. Kinney JM. Metabolic Responses to Injury. Chapter 2. In: Winters RW, Greene
HL, eds. Nutritional Support of the Seriously Ill Patient. New York: Academic
Press, 1983:5-12.
8. Wilmore DW, Black PR, Muhlbacher F. Injured Man: Trauma and Sepsis. Chap-
ter 4. In: Winters RW, Greene HL, eds. Nutritional Support of the Seriously Ill
Patient. New York: Academic Press, 1983:33-52.
9. Ingenbleek Y, Bernstein L. The stressful condition as a nutritionally dependent
adaptive dichotomy. Nutrition 1999; 15:305-320.
10. Kinney JM. Energy Metabolism: Heat, Fuel and Life. Chapter 1. In: Kinney JM,
Jeejeebhoy KN, Hill GL et al, eds. Nutrition and Metabolism in Patient Care.
Philadelphia: W.B. Saunders, Harcourt Brace Jovanovich, 1988:3-34.
11. Jeejeebhoy KN. Nutrient Metabolism. Chapter 3. In: Kinney JM, Jeejeebhoy KN,
Hill GL et al, eds. Nutrition and Metabolism in Patient Care. Philadelphia: W.B.
Saunders, Harcourt Brace Jovanovich, 1988:60-88.
12. Hill GL, King RFGJ, Smith RC et al. Multi-element analysis of the living body by
neutron activaion analysisapplication to critically ill patients receiving intrave-
nous nutrition. Br J Surg 1979; 66:868-72.
13. Ferrannini E. Equations and Assumptions of Indirect Calorimetry: Some Special
Problems. In: Kinney JM, Tucker HN, eds. Energy Metabolism: Tissue Determi-
nants and Cellular Corollaries. New York: Raven Press, 1992:1-17.
14. Young VR, Yong-Ming Y, Fukagawa NK. Whole Body Energy and Nitrogen (Pro-
tein) Relationships. In: Kinney JM, Tucker HN, eds. Energy Metabolism: Tissue
Determinants and Cellular Corollaries. New York: Raven Press, 1992:139-161.
16
The Biology and Practice of Current Nutritional Support
1
15. Jeejeebhoy KN, Baker JP, Wolman SL et al. Critical evaluation of the role of clini-
cal assessment and body composition studies in patients with malnutrition after
total parenteral nutrition. Am J Clin Nutr 1982;35:1117-27.
16. Spiekerman AM, Rudolph RA, Bernstein LH. Determination of malnutrition in
hospitalized patients with the use of group-based reference. Arch Path Lab Med
1993; 117:184.
17. Rypka EW. Methods to evaluate and develop the decision process in the selection
of tests. In: McPherson RA, Nakamura RM, eds. Clinics in laboratory medicine.
Laboratory immunology II. Strategies for clinical laboratory management. Vol 12.
Philadelphia: Saunders, June 1992:351.
18. Rudolph RA, Bernstein LH, Babb J. Information-Induction for the diagnosis of
myocardial infarction. Clin Chem 1988; 34:2031-2038.
19. Shaw-Stiffel TA, Zarny LA, Pleban WE et al. Effect of nutrition status and other
factors on length of hospital stay after major gastrointestinal surgery. Nutr Int
1993; 9:140-145.
20. Bernstein LH, Shaw-Stiffel T, Zarny L et al. An information approach to likeli-
hood of malnutrition. Nutrition 1996; 12(9/10):772-776.
21. Bernstein LH (Chairman). Prealbumin in Nutritional Care Consensus Group. Mea-
surement of visceral protein status in assessing protein and energy malnutrition:
Standard of care. Nutrition 1995; 11:169-171.
22. Mozes B, Easterling MJ, Sheiner LB et al. Case-mix adjustment using objective
measures of severity: The case for laboratory data. Health Services Research 1994;
28[6]:689-712.
23. Verdery RB, Goldberg AP. Hypocholesterolemia as a predictor of death: a prospec-
tive study of 224 nursing home residents. J Gerontol:Med Sci 1991; 46:M84-M90.
24. Sullivan DH. The role of nutrition in increased morbidity and mortality. (Review)
Clin Geriatric Med 1995; 11:661-74.
CHAPTER 1
CHAPTER 2
Current Nutrient Substrates
Wendy Swails Bollinger, Timothy J. Babineau and George L. Blackburn
Introduction
Traditionally, nutrition support was simply the provision of calories and protein.
More recently, however, we have discovered that manipulation of certain nutrients
may significantly alter the response to illness and facilitate the healing process. These
findings suggest that patient-specific feeding with nutrient-specific formulas may
hold promise for improved patient outcome. This chapter discusses some of the
advantages and disadvantages of administering certain nutrient substrates, specifically
branched-chain amino acids, arginine, glutamine, nucleotides, and lipids.
Hepatic Disease and Stress: Branched-Chain Amino Acid
Enriched Diets
Hepatic Disease
The discovery of altered plasma amino acid concentrations (low branched-chain
amino acids and high aromatic and sulfur- containing amino acids) in patients with
hepatic encephalopathy prompted the development of branched-chain enriched
parenteral and enteral formulas. These formulas differ from conventional amino
acid formulas in that they contain a greater concentration of the branched-chain
amino acids (BCAA) leucine, valine, isoleucine and a lower amount (or none) of the
aromatic amino acids (AAA) phenylalanine, tyrosine, tryptophan and the
sulfur-containing amino acid methionine. The modified amino acid profile in these
solutions is thought to counterbalance the altered plasma amino acid concentra-
tions seen in patients with hepatic encephalopathy. These plasma amino acid alter-
ations are a result of an increased utilization of BCAA by the peripheral muscles and
a decreased metabolism of the AAA by the failing liver.
The use of BCAA-enriched formulas in patients with encephalopathy is based
predominantly upon the AAA/false neurotransmitter theory.
1
Fischer postulated that
the decrease in BCAA and increase AAA plasma concentrations seen in patients
with hepatic dysfunction allows a disproportionate amount of AAA to cross the
blood brain barrier. As a result, there is an increase in serum levels of false neu-
rotransmitters (octopamine and phenyethylanine) and a concomitant decrease in
the levels of normal neurotransmitters (dopamine and norepinephrine). In addition,
there is an increased serum serotonin concentration (physiologic neuroinhibitor)
due to excess tryptophan. This altered ratio of BCAA to AAA is believed to contribute,
in part, to the development of encephalopathy. It was Fisher and colleagues who
first noted that the administration of BCAA-enriched, low AAA solutions to animals
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
18
The Biology and Practice of Current Nutritional Support
2
and humans with hepatic encephalopathy resulted in more normal patterns of plasma
amino acid concentrations and an improvement in encephalopathy.
2,3
A number of prospective, randomized clinical trials have investigated the use of
parenteral BCAA solutions when hepatic encephalopathy is present.
3,4-6
Most of
these trials have shown no significant change in mental status. It is important to
note, however, that many of the early trials used solutions containing only BCAA as
opposed to the BCAA-enriched, low AAA formulas typically used today. In an early
multicenter, prospective, randomized trial, 34 patients with cirrhosis of the liver
(predominantly cryptogenic) and grade III to IV hepatic encephalopathy received
either an intravenous solution containing 60 g of BCAA only in 20% dextrose or
lactulose (30-40 g every 4 hours via a nasogastric tube or 200-300 g/day via in-
termittent rectal enemas) plus 20% dextrose.
4
Seventy percent of the patients
receiving the BCAA solution regained consciousness (defined as grade 0 hepatic
encephalopathy) within 48 hours compared to only 47% in the lactulose group.
Although this difference was not statistically significant, the authors concluded that
parenteral administration of BCAA is at least as effective as lactulose in ameliorating
the symptoms of hepatic encephalopathy. Interestingly, these authors found no cor-
relation between the modifications in plasma amino acid levels and an improvement
in the patients mental status. Instead, they noted a significant decrease in plasma
ammonia levels in both groups at the time of mental recovery. Since lactulose is
believed to work by binding excess ammonia, these results suggest that BCAA may
favorably impact on hepatic encephalopathy, at least in part, by decreasing free
plasma ammonia levels.
Wahran, et al
5
also noted a slight improvement in responsiveness in patients
with hepatic encephalopathy who received a BCAA parenteral solution. In this
prospective, double-blind trial, 50 cirrhotic patients with acute hepatic encephal-
opathy (grade II to IV) were randomized to receive either an amino acid free
parenteral solution consisting of dextrose and lipids or the same solution with the
addition of 40 g of a 100% BCAA solution. The carbohydrate and fat portions of
each parenteral solution were isocaloric and provided 30 kcal/kg. In addition, all
patients were prohibited from taking any food by mouth. Although the patients in
the BCAA-treated group showed a statistically significant improvement in their
plasma BCAA to AAA ratios (1.10 0.08 to 1.96 0.22), this ratio never returned
to a normal ratio of 3.0 to 3.5. Fifty-six percent of the patients receiving the BCAA
solution demonstrated an improvement in encephalopathy compared to 48% in
the control group. This difference, however, was not statistically significant. As the
authors readily pointed out, this study had two major shortcomings. First, patients
with active gastrointestinal bleeds were not excluded from the study; a complication
that may worsen encephalopathy. Second, twice as many patients in the control
group received systemic antibiotics which would theoretically decrease the amount
of enteric bacteria and their byproducts and subsequently ameliorate hepatic en-
cephalopathy.
The largest and most complete prospective, double-blind trial was a multicenter
study done by Cerra and colleagues.
6
Seventy-five patients with acute hepatic en-
cephalopathy (grade II or higher; average grade 2.65) due to chronic hepatic disease
(85% alcoholic cirrhosis) were randomized to receive either oral neomycin or a
branched-chain enriched (36%) parenteral solution low in AAA and methionine.
Patients with acute viral hepatitis, acute fulminant hepatitis, hepatorenal syndrome,
significant gastrointestinal bleeding, nonhepatic coma and patients requiring
19
Current Nutrient Substrates
2
severe fluid restriction were excluded from the study. The control group received
25% dextrose intravenously plus oral neomycin (4 g daily divided into 4 doses)
whereas the treatment group received a daily infusion of the branched-chain en-
riched parenteral solution plus placebo tablets. Oral intake was restricted in both
groups until the encephalopathy had resolved. A maximum daily protein intake of
1.1 g/kg was reached by day 3 and was well tolerated in the group receiving the
BCAA-enriched solution. Despite receiving what some clinicians would consider a
high protein load for this patient population, 53% of the patients in the BCAA
group demonstrated complete resolution of their encephalopathy compared to only
17% of the patients in the control group (p<0.05). Not suprisingly, net protein
catabolism was decreased in the group being fed as evidenced by a positive nitrogen
balance by day 4. The group not being fed protein remained in negative nitrogen
balance throughout the study. Moreover, 55% of the patients in the control group
died whereas only 17% of the patients receiving the BCAA-enriched solution died
(p<0.01). These results suggest that administration of BCAA-enriched parenteral
solutions in amounts that provide at least 1 g protein/kg/day is well tolerated in
cirrhotic patients with hepatic encephalopathy, and may improve mental status and
survival. There are, however, some researchers who contend that the improved sur-
vival may have been a result of providing nutritional support in these critically ill
patients rather than due to the BCAA-enriched solution itself.
7
The disparity between the results of these clinical trials may be partially due to
differences in experimental design, patient population, type and amount of BCAA
solution administered, as well as diversity of the control group (Table 2.1). It has
been suggested that because Cerra and collegues
6
excluded patients with serious
complications (i.e., fulminant hepatitis, hepatorenal syndrome, etc.) that would not
be expected to improve by changing the serum BCAA to AAA ratio that this may
explain why the results of their study differed from others.
8
Interestingly, none of
the studies shown in Table 2.1 compared a BCAA solution to a conventional parenteral
amino acid solution. There are, however, several enteral studies that have addressed
this issue.
Eriksson and collegues
9
were among the first to investigate the use of a BCAA
formula delivered orally. Seven patients with liver cirrhosis and chronic hepatic en-
cephalopathy (grade I to II) participated in a 28 day study with a cross-over design.
Patients received each of the following oral supplements, in addition to their regular
diet, for a 14 day period: a BCAA solution containing BCAA only (30 g protein/
day) or a placebo solution devoid of amino acids. The results failed to demonstrate
a significant improvement in mental status when patients consumed the BCAA
solution instead of the placebo (43% vs 29%, respectively). These findings have
been substantiated by several other small, prospective cross-over studies.
10,11
In contrast, Horst, et al
12
noted a significant worsening of mental status in cir-
rhotic patients with encephalopathy receiving a standard oral diet containing a maxi-
mum of 80 g protein/day compared to those receiving a standard oral diet, restricted
to 20 g protein/day, supplemented with an oral BCAA-enriched (35% BCAA) solu-
tion, low in AAA that provided up to a maximum of 60 g protein/day.
Most of the clinical trials using oral BCAA examined the efficacy of using these
formulas over a short time period (i.e. less than one month). Thus, in an attempt to
evaluate the long-term effects of using BCAA during hepatic encephalopathy,
Marchesini, et al
13
conducted a multicenter prospective, randomized, double-blind
trial in which patients were followed for a three-month period. Sixty-four cirrhotic
2
0
T
h
e
B
i
o
l
o
g
y
a
n
d
P
r
a
c
t
i
c
e
o
f
C
u
r
r
e
n
t
N
u
t
r
i
t
i
o
n
a
l
S
u
p
p
o
r
t
2
Table 2.1. Parenteral BCAA clinical trials
Author Patients Experimental Group Control Group Results/Conclusions
Rossi-Fanelli, et al
4
34 patients with liver 100% BCAA (57 g protein/day) Lactulose No significant change in
cirrhosis/grade III to + 20% dextrose + 20% dextrose encephalopathy. BCAA
IV encephalopathy are as effective as lactulose
in reversing hepatic
encephalopathy.
Wahran, et al
5
50 patients with liver 100% BCAA (40 g protein/day) Dextrose + lipid No significant change in
cirrhosis/grade II to + dextrose + lipid encephalopathy.
IV encephalopathy
Cerra, et al
6
75 patients with liver 35% BCAA-enriched (maximum 25% dextrose + Significant improvement in
cirrhosis/grade II to of 85 g protein/day) oral neomycin encephalopathy and survival
IV encephalopathy + placebo tablets in BCAA-enriched group.
21
Current Nutrient Substrates
2
patients (66% alcoholic) with hepatic encephalopathy were randomized to receive
either a 100% BCAA oral supplement or a casein-based oral supplement in addition
to an oral diet containing 45-65 g protein daily. Patients were randomized to receive
either one packet of BCAA/kg body weight (0.24 g 100% BCAA/packet) or one
packet of casein/kg body weight (0.17 g casein/packet: 22% BCAA). Since all pa-
tients weighed between 60 and 80 kg, the oral supplements provided between 14 to
19 g BCAA or 10 to 14 g casein daily. After three months, twice as many patients
receiving the BCAA supplement demonstrated an improvement in mental status
(defined by the portal-systemic encephalopathy index) when compared to those
patients receiving the casein-based supplement (p<0.01). In addition, when the ten
casein-treated patients who showed no improvement in mental status were given the
BCAA supplement, eight of them demonstrated a rapid improvement in their
neuropsychologic function. These results suggest that long-term supplementation
(i.e., 3 months or more) of oral BCAA is superior to casein in terms of improving
mental status in cirrhotic patients with chronic encephalopathy.
The results of these enteral BCAA studies are summarized in Table 2.2. As was
the case with the parenteral BCAA studies, there are several factors which may ac-
count for the different results seen in the enteral studies. First, of the studies re-
ported here, those which failed to demonstrate any difference between BCAA and
standard amino acid solutions had a sample size of less than ten patients. Thus, they
may have been unable to detect any significant differences due to a Type II error.
Second, not all of the studies used the same experimental design (i.e., cross-over
design versus parrallel group comparison) nor did they administer the diets in the
same fashion. Several of the studies gradually increased the daily protein intake until
encephalopathy developed, whereas others adminstered a constant amount of protein
throughout the study. Finally, all of the diets differed in regard to the total percentage
of BCAA, as well as the ratio of each BCAA. Taken together, therefore, it is difficult
to compare the studies or to draw any definite conclusion.
The primary goal of nutrition support during hepatic dysfunction is to provide
sufficient protein in order to support protein synthesis and to promote regeneration
of liver cells. In view of this, perhaps the most important finding of these clinical
trials is that BCAA formulas can be safely administered to this patient population in
amounts that provide 1.0 to 1.5 g protein/kg/day without exacerbating preexisting
encephalopathy. Thus, encephalopathic, cirrhotic patients who are unable to tolerate
low to moderate intakes of standard protein sources may benefit from receiving
BCAA-enriched solutions. In 1997 the European Society for Parenteral and enteral
nutrition published guidelines recommending the aforementioned.
14
In addition,
there is evidence to suggest that administration of BCAA-enriched solutions are
better utilized by cirrhotic patients and can improve hepatic protein synthesis.
15
Stress
The metabolic response to injury is characterized, in part, by an increase in lean
body mass catabolism, a reduction in total body protein synthesis, and an increase
in the use of BCAA by the skeletal muscle. The result is an obligatory negative
nitrogen balance. In view of this, numerous investigators have examined the
protein-sparing effects of administering BCAA-enriched formulas in the setting of
stress, sepsis or trauma. The results of these clinical trials suggest that administration
of BCAA-enriched solutions can reduce nitrogen loss and support protein synthesis
better than standard amino acid solutions in critically ill patients.
2
2
T
h
e
B
i
o
l
o
g
y
a
n
d
P
r
a
c
t
i
c
e
o
f
C
u
r
r
e
n
t
N
u
t
r
i
t
i
o
n
a
l
S
u
p
p
o
r
t
2
Table 2.2. Enteral BCAA clinical trials
Author Patients Experimental Group Control Group Results/Conclusions
Ericksson, et al
9
7 patients with liver 100% BCAA oral supplement Oral supplement No significant improvement
cirrhosis/grade I to II (30 g protein/day) devoid of amino acids) in mental status.
encephalopathy + oral diet + oral diet
McGhee, et al
10
4 patients with liver 35% BCAA oral supplement Oral casein modular No significant improvement
cirrhosis/grade II to + casein based protein module supplement (50 g in mental status.
IV encephalopathy protein)
Christie, et al
11
8 patients with liver 50% BCAA oral supplement Casein-based oral No significant improvement
cirrhosis/grade 0 to II + 40 g protein oral diet supplement (18% in mental status.
encephalopathy BCAA) + 40 g protein
oral diet
Horst, et al
12
37 patients with liver 35% BCAA oral supplement 80 g (maximum) Mental status worsened in
cirrhosis/grade 0 to I (maximum of 60 g protein/day) protein oral diet patients receiving oral
encephalopathy + 20 g protein oral diet diet alone.
23
Current Nutrient Substrates
2
Most of the studies in this area have used 24-hour urinary urea nitrogen excretion
to assess protein catabolism and nitrogen balance. Clinically, this test is an inexpensive
and quick tool for assessing the degree of catabolism a patient is experiencing. The
disadvantage, however, is that it does not allow one to determine whether nitrogen
balance fluctuations are due to changes in the rate of protein synthesis or the rate of
protein breakdown.
16
While being able to make this distinction is not critical in the
clinical setting, it is important in the setting of a clinical trial that is comparing
differences in the protein-sparing effects of various amino acid solutions. Thus, several
researchers have used isotopic kinetic studies in order to determine whole body pro-
tein turnover.
Using this technique, Echenique, et al
17
assessed the value of administering
BCAA-enriched solutions in five critically ill patients, in the intensive care unit,
who had catabolic indexes ranging from 0 to 3 (indicative of moderate stress). Two
different parenteral solutions were compared in each patient: a BCAA-enriched
parenteral solution (50% BCAA) and a standard parenteral solution containing 15.6%
BCAA. Both solutions were isocaloric and isonitrogenous and were administered
over two consecutive 24-hour periods. During the last ten hours of each infusion, an
isotopic tracer (L-[1-
14
C] Leucine) was added in order to estimate protein kinetics (i.e.,
total body leucine oxidation, incorporation of leucine during protein synthesis, and
release of leucine during protein breakdown). Results showed a significant increase
in plasma leucine, isoleucine, and valine concentrations, as well as an increase in
leucine oxidation and net balance (i.e., the difference between the rate of leucine
incorporation into protein and the rate of release from protein). These results suggest
that administration of a BCAA-enriched solution containing 50% BCAA may result
in a significant improvement in amino acid utilization in critically ill patients.
Similarly, Bonau and collegues
18
used an isotopic tracer (
15
N glycine) to determine
whole body protein turnover in surgical patients receiving BCAA-enriched solutions.
Twenty-five patients undergoing elective radical cystectomies for bladder cancer re-
ceived one of four parenteral infusions: 5% dextrose alone (n=4); dextrose plus a
standard amino acid mixture containing 7% amino acids (n=9); dextrose and a
low-leucine, BCAA-enriched solution (45% BCAA; 22 mmol leucine/L) (n=6); or
dextrose and a high-leucine, BCAA-enriched solution (45% BCAA; 120 mmol leu-
cine/L) (n=6). All dextrose and amino acid solutions provided 30 kcal/kg/day and
1.5 g protein/kg/day. Administration of the low leucine, BCAA-enriched solution re-
sulted in a significant decrease in mean cumulative nitrogen balance (1.67 0.74 g
nitrogen/day versus 3.80 1.01 for the high leucine, BCAA-enriched group and
4.38 0.99 for the standard amino acid group) and an increased rate of mean whole
body protein catabolism compared to the other two amino acid groups. The authors
concluded that the optimal dose of leucine required by this patient population in
order to achieve protein sparing effects was 0.13 g/kg/day. In comparison, normal,
healthy subjects only require 11 mg of leucine/kg/day.
19
These results suggest that
the ability of BCAA-enriched solutions to reduce postsurgical muscle catabolism is
related more to the amount of leucine in the solution than to the total percentage
of BCAA.
Renal Failure
Another controversial area in the use of BCAA-enriched solutions is in the setting
of renal failure. The use of BCAA-enriched solutions in renal failure patients with
severe azotemia (i.e., blood urea nitrogen greater than 100 mg percent) may aid in
24
The Biology and Practice of Current Nutritional Support
2
reducing urea and acid production from proteolysis since BCAA are preferentially
used by the body for protein synthesis.
20,21
The ability of BCAA to affect overall patient outcome remains controversial.
However, it is clear that the administration of BCAA does not exacerbate preexisting
encephalopathy. Moreover, BCAA are more efficiently used, promote better nitro-
gen retention, and are less ureagenetic than conventional amino acid formulas.
Thus, when protein intake must be restricted due to encephalopathy or uremia, then
BCAA-enriched solutions may potentially offer certain neurologic and metabolic
advantages over conventional amino acid solutions.
21
Arginine
Traditionally, arginine has been considered to be a semi-essential amino acid.
22
In normal, unstressed adult subjects, arginine requirements can be met through
tissue synthesis. Early animal studies established that arginine was not an essential
amino acid for maintaining nitrogen balance in healthy adult rats. In con-
trast, it was noted that immature growing rats required arginine for optimal
nitrogen balance.
23
Most conventional adult parenteral and enteral formulas contain only a small
amount of arginine (<0.5% of total calories). However, some researchers suggest
that arginine requirements are increased during periods of injury or stress.
24
This
suggestion has been substantiated by a number of animal and human studies dem-
onstrating that supplemental dietary arginine improves nitrogen retention, and
enhances wound healing and immune response following injury.
25-32
These findings
suggest that supplemental arginine may have a potential theurepeutic role in the
clinical setting.
Laboratory Studies
Barbul and collegues conducted many of the early studies that evaluated the
effects of arginine supplementation. In a series of animal studies, supplemental
arginine resulted in increased thymic weight, increased thymocyte response to mi-
togens, and improved wound healing and nitrogen retention.
29,33-35
These experi-
ments prompted other investigators to further explore the relationship between
supplemental arginine and immune response following injury.
Saito and colleges
30
studied the effect of supplemental arginine on immunity in
burned guinea pigs. After receiving a 30% total body surface area burn, animals
were intragastrically fed one of four diets containing either 0%, 1%, 2%, or 4%
arginine. Animals receiving the 2% arginine supplementation demonstrated the
most significant improvement in their cell-mediated immunity and ability to clear
staphylococcus aureus from intradermal injection sites. In addition, those ani-
mals receiving the 1% and 2% arginine supplemented diets had a lower mortality
rate than those receiving the 0% and 4% arginine supplemented diets, although
this difference was not statistically significant. Interestingly, these investigators noted
that 4% arginine supplementation did not result in any beneficial effects which
suggests that administration of excess arginine may, in fact, be detrimental. Thus,
the authors concluded that arginine supplementation in the amount of 2% of total
calories may help to prevent sepsis after burn injury.
Since burn injury is responsible for increased gut permeability to enteric bacteria,
Gianotti, et al
36
conducted a series of experiments to investigate the effects of an
arginine enriched diet on resistance of gut-origin sepsis (i.e., bacterial translocation)
25
Current Nutrient Substrates
2
and survival after peritonitis in the burned animal model. In one experiment, animals
were randomized to receive one of the following diets: rat chow, semipurified diet,
semipurified diet plus 2% arginine, or semipurified diet plus 4% glycine. After 14
days of feeding, the animals were subjected to an injection of E. coli followed by a
20% burn injury. Animals fed with the semipurified diet demonstrated significantly
more bacterial translocation to the mesenteric lymph nodes (as measured by radio-
nuclide counts) compared to all of the other diets. Moreover, analysis of the number
and percentage of viable translocated bacteria in the mesenteric lymph nodes and
spleen showed that the arginine enriched diet significantly improved the animals
ability to kill translocated organisms compared to the other three diets. In another
experiment, animals were fed either the arginine enriched diet, the semipurified
diet, or rat chow for 15 days prior to being subjected to cecal ligation and puncture
followed by a 20% burn injury. Following this, all animals were allowed to feed on
their designated diets ad libitum. Although the arginine enriched group showed a
45% improvement in survival when compared to the animals receiving the
semipurified diet and the rat chow, this difference was not statistically significant.
However, when this experiment was repeated and the animals were transfused with
allogenic blood five days prior to the injury, there was a significant improvement in
survival in the group receiving the arginine enriched diet. Fifty-six percent of the
arginine supplemented animals survived compared to 28% in the semipurified diet
group and 20% in the chow fed group (p<0.02). These experiments suggest that
diets supplemented with arginine may favorably affect survival when provided prior
to the onset of infection.
In order to better define the mechanism by which arginine alters immune function,
Reynolds, et al
31
examined the effects of supplemental arginine on specific components
of the immune response. In this study, mice received an oral diet containing either
1% arginine supplementation or an isonitrogenous glycine supplemented diet for at
least 10 days. Arginine supplementation was noted to significantly enhance cyto-
toxic T-lymphocyte development, increase endotoxin-induced natural killer cell ac-
tivity, and augment interleukin-2 (IL-2) receptor activity on T-lymphcytes stimulated
with the mitogen, conconavalin A. However, basal- and endotoxin-induced mac-
rophage IL-1 and superoxide production were not significantly influenced by supple-
mental arginine. These results suggest that arginine supplementation directly
modulates T-lymphocyte activation which may result in an enhanced production of
cytotoxic T-lymphocytes.
More recently, investigators have explored the ability of arginine to alter the
mRNA expression of inflammatory cytokines in organs. In this study, animals re-
ceiving an enteral diet supplemented with arginine (2.3% of total energy intake) for
seven days after receiving a 30% burn injury demonstrated a significant decrease in
mRNA expression for TNF- in the spleen and lung, IFN- in the lung, IL-1 in
the spleen, and IL-6 in the thymus and liver compared to those animals receiving no
supplemental arginine. In addition, the arginine supplemented animals showed a
significant improvement in survival rate after thermal injury compared to the control
group (100% versus 66.6%;p<.05).
37
Another aspect of arginines ability to modulate immune function relates to its
effects on tumor development. Over the past few decades, there have been numerous
studies demonstrating the anti-tumor properties of arginine in animals with either
chemically induced or transplanted tumors.
38-40
In addition to decreasing tumor
growth in these animal models, arginine supplementation has also been noted to
26
The Biology and Practice of Current Nutritional Support
2
prolong survival. These findings, coupled with the fact that cancer patients are
frequently immunosuppressed, prompted several investigators to examine the
potential clinical applicability of administering arginine in this patient population.
Clinical Trials
In 1988, Daly and collegues
32
conducted the first clinical trial to evaluate the
immunologic effects of arginine supplementation in the surgically stressed patient.
Thirty adults with gastrointestinal malignancies undergoing major surgery were
randomized to receive either an enteral diet supplemented with 25 g arginine daily
(7% of maximum caloric intake) or the same enteral diet supplemented with an
isonitrogenous amount of glycine. Mean daily nitrogen balance was not significantly
different between the two groups, however, a positive nitrogen balance was only
achieved in the arginine supplemented group. There was, however, a statistically
significant improvement in immune function in those patients receiving the arginine
supplementation as compared to the glycine group. Specifically, the arginine supple-
mented group demonstrated a significantly enhanced T-lymphocyte response to
the mitogens, conconavalin A (ConA) and phytohemagglutinin (ConA), as well as
an increase in CD4 (helper T-cells) levels from postoperative day 1 to postoperative
day 7 when compared to the glycine supplemented group. Encouraged by these
results but unsure whether the administration of arginine alone would still cause
the increase in peripheral blood monocyte mitogenesis, the investigators conducted
another clinical trial in an attempt to answer this question.
Thirty adult patients undergoing surgery for lower gastrointestinal malignancy
were randomized to receive intravenously either 20 g arginine hydrochloride in 5%
dextrose and water or one liter of a standard 10% amino acid solution (3.7 g arginine
hydrochloride) daily for 7 days postoperatively. Additional dextrose containing so-
lutions were administered as clinically indicated. Postoperative mean daily nitrogen
balance was similar between the two groups (-8.8 g/day for arginine group versus
-9.2 g/day for mixed amino acid group). There was no significant difference between
the two groups in terms of peripheral blood mononuclear cell proliferative responses
to ConA. In the arginine group, mitogen-stimulated lymphocyte response levels
returned to preoperative levels by postoperative day 7 while the standard amino
acid groups levels were actually below their preoperative levels by postoperative day 7.
In contrast, when peripheral monocytes were stimulated with ConA, the mixed
amino acid group demonstrated a significantly higher stimulation level on postop-
erative day 4 than the arginine group. These results suggest that when arginine is
administered parenterally as the sole nitrogen source with minimal additional calo-
ries, there is no significant enhancement of mitogen-stimulated lymphocyte prolifera-
tion. Thus, arginine may require supplemental protein and calories in order to exert
its maximum effect.
41
While it appears that delivery of some arginine may be beneficial in the clinical
setting, Sigal, et al
41
have suggested that the immunostimulatory effects of arginine
may be due to an interaction between arginine and other dietary substrates rather
than the arginine itself. This point is exemplified in a study by Van Buren, et al
42
in
which mice who were fed a nucloetide-free casein-based diet containing 4% arginine
showed no improvement in allogeneically stimulated lymphocytes responses. In
contrast, those animals receiving the arginine diet supplemented with RNA or fish
oil demonstrated a significant improvement in lymphocyte proliferative responses.
Whether or not these same findings are applicable to humans remains unanswered.
27
Current Nutrient Substrates
2
Moreover, it is not clear if enhanced stimulation of lymphocytes translates into im-
proved clinical outcome. To date, there have been no clinical trials examining the
effects of an arginine supplemented diet versus an arginine supplemented diet that
also contains one or more of the so-called immuno-stimulatory nutrients (i.e.,
RNA, fish oil, or glutamine). There are however, a number of clinical trials comparing
an enteral formula that is enriched with arginine in addition to one or more of these
immuno-stimulatory nutrients to a standard enteral formula that is devoid of
supplemental arginine, RNA, fish oil, or glutamine.
43-51
Although arginine is not an essential amino acid in unstressed adult animals and
humans, it appears to become a conditionally essential amino acid during periods
of injury or stress. Supplementation with arginine has been shown to promote wound
healing, enhance immune function, and improve nitrogen retention in both animals
and humans. In addition, animal studies have shown that supplemental arginine
retards growth in animals with chemically induced or transplanted tumors, and
improves survival by modulating bacterial clearance in animals with gut-derived
sepsis and peritonitis. While the animal studies appear to suggest that a diet containing
2% of total calories as arginine provides the most beneficial effects, the optimal dose
in stressed humans remains unclear. The clinical trials discussed here have adminis-
tered doses ranging from approximately 10 to 25 grams per day. This dose would be
the equivalent of 2 to 6 % of total calories for a 70 kg man receiving 25 kcal/kg. It is
quite possible that the optimal dose will vary depending on the severity of illness,
type of injury, or surgery. One potential complication of arginine administration is
its competition with the essential amino acid lysine for tubular reabsorption.
52
Large
doses of arginine may, therefore, theoretically induce lysine deficiency by increasing
its renal excretion.
53
Thus, additional clinical trials are clearly needed in order to
determine the optimal dose of arginine for a variety of clinical settings. Moreover,
investigators need to pursue the question of whether or not the immunostimulatory
effects of arginine are due to the arginine itself or whether they are a result of inter-
actions with other dietary substrates.
Glutamine
Glutamine is currently classified as a nonessential amino acid because sufficient
quantities can be synthesized by the body in healthy subjects.
19
However, during
periods of stress, the bodys requirement for glutamine exceeds its production.
54-56
Animal studies suggest that provision of glutamine-enriched parenteral and enteral
nutrition maintains gut epithelial structure and integrity, enhances nitrogen retention
and intestinal mucosal immune function, decreases the incidence of bacterial trans-
location and improves survival following injury.
57-59
Furthermore, glutamine-enriched
nutrition administered to surgical and bone marrow transplant patients has been
shown to reduce losses of free glutamine in skeletal muscle tissue,
60,61
reduce infectious
complications,
62,63
decrease length of hospital stay
62,64
and improve six month sur-
vival in critically ill patients.
65
Thus, glutamine, like arginine, may be regarded as a
conditionally essential amino acid.
66
Traditionally, it was thought that glucose was the main source of fuel for the
enterocytes, however, there is now evidence that glutamine is actually the preferred
fuel of the enterocytes, as well as the colonocytes.
67,68
This finding coupled with the
observation of intestinal atrophy in animals receiving parenteral nutrition,
69
prompted
investigators to examine the effects of glutamine supplementation on intestinal
mucosal structure and function.
28
The Biology and Practice of Current Nutritional Support
2
Laboratory Studies
ODwyer, et al
57
performed a series of animal experiments to examine the effects of
glutamine supplementation on the intestine. In the first experiment, rats were in-
travenously fed a standard 10% amino acid solution that was enriched with either
gutamine or glycine in amounts of either 1 or 2 g/100 mL. Animals receiving 2 g
glutamine/100 mL demonstrated a significant increase in intestinal weight, DNA
and protein content, and villus height when compared to the group receiving 2 g
glycine/100 mL (p<0.01). No increase in intestinal parameters was noted in the
group receiving 1 g glutamine/100 mL. The authors then investigated the
dose-response effects of glutamine by feeding the animals an isonitrogenous, isocaloric
solution containing either 0, 2, or 3 g glutamine/100 mL. Increasing the glutamine
intake from 0 to 3 g/100 mL led to a significant increase in intestinal mucosal
weight, DNA and protein content, and villus height. Interestingly, the animals
receiving 2 g glutamine/100 mL demonstrated a significantly greater nitrogen re-
tention compared to the animals receiving 0 or 3 g glutamine/100 mL. These re-
sults suggest that glutamine, an amino acid that is not currently contained in
commercially available parenteral amino acid solutions, may be important for main-
taining intestinal integrity. In addition, there is evidence to suggest that glutamine
may also be essential for maintaining intestinal function following mucosal injury.
Fox and collegues
58
investigated the effects of a 2% glutamine supplemented
elemental diet on nutritional status, intestinal morphology, bacterial translocation,
and survival in rats with methotrexate-induced enterocolitis. Rats receiving the
glutamine supplemented diet exhibited significantly less intestinal damage, less
weight loss, a lower incidence of bacterial translocation, and an improved nitrogen
balance and survival compared to the animals receiving the control diet (2% glycine
supplemented elemental diet). Similar benefits have been reported by ODwyer, et
al
70
and Jacobs, et al
71
who demonstrated that both enteral and parenteral glutamine
supplementation resulted in a rapid regeneration of enterocytes in rats receiving the
chemotherapeutic agent 5-fluoruracil. In addition, provision of oral glutamine has
been shown to accelerate healing of the small intestine and improve outcome in
animals undergoing whole abdominal radiation.
72
However, since glutamine is the
principle fuel used by most rapidly proliferating tumors,
73
it raises the question of
whether or not providing exogenous glutamine during chemo- or radiation therapy
might present more of a risk (promote tumor growth) rather than a benefit (intestinal
preservation).
In an attempt to answer this question, Austgen, et al
74
studied the effects of
administering glutamine supplemented TPN in tumor-bearing rats. The addition
of glutamine to the TPN did not appear to increase tumor size, DNA content, or
glutamine metabolism. Glutamine supplementation did, however, cause a significant
increase in the intratumor ratio of aneuploid cells to diploid cells suggesting a more
aggressive cell variant. Thus, the authors speculated that glutamine supplemented
TPN caused an increase in the number of differentiated tumor cells within a specified
amount of tumor mass without yielding a measurable increase in tumor size.
However, Klimberg and collegues
75,76
have demonstrated in two separate animal
studies that supplemental glutamine does not stimulate tumor growth. In fact,
enteral glutamine supplementation was actually noted to increase the effectiveness
of methotrexate while reducing its morbidity and mortality in cachectic
tumor-bearing animals.
76
29
Current Nutrient Substrates
2
The ability of glutamine supplemented nutrition to attenuate intestinal atrophy
and decrease the incidence of bacterial tranlocation may be, in part, due to changes
in intestinal immune function. Alverdy, et al
59
randomized rats to receive one of
three diets: rat chow, a standard parenteral solution, or a standard parenteral solution
supplemented with 2% glutamine. After one week of feeding, the animals receiving
the standard parenteral solution demonstrated a significant decrease in biliary secretory
immunoglobulin A (S-IgA) levels and intestinal lamina propria IgA-synthesizing
plasma cell (IgA+) levels compared to the chow fed animals. This finding is of par-
ticular importance because S-IgA prevents bacteria from adhering to the intestinal
mucosa which may, in turn, help to decrease the incidence of bacterial translocation. In
addition, there was a significant decrease in CD4 (helper T-cells) and CD8 (sup-
pressor T-cells) levels in the standard parenteral diet group compared to the chow
group. In contrast, animals receiving the glutamine supplemented solution had CD4
and CD8 levels comparable to those of the chow fed animals. These findings suggest
that glutamine may be an essential amino acid for the maintenance of intestinal
immune function during parenteral feeding. Taken together, these animal studies
suggest that the provision of glutamine either enterally or parenterally may increase
the function of various immune cells and therefore potentially lead to enhanced
resistance to infection.
Clinical Trials
Over the past decade, the potential therapeutic use of glutamine supplementation
in humans has been an area of intense research. Ziegler and collegues
77
were the first
to evaluate the safety of administering the free amino acid glutamine to humans. In
a series of dose-response studies, these investigators demonstrated that glutamine
administration in healthy volunteers at daily doses of 0.3 g/kg enterally and 0.57 g/kg
parenterally was well tolerated. The safety of glutamine administration was subsequently
confirmed in the clinical setting when eight patients undergoing bone marrow trans-
plantation recieved glutamine-enriched TPN solution without evidence of adverse
clinical or metabolic effects. Moreover, nitrogen retention was enhanced in this patient
population when glutamine was administered at a dose of 0.57 g/kg/day compared
to a lower dose (0.285 g/kg/day). These findings subsequently spurred researchers
to investigate the efficacy of parenteral glutamine supplementation in patients under-
going elective surgery.
In a randomized, prospective trial conducted by Stehle, et al,
60
twelve patients
undergoing surgical resection for colonic or rectal carcinoma received either standard
TPN or glutamine enriched TPN. The addition of approximately 12 g of glutamine
per day, provided as the dipeptide L-alanyl-L-glutamine, resulted in a diminished
loss of free glutamine in skeletal muscle tissue and improved nitrogen retention.
Similar benefits were reported by Hammarqvist and collegues
61
who administered
TPN supplemented with approximately 20 g of free glutamine daily to patients
undergoing cholecystectomies. More recently, investigators have examined the effects
of administering glutamine supplemented TPN in bone marrow transplant patients.
Ziegler, et al
62
conducted a prospective, randomized, double-blind trial in which
45 patients undergoing allogeneic bone marrow transplantation for hematologic
malignancies were randomized to receive either standard TPN or TPN supplemented
with 0.57 g of free glutamine/kg body weight per day. Based on a mean body weight
of 67.2 kg, patients in the glutamine supplemented TPN group received approximately
38 g glutamine per day for an average of 26 days. The mean duration of parenteral
30
The Biology and Practice of Current Nutritional Support
2
feeding was comparable for patients in the standard TPN group (28 days). Despite an
equivalent caloric and nitrogen intake in both groups, the glutamine supplemented
patients demonstrated a significant improvement in their mean daily nitrogen balance
in comparison to the standard TPN group (-1.4 0.5 g/d versus -4.2 1.2 g/d,
respectively; p=0.002). In addition, fewer patients receiving the glutamine supple-
mented TPN developed infections (13% versus 43% in the standard TPN group;
p=0.041) even though antibiotic administration was similar in both groups. More-
over, the average length of hospital stay following transplantation was 29 1 days
in the glutamine supplemented group compared to 36 2 days in the standard
TPN group (p=0.017). This study demonstrated that the administration of glutamine
supplemented TPN in this patient population resulted in improved nitrogen bal-
ance, decreased incidence of infectious complications, and shortened length of hos-
pital stay compared to patients receiving standard TPN. A subsequent study by this
group showed that bone marrow transplant patients receiving glutamine- supple-
mented TPN had greater numbers of circulating total lymphocytes, T lymphocytes,
and CD4
+
lymphocytes after discharge than patients receiving standard TPN.
78
Schloerb and Amare
64
published results of clinical trial with a protocol similar
to that of Ziegler, et al.
62
Twenty-nine patients undergoing either allogeneic or autolo-
gous bone marrow transplantations were randomized to receive either standard TPN
solution or TPN supplemented with approximately 40 g of free glutamine per day
for approximately one month. One of the parameters that was assessed in the current
trial that was not investigated by Ziegler, et al
62
was the effect of glutamine on total
body water and extracellular water. Total body water, as measured by deuterium
oxide dilution and bioimpedance, was significantly decreased from baseline (before
TPN) to end of study (after TPN) in patients receiving the glutamine supplemented
TPN (p<0.05). This finding suggests that the provision of glutamine may help to
maintain vascular endothelial integrity and prevent the extreme fluid shifts fre-
quently seen during critical illness. In contrast, patients receiving standard TPN
showed a significant increase in the change in their total body water.
In terms of infectious complications, the researchers did not note any significant
difference between the two feeding groups; thirty-eight percent of the patients in
each group developed clinical infections. Patients were then subdivided into those
with hematologic malignancies versus those with solid tumors. In patients with
hematologic malignancies, clinical infections occured in only 20% of those patients
receiving the glutamine supplemented TPN compared to 50% of those receiving
the standard TPN. This difference, however, was not statistically significant. Although
this observation is in contrast to that of Ziegler, et al
59
the authors do not dispute
Ziegler and collegues conclusion that glutamine supplemented TPN decreased the
incidence of clinical infections in patients with hematologic malignancies. Instead,
the authors suggest that differences in patient population may have precluded them
from observing all of the same benefits as Ziegler, et al.
62
In particular, the authors
suggest that they had a patient population with a higher severity of illness than
Ziegler, et al
62
as demonstrated by a higher mortality rate (14% versus 0%, re-
spectively). Schloerb and Amare
64
were, however, able to confirm the finding of
Ziegler, et al
62
that patients receiving the glutamine supplemented TPN had a sig-
nificant reduction in length of hospital stay following transplantation compared to
patients receiving standard TPN.
The use of glutamine-enriched TPN has also been investigated in critically ill
patients. Griffiths, et al
65
reported improved six-month survival in critically ill patients
31
Current Nutrient Substrates
2
receiving glutamine-enriched TPN (an average intake of 21 g glutamine/day) com-
pared to those patients receiving conventional TPN (24/42 patients versus 14/42 pa-
tients; p=.049) The aforementioned studies have yielded promising results with respect
to providing glutamine-enriched parenteral nutrition in select patient populations.
However, some researchers have speculated that in order to meet the glutamine
requirements of the enterocytes and gut-associated lymphoid tissue it might be more
beneficial to provide glutamine enterally rather than parenterally.
Gottschlich, et al
79
were among the first to study the effects of providing glutamine
enterally rather than parenterally in a clinical setting. In a study of 90 burn patients
who were randomized to receive an enteral formula supplemented with either 2, 4,
or 6 g free glutamine/L, serial measurements of plasma glutamine were obtained
during the first four weeks post burn. Results showed that plasma glutamine levels
remained depressed (i.e., < 400 nmol/mL) throughout the four week period in all
feeding regimens. These findings suggest that plasma glutamine levels may be mar-
ginal in burn patients and that enteral glutamine supplementation in excess of 6 g/
L of enteral formula may be warranted in this patient population.
Jensen, et al
80
conducted a prospective, double-blind trial in which 28 critically
ill patients were randomized to receive one of two isocaloric, isonitrogenous enteral
fromulas differing only in glutamine concentration (i.e., six-fold difference). Data
was analyzed for all patients receiving at least 50 cc/hr by day 5 (n=19). Results
demonstrated that the plasma phenylalanine to tryrosine ratio, an indicator of ca-
tabolism, was significantly decreased by day 5 in patients receiving the glutamine
enriched enteral formula. Moreover, immune function, as assessed by CD4/CD8
ratios, was significantly improved in the glutamine enriched group compared to the
standard feeding. A subsequent study by these investigators compared
glutamine-enriched parenteral nutrition with glutamine-enriched enteral nutrition
(isocaloric, isonitrogenous formulas that provided 0.3 g glutamine/kg body weight)
in 17 patients undergoing surgery for gastric or pancreatic carcinomas. Results showed
that both types of feeding resulted in similar amino acid profiles although there was
a trend for serum glutamine levels to recover more slowly in the enterally fed group
compared to the parenterally fed group.
81
More recently, Houdijk and colleagues
63
have investigated the effects of
glutamine-enriched enteral nutrition on the incidence of infectious complications.
In a study of 60 multiple trauma patients, those patients who received the enteral
formula supplemented with glutamine (30.5 g glutamine/100 g protein) within 48
hours of trauma showed a significant reduction in pneumonia (17% versus 45% for
the control group; p<.02), bacteremia (7% versus 42%; p<.005), and sepsis (4% -check
this versus 25%; p<.02) compared to the patients receiving an isocaloric,
isonitrogenous control formula containing 3.5 g glutamine/100 g protein. The
patients receiving the glutamine-enriched enteral formula (an average intake of 31 g
glutamine/day by study day 7) also demonstrated a decrease in TNF-soluble receptors
compared to the patients receiving the control formula. Whether the decrease in
TNF-soluble receptor suggests a modulation of the immune response to the trauma
or is the result of a decrease in the number of infections remains unanswered. A later
study by this same group of investigators
82
suggested that the reduction in infectious
morbidity seen in the glutamine-supplemented trauma patients could not be ex-
plained by a modulation of the humoral stress response and its metabolic consequences.
A study by Aosasa, et al
83
in fifteen patients with colorectal cancer demonstrated
that oral glutamine supplementation (30 g L-glutamine/day) in patients receiving
32
The Biology and Practice of Current Nutritional Support
2
TPN significantly suppressed cytokine production from LPS-stimulated mesenteric
blood mononuclear cells (M-MNC) compared to patients receiving conventional
glutamine-free TPN. There were, however, no significant differences in cytokine
production from LPS-stimulated M-MNC between patients receiving the oral
glutamine supplementation and TPN and those patients consuming a regular diet.
Administration
Although it is too early to define the optimal dose or route of glutamine, these
clinical trials have prompted much discussion regarding the different routes (i.e.,
enteral versus parenteral) and types (i.e., free glutamine versus glutamine as a
dipeptide) of glutamine supplementation. Currently, commercially available
parenteral amino acid solutions do not contain the free amino acid glutamine for
several reasons. First, glutamine was traditionally considered to be a nonessential
amino acid. Second, the free amino acid glutamine has a shorter shelf-life than
the amino acids commonly used in commercially available parenteral amino acid
solutions. However, glutamines stability in parenteral formulas appears to be better
than previously thought. Schloerb and Amare
61
recently reported that their free
glutamine supplemented parenteral solution was able to be stored at 5C for up to
six weeks without loss of more than 5% of the glutamine.
In terms of enteral formulas, almost all commercially available enteral formulas
contain glutamine. The exceptions are a few free amino acid based diets which
contain the amino acid glutamate rather than glutamine, and several products spe-
cifically designed for hepatic and renal failure which contain neither glutamate nor
glutamine. Glutamine in enteral products can exist in two forms: protein bound (in
whole proteins or in peptides) or as the free amino acid. Manufacturers of formulas
containing the free amino acid glutamine list the glutamine content of the formulas
on the product label. In comparison, the glutamine content of enteral formulas
containing whole or partially hydrolyzed protein (peptides) can only be estimated.
Thus, the glutamine content of these formulas is not listed on the product label.
The amount of glutamine present in whole protein or peptide based enteral
formulas depends upon the protein source and amount of protein, as well as the
processing conditions. Whole protein based formulas contain glutamine in amounts
characteristic of their original protein source (casein, whey, soy, etc.) because protein
bound glutamine is stable and will not degrade during processing or storage. In
contrast, enteral formulas containing partially hydrolyzed proteins (so-called peptide
based diets) contain less glutamine than was present in their original intact protein
because hydrolysis of the intact protein to peptides leads to the degradation of a
portion of the glutamine originally present in the intact protein to glutamate
(glutamic acid) and ammonia. The greater the degree of protein hydrolysis of a
peptide based diet, the less peptide bound glutamine remains.
In view of this, it is difficult to estimate the amount of glutamine in peptide
based formulas. Although, it has been reported that more than half of the original
glutamine in these formulas may be converted to glutamate and ammonia during
processing and storage.
84
The amount of protein-bound glutamine in selected com-
mercially available whole protein formulas has been estimated to range from 2.80
to 7.99 g/1000 kcal.
85
In comparison, there are several commercially available en-
teral formulas enriched with free glutamine in amounts that range from 4.9 to 14.2
g/1000 kcal (Table 2.3).
33
Current Nutrient Substrates
2
The animal and human data presented herein strongly suggest that glutamine
should be classified as a conditionally essential amino acid rather than as a non-
essential amino acid. Plasma and skeletal muscle concentrations of free glutamine
which have been shown to be markedly diminished during periods of stress, infection,
and injury can be restored with parenteral and enteral glutamine supplementation.
In addition, there is increasing evidence that glutamine has beneficial effects on
nitrogen balance, lean tissue mass, gut integrity, and immune function. To date,
clinical trials suggest that glutamine supplementation has been shown to have some
beneficial effects after major surgery, after bone marrow transplantation, in critically
ill patients, and in patients with multiple traumas.
Nucleotides
Nucleotides are an important component of a wide variety of biochemical pro-
cesses. These molecules which consist of three main components: a nitrogenous
base (either purine or pyrimidine), a pentose sugar (either ribose or 2-deoxyribose),
and one or more phosphate groups, are perhaps best known for their role in deoxyri-
bonucleic acid (DNA) and ribonucleic acid (RNA) synthesis. However, nucleotides
are also present in adenine triphosphate (ATP), as well as a number of coenzymes
which participate in carbohydrate, protein, and lipid synthesis. In addition, nucle-
otides are required by T-lymphocytes in order to maintain normal cellular immune
responses.
Various tissues in the body, such as the liver, are capable of synthesizing nucleotides
from other substrates. However, certain rapidly dividing cells, such as intestinal epi-
thelial cells and T-lymphocytes, appear to be unable to produce nucleotides. More-
over, during severe metabolic stress, such as sepsis, trauma, and burns, de novo
nucleotide synthesis is not sufficient to meet the needs of these rapidly dividing
cells. Some investigators have subsequently suggested that this is the mechanism for
the immune dysfunction which is often present in stressed patients. This theory
coupled with the fact that standard parenteral and enteral diets, except those made
from blenderized protein-containing food sources, do not contain nucleotides has
prompted some investigators to suggest that the provision of exogenous nucleotides
to stressed, immunocompromised patients may be beneficial.
Laboratory Studies
The role of dietary nucleotides on immune function, specifically lymphocyte
metabolism, has been the focus of intense research. Van Buren and collegues have
pioneered much of the work in this area, and were among the first to demonstrate
that helper/inducer T-lymphocytes require exogenous nucleotides in order to respond
normally following immune stimulation.
86
In addition, there have been numerous
studies demonstrating that a nucleotide-free diet suppresses a variety of T-cell
Table 2.3. Commercially available enteral formulas containing free glutamine
Product Manufacturer g Free Glutamine/1000 kcal
Vivonex Novartis Nutrition 4.9
Immun-Aid B. Braun/McGaw 9.0
Vivonex Plus Novartis Nutrition 10.0
Alitraq Ross Laboratories 14.2
34
The Biology and Practice of Current Nutritional Support
2
mediated immune responses, such as delayed cutaneous hypersensitivity,
87
cardiac
allograft rejection,
88
in vitro response to T-cell mitogens,
89
and production of
interleukin-2.
86
Furthermore, animals receiving a nucleotide-free diet demonstrated
a significantly higher mortality rate following intravenous injections of staphylococ-
cus aureus or candida albicans compared to animals fed diets supplemented with
either 0.25% RNA (a nucleotide) or 0.06% uracil (a pyrimidine nucleotide base).
89-92
However, it is worth mentioning that in all three of these studies there was also a
fourth group of animals who received a diet supplemented with 0.06% adenine (a
purine nucleotide base). Interestingly, in all instances, the adenine supplementation
had no beneficial effect in terms of survival following bacterial or fungal infection.
Thus, it appears that RNA or pyrimidine bases are the key substrates for maintaining
normal cellular immunity.
Numerous investigators have demonstrated that malnutrition can profoundly
suppress immune function. In view of this relationship, Pizzini and co-workers
93
designed several studies to examine the effect of dietary nucleotide deprivation in
both the protein malnourished, as well as the starved animal model. Animals were
randomized to receive one of four diets: standard rodent chow, protein-free,
nucleotide-free, or nucleotide-free supplemented with 0.25% yeast RNA. The pro-
vision of dietary nucleotides in the form of yeast RNA resulted in the reversal of
immunosuppression in both protein malnourished and starved animals. These results
suggest that nucleotides are required to maintain cellular immune function during
times of nutritional stress.
Clincal Studies
The idea that dietary nucleotides could be used to modulate cellular immunity
in humans initally arose from the observation that renal allograft patients supported
by conventional intravenous nutrition, which is devoid of nucleotides, displayed a
suppressed immune response even when traditional pharmacologic immuno- sup-
pressive agents (i.e. cyclosporin) had been reduced.
94
Despite this observation, there
are no prospective, randomized clinical trials that have examined the singular effect
of nucleotides. Instead, the clinical trials have compared an enteral formula that
contains nucleotides (1.2 g yeast RNA/1000 kcal), in addition to other
immunostimulatory substrates (i.e., fish oil, arginine, glutamine) to a standard
commercially available enteral formula.
44-51
Thus, clinicians are left wondering
whether the addition of nucleotides alone would produce the same results.
Dietary sources of nucleotides appear to be important for maintaining optimal
growth and function of metabolically active cells such as lymphocytes, macroph-
ages, and intestinal cells. The daily requirement for purines and pyrimidines com-
bined is estimated to be 450-700 mg/day in healthy adults.
95,96
However, this
requirement may be increased during periods of stress. Moreover, animal studies
have demonstrated that the use of a nucleotide-free diet results in a decrease in
cellular immune function and a diminished resistance to infection. These effects
were able to be reversed with the provision of a diet containing 0.25% yeast RNA,
and subsequently lead to the incorporation of yeast RNA into several commercially
available enteral formulas. Although preliminary animal data suggests that the pro-
vision of exogenous nucleotides is necessary to support optimum immune func-
tion, the clinical data is less definative. Clearly, further prospective, randomized
clinical trials are warrented to determine whether or not nucleotides require the
presense of other immunostimulatory substrates in order to be of benefit in the
35
Current Nutrient Substrates
2
clinical setting. It is quite possible that the additional nutrients cause a further im-
provement in immunocompetence (synergism) that translate into fewer infectious
complications and, ultimately, a shorter length of hospital stay. However, to be sure,
one would need to conduct a trial using an enteral formula that differed only with
respect to the immunostimulatory nutrients; that is, both formulas would be
isonitrogenous and isocaloric but one formula would contain just nucleotides where
as the other would contain nucleotides as well as to one or more additional
immunostimulatory nutrients (i.e. fish oil, arginine, glutamine).
Lipids
Lipids are an essential component in enteral and parenteral formulas because
they provide energy and essential fatty acids, as well as function as carriers of fat-soluble
vitamins and precursors of hormones. For years, long-chain triglycerides were the
standard source of fat in enteral formulas, and, in fact, they are still the sole source of
fat in commercially available intravenous lipid emulsions. In the past two decades,
the role of fat in the diet has been elucidated. There is now compelling evidence to
suggest that manipulation of dietary nutrients such as lipids can have a profound
effect upon serum and cell membrane lipid concentration, immune function, as
well as critical endpoints such as survival.
97-102
Based on these findings, the current
recommendations for fat intake focus not only on the percent of total calories coming
from fat, but also on the composition of the fat.
103,104
Thus, there has been a surge of
investigations in the area of alternative lipid sources such as -linolenic acid,
monounsaturated fatty acids, -3 polyunsaturated fatty acids (particularly fish oil),
medium-chain triglycerides, and structured lipids.
-6 Polyunsaturated Fatty Acids
In the past, naturally occuring vegetable oils consisting of long-chain triglycerides
(LCT) of the -6 family were the conventional fat source because they were readily
available and relatively inexpensive. In addition, these oils are a rich source of the
major essential fatty acid, linoleic acid. Since linoleic acid can not be synthesized by
the body, it must be provided by the diet. Adult requirements for essential fatty
acids are usually met by providing 3 to 4% of total calories as -6 fatty acids.
102
Thus, corn, safflower, soybean, and sunflower oil serve as important sources of li-
noleic acid in nutritional formulations. The amount of linoleic acid provided in the
formula will vary depending upon the type and amount of LCT used. As shown in
Table 2.1, safflower oil contains the highest percentage of linoleic acid and the lowest
percentage of saturated fatty acids when compared to the other -6 fatty acids typically
used in enteral formulas.
106,107
There are a number of commercially available enteral formulas which contain
-6 fatty acids as their sole source of lipids, and, as previously mentioned, all com-
mercially available intravenous lipid emulsions are comprised solely of -6 fatty
acids. Yet, controversy exists over whether -6 fatty acids should be the primary
source of lipids in critically ill patients because of their potentially detrimental effect
on immune function.
Clearly, provision of a small amount of linoleic acid in the diet is necessary for
normal immune function.
108
However, provision of larger amounts of linoleic acid
leads to an increased production of arachidonic acid and its metabolites, prostaglandin
E2 (PGE2) and leukotriene B4 (LTB4). These eicosanoids are known to enhance
vasocontriction, platelet aggregation, neutrophil migration, immunosuppression,
36
The Biology and Practice of Current Nutritional Support
2
cytokine depression, and free radical formation, all of which may predispose patients
to secondary inflammation and sepsis.
109
Although most of the work in this area
has been done in animals,
110,111
at least one prospective clinical trial suggests that
reticulendothelial system (RES) function is impaired when lipid emulsions are in-
fused in the standard intermittent fashion (over 10 hours) for 3 consecutive days.
112
Seidner, et al
112
provided 18 patients receiving parenteral nutrition (amino acids
and dextrose) with a 20% soybean oil emulsion administered over ten hours as a
piggyback infusion. Patients received the intermittent infusion for either 1 or 3
days at a rate that provided 0.13 g lipid/kg/hr or approximately 85 g lipid/day.
Patients receiving the lipid emulsion over 10 hours for 1 day showed no impair-
ment in RES function based on the clearance rate of intravenous technetium-99
sulfur colloid (TSC). However, patients receiving 3 days of intermittent lipid infu-
sion exhibited a statistically significant reduction in TSC. These findings prompted
the researchers to then determine whether administering the same amount of lipids
continuously as a three-in one admixture would have the same effect upon RES
function. In contrast to the intermittent lipid infusion, the continuous administra-
tion did not impair TSC clearance by the RES.
113
Thus, provision of standard LCT
lipid emulsions in a continuous manner may be preferable in critically ill or septic
patients. In addition, these authors recommend a modest lipid intake of 30 to 60 g
daily in this already immunocompromised patient population. These findings,
coupled with current recommendations regarding the optimal dietary fat intake
(i.e., < 30% of total calories), have prompted a search for alternative lipid sources.
-Linolenic Acid
Interest in the potential metabolic benefits of dietary -linolenic acid (GLA), a
plant seed oil found in borage oil and evening primrose oil, has grown as of late.
Dietary supplementation of -linolenic acid, a metabolite of the omega-6 essential
fatty acid, linoleic acid, has been shown to suppress both acute and chronic inflam-
mation in animals, as well as lower plasma cholesterol and triglycerides, and inhibit
platelet aggregation in diabetics.
114,115
More recent studies have demonstrated that
the addition of -linolenic acid to an eicosapentaenoic acid (EPA)-enriched diet
provides additional benefits with regard to lung function during endotoxemia.
116,118
The conversion of linoleic acid to -linolenic acid requires the presence of the
enzyme, -6 desaturase. However, under normal conditions, this enzyme has a low
activity, therefore, only a small portion of the linoleic acid is actually converted to
-linolenic acid which is, in turn, further metabolized to dihomo--linolenic acid
(DGLA). Dihomo--linolenic acid is a precursor of the anti-inflammatory
eicosanoids, prostaglandin E1 (PGE1) and thromboxane A1 (TXA1), as well as a
precursor for arachidonic acid. The conversion of dihomo--linolenic acid to arachi-
donic acid requires the presence of -5 desaturase, an enzyme that is rate limiting
in some macrophages.
119
Thus, the desaturation of dihomo--linolenic acid to arachi-
donic acid is relatively slow, particularly in the presense of EPA, an inhibitor of -5
desaturase.
120
It has been shown in animals that the addition of -linolenic acid (5.0 mole %)
to a diet containing EPA modulates the fatty acid composition of alveolar mac-
rophage phospholipids, thereby promoting a shift toward formation of less inflam-
matory eicosanoids by stimulated macrophages without causing an impairment in
macrophage bactericidal functions.
121
These changes in immune function observed
in animals receiving a diet containing -linolenic acid and EPA are undoubtably
37
Current Nutrient Substrates
2
responsible for the improvements in clinical outcomes seen in patients with acute
respiratory distress syndrome (ARDS) who received a similar diet.
122
In a multicenter trial, 98 patients with ARDS caused by sepsis/pneumonia,
trauma, or aspiration were randomized to receive an enteral formula containing
both EPA and -linolenic acid, as well as antioxidants (vitamins E and C, and
beta-carotene) or an isonitrogenous, isocaloric standard diet. By study day 7, pa-
tients receiving the EPA and -linolenic acid-enriched formula exhibited significant
improvements in pulmonary neutrophil recruitment and inflammation, gas exchange,
requirement for mechanical ventilation, length of intensive care unit stay, and a
reduction in new organ failures.
122
-3 Polyunsaturated Fatty Acids
There is a plethora of research to suggest that -3 fatty acids may have beneficial
effects on plasma cholesterol and triglyceride levels.
123,125
More recently, research in
this area has centered around the ablility of -3 fatty acids to favorably effect im-
mune function through their ability to alter ecoisanoid formation and metabolism.
Eicosapentaenoic acid (EPA) has been shown to be the metabolically active -3
fatty acid because of its structural similarity to the -6 fatty acid that is the usual
ecoisanoid precursor, arachidonic acid. In contrast to the -6 fatty acids, the omega-3
fatty acids favor production of prostaglandins of the 3 series (PGE3) and
leukotrienes of the 5 series (LTB5), which have significantly different biological
activities than the eicosanoids produced by the omega-6 fatty acids.
108
Thromboxane A3, one of the prostanoids formed from EPA, is a moderate vaso-
constrictor yet it does not aggregate platelets. In comparison, thromboxane A2, syn-
thesized from arachidonic acid, is a very potent platelet aggregator and
vaso-constrictor. Leukotriene B5, also derived from EPA, is a much less chemotactic
and aggregatory agent than the leukotriene B4 that is formed from arachidonic acid.
However, both prostacyclin I3, derived from EPA, and prostacyclin I2, synthesized
from arachidonic acid, are potent vasodilators and platelet antiaggregators.
109
In addition to synthesizing different eicosanoids than -6 fatty acids, EPA com-
petes with arachidonic acid as a substrate for the enzymes cyclooxygenase and
5-lipoxygenase, further reducing the formation of proinflammatory ecosanoids.
Furthermore, EPA and docosahexaenoic acid (DHA) have been shown to displace
linoleic acid and arachidonic acid in cell membranes and to reduce arachidonic acid
production through inhibition of the enzyme -6 desaturase.
108
These alterations in
eicosanoid metabolism suggest that provision of lipids rich in EPA may be advanta-
geous in critically ill patients suffering from systemic inflammation and infection.
A number of animal studies appear to support the aforementioned hypothesis.
In one set of experiments, administration of both short-term parenteral (i.e., 3 days)
and long-term enteral (i.e., 6 weeks) diets enriched with -3 fatty acids improved
survival in animals receiving an endotoxin infusion.
126
A similar set of experiments
showed that animals receiving short-term parenteral nutrition (TPN) containing
soybean oil developed significant metabolic and lactic acidosis after being infused
with endotoxin compared to animals receiving TPN enriched with -3 fatty acids
from fish oil.
127
In addition to having improved lactate levels, the animals receiving
the -3 fatty acid containing TPN also demonstrated a significantly higher mixed
venous oxygen than the animals given the TPN containing soybean oil. Administra-
tion of -3 fatty acids found in fish oil appears to attenuate tissue hypoxia and
38
The Biology and Practice of Current Nutritional Support
2
improve survival in animals during endotoxemia, presumably through alterations
in prostaglandin metabolism.
Another area of intense research is the ability of -3 fatty acids to alter cytokine
production. The synthesis of several cytokines, specifically tumor necrosis factor
(TNF) and interleukin-1 (IL-1), is related to the production of prostaglandin E2
(PGE2). The presence of stress or sepsis causes an increased production of PGE2
from monocytes and macrophages, which, in turn, results in an increased production
of cytokines. It has been suggested that prolonged cytokine exposure results in in-
creased muscle degradation,
128
increased hepatic lipogenesis,
129
and hypertrig-
lyceridemia.
130
These findings have prompted some investigators to suggest that
administration of fish oil may help to suppress the deleterious effects of excessive
cytokine production. However, because certain cytokines help to control the bodys
defense system, a substantial reduction in their production may result in impairment
of normal immune response. Thus, researchers continue to search for the optimal
dose of -3 fatty acids with respect to cytokine production.
Hardardottir, et al
131
fed mice diets containing varying amounts of -3 fatty
acids, ranging from 0.15% to 1.5% by weight, for five weeks and noted an increased
production of TNF from peritoneal macrophages in animals receiving the 1.5%
-3 fatty acid diet compared to those receiving lower amounts of -3 fatty acids.
Simlarly, other investivators have noted increased TNF
132,133
and IL-1
133
production
in animals receiving -3 fatty acids compared to those fed corm oil. While other
researchers have found contrasting results,
134
Drs. Meydani and Dinarello
135
at-
tribute these discrepancies to the amount of EPA and DHA in the diet and/or the
duration of feeding.
With respect to human trials, several studies have examined the effects of fish oil
supplementation on eicosanoid and cytokine production in healthy volunteers.
136,137
These studies have consistantly shown a decrease in the production of
proinflammatory cytokines in volunteers receiving the fish oil supplemented diets.
However, one study also noted an impairment of the bodys ability to mount an
immune response in healthy individuals who ate a low-fat (< 30% of total calories),
high-fish (1.23 g EPA plus DHA/day or 121-188 g fish/day) diet for 6 weeks.
138
These individuals demonstrated a significant reduction in percentage of helper T
cells, mitogenic response to T-cell mitogen, delayed-type hypersensitivity skin response,
as well as production of TNF, IL-1, and IL-6 compared to those people receving a
low-fat, low-fish (0.27 g EPA plus DHA/day or 33 g fish/day) diet. Several undesir-
able changes in immune function (i.e. increased IL-6 release and decreased CD4
cell counts) have also been observed in patients with HIV infection who consumed
five food bars daily that provided a total of 1.96 -fatty acids/day for 6 weeks.
139
Chlebowski, et al,
140
however, demonstrated a significant reduction in hospitalizations
in patients with HIV infection who drank 500 mL/day of a commercially available
oral supplement that provided a mere 1.1 g fish oil/day (475 mg EPA plus DHA)
for a 6-month period. These findings suggest that for long-term (i.e., > 6 weeks)
feeding of fish oil to be of benefit in immunocompromised individuals, it must be
provided in modest amounts. With respect to the short-term (i.e., 1-2 weeks) use of
enteral formulas containing fish oil, a number of studies have shown that feeding
fish oil in amounts that provide 1.2-5.0 g -3 fatty acids/1000 kcal in select
populations is safe with respect to immune function.
A number of prospective, randomized trials have demonstrated improved im-
mune function,
44-46,50
fewer infectious complications,
43,45-49,51
and decreased length
39
Current Nutrient Substrates
2
of stay
43,45,47,49
in patients receiving enteral formulas enriched with fish oil, in addition
to other immunostimulatory nutrients, compared to those receiving standard diets
rich in -6 fatty acids (Tables 2.4 and 2.5). Only two studies have compared the
effects of -3 fatty acids alone.
141,142
Taken together, these studies suggest that short
term administration of enteral formulas containing 7 to 11 g fish oil/L (~ 1.4 to 1.7
g EPA plus DHA/L) may be beneficial in certain hospitalized patient populations.
However, further studies are needed to examine the immunological and clinical
effects of feeding such diets for an extended period of time.
As a result of these findings, an ever growing number of enteral formula manu-
facturers have begun to incorporate -3 fatty acids in to their products either in the
form of -linolenic acid from vegetable oils (particularly canola or soybean oil) or
from the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fish oil.
However, a great deal of controversy exists with regard to the difference between
vegetable and animal sources of -3 fatty acids. The main difference between these
two sources of -3 fatty acids is that fish oil contains the preformed EPA and DHA,
whereas, the -linolenic acid in the vegetable oil must be converted in the body to
EPA. This conversion process, however, yields a relatively low amount of EPA when
compared to the amount of EPA obtained from consuming fish oil.
143
Thus, plant
sources, although useful, may not be an adequate substitute for the preformed EPA
and DHA found in fish oil.
Medium Chain Triglycerides
In addition to the naturally occurring and processed -6 and -3 fatty acids
currently used in enteral formulas, medium chain triglycerides (MCT) are a novel
lipid alternative frequently found in many of todays enteral formulas. Although the
incorporation of MCT into intravenous fat emulsions has been studied extensively,
these products are not yet commercially available. Medium chain triglycerides are
principally prepared by hydrolyzing and re-esterifying coconut oil, however, they
can also be derived from palm kernal oil. These lipids are significantly different from
the conventional fats (i.e., LCT) used in enteral formulas and intravenous lipid
emulsions. LCT are absorbed via the lymphatic system and are carnitine-dependent
for chylomicron formation and transport. In contrast, MCT are directly absorbed
via the portal system, are not carnitine-dependent, and do not require chylomicron
formation.
144
Thus, MCT are absorbed and metabolized as rapidly as glucose. Se-
verely catabolic patients may therefore benefit from this rapidly available, high en-
ergy fuel because MCT are less likely to be deposited and more likely to be oxidized
in tissues.
145
Furthermore, animal studies suggest that MCT do not depress RES
function.
110
MCT, however, have their greatest clinical impact in patients with impaired fat
absorption due to pancreatic, biliary, or intestinal dysfunction. In principle, replacing
LCT in the diet with MCT in the setting of impaired fat absorption should help to
decrease stool frequency and volume while concommitantly improving nutrient
absorption.
One important point about MCT is that they are devoid of essential fatty acids.
Thus, the provision of some LCT is necessary in order to meet essential fatty acid
requirements.
144
Most MCT-containing enteral products consist of a physical mixture
of LCT and MCT. However, there is now a new generation of fats known as struc-
tured lipids which combine both MCT and LCT on the same glycerol backbone.
4
0
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e
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i
o
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o
g
y
a
n
d
P
r
a
c
t
i
c
e
o
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r
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e
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i
t
i
o
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a
l
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u
p
p
o
r
t
2
Table 2.4. Summary of studies assessing efficacy of immune-enhancing enteral formulas
Author Patients Diets* Results
Gottschlich, et al
43
50 burn patients Modular diet (containing Significant reduction in length of hospital stay (LOS)
supplemental arginine and fish and incidence of wound infections in modular group
oil) vs. Osmolite with Promix
vs.Traumacal
Cerra, et al
44
20 surgical ICU patients Impact vs Osmolite HN Significant improvement in T-lymphocyte proliferation
with sepsis syndrome in Impact group
Daly, et al
45
85 patients undergoing Impact vs. Osmolite HN Significant reduction in LOS and infectious/wound
surgery for upper GI complications in Impact group
malignancies
Moore, et al
46
98 trauma patients Immun-Aid vs. Vivonex TEN Significant increases in total lymphocytes, T lymphocytes
and T-helper lymphocytes; significantly fewer intra-
abdominal abscesses, and less multiple organ failure
in Immun-Aid group
Daly, et al
47
60 patients undergoing Impact vs. Traumacal Significant decrease in peripheral WBC PGE
2
surgery for upper GI production, LOS, and infectious/wound complications
malignancies in Impact group
Bower, et al
48
326 ICU patients with an Impact vs. Osmolite HN Significant reduction in LOS and frequency of
APACHE score 10 infectious complications in septic patients receiving
Impact
Kudsk, et al
49
35 trauma patients Immun-Aid vs. Promote Significantly fewer major infectious complications
with Casec and shorter LOS in Immun-Aid group
continued on next page
4
1
C
u
r
r
e
n
t
N
u
t
r
i
e
n
t
S
u
b
s
t
r
a
t
e
s
2
Table 2.4. Summary of studies assessing efficacy of immune-enhancing enteral formulas (continued)
Author Patients Diets* Results
Kenler, et al
141
50 patients undergoing Osmolite HN vs. isocaloric, Significant incorporation of EPA into plasma and
surgery for upper GI isonitrogenous fish oil erythrocyte phospholipids, and 50% decline in
malignancies structured lipid-based diet gastrointestinal complications and infections in
FOSL-HN group
Kemen, et al
50
42 patients undergoing Impact vs isocaloric, Significant increase in total T lymphocytes, helper T
surgery for GI malignancies isonitrogenous diet cells, activated T cells, B-lymphocyte indices,
immunoglobin M & G concentrations in Impact group
Swails, et al
142
20 patients undergoing Osmolite HN vs isocaloric, Significant reduction in PGE
2
and 6-keto prostaglandin
surgery for upper GI isonitrogenous fish oil PGF
1a
production from PBMC with endotoxin stimulation
malignancies structured lipid-based diet in FOSL-HN group
(FOSL-HN)
Galban, et al
51
176 septic ICU patients Impact vs. Precitene Hiperproteico Significant reduction in mortality rate, number of
with an APACHE II bacteremias, and number of patients with more than
score > 10 one nosocomial infection in Impact group
Gadek, et al
122
98 patients with ARDS High fat, low carbohydrate Significant improvements in pulmonary netrophil
formula vs. isocaloric, recruitment and inflammation, gas exchange,
isonitrogenous EPA + GLA
**
requirement for mechanical ventilation, length of
lipid-based diet unit stay, and a reduction in organ failures
*Manufacturers of diets and protein modules: Ross Laboratories: Osmolite, Osmolite HN. Novartis Nutrition: Impact, Vivonex T.E.N. B
Braun.: Immune-Aid. Mead Johnson Nutritionals: Traumacal, Casec. Clintec: Promote. Navaco Laboratories: Promix.
**EPA=eicosapentaenoic acid; GLA=-linolenic acid
42
The Biology and Practice of Current Nutritional Support
2
Structured Lipids
Another alternative to LCT are structured triglycerides. These triglycerides are
the product of MCT and LCT that have been hydrolyzed and then re-esterified
after a random distribution of the MCT and LCT has occurred. Depending on the
proportions of oils used, the resulting structured lipid may consist of one MCT
and two LCT or two MCT and one LCT on the same glycerol backbone. This
MCT/LCT mixture provides both rapidly and slowly metabolized fuels, as well as
essential fatty acids.
144,145
Preliminary animal studies suggest that structured lipids result in significantly
better nitrogen balance and weight gain, and increased protein synthetic rates in
both the skeletal muscle and liver when compared to either LCT, MCT, or a physi-
cal mixture of MCT and LCT.
146,147
These results were particularly evident when
the structured lipid contained a mixture of either 60% MCT and 40% LCT or
75% MCT and 25% LCT. In contrast, a 50:50 MCT/LCT mixture yielded no
improvement in the protein-sparing effect. The 75% MCT/25% LCT structured
lipid emulsion was then intravenously infused over a 19-hour period in 9 hospital-
ized patients, and no significant impairment in RES function was observed.
101
Additional clinical trials have shown that provision of parenteral structural lipid
emulsions (40% MCT/60% LCT by weight) are well tolerated
148
and cause a sig-
nificantly higher whole body fat oxidation, without promotion of ketogenesis, in
postoperative patients when compared with the provision of standard parenteral
LCT emulsions.
149
More recently, a parenteral structured lipid emulsion (64% MCT/
36% LCT by weight) was compared to a parenteral MCT/LCT physical mixture
(50% MCT/50% LCT by weight) in forty patients undergoing abdominal surgery.
Liver function tests (ASAT and ALAT) and plasma triacylglycerol levels were sig-
Table 2.5. Commercially available immune-enhancing enteral formulas used
in studies shown in Table 2.4
Per 1000 kcal Impact Immun-Aid
Kcal/mL 1.0 1.0
Carbohydrate 132 (53%) 120 (48%)
(g/% total kcal)
Carbohydrate source Hydrolyzed cornstarch Maltodextrins
Protein (g/% total kcal) 56 (22%) 80 (32%)
Protein source Sodium and calcium Lactalbumin
caseinates L-arginine (14.0 g)
L-arginine (12.3 g) L-glutamine (9.0 g)
Yeast RNA (1.2 g) BCAA (20.0 g)
Yeast extract (1.0 g)
Fat (g/% total kcal) 28 (25%) 22 (20%)
Fat source Structured lipid from MCT; canola oil
palm kernal oil and
sunflower oil; refined
menhaden oil
-3 fatty acids (g) 1.68 1.10
43
Current Nutrient Substrates
2
nificantly increased in the patients receiving the parenteral MCT/LCT physical
mixture compared to those patients receiving the parenteral structured lipid.
150
Presently, in the United States, intravenous structured lipids are still in the ex-
perimental phase. They are, however, present in several commercially available
enteral formulas as a mixture of palm kernal oil (MCT) and sunflower oil or fish oil
(LCT). More recently, a prospective, randomized clinical trial was conducted in
patients undergoing surgery for upper gastrointestinal malignancies using an enteral
formula that incorporated -3 fatty acids from fish oil directly into the structured
lipid.
141,142
Patients receiving the experimental formula demonstrated significant
improvements in renal function, presumably due to changes in eicosanoid metabo-
lism, and liver function, as well as a decrease in the number of patients with multiple
infections compared to patients receiving a commercially available enteral formula
differing only with respect to its lipid composition.
There is good evidence that lipid mixtures designed for special medical purposes
play an important role in the nutritional support of a wide variety of patient popu-
lations. It is clear from both animal and human studies that modulation of the
composition of lipid emulsions can significantly affect the response to disease, in-
jury, and infection. Based on these studies, several recommendations regarding fat
administration in hospitalized patients can be made. First, lipid intake should ide-
ally be limited to providing no more than 30% of total calories. Second, the type of
lipid administered should be based upon the patients disease state. There is con-
vincing evidence that critically ill patients may benefit from the administration of a
lipid mixture that contains -3 fatty acids and MCT in addition to LCT. Patients
undergoing surgery for upper gastrointestinal cancers may also benefit from receiv-
ing such a lipid mixture in the early postoperative period. However, more research is
needed in this area to further define the optimal dose and mixture of lipids that is
best suited for each specific patient population.
Conclusion
Recent evidence suggets that specific nutrients may favorably affect certain as-
pects of organ and immune function independent of their general nutrition effects.
The administration of branched-chain amino acids may be advantageous in patients
with significant renal failure due to the fact that BCAA are preferentially used by the
body for protein synthesis thereby decreasing the rate of urea production. In addi-
tion, the provision of glutamine-enriched nutrition may be efficacious in specific
patient populations. Finally, the addition of such nutrients as arginine, glutamine,
nucleotides, -3 fatty acids from fish oil and -linolenic acid to enteral formulas
administered to critically ill, burn, and trauma patients, as well as those with ARDS
and those undergoing surgical resections for upper gastointestinal malignancies has
been shown to decrease infectious complications and length of hospital stay. De-
spite this exciting promise with respect to nutritional immune moduation and pa-
tient outcome, broad application of the enteral and parenteral products shown to be
effective in specific populations is premature. Additional randomized, prospective
trials are required to evaluate the efficacy of using these products in other patient
populations.
As we forge ahead in the field of bionutrition, we can look forward to the con-
tinual development and refinement of specialized functional formulas-parenteral
and enteral formulas that provide health benefits beyond basic nutrition. In addition,
we can expect to see further advances in the use of ligand-binding proteins, probiotics
and prebiotics, and other natural phytonutrients.
151
44
The Biology and Practice of Current Nutritional Support
2
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130. Hirschberg Y, Pomposelli JJ, Blackburn GI et al. The effects of chronic fish oil
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Current Nutrient Substrates
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supl):397-401.
CHAPTER 3
Biochemistry of Amino Acids:
Clinical Implications
Rifat Latifi, Khawaja Aizimuddin
Introduction
Amino acids, as organic compounds, containing both an amino group and a
carboxylic acid group, are the monomeric and basic constituents of all proteins.
Amino acids occurring in protein are known as alpha-amino acids and have one or
two empirical formulae RCH (NH
+
)COOH
-
or R-CH-(NH
3
)COO
-
. Beta-amino
acids and gamma-amino acids also occur in nature but are not components of pro-
teins, and their significance is not known. This chapter reviews the basic biochemis-
try and physiology of amino acids and their functions as fundamental units of proteins.
Their increasingly recognized and valued role in the metabolic and nutritional man-
agement of critically ill patients will be discussed through out this volume.
Structure of Amino Acid and Proteins
A protein molecule consists of amino acids held together by peptide bonds, which
form a long polypeptide chain. The exact sequence of amino acids in the chain,
referred to as the primary structure of the protein, is determined genetically and
defines how the chain is folded into more complex conformations or shapes.
A polypeptide, which is folded into a helical or pleated sheet configuration, is
referred to as a secondary structure. If the sequence of amino acids is then folded
into a three-dimensional configuration, a tertiary structure is created. Some pro-
teins have a higher level of molecular architecture known as the quaternary struc-
ture, in which several chains aggregate and function as a unit. The amino acid sequence
and protein structure determine the nature and function of protein molecules upon
which virtually every process of life depends. The folding of polypeptide chains into
alpha helix and beta pleated sheets has clinical implications. The alpha helix is a
rod-like structure and contains a tightly coiled polypeptide main chain. Two or
more such alpha helices can entwine to form a cable, which serves as a mechanical
support by forming stiff bundles of fibers. Such alpha-helical coils are found in the
keratin of a hair, myosin and tropomyosin in muscle, epidermis in skin and fibrin in
blood clots. In contrast to the coiled alpha helix, beta-pleated sheets are fully ex-
tended sheets of polypeptide chains. Another type of periodic structure is the col-
lagen helix. Collagen is triple-stranded helical rod which is tightly held together by
the amino acid glycine. By virtue of its very small size, glycine fits into the inner
aspect of the tightly packed helical cable and thereby allows the different polypep-
tide chains to come together. It is easy to see that mutation of a single glycine in
collagen can lead to weak collagen as occurs in osteogenesis imperfecta.
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
53
Biochemistry of Amino Acids: Clinical Implications
3
Although more than 100 different amino acids have been identified in nature,
only 20 amino acids are used to build the enormous number of biologically active
peptides and proteins that comprise most of the dry weight of the human body.
When one realizes that muscle, bone, blood, brain, genes, and other tissues are all
composed of amino acids, it is not difficult to understand the importance of acquir-
ing knowledge of amino acid biochemistry and metabolism, not only for biochem-
ists and basic scientists, but also for surgeons and other physicians.
Amino Acid and Protein Synthesis
Amino acids are building blocks for protein. All proteins are initially synthesized
from 20 amino acids known as common or primary amino acids. Primary amino
acids are defined as amino acids for which a specific codon exists in the DNA ge-
netic code. The genetic code is a directory that provides the correspondence be-
tween a sequence of nucleotide bases and a sequence of amino acids. The codons
represent genetic words in a code composed of three nucleotide bases which are
transcribed from DNA into the messenger RNA (mRNA), and their sequence is
always read from its 5-end (amino-terminal end) to its 3-end (carboxyl-terminal
end). Codons exist for all 20 of the amino acids in the human body. Genetic infor-
mation is transmitted from the DNA sequence by mRNA translation into the amino
acid sequence of a protein. The genetic code is thought to be specific, usually uni-
versal, redundant or degenerate, non-overlapping and commaless. Conventionally,
the code is read from a fixed starting point as a continuous sequence of bases, taken
three at a time.
Protein synthesis is a highly complex biochemical process that requires
1. an amino acid sequence information, as coded by mRNA,
2. activated amino acids assembled as aminoacyl transfer RNA (tRNA)
complex
3. energy in the form of guanosine triphosphate (GTP), and
4. various protein initiation or release factors.
Protein synthesis occurs on the surface of ribosome, or multiprotein, multi-RNA
complexes that provide the enzyme, peptidyl-transferase. This enzyme is one of many
proteins of the larger ribosomal subunit and is imbedded in the surface of the sub-
unit. It catalyzes peptide bond formation and covalent linkage of one amino acid
residue to another. The process of protein synthesis itself is called translation,
because the language of the nucleotide sequence on the mRNA is translated into
the language of an amino acid sequence. The mRNA is translated from its 5-end to
its 3-end producing a protein synthesized from its amino-terminal end to its
carboxyl-terminal end. The direction of translation is precisely defined, with the
amino terminal of the evolving protein being synthesized first and the carboxyl ter-
minal synthesized last. The polypeptide chains produced by translation may be
modified further after translation. Protein synthesis has three steps: initiation, elon-
gation, and termination.
Initiation
Initiation involves assembly of the components of the translational system be-
fore the peptide bonds are formed. Components of the translational system include
two ribosomal subunits, the mRNA to be translated, the specified aminoacyl tRNA
along with GTP and the initiation factors. Eukaryotic initiation, which requires
ribosomal subunits 40S and 60S, mRNA, GTP, initiation factors (IF-1, IF-2, and
54
The Biology and Practice of Current Nutritional Support
3
IF-3) and ATP, first involves the formation of a complex outer 40S ribosomal sub-
unit, and secondly, the addition of the 60S ribosomal subunit to give an 80S
initiation complex.
Elongation
The second step in protein synthesis is elongation of the polypeptide chain. The
necessary components for this process are the 80S initiation complex,
aminoacyl-tRNA, GTP and eukaryotic elongation factors eEF-l alpha, eEF-1 beta
and eEF-2. During elongation, the ribosome moves from the 5-end to the 3-end of
the mRNA that is being translated. At one time, a single mRNA molecule may be
translated by many ribosomes, thereby markedly increasing the efficiency of the
utilization of the mRNA. The group of ribosomes bound to a mRNA molecule is
called a polyribosome. The concluding event of elongation is translocation. Translo-
cation is a process in which the ribosome advances three nucleotide segments to-
ward the 3-end of the mRNA following formation of the peptide bond. It causes the
release of the uncharged tRNA and movement of peptidyl tRNA into the P site.
Termination
The final step of protein synthesis, occurs in response to termination signals,
after the final amino acid residue is placed at the carboxyl terminal of the newly
synthesized protein. This process occurs when one of the three termination codons
(UAA, UAG and UGA) moves into the A site.
These codons are recognized by release factors (RF): RF-1, RF-2, and RF-3 and
cause the newly generated protein molecule to be released from the ribosomal com-
plex, and also effect the dissociation of ribosomes from the mRNA.
Post-Synthetic Modification
The basic set of 20 amino acids can be modified after synthesis of a polypeptide
chain to enhance their capabilities. For example, the amino acid terminals of many
proteins can be acetylated to make them more resistant to degradation. Similarly,
the proline residues in collagen may be hydroxylated to form hydroxyproline, which
stabilizes the collagen fiber. Carboxylation of glutamate is another important step in
the synthesis of coagulation factor.
Protein Function
Protein function may be classified into two categories: dynamic and structural
(static). Dynamic functions include enzymatic catalysis of biochemical reactions,
transport and storage, contraction, generation and transmission of nerve impulses
and immune protection. Structurally, proteins provide the matrix for bone and con-
nective tissue, which give structure and form to the body. Some of these important
functions are discussed in detail below.
Enzymatic Catalysis
Specific enzymes catalyze chemical reactions in living organisms. Several thou-
sand enzymes have been recognized and many of them are essential for the function
and survival of the organism. Nearly all enzymes in biological systems are proteins.
It is easy to see that a defect in the amino acid constitution of an enzyme may lead to
abnormal functioning of that enzyme system.
55
Biochemistry of Amino Acids: Clinical Implications
3
Transport and Storage
Many small molecules and ions are transported or stored by proteins. Oxygen is
transported in blood by hemoglobin and stored in muscles in combination with
myoglobin. Similarly iron is carried in plasma by transferrin and stored in liver as a
complex with ferritin. Thyroxine, cortisol, sex hormone, calcium and copper are
examples of some of the large array of hormones and ions transported by proteins.
Coordinated Motion
Proteins provide the contractile element for the cytoskeleton. Movement of chro-
mosomes during mitosis, movement of organelles within the cell and the propul-
sion of sperms by flagella is produced by coordinated actions of contractile assemblies
consisting of proteins. Most importantly, muscle contraction is accomplished by
sliding motion of two proteins, actin and myosin.
Mechanical Support
Proteins provide the framework for the living organism. Collagen, a fibrous pro-
tein, provides tensile strength to skin and bone.
Immune Protection
Antibodies consist of highly specific amino acid chains, which protect the body
from viruses, bacteria and other exogenous or endogenous antigens. Nutrient sub-
strate deficits may therefore lead to suppressed humoral and delayed type hypersen-
sitivity immune responses
Tissue Repair
Proteins not only play a pivotal role in the inflammatory response but also pro-
vide building blocks for the process of repair after tissue injury.
Generation and Transmission of Impulses
The synaptic receptors at nerve terminals consist of small proteins which are in
turn stimulated by other protein molecules such as acetyl choline. Furthermore,
most membrane functions such as transport of ions or molecules, intercellular com-
munications and energy transduction are mediated by specific proteins that traverse
the cell membrane.
Control of Growth and Differentiation
Many hormones such as growth hormone, insulin and thyroid stimulating hor-
mones are proteins. Further more many of the growth factors such as nerve growth
factor, platelet derived growth factor are also proteins.
Specialized Functions
Some amino acids have specialized functions. For example, glutamine serves as
energy source for lymphocytes and macrophages. It is also required for the
maintenance of the intestinal mucosa. Similarly arginine is important for cell
mediated immunity.
Classification of Amino Acids
Amino acids occurring in biologic proteins are known as alpha-amino acids and
have one of two empirical formulae: R-CH-(NH
2
)-COOH or R-CH-(NH
3
+
)-COO
-
.
Beta amino acids and gamma-amino acids also occur in nature but are not
56
The Biology and Practice of Current Nutritional Support
3
components of proteins, and their significance is not known. The core of an -amino
acid is the -carbon atom next to the carboxylic acid (COOH) group. All -amino
acids, except glycine, are asymmetric, with four different groups bonded to the
a-carbon: a hydrogen atom, a carboxyl group, an amino group (NH2), and a dis-
tinctive R-group. The characteristic acid-base properties of each amino acid and the
variety of possible R-group configurations and interactions make peptides and pro-
teins versatile in structure and function.
Although the primary amino acids can be polymerized to form proteins, each of
the 20 primary amino acids is a unique compound with its own individual biologi-
cal and metabolic functions. Many amino acids of biological significance, such as
thyroxine, triiodothyronine and beta-alanine, are not numbered among the 20 pri-
mary amino acids. Other amino acids, such as ornithine and citrulline, are interme-
diates of the urea cycle and have major roles in the body economy. Some proteins,
such as collagen, elastin, and prothrombin, incorporate special amino acids. For
example, collagen contains 4-hydroxyproline and 5-hydroxylysine; elastin con-
tains desmosine; myosin has n-methyllysine; and prothrombin contains
-carboxyglutamic acid.
Primary amino acids are classified in several ways. Because the nature of the side
chains ultimately dictates the role of an amino acid in a protein, one useful classifi-
cation of amino acids is based on the polarity of the side chain. This classification
identifies and categorizes amino acids as nonpolar (hydrophobic), uncharged polar
(hydrophilic), negatively charged (acidic), and positively charged (basic) (Table 3.1).
Amino acids with non-polar side chains typically do not bind or release protons, or
participate in hydrogen or ionic bonding. Proline is unique in this group in that it
contains an amino group rather than an alpha-amino group.
Amino acids with uncharged polar side chains have zero net charge at neutral
pH, although the side chains (R-groups) of cysteine and tyrosine can lose a proton
in alkaline conditions. Amino acids with acidic side chains (aspartic acid and glutamic
acid) are negatively charged and are proton donors; amino acids with basic side
chains bind protons (arginine, lysine and histidine). The side chains of arginine and
lysine are fully ionized and positively charged at neutral pH. Histidine, on the other
hand, is a weak basic amino acid because as a free amino acid it is largely uncharged
at physiologic pH. As a component of proteins, however, the histidine side chain
can have a positive or neutral charge, depending on the ionic environment. In addi-
tion to basic and acidic amino acids, a large number of amino acids are classified as
neutral. The neutral amino acids are monoamino-monocarboxylic acids and are
characterized by their side chains. This group includes glycine, alanine, valine, leu-
cine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, and the
sulfur-containing amino acids (cysteine, methionine, and cystine).
Another useful classification is based on whether amino acids are glycogenic,
glucogenic and ketogenic, or only ketogenic. Amino acids are classified as ketogenic
or glucogenic according to their metabolic end products. Amino acids that yield
either acetoacetate or one of its precursors, acetyl CoA or acetoacetyl CoA, are keto-
genic. The only amino acids that are exclusively ketogenic are leucine and lysine
because they cannot function as carbon sources for the net synthesis of glucose. On
the other hand, amino acids whose catabolism yields pytuvate or one of the inter-
mediates of the citric acid cycle (such as oxaloacetate) are glucogenic amino acids
(Table 3.2). However, as depicted in Table 3.2, some amino acids have both ketoge-
nic and glucogenic functions.
57
Biochemistry of Amino Acids: Clinical Implications
3
Amino acids may also be classified as essential or non-essential. Whether amino
acids are nutritionally essential (indispensable) or non-essential (dispensable) de-
pends on whether they can be synthesized endogenously and are not necessarily
required in the diet (non-essential), or those that cannot be synthesized endogenously
and, therefore, must be provided in the diet (essential) (Table 3.3). A new category
of amino acids termed conditionally essential is emerging and includes arginine,
taurine, and others. An amino acid falls into this class when its production is either
limited by immature synthetic mechanisms or its requirements are increased under
certain stressful conditions.
Table 3.1. Classification of the 20 amino acids found in proteins according to
the charge and polarity of the side chains (R-groups)
Nonpolar (Hydrophobic) Uncharged Polar (Hydrophilic)
Side Chains Side Chains
Alanine Asparagine
Glycine Glutamine
Leucine Cysteine
Valine Serine
Isoleucine Threonine
Phenylalanine Tyrosine
Tryptophan
Methionine
Proline
Acidic Side Chains Basic Side Chains
Aspartic acid Histidine
Glutamic acid Lysine
Arginine
Table 3.2. Classification of primary amino acids according to metabolic
end products
Glycogenic or Ketogenic Both
Glucogenic
Glycine Leucine Threonine
Serine Lysine Isoleucine
Valine Phenylalanine
Histidine Tyrosine
Arginine Tryptophan
Cysteine
Proline
Alanine
Glutamate
Glutamine
Aspartate
Asparagine
Methionine
58
The Biology and Practice of Current Nutritional Support
3
Amino Acids in Critical Illness and Injury
Arginine is a semi or conditionally essential amino acid, and its requirements are
increased during sepsis and tissue injury. Through its role in the urea cycle, arginine
takes part in the synthesis of other amino acids, urea and nitric oxide. Arginine is
important for cell mediated immunity. It is required for the growth and function of
T lymphocytes in cultures. In vivo, arginine retards thymic involution by encourag-
ing production of thymic hormones and thymocyte proliferation. Arginine also pro-
motes leukocyte-mediated cytotoxicity. Growth hormone receptors are widely
distributed in the immune system, and by releasing growth hormone, arginine may
increase the cytotoxic activity of macrophages, neutrophils, NK cells and cytotoxic
T cells. Furthermore, nitric oxide, a product of arginine metabolism, has important
tumoricidal, anti-microbial and inflammatory activities.
Glutamine is the most abundant amino acid in blood and in the bodys free
amino acid pool. Lymphocytes and macrophages use glutamine as a source of en-
ergy. After entering the cell, glutamine is converted to glutamate and ammonia by
the action of glutaminase in the inner mitochondrial membrane. Further processing
results in production of aspartate and oxidation of about 25% of glutamine to
carbondioxide. This glutaminolysis pathway works in conjunction with the glyco-
lytic pathway to allow the combined use of glucose and glutamine as an energy
source for macrophages and lymphocytes. Thus, a relative deficiency of glutamine
stores that occurs during critical illness, is likely to lead to poor immune responses.
Table 3.3. Classification of primary amino acids based on
dietary requirements
Essential (Indispensable)
Arginine*
Histidine
Methionine
Threonine
Valine
Isoleucine
Lysine
Phenylalanine
Tryptophan
Leucine
Nonessential (Dispensable)
Alanine
Aspargine
Aspartate
Cysteine
Glutamine*
Glutamate
Glycine*
Proline
Serine
Tyrosine*
* These amino acids plus cystine, proline and taurine are considered to be
conditionally indespensable.
59
Biochemistry of Amino Acids: Clinical Implications
3
Glutamine also plays an important role in maintaining the integrity of the intestinal
mucosa. In animal studies it has been shown that addition of glutamine to parenteral
nutrition inhibits gut mucosa atrophy, reduces bacterial translocation across the gut
epithelium and increases the production of secretory IgA.
Glutamine and arginine are mobilized from the skeletal muscles during critical
illness to provide substrate for production of glucose by the liver, to provide energy
substrate for rapidly dividing cells and to take part in the acid base balance. The
concentration of skeletal muscle glutathione also falls during critical illness. Since
glutathione is a scavenger of free oxygen radicals, the reduced levels may predispose
skeletal muscles to free radical injury. The plasma levels of phenylalanine rise after
critical illness and the ratio of phenylalanine to tyrosine has been used as an indica-
tor of the severity of muscle protein catabolism. The excretion of carnitine and
3-methyl histidine in urine is increased in critically ill patients, indicating muscle
breakdown and catabolism of proteins. The rate of excretion of pyridinium cross-liked
breakdown products of collagen is also increased.
Amino Acids in Circulation
Serum levels of free amino acids are generally low. The normal concentration of
total amino acids in the blood is between 35 and 65 mg/dL. Although some amino
acids circulate in higher concentrations than others, serum concentration averages
about 2 mg/dL for each of the 20 amino acids. Although the distribution of amino
acids in the blood can depend on the type of dietary protein ingested, the concen-
trations of some amino acids are regulated by selective synthesis in different types of
cells. The concentration of free amino acids in the intracellular compartment is
considerably higher than the concentration in the extracellular compartment. The
total amount of free amino acids in the body is about 100 g, of which 50% consists
of glutamate plus glutamine, and 10% consists of essential amino acids. Further-
more, because immediately after entering a cell, amino acids form peptide bonds to
create proteins, storage of large quantities of amino acids as such does not occur in
most cells. However, the cells of some tissues such as the liver, kidney, and the intes-
tinal mucosa can store large quantities of amino acids. The plasma concentration of
each amino acid is relatively constant although various hormones secreted by the
endocrine glands affect the balance between tissue proteins and free amino acids.
Digestion of Amino Acids
During digestion, proteins are degraded into peptides and amino acids. Protein
digestion begins during the gastric phase and is influenced by both hormonal and
neural factors. Pepsinogen, which is secreted by gastric chief cells in response to
ingested foods and low gastric pH, is converted by hydrochloric acid to pepsin, the
major gastric protease. Pepsin is an endopeptidase that is specific for disruption of
peptide bonds involving aromatic primary amino acids. Although important for
breaking down dietary proteins, pepsin is not essential for normal protein digestion
and absorption unless pancreatic function is impaired. For example, patients who
have had a total gastrectomy and those with pernicious anemia absorb protein effi-
ciently and can maintain positive nitrogen balance if adequate amounts of protein
are ingested.
The hydrolysis of proteins to free amino acids and their absorption into the
circulation is a stepwise process. Gastric hydrolysis of protein yields peptides that,
when entering the intestine, stimulate intestinal endocrine cells to release cholecys-
tokinin and secretin which, in turn, stimulate the pancreas to secrete enzymes and
60
The Biology and Practice of Current Nutritional Support
3
bicarbonate into the intestinal lumen. When the gastric contents mix with the alka-
line pancreatic juice in the duodenum, pepsin activity is terminated, and digestion
by pancreatic proteases is initiated.
The pancreatic endopetidases (trypsin, chymotrypsin, and elastase) cleave the
proteins at specific interior peptide bonds. These pancreatic proteases are secreted in
inactive forms and are converted to active enzymes by the combined action of enter-
okinase, a brush border mucosal cell enzyme, and trypsin. The end products of the
additive action of endopeptidases and exopeptidases are free amino acids and
oligopeptides. Subsequently, proteases in the brush border cells contribute to the
enzymatic digestion of the oligopeptides (a peptide chain several peptides long).
The brush border oligopeptidases generally cleave the N-terminus amino acids from
their substrate to yield smaller peptides.
Absorption of Amino Acids
The final products of protein digestion, amino acids and small peptides (dipep-
tides and tripeptides) are absorbed by distinct transport systems. Whereas, proteins
are absorbed mainly in the form of small peptides and amino acids, the final mea-
surable amino nitrogen in postprandial portal-vein blood is primarily in the form of
amino acids. Nevertheless, a few small peptides, usually dipeptides and tripeptides,
do appear in portal blood after protein ingestion. Several mechanisms have been
identified for amino acid transport from the gut lumen into the intestinal epithelial
cells, but some amino acids (such as the amino acidsglycine, proline, and hydrox-
yproline) may be transported by more than one mechanism.
Separate transport mechanisms exist for neutral amino acids (alanine, valine,
leucine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan); basic
amino acids (lysine, arginine, and histidine); acidic amino acids (aspartic acid and
glutamic acid); and for beta-amino acids (beta-alanine and taurine). The transport
of amino acids across the special membrane of enterocytes is carrier mediated,
sodium-dependent, and characteristically energy-dependent. The transport is asso-
ciated with the entry of sodium into the cell and is fueled by the energy derived
from the electrochemical sodium gradient. In other words, the downhill entry of
sodium can bring about the uphill concentration of amino acids in the brush
border cells. Once inside the liver cells, amino acids may be catabolized, with the
conversion of their nitrogen to ammonia and urea. Because this process occurs in
the mitochondria, transport mechanisms may exist in the mitochondrial membrane.
Although little is known concerning the intracellular transport of amino acids across
the mitochondrial membrane, the transcellular transport of amino acids in the kid-
neys appears to occur by a special mechanism in which amino acids are covalently
linked to gamma-glutamyl residues of the tripeptide glutathione.
During absorption, peptides and amino acids are taken up by the mucosal cells
by independent processes. While oligopeptides, apparently, can be absorbed by the
intestine without first being broken down into individual amino acids, dipeptides
and tripeptides are actively transported against a concentration gradient by a carrier
mechanism separate from that for amino acids. The propensity for a dipeptide to be
transported is influenced by the dipeptide structure including the specific amino
acid residues, the position relative to the carboxyl and amino terminals, the length
of the side chains, and stereoisomerism. The majority of oligopeptides that are ab-
sorbed undergo additional intracellular hydrolysis.
61
Biochemistry of Amino Acids: Clinical Implications
3
The absorption of small peptides may represent a major mechanism for absorp-
tion of dietary protein and has important physiologic and clinical implications. For
example, consideration of oligopeptide absorption is essential in designing formulas
for optimal enteral nutrition.
Absorption of oligopeptides across the brush border occurs more rapidly than
the transport of free amino acids. Whereas free amino acids are absorbed more rap-
idly in the proximal intestine, the peptides appear to be absorbed well in both the
proximal and distal gut. Resection of long segments of the small bowel, or jejunoileal
bypass in patients undergoing treatment for morbid obesity may result in protein
calorie malnutrition. This malnutrition is related to a reduced rate of amino acid
absorption in the residual functioning jejunum. On the other hand, dipeptide ab-
sorption is not affected significantly by jejunoileal bypass.
Biochemical Transformation of Amino Acids
The process by which an amino group at least in different amino acids (alanine,
arginine, aspartic acid, asparagine, cysteine, glutamic acid, glutamine, isoleucine,
phenylalanine, tryptophan, tyrosine, and valine) is transferred from one carbon chain
to another to form a new amino or keto acid is called transamination. The en-
zymes that catalyze this process, the transaminases (aminotransferases), are widely
distributed and are responsible for an active redistribution of amino groups among
amino acids in vivo. Furthermore, the transfer of the amino group from one carbon
chain to another helps to maintain appropriate ratios of the various amino acids
while individual compounds are undergoing synthesis or degradation.
An essential cofactor for all transaminases, and for many other reactions involv-
ing amino acids, is pyridoxal phosphate. The most important transaminases are
aspartate aminotransferase (AST), also known as glutamine-oxaloacetic transami-
nase (GOT); alanine aminotransferase (ALT), also known as glutamic-pyruvic tran-
saminase (GPT); a-amino acid-a-ketoglutarate aminotransferase and amino
acid-pytuvate aminotransferase. Because transaminases are present in high concen-
trations in the heart muscle and liver, damage to either or both of these organs leads
to transaminase leakage into the plasma or serum. Transamination is of great impor-
tance in the metabolism of amino acids and is the process, which allows a-keto acids
to be used as substitutes for many amino acids in nutrition regimens, especially in
the management of renal failure or insufficiency.
Before oxidation of the carbon group of the amino acid molecule can take place,
the amino group must be detached. Detachment is accomplished by oxidative deami-
nation, a process that occurs mainly in the liver and which, in contrast to transami-
nation, produces free ammonia. The main mechanism for net use or production of
amino acids is a reaction catalyzed by glutamate dehydrogenase. This enzyme cata-
lyzes the following reaction:
Glutamate + NAD (or NADP
+
) + H
2
O -ketoglutarate + NADH
(or NADP
+
) + H
+
+ NH
4
+
.
The reaction direction depends on the relative concentrations of glutamate,
a-ketoglutarate, and ammonia and the ratio of oxidized to reduced cofactors. After
ingestion of a meal containing protein, glutamate levels in the liver are elevated, and
the reaction proceeds in the direction of amino acid degradation and ammonia for-
mation. Glutamate dehydrogenase is located in the mitochondrial matrix space, is
polymorphic, and in vitro uses either NAD or NADP.
62
The Biology and Practice of Current Nutritional Support
3
Glutamate is the only amino acid that undergoes rapid oxidative deamination,
which results in the liberation of the a21mino group as free ammonia. The sequen-
tial action of transamination that results in production of glutamate and its subse-
quent oxidative deamination provides a route by which the amino groups of most
amino acids can be released as free ammonia. Glutamate dehydrogenase therefore
plays a major role in the transport of nitrogen from muscle to liver, although the
major transporters are glutamine and alanine. Glutamine is also the main mode of
transporting NH
3
from the brain. The removal of the a-amino group from an amino
acid is the first step in amino acid catabolism. Once released, the nitrogen molecule
can be incorporated into other compounds or excreted.
Urea is the major disposal form of amino groups derived from amino acids and
accounts for 80% to 90% of the nitrogen-containing components of urine. Urea
nitrogen is produced during the urea cycle. Liver is the exclusive site of urea synthe-
sis, although the enzymes for producing arginine, the precursor of urea, are present
in the brain, kidney, and skin. Urea nitrogen is derived from glutamate, which is
present in both the mitochondrial matrix and the cytosol. While in the cytosol,
aspartate is formed by transamination of glutamate with cytosolic oxaloacetate in
the mitochondrial matrix; nitrogen can arise from glutamate via glutamate dehy-
drogenase and from glutamine via mitochondrial glutaminase. Urea cycle enzyme
levels depend on nutritional patterns; with a high-protein diet or during starvation
(during which glucogenesis from amino acids is increased), the levels of urea-cycle
enzymes increase several-fold. Additionally, the provision of carbamoyl phosphate
to the urea cycle is regulated by acetylglutamate synthetase, an enzyme whose activ-
ity is markedly increased by amino acids, especially arginine. After removal of nitro-
gen, the carbon skeletons of amino acids can be oxidized, providing a source of
energy. Based on their use as an energy source, amino acids may be grouped into a
nonfat-like (histidine and all nonessential amino acids) category and a fat-like cat-
egory that consists of tyrosine and all the essential amino acids except histidine. All
of the amino acids of the nonfat-like group are glucogenic because they either form
pytuvate or enter the tricarboxylic acid cycle. On the other hand, the fat-like group
of amino acids consists of some amino acids that are glucogenic, glycogenic, or both.
Selected References
1. Devlin MT. Textbook of Biochemistry with Clinical Correlations. Fourth edition.
New York: John Wiley & Sons, 1997.
2. Halberston IDK. Biochemistry. Second edition. New York: John Wiley & Sons,
1988.
3. Champe PC, Harvey RA. Biochemistry. Lippincotts Illustrated Reviews. Second
edition. Philadelphia: J.B. Lippincott Company, 1994.
4. Guyton AC, Hall JE. Textbook of Physiology. Ninth edition. Philadelphia: Harcourt
Brace & Company, 1994.
5. Latifi R. Amino Acids in Critical Care and Cancer. Austin: R.L. Landes Company,
1994.
6. Stryer L. Biochemistry. Fourth Edition. W H Freeman and Company, 1995.
7. Shils, ME, Olson JA, Shike M et al. Modern nutrition in health and disease. Ninth
edition. Baltimore: Williams and Wilkins 1997.
CHAPTER 1
CHAPTER 4
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Acute Phase Proteins
in Critically Ill Patients
Khawaja Azimuddin, Rifat Latifi and Rao R. Ivatury
Tissue injury initiates a complex series of rapid homeostatic events.
1-3
. The host
to prevent ongoing tissue damage and to activate the repair process initiates these
events. Classically, inflammation has been recognized as the hallmark of this re-
sponse. More recently, attention has been focused on defining these events at the
cellular, metabolic and molecular level. The physiologic changes that develop after a
traumatic insult occur irrespective of the type of injurious agent and result in a
predictable increase in the level of cortisol, catecholamines, insulin, glucagon, vaso-
pressin and growth factor.
An early non-specific component of this response to systemic tissue injury takes
place in the liver and is termed the Acute Phase Response (APR). It is characterized
by reprioritization of protein synthesis in the liver. While the production of some
proteins is exponentially increased (positive acute phase proteins), the production of
others (negative acute phase protein) is cut down (negative acute phase proteins).
The magnitude of the response is varied and depends upon the severity of the injury.
Role of the Acute Phase Response
The shift in the hepatic production of proteins from constitutive proteins to
acute phase reactants, after major injury or trauma, is aimed at fulfilling the needs of
the immune, coagulation and wound healing process. The most important part of
this protective response is to serve as a check on the injury-induced inflammatory
reaction and to limit further tissue damage by inhibition of serine proteases and
transport of proteins with antioxidant activity. Elimination of microbes, cleanup of
tissue debris and the initiation of the reparative process are other important aspects
of this rapid response system. These functions are further discussed under the indi-
vidual proteins.
The decrease in negative acute phase reactants may serve to reprioritize the body
to conserve nitrogen loss by shifting protein synthesis to those proteins that are
absolutely necessary for survival. Furthermore, the negative acute phase proteins
(albumin, prealbumin and transferrin) can be used to evaluate and monitor the
nutritional status of critically ill patients.
Physiology
Tissue injury or infection leads to a local inflammatory response. Cytokines re-
leased at the site of inflammation gain access to the circulation and are carried to the
liver where they act upon the hepatocytes. Quantitatively, liver is the major pool for
cytokines that circulate in the blood stream because it has the largest number of cells
64
The Biology and Practice of Current Nutritional Support
4
with cytokine receptors and a high density of receptors per cell. The liver responds
to the cytokine signal by a burst of acute phase protein synthesis. These proteins
reach a maximum concentration within few days after the onset of tissue damage
and return to their normal concentrations within a week. Initially it was thought
that cytokines released from locally occurring mononuclear cells (Kupffer cells) in
liver initiate the APR but it is now agreed that circulating cytokines can ini-
tiate this reaction.
4
A variety of cytokines have been implicated in the production of acute phase
proteins from the liver, including interleukin (IL-1, IL-6) and Tumor necrosis
factor-alpha (TNF). IL-6 is the most potent of these stimuli and has been termed
the hepatocytes-stimulating factor. It is thought to be responsible for the induction
of a variety of APP in vivo and in vitro.
4
Although IL-6 may act on the hepatocytes
after being produced locally by the Kuppfer cells, it mainly acts as a long-distance
alarm signal that alerts the hepatocytes to the presence of tissue damage in periph-
eral tissues. It is secreted by monocytes, fibroblasts and several other cells at the site
of inflammation.
The serum levels of IL-6 increase dramatically after injury. The pattern of ap-
pearance of various cytokines has been studied in animals. TNF level peaks at about
90 minutes, while IL-1 peaks around three hours. IL-6 levels continue to rise up to
eight hours after injury.
It has been suggested that IL-6 act by binding with a specific receptor on the
surface of hepatocytes.
4
This interaction leads to a series of events, which result in
the re-orchestration of the pattern of gene expression for secretory proteins in the
hepatocytes.
5
This results in an increase in the expression of mRNA of various APP.
6
It has been shown that IL-6 transcriptional regulation of the acute phase response is
mediated through activation of transacting transcription factors of the C/EBP fam-
ily which bind to IL-6 response elements identified in the promoter regions of acute
phase response genes.
7,8
IL-6 can also downregulate one isoform of the C/EBP fam-
ily, C/EBP alpha, which binds to the albumin gene promoter.
9
This can explain the
mechanism of how cytokines induce a positive and negative acute phase response.
8
Other metabolic changes associated with injury may also be involved in regulat-
ing the acute phase response. Glucocorticoids have a permissive role, enhancing
IL-6 stimulation of acute phase protein synthesis.
7,8
However the presence of
glucorticoids is not an absolute requirement for induction of acute phase protein
synthesis by IL-6 in human hepatocytes.
4
In vitro, insulin is a nonspecific inhibitor
of the cytokine stimulation of acute phase protein secretion.
10
Insulin inhibition of
acute phase protein gene expression appears independent of C/EBP-mediated
transactivation, although other upstream promoter elements may be involved. Un-
like insulin, glucagon, catecholamines, growth hormone and triiodothyronine have
no effect.
Both IL-1 and TNF secreted by monocytes and macrophages at the site of in-
flammation are also responsible for the induction of acute phase response. However
these cytokines tend to produce a limited spectrum of acute phase proteins only.
Unlike IL-6, these cytokines, once produced by Kupffer cells in the liver, act in a
local or paracrine fashion only. In addition to its direct effects on the APR, TNF
may also indirectly increase the levels of IL-1 and IL-6.
4,11
65
Acute Phase Proteins in Critically Ill Patients
4
Sequence of Events During Acute Phase Response
Immediately after tissue injury or sepsis, there is a predictable pattern in the
alteration of the acute phase proteins. First, there is a decrease in the serum concen-
tration of most of the acute phase proteins, both for positive and negative reactants.
Redistribution of the body protein pool from intravascular to extravascular space
occurs immediately following injury as a result of increased microvascular perme-
ability and vascular stasis and accounts for part of the initial decline in acute phase
proteins. Later there is a decrease in the hepatic synthesis of negative acute phase
proteins and the concentration of serum albumin remains depressed for days to
weeks after injury. Albumin reaches a nadir by the fifth post-injury day. Whether
nutritional support in the immediate post-injury phase can alter this response has
not been adequately studied. In one study,
2
prealbumin concentrations increased
within the first week of injury, although lagging behind increased protein-calorie
intake and nitrogen balance, while serum albumin levels slowly declined over the
same time and were still decreased 18 days after injury. The positive acute phase
protein concentrations begin to rise after a lag period of six hours.
12
C-reactive pro-
tein (CRP) is the earliest acute phase reactant to respond and its serum concentra-
tion peaks at 48 hours.
The serum protein concentrations of the positive acute phase reactants in minor
injury returns to normal by the end of the first week. Failure of return indicates
ongoing tissue injury. It has been shown that in patients who survive thermal injury,
the APR quickly returns to normal.
13
Continued and prolonged production of acute
phase reactants in the critically ill patients may be an indicator of ongoing sepsis and
tissue damage and it has been shown that prolonged expression of alpha-1 acid
glycoprotein in burned animals is associated with higher mortality rates.
14
Measure-
ments of the acute phase response can therefore be used to detect the presence of
ongoing inflammation or sepsis following injury.
15
Modulation of the Acute Phase Response
The modulation of protease/antiprotease activity at the focus of injury is deli-
cately balanced to enhance efficient tissue repair without prolonged inflammation.
It has been suggested that the least intense APR and its timely recovery are most
beneficial in terms of survival after burn injury.
13
Pharmacological manipulation of certain aspects of the APR is possible and may
provide new modes of therapy in patients with major trauma. Adjuvant recombi-
nant human growth hormone (rhGH), which improves whole body protein synthe-
sis in severely injured trauma patients, can modulate the APR to the benefit of the
patient. It has been shown that rhGH therapy exerts an inhibitory effect on the
positive acute phase proteins and an additive effect on the constitutive proteins.
13,16,17
It has been shown that serum levels of most of the positive acute phase proteins,
except CRP, increase during the administration of total parenteral nutrition (TPN).
The entire negative APP also increase during administration of TPN.
18
The Acute Phase Proteins
As mentioned above, the acute phase response is bidirectional. The concentra-
tion of (CRP), Alpha-1 Acid Glycoprotien, alpha-l-antitrypsin, serum amyloid A,
fibrinogen, haptoglobulin, ceruloplasmin and complement factor C-3 is increased
during the response. The positive acute phase response seems to be a protective
response to tissue injury and appears to serve as a check on the injury-induced
66
The Biology and Practice of Current Nutritional Support
4
inflammatory response. These reactants have diverse functions such as antioxidants,
proteolytic inhibitors, and mediators of coagulation, which may in part prevent
excessive tissue damage and hemorrhage from injury. The negative acute phase reac-
tants include the serum transport proteins: albumin, prealbumin (PA), retinol-binding
protein and transferrin. The serum concentrations of these proteins fall immedi-
ately and in proportion to the severity of the injury. These negative acute phase
proteins are used to monitor the nutritional status of acutely ill patients. Following
the trends in the serum concentration of these proteins may give valuable informa-
tion to the clinician about the improving or deteriorating nutritional status of
these patients.
Albumin
Albumin is a negative acute-phase reactant. Levels of albumin may drop up to
30-50% after severe injury. Inflammation reduces the hepatic mRNA level of albu-
min, which leads to decreased production of this protein. Also albumin is lost in the
interstitial space as a result of increased vascular permeability during periods of acute
stress and third spacing. Since albumin is a major transport protein, the reduced
levels seen during inflammation and infection may play a role in minimizing the
delivery of nutrients to microbes during infection.
Albumin is frequently used to assess and monitor nutritional status in the criti-
cally ill patients. However the use of albumin as a nutritional index has several draw-
backs. The half-life of albumin is approximately 21 days, and changes in the serum
concentration of albumin, in response to increased or decreased protein-calorie in-
take, takes weeks and not days to manifest. Therefore, albumin is a poor marker of
protein-calorie malnutrition. Even in severe malnutrition states like marasmus, the
serum albumin concentration may be normal. Albumin also has a large body pool,
with an extravascular-to-intravascular distribution ratio of 1:5.
3
Redistribution from
one space to the other can potentially mask a concurrent change in albumin synthe-
sis rate. The serum concentration of albumin can also be affected by non-nutritional
entities including liver disease, renal dysfunction and total body water composition.
Additionally, post-injury, critically ill patients may require albumin infusions, which
will alter its serum concentration irrespective of the nutritional status of the patient.
Despite these disadvantages albumin is widely used as a marker of nutrition status
perhaps because of the its widespread availability and low cost. Serum albumin lev-
els obtained at the time of admission re reasonably accurate markers of nutrition
status, and low levels have been shown to correlate with prolonged hospital
stay and mortality.
19,20
Serum hepatic secretory proteins with a shorter half-life are preferable indicators
of short-term changes in protein-calorie intake and correlate better with the nitro-
gen balance.
2,3
Several studies have evaluated the longitudinal response of short
half-life proteins to injury. However, few have evaluated their usefulness in monitor-
ing effects of nutritional support.
2,21
Boosalis et al
2
serially measured protein-calorie
intake, nitrogen balance, and serum albumin and prealbumin levels in trauma pa-
tients from the time of admission until 18 days post-injury. In the short-term,
prealbumin was a better indicator of nutritional intervention than albumin. Within
one week of increasing protein-calorie intake and improved nitrogen balance, the
prealbumin concentration increased while the serum albumin level continued to
decline during the first two weeks after injury.
2
67
Acute Phase Proteins in Critically Ill Patients
4
Prealbumin
Prealbumin (transthyretin) is a serum transport protein for thyroid hormone
and the vitamin A-retinol binding protein complex.
12,22
It has a short half-life of
18-24 hours. Compared with albumin, prealbumin has a smaller body pool with a
greater intravascular-to-extravascular distribution. Numerous studies in non-trauma
patients have demonstrated a consistent correlation between the serum prealbumin
concentration and parallel increases or decreases in protein-calorie intake or nitro-
gen balance.
2,22,23
The response time is usually within the order of several days.
Non-nutritional factors including cirrhosis and hepatitis can lower prealbumin level
whereas increased levels of prealbumin occur with chronic renal failure.
Retinol-Binding Protein
Retinol-binding protein (RBP) has an even shorter half-life of 12 hours, though
clinically this does not improve its sensitivity as a nutritional marker over
prealbumin.
12
RBP transports vitamin A from the liver to peripheral tissues. Serum
RBP concentration is dependent on vitamin A stores which regulate hepatic release
of RBP. Aside from vitamin A deficiency, RBP concentration is decreased in chronic
liver diseases, cystic fibrosis, zinc deficiency and hyperthyroidism. Increased RBP
levels occur with chronic renal failure.
Both prealbumin and retinol-binding protein are accurate markers of nutrition,
and their serum concentrations are highly correlated.
24
However because prealbumin
can be easily monitored and its assay is subject to few interfaces, it is the preferred
biochemical index of follow the nutritional status of the critically ill patient.
Transferrin
Transferrin is also commonly used as a nutritional marker. Its mainly intravascu-
lar distribution and shorter half-life are advantageous. As the primary function of
transferrin is to transport iron, its serum concentration is dependent on the iron
stores of the individual. Another shortcoming of transferrin is its serum half-life of
7-10 days which, like albumin, significantly delays its response to changes in nutri-
tional repletion. An increasing concentration of transferrin is a good indicator of
positive nitrogen balance. However, a decreasing transferrin level is a poor indicator
of nitrogen loss.
3
Transferrin is also an unreliable index of nutritional status when
patients are receiving high doses of certain antibiotics.
25
Levels of serum transferrin
decrease 30-50% after injury. The decrease in circulating transferrin along with a
concomitant increase in intrahepatic transferrin helps to decrease the availability of
iron to peripheral sites of infection.
C-Reactive Protein
During the acute-phase response, there is almost a 1000-fold increase in the
circulating levels of CRP. Since the level of this pentameric protein is very low in the
non-stressed resting period, it has been suggested that the sharp rise in serum levels
indicates a central role for this protein during periods of stress. It has therefore been
suggested that CRP levels can be used for detecting and following septic complica-
tions and intra-abdominal infections.
26,27
CRP participates in complement activa-
tion and opsonization. It attaches to the phosphorylcholine containing membranes
of certain microorganisms including pneumococcus thereby activating the comple-
ment cascade. Digestion of CRP by neutrophil protease releases chemotactic pep-
tides including tuftsin and a component of the Fc segment of immunoglobulin (Ig)
68
The Biology and Practice of Current Nutritional Support
4
heavy chains. In addition, the binding of CRP to necrotic host tissues may protect
against autoimmune responses by promoting the rapid removal of self-molecules
from circulation.
28
The serum levels of CRP are closely liked to changes in plasma levels of IL-6 and
it has therefore been suggested that this cytokine is the major mediator of CRP
production in liver during periods of stress.
Ceruloplasmin
Ceruloplasmin is a major copper binding protein. It also removes iron from the
sites of inflammation and may act as an oxygen radical scavenger.
Fibrinogen
Fibrinogen is the major protein involved in the coagulation process. It causes
bacterial clumping thereby preventing the dissemination of bacteria. It also creates a
fibrin scaffold, which helps the macrophages and neutrophil in the phagocytosis of
bacteria. In addition, by-products of fibrin formation (fibrinopeptides) can increase
vascular permeability and induce chemotaxis. The plasma level of fibrinogen in-
creases 2- to 2.5-fold after an inflammatory stimulus and the elevation persists for
several weeks.
Complement
During the acute phase response the levels of two important components of
complement, C3 and properdin are increased. Both are involved in bacterial
opsonization and their increase represents a state of readiness of the human body to
fight infection.
Amyloid
The level of serum amyloid increases drastically during the acute phase response.
Though the increase is almost as high as the 1000 fold increase in CRP level, the
exact role of amyloid in acute phase response is not well understood. A rising level of
serum amyloid A may be used as an indicator of transplant rejection. Amyloid, A
which binds to the extracellular matrix, is also a major component of the deposits
seen in secondary amyloidosis and thus may play a role in chronic inflammation.
Alpha 1 Acid Glycoprotein
The levels of alpha-1 acid glycoprotein (AAG) also increase 2-5 fold during the
acute phase response. It may play a role as inhibitor of platelet activation and as a
modulator of T-lymphocyte function. AAG has a short half-life of 12-18 hours and
is therefore a useful nutritional marker for the acutely ill patient.
Alpha-1 Protease Inhibitor
Proteinases released by dead or dying cells at the site of injury can further propa-
gate tissue destruction. Alpha-1 protease inhibitor is a major inhibitor of neutrophil
proteases, especially elastase. It is synthesized in liver as well as in the periphery by
monocytes and macrophages. The elastase released from neutrophil regulates the
synthesis of alpha-1 protease inhibitor, thereby providing an auto feedback mecha-
nism for preventing excessive tissue destruction at the sites of inflammation.
69
Acute Phase Proteins in Critically Ill Patients
4
Monitoring Nutrition in the Critically Ill Patient
Following tissue injury a hypermetabolic, catabolic state exists. Energy require-
ments, depending on the nature of injury, can range from 1.5 to twice the basal
metabolic rate. Protein needs are also very high and increased amounts of protein
are required to yield a non-protein calorie to nitrogen ratio in the range of 150:1.
Once nutritional therapy is instituted the question is how to best monitor the re-
sponse to treatment. Over-feeding a patient can be as deleterious as under-nutrition.
An ideal monitor should respond quickly to changes in nutritional status, remain
uninfluenced by physiologic changes induced by trauma and pharmacological sup-
port of patients or sepsis and by pharmacological support of patients and should
provide easy and reproducible measurements.
The physical consequences of surgery can limit the use of traditional nutritional
parameters. Postoperatively, anthropometric measurements can be difficult to ascer-
tain and may be unreliable as nutritional indices. Fluid resuscitation or the applica-
tion of large dressings, casts, splints and so forth may alter body weight. Daily weights
are not always feasible in a critically ill patient. Skinfold thickness is often unattain-
able, for example in burn patients, and is not a reliable measurement in an edema-
tous patient. Skinfold thickness also responds to changes in nutritional intervention
in terms of weeks and not days. Arm muscle circumference or area has similar
limitations.
Biochemical indices such as nitrogen balance have their own restrictions, which
can be accentuated by the result of tissue injury.
21
The multiple trauma or burn
patient may have increased extraurinary nitrogen losses from fistulas, wounds, diar-
rhea or the burn surface area which, if unaccounted for, will lead to an overestima-
tion of nitrogen balance. Generally, nitrogen equilibrium is not attained until 2-12
days after a change in protein intake. Often nutritional support in critically ill pa-
tients needs to be intermittently interrupted to perform diagnostic tests or in prepa-
ration for surgery, making it difficult to sustain a consistent day-to-day protein-calorie
intake necessary to obtain nitrogen equilibrium for correct interpretation of nitro-
gen balance studies.
Other biochemical parameters, especially visceral serum proteins, have been uti-
lized as monitors of nutritional repletion in critically ill patients.
1,2
Ideally, to be a
clinically useful marker of nutritional repletion, a change in the concentration of a
serum protein should reflect only its synthetic rate, which in turn is dependent on
the provision of sufficient calories and proteins during the hypermetabolic state.
The serum protein should also have a short serum half-life, a small body pool, rapid
rate of synthesis and a constant catabolic rate.
3
A number of visceral proteins are
used to measure the nutritional status of the surgical patient. None of these meet all
of the above requirements and have one or more shortcomings. In practice there-
fore, a number of proteins are measured simultaneously in conjunction with weekly
anthropometric measurements. By serially measuring the serum concentrations of
several proteins with different half-lives together, we can better monitor the short
and long-term response to nutritional support. For example, in a patient with dete-
riorating weight, skinfold thickness and mid-arm muscle circumference, the benefit
of increasing the daily caloric intake should in several days be reflected by an in-
crease in AAG and pre-albumin, levels, later followed by an increase in transferrin.
Hopefully, albumin levels will rise and finally even later anthropometric measure-
ments will improve. Conversely, with nutritional depletion, AAG and prealbumin
70
The Biology and Practice of Current Nutritional Support
4
levels will decrease first without a change in transferrin. Finally, albumin levels will
rise, and eventually anthropometric measurements will improve. Conversely, with
nutritional depletion, AAG and pre-albumin levels will decrease at first without a
change in transferrin, albumin or anthropometric measurements. Measuring several
proteins with similar half-lives eliminates some of the problems in misinterpreting
changes in their serum levels due to non-nutritional factors since each protein is
affected differently. These proteins are measured by nephelometry so results are avail-
able in less than 24 hours, and only 100 microliters of serum is required for the
entire panel.
Following tissue injury a hypermetabolic, catabolic response occurs which, left
unabated, will lead to depletion of somatic and visceral protein stores, delayed wound
healing and impaired immune response. Despite increased protein synthesis
post-injury, the magnitude of protein breakdown is so great that a state of negative
nitrogen balance exists. Adequate calorie (based on indirect calorimetric studies)
and protein supplementation during this time period will improve nitrogen reten-
tion but not sufficiently to achieve positive nitrogen balance.
29
Nutritional support
improves nitrogen retention by enhancing protein synthesis. However, it may not
effect whole body protein breakdown.
30
Post-injury there also appears to be less
efficient recycling of nitrogen.
11
Furthermore the mobilized protein may be
reprioritized from nitrogen recycling to provide carbon substrates for energy pro-
duction. Possibly, mediators of the inflammatory response dually regulate the en-
hanced post-injury protein catabolism and the negative acute phase response. In the
future nutritional support may involve selectively antagonizing the metabolic ef-
fects of cytokines and other mediators of the acute-phase response to preserve body
protein stores.
Selected References
1. Kudlackova M, Andel M, Hajkova H et al. Acute phase proteins and prognostic
inflammatory and nutritional index (PINI) in moderately burned children aged
up to three years. Burns 1990; 16:53-56.
2. Boosalis MG, Ott L, Levine AS et al. Relationship of visceral proteins to nutri-
tional status in chronic and acute stress. Crit Care Med 1989; 17:741-774.
3. Church JM, Hill GL. Assessing the efficacy of intravenous nutrition in general
surgical patients: Dynamic nutritional assessment with plasma proteins. JPEN 1987;
11:135-139.
4. Castell JV, Gomez-Lechon MJ, David M et al. Acute-phase response of human
hepatocytes: Regulation of acute-phase protein synthesis by interleukin-6.
Hepatology 1990; 12:1179-1186.
5. Fey GH, Gauldie J. The acute phase response to the liver in inflammation. Prog
Liver Dis 1990; 9:89-116.
6. Wu JZ, Ogle CK, Fischer JE et al. The m-RNA expression and in vitro production
of cytokines and other proteins by hepatocytes and Kuppfer cells following ther-
mal injury. Shock 1995; 3:268-273.
7. Baumann H, Morella KK, Campos SP et al. Role of CAAT-enhancer binding
protein isoform in the cyrokinc regulation of acute phase protein genes. J Biol
Chem 1992; 627:19744-19751.
8. Ramji DP, Vitelli A, Tranche F et al. The two C/EBP isoforms, IL-6DBP/NFIL6
and C/EBP8/NF-IL6p are mediated by IL-6 to promote acute phase gene tran-
scription via different mechanism. Nuc Acid Res 1993; 21:289-294.
9. Issihiki H, Akira S, Sugita T et al. Receprocal expression of NF-IL6 and C/EBP in
hepatocytes: possible involvement of NF-IL6 in acute phase protein gene expres-
sion. New Biol 1991; 3(1):63-70.
71
Acute Phase Proteins in Critically Ill Patients
4
10. Campos SP, Baumann H. Insulin is a prominent modulator of the cytokine stimu-
lated expression of acute phase plasma protein genes. Mol Cell Biol 1992;
12:1789-1792.
11. Bankey PE, Mazuski JE, Ortiz M et al. Hepatic acute phase protein synthesis is
indirectly regulated by tumor necrosis factor. J Trauma 1990; 30:1181-1187.
12. Fleck A, Colley CM, Myers MA. Liver export proteins and trauma. Brit Med Bull
1985; 41:265-273.
13. Jarrar D, Wolf SE, Jeschke MG et al. Growth hormone attenuates the acute-phase
response to thermal injury. Arch Surg 1997; 132:1171-1176.
14. Sevaljevic L, Glibetic M, Poznanovic M et al. Thermal injury-induced expression
of acute phase proteins in rat liver. Burns. 1988; 14:250-256.
15. Kudsk KA, Minard G, Wojtysiak SL et al. Visceral protein response to enteral
versus partenteral nutrition and sepsis in patients with trauma. Surgery 1994;
116:516-523
16. Jeschke MG, Wolf SE, DebRoy MA et al. The combination of growth hormone
with hepatocyte growth factor alters the acute phase response. Shock 1999;
12:181-187.
17. Jeschke MG, Wolf SE, DebRoy MA et al. Recombinant human growth factor
(rhGH) downregulates hepatocyte growth factor (HGF) in burns. J Sur Res 1998;
76:11-16.
18. Peterson SR, Jeevanandam M, Shahbazian LM et al. Reprioritization of liver pro-
tein synthesis resulting from recombinant human growth supplementation in
parenterally fed trauma patients: The effect of growth hormone on the acute-phase
response. J Trauma 1997; 42:987-996.
19. McEllistrum MC, Collins JC, Powers JS. Admission serum albumin level as a
predictor of outcome among geriatric patients. South Med J 1993; 86:1360-1.
20. DErasmo E, Pisani D, Ragno A et al. Serum albumin level at admission: mortality
and clinical outcome in geriatric patients. Am J Med Sci 1997; 314:17-20.
21. Mattox TW, Brown RO, Boucher BA et al. Use of fibronectin and somatomedinC
as markers of enteral nutrition support in traumatized patients using a modified
amino acid formula. JPEN 1988; 12:592-596.
22. Winkler MF, Gerrior SA, Pomp A et al. Use of retinol-binding protein and
prealbumin as indicators of the response to nutrition therapy. J Amer Diet Assoc
1989; 89:684-687.
23. Tuten MB, Wogt S, Dasse F et al. Utilization of prealbumin as a nutritional pa-
rameter. JPEN 1985; 9:709-711.
24. Sachs E, Bernstein LH. Protein markers of nutrition status as related to sex and
age. Clin Chem 1986; 32:339-41.
25. Spickerman AM. Proteins used in nutritional assessment. Clin Lab Med. 1993;
13:353-396.
26. Mustard RA, Bohnen JMA, Haseeb S et al. C-reactive protein levels predict post-
operative septic complications. Arch Surg 1987; 122:69-73.
27. McCartney AC, Grange GV, Pringle SD et al.. Serum C-reactive protein in infec-
tive endocarditis. J Clin Path 1988; 41:44-48.
28. Volanakis JE. Complement activation of C-reactive protein complexes. Ann NY
Acad Sci 1982; 389:235-242.
29. Jeevanadam M, Young DH, Schiller WR. Endogenous protein-synthesis efficiency
in trauma victims. Metabolism 1989; 38:967-973.
30. Shaw JHF, Wolfe RR. An integrated analysis of glucose, far, and protein metabo-
lism in severely traumatized patients. Ann Surg 1989; 209:63-72.
CHAPTER 5
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Arginine Metabolism in Critical Care
and Sepsis
Rima I. Kandalaft, V. Bruce Grossie, Jr.
Arginine and ornithine are naturally occurring amino acids that exist in close
metabolic relationship in the urea cycle. These amino acids differ significantly, how-
ever, in their metabolism and their nutritional significance. Arginine is considered
to be an essential amino acid for growth, but the requirements of the adult man, rat,
and other species for arginine appear to be met by endogenous synthesis. Although
of considerable biological significance, ornithine is not considered a dietary essen-
tial amino acid and all of its cellular requirements are apparently supplied via the
urea cycle.
The concept of essential amino acids has changed over the past few years. The
classic definition used by Rogers et al
1
stated that an amino acid was essential if it
was required for growth. Recently
2,3
it has been suggested that certain amino acids
that are classified as nonessential under normal conditions may be essential under
certain disease conditions such as cancer, trauma, or sepsis. These are called condi-
tionally essential amino acids. The results of numerous studies in man and experi-
mental animals have shown that supplementation of arginine to otherwise balanced
diets
4,5
is beneficial during stress suggesting that arginine should be consid-
ered as a conditionally essential amino acid. This has not been a universal
conclusion, however.
6-8
Pathways of Arginine and Ornithine Metabolism
Urea Cycle
Arginine, a major component of the urea cycle (Fig. 5.1), is converted to orni-
thine and urea by arginase. Results from our laboratory
8
as well as others,
9,10
demon-
strate that ornithine can be substituted for arginine in its role of maintaining
appropriate ammonia levels but appears unable to replace arginine for cell growth.
As shown in Figure 5.1, ornithine is a precursor for several biologically active com-
pounds such as polyamines, proline and glutamate, that are significant cofactors for
cell growth.
11
Ornithine and it metabolites, therefore, may be the biological mecha-
nism that is responsible for the changes that occur when arginine is added to parenteral
and enteral regimens. In studies that evaluated amino acid concentrations, the con-
centration of ornithine in plasma
13,14
and liver
15,16
was altered in the same manner as
arginine, suggesting that a major part of the response seen when arginine is supple-
mented may be associated with an increase in ornithine concentrations. A mecha-
nism for this hypothesis, however, has not been critically evaluated. Our results
8,12
73
Arginine Metabolism in Critical Care and Sepsis
5
suggest that the tissue content of arginine is rate limiting to the TPN-associate en-
hanced growth of a Ward colon tumor. Tumor growth was enhanced during TPN
with arginine as part of the regimen but not when ornithine was substituted. The
polyamine content of the tumors was not changed when ornithine was substituted
while the arginine content was significantly decreased.
12
This may reflect a differing
requirement for arginine by normal and tumor cells.
Nitric Oxide Synthesis
A pathway of arginine metabolism that has become of major importance in the
past decade is that of nitric oxide synthesis. As is shown in Figure 5.2, arginine is
converted directly to citrulline with the release of nitric oxide. This conversion is
controlled by the enzyme nitric oxide synthase (NOS). The activity of NOS is tightly
regulated and exists as three isoforms which are structurally similar
17
but have differ-
ent cofactor requirements. Normal tissue requirements utilize a small amount of
nitric oxide at any one time. Epithelial and neuronal isoforms of NOS (eNOS and
nNOS, respectively) control these levels of nitric oxide and are normally present at
low activities in most tissues.
18
Another isoform is inducible (iNOS) by a number of
exogenous agents, such as those associated with sepsis, and can be induced to syn-
thesize a large amount of nitric oxide in a brief period of time.
One measure of nitric oxide synthesis by the host, used extensively to measure
acute changes in activity, is the plasma or urine concentration of nitrate/nitrites
(NO
x
). Nitric oxide is a stable gas that diffuses readily through cell membranes.
NO
x
are stable end products of nitric oxide that can be measured in biological fluids,
tissues, and cell culture media. Although not a stoichiometric reaction, an increase
in plasma NO
x
is correlated with an enhanced nitric oxide synthesis.
7
Fig. 5.1. Metabolism of arginine through the urea cycleornithine metabolites. ODC,
ornithine decarboxylase; OAT, ornithine amino transferase; OCT, ornithine carbamyl
transferase.
74
The Biology and Practice of Current Nutritional Support
5
Arginine Availability for Nitric Oxide Synthesis
The cell has many mechanisms to insure that the arginine supply for NOS and
other essential metabolic pathways is maximal. Competition for arginine is mainly
through the urea cycle (arginine
arginase
>ornithine) (Fig. 5.1), which would in-turn
support the many diverse pathways of ornithine. The conversion of citrulline
ASS
>
ASL
> arginine (Fig. 5.1) has been reported to be the major urea cycle enzyme path-
way in kidneys, making host arginine synthesis possible. As will be reviewed later in
this chapter, this pathway may be induced during times of increased arginine re-
quirements. Thus, a change in the activity of arginase, ASS, or ASL will affect the
cellular supply of arginine.
The requirement for an exogenous source of arginine to support the synthesis of
nitric oxide has not been adequately defined but may be of importance to the deter-
mination of what may be expected from administration of exogenous arginine or
ornithine. Schott et al
19
demonstrated that the infusion of LPS at 10 mg/kg/hr for
50 min resulted in no change in the arginine content of plasma or aortic rings.
These authors concluded that circulating L-arginine was sufficient to maximally
activate the synthesis of nitric oxide in the aorta of endotoxemic rats. Pastor et al
20
demonstrated that for livers isolated from rats treated with LPS and perfused for 20
min with Krebs-Henseleit-bicarbonate buffer, the intracellular arginine was not suf-
ficient to support maximal nitric oxide synthesis. Although livers expressing iNOS
released high levels of NOx, this release could be enhanced by adding arginine to
the perfusate. Adding ornithine to the perfusate did not affect the NOx output. A
study to evaluate the requirements of specific organs under differing levels of stress
is needed to further define the arginine requirement of the host.
Absorption and Cellular Uptake of Arginine
The circulating levels of arginine can be significantly affected by trauma, sepsis
or injury. The absorption of arginine by the rat intestine using everted sacs in vitro
Fig. 5.2. Pathway of nitric oxide synthesis and its relationship with the urea cycle.
75
Arginine Metabolism in Critical Care and Sepsis
5
was decreased by experimental sepsis induced by cecal legation and puncture or
after administration of endotoxin,
21
presenting some potential problems with the
oral administration of arginine. A role for the gut in absorption/synthesis was also
suggested from observations of a patient with short bowel syndrome and renal fail-
ure .
22
The arginine, ornithine, and citrulline concentrations of the plasma from this
patient was significantly reduced which resulted in hyperammonemia. An I.V. supple-
ment of arginine normalized the arginine, ornithine, and citrulline levels and de-
creased plasma ammonia concentrations. It is of importance to this discussion that
during the arginine infusion (10.8 mg/kg/day) the patient developed hypotension
and fell into shock during hemodialysis. After this episode, the arginine supplemen-
tation was decreased to every other day and the patient survived for an additional 5
months. Although no data was presented, the possibility of an increased nitric oxide
synthesis during arginine infusion was suggested. Data to support this possibility
will be presented later in this chapter.
It has also been demonstrated that the plasma levels of arginine, ornithine and
citrulline were decreased in patients within 2-18 hours after gun shot injury.
14
The
results suggested that the changes in plasma concentrations of arginine, ornithine,
and citrulline were of systemic origin and not related to the type of injured tissues.
The results of other studies,
23-25
however, show that the uptake of arginine by
individual cells in vitro is enhanced by endotoxin. Our results (Fig. 5.3) show that
the plasma concentration of arginine in the rat is decreased as early as two hours
after a nonlethal dose of endotoxin (5 mg/kg, ip). The plasma concentration of
citrulline, but not ornithine, was increased at 5 hours after endotoxin. In addition,
the plasma concentration of NO
x
(Fig. 5.4) and liver iNOS protein content (Fig.
5.5) was increased at 5 hours but not at 2 hours. Subsequent results
26
demonstrate
that the plasma NO
x
begins to increase significantly between 120 and 180 minutes
after this dose of endotoxin. The early decline in plasma arginine concentration,
accompanied by a constant concentration of ornithine and citrulline (2 hours), sug-
gest an increase in arginine uptake by tissues. This would be significant since the
iNOS protein content of the liver (Fig. 5.5), intestine,
26
and spleen (data not shown)
does not differ from the control at 120 min.
Arginase
An increase in NOS activity would significantly increase the cellular require-
ment for arginine. Since ornithine is a direct metabolite of arginine (Fig. 5.1), argi-
nase activity would also be expected to have a significant effect. With arginine being
the only substrate for the synthesis of nitric oxide, a depletion of the available argi-
nine might serve to reduce the nitric oxide related effects. Hey et al
27
presented
results demonstrating that LPS shifted the available arginine away from the synthe-
sis of ornithine to nitric oxide synthesis for rat macrophages in vitro. Sonoki et al
28
reported that the mRNA for iNOS and arginase I in rat peritoneal macrophages
were induced in a dose-dependent manner. Bacterial LPS treatment of rats in vivo
resulted in a rapid increase of iNOS mRNA for lung and spleen reaching a peak at
2-6 hrs after LPS while the arginase I mRNA was increased rapidly but did not reach
a peak until 12 hours after LPS. Shearer et al
29
, however, demonstrated that when
nitric oxide synthesis was increased with Interferon (IFN- and LPS, the arginase
activity in mouse peritoneal exudate cells was decreased. These authors also demon-
strated that the products of nitric oxide synthasenitric oxide and citrullinein-
hibited arginase activity. Benninghoff et al
30
demonstrated that in mouse peritoneal
macrophages, combining IFN- with TNF or LPS treatment in vitro resulted in a
76
The Biology and Practice of Current Nutritional Support
5
shift from increasing ornithine synthesis to increased citrulline synthesis. In these
studies, however, no further metabolism of ornithine to citrulline was evaluated.
Gotoh et al
31
reported that the mRNA for arginase II and NOS was coinduced by
LPS for RAW 264.7 cells. Since arginase I is located predominantly in the liver and
arginase II in extrahepatic tissues, any alteration in the activity of either of the isoforms
of arginase could have a significant impact on the arginine available for nitric oxide
synthesis in all tissues. Boucher et al,
32
Buga et al,
33
and Daghigh et al
34
reported that
an intermediate in the arginine to nitric oxide pathway, N
-hydroxy-L-arginine,
will inhibit arginase I activity of rat liver and murine macrophages. Nitric oxide has
been reported by Hrabak et al
35
to inhibit arginase. Although the enzyme arginase
may be have a role in down-regulating nitric oxide synthesis, direct impact of its
metabolic product, ornithine, has not been demonstrated. Recent results (Grossie
unpublished observations) show that adding ornithine to a parenteral regimen
containing arginine will not significantly alter the plasma NO
x
concentration 5
hours after an endotoxin challenge, suggesting that ornithine does not have an effect
on nitric oxide synthesis.
A treatment strategy may be to reduce the available arginine for nitric oxide
synthase. Bune et al
36
reported that reduction of arginine by arginase treatment
significantly decreased the synthesis of nitric oxide by the liver, kidney, lung, and
spleen and reduced the blood NO
x
concentration. Results from my laboratory show
that the endotoxin-induced increase in NO
x
from rats given a parenteral diet with
ornithine substituted for arginine was significantly decreased (Fig. 5.6) as compared
with that of isonitrogenous arginine. The plasma arginine concentration was also
significantly decreased (Fig. 5.7).
Fig. 5.3. Plasma arginine, ornithine, and citrulline concentration of endotoxemic rats.
Fischer 344 male rats (3-4/group) were given endotoxin (5 mg/kg, ip), anesthesized with
Ketamine/xylazine at 2 or 5 hours and blood and tissues removed. The controls received
0.85% NaCl ip. The data is presented as the mean sd. Means were compared using a
one-way ANOVA analysis using StatView
-hydroxyl-L-arginine, an intermediate in
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80. Whittle BJR, Lopez-Belmonte J, and Moncada S. Regulation of gastric mucosal
integrity by endogenous nitric oxide: interactions with protaoids and sensory neu-
ropeptides in the rat. Br J Pharmacol 1990; 99:607-611.
81. Shoskes DA, Xie Y, Gonzalez-Cadavid NF. Nitric oxide synthase activity in renal
ischemia-reperfusion injury in the rat. Transplantation 1997; 63:495-500.
82. Schleiffer R, Raul F. Prophylactic administration of arginine improves the intesti-
nal barrier function after mesenteric ischemia. Gut 1996; 39:194-198.
83. Raul F, Galluser M, Schleiffer R et al. Beneficial effects of L-arginine on intestinal
epithelial restitution after ischemic damage in rats. Digestion 1995; 56:400-405.
84. Kurose I, Wolf R, Grisham MB et al. Modulation of ischemia/reperfusion-induced
microvascular dysfunction by nitric oxide. Circ Res 1994; 74:376-382.
85. Di Lorenzo M, Bass J, and Krantis A. Use of L-arginine in the treatment of experi-
mental necrotizing enterocolitis. J Ped Surg 1995; 30:235-241.
86. Grossie VB Jr, Mailman D. Influence of the Ward Colon tumor on the host re-
sponse to endotoxin. J Cancer Res Clin Oncol 1997; 123(4):189-194.
87. Gossie VB Jr. Influence of the Ward Colon tumor on the innate and endotoxin-
induced inflammatory response of the rat. Cancer Invest 2001; 19(7):698-705.
CHAPTER 6
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Wound Healing and the Role
of Nutrient Substrates
David A. Lanning, Rifat Latifi
Basic Principles of Wound Healing
The details of the wound healing process vary depending upon the location and
type of wound. However, there are basic principles of the wound healing process
that are essentially common to all sites of healing wounds. Since more is known and
published in regards to cutaneous wound healing, the principles of wound healing
as they occur in the skin will be described below.
Normal wound healing occurs by a sequence of events in which cellular, soluble
factors, and matrix components act in concert to repair a wound. The healing re-
sponse can be described in four broad, overlapping phaseshemostasis, inflamma-
tion, proliferation, and remodeling.
1
The disruption in the integrity of the vascular
endothelium activates the coagulation cascade, which results in the formation of a
clot consisting of fibrin, platelets, and erythrocytes. The initial wound matrix of
fibrin acts as a scaffold upon which inflammatory cells enter the wound.
2
The injury
also stimulates the release of various mediators of cell-cell and cell-matrix interac-
tions, such as eicosanoids and cytokines. Eicosanoids are metabolites of cell mem-
brane essential fatty acids and function mainly as messengers in the wound and
initiate the signs and symptoms of inflammation, such as redness, swelling, and
pain. Included in this group are prostaglandins and thromboxanes, which are formed
via the cyclooxygenase pathway, and leukotrienes, which are formed via the
lipoxygenase pathway. Cytokines, such as platelet derived growth factor (PDGF)
and transforming growth factor- (TGF-), are polypeptides that mediate the early
inflammatory response but also modulate this and the immune response. Further-
more, cytokines are chemoattractants, mitogens and stimulators of extracellular matrix
(ECM) deposition for cells that enter the wound.
3-5
Initially, neutrophils are present
in increased numbers and are important in phagocytosis of foreign material and
bacteria. Shortly thereafter, monocytes migrate into the tissue, transform into mac-
rophages, and become the predominant inflammatory cell type. Similar to the neu-
trophils, macrophages continue to phagocytose foreign material and release various
cytokines.
6
Lymphocytes also appear in increased numbers in the wound at a de-
layed point and secret cytokines but are not able to phagocytose material. Studies
have demonstrated that only the macrophage is critical for normal healing. How-
ever, all of the cells contribute to the organized repair of a wound by cleaning the
wound site and releasing mediators of cell-cell and cell-matrix interactions, such as
eicosanoids and cytokines. In addition to that seen from the inflammatory cells,
platelet aggregation and degranulation result in the release of cytokines. The ECM
89
Wound Healing and the Role of Nutrient Substrates
6
contains various proteins, glycosaminoglycans (GAG), glycoproteins, and
proteoglycans. For example, the glycoprotein fibronectin, which is synthesized by
fibroblasts and epithelial cells, facilitates cellular attachment and migration.
7
The
GAG hyaluronan (HA) is also thought to be important in cell motility in the imme-
diate post-wounding period. Type II and III collagen are the predominant ECM
proteins deposited at the wound site resulting in a scar, which continues to be re-
modeled for years.
8
Approximately 10% to 20% of the collagen seen in the skin are
Type III, with increased levels seen prenatally and in the early wound. Studies have
suggested that it is deposited in a more organized pattern and can by remodeled
more easily. Fibroblasts interact with the ECM and other cells through heterodimeric,
transmembrane receptors called integrins. These cell-surface receptors are composed
of two subunits, one and one and are important in cell-cell and cell-ECM
interactions.
9
More specifically, the integrins 21 and 11 are thought to be the
receptors associated with wound contraction.
10,11
Despite extensive investigation, the mechanisms responsible for wound contrac-
tion remain unknown. There is continued controversy over this aspect of wound
healing, primarily amongst those investigators that believe that the myofibroblast
vs. the fibroblast is the effector cell in this process. The myofibroblast is character-
ized histologically by large cable-like actin-rich stress fibers.
12
Alpha-smooth muscle
(SM) actin is the actin isoform typical of contractile vascular SM cells and is also
expressed by practically all myofibroblastic populations in vivo.
12
Increased numbers
of this cell type are seen in contracting wounds and primarily at the wound edge,
which suggested that they contribute to closure of the wound. Furthermore, studies
have demonstrated that if the peripheral wound edge was excised, contraction wound
be prevented. However, additional studies by other investigators using in vitro and
in vivo models suggest that the fibroblast is in fact responsible for contraction.
The final phase of normal adult wound healing consists of continued remodel-
ing of the wound site with ongoing collagen deposition and resorption. The small
amount of collagen Type III, as well as Type II collagen are broken down and
replaced with Type II collagen. At approximately 21 days after wounding, the net
accumulation of collagen becomes stable.
13
The strength of the scar gradually in-
creases as it is remodeled up to its peak strength at 6 months after injury at which
point it remains about 80% of that seen in normal skin.
The complex mechanisms involved in wound healing on a molecular and cellu-
lar level remain poorly understood. In addition, the genes that regulate the mecha-
nisms seen in wound healing have not been determined. As a result, the implication
of malnutrition and the role of supplemental nutrition on wound healing are only
now beginning to be appreciated.
Malnutrition and Wound Healing
Even despite poor nutritional status and/or post injury starvation, the body is
able to heal most wounds. Reallocation of nutritional resources through the mobili-
zation of lean body mass occurs in order to provide substrates to the wound. The
bodys ability to mobilize substrates for healing is not unlimited as demonstrated in
studies of animals with multiple injuries. Those with femur fractures have reduced
tensile strength in incisional wounds compared to control animals without frac-
tures.
14
Also, wound implants placed in patients with concurrent major trauma were
found to contain lower hydroxyproline levels than in normal volunteers.
15
The causal
relationship between poor nutritional status and poor wound healing has been
90
The Biology and Practice of Current Nutritional Support
6
suspected for many years yet the details of how nutrition affects the biology of the
healing wound continue to be investigated.
The healing of incisional wounds in mice that had restricted diets was performed
by Greenhalgh et al.
16
The authors demonstrated that the strength-to-disruption of
incisional cutaneous wounds in the group that underwent cecal ligation and punc-
ture (CLP) was less than that of wounds in sham-operated control animals up to 14
days after wounding. However, there was no difference in wound breaking strength
between the groups 3 to 5 weeks after wounding. In review of the groups, the ro-
dents in the CLP-wounded group lost weight and consumed 40% less food during
the first post-operative week than the control wounded group. A subsequent experi-
ment used pair feeding of animals with incisional skin wounds with and without
CLP and revealed a similar reduction in tensile strength of the incisional wounds in
those with CLP as those in the sham-operated group. These data supported the
conclusion that decreased food intake led to weaker wounds and not the concurrent
sepsis in the CLP group.
Another study looked at the effect of seven weeks of a protein-free diet on the
healing of colonic anastomoses in rats.
17
The investigators demonstrated that
colonic-bursting pressure and colonic-bursting wall tension was diminished in the
protein-starved group compared to the control group. Furthermore, there was a
34% weight loss in the protein-deprived group again implicating severe malnutri-
tion as a contributing factor to the altered anastomotic healing.
A number of studies have implicated the importance of nutrition in wound heal-
ing by demonstrating poor healing or high wound complication rates in patients
with hypoalbuminemia.
18
Other researchers have studied hydroxyproline levels in
subcutaneously-placed implants such as polytetrafluoroethylene (PTFE) tubing as a
wound-healing model.
19
One group utilized weight history, anthropometric mea-
surements, and recent dietary-recall history to determine nutritional status and found
decreased hydroxyproline levels in those that were malnourished by a weight loss
history of 10% 5% of original body weight.
20
One group using fasting guinea pigs investigated the cause of reduced hydrox-
yproline levels in subcutaneously-placed implants.
21
These authors found that the
level of collagen synthesis was significantly lower in the group starved for four days
than the control group. However, the level of collagen synthesis was restored within
four days of restarting feeds. Furthermore, there was no evidence of collagen degra-
dation and low levels of messenger RNA levels were confirmed in the fasting group.
Alterations in the level of various hormones were implicated in the reduced level of
collagen synthesis. A reduction of insulin and somatomedin levels but an increase in
glucocorticoids were some of the changes in fasting-induced hormones cited by the
authors. The importance of these hormones in wound healing were noted in that
somatomedin C, or insulin-like growth factor-1, is a competence growth factor and
promotes angiogenesis and collagen synthesis. In addition, glucocorticoids are known
to have anti-inflammatory and antihealing effects in wounds.
Many of these animal studies need to be reviewed in a critical manner in that
wounds in rodents heal differently than in humans and their response to protein-free
diets or complete starvation vary from the human. Furthermore, many of these
studies may show a reduced level of collagen in an implant or wound site but this is
at one time-point and the level of collagen does not necessarily correlate with the
quality of healing. Furthermore, the wounds in many of these studies were not evalu-
ated clinically using measurements such as tensile strength.
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Wound Healing and the Role of Nutrient Substrates
6
A number of human studies have been performed to address wound healing and
overall outcome after surgical intervention with and without associated malnutri-
tion. In a prospective study of female patients with femoral neck fractures that un-
derwent surgery, outcomes were determined in relation to nutritional status.
22
Those
that were greater than two standard deviations below the mean body weight had a
more prolonged period of rehabilitation and a higher overall mortality. Another
prospective study in over 200 non-cancer patients determined pre-operative nutri-
tional status as measured by percent ideal body weight, percent weight loss, serum
albumin levels, and arm muscle circumference and correlated these findings with
surgical outcome.
23
The group of patients that had one of the above indicators of
poor nutritional status were found to have a significant increase in overall complica-
tions, major complications, and in length of stay compared to the control group.
Nutritional Supplementation and Wound Healing
As a result of the numerous studies that have demonstrated that poor nutritional
status correlates with poor wound healing, much investigation has ensued in an
attempt to identify the ideal amount, timing, and content of nutritional supple-
mentation in patients undergoing surgery or after traumatic injury.
One study examined hydroxyproline content in subcutaneous PTFE grafts in
patients that received total parenteral nutrition (TPN).
24
Researchers found that
lower levels were found in patients that were considered to be malnourished when
compared to normal controls. However, levels were increased after patients had re-
ceived TPN for variable periods of time before wounding. Furthermore, patients
that received TPN pre- and postoperatively had greater hydroxyproline levels in
experimental wounds than those that received TPN only after surgery. Enteral feed-
ing has also been demonstrated to affect hydroxyproline levels in implants.
25
Pa-
tients that received four days of enteral nutrition post-operatively had elevated levels
in PTFE implants inserted at the time of surgery and harvested one week later.
A large study that addressed the relationship of perioperative TPN with surgical
outcome and wound healing was the Veterans Affairs Cooperative Study.
26
It en-
rolled 395 malnourished patients that had abdominal or thoracic surgical proce-
dures. Suprisingly, the TPN group had a higher rate of infectious complications
compared with the unfed control group. While the patients that were borderline or
mildly malnourished had no demonstrable benefit from TPN, those patients that
were severely malnourished had fewer wound complications such as anastomotic
leaks and bronchopleural fistulas.
The role of preoperative enteral hyperalimentation in malnourished surgical pa-
tients was assessed in a study by Shukla et al.
27
Patients that were randomized to
receive nasogastric feeds had significant improvement in body weight, serum pro-
tein levels, and multiple anthropometric measures compared with the patients in
the control group. These parameters have routinely been correlated with nutritional
status and the quality of wound healing and, in this study, the enteral
hyperalimentation group had significantly lower rates of mortality and wound in-
fection rates.
As previously mentioned, Bastow et al performed a randomized control trial to
determine the effect of nocturnal feeds in patients that were undergoing surgery for
femoral neck fractures.
22
Over 700 patients were grouped at the time of surgery
according to anthropometric measurements. Patients were either categorized as
well-nourished, thin (between 1 and 2 standard deviations below the mean), or very
92
The Biology and Practice of Current Nutritional Support
6
thin (greater than two standard deviations below the mean). Patients in the thin and
very thin groups were then randomized to receive noctural tube feeds in addition to
a standard diet or just standard diet alone. In both the thin and very thin groups, the
patients that received the nocturnal feeds in addition to the standard diet had sig-
nificant reductions in their rehabilitation times compared to their matched control
groups that had standard diets only.
Kiyama et al recently investigated the effect of enteral vs. parenteral nutrition on
gastrointestinal anastomotic healing.
28
Using 20 male Sprague-Dawley rats, a distal
colonic anastomosis was performed in an inverted, single-layer manner. Identical
nutrient infusates of amino acids, dextrose, and vitamins were either given via a
parenteral or enteral route. While there was no difference in nutritional parameters
at five days, colonic anastomotic bursting pressures were significantly higher in the
enterally fed group and the measured insoluble collagen and total protein content in
anastomotic tissue was enhanced. The authors conclude that the preservation of
colonic structural collagen in the enteral group may improve the ability of the gut to
hold sutures and thus improve anastomotic healing. In a similar study by another
group of investigators, rat colonic anastomotic bursting pressures were tested after
the intravenous infusion of n-butyrate.
29
Total collagen content was not altered but
the bursting pressures were significantly increased compared to control rats that
received TPN without additional n-butyrate. The role of enteral and parenteral supple-
mentation in improving the strength of anastomotic healing is yet to be determined.
A group of orthopedic surgeons from Sweden assessed whether supplemental
nutrition would improve healing and decrease mortality in patients that underwent
transtibial amputation for occlusive arterial disease.
30
In a prospective study, 28
malnourished patients were given pre and postoperative supplemental nutrition to
an average intake of 2098 kcal/day for a total of at least 16 days. A group of 32,
well-matched patients served as the controls and did not receive supplemental nu-
trition. Healing occurred in 26 of the nutrition group compared with 13 in the
control group, which was statistically significant. While mortality was not altered in
this study, supplemental nutrition did improve healing of transtibial amputation wounds.
Specific Nutrients, Vitamins, and Trace Elements
Arginine
Arginine is a nonessential amino acid that can become an essential dietary nutri-
ent with severe stress. It has multiple pharmacologic and biologic effects including
stimulation of various immune parameters, acting as a pituitary and pancreatic secre-
tagogue, and increasing angiogenesis in response to ischemic injury. In addition,
arginine may also serve as a local precursor for collagen-bound proline. More im-
portantly, the amino acid is the unique precursor of the highly reactive radical nitric
oxide (NO).
31
Various studies suggest that NO plays a critical role in wound heal-
ing. It is known to act as a messenger molecule for different physiological actions.
32
After injury, NO synthesis occurs for prolonged periods and macrophages appear to
be a major cellular source for it.
33
Schaffer et al investigated the role of NO in acutely malnourished rats that had
subcutaneously implanted polyvinyl alcohol (PVA) sponges.
33
The authors postu-
lated that wound NO production plays a regulatory role in wound collagen synthe-
sis in normal and impaired healing and that levels would be altered in the
malnourished group. The rats that had a 50% reduction of food intake lost 10% of
their weight while control animals gained 18% of their original body weight. Wound
93
Wound Healing and the Role of Nutrient Substrates
6
collagen accumulation and Types I and III collagen gene expression were measured
in the subcutaneously placed sponges. Nitric oxide synthesis was also determined in
wound fluid and from wound cell culture supernatants. Collagen content as mea-
sured by hydroxyproline levels in the sponges from the protein-calorie malnour-
ished animals was significantly less than compared to the control group. The gene
expression of Type III collagen, but not Type I collagen, was also reduced in the
malnourished group. The concentration of nitrite, nitrate, and citrulline, which are
stable end products of NO were also reduced in the wound fluid and wound cell
supernatants of the malnourished rats, indicating a net decrease in NO production.
The investigators concluded that impaired wound collagen accumulation caused by
protein-calorie malnutrition may be a reflection of reduced NO synthesis within
the wound.
To further investigate the mechanism by which NO affects wound healing, a
group of investigators utilized iNOS knockout (KO) mice to determine if arginine
acts through this enzyme in producing its vulnerary effects.
34
Twenty wild type and
20 iNOS knockout mice were randomized to receive either normal food and water
or food and water supplemented with 0.5% arginine. A 2.5-cm dorsal skin incision
was then made through which four PVA sponges were implanted into subcutaneous
pockets. The animals were sacrificed on post-operative day 14 and the dorsal wound
was tested for breaking strength and the sponges were assayed for hydroxyproline
content and total wound fluid nitrite and nitrate concentration. Wound breaking
strength and collagen deposition was increased in the wild type group but not in the
iNOS-KO group with dietary arginine supplementation. Also, wound fluid nitrite
and nitrate levels were higher in the wild type group compared to the iNOS-KO
group but were not significantly influenced by additional arginine. These data sup-
ported previous studies that demonstrated that supplemental dietary arginine en-
hances wound healing in normal mice. However, the loss of a functional iNOS gene
abrogates the beneficial effect of arginine in wound healing. The authors concluded
that the iNOS pathway is at least partially responsible for the enhancement of wound
healing by arginine and that exogenous arginine and its associated NO production via
iNOS most likely enhance wound healing through multiple physiologic mechanisms.
While arginine has been demonstrated to increase collagen deposition and break-
ing strength of cutaneous wounds, its role in altering the healing of intestinal anas-
tomoses is unclear. In an effort to determine if supplemental arginine improved
colonic anastomoses, a group of researchers fed 42 Sprague-Dawley rats either 0, 1,
or 3% arginine diets for three preoperative and three postoperative days prior to
transection and reanastomosis of the transverse colon.
35
Animals were harvested on
either postoperative day 6, 10, or 14 and the bursting pressure, histologic inflamma-
tion, and collagen content of the hand-sewn anastomoses were determined. Rats
that were fed a 0% arginine diet showed a significantly lower bursting anastomotic
pressure on postoperative day 6 than those fed 1 and 3% arginine diets, but no
bursting pressure differences by diets were noted by days 10 or 14. There were no
differences in the degree of inflammation in stained anastomotic tissue upon histo-
logic evaluation nor was there any difference in collagen content between the vari-
ous groups. Perioperative arginine deficiency resulted in reduced bursting pressures in
this model of rat colon anastomoses suggesting impaired healing. However, supranormal
levels of dietary arginine did not increase the bursting pressure of anastomoses above
the normal level of arginine. This study reinforces the importance of adequate nutri-
tion in the surgical patient, especially those with gastrointestinal anastomoses.
94
The Biology and Practice of Current Nutritional Support
6
In an attempt to further define the mechanisms responsible for collagen biosyn-
thesis and the role of NO, Shukla et al. studied the effect of topical arginine and the
NO releaser, sodium nitroprusside (SNP) in full thickness excisional wounds in
rats.
36
Interestingly, the SNP decreased the collagen content of the wounds at all
doses as demonstrated by reduced hydroxyproline levels and confirmed histologi-
cally, yet L-arginine decreased collagen content. Various doses of N-nitro-L-arginine
methyl ester (L-NAME), a competitive inhibitor of NOS, significantly increased
wound collagen when administered intraperitoneally and compared to untreated
and SNP treated animals. In addition, thick collagen bundles, proliferation of fibro-
blasts, and increased angiogenesis were seen on review of the wound histology from
the L-NAME treated group. An inactive isomer of the inhibitor, N-nitro-D-arginine
methyl ester did not affect wound collagen levels. Administering L-arginine to
L-NAME pretreated rats resulted in significantly elevated wound collagen content.
The authors postulate that NO could decrease collagen by inhibiting prolyl hy-
droxylase, which is an oxygenase type of enzyme. Also, they point out that the re-
duced collagen content may be as a result of the route of administration since arginine
given intraperitoneally resulted in a trend towards increased collagen content and
other studies have shown that systemically given arginine increases the level of wound
collagen. The authors conclude that NO plays a pivotal role in regulating the bio-
synthesis of collagen. Also, NOS inhibitors administered systemically may help to
lower NO concentration at the injury site as well as in whole body so as to enhance
collagen synthesis and to lower the inflammatory response for better healing.
Barbul et al investigated the effect of oral arginine supplementation on human
collagen synthesis and T-cell function in 36 healthy human volunteers.
37
After a 5
cm segment of PTFE tubing was inserted into a subcutaneous pocket in the deltoid
region, the volunteers where then randomly assigned to receive daily oral supple-
ments of either arginine hydrochloride (25 gm free arginine), arginine aspartate (17
gm free arginine), or a placebo for two weeks. Mitogenic responses of peripheral
blood lymphocytes to phytohemaglutinin and concanavalin A were determined at
0, 1, and 2 weeks after supplementation. The catheters were removed after two
weeks and the amount of hydroxyproline was determined. Both arginine-supple-
mented groups had increased amounts of hydroxyproline deposited in the grafts as
well as increased lymphocyte mitogenesis in response to phytohemaglutinin and
concanavalin A. These data suggested that arginine may be of clinical benefit in
improving wound healing and immune responses.
Another study by the same group of investigators addressed the affect of arginine
on wound healing and immune function in elderly patients.
38
In this double-blind,
randomized study, 15 patients received either arginine aspartate (17 gm free argin-
ine) while another 15 patients received a placebo syrup. PTFE catheters were placed
in a subcutaneous position in the deltoid region and a 2 x 2 cm split thickness
wound was created on the lateral aspect of the upper thigh. The catheters were
analyzed for -amino nitrogen to determine total protein accumulation, hydrox-
yproline content, and DNA accumulation. The mitogenic response of peripheral
blood lymphocytes to concanavalin A, phytohemaglutinin, pokeweed mitogen, and
allogeneic stimuli was determined at the beginning and end of the experiment. The
catheters were removed at two weeks and found to contain significantly more
hydroxyproline in the arginine supplemented group. There was no difference in
cellularity of the catheter as assessed by DNA content nor was there any difference
in time to complete epithelialization of the skin defect. However, the blastogenic
95
Wound Healing and the Role of Nutrient Substrates
6
response of peripheral blood mononuclear cells to all the mitogens as well as to
allogeneic stimulation was significantly greater in the arginine supplemented group
compared to the control group. Furthermore, insulin-like growth factor-1 levels
were significantly elevated in the arginine group. These findings support previous
studies that demonstrated arginine supplementation increases protein and collagen
deposition and T-cell activity in experimental wounds.
Barbul and his colleagues have continued to study arginine and NO and, in a
series of papers over the last several years, they have provided additional convincing
evidence that inducible NO plays a critical role in the wound healing process. Using
Balb/C mice that had cutaneous incisional wounds and had PVA sponges implanted,
they demonstrated decreased wound breaking strength and wound collagen accu-
mulation when NO synthesis was inhibited by S-methyl isothiouronium, a com-
petitive inhibitor of NO synthase.
39
Furthermore, rat colon anastomoses were found
to have increased, localized expression of inducible NO synthase that, when blocked
with S-methyl isothiouronium, had lower bursting pressures than control anasto-
moses.
40
The investigators also demonstrated that impaired diabetic wound healing
was associated with decreased wound NO synthesis in Sprague-Dawley rats ren-
dered diabetic after streptozotocin administration.
41
Lastly, Barbul was able to successfully transfect male rats with plasmid DNA that
contained murine iNOS gene driven by a CMV promoter and demonstrated that
increased production of iNOS was associated with a localized increase in collagen
production.
42
These studies have strengthened the link between arginine, NO, and
wound healing but further investigation is necessary to understand the mechanisms
by which they participate in this process.
Glutamine
Glutamine is an amino acid that is considered to be a conditionally essential
amino acid during serious injury or illness but is nonessential in healthy adults.
43
It
is the most abundant amino acid in plasma and skeletal muscle, but levels in blood
and tissues fall acutely after injury, infection, or surgery.
44
This amino acid is a pre-
cursor for synthesis of nucleotides and may be a regulator of protein turnover.
45
More importantly, it has been recognized as a major oxidative substrate for enterocytes,
colonocytes, and cells for the immune system.
46,47
In the gastrointestinal tract,
glutamine has trophic actions that may decrease bacterial translocation and in ani-
mal studies it has been shown to improve growth and repair of small bowel and
colonic mucosa after injury.
48
However, limited studies have looked at its direct
effect on wound healing.
Demetriades et al examined the effect of early postoperative enteral administra-
tion of glutamine on the healing of gastrointestinal anastomoses in rats.
49
Four groups
of 15 rats were randomly assigned to receive 1 of 4 diets, one of which included
glutamine, after undergoing a colonic anastomosis. After seven days, the rats were
sacrificed and the anastomotic bursting pressure was determined for each animal as
well as histologic examination of each anastomosis. The rats fed with enteral diets
that contained glutamine had significantly higher bursting pressures and decreased
inflammation. The authors concluded that early postoperative enteral feeding with
glutamine improves healing of experimental colonic anastomoses in rats.
Vitamin C
L-ascorbic acid functions as a biologic cofactor in many diverse biochemical
reactions and as a nonspecific antioxidant.
50
Numerous studies have demonstrated
96
The Biology and Practice of Current Nutritional Support
6
that Vitamin C facilitates collagen synthesis in the posttranslational hydroxylation
stage but also by influencing collagen messenger RNA levels.
51
Vitamin C defi-
ciency or scurvy results in scorbutic wounds that are characterized by decreased
accumulation of ECM, abnormal angiogenesis with hemorrhage, very little collagen
deposition, and markedly retarded gain in tensile strength.
52
In addition, there is an
increased susceptibility to wound and more severe infections secondary to reduced
production of neutrophil superoxide, complement components, and various gamma
globulins.
52
Interestingly, plasma concentration and urinary excretion of ascorbate
are markedly decreased in injured humans, and tissue saturation for ascorbate is
remarkably reduced in the early hours after injury.
53
Some postulate that this aspect
of ascorbate metabolism may contribute to the alterations in wound healing seen in
polytraumatized patients.
The effects of Vitamin C deficiency on wound healing are generally seen only
after a prolonged period of ascorbate deprivation. Crandon et al demonstrated that
clinical scurvy and impaired healing was present only after patients were deprived of
Vitamin C for 180 days.
54
Cutaneous wounds at 90 days healed without difficulty.
Another study showed that patients that were deprived of Vitamin C for seven months
had reduced tensile strength of cutaneous wounds compared to those on an
ascorbate-supplemented diet, but only for the first ten days after injury.
55
These
studies demonstrate that while Vitamin C is important in wound healing, this pro-
cess is fairly resilient to simple ascorbate deficiency in animals and humans.
Pharmacologic doses of Vitamin C have been proposed to improve wound heal-
ing in a handful of studies. However, many elderly patients, as well as smokers and
cancer patients, have low plasma and leukocyte ascorbate concentrations and levels
can be depressed in the acute injury setting. Therefore, improved wound healing is
most likely as a result of injury or surgery in patients that have marginal ascorbate
levels initially. As a result, dietary supplementation with Vitamin C may be beneficial.
Vitamin B
The B vitamins are coenzymes that function interdependently as coenzymes in a
wide variety of reactions involving carbohydrate, fat, and protein metabolism, as
well as being important in DNA synthesis.
56
Deficiencies of some of the B vitamins
can alter wound healing by impairing the relatively rapid turnover rate of cells that
is required for tissue repair and the immune response.
56
Vitamin B deficiency is
usually associated with poor food choices as a result of poverty, ignorance, illness, or
poor health habits such as alcohol abuse.
Vitamin A
The mechanisms responsible for the vulnerary effects of Vitamin A are not com-
pletely known. However, it is well known that Vitamin A counteracts the deleteri-
ous effects of glucocorticoids on wound healing in both animals and humans.
57
Supplementation with Vitamin A increases collagen content and breaking strength
of experimental cutaneous wounds and colonic anastomoses in normal rats.
58
In
addition, alterations in wound healing as a result of femoral fractures, whole body
irradiation, or streptozotocin-induced diabetes, were reversed with administration
of Vitamin A.
59-61
One of the theories for how Vitamin A exerts its effect is by
inducing fibroblast differentiation and collagen secretion.
62
In fact, topical applica-
tion of Vitamin A accelerated healing of cutaneous wounds that were healing poorly
secondary to steroids.
62
Alternatively, Vitamin A may exert its effects systemically by
97
Wound Healing and the Role of Nutrient Substrates
6
upregulating overall immune responses as demonstrated by its prevention of thymic
involution after trauma.
63
It also increases cell-mediated reactivity as demonstrated
by skin graft rejection in animals consuming supplemental Vitamin A.
63
Despite
concerns about the increased incidence of intra-abdominal adhesions found in ani-
mals given Vitamin A, patients with severe injuries and those receiving steroids should
receive diets supplemented with standard doses of Vitamin A every day.
58
Vitamin E
Vitamin E is an antioxidant and free-radical scavenger that helps prevent the
oxidation of cell membrane polyunsaturated phospholipids.
64
Supplemental vita-
min E has been shown to increase the healing strength of wounds that are slow to
heal after radiotherapy.
65
However, excess dietary vitamin E has been found to delay
wound healing, slow allograft rejection, lessen postoperative adhesion formation,
and interfere with the beneficial effects of vitamin A.
58
Interestingly, serum concen-
trations of this vitamin are reduced in burn patients due to consumption by oxygen
radical release and subsequent systemic inflammation.
66
Vitamin D
Vitamin D is not only required for normal calcium metabolism and bone forma-
tion, but it also appears to be required for normal collagen production.
67
However,
deficiency states are uncommon in that Vitamin D can be synthesized by the
body with adequate exposure to sunlight. Supplementation may be necessary
in selected patients.
Vitamin K
While vitamin K is synthesized by intestinal bacteria, dietary sources are neces-
sary to meet the bodys total need. This vitamin is involved in the formation of at
least four protein-clotting factors and also a calcium-binding protein required
for bone metabolism.
68
A vitamin K deficiency can lead to impaired healing
and infection.
68
Copper
Copper is involved in the maturation of collagen by lysyl oxidase, a copper met-
alloenzyme that catalyzes the oxidation of lysyl residues on collagen.
69
Hydroxylysyl
groups add to the strength of the scar through cross-linking of extracellular collagen.
Copper deficiency results in anemia, neutropenia, leukopenia, and skeletal dem-
ineralization.
50,70
Zinc
Zinc is an essential component of multiple metalloenzymes, including RNA-
and DNA-polymerases.
71
The physiologic functions of zinc include tissue growth
by nucleic acid metabolism, protein synthesis, bone formation, skin integrity, and
the maintenance of host defense mechanisms.
50,58
Zinc deficiency in animals results
in alterations in the immune system including thymic atrophy, lymphopenia, T-cell
impairment, and decreased granulocyte function.
72
The role of zinc in wound heal-
ing was investigated in patients with pilonidal sinuses.
73
Oral administration of zinc
resulted in a more rapid rate of reepithelialization. Another study demonstrated that
zinc supplementation accelerated the healing of chronic venous leg ulcers but only
in those patients with a low pretreatment serum zinc level.
74
Since a significant
portion of hospitalized patients have been shown to have low serum zinc levels,
98
The Biology and Practice of Current Nutritional Support
6
especially those that have poor food intake, diarrhea, a gastrointestinal fistula, or
malabsorption, supplementation of patients diets with zinc is recommended.
Other Trace Elements
Manganese, selenium, and silicon are a few of the additional trace elements that
participate in the wound healing process. Manganese is necessary for the function of
O-lysyl galactosyltransferase, the enzyme responsible for the glycosylation of
procollagen fibers.
75
This element is also involved in the production of HA, chon-
droitin sulfate, heparin, and other mucopolysaccharides that are important compo-
nents of the ground substance in healing wounds.
76
Selenium-dependent glutathione
peroxidase is an enzyme that protects the cell from oxidative damage by catalyzing
the reduction of hydrogen peroxide.
76
Altered macrophage and polymorphonuclear
cell function may result with selenium deficiency.
76
Lastly, silicon may stimulate the
production of collagen and mucopolysaccharides and deficiency of this trace ele-
ment has been linked to altered connective tissue matrix formation.
77
Fatty Acids
Several studies have shown that -3 fatty acids, which are abundant in fish oils,
have significant anti-inflammatory effects that appear to be mediated through the
inhibition of proinflammatory eicosanoid production.
78
Tumor necrosis factor-,
interleukin-1, and platelet-activating factor production are also decreased in pa-
tients with diets high in these compounds.
79,80
The anti-inflammatory effect pro-
duced has been shown to alter cutaneous wound healing in a study by Albina et al.
81
Animals that were fed diets rich in -3 fatty acids had weaker wounds when com-
pared to wounds in the control animals. These differences were attributed to altered
collagen spacing or cross-linking and not collagen production.
Conclusion
The quality and rate of the wound healing process is intricately dependent upon
the availability of a number of nutritional substrates. Reduced levels of one or more
of these substrates results in delayed or inadequate wound healing. Furthermore,
supplementation of various substrates to correct deficiencies or to produce
supranormal levels can increase the rate and/or quality of the healing process follow-
ing wounding and reduce the number of complications. Further research into the
mechanisms of wound healing and role of nutrient substrates will continue to reveal
new biological and chemical pathways that can be altered to reduce the morbidity
and mortality associated with injury, disease, and surgery in all patients.
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31. Albina JE, Mills CD, Barbul A. Arginine metabolism in wounds. Am J Physiol
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33. Schaffer MR, TantryU, van Wesep RA et al. Nitric oxide metabolism in wounds. J
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36. Shukla A, Rasik AM, Shankar R. Nitric oxide inhibits wound collagen synthesis.
Mol Cell Biochem 1999; 200:27-33.
37. Barbul A, Lazarou SA, Efron DT et al. Arginine enhances wound healing and
lymphocyte immune responses in humans. Surgery 1990; 108:331-337.
38. Kirk SJ, Hurson M, Regan MC et al. Arginine stimulates wound healing and im-
mune function in elderly human beings. Surgery 1993; 114:155-160.
39. Schaffer MR, TantryU, Gross SS et al. A. Nitric oxide regulates wound healing. J
Surg Res 1996; 63:237-240.
40. Efron DT, Thornton FJ, Steulten C et al. Expression and function of inducible
nitric oxide synthase during rat colon anastomotic healing. J Gastrointest Surg
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41. Schaffer MR, TantryU, Efron PA et al. Diabetes-impaired healing and reduced
wound nitric oxide synthesis: A possible pathophysiologic correlation. Surgery 1997;
121:513-519.
42. Thornton FJ, Schaffer MR, Witte MB et al. Enhanced collagen accumulation
following direct transfection of the inducible nitric oxide synthase gene in cutane-
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43. Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutr
Rev 1990; 48:297-309.
44. Askanazi J, Carpentier YA, Michelsen CB. Muscle and plasma amino acids follow-
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45. Jepson MM, Bates PC, Broadbent P. Relationship between glutamine concentra-
tion and protein synthesis in rat skeletal muscle. Am J Physiol 1988; 18:E166-172.
46. Windmueller HG. Glutamine utilization by the small intestine. Adv Enzymol 1982;
53: 201-237.
47. Ardawi MSM, Newsholme EA. Glutamine metabolism in lymphocytes of the rat.
Biochem J 1983; 212:835-842.
48. Klimberg VS, Salloum RM, Kasper M. Oral glutamine accelerates healing of the
small intestine and improves outcome following whole abdominal radiation. Arch
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52. Anderson TW. Vitamin C. Nutr Today 1977; 12:6-13.
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53. Levenson SM, Green RW, Taylor FHL. Ascorbic acid, riboflavin, thiamine, and
nicotinic acid in relation to severe injury, hemorrhage, and infection in the hu-
man. Ann Surg 1946; 124:840-856.
54. Crandon JH, Lund CC, Dill DB. Experimental human scurvy. N Engl J Med
1940; 223:353-369.
55. Wolfer JA, Farmer CJ, Carroll WW. An experimental study in wound healing in
Vitamin C depleted human subjects. Surg Gynecol Obstet 1947; 84:1-15.
56. Lakshmi R, Lakshmi AV, Bamji MS. Skin wound healing in riboflavin deficiency.
Biochem Med Metab Biol 1989; 42:185-191.
57. Ehrlich HP, Hunt TK. Effect of cortisone and vitamin A on wound healing. Ann
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CHAPTER 1
CHAPTER 7
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Protein Metabolism in Liver and Intestine
During Sepsis: Mediators, Molecular
Regulation, and Clinical Implications
Timothy A. Pritts, Eric Hungness and Per-Olof Hasselgren
Introduction
Sepsis is associated with pronounced metabolic alterations in various organs and
tissues. In particular, changes in protein metabolism are prominent in muscle, lungs,
liver and intestine.
1
Whereas the response to sepsis and severe injury, including burn
injury, is that of catabolism in muscle and lungs,
2-4
sepsis results in increased protein
synthesis in liver and intestine.
5,6
One of the consequences of protein breakdown in
peripheral tissues is net release of glutamine and other amino acids. A large portion
of these amino acids is taken up by the liver to serve as precursors for gluconeogen-
esis and acute phase protein synthesis, and by the small intestine where they serve as
an important energy source (Fig. 7.1). Glutamine is also taken up by cells in the
immune system and is important for maintained function of these cells.
7
Increased
production of acute phase proteins in the liver
5
and stimulated protein synthesis in
the mucosa of the small intestine
6
support the concept of an anabolic response to
sepsis in these tissues.
The metabolic response to sepsis in the liver and intestine is important from a
clinical standpoint for a number of reasons. Several of the acute phase proteins serve
as immunomodulators or participate in tissue repair. In previous studies, survival in
septic patients was dependent on a well-maintained protein synthesis in the liver.
Recent studies provided evidence that acute phase proteins are synthesized not only
by the hepatocyte but by the enterocyte as well,
8-10
and the intestine may be an
additional source of acute phase proteins during sepsis and other critical illness. Part
of the sepsis-induced increase in intestinal protein synthesis reflects increased pro-
duction in the enterocyte of gut peptides, including vasoactive intestinal peptide
(VIP) and peptide YY (PYY).
11
Some of the gut peptides may be involved in sepsis-
induced hemodynamic changes and in altered gastrointestinal motility.
In this Chapter, sepsis-induced changes in protein metabolism in liver and intes-
tine are reviewed together with mediators and molecular regulation. In addition,
clinical implications of the metabolic changes are discussed.
Liver
The Acute Phase Response
Acute phase proteins have been defined as plasma proteins whose concentrations
in blood are increased 25 % or more by various stimuli, including inflammation,
104
The Biology and Practice of Current Nutritional Support
7
injury and sepsis. More recently, it has been suggested that the term should be limited
to proteins that are induced by cytokines derived from an inflammatory focus.
12
. In
contrast to these proteins, certain plasma proteins, most notably albumin, are re-
duced during sepsis and critical illness, and these proteins are usually referred to as
negative acute phase reactants. Thus, during sepsis and following severe injury, the
synthesis and release of certain proteins are reprioritized.
The acute phase proteins can be divided into different groups depending on the
degree of reactivity; some acute phase proteins show an increase of up to 1,000-fold,
whereas other proteins show a more moderate (2- to 10-fold) increase following
stimulus.
13
The acute phase response is species specific. In man, for example, C-reactive
protein (CRP) is a particularly strong reactant, showing increased levels even after mod-
erate trauma (Fig. 7.2),
14
whereas in rats,
2
-macroglobulin and
1
-acid glycoprotein
show pronounced increases in plasma concentrations during the acute phase response.
13
The biological functions of different acute phase proteins have been reviewed
elsewhere.
12
In general, the acute phase proteins serve a number of important func-
tions in the inflammatory response and in restoring homeostasis following injury
and sepsis. Considering the wide range of biological functions of the acute phase
proteins, it is not surprising that they are essential for the outcome in sepsis and
injury. Several authors have found evidence that survival in septic patients is depen-
dent on a well-maintained protein synthesis in the liver.
Fig. 7.1. Sepsis is associated with a catabolic response in skeletal muscle and lungs,
resulting in release of glutamine and other amino acids. The function of cells in the
immune system and in the gut and the synthesis of acute phase proteins in the liver are
supported by changes in protein turnover in muscle and lungs. Reprinted with permis-
sion from Hasselgren PO, Protein Metabolism in Sepsis, Austin: RG Landes, 1993.
105
Protein Metabolism in Liver and Intestine During Sepsis
7
Most clinical evidence for increased acute phase protein synthesis during sepsis
and other critical illness has been derived from elevated plasma levels of the pro-
teins. Direct evidence for stimulated protein synthesis in the liver during sepsis has
been reported in animal experiments using various experimental models and differ-
ent techniques to measure protein synthesis. Results from those experiments suggest
that sepsis stimulates the synthesis not only of secreted plasma proteins but of en-
dogenous (non-secreted) proteins as well, such as intracellular enzymes and struc-
tural proteins, and this is one of the reasons why liver weight and protein content
are typically increased during sepsis and inflammation.
5,15
Increased hepatic protein
Fig. 7.2. Changes in plasma levels of acute phase proteins following uncomplicated
open cholecystectomy. C-reactive protein (CRP) is a particularly strong acute phase re-
actant in man. Reprinted with permission from Aronson KF et al, Scand J Clin Lab Invest
1972; 29:127-136.
106
The Biology and Practice of Current Nutritional Support
7
synthesis is not unique to sepsis, but occurs in a number of inflammatory condi-
tions, including endotoxemia, bacteremia, surgical trauma, and burn injury.
5,15
In addition to changes in the synthesis rates, plasma levels of the acute phase
proteins can also be influenced by changes in the secretion of the proteins. Plasma
proteins usually reach the cell surface of the hepatocyte within 20-25 min after their
synthesis. There is evidence that this time is shortened for some proteins during the
acute phase response. Thus, both synthesis and secretion of acute phase proteins
may be upregulated during sepsis. A more detailed discussion of mechanisms in-
volved in the production and secretion of secretary proteins is given below.
Cellular Mechanisms of the Acute Phase Response
The cellular mechanisms of the acute phase response are to a certain extent influ-
enced by the unique microanatomy of the liver. Sepsis and inflammation do not
affect all hepatocytes in a homogeneous fashion. Thus, at least during the early
phase of the acute phase response, protein synthesis is stimulated mainly in the
periportal hepatocytes. The inhibition of albumin synthesis also affects hepatocytes
in a heterogeneous fashion, with the most pronounced changes occurring in the
periportal hepatocytes.
16
This heterogeneous response in hepatocytes located in dif-
ferent regions of the liver lobule probably reflects gradients in oxygen, nutrients,
and inflammatory mediators with falling concentrations from the periportal area
towards the central vein. Although not all hepatocytes are recruited for the acute
phase response, at least not initially, each individual hepatocyte that participates in
the acute phase response is capable of exhibiting a complete response, i.e., simulta-
neously increasing the synthesis of multiple acute phase proteins and decreasing the
production of albumin.
The liver contains several different cell types (hepatocytes, endothelial cells,
Kupffer cells, Ito cells, pit cells and neutrophils), most of them arranged in well-
organized, repeating units. The anatomic and functional organization of the hepatic
architecture was reviewed recently by Clemens et al (Fig. 7.3).
17
Because the mi-
croanatomy of the liver is important for the understanding of the metabolic re-
sponse to sepsis and inflammation, it is briefly reviewed here with special emphasis
on the functional organization and the communication between different cell types.
The parenchymal cells of the liver, the hepatocytes, are arranged in cords with
sinusoids surrounding them. In addition to the heterogeneous function of the hepa-
tocytes caused by gradients in oxygen, nutrients and inflammatory mediators from
the terminal portal vein branches to the central vein, the hepatocytes exhibit differ-
ences in metabolic activity in different regions because of variations in enzymatic
activities. One example of this is the high activity of glutamine synthase in perivenous
hepatocytes by which NH
3
generated by upstream hepatocytes is cleared. This inter-
action between periportal and perivenous hepatocytes has led to the concept of a
perivenous scavenger system
18
in which substances left behind by periportal cells
are removed by perivenous hepatocytes.
The sinusoids are lined by endothelial cells which are characterized by large fenes-
trae, spaces between the cells, and lack of a well-developed basement membrane.
This arrangement allows for an easy exchange of large molecules, including acute
phase proteins secreted by the hepatocytes, between the sinusoidal and perisinusoidal
(Disses) spaces. Similar to other vascular beds, the endothelial cells in the liver are
metabolically active and may exhibit phagocytosis, in particular when the capacity
of the Kupffer cells has been saturated.
107
Protein Metabolism in Liver and Intestine During Sepsis
7
The Kupffer cells are located within the sinusoids (Fig. 7.3) and constitute the
majority of the fixed macrophages in the body. They are most numerous in the
periportal sinusoids and are also most active in this location. Following stimulation
with endotoxin, the Kupffer cells release a number of inflammatory mediators, in-
cluding cytokines, prostaglandins, oxygen radicals, and nitric oxide.
19,20
The inter-
action between Kupffer cells and the hepatocytes is of particular significance in the
regulation of the acute phase response (see below).
The Ito cells are specialized fat and vitamin A storing cells located in Disses
space where they encircle the sinusoids and also make contact with adjacent Ito cells
by long stellate processes; the Ito cells are also known as stellate cells.
21
In addition to
being a primary site of vitamin A storage in the body, activated Ito cells are contrac-
tile in response to mediators such as endothelin, prostaglandin F
2
(PGF
2
) or throm-
boxane A
2
and may act as postsinusoidal sphincters. The Ito cells may, therefore, be
important in mediating changes in the distribution of sinusoidal blood flow in vari-
ous pathophysiological conditions, such as sepsis and endotoxemia.
The pit cells are mononuclear cells located within the sinusoidal space and prob-
ably originate from infiltrating lymphocytes. They may be important for the host
defense response.
Neutrophils infiltrate the liver in large numbers during inflammatory states and
accumulate primarily in the sinusoids and hepatic venules.
22
Accumulation of neu-
trophils in the sinusoids may be particularly important since substances released
Fig. 7.3. Three-dimensional view of the microanatomy of the liver. The hepatocytes (H)
are arranged in cords surrounded by sinusoids. The sinusoids are lined by a discontinu-
ous endothelium, allowing for communication between the vascular and perisinusoidal
(Disses space) spaces. The Kupffer cells (K) are present in the sinusoidal lumen. The Ito
cells are located in Disses space where they wrap around the sinuoid. Reprinted with
permission from Clemens MG et al, Shock 1994; 2:1-9.
108
The Biology and Practice of Current Nutritional Support
7
from the neutrophils in this position may influence the activity in other
nonparenchymal liver cells as well as in the hepatocytes. Recent studies suggest that
substances released from neutrophils are more important for reduced blood flow in the
postischemic liver than the mechanical blockade caused by accumulated neutrophils.
23
The morphological arrangement of the different types of liver cells is important
for the intercellular communication during sepsis, shock and inflammation. Com-
munication within the liver can be paracrine, juxtacrine, autocrine or gap junc-
tional. The acute phase response is probably influenced by all these mechanisms. In
this respect, the interaction between Kupffer cells and hepatocytes is the most im-
portant example of paracrine regulation of protein synthesis during sepsis and in-
flammation. The communication between Kupffer cells and hepatocytes is probably
bidirectional, with Kupffer cells talking to the hepatocytes and the hepatocytes talk-
ing back to the Kupffer cells.
Juxtacrine communication can take place when cells are in close apposition. For
example, activation of neutrophils by platelet-activating factor bound to the plasma
membrane of endothelial cells occurs through juxtacrine communication.
Autocrine regulation of protein synthesis and cytokine release occurs in both
Kupffer cells and hepatocytes. The production of nitric oxide (NO) and cytokines
in Kupffer cells is regulated by cytokines and prostaglandins produced in the same
Kupffer cells.
24
In addition to Kupffer cells, the hepatocytes release NO. Recent
studies suggest that acute phase proteins may down-regulate the production of
cytokines, possibly by an autocrine mechanism.
25
Gap junctions are large channels that connect the cytoplasms of adjacent cells.
26
The channels are formed by specific proteins (connexins) in each cell membrane
that align to form a pore between the cells. Connexins with different molecular
weights have been described; in the liver, connexins with a molecular weight of 26
and 32 kDa (Cx 26 and Cx 32) form gap junctions between hepatocytes; Cx 43
forms gap junctions between Ito cells.
26
Gap junctions allow for the passage of small molecular weight substances (less
than 1,000 daltons) such as cAMP, cGMP and inositol triphosphate, as well as ions
such as Ca
2+
, and electrical current. The nature of the substances that can pass through
the gap junctions supports the significance of this intercellular communication for
metabolic regulation. The speed of intercellular communication by gap junctions is
regulated by endotoxin. The function of the gap junctions is regulated at the mo-
lecular level. For example, the 26 and 32 connexin genes are differentially regulated
during inflammation.
Molecular Regulation of Acute Phase Proteins
Most acute phase protein genes have been cloned, making it possible to study
the acute phase response at the molecular level. Previous studies provided evidence
that the acute phase response is regulated at the transcriptional level, and this is
probably true for both positive and negative acute phase reactants. In rats, fibrino-
gen mRNA levels in liver tissue were increased and albumin mRNA levels were
reduced following induction of inflammation with turpentine injection.
27
Increased
mRNA levels for acute phase proteins were also noticed in isolated and cultured
hepatocytes following stimulus, further supporting the concept of upregulated gene
activity during the acute phase response. This increase in gene activity reflects the
activation of transcription factors which are cellular proteins that bind to responsive
elements in the gene promoter. By doing so, these proteins interact with the basal
109
Protein Metabolism in Liver and Intestine During Sepsis
7
transcription machinery and modulate mRNA production. Of the many transcrip-
tion factors involved in the inflammatory response, nuclear factor kappa B (NF-
B), activating protein-1 (AP-1), CCATT/enhancer-binding proteins (C/EBP), and
cAMP responsive element binding protein (CREB) are particularly important. It
should be noted that although transcriptional regulation is important for acute phase
protein synthesis, regulation probably occurs at the post-transcriptional level as well.
Because the acute phase proteins are secretory proteins, regulation of the intrac-
ellular sorting and processing of these proteins may be as important as the regula-
tion of the synthesis itself. The sorting and processing of secretory proteins and the
molecular regulation of these events were reviewed recently.
28
Secretory proteins are
synthesized in the rough endoplasmic reticulum from where they are transported to
the Golgi complex. Typically, proteins are secreted via a regulated or a constitutive
pathway, both of which involve transfer of vesicles or granules to the plasma mem-
brane followed by the secretary process itself, i.e., exocytic discharge of the vesicle or
granule contents. Most secretary proteins are synthesized as precursors carrying a
signal peptide. This peptide is cleared from the protein rapidly after the complex
enters the Golgi apparatus.
Recent evidence suggests that an alternative pathway exists in which proteins
may be secreted directly from the cytosol via membrane transporters or translocators
or as a result of localized evagination of the plasma membrane. Interestingly, this
novel pathway is involved in the secretion of certain cytokines, including interleukin-l.
The Golgi complex consists of the cis-Golgi network (CGN), the Golgi stacks
and the trans-Golgi network (TGN). It is in the TGN that proteins destined for the
regulated secretary pathway are sorted from those to be secreted via the constitutive
pathway (Fig. 7.4). In addition, proteins are diverted to lysosomes or to be retained
within the Golgi compartments. Regulation of secretion via the regulated pathway
occurs at the level of exocytosis itself, the most distal step in the pathway, and may
allow for the rapid release of large quantities of proteins stored in granules following
the appropriate stimulus. In contrast, exocytosis from the constitutive pathway is a
continuous process limited by the availability of product.
The molecular events involved in the intracellular sorting and processing of sec-
retary proteins are complex, and several important features involving both the sort-
ing mechanisms and the post-translational modification of proproteins to proteins
by conversion endoproteases remain unknown. The influence of sepsis and inflam-
mation on these cellular processes are also largely unknown and will be an impor-
tant field for future studies, in particular in liver and intestine, where inflammatory
stimuli have a significant impact on the synthesis of secretary proteins.
Mediators of the Acute Phase Response
The regulation of acute phase protein synthesis in the liver is complex, with a
number of substances influencing protein synthesis in the hepatocyte, either by act-
ing alone or as cofactors to other mediators. The three groups of substances that are
particularly important for regulation of the acute phase response are cytokines, glu-
cocorticoids, and nitric oxide (NO).
Cytokines
Among the cytokines, interleukin-6 (IL-6) is the most important regulator of
the acute phase response in the liver. The role of IL-6 in the acute phase response has
been reviewed in greater detail elsewhere.
13,29
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The Biology and Practice of Current Nutritional Support
7
There are several lines of evidence that support a role of IL-6 in the acute phase
response. Circulating levels of IL-6 are increased in patients with sepsis and follow-
ing infusion of endotoxin in healthy volunteers. In a group of patients with severe
sepsis, high IL-6 levels were associated with high serum concentrations of CRP,
30
consistent with the concept that IL-6 is a mediator of acute phase protein synthesis
in man. In other studies, correlations were found between IL-6 levels and severity
score and outcome, indicating that serum IL-6 levels may be useful as a marker of
severity of sepsis and as a predictor of survival.
31
When IL-6 was administered in vivo to rats, mRNA levels in liver tissue for
2
-
macroglobulin, -fibrinogen, cysteine protease inhibitor and
1
-acid glycoprotein
increased and albumin mRNA levels decreased, indicating that an almost complete
acute phase response can be induced by this cytokine. Also in mice, administration
of IL-6 resulted in an acute phase response. Evidence for a direct effect of IL-6 was
found in in vitro experiments in which acute phase protein synthesis was stimulated
in human hepatocytes, cultured in the presence of IL-6.
32
The predominant source of IL-6 during sepsis and inflammation is the Kupffer
cell, although other cell types, including the hepatocyte itself, have been found to
secrete IL-6. Recent studies in our laboratory suggest that the enterocyte may be an
Fig. 7.4. Sorting of secretory proteins in the Golgi complex. Proteins received from the
rough endoplasmic reticulum are transferred from the cis-Golgi network (CGN) to the
trans-Golgi network (TGN) via the Golgi stacks in non-clathrin-coated vesicles (NCV).
In the TGN, lysosomal proteins and regulated secretory proteins are actively sorted to
corresponding clathrin-coated regions. Delivery to the constitutive release takes place
by default. Reprinted with permission from Halban PA et al, Biochem J 1994; 299:1-18.
111
Protein Metabolism in Liver and Intestine During Sepsis
7
additional source of IL-6 during sepsis and endotoxemia.
33,35
Thus, it is possible that
acute phase protein synthesis in the hepatocyte is regulated by IL-6 both in an
autocrine (IL-6 produced in the hepatocyte), paracrine (IL-6 produced in Kupffer
cells) and endocrine fashion (IL-6 produced in the intestine and reaching the liver
through the portal vein).
The molecular regulation of IL-6-induced acute phase protein synthesis has been
extensively studied in recent years. When IL-6 binds to its receptor on the hepato-
cyte, a number of different transcription factors are activated to stimulate acute
phase protein genes. The induction of the acute phase protein expression is a fast
process with increased mRNA levels noticed already 1-2 h after stimulus.
In addition to IL-6, other cytokines as well are involved in the regulation of the
acute phase response, although these cytokines usually do not induce a complete
acute phase response. In experiments in our laboratory, administration of rIL-1_ to
rats during three days resulted in increased synthesis in perfused liver of total se-
creted proteins, complement component C3 and
1
-acid glycoprotein, whereas the
synthesis of albumin was unchanged and not reduced as expected.
36
There is evidence that TNF as well regulates the acute phase response. The liver
is an important source of TNF following injury and during sepsis and endotoxemia.
Treatment of cultured rat hepatoma cells with TNF in vitro stimulated the synthesis
of
1
-acid glycoprotein and inhibited the production of albumin, and these effects
of TNF were probably regulated at the transcriptional level since mRNA levels for
1
-acid glycoprotein were increased and those for albumin were decreased.
37
In the
same report, TNF had no effect on fibrinogen mRNA, consistent with a partial
acute phase response induced by TNF. Recent studies suggest that the effect of TNF
on hepatocyte protein synthesis is influenced by insulin and glucose substrate avail-
ability.
38
Thus, exposure of cultured rat hepatocytes to TNF did not affect albumin
synthesis in glycogen-depleted cells, whereas TNF inhibited albumin synthesis by
10-25% in cells exposed to insulin or in cells that were not glycogen-depleted. The
results are important because they imply that the acute phase response may be influ-
enced by an interaction between cytokines and nutritional and/or hormonal factors.
In addition to IL-6, IL-1 and TNF, other cytokines as well may be involved in
the regulation of acute phase protein synthesis. Those cytokines include interferon
(IFN)-, transforming growth factor , leukemia inhibiting factor, IL-11 and
oncostatin M. The large number of substances that regulate the acute phase re-
sponse illustrates the complexity of the system.
Glucocorticoids
Acute phase protein synthesis is under hormonal regulation and is influenced by
both catecholamines, glucocorticoids, and glucagon.
39
Most evidence suggests that
glucocorticoids act as an important or perhaps essential cofactor to IL-6 and other
cytokines in the induction of the acute phase response, and this interaction is regu-
lated at the molecular level.
40
The activated glucocorticoid receptor, i.e., the recep-
tor with bound hormone, may influence acute phase protein genes through a direct
activation of a glucocorticoid receptor element in the promoter or through a pro-
tein-protein interaction with other transcription factors or with nuclear coactivating
factors.
41
Treatment of isolated rat hepatocytes with cytokines induce an acute phase
response only in the presence of dexamethasone. In other studies, dexamethasone
potentiated several-fold the effects of IL-1 and IL-6 on the synthesis of plasma pro-
teins in cultured human hepatoma cells. In contrast, dexamethasone alone did not
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The Biology and Practice of Current Nutritional Support
7
influence the expression of plasma proteins. Evidence for a permissive role of gluco-
corticoids was found in vivo as well. Administration of IL-6 to rats stimulated the
acute phase protein expression in the liver, but glucocorticoids were needed to achieve
a maximal response to the cytokine.
An interaction between glucocorticoids and cytokines is important not only at
the cellular level for induction of the acute phase response, but also more proxi-
mally. Thus, a number of cytokines, including IL-1, IL-6 and TNF, stimulate the
hypothalamic-pituitary-adrenal axis to secrete ACTH and glucocorticoids. Gluco-
corticoids, in turn, inhibit the release of cytokines from macrophages in a negative
feedback manner.
The complexity of the regulation of acute phase proteins is further illustrated by
the fact that different classes of the proteins are individually regulated at the mo-
lecular level. The acute phase genes have been divided into two major classes: class I
genes (including the rat haptoglobin, C3,
1
-acid glycoprotein and the human CRP
gene) are regulated by IL-1, combinations of IL-1 and IL-6, and combinations of
these two cytokines with glucocorticoids;
42
class 2 genes (including the
1
-antitrypsin,
1
-antichymorrypsin, fibrinogen, and
2
- macroglobulin genes) are mainly regu-
lated by IL-6 and leukemia inhibitory factor and by combinations of these cytokines
with glucocorticoids. In studies using cultured human hepatoma cells, IL-6 activated
two different classes of acute phase genes and this activation, which was strongly poten-
tiated by glucocorticoids, was mediated by different transcription factors.
40
Nitric Oxide (NO)
NO is an important biological mediator released by a number of different cell
types, including endothelial cells, Kupffer cells and other macrophages, hepatocytes,
cerebellar neurons and neutrophils. The biological functions of NO as well as the
molecular regulation of NO production by constitutive and inducible NO synthase
have been extensively reviewed elsewhere.
43
The possible role of NO in the regulation of liver protein synthesis was initially
described in in vitro experiments in which rat Kupffer cells or peritoneal macroph-
ages were co-cultured with isolated hepatocytes. When this co-culture system was
treated with endotoxin, hepatocyte protein synthesis was inhibited. Subsequent stud-
ies provided evidence that the inhibition of protein synthesis was mediated by NO,
mainly released from the Kupffer cells and acting on the hepatocytes in a paracrine
fashion, but also released by the hepatocytes themselves and acting in an autocrine
fashion. The production of NO in the hepatocytes is probably regulated by cytokines
released from stimulated Kupffer cells. Thus, when supernatant from cultured Kupffer
cells that had been stimulated by endotoxin and IFN- was added to cultured hepa-
tocytes, the hepatocytes produced increased amounts of NO.
44
At the same time,
hepatocyte protein synthesis was reduced. The endotoxin-induced release from
Kupffer cells of substances that stimulated NO release from the hepatocytes was
regulated by cytokines and was maximal when a mixture of IL-1, TNF and IFN-
was added to the endotoxin-stimulated Kupffer cells.
45
Although most of the experiments described above were performed in hepato-
cytes from rats, other studies suggest that similar regulatory mechanisms are present
in humans as well. Plasma concentrations of nitrite/nitrate (NO
2
/NO
3
), the stable
end- products of NO, are increased in patients after trauma and during sepsis, and
NO production can be induced in human hepatocytes by a mixture of TNF, IL-1,
IFN- and endotoxin.
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Protein Metabolism in Liver and Intestine During Sepsis
7
It should be noted that although in vitro experiments suggest that NO inhibits
hepatic protein synthesis, the role of NO for the regulation of hepatic protein syn-
thesis in vivo is not clearly understood. Several studies suggest that NO may be
protective in vivo and even increase hepatic protein synthesis. In studies in our labo-
ratory, treatment of endotoxemic rats with the NO synthase inhibitor N
G
-nitro-L-
arginine effectively blocked the increase in plasma levels of NO
2
/NO
3
and significantly
reduced the endotoxin-induced increase in in vivo hepatic protein synthesis.
46
The
results suggest that NO may participate in the stimulation of hepatic protein syn-
thesis in vivo during sepsis and endotoxemia. The mechanism of this effect of NO is
not known, but may be improved hemodynamics, perhaps at the microcirculatory
level, secondary to the vasodilatory effect of the substance or to prevention of plate-
let aggregation and adhesion.
Intestine
It is only relatively recently that the influence of sepsis and systemic inflamma-
tion on intestinal protein synthesis has been studied.
1,6
Changes in intestinal protein
synthesis are important from a clinical standpoint for several reasons. The intestine
has one of the highest protein turnover rates in the body, accounting for 10-15% of
total body protein production under normal conditions. Consequently, changes in
intestinal protein synthesis rates may have a significant impact on whole body pro-
tein economy. The intestine is the production site for a number of proteins with
important biological functions, such as digestive enzymes, gastrointestinal hormones,
mucin and immunoreactive protein. In addition, recent studies, including studies
in our laboratory, suggest that the intestine is an important source of cytokines
during sepsis, endotoxemia and shock.
33-35,47-49
The potential importance of the gut
during sepsis and endotoxemia is underscored by the fact that proteins (including
cytokines) synthesized in the intestinal mucosa can reach the liver directly via the
portal vein and may therefore be able to influence metabolic processes in the liver.
This concept is referred to as the gut-liver axis (Fig. 7.5) and is supported by a
recent report from our laboratory in which levels of several gut hormones were el-
evated in the portal, but not systemic, circulation following induction of sepsis.
50
Finally, changes in the production of IgA, mucin, and perhaps other proteins as
well, may be essential for bacterial translocation across the gut mucosa.
Sepsis Stimulates Intestinal Protein Synthesis
Initial studies concerning the potential role of the intestinal mucosa in the meta-
bolic response to sepsis examined the effect of sepsis on mucosal protein synthesis.
When sepsis was induced by cecal ligation and puncture (CLP) in rats, the protein
synthesis rate was increased by approximately 15% in jejunal mucosa after 8 h and
by 50-60% in jejunal and ileal mucosa after 16 h.
6
This increase was greatest in
jejunal mucosa, but also involved ileal mucosa and jejunal and ileal seromuscular
layers. Parenteral administration of the pro-inflammatory cytokines TNF- or IL-1
was also associated with increased mucosal protein synthesis, suggesting that the
response to sepsis may be mediated, at least in part, by these cytokines.
Interestingly, increases in mucosal protein synthesis rates during sepsis varied
among different regions of the gastrointestinal tract. Sepsis stimulated protein syn-
thesis in different regions of the small and large bowel, from the duodenum to the
anus.
51
In sharp contrast, protein synthesis in gastric mucosa was significantly re-
duced during sepsis (Table 7.1). The mechanism of this differential effect of sepsis
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The Biology and Practice of Current Nutritional Support
7
on protein synthesis in the stomach and the rest of the gastrointestinal tract is not
known, but may be differences in blood flow; gastric perfusion is reduced whereas
intestinal blood flow is unchanged or even increased during sepsis.
52
It may be specu-
lated that reduced protein synthesis in gastric mucosa during sepsis in part reflects
reduced production of mucin and other substances important for the protection of
the gastric mucosa. The finding, therefore, may be important for the understanding
of the pathogenesis of gastric stress ulcers, commonly observed in patients with
sepsis or other critical illness. Further studies are necessary to elucidate the implica-
tions of reduced protein synthesis in gastric mucosa during sepsis.
Studies in other laboratories confirmed our results of increased intestinal protein
synthesis during sepsis.
53
They found that protein synthesis in mucosa of small in-
testine was increased 20 h after the intravenous injection of live E. coli bacteria and
the increase in protein synthesis was more pronounced in the jejunum than in il-
eum, similar to our findings.
6
Interestingly, in those studies,
53
mucosal protein syn-
thesis was further stimulated in septic rats that were treated with glutamine-enriched
total parenteral nutrition.
In our previous experiments,
6
mucosal protein synthesis rates were measured by
using a flooding dose technique. Because that method measures total mucosal pro-
tein synthesis, it was not possible to delineate with cell type(s) were involved. In
addition to enterocytes, a number of other cell types are present in the intestinal
Fig. 7.5. The gut-liver axis. Substances synthesized by the gut may reach (and influ-
ence) the liver directly via the portal circulation. Reprinted with permission from
Hasselgren PO, in Cytokines and Abdominal Surgery, Schein M, Wise L, eds., Austin:
RG Landes, 1998:197-213.
115
Protein Metabolism in Liver and Intestine During Sepsis
7
mucosa, including endothelial cells, smooth muscle cells, lymphocytes, macroph-
ages and pericryptal myofibroblasts. To examine this issue, we measured protein
synthesis rates in enterocytes isolated from the jejunum of control and septic rats.
54
Results from those experiments suggest that sepsis stimulates protein synthesis in
enterocytes and that the effect of sepsis is particularly pronounced in crypt cell. In
other experiments in the same report, the subcutaneous injection of endotoxin in
rats gave rise to an almost identical metabolic response in jejunal enterocytes, indi-
cating that that findings in septic rats were not caused by the local effects of septic
peritonitis (induced by CLP), but that increased enterocyte protein synthesis is part
of the systemic response to sepsis.
Synthesis and Release of Secretory Proteins, Including Certain
Gut Peptides
When endogenous and secreted proteins were separately measured in enterocytes
isolated from the jejunum of control and septic rats, results showed that sepsis stimu-
lates the synthesis of both these classes of proteins (Fig. 7.6).
11
One important group
of proteins synthesized and released from the intestine are gastrointestinal hormones.
In previous studies, circulating levels of vasoactive intestinal peptide (VIP) were
increased during sepsis or endotoxemia. More recently, we found that plasma con-
centrations of VIP, peptide YY (PYY) and secretin were increased in septic rats.
Plasma levels of VIP and PYY were higher in portal than in peripheral blood, consis-
tent with a gut origin of these peptides.
To further elucidate the origin of gut peptides during sepsis, we measured the
release of PYY and VIP in isolated jejunal enterocytes .
11
The amount of VIP re-
leased into the incubation medium (determined by radioimmunoassay) was increased
10- to 15-fold in enterocytes from septic rats as compared with non-septic control
rats. Sepsis stimulated VIP release in enterocytes from different regions of the villi,
but the effect of sepsis was particularly pronounced in cells from the tips of the villi.
Table 7.1. Specific radioactivity of protein bound (S
B
) and tissue free (S
A
)
leucine and protein synthesis rate (K
S
) in mucosa of different parts
of the gastrointestinal tract of sham-operated and septic rats
Sham CLP
S
B
S
A
K
S
S
B
S
A
K
S
Stomach 0.430.03 986 655 0.220.03* 775 414*
Duodenum 0.560.03 873 944 0.760.04* 803 1395*
Jejunum 0.520.03 865 897 0.640.07* 814 1159*
Ileum 0.400.05 873 676 0.530.05* 876 917*
Ascending Colon 0.260.03 10314 405 0.560.07* 13913* 616*
Descending Colon 0.290.04 914 456 0.650.05* 13019* 748*
Rectum 0.410.04 9514 668 1.100.20* 13116* 12315*
S
B
and S
A
are given as dpm/nmol; K
S
is given as %/day
Protein synthesis rates in mucosa of different parts of the gastrointestinal tract were
determined following a flooding dose of
14
C-leucine. The studies were performed
16 h after sham-operation or CLP. Results are means SEM. The number of rats in
each group was eight. *p<0.05 vs sham. Reprinted with permission from
Higashiguchi T et al, Clin Sci 1994; 87:207-211.
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The Biology and Practice of Current Nutritional Support
7
Fig. 7.6. Effect of sepsis, induced by cecal ligation and puncture (CLP), on synthesis of
non-secreted (left panel) and secreted (right panel) proteins in jejunum of rats. Control
animals were sham-operated. *p<0.05 vs. corresponding sham-operated group. Based
on data in Higashiguchi T et al, Am J Surg 1994; 168:251-256.
117
Protein Metabolism in Liver and Intestine During Sepsis
7
The release of PYY from incubated enterocytes was also increased during sepsis, but
the changes were less pronounced than those for VIP. Studies using the protein
synthesis blocker cycloheximide suggested that the increased release of VIP and PYY
by enterocytes from septic rats reflected both stimulated de novo synthesis and re-
lease of preformed intracellular stores of the peptides. Thus, sepsis seems to stimu-
late both the synthesis and release of certain gut peptides.
Increased synthesis and release of gut peptides may have several important clini-
cal implications. Certain gut peptides may delay gastric emptying and impair intes-
tinal motility and may therefore play a role in the pathogenesis of abnormal
gastrointestinal motility during sepsis. VIP may stimulate glycogenolysis and lipoly-
sis during sepsis, and may also influence the hemodynamic changes induced by
sepsis through its vasodilatory and positive inotropic effects. In vitro experiments
have provided evidence that gut peptides may have a direct effect on enterocyte
metabolism. Other studies suggest that PYY may stimulate cellular proliferation in
the intestinal epithelium. Finally, because secreted gut peptides reach the liver at
high concentrations through the portal vein, it may be speculated that the peptides
influence hepatocellular functions. Thus, changes in intestinal protein synthesis
during sepsis may be important for the regulation of metabolic activity in the liver,
consistent with a functional gut-liver axis.
Sepsis and Mucosal Cytokine Production
Several lines of evidence suggest that the proteins secreted by the intestinal mu-
cosa during sepsis may include a wide variety of cytokines. In recent years, the gut
has been increasingly recognized as an important source of cytokines, during both
local and systemic inflammation.
33-35,47-49
There is evidence that enterocytes as well
as mononuclear cells in the lamina propria can produce cytokines.
34,35,49
In a previ-
ous report, endotoxemia in mice was associated with increased tissue levels of IL-1
in mucosa of small intestine and this increase in IL-1 production was regulated at
the transcriptional level.
47
Other studies have provided evidence that mucosal pro-
duction of TNF may also be increased during sepsis and endotoxemia.
Recent studies in our laboratory focused on the influence of sepsis and
endotoxemia on mucosal production of IL-6. Release of IL-6 from intestinal mu-
cosa may be of even greater significance than TNF and IL-1 considering the impor-
tant role of IL-6 in the regulation of acute phase protein synthesis, both in the liver
13
and locally in the intestinal mucosa.
8-10
Endotoxemia in mice resulted in increased
tissue levels of IL-6 in jejunal mucosa consistent with stimulated local production of
the cytokine (Fig 7.7, upper panel). Reverse transcriptase PCR analysis of RNA
extracted from jejunal mucosa demonstrated that the elevated mucosal IL-6 levels
were associated with increased IL-6 mRNA levels (Fig. 7.7, lower panel), consistent
with the concept that sepsis and endotoxemia may stimulate mucosal IL-6 produc-
tion at the transcriptional level.
33
The studies described above did not define in which cell type IL-6 production
was increased. In studies using cultured intestinal epithelial cells, we found evidence
that the enterocyte may be an important source of IL-6 during sepsis and
endotoxemia. Endotoxin treatment resulted in IL-6 protein and mRNA production
in IEC-6 cells (a rat intestinal epithelial cell line) in a time- and dose-dependent
fashion.
49
In Caco-2 cells, a human intestinal epithelial cell line, the pro-inflamma-
tory cytokine IL-1 stimulated IL-6 secretion into the culture medium (Fig. 7.8,
upper panel).
34
IL-6 mRNA levels were likewise increased, suggesting that
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The Biology and Practice of Current Nutritional Support
7
IL-1-induced IL-6 production is regulated at the transcriptional level (Fig. 7.8,
lower panel). In more recent studies utilizing examination of jejunal mucosa by
immunohistochemistry, we found that enterocytes, in addition to cells present in
the lamina propria, produced IL-6 in vivo during endotoxemia.
35
Thus, studies from our and other laboratories suggest that sepsis and endotoxemia
result in increased production in intestinal mucosa of TNF, IL-1, and IL-6 and that
the enterocyte may be an important source of cytokines in these conditions. Mu-
cosal production of cytokines is significant because they may influence enterocyte
metabolism locally in an autocrine or paracrine fashion. In addition, they may reach
the liver through the portal vein and may therefore influence the metabolic response
to sepsis in the liver.
Fig. 7.7 Effect of endotoxin (LPS) on IL-6 protein (upper panel) and mRNA levels (lower
panel) in jejunal mucosa as determined by ELISA and RT-PCR, respectively. *p<0.05 vs.
saline. -actin was used to control for equal mRNA loading. Reprinted with permission
from Meyer TA et al, Surgery 1995; 118:336-342.
119
Protein Metabolism in Liver and Intestine During Sepsis
7
Fig. 7.8. Effect of IL-1 on IL-6 protein (upper panel) and mRNA levels (lower panel) in
Caco-2 cells as determined by ELISA and RT-PCR, respectively. *p<0.05 vs. respective
control group. -actin was used to control for equal mRNA loading. Reprinted with
permission from Parikh AA et al, Shock 1997; 8:249-255.
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The Biology and Practice of Current Nutritional Support
7
Regulation of Cytokine Production in Intestinal Mucosa
Recent studies have examined the regulation of cytokine production in the
enterocyte and intestinal mucosa. Early experiments indicated that IL-6 production
in cultured intestinal epithelial cells was augmented by addition of other inflamma-
tory mediators to the culture medium. For example, prostaglandin E
2
interacted
synergistically with endotoxin to increase IL-6 production in IEC-6 cells
55
and in-
terferon- treatment augmented IL-1-induced IL-6 production in Caco-2 cells.
34
More recently, our and other laboratories have begun to explore the potential
role of transcription factors in cytokine and acute phase protein production in the
enterocyte and intestinal mucosa. Transcription factors are proteins that act to regu-
late gene transcription rates, leading to either increased or decreased transcription of
the target gene. A given transcription factor may influence the transcription of mul-
tiple genes, making these proteins attractive potential targets through which the
inflammatory response may be manipulated in a therapeutic fashion.
One transcription factor that my play an important role in the inflammatory
response of the intestinal mucosa to sepsis and endotoxemia is nuclear factor-kappa
B (NF-B). NF-B is a dimer consisting of various subunits, most commonly p50
and p65, and is normally sequestered in the cytoplasm in an inactive form by the
inhibitory protein IB (for review see ref. 56). Multiple proinflammatory media-
tors, including IL-1, LPS, and TNF-, can activate NF-B in different cell types.
Through various signaling pathways, these stimuli lead to phosphorylation of IB.
After phosphorylation, IB is ubiquitinated and degraded by the proteasome, free-
ing NF-B to translocate to the nucleus and bind to its target sequences. NF-B
activation is usually rapid, transient, and self-limited. In addition to other target
genes, NF-B also encourages transcription of the IB proteins, which then serve to
terminate NF-B activation and re-sequester NF-B in the cytoplasm. A simplified
diagram of the NF-B activation pathway is presented in Fig. 7.9.
Recent studies have examined NF-B activation in the enterocyte and intestinal
mucosa. Initial reports from this
57
and another
58
laboratory demonstrated that IB-
degradation and increased NF-B DNA binding activity occurred in cultured hu-
man intestinal epithelial cells after treatment with IL-1, concurrent with increased
expression of the NF-B-associated genes for IL-6 and IL-8. Subsequent studies
indicated that IB degradation and NF-B activation also occurred in cul-
tured intestinal epithelial cells in response to TNF-, LPS, bacterial adhesion,
and bacterial invasion.
Recent studies have begun to examine NF-B activation in the gastrointestinal
tract in vivo. In a report from our laboratory, the effect of endotoxin on IB-
protein levels and NF-B DNA binding activity was examined in jejunal mucosa.
59
We found that endotoxin injection resulted in rapid decrease in IB- levels, with a
concomitant increase in NF-B DNA binding activity, consistent with NF-B acti-
vation in this tissue (Fig. 7.10).
Additional experiments have indicated that NF-B activation varied in different
regions of the gastrointestinal mucosa during endotoxemia.
60
Interestingly, the je-
junum was the region most sensitive to endotoxemia, similar to our findings with
mucosal protein synthesis,
6
IL-6,
61
and complement C3 production.
62
In addition to NF-B, several other transcription factors likely play important
roles in regulating protein metabolism in intestinal mucosa during sepsis. We re-
cently found evidence that activating protein-1 (AP-1) and members of the C/EBP
transcription factor family, including CEBP- and CEBP-, are activated in cultured
121
Protein Metabolism in Liver and Intestine During Sepsis
7
intestinal epithelial cells in response to IL-1.
63,64
Further studies are needed to
determine the relative role of the different transcription factors in increased cytokine
and acute phase protein production in the enterocyte and intestinal mucosa during
acute inflammation.
The identification and characterization of the transcription factors activated in
the enterocyte and intestinal mucosa during sepsis may enable therapeutic modifi-
cation of the metabolic and inflammatory responses in gut mucosa. For example,
inhibition of NF-B activation by proteasome inhibitors resulted in decreased IL-8
production in cultured enterocytes. In other studies, treatment of cells with various
NF-B inhibitors decreased IL-1-induced IL-6 and complement component C3
Fig. 7.9. Schematic diagram showing the pathway leading to IB- degradation and
NF-B activation in response to pro-inflammatory stimuli. Reprinted with permission
from Perkins ND, Int J Biochem Cell Biol 1997; 29:1433-1448.
122
The Biology and Practice of Current Nutritional Support
7
production.
65,66
The further modification of sepsis-induced changes in protein pro-
duction and metabolism will be an important goal for future work in this field.
Cytokines Induce a Sepsis-Like Response in Intestinal Mucosa
Several of the metabolic changes induced by sepsis and endotoxemia in intesti-
nal mucosa can be duplicated by cytokines. For example, administration of rIL-l
or rTNF- to rats resulted in increased protein synthesis in jejunal and ileal mucosa,
similar to the response seen during sepsis.
6
In other experiments, administration of
TNF in rats gave rise to increased portal plasma levels of PYY.
50
In contrast, no
changes in circulating gut peptide concentrations were noted following the admin-
istration of IL-1, suggesting a differential role of the two cytokines in the regulation
of gut peptide release.
For the interpretation of results seen following the administration of cytokines,
it is important to remember that cytokines interact with each other and with gluco-
corticoids. It is possible that metabolic changes observed following the administra-
tion of TNF are caused by IL-1, IL-6 and/or glucocorticoids since TNF induces the
release of other cytokines as well as glucocorticoids. Several of the in vitro studies
described above lend strong support to the concept that proinflammatory cytokines
are important mediators of metabolic changes in the enterocyte and that these changes
are caused by direct effects of the cytokines on the enterocyte.
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say (lower panel) and IB- levels determined by Western blotting (upper panel) in
jejunal mucosa at various timepoints after injection of saline (left panel) or LPS (right
panel) in mice. Reprinted with permission from Pritts TA et al, Arch Surg 1998;
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Protein Metabolism in Liver and Intestine During Sepsis
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25. Tilg H, Vannier E, Vachino G et al. Antiinflammatory properties of hepatic acute
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28. Halban PA, Irminger JC. Sorting and processing of secretary proteins. Biochem J
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30. Damas P, Ledoux D, Nys M et al. Cytokine serum levels during severe sepsis in
human: IL-6 as a market of severity. Ann Surg 1992; 215:356-362.
31. Calandra T, Gerain J, Heumann D et al. High circulating levels of interleukin-6 in
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32. Castell JV, Gomez-Lechon MJ, David M et al. Interleukin-6 is the major regulator
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33. Meyer TA, Wang JJ, Tiao G et al. Sepsis and endotoxemia stimulate intestinal IL-6
production. Surgery 1995; 118:336-342.
34. Parikh A, Salzman AL, Fischer JE et al. Interleukin-1 and interferon- regulated
interleukin-6 production in human intestinal epithelial cells. Shock 1997;
8:249-255.
35. Wang Q, Wang JJ, Boyce S et al. Endotoxemia and IL-1 stimulate mucosal IL-6
production in different parts of the gastrointestinal tract. J Surg Res 1998; 76:27-31.
36. Pedersen P, Hasselgren PO, Li S et al. Synthesis of acute phase proteins in perfused
liver following administration of recombinant interleukin-1 to normal or adrena-
lectomized rats. J Surg Res 1988; 45:333-341.
37. Andus T, Geiger T, Hirano T et al. Regulation of synthesis and secretion of major
rat acute phase proteins by recombinant human interieukin-6 (BSF-2/IL-6) in
hepatocyte primary cultures. Eur J Biochem 1988; 173:287-293.
38. Dahn MS, Hsu CJ, Lang MP et al. Effects of tumor necrosis factor- on glucose
and albumin production in primary cultures of rat hepatocytes. Metabolism 1994;
43:476-480.
39. van Gool J, Boers W, Sala M et al. Glucocorticoids and catecholamines as media-
tors of acute-phase proteins, especially rat -macrofetoprotein. Biochem J 1984;
220:125-132.
40. Hocke GM, Barry D, Fey GH. Synergistic action of interieukin-6 and glucocorti-
coids is mediated by the interleukin-6 response element of the rat
2
macroglobu-
lin gene. Mol Cell Biol 1992; 12:2282-2294.
41. Pfahl M. Nuclear receptor/AP-1 interaction. Endocr Rev 1993; 14:651-658.
42. Baumann H, Gauldic J. Regulation of hepatic acute phase plasma protein genes by
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43. Zamora R, Vodovotz Y, Billiar TR. Inducible nitric oxide synthase and inflamma-
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44. Curran RD, Billiar TR, Stuehr DJ et al. Hepatocytes produce nitrogen oxide from
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45. Curran RD, Billiar TR, Stuehr DJ et al. Multiple cytokines are required to induce
hepatocyte nitric oxide production and inhibit total protein synthesis. Ann Surg
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46. Frederick JA, Hasselgren PO, Davis S et al. Nitric oxide may upregulate in vivo
hepatic protein synthesis during endotoxemia. Arch Surg 1993; 128:152-157.
47. Mester M, Tompkins RG, Gelfand JA et al. Intestinal production of interleukin-
1 during endotoxemia in the mouse. J Surg Res 1993; 54:584-591.
48. Deitch EA, Xu D, Franko L et al. Evidence favoring the role of the gut as a cytokine-
generating organ in rats subjected to hemorrhagic shock. Shock 1994; 1:141-146.
49. Meyer TA, Noguchi Y, Ogle C et al. Endotoxin stimulates IL-6 production in
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50. Zamir O, Hasselgren PO, Higashiguchi T et al. Effect of sepsis or cytokine admin-
istration on release of gut peptides. Am J Surg 1992; 163:181-185.
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production in different parts of the gastrointestinal tract. J Surg Res 1998; 76:27-31.
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CHAPTER 8
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Biochemical Assessment and Monitoring
of Nutritional Status
Robert S. DeChicco, Laura E. Matarese, Douglas Seidner and Ezra Steiger
The Incidence of Malnutrition
The prevalence of malnutrition in hospitalized patients ranges from 30 to 50%
(Table 8.1).
1-11
The incidence of malnutrition actually increases if patients are hospi-
talized for two or more weeks.
7
Although the criteria used to define malnutrition
and the types of patients and hospitals varies, the prevalence has remained relatively
constant throughout the years.
Malnutrition in the hospital setting has far-reaching implications. Malnutrition
has been associated with longer hospital stays,
7,13-17
delayed wound healing,
18-21
in-
creased morbidity and mortality,
1,7,11,13,17, 22-32
and ultimately, higher health care
costs.
15-17, 33-35
There is no clinical situation which benefits from malnutrition.
Methods of Nutrition Assessment
Changes in nutritional status, particularly in the critically ill patient, are often
subtle and influenced by many factors. It is important to have an objective assess-
ment tool to identify patients who are at nutritional risk and to document the effi-
cacy of therapy. Unfortunately, there is no single tool which can be used to identify
malnutrition. Thus, a variety of methods are used including patient history, physical
examination, anthropometric measurements, biochemical indices, and tests of im-
mune function.
History
The history comprises the basis of any assessment. For the purposes of determin-
ing nutritional status, the history can be divided into medical and nutrition. The
history should include an investigation of unexplained weight loss, abnormal or
inadequate nutrient intake, recent surgery or illness, chronic illness, and hypermeta-
bolic states (Table 8.2).
Malnutrition is classified as primary or secondary. Primary malnutrition results
from inadequate diet or excessive intake of certain nutrients (e.g., vitamins, calo-
ries). This type of malnutrition is generally a socioeconomic phenomenon but also
involves age, sex, and race. Secondary, or conditional malnutrition occurs when
nutrients are not absorbed or utilized appropriately, generally as a consequence of a
disease process. Causes of secondary malnutrition include the impaired ability to
ingest foods (e.g., esophageal cancer), the impaired ability to digest, absorb, or uti-
lize nutrients (e.g., Crohns disease, ulcerative colitis), and increased nutritional
127
Biochemical Assessment and Monitoring of Nutritional Status
8
requirements (e.g., sepsis, trauma). Nutritional deficiencies can also develop as a
result of drug-nutrient interactions.
The nutrition history should provide detailed information about the patients
general health, eating patterns, and nutrient intake. There are several methods avail-
able to assess nutrient intake including a 24-hour diet recall and a food frequency
questionnaire. The adequacy of the diet should be evaluated, usually by comparing
nutrient intake with estimated energy and protein requirements adjusted for disease
state, if necessary.
Physical Examination
Along with a medical and nutrition history, a physical examination is an essen-
tial component of a comprehensive nutrition assessment. A physical examination
consists of observing physical signs or symptoms that may be associated with nutri-
tional deficiencies (Tables 8.3 and 8.4). The appearance of symptoms of a nutri-
tional deficiency depends upon the specific nutrient in question. However, single
nutrient deficiencies are rare. An individual with symptoms of a single nutrient
deficiency is likely to have multiple deficiencies. Some fat soluble vitamins and min-
erals have body stores which require long periods, up to a year or longer, to become
depleted.
36
Conversely, some of the water soluble vitamins have more labile body
pools which result in physical manifestations of deficiencies after a much shorter
period, less than one month in some cases.
37
Recognizing signs of nutritional deficiencies requires experience and skill be-
cause the symptoms can vary in time of appearance and severity, and interpretation
of these symptoms can be affected by examiner and subject bias. Since most symp-
toms are non-specific and the criteria are not well-defined, there may be a lack of
consistency between observers.
Clinical Anthropometry and Body Composition Analysis
Anthropometry is the science in which the body is described by a series of mea-
surements of the external morphology. Anthropometry is used to assess nutritional
Table 8.1. The prevalence of malnutrition*
Investigator Date % Malnourished Patient Type Hospital Type
Bistrian et al
3
1974 50 General Surgical Urban Teaching
Bistrian et al
4
1976 44 or more General Medical Urban Teaching
Hill et al
5
1977 50 Surgical General Teaching
Mullen et al
6
1979 35 Elective Surgical Urban VA
Weisner et al
7
1979 48 on admission General Medical Teaching
69 after 2 weeks
Willard et al
8
1980 31.5 General Med/Surg Private
Community
Bastow et al
9
1983 53 Elderly Female University
Orthopedic
Sullivan et al
10
1989 39 Elderly General VA University
Medical/Surgical Affiliated
Coates et al
11
1993 38 on admission General Medical Teaching
48 after 2 weeks
* Adapted from: Mosner M and Bader S.
12
128
The Biology and Practice of Current Nutritional Support
8
status and monitor the efficacy of therapy. Height, weight, skinfold and circumfer-
ence measurements are the most common anthropometric measurements used in
the clinical setting.
Height
Height (stature) can be obtained via recall from the patient of from the medical
archives but should be measured if possible because it is often misreported.
38
Accu-
rate assessment of stature is important because it is compared to weight to deter-
mine degree of adiposity and used in formulas to estimate energy and protein
requirements and to calculate creatinine height index and body mass index. There
are several methods available to measure height in nonambulatory patients.
39, 40
Frame Size
Frame size is useful in assessing body weight because it can affect weight inde-
pendent of stature and percent body fat. Frame size includes body width, muscular-
ity, bone thickness, and truncal length relative to weight.
41
There are several techniques
to estimate frame size including measurements of wrist circumference and elbow
breadth
42-44
although no consensus has been reached regarding the ideal method.
Weight
Weight can be used a gross estimate of muscle and adipose tissue stores. This
relationship is more meaningful when weight is corrected for height and frame size.
Serial measurements are also useful in monitoring the efficacy of nutrition therapy.
However, weight must be interpreted with caution since it may not accurately re-
flect an individuals body composition due to altered fluid status or tumor growth.
Weight is generally interpreted based on comparison with two parameters:
Table 8.2. Medical and nutrition history
Medical History
* Medication profile
* Diagnostic procedures
* Chronic illnesses
* Surgical procedures
* Weight history
Nutrition History
* Nausea/vomiting
* Anorexia
* Early satiety
* Dysgeusia
* Psychosocial history
* Previous dietary modifications and compliance
* Living conditions
* Ability to purchase and prepare food
* Food preferences
* Food allergies
* Use of vitamin/mineral supplements
* Alcohol intake
* Elimination habits
* Activity level
* Cultural/religious observances
129
Biochemical Assessment and Monitoring of Nutritional Status
8
1. The individuals usual or pre-morbid weight; and,
2. Ideal or desirable weight of a healthy population (Table 8.5).
The use of the term ideal or Adesirable in reference to weight is misleading
because there is no consensus regarding what set of values are truly ideal and these
values may change according to the population under study. In clinical practice,
ideal body weight is usually based on a set of established standards such as the Met-
ropolitan Life Insurance Company Height-Weight Tables
47
or calculated using the
following formula:
47
Males: allow 106 pounds for the first five feet of height and six pounds for
every additional inch
Females: allow 100 pounds for the first five feet of height and five pounds for
every additional inch
Ideal body weight should be adjusted for frame size by adding 10% for a large
frame and subtracting 10% for a small frame. Ideal body weight should also be
Table 8.3. Organ function alteration secondary to nutrient deficiencies
Cardiovascular Decreased RBC production
Decreased blood volume
Decreased cardiac output, stroke volume, and contractility
Decreased blood pressure
Decreased heart muscle mass
Decreased venous return
Bradycardia
Postural hypotension
Hemodilution
Anemia
Cutaneous Cheilosis, glossitis, ecchymosis, dermatosis, follicular
hyperkeratosis, petechiae
Gastrointestinal Decreased brush border enzymes
Maldigestion and malabsorption
Decreased mucosal cell integrity
Decreased bile production
Intestinal villus atrophy
Hepatic Decreased liver weight
Decreased visceral protein synthesis
Hepatic insufficiency
Fatty infiltration
Pulmonary Respiratory infections
Decreased functional, vital and maximum breathing capacities
Decreased response to hypoxia
Renal Decreased plasma flow
Reduced glomerular filtration rate
Decreased tubular function
Polyuria
Metabolic acidosis
Summarized from: Keys, A. Biology of Human Starvation and Torum B and Viteri
FE: Protein-calorie malnutrition. In: Shils M and Young V (eds). Modern Nutrition
in Health and Disease. Lea and Fibiger, 1988;746-773, and Baker JP, Detsky AS,
Wesson DE et al, N Engl J Med 1982;306(16):969.
130
The Biology and Practice of Current Nutritional Support
8
adjusted for persons with amputations by subtracting the weight of the missing
body part as a percentage of the total weight.
48
Weight loss over time is another useful tool in assessing nutritional status be-
cause it reflects gross changes in energy and nitrogen balance and has a prognostic
Table 8.4. Physical signs of malnutrition
Body Part Symptoms/Signs Possible Deficiency
or System
Hair Lackluster, thinness, sparseness, Protein, protein-calorie, zinc,
dryness, dyspigmentation, easy copper, biotin
pluckability, texture change
Face Paleness, moon face (swollen), Riboflavin,niacin,pyridoxine,
greasy, scaling around nostrils iron
(nasolabial seborrhea)
Eyes Pale whites of eyes and eyelid lining Iron, vitamins A, C, and B12,
(pale conjuctivae), redness and riboflavin,pyridoxine, folate
fissuring of eyelid corners, dullness
and dryness (corneal or conjuctivae
(Bitots spots)
Mouth Angular redness, lesions or scars at Riboflavin,niacin,pyridoxine,
corners of mouth (stomatitis), iron
swelling and redness of lips and
mouth (cheilosis)
Tongue Smoothness, slickness (filiform Niacin, pyridoxine,riboflavin,
papillary atrophy), beefiness, vitamin B12, folate, iron
redness, pain (glossitis), swollen,
magenta color
Gums Swelling, sponginess, bleeding, Vitamin C
receding
Skin Dryness;scaling;lightening of skin Vitamins A, C, and K, zinc,
color often centrally on the face essential fatty acids, protein.
(diffuse pigmentation); rough,
goose-flesh skin (follicular hyper-
keratosis); small skin hemmorrhages
(petechiae); excessive bruising;
hyperpigmented patches that may
peel off, leaving superficial ulcers of
hypopigmented skin (flaky paint
dermatosis); edema, delayed
wound healing
Nails Spoon-shape (koilonychia), pale, Iron
brittle, ridged
Glands Enlarged thyroid or parotid Protein, iodine
Musculo- Bowlegs, knock knees, enlarged Protein-calorie, vitamins C
skeletal joints, hemorrhages, muscle and and D, calcium
fat wasting
Neurological Mental confusion, irritability, Thiamin, vitamin B12
psychomotor changes, motor
weakness, sensory loss
Nutrition Assessment. In: Manual of Clinical Dietetics, American Dietetic
Association, 1992:3-30.
131
Biochemical Assessment and Monitoring of Nutritional Status
8
value. An unintentional weight loss of 10% or greater within a period of six months
or less is considered severe.
49
Percent weight loss can be determined using the fol-
lowing formula:
Percent weight loss = usual body weightactual body weight x 100
usual body weight
Skinfold and Circumference Measurements
Skinfold and circumference measurements are indirect methods of estimating
body composition. These measurements are commonly used in the clinical setting
because they are simple, noninvasive, inexpensive, and require limited technical skill
from the observer or cooperation from the patient.
Skinfold measurements provide a gross estimate of body fat. The triceps skinfold
(TSF) is the most common site measured in the clinical setting. Circumference
measurements are used in estimating somatic protein stores. Results are compared
to sex and age standards, usually based on data from the National Health and Nutri-
tion Examination Survey. Results between the 15th and 85th percentiles are consid-
ered within the normal range. Patients with measurements below the 15th percentile
are at risk for nutritional depletion and above the 85th percentile are at risk for
obesity.
43
Alternatively, skinfolds can be compared with standards based on average
measurements for age and sex. A measurement 60-90% of the standard is consid-
ered a moderate nutritional deficit while less than 60% is considered severe.
45
An-
thropometry is specific but lacks sensitivity since skinfold and circumference
measurements change more slowly than other nutritional indices, making it diffi-
cult to detect short term changes.
Body Mass Index
Body mass index (BMI) is a method of evaluating body weight corrected for
height based on the assumption that it is correlated to degree of adiposity and corre-
sponding health risks associated with obesity
50, 51
(Table 8.6). The higher the BMI,
the greater the degree of body fat as a percentage of body weight.
53
BMI is not valid
in extremely muscular individuals or in cases in which weight is altered by fluid
status or pregnancy.
Table 8.5. Evaluation of weight
A. Percent usual body weight
Formula: Percent usual body weight = actual body weight x 100
usual body weight
Interpretation:
45
85-90% Mild nutritional depletion
75-84% Moderate nutritional depletion
< 75% Severe nutritional depletion
B. Percent ideal body weight
Formula: Percent ideal body weight = actual body weight x 100
ideal body weight
Interpretation:
45
200% Morbidly obese
130% Obese
110-120% Overweight
80-90% Mild malnutrition
70-79% Moderate malnutrition
69% Severe malnutrition
132
The Biology and Practice of Current Nutritional Support
8
Direct Measurements of Body Composition
Body composition can be measured directly by a variety of methods such as
neutron activation and whole body conductivity but these tests usually require ex-
pensive equipment that is not widely available. These methods can be extremely
accurate compared with more traditional techniques of assessing body composition
in the clinical setting such as anthropometry. However, many of these methods have
been tested only in healthy individuals and their applicability to an ill population
remains in question. Radiographic techniques including ultrasound, computed to-
mography and magnetic resonance imaging have also been use to study body com-
position
54,55
and can provide cross-sectional images which clearly define muscle, fat,
and visceral organs. Since the images are cross-sections, these techniques are more
useful in determining regional fat distribution than overall body composition
Dual energy x-ray absorptiometry (DEXA) is emerging as an important technol-
ogy in the area of nutrition support and body composition analysis. It uses a
low-energy x-ray tube coupled to a filter that results in two energies of about 40 and
70 keV. DEXA provides independent assessments of bone mass, fat mass, and lean
body mass.
57
Biochemical Assessment and Monitoring of Nutritional Status
Creatinine Height Index (CHI)
Somatic protein stores can be estimated based on the amount of creatinine ex-
creted in the urine over a 24-hour period since creatinine is a byproduct of protein
metabolism and is excreted proportional to muscle mass. The actual amount of
creatinine excreted is compared to the amount of creatinine expected for sex and
height (Table 8.7). One method to determine expected creatinine is to use 23 mg/
kg for males and 18 mg/kg for females. There are several limitations of CHI which
prohibit its widespread use as a nutrition assessment tool. CHI requires an accurate
urine collection and can be affected by a number of non-nutritional factors such as
emotional stress, fever, and trauma.
Urinary 3-Methylhistidine
Measuring urinary 3-methylhistidine (3MH) is another biochemical method of
estimating somatic protein stores since 3MH is a nonrecyclable component of muscle
breakdown and excreted proportional to muscle mass. Similar to CHI, a valid test
requires adequate renal function and an accurate urine collection. Urinary 3MH is
not commonly used in clinical practice because it requires an amino acid analyzer
which is not widely available and no universally accepted standards exist for inter-
preting the results.
Table 8.6. Body mass index (BMI)
Formula: BMI = weight (kg)
height
2
(m)
Interpretation:
50,52
Males Females
Lean <18.5 <19.5
Normal 18.5 - 23.5 19.5 - 24.5
Excess weight >23.5 - 29.5 >24.5 - 29.5
Obese >29.5 > 29.5
133
Biochemical Assessment and Monitoring of Nutritional Status
8
Serum Proteins
Nutrition assessment parameters may be classified into somatic and visceral
compartments of the body. The somatic portion comprises primarily skeletal muscle
and adipose tissue; whereas, the visceral portion refers to the enzymatic and struc-
tural components of the remaining organ systems. Serum proteins such as albumin,
transferrin, prealbumin, and retinol binding protein, are commonly used to assess
the visceral protein compartment of the body, and recently other proteins such as
fibronectin and somatomedin-C have been studied in this capacity. Normal values
may vary slightly among laboratories but the results can help assess the degree of
malnutrition (Table 8.8).
Albumin
Serum albumin, produced by the liver, is the most abundant plasma protein,
representing approximately 60% of total body proteins. Albumin is necessary for
maintenance of oncotic pressure and functions as a carrier protein for zinc, magne-
sium, calcium, fatty acids and many drugs. Due to its large body pool and relatively
long half-life of 20 days, albumin is insensitive to acute changes in nutritional status
and is more reflective of chronic rather than acute protein depletion. Serum albu-
min concentration is commonly used as a screening indicator of nutritional status in
hospitalized patients since its measurement is routinely ordered, and it has been
shown to correlate with clinical outcome.
58,59
Caution should be exercised when evaluating albumin levels in stressed hospital-
ized patients because serum concentrations of albumin and other acute phase pro-
teins will decrease after trauma, surgery, or stress, primarily due to a redistribution
of albumin into extravascular compartments and through external losses of albumin
as in ascites, draining wounds, and burns. It is sometimes difficult to determine
whether a reduction in a patients serum albumin reflects protein-calorie malnutri-
tion or the metabolic response to trauma and stress. Plasma albumin levels will
generally not increase in stressed patients until the cause of the stress is removed.
Other non-nutritional causes of hypoalbuminemia include fluid overload, liver dis-
ease, infection, multiple myeloma, acute or chronic inflammation, hypervitamino-
sis A, and rheumatoid arthritis. Increased losses of albumin are seen in nephrotic
syndrome, protein-losing enteropathy, burns, and open wounds.
64
Exogenous albu-
min is sometimes used in critically ill patients to maintain fluid within the vascular
space. This results in a transient increase in the serum albumin level, thereby limit-
ing the use of serum albumin as a nutritional marker.
Transferrin
Transferrin is a beta globulin synthesized in the liver. Transferrin functions to
transport iron and prevents binding of gram negative bacteria with free iron. The
half-life of transferrin ranges from eight to ten days. Serum transferrin is thought to
Table 8.7. Creatinine height index (CHI)
Formula: % CHI = 24 hr urinary creatinine
ideal urinary creatinine
Interpretation:
49
90-100% Normal
60-80% Moderate malnutrition
< 60% Severe malnutrition
134
The Biology and Practice of Current Nutritional Support
8
be a more sensitive indicator of acute changes in nutritional status compared with
albumin due to its shorter half-life and more rapid equilibration with the extravas-
cular compartment. Non-nutritional factors that can affect serum transferrin in-
clude pregnancy, iron deficiency anemia, blood transfusions, acute hepatitis, and
oral contraceptives.
42
Transferrin appears to be as effective as other visceral proteins
with shorter half-lives in assessing nutritional status. Levels of serum transferrin can
be obtained directly by radial immunodiffusion, or indirectly by measurement of
total iron-binding capacity as suggested by the following formula:
serum transferrin level = (0.8 x TIBC) - 43
Thyroxine-Binding Prealbumin
As a plasma transport protein, thyroxine-binding prealbumin (TBPA) carries
thyroxine and assists in the transport of retinol-binding protein (RBP). With a half-life
of 2.5 to 3.0 days, prealbumin responds rapidly to protein deprivation and rises
quickly with resumption of adequate intake. Since TBPA is synthesized in the liver
and degraded in the kidney, it is not valid in patients with severe hepatic or
renal insufficiency.
Retinol-Binding Protein (RBP)
Retinol-binding protein (RBP) is another plasma protein synthesized in the liver
and used as an indicator of visceral protein status. In addition to TBPA, RBP func-
tions to transport retinol, the alcohol form of vitamin A. With a half-life of 12
hours, RBP reflects acute changes in nutritional status. Plasma RBP is very sensitive
to calorie and protein restriction, however, measurement of RBP is reserved for
research purposes because it is difficult to obtain and is not practical for routine
clinical use.
Fibronectin (Fn)
Fibronectin (Fn) is a glycoprotein which functions in cell-to-cell adherence, cell
and tissue differentiation, wound healing, microvascular integrity, and the
opsonization of particulate. Endothelial cells, peritoneal macrophage, hepatocytes,
and fibroblasts are considered sites for synthesis of Fn. The half-life of Fn is 12
hours. Fn is considered a sensitive indicator of nutrition support and a potential
marker of visceral protein status because it increases regardless of the presence or
absence of inflammation. Fibronectin concentrations decline during starvation and
increase in response to refeeding in healthy subjects and hospitalized subjects receiv-
ing nutrition support.
61,62
Somatomedin-C
Somatomedin-C (SM-C), also called insulin-like growth factor-I (IGF-I), is a
peptide growth factor synthesized in the liver. SM-C is postulated to mediate the
growth promoting effects of growth hormone. Normal plasma concentrations of
Table 8.8. Standards for laboratory studies
57
Mildly Moderately Severely
Normal Depleted Depleted Depleted
Albumin (g/dL) 3.5-5.0 3.0-3.4 2.1-2.9 < 2.1
Transferrin (g/dL) 176-315 134-175 117-133 <117
Prealbumin (g/dL) 18-45 10-17 5-9 < 5
135
Biochemical Assessment and Monitoring of Nutritional Status
8
SM-C range from 1.0 to 1.7 U/mL. SM-C levels are low in chronically malnour-
ished as well as acutely starved patients and rapidly rise with refeeding.
63-65
Although
measurement of SM-C offers potential as a useful means of documenting the effi-
cacy of nutrition therapy, laboratory testing of this peptide is not routinely available.
Immunocompetence
Immunocompetence results from the interaction of three complex systems:
1. Cell-mediated immunity;
2. Humoral antibody response; and
3. Nonspecific immune response.
Protein-calorie malnutrition can compromise immune function and is the most
common cause of anergy in hospitalized patients.
66,67
Nutrition intervention has
been reported to reverse immunosuppression.
68,69
Total Lymphocyte Count (TLC)
The blood lymphocyte count has been recognized as one of the most simple and
reliable immunologic measurements of nutritional status. With protein malnutri-
tion, the TLC is reduced.
70
A reduced TLC has been associated with increased mor-
bidity and mortality in hospitalized patients.
28,70,71
Preoperative lymphocytopenia
has been identified as a risk factor in post-operative sepsis
72
and septic episodes in
thermally injured patients.
71
Factors other than malnutrition may cause or contrib-
ute to lymphocytopenia including pneumonia, sepsis, administration of
glucocorticosteroids and chemotherapeutic agents, as well as diseases of the immune
system.
60
TLC is obtained from a routine complete blood count with a differential
using the following formula:
TLC (mm
3
) = percent lymphocytes x white blood cell count
100
Delayed Cutaneous Hypersensitivity Skin Testing
Delayed cutaneous hypersensitivity skin testing (DHST) is an inexpensive, con-
venient, and widely available measure of cell-mediated immunity. Testing involves
an intradermal injection of an antigen to which the individual has been previously
exposed. Antigens generally utilized include: purified protein derivative (PPD), tri-
chophyton, candida albicans, and mumps. A positive reaction is considered an in-
duration of 5 mm or greater at 24 to 72 hours post-injection. Anergy is the absence
of a reaction to an antigen that normally would elicit a response. Immunocompe-
tence is generally classified as anergy, relative anergy, or normal.
Although higher rates of sepsis and mortality have been documented in anergic
patients compared with patients with a normal skin test response,
67,68
the utility of
skin testing in nutrition assessment remains unproven.
73
Many non-nutritional in-
fluences, such as administration technique, age of the patient, drugs, surgery, anes-
thesia, and presence of disease may affect DHST and must be considered when
evaluating an individuals response.
73
Prognostic Indices
Attempts to determine the value of various nutrition assessment parameters in
predicting clinical outcome has led to the development of prognostic indices. The
prognostic nutrition index (PNI) is a linear predictive model that relates the risk of
operative morbidity and mortality to nutrition status (Table 8.9).
23
The risk of compli-
cations and death increase with increasing PNI. The PNI model has been validated in
136
The Biology and Practice of Current Nutritional Support
8
surgical patients; however, clinical usefulness in other patient groups is limited. The
Hospital Prognostic Index (HPI)
74
and Nutritional Risk Index (NRI)
75
are other
prognostic indices.
Assessment of Energy Requirements
Energy requirements are based on the age, sex, body build, activity level, and
disease state of an individual. Basal energy expenditure (BEE) is the energy required
to perform essential body functions such as respiration, cardiac function, and main-
tenance of body temperature. Resting energy expenditure (REE) is defined as the
energy expended at rest in a supine position and included physical and psychologi-
cal stress, and variations in ambient or body temperature. Measured REE is approxi-
mately 10% higher than BEE. Total energy expenditure (TEE) is comprised of REE,
diet-induced thermogenesis, shivering and non shivering thermogenesis, and physi-
cal activity. REE represents the major portion (i.e., 75-100%) of TEE in hospital-
ized patients. Energy needs may be assessed by direct and indirect calorimetry or
through use of predictive equations and nomograms.
Calorimetry
Direct calorimetry is the process of measuring heat production as the tempera-
ture change of a medium (e.g., water) and is reserved for research purposes because
it is expensive and time-consuming. Indirect calorimetry is the determination of
energy requirements by measuring oxygen consumption and carbon dioxide pro-
duction during respiratory gas exchange. Indirect calorimetry provides the clinician
with a measurement of energy expenditure and an assessment of substrate utiliza-
tion in the respiratory quotient (RQ). In hospitalized patients, REE is usually de-
rived from a 20 minute gas exchange measurement. Measurement of REE should be
done more than two hours post prandially in a thermoneutral environment. The
thermic effect of continuous enteral or parenteral nutrition is stable but should be
considered in interpreting the test. Measurements of O
2
consumption and CO
2
production are translated into REE by the Weir formula.
76
To account for other
activities during the day such as sitting in a chair, dressing changes, physical therapy,
and diurnal variations, REE is multiplied by 1.1 to 1.3 to determine TEE.
77
The RQ is the ratio of carbon dioxide produced to oxygen consumed (VCO
2
/
VO
2
). The physiologic range for RQ is 0.67 to 1.30 (Table 8.10).
78
Possible causes
for an RQ less than 0.71 include oxidation of ethanol or ketone bodies, lipolysis,
underfeeding, and hypoventilation. Reasons for an RQ greater than 1.0 include
hyperventilation, excess CO
2
production, hydrogen ion buffering by bicarbonate
generating carbon dioxide, lipogenesis, and overfeeding. If the RQ is equal to or
greater than 1.0, the total calories and/or carbohydrate should be decreased. If the
RQ is less than 0.8, total calories should be increased.
Predictive Equations
Over 190 equations to predict energy expenditure exist based on some combina-
tion of height, weight, age, and sex.
79
The Harris-Benedict equation
80
is frequently
used in clinical practice to estimate basal energy requirements (Table 8.11). The
Harris-Benedict is more reflective of REE than BEE and is usually multiplied by
activity and injury factors to determine TEE. The advantage of predictive equations
is that they are quick and easy to use without the need of expensive equipment.
However, they offer an estimate rather than a measurement of energy needs and can
be affected by the weight used in the calculation. Current or dry body weight should
137
Biochemical Assessment and Monitoring of Nutritional Status
8
be used unless the patient is considered obese (i.e., BMI 30 to 50). In obese patients,
an adjusted body weight (AdjBW) should be used in calculating energy expenditure
using the following formula:
82
AdjBW = [ (actual body weightideal body weight) 0.5] + ideal body weight
REE can also be estimated in patients with a pulmonary artery catheter by using
the Fick equation and the known caloric value of oxygen.
83
This requires the mea-
surement of cardiac output and arterial and mixed venous oxygen (Table 8.12). The
Fick equation has been correlated with indirect calorimetry
83
but requires an accu-
rate measurement of cardiac output and oxygen saturation and only provides a snap-
shot of energy expenditure at the moment the blood samples were drawn.
Assessment of Protein Requirements
Predictive Equations
There are several methods to estimate protein requirements. The requirement
for protein can be viewed as it relates to calorie needs. The nonprotein calorie to
nitrogen ratio (NPC:N) refers to the amount of nonprotein calories per gram of
nitrogen. In a typical oral diet, the NPC:N is 300:1. The greater the stress, the
higher the requirement for protein. Patients receiving parenteral nutrition may re-
quire 80 to 150 NPC/g N for tissue synthesis.
78
Protein may also be administered based on body weight and stress level (Table
8.13).
42
Adjustments in protein load should be made according to the patients clinical
response, and through monitoring laboratory and nitrogen balance techniques.
Nitrogen Balance
Nitrogen balance studies are utilized to assess protein requirements, stress level,
and efficacy of nutrition support therapy. Nitrogen lost in the urine measured from
Table 8.9. Prognostic nutritional index (PNI)
Formula: PNI % = 158 - 16.6 (ALB) - 0.78 (TSF) - 0.20 (TFN) - 5.8 (DH)
where ALB = serum albumin (g/dL)
TSF = triceps skinfold (mm)
TFN = serum transferrin (mg/dL)
DH = cutaneous delayed hypersensitivity reactivity to any of
the four recall antigens graded as 0 (nonreactive), 1
(< 5 mm induration), or 2 (> 5 mm induration).
Interpretation > 50 % = high risk
40 - 49 % = intermediate risk
<40% = low risk
Table 8.10. Respiratory quotient (RQ)
Substrate RQ
Alcohol 0.67
Fat 0.71
Protein 0.82
Mixed 0.85
Carbohydrate 1.00
138
The Biology and Practice of Current Nutritional Support
8
a 24 hour urine urea nitrogen (UUN) is added to an estimate of nitrogen lost from
the skin, hair, nails, and GI tract and subtracted from nitrogen intake using the
following formula:
Nitrogen balance = Protein intake (g) (UUN + 2 to 4)
6.25
Additional nitrogen losses from draining wounds or burns must also be mea-
sured or estimated.
The goal of nitrogen balance is to be positive 2 to 4 g/d which is indicative of an
anabolic state and suggests accumulation of lean body mass (LBM). However, this
may be difficult to obtain in the critically ill patient. In these patients it may be
more realistic to strive for neutral balance or equilibrium which implies adequate
energy and protein support for preservation of LBM. A negative nitrogen balance
suggests a state of catabolism with progressive loss of LBM. Losses of 5 to 10 g/d
have been suggestive of mild catabolism, 10 to 15 g/d of moderate catabolism, and
more than 15 g/d of severe catabolism.
84
Determination of a valid nitrogen balance
is dependent primarily on an accurate urine collection and stable renal function.
Urea Kinetic Modeling
Urea kinetics is a pharmacokinetic model initially developed for use in hemodi-
alysis patients to assess protein balance and is based on the premise that the patients
protein catabolic rate is directly proportional to the rate of urea nitrogen genera-
tion.
85
Unlike the traditional nitrogen balance study in which urea measurements
become less accurate under conditions of renal insufficiency and changes in urea
pool, urea kinetic modeling accounts for the changing urea pool and allows for
changes in BUN and extrarenal losses or urea.
Urinary Nitrogen Appearance
Urinary nitrogen appearance (UNA) attempts to quantify changes in BUN and
is useful in clinical situations in which increased BUN levels and variations in weight
secondary to renal function exist.
86
This formula is applicable to measurements done
over one to three days and in dialysis patients during interdialytic interval. In stable
patients nitrogen balance may be estimated from the difference between nitrogen
Table 8.11. Estimating energy requirements
Basal Energy Expenditure (BEE)
Harris-Benedict Equation:
80
Men BEE (kcals/d) = 66.47 + (13.75 x W) + (5.0 x H) - (6.76 x A)
Women BEE (kcals/d) = 655.10 + (9.56 x W) + (1.75 x H) - (4.68 x A)
where W = weight in kg
H = height in cm
A = age in years
Activity and Injury Factors
81
Activity Factor: Confined to bed 1.2
Out of bed 1.3
Injury Factor: Minor surgery 1.2
Skeletal trauma 1.3
Major sepsis 1.6
Severe burns 2.1
139
Biochemical Assessment and Monitoring of Nutritional Status
8
intake and UNA. UNA is not an accurate reflection of total nitrogen output in
patients on peritoneal dialysis due to protein lost in the dialysate.
Determining an Endpoint of Nutrition Therapy
The purpose of the nutrition assessment is two-fold:
1. To determine the degree and type of malnutrition, and
2. To document the efficacy of therapy.
In resolving nutritional deficiencies, it is important to ensure that nutrients are
delivered safely and accurately in the amounts prescribed to meet the patients re-
quirements. This type of monitoring becomes integrated into the comprehensive
nutrition assessment. The amount of time required to improve nutritional status
will depend on the degree and type of malnutrition, surgical risk, medical treat-
ments and overall clinical course.
The follow-up assessment should occur at regular intervals (Fig. 8.3). The fre-
quency will depend on the depth of the assessment. For example, a daily assessment
of fluid and electrolyte status may be necessary for the patient receiving parenteral
nutrition; whereas an assessment of visceral protein status or lean muscle mass may
occur less frequently.
Monitoring the results of nutrition support requires the use of many nutrition
assessment parameters. The usefulness of each parameter will depend on the length
of time the patient is on nutrition support, the disease process and prior nutritional
status. Body weight is measured to monitor fluid status and effectiveness of nutri-
tion therapy. Although many patients gain weight during nutrition therapy, this
weight gain generally represents an increase in body water and adipose tissue rather
than lean body mass. Weight gain greater than a half pound per day probably repre-
sents fluid accumulation and not tissue synthesis. The composition of weight change
can be estimated if a nitrogen balance study is available using the following formula:
FFM = ( + g N balance x 6.25 g dry protein/g nitrogen) x 4.6 g FFM/g dry
protein
FM = ( + g body weight change) - ( + g FFM)
where FFM = fat free mass
FM = fat mass
+@ = gain or loss of that compartment
Table 8.12. Fick equation
CO = Hgb (SaO
2
- SvO
2
) x 95.18
where CO = cardiac output (L/min)
Hgb = hemoglobin
SaO
2
= arterial oxygen saturation
SvO
2
= mixed venous oxygen saturation
Table 8.13. Estimating protein requirements
No stress 0.7 to 0.8 g/kg/d
Mild stress 0.8 to 1.0 g/kg/d
Moderate stress 1.0 to 1.5 g/kg/d
Severe stress 1.5 to 2.0 g/kg/d
140
The Biology and Practice of Current Nutritional Support
8
This is an estimate and will be influenced by fluid balance and accuracy of the
nitrogen balance study. Anthropometric measurements, although very specific, lack
the sensitivity to assess short-term changes in adipose tissue or lean body mass and
are more useful for monitoring long-term patients.
Energy and proteins requirements need to be reevaluated periodically to ensure
the patient is receiving adequate nutrition. The patients energy expenditure may
change during the course of nutrition therapy as clinical status changes. Protein
requirements can be assessed by performing a nitrogen balance study. For those
patients who do not have normal renal function, urea kinetics can be employed.
Changes in visceral proteins depend on their half-life, and total body pool. Se-
rum albumin, due to its relatively long half-life, may not return to normal levels
until well after nutrition support has been discontinued. Transferrin and
thyroxine-binding prealbumin are considered more sensitive nutritional markers
since each has a shorter half-life and smaller body pool than albumin. Total
Fig. 8.1. Reassessment of Nutritional Status. Adapted from Matarese LE. Reassessment
and determining an endpoint of therapy. Adapted from Dynamics of Nutrition Support.
Appleton-Century-Crofts, 1986.
141
Biochemical Assessment and Monitoring of Nutritional Status
8
lymphocyte count and delayed hypersensitivity skin testing has been corre-
lated with morbidity and mortality but both can be affected by a number of
non-nutritional factors.
Mineral and electrolyte imbalances can occur rapidly, especially in critical ill
patients receiving nonvolitional feeding. Clinical signs of vitamin and mineral defi-
ciencies as well as biochemical aberrations will reverse with therapeutic doses of the
limiting vitamin or mineral. However, the patients stores may take weeks to months
to replenish.
It is important to note that many patients will not return to normal or even
premorbid nutritional status until well after discharge. Because nutrition assessment
parameters are so nonspecific, one can not look for a single laboratory value or
parameter to determine the endpoint of therapy. While all of the parameters must
be evaluated within the context of the patients clinical condition, it is probably
more useful to look for trends in improving nutritional status.
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1986:233.
CHAPTER 1
CHAPTER 9
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Optimizing Drug Therapy
and Enteral Nutrition: Detecting
Drug-Nutrient Interactions
Marcia L. Brackbill, Gretchen M. Brophy
Introduction
Recent clinical studies in surgical, trauma, and burn patients have demonstrated
the benefits of early initiation of enteral feedings over delayed enteral nutrition or
total parenteral nutrition (TPN).
1-7
Benefits include preservation of gut mucosa,
reduction of bacterial translocation, enhancement of immune function, improved
control of hypercatabolic state, reduction of septic complications, and improved
patient outcomes.
1-7
Surgical and endoscopic advancements allow health care prac-
titioners to place tubes for feeding access earlier in the hospital stay, with subsequent
initiation of enteral nutrition.
Although advantageous, enteral nutrition may be problematic. Critically ill pa-
tients receive numerous drugs that may directly effect the delivery of enteral formu-
las. Conversely, enteral formulas may alter the absorption of a drug, resulting in
clinically significant drug-nutrient interactions. Information regarding drug-enteral
nutrition interactions is sparse. Most of the literature consists of small pharmacoki-
netic studies and anecdotal case reports. A basic understanding of drug-nutrient
interactions and proper administration techniques will optimize drug therapy and
improve delivery of enteral feeds. This chapter will address clinically significant
drug-nutrient interactions in patients receiving enteral nutrition and provide sug-
gestions for avoiding these interactions. Specific guidelines for administering medi-
cations via feeding tubes are also provided.
Avoiding Tube Occlusions
Physical Incompatibilities
Physical incompatibilities between medications and enteral formulas may mani-
fest as a change in formula flow rate, texture, or viscosity; or cause separation or
precipitation of the formulation. One study evaluated the physical compatibility of
52 medications with Ensure
, Ensure Plus
, and Osmolite
.
8
Most suspensions,
elixirs, and emulsions were physically compatible with the enteral formulas. Medi-
cations known to be incompatible with enteral formulas are listed in Table 9.1.
Acidic syrups or those buffered to a pH below 4 were responsible for most physical
incompatibilities, which included gel formation and granulation of the enteral for-
mula. These incompatibilities resulted in consistent clogging of the feeding tube
146
The Biology and Practice of Current Nutritional Support
9
and were not prevented by diluting the syrup with water or enteral formula. The use
of alternative dosage forms (i.e., tablets) is suggested in order to avoid problem
syrups.
To avoid physical incompatibilities, mixing of any medications with enteral
formulas is discouraged.
The investigators of one study evaluated the physical effects of a fiber-containing
formula (Enrich
)
Brompheniramine/phenylpropanolamine elixir (Dimetapp
)
Calcium glubionate syrup (Neo-Calglucon
)
Chlorpromazine concentrate (Thorazine
)
Ferrous sulfate elixir (Feosol
)
Guaifenesin elixir (Robitussin
)
Lithium citrate syrup (Cibalith-S
)
Medium chain triglyceride oil (MCT Oil
)
Methenamine suspension (Mandelamine Forte
)
Potassium chloride liquid 10% and 20%
Potassium chloride syrup (Klorvess
)
Pseudoephedrine syrup (Sudafed
)
Sodium bisphophate (Fleets Phospho-soda
)
Thioridazine oral solution (Mellarill
)
147
Optimizing Drug Therapy and Enteral Nutrition
9
occluding the tube. If the feeding tube frequently occludes and the patient is receiv-
ing an intact protein formula, consider moving the distal end of the feeding tube
into the small intestine.
11,12
Acid suppression therapy may be initiated to increase
the pH of the stomach and decrease the likelihood of further precipitation.
Non-Compatible Drug Formulations
Clogged feeding tubes are a major complication of physical incompatibilities. It
is common practice to crush tablets into fine particles and dissolve them with water
to ease administration through feeding tubes to avoid occlusion. Several solid dos-
age forms should never be crushed and administered via feeding tubes, these include
sublingual tablets, buccal preparations, encapsulated beads, extended-release and
controlled-release tablets, and wax matrix dosage forms. Physical alteration of any
medication before administration via a nasogastric tube will alter the drugs dissolu-
tion properties, ultimately affecting the bioavailability of the drug. Crushing
extended-release or controlled-release tablets for administration into an enteral tube
destroys the specialized matrix or enteric coating which convey the controlled-release
properties to the tablet or capsule. These medications are typically very difficult to
crush and result in rough, heterogeneous particles which may clog the feeding
tube. Another potential complication of administering extended-release or
controlled-release medications through a feeding tube is the possibility of toxic peak
concentrations and subtherapeutic trough concentrations later in the dosing inter-
val. Substitution of immediate-release products for controlled-release products will
prevent erratic serum concentrations and decrease the possibility of tube obstruc-
tion. Medications which should not be crushed are included in Table 9.2. A com-
prehensive list is published periodically in Hospital Pharmacy.
13
Methods of Restoring Tube Patency
Administration of an enzymatic solution into a clogged tube is an effective method
to restore tube patency.
In one study, a pancreatic enzyme solution was successful in
restoring tube patency in 96% of cases where the formula was believed to be the
cause of the occlusion.
14
The authors first injected 5 ml of warm water into the
feeding tube and capped it for 5 minutes. If the tube remained occluded, one tablet
of pancrelipase (Viokase
(EC granules)
Lithium (CR, SR)
Methylphenidate (SR)
Metoprolol (XL)
Morphine (SR)
Nifedipine (XL)
Nitroglycerin (SL)
Omeprazole*
(EC granules)
Pancrelipase (EC)
Pentoxifylline (CR)
Potassium Chloride (XL)
Procainamide (SR)
Propranolol (LA)
Quinidine (Extentabs) Theophylline (ER)
Verapamil (SR)
EC = enteric coated SR = sustained-release XL = extended-release LA = long-acting
CR = controlled-release SL = sublingual
* Capsules may be opened and the contents may be administered via a nasogastric
tube without crushing
formula.
28
Area
under the concentration-time curves, maximum serum concentrations and absorp-
tion were significantly reduced by Ensure
formula reduced the absorption of ciprofloxacin significantly more than the ofloxacin.
Subsequent studies evaluating the ciprofloxacin-enteral formula interaction have
not confirmed these findings. A study evaluated the bioavailability of ciprofloxacin
administered three ways: orally, through a nasogastric tube without enteral feeds,
and through a nasogastric tube while receiving enteral feeds.
29
No statistically sig-
nificant difference between treatment groups were found in terms of area under the
curve, maximum concentration in the serum, and time to peak concentration. An-
other study evaluated several pharmacokinetic properties in critically ill patients
receiving 750 mg of ciprofloxacin every 12 hours via nasogastric tube with enteral
feedings.
30
Although the absorption of ciprofloxacin was decreased, the serum con-
centrations of ciprofloxacin were well above the minimum inhibitory concentra-
tions for many pathogenic organisms.
Published studies suggest that the bioavailability of ciprofloxacin is variable in
patients receiving enteral nutrition. It is recommended to give ciprofloxacin 1 hour
before and 2 hours after bolus nasogastric feeds and separate the dose from any
cation administration. If a patient is on continuous feedings and not responding to
ciprofloxacin therapy, especially when treating a ciprofloxacin sensitive organism, it
may be reasonable to hold tube feeds for 1 hour before and after ciprofloxacin ad-
ministration or switch to an intravenous formulation. The enteral tube feeding rate
should be adjusted to meet the patients nutritional goals if tube feeds are held for
medication administration.
Pharmacodynamic Interactions
A pharmacodynamic interaction is one in which the effects of a drug are altered,
in this scenario because of enteral nutrition. There are many case reports of warfarin
151
Optimizing Drug Therapy and Enteral Nutrition
9
resistance in patients who receive concomitant warfarin and enteral feedings.
31-34
Researchers have shown that patients receiving enteral feedings require higher doses
of warfarin to achieve therapeutic effects and a reduction in dose is necessary when
feeds are discontinued.
32
Investigators originally postulated that warfarin resistance
was due to inhibition of warfarin by excessive amounts of vitamin K in enteral
formulas. Manufacturers have reformulated most enteral formulas to contain only
small amounts of vitamin K; however, warfarin resistance remains a problem. Newer
evidence now suggests that warfarin is bound to several components of enteral for-
mulas, such as soy protein or proteinaceous caseinate salts.
35
Warfarin malabsorp-
tion has also been proposed as a possible mechanism of warfarin resistance.
36
When approaching this problem, clinicians should first consider the quantity of
vitamin K present in the enteral formula being administered. The vitamin K con-
tent/1000 ml of selected commercially available enteral formulas and are listed in
Table 9.3. Vitamin K can antagonize the pharmacologic effect of warfarin in doses
as low as 140 micrograms/day.
31,34
Therefore, vitamin K intake < 140 micrograms/
day will optimize effect in a warfarin resistant patient. Minimizing protein in the
enteral formula may also be prudent as warfarin is highly protein bound. Monitor-
ing INR is essential when titrating warfarin or changing the enteral feeding formu-
lation or regimen.
Influence of Tube Placement on Drug Efficacy
A small number of medications require a specific pH to be absorbed and an
understanding of these drug characteristics is crucial to prevent drug therapy failure.
Ketoconazole (Nizoral
, are suitable aqueous fluids and have been used successfully to improve
Ketoconazole absorption.
37,38
The absorption of itraconazole, a triazole antifungal,
is dependent upon the dosage form being used. Itraconazole capsule absorption
requires an acidic pH. The capsules should be opened and dissolved and given into
the stomach with enteral feedings to improve solubility and absorption. Clinically
significant differences in bioavailability occur if not given with food.
39,40
Itraconazole
oral solution absorption is not pH dependent, can be given via nasogastric or jejun-
ostomy tube and should be separated from enteral feedings. Fasting conditions are
not required, but such conditions will increase bioavailability.
40
Sucralfate is an oral anti-ulcer agent commonly used to prevent upper gastrointes-
tinal bleeding in ventilated patients in the ICU setting. It works by binding to pro-
teins in the stomach, forming a protective barrier over ulcers. Sucralfate can bind to
the protein components of enteral formulas and form insoluble complexes. It has
been implicated in causing bezoar formation in patients receiving enteral feeds
(Isocal
).
41,42
Not all patients receiving sucralfate appear to be at risk.
42,43
Sucralfate
should be administered directly into the stomach via a nasogastric tube or gastros-
tomy tube at least one hour before an enteral feeding, to facilitate drug binding to
the stomach. Sucralfate should not be administered into the small intestine as it will
fail to provide any clinical benefit.
152
The Biology and Practice of Current Nutritional Support
9
Lansoprazole and omeprazole are proton pump inhibitors used for gastrointesti-
nal bleeding in ventilated patients and have special administration issues in patients
with feeding tubes. These drugs are available as capsules which contain acid labile
enteric-coated granules designed to dissolve in the alkaline environment of the small
intestine. When the enteric-coated granules are placed in water, the granules be-
come soft, sticky, and clump together; greatly increasing the possibility of tube ob-
struction. To avoid tube obstruction with lansoprazole, mix the uncrushed
enteric-coated granules with 40 ml of apple juice and administer into the nasogastric
tube.
44
Flush the tube with an additional 40 ml of apple juice to make sure the
granules enter the stomach. The apple juice is acidic and will not affect the enteric
coated granules; therefore, drug bioavailability is not compromised. Omeprazole
pellets have been successfully administered through a jejunostomy tube after the
omeprazole pellets were crushed and dissolved in a sodium bicarbonate solution (8
mmol/50 ml).
45
Another study evaluated nasogastric administration of omeprazole.
46
In this study, omeprazole pellets were dissolved in a syringe with 20 ml of 8.4%
sodium bicarbonate injection. The nasogastric tube was flushed with 20 ml of wa-
ter, the dose was administered, and the nasogastric tube was clamped for an hour.
Data demonstrate that both omeprazole and lansoprazole formulations can be ad-
ministered via the nasogastric and jejunostomy routes.
Optimizing Tolerance to Enteral Nutrition and Drug Therapy
Gastric Residuals
Increased gastric residuals are a possible manifestation of formula intolerance.
Under these circumstances, prokinetic agents, such as metoclopramide (Reglan
)
and erythromycin (E-mycin
and Groshong
catheters (Bard Access Systems, Inc., Salt Lake City, Utah) are the
most common in home patients, but a percutaneously placed subclavian catheter
(Hohn
catheter, Bard Access Systems, Inc., Salt Lake City, Utah) has been found
useful for short term patients requiring less than six weeks of parenteral therapy.
279
Pharmacologic Aspects of Short Bowel Syndrome
18
The use of heparin placed in the TPN solution or oral administration of low
dose warfarin can help decrease the incidence of venous thrombosis.
25-27
This be-
comes increasingly important as thrombosis usually means that the site will not be
usable again for intravenous access, and there are a limited number of large vessels
that can be used for this type of hyperosmolar infusion.
21
Patient Variation
Drug Absorption
The oral absorption of medications is affected by several factors, including whether
or not the gastrointestinal (GI) tract is intact or has been resected. The extent of
drug absorption is determined by the physiological capabilities of the remaining GI
tract, formulation, physicochemical properties, pharmacodynamics and pharmaco-
kinetics of the drug. Changes in any of these parameters will markedly determine
the amount of drug available to produce its pharmacodynamic effect. The overall
impact of changes in absorption will be the extent to which therapeutic effi-
cacy is achieved.
An increase in the variability of absorption is observed when a portion or all of
the GI tract is removed. A decrease in intestinal length will result in a decrease in
absorptive surface area. If all other factors affecting drug absorption were to remain
constant, the extent of absorption would be limited to the length of residual bowel.
However, not all factors affecting drug absorption remain constant when intestinal
resection occurs. Physiological changes in the mucosal integrity and intestinal mo-
tility occur, resulting in an increase or decrease in absorption, depending on how the
GI tract adapts to this anatomical change. Thus, GI physiology is directly affected
by GI anatomy, but the effects on drug absorption may not be the same.
The extent of a drugs absorption as determined by its formulation, physico-
chemical properties and pharmacokinetics, is evaluated with the assumption that
GI anatomy and physiology are normal. Resection of the GI tract will alter any or all
of these parameters, resulting in a single or multifactorial effect on absorption. Drugs
are formulated in a variety of ways to be released in various areas of the GI tract to
take advantage of the physicochemical requirements to enhance absorption. Such
modes of release include tablets, capsules, suspensions, elixirs, enteric coated tablets,
film coated tablets and sustained release tablets and capsules. However, a sustained-
release capsule that is designed to release medication throughout the entire small
intestine may not be therapeutically useful if there is not enough small bowel surface
area for absorption to effectively take place.
The physicochemical requirements that enhance a drugs absorption may in-
clude, but are not limited to,
1. solubility;
2. an acidic or alkaline environment;
3. the presence of bile acids;
4. the presence of an ileum; or,
5. the presence of site-specific receptors.
Removal of the section of bowel responsible for meeting these requirements could
result in minimal drug absorption. Physicochemical properties that enhance the
absorption of certain drugs are listed in Table 18.2.
Pharmacokinetic parameters that influence drug absorption include the site, ex-
tent, and rate of absorption. At the site of absorption, drugs bind to or localize in the
280
The Biology and Practice of Current Nutritional Support
18
tissues. Depending on the physicochemical requirements of the drug, biotransfor-
mation may take place to allow for absorption. The molecule may become ionized
or an enzymatic process may take place to affect absorption. Circulation to the
absorption site will determine the extent and rate of absorption into the blood-
stream. Once absorbed, the drug will distribute to various body compartments. It
may or may not be metabolized before being eliminated.
Administration of some drugs via a jejunal tube, for example, markedly affects
their absorption, distribution, metabolism and elimination. Normally a drug dis-
solves in the stomach and is absorbed in the duodenum. Intrajejunal administration
of propranolol oral solution, for example, results in significantly higher serum con-
centrations of the drug.
28
The absorption of propranolol occurs in the duodenum
and then passes directly through the blood stream to the liver. A significant first-pass
metabolism occurs and markedly reduces the serum concentrations. With intrajejunal
administration the portal system (and first-pass metabolism) is bypassed, the drug is
absorbed, and higher serum concentrations result. This example demonstrates the
importance of the site, extent and rate of absorption on the pharmacokinetics
of propranolol.
Two other clinically significant factors that influence drug absorption are food
and other drugs.
29
The presence of food in the GI tract may increase or decrease the
extent and/or rate of absorption. A dose of theophylline oral syrup, for example,
may be completely absorbed, but the rate of absorption is slower, resulting in de-
creased peak serum concentrations. A dose of levofloxacin, administered with a dose
of a calcium-containing antacid, will be poorly absorbed (i.e., decreased extent of
absorption) because of calcium chelation with the drug.
30
A second type of drug-drug interaction that affects the relative absorption of
drugs involves the effects one drug may have on metabolism or elimination of an-
other. Once the drug is absorbed, metabolism may be increased or decreased result-
ing in serum concentrations that are lower or higher, respectively, than expected.
Phenobarbital, for example, may induce the metabolism of phenytoin, decreasing
serum concentrations of the latter. Cimetidine, for example, may inhibit the me-
tabolism of theophylline, thereby increasing the theophyllines serum concentration.
Table 18.2. Select drugs and the physicochemical properties that enhance
their absorption
Physicochemical Property Select Drugs
Acidic environment Ketoconazole
penicillin
Alkaline environment nitrofurantoin
procainamide
Bile acids cyclosporine
ergocalciferol
Drug-drug interactions ferrous sulfate
levofloxacin
Food-drug interactions penicillin
sucralfate
Ileal absorption cyanocobalamin
Receptor site dynamics diazepam
propranolol
281
Pharmacologic Aspects of Short Bowel Syndrome
18
When the small bowel is resected, the most significant impact on absorption
occurs because of the reduction or removal of the site of absorption. Consequently
the extent of absorption will change; the rate of absorption may be affected if the
necessary enzymatic transformation does not occur. The extent of this effect will be
directly proportional to the amount of bowel removed. Unfortunately, for the pa-
tient with SBS, drug absorption is almost always reduced, requiring the use of alter-
nate therapy or higher oral doses. Furthermore, the food-drug and drug-drug
interactions described above must be accounted for when administering medica-
tions to SBS patients via the oral route. Alternative routes may have to be considered.
Limited research has been conducted to quantify the pharmacokinetic effects of
bowel resection on drug absorption. The administration of oral doses of nortrip-
tyline, amitriptyline, procainamide, warfarin, digoxin, cyclosporine and tacrolimus
to patients with SBS has been reported.
31-43
In these case reports, various lengths and
segments of bowel had been resected. Serum concentrations were obtained to modify
dosing necessary to achieve a therapeutic concentration, as in the case of digoxin, or
desired therapeutic effect, as in the case of warfarin. The process of using serum
concentration determinations to manage therapy is the most useful information
presented. The information in these case reports is not generalizable due to their
limited utility.
Broyles et al discussed oral administration of nortriptyline to one SBS patient
with 5-6 feet of small intestine and 40-50 cm of colon remaining.
31
Normal serum
concentrations (50-140 ng/ml) were achieved with a nortriptyline dose of 25 mg
every morning and 50 mg every night. Approximately two months after initiating
therapy, the serum concentration was 90 ng/ml.
Robbins and Reiss administered amitriptyline buccally to a SBS patient with
approximately 18 inches of small bowel remaining.
32
Dosage titration to 75 mg of
amitriptyline lead to a therapeutic combined amitriptyline and nortriptyline con-
centration (100-250 ng/ml) for 12 consecutive months. Subjective improvement in
the patients depressive symptoms were also noted. In these two reports, following
serum nortriptyline or combined amitriptyline/nortriptyline concentrations
was an effective way to determine the extent of drug absorption and subse-
quent clinical response.
Felser and Hui evaluated oral administration of procainamide to one SBS pa-
tient with 6 cm of jejunum and 20 cm of terminal ileum remaining.
33
Serum trough
concentrations greater than 4 g/ml were achieved after 24 hours with a dose of 500
mg every four hours (therapeutic range of 4-12 g/ml) and suppression of the patients
ventricular arrhythmia was observed when in this range. Careful monitoring of se-
rum procainamide concentrations was instrumental in determining the extent of
absorption in this patient.
Four separate case reports describe experience with oral warfarin administration
to patients with SBS.
34,35,37,39
Mitchell et al describe the oral administration of war-
farin to one SBS patient with 100 cm of small bowel remaining.
39
The normal length
of the small intestine was approximated at 350-600 cm. Warfarin therapy was initi-
ated at 10 mg per day and adjusted to maintain therapeutic prothrombin time (PT)
values. Serum warfarin concentrations were not obtained. Absorption was assumed
based on the PT values observed, but was not quantified.
Lehman et al described oral administration of warfarin to one SBS patient with
12-15 cm of jejunum remaining.
34
After administering a loading dose of 20 mg, the
warfarin dose was titrated downward to maintain a PT between 1.5-2.0 times control.
282
The Biology and Practice of Current Nutritional Support
18
By day 59 of therapy, a PT of 1.6 times control was maintained using a dose of 2.5
mg per day. Jejunostomy drainage collections were made after a 10 mg and 2.5 mg
dosage, at different times during therapy, to determine the amount of warfarin ab-
sorbed. The estimated percent of absorption was 92.8 and 96.1, respectively. This
compares to values obtained in healthy volunteers, having percentage absorption
greater than 90%. This is to be expected, since warfarin is nonpolar at pH 5.1 or less
and would be expected to be almost completely absorbed in the duodenum. In this
case, warfarin concentrations in the jejunostomy drainage, instead of serum concen-
trations, were used to determine absorption.
Kearns and OReilly described oral administration of warfarin to a SBS patient
with 30 cm of jejunum remaining.
37
After five weeks of therapy, a daily dose of 5 mg
was necessary to maintain a desired PT between 16-20 seconds. Serum and fecal
concentrations were obtained during the fasting and fed states to determine the
extent of absorption. The serum values observed were comparable or better than
those observed in normal patients. Neither warfarin nor its metabolites were re-
trieved from the stool samples. Hence, serum concentrations proved useful in quan-
tifying drug absorption.
Brophy et al described a warfarin-resistant SBS patient who needed anticoagula-
tion for recurring deep venous thrombosis.
35
The patient had a total duodenectomy,
gastrojejunostomy (unknown length of jejunem) with a completely retained ileum.
Anticoagulation was initiated with warfarin 5 mg daily and titrated to a dosage of
20 mg daily over a period of 14 days. No change in the International Normalized
Ratio was demonstrated with a peak value of 1.2. Warfarin serum concentrations
were not evaluated. This report emphasizes the pharmacokinetic properties of war-
farin. Warfarin is absorbed primarily within the proximal small bowel, specifically
the duodenum. All of the previous cases included patients with intact duodenum
with ultimately successful anticoagulation. These reports demonstrate that SBS pa-
tients may be successfully anticoagulated if the proximal small bowel, including the
duodenum, is retained.
Oral administration of digoxin has been reported in three separate patients with
SBS.
36,38,40
Beerman et al described a patient from which the distal jejunum and
ileum, approximately 4 meters, and ascending colon had been removed.
40
Radiola-
beled digoxin, 0.25 mg, was administered, followed by GI aspiration after three
hours. Aspirates were assayed to determine the absorption of radioactivity. Seventy-
two percent of the drug was retrieved from the duodenum, suggesting only 28%
absorption. Since only a single dose of digoxin was administered, the results of this
report are of limited clinical utility.
Krausz et al described a patient with the duodenum and only 15 cm of jejunum
remaining.
38
After a two day digitalization period, 0.25 mg daily was administered
as indicated. Serum digoxin concentrations were maintained within the therapeutic
range of 0.8-2.2 ng/ml. Renal clearance of the drug was normal. Therapeutic effi-
cacy, as evidenced by a decrease in heart rate, was achieved with no reported side
effects. Therapeutic serum concentrations suggest that the extent of absorp-
tion was adequate.
Vetticaden et al described a patient with the duodenum and 12-15 cm of je-
junum remaining.
36
Digoxin elixir, 0.5 mg, was administered for nine days, after
steady-state was achieved using 0.25 mg of digoxin intravenously. Serum and jejun-
ostomy drainage concentrations were assayed. The trough serum concentration was
0.77 ng/ml and the cumulative amount of digoxin in the drainage, after 24 hours,
283
Pharmacologic Aspects of Short Bowel Syndrome
18
was 0.302 mg. This suggests that approximately 60% of the 0.5 mg dose was ab-
sorbed. Since the trough serum concentration was less than the therapeutic concen-
tration of 0.8 ng/ml, a higher dose of digoxin may be necessary to achieve a therapeutic
serum concentration.
The oral administration of cyclosporine and tacrolimus in SBS patients has been
reported.
41-43
Roberts et al described two patients in whom therapeutic serum con-
centrations of cyclosporine could not be achieved when administered orally.
41
How-
ever, desired concentrations were achieved with intravenous therapy. Whittington
et al found a relationship between the length of the small intestine and the oral dose
of cyclosporine necessary to achieve therapeutic serum concentrations in children
after liver transplant.
42
Patients received both intravenous and oral cyclosporine to
maintain a therapeutic serum concentration. As the intravenous dose was decreased,
the oral dose was increased. Large doses of oral cyclosporine were required to achieve
therapeutic concentrations; these doses were inversely proportional to the length of
the small bowel. That is, the shorter the small bowel, the larger the dose required to
achieve serum concentrations in the therapeutic range.
Thielke et al described the pharmacokinetic evaluation of cyclosporine,
microemulsion cyclosporine and tacrolimus in a SBS patient with approximately
two feet of small intestine.
43
Single doses of 250 mg cyclosporine, 250 mg
microemulsion cyclosporine and 5 mg tacrolimus were administered on separate
occasions. The results demonstrated undectable blood concentrations with conven-
tional cyclosporine. Both microemulsion cyclosporine and tacrolimus pharmacoki-
netic parameters were slightly reduced compared to normal reference values. The
results suggested that increased doses of the microemulsion cyclosporine formula-
tion or tacrolimus may be successfully orally administered with blood concen-
tration evaluation.
Quantifying Drug Absorption
The cases described above substantiate the usefulness of determining drug con-
centrations, in serum and other body fluids, to evaluate the extent of absorption in
the SBS patient. For many medications, a therapeutic range for serum concentra-
tions has been established; however, the efficacy of other medications may be inde-
pendent of the serum concentration. Regardless of the establishment of a therapeutic
range, the ability to quantitatively and qualitatively measure drug concentrations in
various body fluids may be of tremendous help to the clinicians managing the SBS
patient. Quantitative measurements reflect the approximate amount of drug in the
sample. Qualitative measurements reflect the presence of a drug only in the sample.
Most hospital toxicology laboratories are capable of determining concentrations
of aspirin, acetaminophen, tricyclic antidepressants, anticonvulsants, cyclosporine,
tacrolimus, digoxin, warfarin, barbiturates, methylxanthines, benzodiazepines, opi-
ate agonists, and class 1a antiarrhythmics (e.g., procainamide, quinidine). Body fluid
concentrations of other drugs may be measured, both qualitatively and quantita-
tively, at other laboratories. Table 18.3 offers a representative, but not exhaustive,
list of drugs other than the common ones listed above, that may be measured.
Routes of Administration
Medications may be administered by several routes and categorized as either
enteral, parenteral or topical, as shown in Table 18.4. Enteral drug delivery includes
oral, buccal, sublingual, gastric tube, jejunal tube and rectal routes of administration.
284
The Biology and Practice of Current Nutritional Support
18
Table 18.3. Qualitative and quantitative assessment of drug absorption
Drug Qualitative Quantitative
acyclovir X
allopurinol X
atenolol X
bethanechol X
brompheniramine X X
captopril X
carbidopa X
chlorthiazide X
chlorpheniramine X X
cimetidine X X
clonidine X
colchicine X
dapsone X
diclofenac X
diflunisal X
diltiazem X X
dipyridamole X
enalapril X
ergotamine X
famotidine X
fenoprofen X
fluphenazine X
glipizide X
glyburide X
haloperidol X X
hydralazine X
hydrochlorothiazide X
hydroxychloroquine X
ibuprofen X X
indomethacin X
ketoprofen X
labetalol X
levadopa X
lisinopril X
lithium X
loperamide X
meclizine X
meclofenamic acid X
mercaptopurine X
methocarbamol X
methyldopa X
metoclopramide X
metolazone X
metoprolol X X
metronidazole X
naltrexone X
naproxen X
nifedipine X X
oxybutynin X
pentazocine X X
continued on next page
285
Pharmacologic Aspects of Short Bowel Syndrome
18
In the SBS patient, buccal, sublingual, and rectal administration may be suitable
routes since the small intestine has been resected. Enteral drug delivery is the least
expensive, and should be utilized whenever possible, even if higher doses of medica-
tion need to be administered to obtain the desired effect. However, many oral dos-
age forms have neither been formulated nor administered sublingually, buccally, or
rectally. Consequently, other methods of drug delivery must be utilized.
Parenteral drug delivery includes subcutaneous, intra-arterial, intramuscular,
intrathecal, intraperitoneal, intravenous, and intraventricular routes of administra-
tion. Of the parenteral routes, subcutaneous (SC), intramuscular (IM), and intrave-
nous (IV) administration of medications to SBS patients are the most common.
Prolonged release of drug from the administration site e.g., depot formulations may
decrease the frequency of dosing a drug when it is administered IM or SC. In fact,
some medications may be given IM as infrequently as every 28 days. IV delivery of
medications may either be continuous or intermittent. Continuous infusions are
usually used for medications requiring a constant serum concentration and having a
very short half-life. Intermittent infusions are usually used for medications requir-
ing peak and trough serum concentrations, such as antibiotics.
Table 18.3. Qualitative and quantitative assessment of drug absorption
(continued)
Drug Qualitative Quantitative
pentoxyfylline X
perphenazine X X
phenylbutazone X
phenylpropanolamine X X
piroxicam X
probenecid X
propoxyphene X X
propranolol X X
propylthiouracil X
pseudoephedrine X
ranitidine X
rifampin X
sulfamethoxazole X
terbutaline X
terfenadine X
thioridazine X X
thiothixene X X
tolbutamide X X
tolmetin X
trifluoperazine X X
trihexyphenidyl X
trimethoprim X
triprolidine X
verapamil X X
The above list was compiled from the following sources: 1) 1991 Professional
Service Manual. American Medical Laboratories, Inc., Fairfax, Virginia; 2) January
1990 Professional Manual. National Medical Services, Willow Grove,
Pennsylvania.
286
The Biology and Practice of Current Nutritional Support
18
Topical drug delivery includes respiratory, nasal, ophthalmic, otic, implantable,
mucous membrane and skin routes of administration. Drugs administered to the
mucous membranes that do not include the buccal, sublingual and rectal routes
may be in the form of vaginal suppositories, creams, ointments and aerosols. Drugs
administered to the skin may be in the form of ointments, creams, gels, pastes,
powders, or transdermal patches. In many cases, topical drug delivery is intended
for its topical effect; however, systemic absorption of medications via the topical
route is necessary in some cases.
Buccal and Sublingual Administration
Buccal administration of a medication refers to placement of a solid oral dosage
form (e.g., tablet) into the cheek, where it dissolves and is absorbed. Sublingual
administration refers to placement under the tongue. Absorption from the buccal
and sublingual sites is enhanced when the mucosal pH and lipid solubility increase
until the pH is 2 units above the pKa of the drug, then absorption tapers off.
44
The
advantages of these sites of administration for SBS patients include the following:
1. high systemic and lymphatic vascularity allows for rapid absorption and
onset of effect;
2. therapy may be interrupted abruptly if necessary;
Table 18.4. Common methods of drug delivery
Enteral
Oral
Buccal
Sublingual
Rectal
Parenteral
Subcutaneous
Intra-arterial
Intramuscular
Intrathecal
Intraperitoneal
Intravenous
Intermittent vs. continuous
Intraventricular
Pulmonary
Aerosol
Dry-powder
Topical
Eye
Implantable
Mucous membrane
Skin
Ointment
Transdermal
Cream
Reprinted with permission from McFadden MA, DeLegge MH, Kirby DF. JPEN
1993; 17:180-186.
287
Pharmacologic Aspects of Short Bowel Syndrome
18
3. direct delivery to the systemic circulation occurs, bypassing first-pass he-
patic and intestinal metabolism;
4. the tablet may be retained for an extended period of time to provide a
sustained effect; and,
5. intestinal absorption is not necessary to achieve the desired therapeutic
effect.
44
Buccal and sublingual administration may be limited when
1. the tablet is accidentally chewed or swallowed;
2. the dosage form dissolves too quickly; and,
3. the taste of the tablet is not pleasing to the patient.
Medications that may be administered by the buccal and sublingual routes are
listed in Table 18.5.
44-82
Rectal Administration
Rectal administration refers to the placement of a dosage form, whether liquid
or solid, into the rectum. Rectal suppositories and enemas have been specifically
formulated for such administration. Some of these formulations are commercially
available; others have to be compounded extemporaneously. When a suppository
cannot be prepared, some liquids which have been formulated for oral and intrave-
nous use may be given rectally. Drug absorption from the rectum is determined by
the drug form administered, the surface area of the rectum, the pH of the rectum,
the pK
a
of the drug, and the extent of first-pass metabolism that may occur. It may
be enhanced when the drug is in solution and is highly lipophilic.
The advantages of rectal administration are recognized when a patient is acutely
ill and neither oral nor intravenous administration is desirable. In the chronically ill
patient, such as the SBS patient, rectal administration may preclude the less desir-
able intramuscular or intravenous route. Rectal administration may also lead to en-
hanced bioavailability as a result of decreased first pass metabolism.
46,83
For example,
metoprolol, an agent with extensive first pass metabolism, has demonstrated in-
creased serum concentrations when administered rectally as compared to oral ad-
ministration.
83
The disadvantages of the rectal route include the following:
1. an unpredictable extent of absorption;
2. an unpredictable onset of action;
3. difficulty in achieving therapeutic serum concentrations; and,
4. difficulty maintaining the medication in the rectal cavity until it is ab-
sorbed.
Medications that have been administered rectally include antiemetics, antide-
pressants, anticonvulsants, antihypertensives, antipyretics, anti-inflammatories, seda-
tive/hypnotics and laxatives. Table 18.6 lists specific medications; some are not
commercially available, but may be compounded by a pharmacist.
45,83-129
Subcutaneous Administration
Subcutaneous (SC) administration is the direct parenteral injection of a medica-
tion into the top half-inch of skin. The extent and rate of drug absorption will be
determined by the site of injection and the extent of vascular circulation to the area.
In most cases, the medication will be absorbed more slowly than in intravenous (IV)
administration, but not as slowly as the intramuscular (IM) route. The advantages
of SC administration are recognized when the oral or IV routes are neither available
nor desirable and when a prolonged duration of effect may be desired. The
288
The Biology and Practice of Current Nutritional Support
18
disadvantages of SC administration include pain on injection, unpredictable peak
serum concentrations and tissue hypertrophy that may occur after multiple injec-
tions. Table 18.7 lists medications that may be administered using the SC route.
130-133
Intramuscular Administration
Several medications prepared for IV use may be given by the IM route; however,
some may be administered as depot injections. Depot injections are administered
deep into a muscle, primarily the deltoid, gluteals or the thigh. These drugs are
formulated to allow a dose of medication to be released slowly over an extended
period of timeas long as a month in some cases. Absorption, therefore, is slow and
continuous giving a steady concentration of drug in the serum. The advantages of
such administration include decreased frequency of injections, fewer dermal com-
plications, an alternate route when the oral and intravenous routes are not desirable
and a prolonged duration of effect. The disadvantages of IM depot injection include
pain on injection and difficulty reversing the drugs therapeutic or adverse effects
once administered. Table 18.8 lists medications that may be administered by IM
depot injection.
134-135
Continuous Infusion
Intravenous, or direct, administration of medications into the systemic circula-
tion allows for complete drug absorption. When no other alternatives are available,
some medications may have to be administered by continuous infusion to the SBS
patient. When a continuous effect is desired and a medication has a short elimina-
tion half-life, a constant IV infusion may be required. The advantages of continuous
infusion include continuous effect and use when the oral route is not desirable. The
disadvantages of continuous infusions include the requirement for continuous in-
travenous access, interrupted therapeutic effect when the infusion is disrupted, an
increased risk for thrombophlebitis and extravasation at the site of infusion and
higher costs. The medications most commonly infused include opiate analgesics,
heparin, immunosuppressants, insulin and H
2
-antagonists. Table 18.9 lists medica-
tions administered by continuous infusion.
136
Some of these medications may be
admixed with TPN and administered simultaneously.
Table 18.5. Drugs that can be used by buccal and sublingual routes*
Buccal Sublingual
amitriptyline alprazolam methyltestosterone
amphetamine buprenorphine midazolam
fentanyl captopril morphine
methylamphetamine desmopressin nifedipine
methyltestosterone ergoloid mesylates nitroglycerin
midazolam ergotamine mesylate prazepam
morphine fentanyl propranolol
nicotine hyoscyamine sulfate sotalol
nitroglycerin isosorbide dinitrate triazolam
pemoline lorazepam
prochlorperazine
testosterone
*References 44-82
289
Pharmacologic Aspects of Short Bowel Syndrome
18
Oral and Nasal Inhalation
Medications may be inhaled by either the oral or nasal route and be adminis-
tered by using a nebulizer or inhaler. The process of nebulization involves the dis-
persion of liquid medication via oxygen or compressed air into a mask from which
the patient breathes orally and/or nasally. Inhalers are provided for either nasal or
oral use. The nasal, and some oral, inhalers deliver medication that is dispersed via a
propellant. Other oral inhalers involve the use of dispersing powdered drug from a
capsule that is placed inside an activating device or dry powder that is released from
a breath-actuated inhaler. In every case, the topical effect of the medication brings
about a therapeutic systemic effect. In some cases, the amount of drug absorbed
systemically is significant enough to cause side effects, but they are not nearly as
significant as those resulting from oral or systemic administration.
The advantages of administering medications by inhalation include minimal
systemic effect and they do not require a functioning GI tract. The disadvantages
Table 18.6. Drugs that can be used by rectal administration*
acetaminophen methadone
allopurinol methohexital
aminophylline metoclopramide
amitriptyline metoprolol
aspirin metronidazole
atropine midazolam
bisacodyl mineral oil
bumetanide morphine
carbamazepine N-acetylcysteine
chloral hydrate nalbuphine
chlorpromazine naproxen
cimetidine nifedipine
clonazepam omeprazole
clonidine ondansetron
codeine oxybutynin
dextroamphetamine paraldehyde
diazepam pentobarbital
diclofenac phenobarbital
digoxin piroxicam
dimenhydrinate prochlorperazine
docusate progesterone
doxepin promethazine
ergotamine propranolol
fluoxetine propylthiouracil
glycerin sodium phosphate
hydrocortisone sodium polystyrene
ibuprofen sorbitol
indomethacin sulfasalazine
insulin sumatriptan
isoproterenol temazepam
ketoprofen thiopental
lactulose trimethobenzamide
levodopa/carbidopa valproic acid
*References 45,83-129
290
The Biology and Practice of Current Nutritional Support
18
are usually limited to the patients ability to properly administer the doses and the
irritation to the throat/nares that may occur with the oral/nasal inhalers. Table 18.10
lists medications that may be administered by nasal and/or oral inhalation.
137-156
Topical Administration
Topical routes include ointments, transdermal systems, implantable devices, and
creams that can be used on the skin and some are used vaginally. Table 18.11 sum-
marizes the topical medications available.
157-181
Transdermal drug administration refers to the delivery of medication from a
drug reservoir through the skin and into the systemic circulation. The degree of
Table 18.7. Drugs that can be used by subcutaneous injection*
bethanecol heparin
buprenorphine insulin
corticotropin insulin aspart
dalteparin insulin glargine
danaparoid insulin lispro
deferoxamine interferon
desmopressin isoproterenol
dihydroergotamine morphine
enoxaparin naloxone
ephedrine prochlorperazine
epinephrine pyridostigmine
erythropoietin somatostatin
ethacrynic acid terbutaline
G-CSF thyrotropin
GM-CSF tinzaparin
glucagon triamcinolone
vitamin K
*References 130-133
Table 18.8. Drugs that can be used by intramuscular depot injection*
aurothioglucose
benzathine penicillin
bromocriptine
estradiol
estradiol + testosterone
fluphenazine decanoate
haloperidol decanoate
methylprednisolone
medroxyprogesterone
octreotide
testosterone
*References 134-135
291
Pharmacologic Aspects of Short Bowel Syndrome
18
Table 18.9. Drugs that can be used by continuous intravenous infusions
cimetidine
famotidine*
fentanyl
heparin
hydromorphone
insulin
meperidine
morphine
octreotide
ranitidine
tacrolimus
*In vitro compatibility data only.
136
Table 18.10. Drugs that can be used by nasal and oral inhalation*
albuterol lidocaine
amikacin metaproterenol
amphotericin liposomal methylprednisolone
atropine midazolam
azelastine mometasone
beclomethasone naphazoline
budesonide nedocromil
butorphanol nicotine
colistin nitroglycerin
cromolyn sodium oxymetazoline
deferoxamine oxytocin
desmopressin acetate pentamidine
dexamethasone propylhexedrine
ephedrine phenylephrine
epinephrine propranolol
ergotamine salmeterol
fentanyl sufentanil
flunisolide sumatriptan
fluticasone terbutaline
gentamicin tetrahydrozoline
glycopyrrolate tobramycin
ipratropium triamcinolone
isoetharine vasopressin
isoproterenol zanamivir
levalbuterol
*References 137-156. Adapted and updated with permission from McFadden MA,
DeLegge MH, Kirby DF. JPEN 1993; 17:180-186.
292
The Biology and Practice of Current Nutritional Support
18
drug absorption is comparable to that of a continuous infusion without the use of
an IV catheter. The advantages of transdermal drug delivery include the following:
1. provides a steady serum concentration of drug;
2. does not require GI tract for absorption;
3. it has less variability in absorption when compared to GI absorption;
4. therapy may be discontinued abruptly if necessary;
5. dosing may be as infrequent as once weekly; and,
6. patient adherence may be better.
181
The disadvantages of these systems are primarily related to the limited number
of medications which may be administered transdermally.
Special Considerations
Home Antibiotics
Patients with SBS may require central venous access to provide adequate nutri-
tion and to administer intravenous medications. In-dwelling catheters pose a sig-
nificant risk of infection. This, coupled with the potential for other infections, may
necessitate the use of intravenous antimicrobials. In an effort to minimize cost, pa-
tients may be managed at home with IV antimicrobial therapy. Common catheter-
related infections result from Staphylococcus aureus (S. aureus ) and Candida species
(C. species) including C. albicans and Torulopsis glabrata (T. glabrata). Other infec-
tions caused by Gram-negative organisms may need to be managed as well. In many
cases, S. aureus is resistant to methicillin, requiring the use of vancomycin. Oxacillin
or nafcillin may be used if the organism is sensitive. Amphotericin B is the drug of
choice for sepsis caused by C. species. Fluconazole is an acceptable alternative in the
case of a C. albicans line infection. C. krusei and T. glabrata are primarily fluconazole-
resistant species and necessitate the use of amphotericin.
182
The aminoglycosides
and third generation cephalosporins are commonly utilized to manage infections
caused by Gram-negative organisms. Table 18.12 lists some useful antimicrobials
for outpatient therapy home use based on their dosing regimens, solution stability
and the bacterial/fungal coverage.
30,182-197
Table 18.11. Drugs that can be used by topical route
I. Ointment
nitroglycerin
II. Transdermal patches*
clonidine estradiol fentanyl
nicotine nitroglycerin salicylic acid
scopolamine testosterone
III. Implantable devices
levonorgestrel
IV. Cream
betamethasone capsaicin clotrimazole
conjugated estrogen fluocinonide hydrocortisone
miconazole nystatin triamcinolone
terconazole
*References 157-181. Reprinted with permission from McFadden MA, DeLegge
MH, Kirby DF. JPEN 1993; 17:180-186.
293
Pharmacologic Aspects of Short Bowel Syndrome
18
Table 18.12. Useful antibiotics for home therapy
Antibiotic Name Half-Life* Dosing Interval Special Information
Amikacin 2-3 hours Every 8-24 hours Monitor serum concentra-
tions and renal function
Amphotericin up to 15 days Every 24 hours Monitor renal function and
potassium, phosporus and
magnesium
Cefazolin 1-2 hours Every 8 hours Gram + coverage including
methicillin sensitive S. aureus
Ceftazidime 1.5-2 hours Every 8 hours Good coverage
Pseudomonas aeruginosa and
acinetobacter
Ceftriaxone 5-11 hours Every 12-24 hours Good gram + coverage, but
not enterococci, listeria or
methicillin resistant S. aureus,
many pseudomonas resistant
Cefoxitin < 1 hour Every 6 hours Gram coverage including
anaerobic bacteria
Ciprofloxacin 3-4 hours Every 12 hours Gram coverage including
Pseudomonas aeruginosa
Clindamycin 2-3 hours Every 8 hours Gram + aerobic and
anaerobic coverage; diarrhea
with Clostridium difficile
Gatifloxacin 7-14 hours Every 24 hours Gram + and gram- coverage
including Streptococcus
pneumoniae
Gentamicin 2-3 hours Every 8-24 hours Monitor serum concentra-
tions and renal function
Levofloxacin 6-7 hours Every 24 hours Gram + and gram- coverage
including Streptococcus
pneumoniae
Nafcillin < 1 hour Every 4-6 hours Gram + coverage including
methicillin sensitive S. aureus
Oxacillin < 1 hour Every 4-6 hours Gram + coverage including
methicillin sensitive S.
aureus; strong association
with phlebitis
Ticarcillin- 1 hour Every 4-6 hours Gram + coverage including
Clavulanate methicillin sensitive S.
aureus; Gram - and
anaerobic coverage including
Bacteroides fragilis
Tobramycin 2-3 hours Every 8-24 hours Monitor serum concentra-
tions and renal function
Vancomycin 4-6 hours Every 12-24 hours Monitor renal function and
serum concentrations when
appropriate
*References 30,182-197. Reprinted with permission from McFadden MA, DeLegge
MH, Kirby DF. JPEN 1993; 17:180-186
294
The Biology and Practice of Current Nutritional Support
18
Culture and sensitivity data are always important in the final decision of antimi-
crobials to assure that the patient is being effectively managed. The dosage regimen,
solution stability, and toxicity must also be considered to provide optimal care.
183-185
Minimizing the number of doses that need to be administered will decrease cost and
increase patient compliance.
194
The implementation of portable multiple-dose elec-
tronic infusion pumps have allowed easier antimicrobial administration.
183
These
infusion pumps deliver medication via drug reservoirs for either intermittent or
continuous infusions. These pumps negate the need for IV administration sets for
each dose. The cost of these systems are increased but a wider variety of antimicro-
bials may be utilized in the outpatient setting.
183
Monitoring serum concentrations and renal function is encouraged with the use
of the aminoglycosides. Assessment of renal function is also necessary with vanco-
mycin. Vancomycin trough concentrations should only be measured if renal func-
tion deteriorates or a poor clinical response is demonstrated.
198
Amphotericin B
may have significant effects on renal function and electrolyte homeostasis; routine
monitoring is suggested.
Some TPN vendors who supply TPN for the home patient use two-in-one infu-
sions while other companies use three-in-one infusions. Table 10.13 shows com-
patibility data of whether the antimicrobial may be co-infused or put into the
TPN directly.
195
Cyclic Infusion Techniques
The infusion of total parenteral nutrition (TPN) over a 24-hour period is com-
monly practiced when a patient is in the hospital. This practice may not be optimal
for the outpatient, particularly when a relatively active lifestyle may be maintained.
If the SBS patient has central venous access, the duration of TPN infusion may be
decreased from the usual 24 hour period to a 10-12 hour period. Several approaches
may be taken to achieve this goal. One method may involve maintaining the same
volume and dextrose concentration while decreasing the infusion time a couple hours
each day until the patient tolerates a 10-12 hour infusion. The rates of infusion may
be increased or decreased when initiating and discontinuing the TPN infusion, re-
spectively. However, Krzywda et al suggest that patients may tolerate abrupt initiation
and discontinuation of 3-in-1 TPN without significant hyper- or hypoglycemia.
196
Home Infusion Devices
The infusion of IV fluids, medications and TPN at home may be accomplished
by the use of several devices. Standard infusion pumps may be utilized to administer
large volumes of fluid, particularly TPN and fat emulsion. H
2
-antagonists that have
been admixed with the TPN would consequently be delivered by the same method.
Antibiotics, provided in piggyback form or in concentrated drug reservoirs, could
be co-infused with an IV fluid or TPN using the same device. However, when anti-
biotics are provided in predrawn syringes, the use of a syringe pump may be more
practical, especially when the extra fluid from the IV infusion and piggyback may
compromise patient care.
Narcotic analgesics, including fentanyl, hydromorphone, meperidine and mor-
phine, may be infused for management of chronic pain. This may be accomplished
using microinfusion devices that allow fairly concentrated solutions to be adminis-
tered continuously. Still other infusion devices are designed to allow for continuous,
subcutaneous administration. The medication most commonly infused by this
295
Pharmacologic Aspects of Short Bowel Syndrome
18
Table 18.13. Medication administration with TPN
Medication 2 in 1 3 in 1
Co-Infusion In Solution Co-Infusion In Solution
Acyclovir No ND* ND ND
Amikacin Yes ND No ND
Aminophylline Equivocal Yes ND Yes
Amiodarone ND ND ND ND
Amphotericin No ND ND ND
Amphoterin cholesterol
sulfate complex ND ND ND ND
Ampicillin Equivocal Equivocal Yes ND
Azithromycin ND ND ND ND
Aztreonam Yes ND ND ND
Cefazolin Equivocal Yes Yes ND
Cefepime ND ND ND ND
Cefotaxime Yes Yes ND ND
Cefoxitin Yes Yes Yes ND
Ceftazidime Yes Yes ND ND
Ceftriaxone Yes Yes ND ND
Cefuroxime Yes Yes ND ND
Cidofovir ND ND ND ND
Cimetidine Yes Yes ND Yes
Ciprofloxacin No ND ND ND
Clindamycin Yes Yes Yes ND
Cyclosporine Equivocal ND ND ND
Digoxin Yes ND Yes ND
Doxycycline Yes ND ND ND
Erythromycin Yes ND Yes ND
Famotidine Yes Yes ND Yes
Fentanyl Yes ND ND ND
Fluconazole Yes ND ND ND
Foscarnet Yes ND ND ND
Furosemide Equivocal ND Yes ND
Ganciclovir Equivocal No ND ND
Gatifloxacin ND ND ND ND
Gentamicin Equivocal Yes Yes ND
Heparin Yes Yes ND ND
Hydromorphone Yes ND ND ND
Imipenem-Cilastin Yes No ND ND
Insulin Yes Yes ND ND
Iron Dextran Equivocal Yes ND Equivocal
Levofloxacin ND ND ND ND
Linezolid ND ND ND ND
Meperidine Yes Yes ND ND
Meropenem ND ND ND ND
Methicillin Yes Yes ND ND
Metoclopramide No Yes ND ND
Metronidazole Yes ND ND ND
Morphine Yes Yes ND ND
Nafcillin Yes Yes ND ND
Ofloxacin Yes ND ND ND
continued on next page
296
The Biology and Practice of Current Nutritional Support
18
method is insulin. In the case of chronic iron toxicity, deferoxamine may also be
infused by this method.
Conclusion
The chronic care of the SBS patient can be extremely rewarding, yet challenging.
It may often tax the ingenuity of the most resourceful clinician. The availability of
newer drugs and delivery systems has made it easier, but it is clear that more work is
needed in the pharmacologic approach to patients with limited GI absorption. The
new millenium holds the promise of even greater advancements and improvements
in the quality of life for these patients.
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CHAPTER 19
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Nutritional Support in Inflammatory
Bowel Disease
John H. Seashore, Melissa F. Perkal
Introduction
Crohns disease and ulcerative colitis are chronic remitting diseases of unknown
etiology characterized by abdominal pain, diarrhea and other gastrointestinal symp-
toms. Both diseases, but Crohns in particular, are associated with nutritional defi-
ciencies for a variety of reasons including malabsorption, increased nutrient losses,
increased energy requirements and inadequate nutrient intake. Acute malnutrition,
evidenced by weight loss, anemia and hypoalbuminemia, is common during acute
attacks of inflammatory bowel disease (IBD). A smaller number of patients have
chronic malnutrition with cachexia and multiple nutrient deficiencies. Malnutrition
may be responsible for considerable morbidity and even mortality in inflammatory
bowel disease (IBD), although there is no evidence that it exacerbates either condition.
The classic papers by Dudrick and Wilmore in 1968 describing the first success-
ful method for total parenteral nutrition sparked a resurgence of interest in clinical
nutrition and led to the development of new techniques and formulas for both
parenteral and enteral nutrition.
1,2
There has been intense interest in the role of
nutritional therapy in IBD during the 25 years since. Much of the literature is based
on anecdotal, retrospective or uncontrolled data, and spontaneous remissions and
exacerbations are characteristic of IBD which makes it difficult to know whether a
specific treatment is responsible for observed improvement. However, the large
amount of information and the available prospective, randomized, controlled stud-
ies make it possible to draw some general conclusions.
Malnutrition in Inflammatory Bowel Disease
Incidence
Acute malnutrition, as evidenced by weight loss of more than 10% or serum
albumin less than 3 g/dl, has been reported in 30-60% of patients during flare-ups
of Crohns disease.
3,4
Chronic malnutrition, or undernutrition is less common but
probably occurs in about 10% of adult patients. Ulcerative colitis is characterized by
long periods of well being and periodic severe flare-ups of disease. It is not surpris-
ing, then, that acute malnutrition occurs in 50-75% of patients, but chronic malnu-
trition is quite rare.
Approximately 85% of children have weight loss during acute attacks of Crohns
disease, and 65% suffer weight loss during flares of ulcerative colitis.
4
Chronic
malnutrition is a particular problem in children because of their unique growth
307
Nutrition Support in Inflammatory Bowel Disease
19
requirements. About 20% of patients have onset of IBD in childhood, usually
during adolescence, when children normally have a rapid increase in skeletal growth
and muscle mass, and undergo sexual maturation.
5
Growth failure occurs in 15-30%
of children with Crohns disease and 10% of children with ulcerative colitis.
5,6
Mechanisms of Malnutrition
Table 19.1 lists a host of factors which may contribute to malnutrition in pa-
tients with IBD.
Malabsorption
Malabsorption is most likely in the face of extensive mucosal disease, decreased
transit time from active disease, multiple resections resulting in short bowel syn-
drome, or bacterial overgrowth which occurs in up to 30% of patients with Crohns
disease.
8
Carbohydrate absorption, measured by D-xylose studies, was reported to
be abnormal in 16-40% of adults and children with Crohns disease.
8,9
Lactose in-
tolerance is the most common manifestation of malabsorption in IBD and has been
assumed by many clinicians to be nearly universal. However, decreased lactase levels
in jejunal biopsy specimens could be demonstrated in only 9-12% of patients.
10
Transient lactose intolerance is probably somewhat more common during acute
attacks of disease. The hydrogen breath test, a sensitive indicator of lactose malab-
sorption, was abnormal in 15% of children with ulcerative colitis and 34% of chil-
dren with Crohns disease.
11
Extensive ileal disease or resection may disrupt the enterohepatic circulation and
lead to depletion of the bile salt pool resulting in fat and fat soluble vitamin malab-
sorption. Many patients with bile salt deficiency have difficulty maintaining a nor-
mal weight. Deficiency of vitamins A, D, E, and K have been reported, but the
incidence is not known.
9
Vitamin B12 is absorbed in the terminal ileum indepen-
dent of bile salts and may also become depleted.
9
Serum zinc levels are low in IBD
patients as in other diarrheal diseases.
12,13
Many of the common medications used to treat IBD may exacerbate malabsorp-
tion. Corticosteroids inhibit calcium absorption, sulfasalazine impairs folate absorp-
tion by competitive inhibition and cholestyramine binds bile acids and aggravates
bile salt deficiency.
Increased Gastrointestinal Losses
Acute or chronic GI bleeding from the inflamed mucosal surfaces is very com-
mon in IBD. The bleeding may be occult or gross, the latter more prominent in
ulcerative colitis. Iron deficiency anemia is therefore common, but since other mi-
cronutrient deficiencies can cause anemia (folate, B
12
), further evaluation may be
necessary. Mean corpuscular volume less than 80 and a serum ferritin less than 18
mg/ml are the best evidence of iron deficiency anemia.
14
The inflamed mucosa characteristic of IBD may lead to an exudative enteropa-
thy and loss of protein from the gut, above and beyond protein malabsorption. This
excessive protein loss may exacerbate hypoalbuminaemia and other protein defi-
ciency. Increased losses of protein from the gut have been demonstrated by abnormal
fecal excretion of
51
chromium labeled albumin or clearance of alpha-1-antitrypsin.
15
The diarrhea seen during acute attacks of IBD is multifactorial in origin, but is
in part a secretory diarrhea causing active loss of water and electrolytes through
the diseased mucosa. Excessive losses of trace metals, including, zinc, copper and
magnesium have also been reported.
16,17
308
The Biology and Practice of Current Nutritional Support
19
Increased Nutritional Requirements
Fever associated with active disease, sepsis, peritonitis or abscess increases en-
ergy expenditure substantially and therefore increases caloric requirements.
18
In the
absence of fever, however, most of the evidence suggests that patients with IBD do
not have an increased caloric requirement.
19
Motil et al showed that Crohns disease
patients have the same whole body nitrogen flux, rates of protein synthesis and
breakdown and net protein retention as normal controls.
20
Chan, et al found that
the measured energy expenditure(by indirect calorimetry) in patients with Crohns
disease was virtually identical to that predicted by the Harris-Benedict equation for
normal adults.
21
Inadequate Oral Intake
This is the single most important reason for nutritional deficiency. Nausea, cramps
and diarrhea tend to be worse after eating and may condition patients to food avoid-
ance. The anorexia which accompanies many chronic illnesses may contribute. Spe-
cific complications including obstruction and fistula clearly impair eating. Self-se-
lected or physician-recommended diets may restrict intake by eliminating desired
foods and by interfering with palatability. The most compelling evidence that inad-
equate intake is responsible for malnutrition comes from studies showing that chil-
dren with growth failure can achieve normal growth rates when their diet is supple-
mented with parenteral or enteral nutrition.
Table 19.1. Possible causes of malnutrition in inflammatory bowel disease
Inadequate intake
Anorexia, altered taste, avoidance behavior
Abdominal pain, diarrhea, nausea, vomiting
Restrictive diets
Malabsorption
Diminished digestive function secondary to decreased bile salt concentration or
bacterial overgrowth
Decreased absorptive surface area secondary to extensive disease and/or previous
bowel resections
Drug-induced malabsorption(e.g., steroids/calcium; sulfasalazine/folate;
cholestyramine/fat-soluble vitamins
Increased gastrointestinal losses
Protein-losing enteropathy
Gastrointestinal bleeding
Electrolyte and mineral loss
Increased nutritional requirements
Fever, fistula, infection
? corticosteroid therapy
Need for repletion of body mass
Reproduced with permission of WB Saunders Co from Perkal, MF and Seashore,
JH. Nutrition and inflammatory bowel disease. Gastroenterology Clin NA, 1989;
18(3):567-578.
7
309
Nutrition Support in Inflammatory Bowel Disease
19
Nutritional Support in Inflammatory Bowel Disease
Patients with inflammatory bowel disease are at risk for developing nutritional
deficiencies which may in turn increase morbidity and mortality. Maintenance of
good nutrition is a desirable goal, but the best methods, timing and route of nutri-
tional support are not always clear. The role of nutritional therapy in IBD can be
considered in the following areas.
Nutritional Management of Acute Attacks and Induction
of Remission
Corticosteroids have long been the mainstay of medical treatment for IBD. In
the National Cooperative Crohns disease Study, treatment of active Crohns disease
with prednisone achieved a 47% rate of remission of symptoms compared with
26% in placebo treated patients.
22
Truelove described treating severe attacks of IBD
with a period of bowel rest and intravenous steroids with good results.
23
This ap-
proach has become commonplace in the management of IBD. However, even healthy,
well nourished adults may develop evidence of malnutrition after 10 days NPO.
Patients who are already malnourished from IBD should not be allowed to starve for
more than a few days. Finally, most patients who fail medical therapy require sur-
gery which is better tolerated in the nutritionally repleted patient. For all these rea-
sons, it is prudent to give parenteral nutrition to patients who are NPO during
treatment with steroids and bowel rest.
The concept of bowel rest in the treatment of gastrointestinal inflammatory pro-
cesses is based on several theoretical considerations. Peristalsis is decreased in the
absence of enteral feeding so there is less physical movement of the bowel which
could function as a medical splint to aid in healing of the inflammatory process.
Withholding oral feedings minimizes gastrointestinal secretions. In the absence of
digestion and absorption, the metabolic work and oxygen consumption of the gut
mucosa is minimal, which may also permit better healing. It has been suggested that
the multiplicity of foreign antigens introduced into the gut with oral feeding may
worsen the disease.
24
There is no direct evidence to support these hypotheses, but
bowel rest has been widely used in the treatment of gastrointestinal disease.
The introduction of total parenteral nutrition (TPN) in 1968 made it possible
to provide intravenous nutrition for more than a few days. There has been con-
siderable interest over the years in using longer periods of bowel rest for treating
IBD leading to the concept of TPN as primary therapy. Early experience was en-
couraging and led to widespread use of a 3-12 week period of bowel rest with in
hospital and home TPN. Greenberg, et al reported a 77% remission rate in 43
patients, 79% of whom remained well for 2 years.
25
A subsequent prospective but
non-randomized study of 100 patients from the same institution again reported a
77% remission rate in hospital and 54% of patients still in remission at 1 year.
26
Most of the patients continued to receive steroids during TPN. Other workers
have not been able to duplicate these results, however. Reported remission rates
have been from 30-70%.
27-35
More important, remissions have not generally been
sustained, relapses or surgical intervention occurring in 15-80% of patients within
1-2 years. Muller et al reported that 83% of patients had remission and avoided
surgery acutely, but that the recurrence rate was 65% at 2 years and 85% at 4
years.
36
This relapse rate was 4 times higher than that following surgical resection.
One of the few prospective, randomized, controlled studies was reported by
Dickinson, et al who found no difference in outcome between those patients
310
The Biology and Practice of Current Nutritional Support
19
treated with standard medical therapy alone and those treated with medical therapy
plus TPN.
37
While most of the studies in the literature are retrospective and uncon-
trolled and the definitions of disease severity, remission and relapse vary somewhat,
certain conclusions seem appropriate. A prolonged period of bowel rest and TPN
may be more effective in inducing remission than the standard 10 day course of
treatment, but the cost and complications of TPN must be considered. Remission is
not well sustained compared with long term steroid therapy or surgical resection.
The role of TPN is adjunctive rather than primary.
The concept of bowel rest has been challenged in recent years for several rea-
sons.
35,38,39
As noted above, there is no hard evidence that bowel rest works. Second,
there is accumulating evidence that prolonged bowel rest is damaging to the gut.
Small bowel mucosal atrophy as measured by villous height, DNA content and
mucosal wet weight, occurs in patients who are NPO and receiving TPN.
40,41
It is
now recognized that mucosal atrophy may be associated with bacterial translocation
from the bowel lumen to the portal circulation and may be a source of sepsis in TPN
patients.
42
Intraluminal nutrients, especially glutamine, appear to be critical to main-
tain the health of the small bowel mucosa.
41,43
Third, recent studies suggest that bowel rest may not be necessary in the treat-
ment of acute episodes of IBD. OMorain, et al in 1980 reported substantial clinical
improvement in 27 patients treated with an elemental diet with or without steroids
for acute exacerbations of Crohns disease.
44
Morin, et al induced remission in 10
newly diagnosed children with moderately severe Crohns disease using elemental
diet without steroids.
45
Since then, a number of prospective, randomized controlled
studies have confirmed that elemental diets, with and without steroids, are effective
in inducing remission during acute attacks of IBD.
46-52
Remission rates in these
studies range from 60-90%. Elemental diet was equal or superior to steroids,
46-48,50
bowel rest, TPN and bowel rest
49,52
or polymeric diet,
51
in inducing remission in
both children and adults. Results were generally maintained for up to 3 months, but
most of these studies did not provide long-term follow-up. One retrospective study
that did report long term follow up data showed a 22% relapse rate at 6 months,
then an 8-10% annual relapse rate thereafter.
53
A third study from the Toronto
group, this one prospective and randomized, found no significant differences in
outcome among groups treated with:
1. TPN, bowel rest and steroids,
2. elemental diet and steroids, and
3. regular diet plus steroids.
54
In this study, remission was maintained in over 50% of patients for up to 2 years.
Teahon, et al showed that the abnormal permeability of the bowel mucosa found in
active Crohns disease was reversed during treatment with an elemental diet, sug-
gesting improved integrity of the mucosal barrier.
55
These studies clearly demonstrate that bowel rest is not essential in the manage-
ment of acute attacks of IBD. Elemental diets are superior in most cases and obviate
the need for TPN with its attendant cost and risks. However, there is still a place for
a short course of TPN and bowel rest in patients who fail other therapy.
Nutritional Management in the Maintenance of Remission
Once remission has been achieved, the goal of treatment is to keep patients
symptom free while they return to their usual activities and diet. Dietary manage-
ment in this phase remains controversial. Restrictive diets often lead to inadequate
311
Nutrition Support in Inflammatory Bowel Disease
19
nutrition because of exclusion of favorite foods or unpalatability and should be avoided
unless there is good evidence of need and efficacy.
24,39
A low residue or low fiber diet
has traditionally been recommended in IBD, but there is no scientific evidence that
it works. Levenstein et al randomized patients to either a regular or a low fiber diet
and found no difference in symptoms or relapse.
56
Heaton et al treated a group of
patients with a diet low in refined carbohydrate and high in fiber content.
57
They
found a lower incidence of hospitalization and surgery in the diet treated patients
compared with historical controls taking a regular diet. A subsequent larger, ran-
domized study failed to confirm this observation.
58
Many clinicians advise their
patients to eat a regular diet, avoiding only those foods which bother them. Alun-
Jones provides some evidence for this approach in a small randomized study
59
and a
larger non-randomized study
49
in which one new food was introduced each day.
Any food which caused symptoms was eliminated from the patients diet. The ma-
jority of the patients were sensitive to 1-4 foods, the most common being wheat,
dairy products, corn, yeast, tomatoes, citrus and eggs. A prospective multicenter
trial using a similar exclusion diet technique found a 2 year relapse rate of 62%
compared with 79% in patients treated with steroids and regular diet.
60
Growth Failure in Children
About 20 % of patients with inflammatory bowel disease have onset of symp-
toms in childhood.
5
Children suffer the same nutritional consequences of IBD as
adults, namely acute weight loss, chronic undernutrition and micronutrient defi-
ciencies. In addition, children normally are growing, especially during the pubertal
growth spurt, and significant numbers of children with IBD have impaired linear
growth and delayed sexual maturation. Growth failure occurs in 15-40% of chil-
dren with Crohns disease and 10% of children with ulcerative colitis.
4,61-63
Growth
failure, as opposed to weight loss, is most commonly defined as a height for age less
than the 5th percentile on standard growth curves. A single static measurement of
growth, however, may represent constitutional short stature rather than the effect of
disease. Estimating predicted adult height from mean parental height may be help-
ful. Even better is to obtain old height measurements and plot the childs growth
history over time on the standard growth charts. Adult height can be predicted fairly
accurately if a child has been growing steadily along a particular percentile curve. If
height begins to cross percentiles over a year or two, the child almost certainly has
growth failure from disease. The most accurate method to assess growth failure is to
plot linear growth (cm/year) on normal growth velocity curves
64
A child whose lin-
ear growth is less than the 3rd percentile (2 SD below the mean) may be considered
to have growth failure. Growth velocity measurements are particularly useful to as-
sess the nutritional effects of treatment. The majority of studies in the literature,
however, have used height for age percentile as the initial definition of growth fail-
ure and changes in height percentile as the outcome measurement.
The etiology of growth failure in children is not entirely clear and may well be
multifactorial. The nutritional consequences of IBD discussed earlier could cer-
tainly contribute to poor growth, but these are usually operative during acute attacks
of the disease, whereas growth failure is a chronic problem. One of the striking obser-
vations about Crohns disease in children is that growth failure often predates gas-
trointestinal symptoms by a year or more.
65
In one study, 46% of children with
Crohns disease had a decrease in height velocity before the onset of symptoms,
66
which
suggests the presence of a systemic factor. It is not uncommon for children who
312
The Biology and Practice of Current Nutritional Support
19
eventually develop Crohns disease to be referred to an endocrinologist for evalua-
tion of short stature. Endocrine evaluation is invariably normal. Several studies have
shown normal pituitary and adrenal function, and normal secretion of thyroid hor-
mone, growth hormone and somatomedin.
6,67,68
Thus, there is no evidence of an
endocrine basis for growth failure in Crohns disease.
Corticosteroids are a mainstay of therapy for moderate to severe Crohns disease
and have well known antianabolic properties. Long term treatment with high dose
corticosteroids may contribute to growth failure,
69
but patients who require high
dose therapy are more likely to have severe disease and poor nutrition, and it is not
clear that corticosteroid use is an independent variable. Most patients are treated
with relatively low dose and/or alternate day steroids which are less likely to impair
growth.
70,71
Motil et al found no association between corticosteroid use and rates of
protein synthesis or breakdown
20
The most likely explanation for growth failure is inadequate nutrition. Several
balance studies have shown that children with Crohns disease and growth failure
spontaneously take in only 50-80% of their estimated caloric requirements.
6,67,72
Some studies also suggest that energy expenditure may be higher than normal in
these children which would further compound the effect of poor intake.
73
It is par-
ticularly difficult for adolescents to eat enough to achieve normal pubertal growth
rates. The most convincing evidence that inadequate intake is responsible for growth
failure is the excellent response to caloric supplementation which has been docu-
mented in numerous studies.
Layden et al first demonstrated enhanced growth in children with Crohns dis-
ease using bowel rest and total parenteral nutrition for 4-6 weeks.
73
Kelts et al
67
and
Strobel et al
74
also reported increased growth velocity during TPN. Some, but not
all, of these children had continued improved growth for up to a year after TPN was
stopped. Subsequent studies by Morin et al,
75
Kirschner et al
72
and Motil et al
20
have
shown that the same result can be achieved using enteral supplementation. Dietary
counseling and the use of high calorie snacks and liquid oral supplements may be
sufficient to achieve adequate nutrition in some children. If growth is still not ad-
equate, administration of a defined formula diet at night through a nasogastric tube
will usually work.
76
Parenteral nutrition as primary treatment for growth failure
should be reserved for children who have documented failure of enteral supplements.
It is particularly important to attend to the nutritional needs of adolescents dur-
ing the period of rapid growth and sexual maturation beginning at puberty. Perma-
nent short stature may result if the epiphyses close before normal pubertal growth is
complete. Small size and delayed appearance of secondary sex characteristics can be
emotionally devastating to teenagers who are already struggling with the problems
of chronic disease. Control of the disease by medical and/or surgical therapy and
careful monitoring of caloric intake and growth rates are essential.
Perioperative TPN
Morbidity and mortality rates following major abdominal surgery are clearly
higher in malnourished patients than in those who are nutritionally replete.
77-79
Since
many patients with inflammatory bowel disease have significant malnutrition, it is
logical to assume that nutritional support in the perioperative period might decrease
postoperative complications. Unfortunately, there are no prospective studies which
examine the role of either preoperative or postoperative TPN in patients with IBD.
Mullen, et al reported a retrospective series of general surgical patients with a variety
313
Nutrition Support in Inflammatory Bowel Disease
19
of gastrointestinal conditions including some with IBD.
80
Among patients who were
malnourished preoperatively, the complication rate was significantly lower in those
who had received at least 7 days of preoperative TPN.
81
Other studies show no
benefit from preoperative TPN.
82,83
Most patients scheduled for elective surgery for
IBD are only minimally malnourished, and there are no data to support preopera-
tive TPN. Many patients come to surgery urgently after failure of medical therapy
for acute exacerbation or complication of IBD and these patients often have a sig-
nificant period of time with inadequate enteral intake of calories. TPN during this
time may prevent or treat malnutrition and in turn reduce the morbidity of subse-
quent surgery.
84
Whether surgery should be deferred to allow a period of preopera-
tive TPN must be decided on an individual basis. Severely malnourished patients
might benefit, but other patients may have worsening nutritional status from ongo-
ing fever and loss of blood and protein from the gut.
85
Routine postoperative TPN
is not indicated, but it is appropriate to give TPN to patients who have moderate to
severe malnutrition or whose postoperative course may be prolonged.
86
Enterocutaneous Fistula
Entero-enteral and entero-vesical fistulas are well known complications of Crohns
disease as a result of chronic inflammation and transmural disease. Entero-cutane-
ous fistulas may occur spontaneously but are more common as a postoperative com-
plication. Entero-cutaneous fistulas are much less common in ulcerative colitis and
are almost always postoperative. Loss of fluid and electrolytes, rapid transit time,
malabsorption and bypass of distal bowel all contribute to malnutrition in patients
with fistulas, particularly fistulas from the proximal gastrointestinal tract. Wound
healing is impaired in patients with moderate to severe malnutrition; the longer the
fistula persists, the worse the malnutrition and the ever diminishing likelihood of
spontaneous closure, in the absence of nutritional support. The devastating conse-
quences of enterocutaneous fistulas were well described by Edmunds, et al, who
reported a 63% rate of malnutrition and a 59% mortality rate in patients with
enterocutaneous fistula from a variety of causes, including Crohns disease.
87
Death
is usually due to a combination of malnutrition and failed attempts at surgical clo-
sure of the fistula.
Since the introduction of TPN, there has been considerable interest in the role
of nutritional support in the management of patients with enterocutaneous fistulas,
and early reports of spontaneous closure using TPN to restore and maintain normal
nutritional status were encouraging.
88-90
Various retrospective series of patients with
fistulas from a spectrum of causes have shown spontaneous healing in 20-80% of
patients treated with bowel rest and nutritional support, as reviewed by Meguid.
91
The reported mortality in these series was 5-28%. However, there have been no
prospective or randomized studies, so it is not known how much of the improve-
ment compared with historical controls is a result of TPN and how much to other
factors such as improved general care, ICUs, newer antibiotics, etc.
The results with enterocutaneous fistulas in inflammatory bowel disease have
been less encouraging. The rate of spontaneous permanent closure of fistulas has
ranged from 10-50%.
26,29,32,80
This is perhaps not surprising since chronic inflam-
mation and infection are well known impediments to healing. High dose intrave-
nous steroids to treat active IBD may also interfere with healing.
In the absence of prospective studies, it is not possible to draw firm conclusions
about the treatment of enterocutaneous fistulas in IBD. Given the high incidence of
314
The Biology and Practice of Current Nutritional Support
19
malnutrition in these patients, it is imperative to provide some sort of nutritional
support which can often be as an enteral elemental diet for distal small bowel or
colonic fistulas, but usually should be as TPN and bowel rest for proximal fistulas.
Whether nutritional support has a primary therapeutic benefit above and beyond its
adjunctive role is uncertain. It seems reasonable to offer a short course(2-6 weeks) of
nutritional support with or without bowel rest, combined with medical treatment
of active disease and appropriate management of infection. If the fistula has not
closed in that time, surgical treatment is usually indicated.
Short Bowel Syndrome and Home TPN
A small but significant number of patients with Crohns disease(rarely ulcerative
colitis) are nutritional cripples and become dependent on TPN. Some patients have
intractable symptoms, non-closing fistulas, high output stomas or other complica-
tions of the disease, and are unable to eat because of symptoms or cannot maintain
adequate nutrition with enteral feeding alone. Other patients have diffuse disease
throughout the gastrointestinal tract and are poor candidates for operation. Still
others have had multiple resections leaving them with short gut syndrome and chronic
malnutrition. Prolonged TPN both in the hospital and at home may be life-saving
for these unfortunate patients. In the large Home TPN Registry maintained by the
Oley Foundation, Crohns disease is the second most common indication for home
TPN, accounting for 17% of all patients through 1987.
92
The reported experience
with long-term TPN is similar to that already described for short to medium dura-
tion TPN, which is that the patients nutritional status improves, but the overall
course of the disease is not changed. Fleming reported a small group of patients who
had severe, intractable Crohns disease who were treated with home TPN for up to
17 months.
93
Weight and albumin improved, but none of the patients achieved
sustained remission. Strobel treated 17 adolescents with home TPN(2-12 months)
for moderately severe Crohns disease and also found improved nutrition, including
increased growth velocity and catch up growth in 10.
74
One-third of the children
had sustained remission of symptoms for a mean of 331 days, but the majority had
persistence or relapse requiring ongoing medical or surgical treatment. More re-
cently, the Cleveland Clinic group reported 41 patients with Crohns disease who
were treated by bowel rest and home TPN for 1-8 years after failure of medical and
surgical treatment.
94
Nutritional status as measured by albumin and transferrin,
improved in most patients as did quality of life scores. However, the frequency of
operations did not change compared with the pre-TPN period, and the frequency
of hospitalization actually increased, primarily due to complications related to the
TPN. It is clear that TPN is effective in restoring and maintaining good nutrition
but has little primary therapeutic benefit. Patients with severe IBD ultimately need
definitive medical or surgical treatment of their disease, and a prolonged course of
TPN hoping to avoid such treatment is probably fruitless. A modest course of treat-
ment to replete a malnourished patient, to allow intra-abdominal inflammation to
settle down, or to provide time to prepare the patient for operation may be useful
but should not be prolonged unduly. Long-term home TPN is reserved for those
few patients who have failed all conventional treatment or who are not candidates
for surgery.
Summary
Nutrition and inflammatory bowel disease are inextricably related. The nutri-
tional requirements of these patients need constant attention. Micronutrient
315
Nutrition Support in Inflammatory Bowel Disease
19
deficiencies are relatively common and require dietary supplementation. Macronu-
trient deficiency may lead to acute or chronic protein-calorie malnutrition, and
increased morbidity and mortality. Growth failure is a particular problem in adoles-
cent children. Nutritional support, either enteral or parenteral, is effective in treat-
ing or preventing malnutrition and is an essential part of management. Enteral nu-
trition is at least as effective as TPN to induce remission, maintain remission and to
treat growth failure; it is also safer and less expensive, and protects the integrity of
the intestinal mucosal barrier. There is no clear evidence for a primary therapeutic
role for TPN in these patients; prolonged courses of bowel rest and TPN do not
alter the ultimate course of the disease. Definitive medical or surgical treatment
should be provided once the patient is nutritionally repleted and stable. Nutritional
support is an important adjunct perioperatively and in the management of compli-
cations including enterocutaneous fistula and short bowel syndrome. Prolonged,
potentially lifelong, TPN at home is lifesaving and provides a reasonable quality of
life for patients with short bowel syndrome or whose disease is refractory to medical
and surgical therapy.
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CHAPTER 20
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Nutrition Support of Acute Pancreatitis
Rifat Latifi, Stanley J. Dudrick
Introduction
Acute pancreatitis ranges in severity from a minimal edematous in-flammation,
which usually resolves spontaneously and completely, to a fulminant process that
can progress to an often fatal, necrotizing hemorrhagic pancreatitis. Mild forms of
pancreatitis are manifested by abdominal pain, nausea, vomiting, and anorexia and
may be confused with many other gastrointestinal disorders. About l0-20% patients
with acute pancreatitis develop severe necrotizing pancreatitis, which is character-
ized by profound hemodynamic, cardiovascular, pulmonary, renal, hematologic, and
metabolic aberrations and is associated with high mortality.
1,2
Total parenteral nutri-
tion (TPN) and metabolic support are essential in patients with severe acute pancre-
atitis and should be started as soon as possible when the patient has developed more
than two of Ransons prognostic criteria. When prescribing nutrient substrates in
acute pancreatitis, consideration must be given to their specific effects on pancreatic
enzyme secretion, as well as their general effects on nutritional and metabolic ho-
meostasis. This chapter deals with the pathophysiology of acute pancreatitis includ-
ing the effects of alcohol, biliary disease, oxygen-derived free radicals, and the role of
pancreatic ischemia in inducing acute pancreatitis. Furthermore, associated meta-
bolic changes, nutritional support with TPN as an essential component of the care
of these patients, and rationales for the use of TPN, as well as the effects of the
nutrient substrates in this disorder are elaborated.
Pathophysiology of Acute Pancreatitis
A variety of factors can predispose a patient to acute pancreatitis. Depending on
the population studied, a history of alcohol abuse and biliary tract disease is found
in 80-90% of patients with acute pancreatitis. In addition to these primary causes of
acute pancreatitis, other operative, traumatic, metabolic, infectious, and pharmaco-
logic factors have been implicated in the pathogenesis of this disease (Table 20.1).
The mechanism by which these multiple factors initiate and sustain pancreatic in-
flammation have not been established. It is apparent, however, that pancreatic en-
zymes are activated from within the pancreas and are released into the interstitium
of the pancreas, leading to the subsequent autodigestion of the gland, which may
have devastating effects on its function. The activated pancreatic enzymes subse-
quently enter the bloodstream and leak into the peripancreatic tissue producing
characteristic fat necrosis and exudation. Activation and release of proteolytic en-
zymes (trypsinogen, chymotrypsinogen, proelastase, and phospholipase A) are stimu-
lated by a variety of factors, such as endotoxins, exotoxins, ischemia, anoxia, trauma,
3
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Table 20.1. Causes of acute pancreatitis
Nutritional Operative, Infectious Drugs Others
and Metabolic Traumatic,
Obstructive
Alcohol ingestion Intra-abdominal operations Mumps Steroids Idiopathic
Biliary tract disease ERCP Viral hepatitis Azathioprine Systemic lupus
Hypertriglyceridemia Biopsy of pancreas Coxsackie Virus Thiazides erythematosus
Tropical pancreatitis Kidney transplant Echovirus Estrogens Necrotizing angiitis
Hypercalcemia Abdominal trauma Ascariasis Tetracycline Thrombocytopenic
Hyperparathyroidism (open or blunt) Mucoplasma Valproic acid purpura
Renal failure CABG Rotavirus Chlorthalidone Vascular disease
Fatty liver of pregnancy Translumbar aortography Ethacrynic acid (mesenteric
Biliary sludge Neoplastic obstruction Procainamide thrombosis)
of ampulla of Vater L-asparaginase Hereditary
Crohns disease Sulfamethoxaz Food allergy
Duodenal diverticulum ole-Trimethoprin
Penetrating peptic ulcer Oleic acid
Pancreatic divisum
Gastrostomy tube
Foreign body in the duodenum
322
The Biology and Practice of Current Nutritional Support
20
viral infections, lysomal hydrolases, etc. Trypsin activates all of the pancreatic zy-
mogens that participate in autodigestion, which starts with erosion of the cellular
membranes and may end with extensive destruction of pancreatic tissue.
It appears, at least in experimental pancreatitis, that the secretion of zymogen
granules is blocked in individual acinar cells.
3
In turn, this blockade results in the
fusion of zymogen granules with intracellular lysosomes. Consequently, lysosomal
enzymes activate the zymogen proenzyme trypsinogen, yielding active intracellular
trypsin which is capable of cellular autodigestion.
4
The findings of acinar cell zy-
mogen granule enlargement and the formation of large auto-phagosomes during
acute pancreatitis were confirmed by pathologic examination of human tissue by
electron microscopy.
3
The constellation of morphologic changes in acute pancreati-
tis may include interstitial edema, proteolysis, vascular damage with pancreatic hem-
orrhage, fat necrosis, and parenchymal necrosis. The ultimate consequences may be
abscess formation, infection, sepsis, and pancreatic failure, which can progress to
multiple organ systems failure and death.
Alcohol and Biliary Disease
Many theories have been proposed to explain the cause and progression of acute
pancreatitis. Alcohol, the major cause of acute pancreatitis, is thought to induce
pancreatic enzyme secretion by way of chlorhydric-acid-induced secretin release and
increased ampullary sphincter tone. Alcohol is thought to cause pancreatitis by:
a. pancreatic enzyme extravasation, which is facilitated by an increase in
pancreatic ductal permeability during exocrine hypersecretion and par-
tial ampullary obstruction;
b. protein plugging of a pancreatic duct, which may initiate extravasation
and injury; and
c. transient hypertriglyceridemia. Toxic levels of free fatty acids released from
the lipolysis of triglycerides may damage acinar cells or induce endothe-
lial injury.
The mechanism by which biliary tract disease causes pancreatitis is not clear.
Recent experiments in animals suggest that pancreatic duct obstruction is the criti-
cal event that triggers acute pancreatitis in the opossum, however, bile duct obstruc-
tion alone or the reflux of bile into the pancreatic duct are important determining
factors in the development of acute pancreatitis.
5
Furthermore, bile reflux into the
pancreatic duct, via a common biliopancreatic channel, is not necessary for the de-
velopment of pancreatitis and does not worsen the severity of pancreatitis associated
with pancreatic duct obstruction.
5
Oxygen-Derived Free Radicals
The cellular and molecular mechanisms involved in the actual pancreatic injury
and extrapancreatic organ involvement are unknown. Regardless of experimental
models of acute pancreatitis (gallstones, ischemia, or alcohol), endothelial injury
and increased capillary permeability have been documented. Alterations in the pan-
creatic microvasculature have been attributed to increased activity of oxygen-de-
rived free radical activity. These unstable but highly reactive toxic metabolites of
molecular oxygen have wide-ranging effects on cells and tissues, including peroxidizing
lipids, denaturing enzymes and proteins, and accelerating tryptic activity. The
effects of oxygen-free-radical activity, and inhibition with superoxide dismutase,
were examined recently in experimental pancreatitis.
6
In this study, chemilumines-
cence (a phenomenon based on emission of light during chemical reactions that
323
Nutrition Support of Acute Pancreatitis
20
depends on oxygen-free-radical activity) was used as an index of oxygen-free-radical
activity. Rats treated with superoxide dismutase, the activity of which depends on
scavenging free radicals, after induction of severe hemorrhagic pancreatitis with so-
dium taurocholate, had significantly reduced chemiluminescence and hyper-
amylasemia. Increased oxygen-free radical activity paralleled evolving pancreatitis,
and superoxide dismutase was thought to have a therapeutic role in pancreatitis.
Whether superoxide dismutase will induce the same effects if administered systemi-
cally remains to be seen. However, when experimental pancreatitis was induced in
dogs by the intraductal infusion of activated trypsin and taurocholate, pretreatment
with catalase and superoxide dismutase prevented the rise in mean blood pressure,
moderated the rise in pulmonary vascular resistance, and decreased the rate and
extent of the fall in cardiac index.
7
Furthermore, with an ex vivo blood-perfused
canine lung lobe, the lung injury induced by -chymotrypsin was significantly at-
tenuated by pretreatment with a combination of the reactive oxygen scavengers,
superoxide dismutase and catalase.
8
However, pretreatment of the lobe with super-
oxide dismutase alone did not protect the lobe from -chymotrypsin-induced in-
jury in this study.
8
The data suggest that reactive oxygen metabolites may play some
role in extra-abdominal organ manifestations, such as early cardiopulmonary changes
of acute pancreatitis, in addition to local effects.
Pancreatic Ischemia in Experimental Acute Pancreatitis
Necrosis of pancreatic and peripancreatic tissue is a key factor in the evolution of
pancreatitis from mild to severe. The question as to whether necrotizing injury is
caused by enzymes or ischemia is receiving more and more attention.
9
That ischemia
is the initiating or aggravating factor in acute pancreatitis is well documented. Hem-
orrhagic-necrotizing pancreatitis has been produced with intra-arterial injection of
8 m to 20 m microspheres that irreversibly obstruct terminal arterioles. On the
other hand, obstruction of larger, more proximal vessels results only in pancreatic
edema.
10
Furthermore, ischemia superimposed on pancreatic edema leads to necro-
tizing pancreatitis. The relationship between splanchnic hypoperfusion and acute
pancreatitis has been identified,
11
and changes in pancreatic microcirculation dur-
ing acute pancreatitis are well documented.
9
These specific disturbances of pancre-
atic microcirculation are characterized by heterogeneous and low capillary blood
flow and increased blood viscosity. Possible contributory mechanisms for these
changes include chemical-induced vasoconstriction, injury to a vessel wall, intravas-
cular coagulation, and increased endothelial permeability resulting in pancreatic
edema, hemoconcentration, and impaired venous drainage. Protecting the pancreas
from secondary injury caused by the early ischemic phase of acute pancreatitis, or
correcting existing changes in microcirculation by restoring volume with a dextran
preparation and increasing pancreatic perfusion, may prove to be the indicated treat-
ment at the early stages of this potentially fatal disease.
9
Metabolic Changes and Other Complications
in Acute Pancreatitis
Regardless of the cause and mechanism of acute pancreatitis, a broad spectrum
of systemic disturbances can ensue secondary to circulating hydrolytic enzymes and
toxins, compounding the severity of local or regional disturbances (Table 20.2).
Local activation of inflammatory cells may result in the systemic release of inflam-
matory mediators that not only relate to the severity of the pancreatitis, but that can
3
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Table 20.2. Potential complications of acute pancreatitis
Local and Regional Systemic
Pancreatic phlegmon METABOLIC PULMONARY
Pancreatic abscess Hypoproteinemia Pleural effusion
Pancreatic pseudocyst Hypoalbuminemia Atelectasis
Pain Hyperglycemia Pneumonitis
Rupture Hypertriglyceridemia Mediastinal abscess
Hemorrhage Hypocalcemia Adult respiratory distress syndrome
Obstruction of GI tract Hypomagnesemia
(stomach, duodenum, colon) Hyperamylasemia RENAL
Paralytic ileus Hyperlipasemia Oliguria
Pancreatic ascites Hyperbilirubinemia Azotemia
Disruption of main pancreatic duct Abnormal liver function Renal artery and/or renal vein thrombosis
Leaking pseudocyst Pancreatic encephalopathy
Involvement of contiguous organs Fat necrosis HEMATOLOGIC
by necrotizing pancreatitis Decreased BCAA/AAA ratio Anemia
Massive intraperitoneal hemorrhage Thrombocytopenia
Thrombosis of blood vessels CARDIOVASCULAR Disseminated intravascular coagulopathy
Bowel infarction Hypotension
Common bile duct obstruction Hypovolemia CNS
Sudden death Psychosis
Nonspecific ST-T changes in Fat emboli
electrocardiogram simulating
myocardial infarction
Pericardial effusion
325
Nutrition Support of Acute Pancreatitis
20
subsequently influence gut permeability. Among the inflammatory products identi-
fied in early pancreatitis, granulocyte elastase and interleukin 6 (IL-6) correlate best
with severity of pancreatitis and mortality of the disease.
12
These products and other
mediators, such as interleukin-1, tumor necrosis factor (TNF), or histamine, may
directly or indirectly alter gut permeability by damaging intestinal mucosa. Increased
gut macromolecular permeability in early acute pancreatitis has recently been docu-
mented and also correlates with the extent of injury in patients with burns.
13,14
Fur-
thermore, a direct relationship between gut permeability and the severity of pancre-
atitis has also been shown, although the clinical implications of enhanced gut
permeability in this disease is still ill-defined. The gut permeability that was seen
only in the presence of pancreatitis was thought to be a response to changes in
homeostasis or to the acute inflammatory reaction initiated by the pancreas.
Although acute pancreatitis originates locally, extensive tissue destruction may
generate profound systemic metabolic derangements, adversely affecting multiple
organ systems accompanied by hemodynamic and cardiovascular changes. Acute
pancreatitis induces hypermetabolism with increased protein hypercatabolism. Of-
ten, this disease occurs in patients with severe nutritional depletion secondary to
extensive alcohol intake, chronic liver or biliary tract disease, and protein malnutri-
tion. The increased metabolic rate further accelerates depletion of endogenous pro-
tein and fat stores. The severity of the metabolic disorders or nutritionally related
complications correlates well clinically with the severity and duration of acute pan-
creatitis. Resting energy expenditure (as a percent of predicted energy expenditure)
was significantly (p<.02) greater in patients with pancreatitis complicated by sepsis
(120% 11%) than in patients with non-septic chronic pancreatitis (105% 14%).
15
Patients with severe acute pancreatitis (more than three prognostic signs) had a mean
energy expenditure of 126% to 149% of predicted energy compared with those
having two or less prognostic signs (111% 15%) (p<.03).
15
Patients with severe
acute pancreatitis, defined by poor general physical condition, multiple organ sys-
tems failure, positive peritoneal signs, ascites, pancreatic enlargement with exudate
confirmed by non-invasive imaging techniques (ultrasound, CAT scan or magnetic
resonance imaging), and at least two abnormal clinical chemistries, usually present
with significant metabolic alterations.
16,17
Biochemical Abnormalities
Patients with severe acute pancreatitis present with metabolic, cardiovascular,
and hemodynamic features similar to those observed in sepsis. In addition to glu-
cose intolerance, ureagenesis is increased, net protein catabolism is accentuated by
70%-80%, and in some patients with acute pancreatitis, net nitrogen losses increase
to as much as 20 g to 40 g/day.
18,19
Decreased levels of total plasma proteins and
rapid turnover proteins, together with a marked decrease of the branched-chain
amino acid/aromatic amino acid (BCAA/AAA) ratio, further illustrate a
hypercatabolic state with significant protein breakdown. Significant decreases in
plasma essential amino acids, with marked reductions of almost all amino acids in
the liver and increased uptake of endogenous amino acids by the skeletal muscle
mass, have been reported clinically and experimentally.
17
Other biochemical abnormalities are also present and are considered to be useful
indicators of the severity of acute pancreatitis. Gross elevations in plasma concentra-
tions of the pancreatic enzymes usually accompany severe forms of the disease. How-
ever, although widely used in the clinical setting, the degree of elevation of plasma
326
The Biology and Practice of Current Nutritional Support
20
amylase does not correlate well with the degree of severity of acute pancreatitis.
20
However, the ratio of the amylase clearance to the creatinine clearance has not been
found to be reliable in diagnosing acute pancreatitis.
Other enzymes that may be elevated in severe acute pancreatitis include plasma
lipase, phospholipase A, elastase, trypsin, chymotrypsin, and acid catalase. Plasma
levels of glucose, bilirubin, alkaline phosphatase, lactic dehydrogenase, and triglyc-
erides become moderately to highly elevated as the severity of the disease increases.
Increased plasma concentration of pancreas-specific protein (PASP) has been
found in acute pancreatitis and offers some promise as a novel assay for pan-
creatic cellular damage.
21
Recently, an acute-phase protein, the pancreatitis-associated protein (PAP), has
been found to be increased at least l00-fold in pancreatic tissue during the acute
phase in experimentally induced pancreatitis in rats.
22
This new protein was first
observed 6 hours after induction of experimental pancreatitis with taurocholate or
cerulein, reached maximal levels at 48 hours, and disappeared during recovery (day
5). This molecule is synthesized on the rough endoplasmic reticulum and stored in
zymogen granules before being secreted as are other pancreatic secretory proteins.
Other substances produced by the pancreas are reported to be increased during
acute pancreatitis. Among them, serum pancreatic phospholipase A
2
(PLA
2
), which
is secreted by pancreatic acinar cells as an enzymatically inactive proenzyme (pro
PLA
2
) but that is activated by trypsin, is significantly increased in patients with
acute pancreatitis and in the active phase of chronic pancreatitis. This enzyme is also
increased in patients in the early stage of pancreatic cancer; however in the terminal
state of pancreatic cancer, the serum PLA
2
level is low.
An important biochemical abnormality resulting from acute pancreatitis is the
depletion of intravascular albumin. Consequently, circulating protein-bound cal-
cium decreases, precipitating hypocalcemia, which may be accompanied by increased
plasma levels of parathormone and calcitonin.
23
In addition, plasma magnesium
levels decrease in patients with the more severe forms of acute pancreatitis. Other
trace elements are depleted
24
as a result of long standing secondary malnutrition and
not primarily because of the pancreatitis itself.
Lung Injury
Acute respiratory distress syndrome is a well recognized complication of acute
pancreatitis. Although the mechanism of action is unknown, the effects of pancre-
atic elastase in pulmonary vascular injury has been suggested.
25
Recent studies have
found that circulatory pancreatic proteases (alpha-chymotrypsin) can cause acute
lung injury that is mediated, at least in part, by toxic oxygen metabolites that are not
of neutrophil origin.
8
Elevated levels of free fatty acids or phospholipase associated
with pulmonary surfactant destruction, which consequently leads to the develop-
ment of atelectasis and fluid exudation, have been proposed as possible mechanisms
of injury.
26
Chymotrypsin may trigger proteolytic conversion of xanthine dehydro-
genase into the oxygen radical-producing xanthine oxidase in pulmonary artery en-
dothelial cells. Furthermore, alpha-chymotrypsin may stimulate radical oxygen me-
tabolite production in pulmonary endothelial cells.
8
Nutritional Management in Acute Pancreatitis
The severity of acute pancreatitis depends on the action of elevated pancreatic
enzymes associated with an inflammatory response of variable intensity that is
327
Nutrition Support of Acute Pancreatitis
20
mediated by the activation of proteolytic systems and inflammatory cells. The preva-
lence of specific nutritional deficiencies in patients with acute pancreatitis depends
also on a number of other factors. Among them, the cause of the pancreatitis and
the severity of the disease, combined with premorbid nutritional status are the most
important. Because almost 80-90% of episodes of acute pancreatitis are short and
self-limited, exceptional nutritional measures in these patients are rarely indicated.
However, in those patients with severe pancreatitis who manifest more than two
adverse prognostic factors
27-30
(Table 20.3) at admission or who experience them
subsequently during the first 48 hours of hospitalization, individualized nutritional
support should be started as soon as possible.
The current general therapeutic principles in the nutritional management of
acute pancreatitis involve: aggressive nutritional support, essential to insure optimal
provision of nutrient substrates, and reducing pancreatic exocrine secretion and
maintaining the gastrointestinal tract and the pancreas at rest. Several reports
have confirmed that total parenteral nutrition (TPN) has substantially reduced mor-
bidity and mortality in this disease.
31-35
In one series, TPN reduced mortality from
26.1% to 14%.
33
In another study of 29 patients with moderate to severe pancreati-
tis, those receiving TPN had a mortality rate of 7% whereas those receiving only
conventional intensive therapy but without TPN had a mortality rate of 45%.
17
Yet others found no distinct advantage to the use of early TPN in acute pancreatitis
as measured by the number of days before oral feeding was started, length of hospi-
tal stay, and number of complications.
36
This failure to show an advantage of
TPN early in the course of acute pancreatitis may be secondary to the study
population and design, and perhaps the composition of TPN formula. Most
of the patients had mild pancreatitis, which would resolve anyway, and in patients
with fulminant pancreatitis and in those with multiple organ systems failure, nutri-
tional support was not carefully and individually tailored. The high rate of cath-
eter-related infections in this study was not explained.
Recently, TPN was found to be beneficial in patients with complex metabolic
alterations resulting from severe acute pancreatitis and in patients with underlying
malnutrition, before or after surgical intervention.
37
Thus, early aggressive nutri-
tional support is strongly recommended in these subgroups of patients. This recom-
mendation is based primarily on the potential benefits of TPN in acute pancreatitis,
which include, among others, the preservation or restoration of nutritional status in
patients who have not been fed for long periods, yet who are in a hypercatabolic
state with increased caloric and nitrogen demands, and on the beneficial impact of
TPN on the disease process by suppressing pancreatic secretion.
The Effects Of Nutrient Substrates
The effects of specific nutrient substrates on the exocrine pancreas and the best
route of their administration have been debated. Ingested nutrients stimulate
exocrine pancreatic secretion by activating enterohepatic reflexes and enteral hor-
mones and by directly affecting the pancreas. Total parenteral nutrition not only
provides all the nutrients but bypasses the effects of enterohepatic reflexes and en-
teral hormones. Intravenous infusion of 20% dextrose or 30% dextrose and 12%
amino acid solution significantly inhibited the secretion of secretin-pancreozymin
stimulated pancreatic juice and amylase in dogs with chronic fistulas.
38
Intravenous
administration of some amino acids, individually or in combination, also depressed
pancreatic exocrine secretions.
38,39
Moreover, it is well known that free amino acids
infused into the duodenum also decrease pancreatic secretion.
328
The Biology and Practice of Current Nutritional Support
20
Inhibition of Pancreatic Secretion
Somatostatin is considered to be the best inhibitor of pancreatic secretion, and
its use in the treatment of acute pancreatitis, to directly inhibit pancreatic secretion,
is becoming standard clinical practice. In a large multicenter study, somatostatin,
when used with TPN, yielded the best results in a group of patients with necrotiz-
ing-hemorrhagic pancreatitis.
40
In humans, somatostatin inhibits HCL-induced and
alcohol-induced secretin secretion; inhibits cholecystokinin release; markedly in-
hibits pancreatic enzyme secretion; may reduce duodenal output of trypsin, chy-
motrypsin, and amylase by 65% to 90%; affects gut motility; slows gallbladder and
gastric emptying rates; and reduces the sphincter of Oddi basal pressure.
41
To sup-
press or neutralize pancreatic enzymes, the synthetic anti-proteases (gabexate mesilate
and nafamostat mesilate) have also been used to treat acute pancreatitis. In a recent
study, these two agents were useful in the treatment of experimental acute pancreati-
tis.
42
The strongest depressant of pancreatic exocrine secretion, other than soma-
tostatin and glucagon, is the infusion of hypertonic salts and dextrose into the je-
junum. On the other hand, hydrochloric acid, meat extracts, antral distention, fat,
protein, calcium, and magnesium all increase pancreatic exocrine secretion.
In acute experimental pancreatitis, pancreatic exocrine secretion has been found
to be suppressed.
43
The secretory blockade was found in different models of acute
pancreatitis and reflected the severity of the disease. Cholecystokinin-stimulated
secretion was almost abolished in vivo and in vitro at the time of maximal histologi-
cal damage.
43
Clinical studies indirectly evaluating pancreatic secretory function in-
dicated that pancreatic secretion is reduced in most patients between 3 and l0 days
after the onset of pancreatitis,
44
but secretions gradually improve in most patients
after a few months, although, in patients with severe necrotizing pancreatitis, com-
plete functional recovery may take more than one year.
45
Because pancreatic secre-
tion, especially pancreatic secretory response to cholecystokinin, is reduced during
Table 20.3. Factors adversely influencing survival in acute pancreatitis
I. At admission to hospital
Age >55 years
Hypotension
Abnormal pulmonary findings
Abdominal mass
Hemorrhagic or discolored peritoneal fluid
Increased serum LDH levels (> 350 IU/dL)
SGOT >259 U/dL
Leukocytosis (> l6,000/mm
3
)
Hyperglycemia (>200 mg/dL, no diabetic history)
Neurologic deficit (confusion localizing signs)
II. During initial 48 h of hospitalization
Fall in hematocrit > 10% with hydration and/or hematocrit <30%
Necessity for massive fluid and colloid replacement
Hypocalcemia (< 8 mg/dL)
Arterial PO
2
< 60 mm Hg with or without adult respiratory distress syndrome
Hypoalbuminemia (< 3.2 g/dL)
Base deficit > 4 mEq/L
Azotemia
329
Nutrition Support of Acute Pancreatitis
20
acute pancreatitis, experimentally and possibly clinically, this secretory blockade
might, at least in part, explain why acute pancreatitis is not treated effectively by inhib-
iting secretion with atropine, cimetidine, glucagon, calcitonin, and somatostatin.
41
Rationale for TPN in Acute Pancreatitis
The indications for the use of TPN in severe acute pancreatitis are multiple and
usually urgent.
28,32,46,47
Not only may the nutritional status of these patients deterio-
rate rapidly, but prolonged ileus, respiratory and renal failure, severe metabolic aber-
rations, and multiple major surgical interventions will interfere with adequate oral
or enteral feeding, further complicating existing malnutrition. Indeed, providing
complete nutrient substrates via TPN while allowing pancreatic rest has been an
effective modality of nutritional support and has reduced morbidity and mortality
in these patients.
48-50
Other investigators
17,34
have concluded that the use of TPN in
the treatment of acute severe pancreatitis has decreased complications, has effec-
tively suppressed exocrine secretion, and has been an essential adjunct to conven-
tional intensive care. Adequate nutrition provided parenterally not only promotes
restoration of damaged pancreatic tissue, but enhances spontaneous closure of pan-
creatic fistulas,
48,51
and stimulates and maintains immunocompetence, thus poten-
tially improving the patients general condition before and after surgery. This will
allow surgical treatment of late-stage complications, such as pseudocyst, pancreatic
abscesses or fistulas.
52
Additionally TPN bypasses the cephalic, gastric, and intesti-
nal phases of pancreatic secretion, reducing by up to 50% the pancreatic acinar
nuclear volume, cell volume, and synthetic activity and substantially reducing the
basal pancreatic and proteolytic and bicarbonate secretions.
28,53,54
If, on the other
hand, the patient undergoes pancreatic debridement, surgeon should obtain long
term gut access by placing a surgical jejunostomy or at least a naso-jejunal feeding
tube, and start enteral feedings as soon as possible.
Dextrose and Amino Acids
Intravenous nutritional formulations should be selected on the basis of the ef-
fects that the individual nutrient substrates have on pancreatic secretions. Each nu-
trient has a different specific effect and a different potency for stimulating the re-
lease of each peptide hormone. Intravenous hypertonic dextrose suppresses both the
fluid volume and the proteolytic enzyme concentration of pancreatic secretion, an
action attributed in part to increased serum osmolality. The effect of amino acids in
suppressing pancreatic exocrine secretion is also well known. Even though patients
with severe acute pancreatitis are metabolically similar to septic patients with sig-
nificantly depressed uptake of the exogenous carbohydrate load, dextrose remains
the nutrient of choice as the main energy source in acute pancreatitis.
Patients with hemorrhagic necrotizing pancreatitis show persistent nitrogen loss
with low intracellular glutamine concentrations in skeletal muscle,
17
in addition to a
marked decrease in the BCAA/AAA ratio that correlates inversely with the progres-
sion of the disease.
38
Therefore, administering highly concentrated amino acid solu-
tions, augmented with extra valine, isoleucine, alanine, and arginine, which are sig-
nificantly decreased in plasma and tissue, has been recommended in the nutritional
support of patients with severe acute pancreatitis.
38
Nitrogen balance and amino
acid profiles have also improved when metabolically stressed patients were given
BCAA enriched solutions.
55
330
The Biology and Practice of Current Nutritional Support
20
Lipids
The use of intravenous lipids as an energy source during acute pancreatitis has
been controversial.
56
Although infused intravenous lipid emulsions may appear to
be a safe and effective calorie source and may be helpful in acute pancreatitis com-
pounded by severe lung failure and by an elevated pCO
2
, each patient must be
closely monitored because fat infusion may aggravate pancreatitis in a significant
number of patients.
57
Intravenous fat administration has actually been identified as
the cause of pancreatitis in a patient with Crohns disease being treated with lipid-
based TPN, and patients receiving lipid-based TPN formulations have been known
to have significantly elevated serum AST.
56
A reduction in survival rate occurred in
patients receiving lipid emulsion combined with dextrose compared with patients
who received dextrose as their only energy source in the parenteral nutrition regi-
men.
17
Lipid emulsions should be avoided in patients with acute pancreatitis and
abnormal triglyceride metabolism . In laboratory animals with acute severe pancre-
atitis, studies with infused radioactive lipid emulsions have indicated that uptake of
the emulsion with production of CO
2
was slightly to moderately depressed, de-
pending on the structure of the fatty acids.
38
Others
50
have suggested that excess free
fatty acids damage capillary membranes and cause the consequent release of pancre-
atic enzymes, implying that elevated fatty acid levels may promote pancreatic exo-
crine secretion. Increased plasma triglyceride levels also cause acute pancreatitis.
Another clear contraindication to the use of intravenous lipid emulsions as the ma-
jor energy source in patients with acute pancreatitis is a lipid disorder (type I, IV and
V hyperlipoproteinemia). Because intravenous lipids also significantly increase pan-
creatic output in the form of bicarbonate and protein concentrations,
58
it appears
that the best dietary formulation for patients with severe pancreatitis is a fat-free
intravenous solution of crystalline amino acids and hypertonic dextrose to which
appropriate daily requirements of electrolytes, vitamins, minerals and trace elements
have been added.
Administration and Monitoring of TPN
Total parenteral nutrition is administered continuously over 24 hours, with ap-
propriate adjustments to infusion rate and nutrient concentration and composi-
tion.
46
Conscientious and meticulous biochemical and hematologic monitoring of
these patients is necessary to identify and promptly prevent and treat any renal fail-
ure, hepatic decomposition, or fluid, electrolyte and trace element imbalances that
might accompany unrelenting disease. Restoring nitrogen balance has a striking
beneficial influence on survival of the patient with severe pancreatitis, whereas
failure to achieve nitrogen balance has been associated with a ten-fold increase in
mortality (2.5% vs. 2l.4%, p<.0l).
56
H
2
receptor blockers should be added to the
infusion in standard intravenous doses to thwart gastric secretion, and human insu-
lin should be added as needed to control hyperglycemia. Both are compatible with
TPN formulations. Patients with severe necrotizing hemorrhagic pancreatitis may
require rather large amounts of insulin to maintain normal blood glucose levels,
especially in the presence of uncontrolled infection, occult abscesses or frank sepsis,
and diabetic ketoacidosis, alone or in combination.
The preferred route of nutritional support depends on the acuity and severity of
the disease, as well as an understanding of the physiology of pancreatic stimulation.
While parenteral nutrition has become a standard component of therapy in the
treatment of severe acute pancreatitis, enteral feedings, preferably immune-enhancing
331
Nutrition Support of Acute Pancreatitis
20
diets, should be used whenever possible. Enteral feeding may supply nutrients if the
major responses to cephalic, gastric, and intestinal phases of pancreatic stimulation
are bypassed by infusion distal to the duodenum. Significant increases in pancreatic
secretions and protein output mediated by CCK-PZ stimulation are induced with
intraduodenal infusion of elemental diets in dogs;
59
therefore, intrajejunal feeding is
the method of choice. However, small bowel obstruction, enteritis, entero-enteric
and entero-cutaneous fistulas, or severe paralytic ileus often preclude enteral feeding
in patients with severe pancreatitis.
Maintenance of intestinal mucosal integrity and the gut mucosal barrier has
been suggested as a potential benefit of enteral feeding.
60
However, the most practi-
cal feeding method in patients with severe pancreatic inflammation, abscesses, and
fistulas is TPN. Failure to reduce pancreatic stimulation and to reverse malnutrition
as a major complication of severe acute pancreatitis may profoundly affect survival
of these patients.
56
Total parenteral nutrition should be continued until the symptoms abate, pan-
creatic encephalopathy and ileus resolve, and all serious metabolic derangements
disappear. Only when enteral intake can maintain optimal nutrition without exac-
erbating the symptoms of pancreatitis should TPN be discontinued.
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3. Kloppel G, Dreyer T, Willemer S et al. Human acute pancreatitis: its pathogenesis
in the light of immunocytochemical and ultrasound findings in acinar cells. Virch
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4. Steer ML, Meldolesi. The cell biology of experimental pancreatitis. NEJM 1987;
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5. Lerch MM, Salnja A, Kunzi M et al. Pancreatic duct obstruction triggers acute
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8. Toung JKT, Senda KJ, Rosenfeld BA et al. Lung injury produced by pancreatic
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9. Klar E, Messmer K, Warshaw AL et al. Pancreatic ischaemia in experimental pan-
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Ann Surg 1984; 188:197-201.
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centration precedes acute-phase response and reflects severity in acute pancreatitis,
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13. Ryan CM, Yarmush ML, Burkee JF et al. Increased gut permeability early after
burns correlates with extent of injury. Crit Care Med 1992; 20:1508-1512.
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15. Dickerson RN, Wehe KL, Mullen JL et al. Resting energy expenditure in patients
with pancreatitis. Crit Care Med 1991; 19:484-490.
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A, eds. Nutritional Support in Organ Failure. Amsterdam: Elsevier Science Pub-
lishers, 1990.
18. Bouffard YH, Delafosse BX, Annat GJ et al. Energy expenditure during severe
acute pancreatitis. JPEN 1989; 13:26.
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pancreatitis. Ann Surg 1986; 406:665.
20. Imrie CW, Wilson C. Systemic manifestations and the hematological and bio-
chemical consequences of acute pancreatitis. In: Glager G and Ransom JHC, eds.
Acute pancreatitis. Bailliere Tindall, 1988.
21. Fernstad R, Pousette A, Carlstrom K et al. A novel assay for pancreatic cellular
damage: Serum concentrations of pancreas-specific protein (PASP) in acute pan-
creatitis and other abdominal diseases. Pancreas 1990; 5:1:42-49.
22. Klein V, Iovanna JL, Rohr G et al. Characterization of a rat pancreatic secretory
protein associated with pancreatitis. Gastroenterol 1991; 100:775-782.
23. Imrie CW, Allam BF, Ferguson JC. Hypocalcemia of acute pancreatitis: the effect
of hypoalbuminemia. Current Medical Research and Opinion 1976; 4:101-116.
24. William RB, Russel RM, Dutta SK. Alcoholic pancreatitis - patients at high risk of
acute zinc deficiency. Am J Med 1979; 66:889-893.
25. Lungarella G, Gardi C, De Santi MM et al. Pulmonary vascular injury in pancre-
atitis: evidence for a major role played by pancreatic elastase. Exp Mol Path 1985;
43:44-49.
26. Guice KS, Oldham KT, Wolfe RR et al. Lung injury in acute pancreatitis: primary
inhibition of pulmonary phospholipid synthesis. Am J Surg 1987; 153:54-61.
27. Grant JP, James S, Grabowski V et al. Total parenteral nutrition in pancreatic dis-
ease. Ann Surg 1984; 200:627-631.
28. Pitchumoni CS, Scheele GA. Interdependence of nutrition and exocrine pancre-
atic function. In: Go VLW, Dimagno EP, Gardner JD et al, eds. The pancreas:
biology, pathobiology and disease, 2nd ed. New York: Raven Press 1993:449-473.
29. Ranson JHC. Etiological and prognostic factors in human pancreatitis: a review,
Am J Gastroenterol 1983; 77:663-668.
30. Ranson JHC. Prognostication in acute pancreatitis. In: Glazer G, Ranson JHC,
eds. Acute pancreatitis, Bailliere Tindal, 1988.
31. Blackburn GL, Williams LF, Bistrian B et al. New approaches to the management
of severe acute pancreatitis. Am J Surg 1976; 131:114-124.
32. Copeland EM, Dudrick SJ. Intravenous hyperalimentation in inflammatory bowel
disease, pancreatitis and cancer. Surg Ann 1980; 12:83-101.
33. Feller JH, Brown RA, Toussaint GPM et al. Changing methods in the treatment of
severe pancreatitis. Am J Surg 1974; 127:196-201.
34. Funakoshi A, Yamada Y, Migita Y et al. Simultaneous determination of pancreatic
phospholipase A
2
and prophospholipase A
2
in various pancreatic diseases. Dig Dis
Scien 1993; 38;3: 502-506.
35. Goodgame JT, Fischer JE. Parenteral nutrition in the treatment of acute pancreati-
tis: effect on complications and mortality. Ann Surg 1977; 186:651-658.
36. Sax HC, Warner BW, Talanimi MA et al. Early total parenteral nutrition during
acute pancreatitis: lack of beneficial effects. Am J Surg 1987; 153:117-124.
37. Robin AP, Campbell R, Palani CK et al. Total parenteral nutrition during acute
pancreatitis: clinical experience with l56 patients. World J Surg 1990; 14:572-579.
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38. Ohyanagi H, Usami M, Nishimatsu SH et al. Metabolic changes and their man-
agement in acute pancreatitis. In Tanaka T, Okada A, eds.. Nutritional support in
organ failure. Amsterdam: Elsevier Science Publishers, 1990:351-363.
39. Saitoh Y, Honda T, Matsuno S et al. Effect of eight amino acids on the exocrine
and endocrine function. Tohoku J Exp Med 1979; 129:257-272.
40. Ladas SD, Raptis SA. Conservative treatment of acute pancreatitis: the use soma-
tostatin. Hepato-Gastroenterol 1992; 39:466-469.
41. DAmico D, Favia G, Biasiato R et al. The use of somatostatin in acute pancreati-
tis: results of a multicenter trial. Hepato-Gastroenterol 1990; 37:92-98.
42. Dobosz M, Sledzinski Z, Babicki A et al. Synthetic antiproteases in acute pancre-
atitis. Mount Sinai J Med 1992; 59:43-46.
43. Niederau C, Niederau M, Lthen R et al. Pancreatic exocrine secretion in acute
experimental pancreatitis. Gastroenterol 1990; 99:1120-1129.
44. Mitchell CJ, Playforth MJ, Kelleher J et al. Functional recovery of exocrine
pancreas after acute pancreatitis. Scand J Gastroenterol 1983; 18:5-8.
45. Angelini G, Pederzoli P, Caliary et al. Long-term outcome of acute necrohemorrhagic
pancreatitis. Digestion 1984; 30:131-137.
46. Latifi R, McIntosh JK, Dudrick SJ. Nutritional management of acute and chronic
pancreatitis. Surg Clin North Am 1991; 73:579-595.
47. Mooton G, Pistorelli C, Fracastoro G et al. Role of complete parenteral treatment
nutrition in acute pancreatitis. In: Hollender LF, ed. Controversies in Acute pan-
creatitis. Berlin: Springer-Verlag, 1982:293-296.
48. Dudrick SJ, Wilmore DW, Steiger E et al. Spontaneous closure of traumatic
pancreatoduodenal fistulas with total intravenous nutrition. J Trauma 1970;
10:542-553.
49. Variam FP. Central vein hyperalimentation in pancreatic ascites. Am J Gastroenterol
1983; 78:178-181.
50. White TT, Heinbach DM. Sequestrectomy and hyperalimentation in the treat-
ment of hemorrhagic pancreatitis. Am J Surg 1976; 132:270-275.
51. Rowlands BJ, Dudrick SJ. Nutritional support of the infected patient. In: Powanda
MC, Canonica PG, ds. Infection: The Physiologic and Metabolic Responses of the
Host. Amsterdam: Elsevier Science Publishers, 1981:359-397.
52. MacFadyen BV, Dudrick SJ, Ruberg RL. Management of gastrointestinal fistulas
with parenteral hyperalimentation. Surgery 1973; 74:100-105.
53. Johnson LR, Schanbacher LM, Dudrick SJ et al. Effect of long-term parenteral
feeding on pancreatic secretion and serum secretin. Am J Physiol 1977;
233:E524-E529.
54. Paviat WA, Rodgers W, Cameron JL. Morphologic analysis of pancreatic acinar
cells from orally fed and intravenously fed rats. J Surg Res 1975; 19:267-276.
55. Havalo T, Shrouts E, Cerra F. Nutritional support in acute pancreatitis. Gastroenterol
Clinic North Am 1989; 18:528-541.
56. Sitzman FJ, Steinborn PA, Zinner MJ et al. Total parenteral nutrition and alter-
nate energy substrates in treatment of severe acute pancreatitis. Surg Gyn Obstet
1989; 168:311-317.
57. Leibowitz AB, OSullivan P, Iberti TJ. Intravenous fat emulsions and the pancreas:
a review. Mount Sin J Med 1990; 59:38-42.
58. Konturek SJ, Tasler J, Cieszkowski M et al. Intravenous amino acids and fat stimu-
lation of pancreatic secretion. Am J Physiol 1979; 233:E 678-684.
59. Wolfe BM, Keltner FM, Zkraminski DL. The effect of an intraduodenal el-
emental diet on pancreatic secretion. Surg Gyn Obstet 1975; 140:241-245.
60. Deitch EA, Bridges RM. Effect of stress and trauma on bacterial translocation
from gut. J Surg Res 1987; 42:536-.
CHAPTER 21
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Nutritional Management of Chronic
Pancreatitis: Current Concepts
Rifat Latifi, Paul G. Perch and Stanley J. Dudrick
Introduction
Chronic pancreatitis is characterized histologically by progressive, destructive,
irregular, and irreversible fibrosis of the pancreas. Ultimately, it is manifested by
intermittent or persistent abdominal pain and signs and symptoms related to the
loss of pancreatic exocrine and endocrine functions, including maldigestion and
malabsorption, diarrhea, steatorrhea, and azotorrhea with subsequent muscle wast-
ing, weight loss, and pancreatic diabetes. The recurrent inflammatory process re-
sults in constrictive fibrosis and destruction of pancreatic tissue, leading to a significant
reduction of pancreatic cell mass. An anatomical and functional deterioration of the
pancreas progresses with each recurrence of inflammation. The most prominent
complaints are persistent dull epigastric pain radiating to the back particularly in
the region of the upper lumbar vertebrae, accompanied by anorexia, nausea, vomit-
ing and diarrhea that are intensified by eating. These unpleasant, uncomfortable
and often recalcitrant signs and symptoms regularly result in the systemic complica-
tions of malabsorption and malnutrition, multiple operations, narcotic dependency,
and associated debilitating psychological and social problems.
In addition, chronic pancreatitis may be manifested by a number of well-recog-
nized secondary complications such as common bile ductobstruction, gastric outlet
or duodenal obstruction, pancreatic ductstones, strictures or obstruction, pancre-
atic pseudocysts, pancreatic fistulas, (pancreatico-pleural, pancreatico-enteric,
pancreatico-cutaneous), portal vein thrombosis and splenic vein thrombosis.
12
These
serious conditions often indicate the need for complex surgical interventions, which
further aggravate overall poor nutritional and metabolic status of these patients.
Other less common complications associated with chronic pancreatitis include gas-
trointestinal bleeding, ascites, pleural effusion, development of carcinoma, retinal
changes, metastatic fat necrosis, intermedullary calcification and parotid hypertro-
phy. Physiologic changes in gallbladder motility and CCK secretion are also associ-
ated with pancreatic insufficiency due to chronic pancreatitis.
53
It has also been
demonstrated that the chronic inflammatory process in chronic pancreatitis alters
the distribution and function of immunocompetent peripheral blood lymphocytes.
49
The pancreas has multiple important functions, treating a patient who has lost
pancreatic function and has persistent and intractable abdominal pain represents a
very difficult challenge for all involved. Correcting nutritional deficiencies and
maintaining optimal nutritional and metabolic status for these patients is of utmost
335
Nutritional Management of Chronic Pancreatitis
21
importance in achieving a favorable outcome. This chapter reviews current concepts
in nutritional and metabolic support of patients with chronic pancreatitis, with
special attention to the role of exogenous pancreatic enzyme administration for the
optimal enhancement of digestion and absorption.
Etiologic and Risk Factors of Chronic Pancreatitis
The most common cause of chronic pancreatitis is excessive and prolonged alco-
hol consumption (about 75% of all cases). The remaining 25% of patients with
chronic pancreatitis have idiopathic, nutritional, hereditary, post-traumatic, con-
genital or metabolic etiologies.
3
Among the metabolic initiating factors, hyperpar-
athyroidism, hyperlipidemia, diabetes mellitus, and renal failure are the most
common. Other less common conditions or etiologies which are known to induce
chronic pancreatitis include pancreas divisum, cystic fibrosis, Ehlers-Danlos syn-
drome, vascular insufficiency, Crohns disease, and tuberculosis. The precise role of
gallstones or dysfunction of the sphincter of Oddi in the etiology of chronic pancre-
atitis remain controversial but it appears at the least to be a significant collateral
factor. Although many alcoholic patients also smoke, an independent and separate
causal relationship between smoking and chronic pancreatitis may exist, especially
in men. Other factors placing the patient at increased risk for chronic pancreatitis
include protein deprivation, cyanogenetic glycosides in cassava and chronic cyanide
toxicity (from smoking or cassava).
1
Deficiencies of trace elements such as zinc,
selenium, or copper may also play a role in the development of chronic pancreatitis.
Regardless of the original cause of chronic pancreatitis, recurrent inflammation
can lead to an obstructive process in the minor ducts. The morphologic changes
observed at the microscopic level include acinar cell apoptosis, ductular prolifera-
tion and fibrosis. In addition the pancreatic ducts exhibit tortuosity and periductal
fibrosis. These alterations are the suspected result of a defensive assault against el-
evated pancreatic duct pressures.
58
Eventually, ductal obstruction leads to a general-
ized deleterious effect throughout the entire organ with atrophy of both the acinar
and islet cells. The tissue remodeling that occurs appears to be correlated with the
up regulation of the lectins, galectin-1 and galectin-3.
59
However, these morpho-
logic changes will only result in the clinical manifestation of pancreatic exocrine
insufficiency if more than 90% of the gland has been destroyed and pancreatic li-
pase and trypsin output has decreased to less than 10% of normal.
Nutritional Deficiencies in Chronic Pancreatitis
In pancreatic failure caused by chronic pancreatitis, incomplete digestion of nu-
trients secondary to deficiencies of proteolytic, lipolytic, and amylolytic enzymes
occurs gradually but progressively. As dietary fat, protein, and vitamins are lost in
the stool, full-blown malabsorption eventually occurs with diarrhea, steatorrhea,
and azotorrhea. In normal individuals, fecal fat content does not change appreciably
after the ingestion of a high-fat diet. In contrast, the patient with chronic pancreati-
tis may have normal fecal fat levels while consuming a normal-fat diet, but will have
a high fecal fat level after ingesting a high-fat meal. Incomplete triglyceride diges-
tion is generally believed to be the primary cause of steatorrhea and eventual weight
loss. The patient with chronic pancreatitis may also reach a stage in which not only
fat is lost in the stool, but also incompletely hydrolyzed proteins resulting in im-
paired visceral and skeletal protein synthesis and muscle wasting. Deficiencies of the
fat soluble vitamins, A, D, E and K, are occasionally manifested as syndromes that
336
The Biology and Practice of Current Nutritional Support
21
include night blindness, osteomalacia, neuropathy and coagulopathy, respectively.
Vitamin B
12
malabsorption and its secondary hematologic and neurologic effects
can occur secondary to deficiency of pancreatic protease, which is necessary to de-
grade the proteins bound to vitamin B
12
R-binding protein. Deficiencies of other
nutrients and essential minerals such as iron, magnesium, zinc, copper, and sele-
nium also occur.
4
Pancreatic Diabetes
Although islet cells account for only1-2% of the total pancreatic cellular mass,
this is ordinarily sufficient to maintain glucose homeostasis in the body. In chronic
pancreatitis patients, qualitative changes occur with fibrotic infiltration into the
islets of Langerhans, often splitting the islets into separate lobules.
5-7
Fasting serum
insulin levels in patients with chronic pancreatitis are normal to mildly elevated,
whereas insulin release is reduced after glucose stimulation, indicating a depletion of
insulin reserve. These effects on serum insulin levels have been hypothesized to be
secondary not only to a decrease in islet cell mass, but also to fibrosis that adversely
affects islet integrity by impairing local circulation and glucose diffusion. Beta cells
exhibit more susceptibility to sclerotic changes than cells.
6
Studies to date have
not demonstrated abnormalities in the function or number of cells in chronic
pancreatitis. Abnormalities in glucose metabolism in chronic pancreatitis occur as a
result of a combination of diminished production of endogenous insulin together
with insulin resistance.
8
Furthermore, new evidence also suggests that the insulin
mediated reduction of the facilitative glucose transport protein GLUT2 is impaired
in chronic pancreatitis and may also contribute to impaired glucose tolerance.
48
The overall incidence of impaired glucose tolerance in chronic pancreatitis varies
between 40-90%, yet overt diabetes develops in only 20-30% of these patients.
9
The usual onset of apparent diabetes in patients with chronic pancreatitis occurs
between 7 and 15 years after the initial diagnosis of pancreatitis.
Pancreatic diabetes may not differ clinically from other forms of diabetes, but
nonetheless has unique characteristics. Unlike other diabetics, chronic pancreatitis
patients generally have low plasma cholesterol and lipid levels, especially if steator-
rhea is pronounced. Furthermore, although regarded as insulin dependent, pancre-
atic diabetes has a number of metabolic characteristics that distinguish it from Type
I diabetes. For example, long-term complications such as retinopathy and nephr-
opathy are less frequent.
10
Vasculitis also an infrequent finding in pancreatic diabe-
tes. Keto-acidosis and diabetic coma occur only rarely, and when it occurs, the coma
is usually hyperosmolar and nonketotic.
Diagnosis of Malabsorption in Chronic Pancreatitis
A reduction in exocrine pancreatic cell mass results from the irreversible pancre-
atic fibrosis which occurs inevitably with chronic pancreatitis. Under normal condi-
tions, the acinar cells synthesize pro-teolytic, lipolytic, and amylolytic enzymes that
are secreted ultimately into the pancreatic ducts. However, small amounts of these
pancreatic enzymes are secreted into the bloodstream when their intraductal passage
has been partially or completely obstructed. As fibrosis progresses, the integrity of
the pancreatic tissue is disrupted, and large amounts of these enzymes diffuse into
the blood stream causing plasma amylase, lipase, and trypsin levels invariably to
become elevated. However, in chronic pancreatitis the plasma pancreatic enzyme
levels vary with the course and severity of the disease. The progressive destructive
337
Nutritional Management of Chronic Pancreatitis
21
fibrosis of the gland eventually causes plasma enzyme levels to decrease as the num-
ber of remaining functioning acinar cells capable of secreting digestive enzymes is
significantly reduced. During a relapse of chronic pancreatitis, the plasma enzyme
levels often rise transiently, but rarely to the levels seen in acute pancreatitis. On the
other hand, patients with chronic pancreatitis who have pseudocysts frequently
present with elevated plasma enzyme levels.
The two principal biochemical techniques for investigating exocrine pancreatic
function in patients with pancreatic inflammation involve direct and indirect meth-
ods. Direct function tests measure the composition of pancreatic secretions (bicar-
bonate and enzymes) obtained by intubation of the duodenum either in the normal
state or following a 90-minute intravenous infusion of secretin and cerulein.
11
Dem-
onstration of subnormal pancreatic enzymes or bicarbonate secretion is diagnostic
of chronic pancreatitis, however, pancreatic cancer must be excluded.
Indirect testing estimates the diminished digestive capability in pancreatic insuf-
ficiency by measuring plasma chymotrypsin and trypsin.
12
These tests are able to
demonstrate only severely decreased exocrine function, which is characteristic of
late stages of chronic pancreatitis, but not early stages of the disease. Other measure-
ments of intraluminal digestion such as stool examination for undigested meat fi-
bers, or determining enzyme effectiveness by fecal fat quantitation or plasma amino
acid levels following hormonal stimulation may also be useful in assessing pancre-
atic insufficiency.
13
In general, if pancreatic function tests are carried out appropri-
ately, they are reliable in documenting the severe exocrine insufficiency of chronic
pancreatitis. For example, direct intubation of the duodenum has a sensitivity of
97% and a specificity of 98%.
11
The
14
C-triolein breath test has been shown to be
sensitive and sufficiently specific to screen for fat malabsorption. More recently the
cholesterol 13C-octanoate breath test has been introduced and offers unique possi-
bilities. Unlike direct duodenal intubation, this new technique measures the overall
functional level of lipase activity in the intestinal lumen.
14
However, the relevance of
these tests is greater in the management of mild or moderate cases of chronic pan-
creatitis, in which they can not only predict the necessity for supplemental enzyme
therapy, but also stage the severity of the disease.
12
Although the previously
outlined studies are reliable in diagnosing chronic pancreatitis, none the less
these procedures can be cumbersome, time consuming, unpleasant for patients
and potentially dangerous.
Principles of Clinical Management of Chronic Pancreatitis
Regardless of whether an episode of pancreatitis is an initial presentation of acute
pancreatitis or an acute exacerbation of chronic pancreatitis, the preeminent symp-
tom is usually a rather constant, severe, and unrelenting pain in the epigastrium and
mid-abdomen that penetrates directly posterior to the vertebral column and is ag-
gravated by oral ingestion. Postprandial abdominal pain is very common in chronic
pancreatitis, and fear of pain may further contribute to reduction of food intake.
Persistent anorexia, nausea, and vomiting will eventually lead to weight loss,
as discussed earlier.
The nutritional management of chronic pancreatitis depends on the stage of the
disease. For critically ill patients in the acute phase, absolute restriction of all food
intake is required in order to minimize and to prevent exacerbations of the disease
by preventing stimulation of the gland. Nutrients should be supplied by total
parenteral nutrition (TPN) to ensure maximal rest of the pancreas and to maintain
338
The Biology and Practice of Current Nutritional Support
21
an optimal nutritional and metabolic status. For less severely ill patients who are
able to maintain nourishment by mouth, the main goals of judicious dietary inter-
vention are: to correct existing nutrient deficiencies, to compensate for exocrine
pancreatic deficiency, and to attempt to relieve or obviate pain.
The initial approaches to treatment of such patients is dependent to some extent
upon the nature and severity of the pancreatitis, on the training and experience of
the responsible physicians, and on the resources and technology available.
15-17
The most mild forms of pancreatitis can usually be managed conservatively by
admitting the patient to the hospital and instituting a regimen of adequate analge-
sia, H
2
receptor blockers, and a low-fat diet. Should severe pain and vomiting persist
or should the patients general condition deteriorate, more aggressive management
may be required which may include prohibition of oral intake, nasogastric suction,
and various invasive diagnostic and drainage procedures. Excessive alcohol intake
and/or dietary indiscretions are the most frequent precipitating factors of acute ex-
acerbations of chronic pancreatitis. Thus, it is essential to insist upon absolute absti-
nence from alcoholic beverages in all patients with chronic pancreatitis not only for
the purposes of prophylaxis and treatment of the primary disorder, but to maintain
long-term optimal nutrition status. Dietary carbohydrates should be limited in pa-
tients manifesting glucose intolerance. On the other hand, protein is usually well
tolerated in patients with chronic pancreatitis. A high protein, high carbohydrate
diet is the primary nutritional goal, supplemented with medium-chain triglycerides
as tolerated. TPN should be instituted when these measures fail to meet nutritional
requirements. In addition to providing adequate energy and protein intake, other
important components of comprehensive oral therapy include multiple vitamins,
minerals, trace elements and pancreatic enzymes.
Enteral Feeding
Hypercatabolism associated with chronic pancreatitis can lead to prolonged nega-
tive nitrogen balance, making nutritional support vital to these patients. A trial of
pancreatic rest is considered beneficial because it results in reduction of pancreatic
secretions and minimizes exposure of damaged tissues to endogenous proteolytic
enzymes. The fundamental goal of therapy in chronic pancreatitis, therefore, is to
provide optimal nutritional support with minimal stimulation of pancreatic exo-
crine secretory function while allowing the inflammatory process to resolve. Whereas
oral feeding of regular food obviously stimulates pancreatic exocrine secretion, oral
elemental diets produce much less pancreatic volume and enzyme secretion.
18,19
If
elemental diets are infused by tube into the duodenum rather than into the stom-
ach, the volume of pancreatic secretions is reduced further, but without a concomi-
tant decrease in enzyme secretion, in a manner similar to the response produced by
intravenous CCK infusion.
20,21
The effects of jejunal infusion of elemental diets
have been variable and controversial.
22,23
It appears, however, that pancreatic rest
with enteral feeding can be best achieved if elemental diets are in fused intrajejunally
or nasojejunally rather than intragastrically or intraduodenally. Obviously, the deci-
sions regarding the route and type of feeding must be individualized. Although
patients with mild forms of chronic pancreatitis can often be managed with
intrajejunal feeding of an elemental formula, satisfying the requirements for calories
and protein may be difficult to achieve enterally, primarily because enteral feeding
must be introduced at low volumes and concentrations and increased gradually and
slowly, and intestinal intolerance of the feedings may require that the infusion be
339
Nutritional Management of Chronic Pancreatitis
21
reduced to a less than optimal rate and volume. Moreover, enteral feeding is often
precluded by ileus or some other gastrointestinal malfunction, often related to a
complication of the primary disease. Should a patient require operative intervention
for any reason, a feeding jejunostomy should be inserted for postoperative nutrient
infusion controlled by a continuous pump equipped with safety monitors and alarms.
Total Parenteral Nutrition
TPN has become an important adjunct to conventional medical and surgical
therapy, particularly in a patient having an acute exacerbation of chronic pancreati-
tis. TPN can replenish previously acquired nutritional deficiencies and restore im-
mune function to normal, thus reducing morbidity and increasing survival.
24
During
anacute exacerbation of chronic pancreatitis, time honored supportive management
requires the cessation of all oral intake. Nasogastric tube aspiration may further
reduce the stimulatory effect of intraluminal contents on pancreatic secretions. These
measures obviously compound existing nutritional depletion, which may be reduced
or obviated by early initiation of TPN. An additional beneficial effect of TPN is that
the nutrient infusion greatly reduces both the volume and enzyme content of pan-
creatic exocrine secretion to basal levels. In general, TPN is usually indicated early in
the course of severe disease and early post operatively, wit h gradual conversion to
enteral feeding as the patient s condition improves.
Nutrient Substrates in Chronic Pancreatitis
Amino Acids
TPN regimens should consist initially of only dextrose and amino acids together
with essential vitamins, minerals and trace elements until levels of serum triglycer-
ides and lipids have been determined. Although daily energy requirements can be
estimated by various techniques with appropriate activity factors and stress factors
added, the total nonprotein calorie ration required is usually less than 2500 kcal/
day. Since the calorie:nitrogen ratio should be approxi-mately 100:1, the total pro-
tein provided should be approximately 2-2.5 g/kg/day. In patients with severe pan-
creatitis, the changes in skeletal muscle protein metabolism and amino acid
concentrations are similar to those observed in patients following major operations
or major trauma, during sepsis, or with multiple systems organ failure.
24
The total
free amino acid pool decreases to about 40% of normal, and intracellular skeletal
muscle glutamine declines to levels as low as 15% of normal. These changes in
specific amino acid concentrations indicate that parenteral infusion of replacement
nutrient solutions richin branched chain amino acids and/or in glutamine may sup-
port the underlying metabolic derangement and may be beneficial clinically to pa-
tients with severeforms of pancreatitis. No clinical studies to date, however, have
demonstrated that the administration of branched chain amino acid preparations,
nor of glutamine, have a beneficial effect on the ultimate outcome of severe
chronic pancreatitis.
Dextrose
In seriously ill patients with pancreatitis, glucose clearance and utilization may
be significantly impaired and below maximal capacity. Accordingly, intravenous dex-
trose substrates should never be administered in excess of the maximal capacity to
metabolize glucose (4-5 mg/kg/min). Moreover, if dextrose is infused in an amount
exceeding the glucose utilization rate, hepatic steatosis will inevitablydevelop.
25
340
The Biology and Practice of Current Nutritional Support
21
Therefore, dextrose should provide no more than 60% of a patients total caloric
needs and should not be infused at a rate greater than 3.0 mg/kg/min.
8
Insulin can
be added to the nutrient mixture or, if preferred, in a separate infusion as required to
achieve this goal without exceeding it. Serum glucose levels should be closely moni-
tored, and insulin should be added either as a separate peripheral infusion ordirectly
to the TPN solution in order to maintain the serum glucose level below 200 mg/dL.
Lipids
The use of lipid emulsions in the nutritional management of patients with chronic
pancreatitis continues to be controversial primarily because of the etiologic associa-
tion of hyperlipidemia with pancreatitis.
26-30
Because some patients may have a pre-
viously unrecognized lipid disorder or impaired ability to metabolize lipids, the
administration of lipid emulsions to patients with pancreatitis requires careful con-
sideration and observation. Patients who have had previous episodes of pancreatitis
may have an impaired ability to clear circulating lipid and may, therefore, be suscep-
tible to the development of hyperlipidemia while receiving an infusion containing
fat emulsion. Thus, it is imperative to determine serum lipid levels both before
infusion in patients with pancreatitis and after infusion to demonstrate adequate
clearance of the lipid from the plasma. Numerous clinical trials have reported the
relative safety of administration of intravenous fat emulsions in patients who have
pancreatitis and in whom hypertriglyceridemia was not an etiologic factor for their
disease. If it is determined that the serum triglyceride level is normal and intrave-
nous lipids are desirable to meet caloric needs, the TPN regimen should supply no
more than 1.5 g fat/kg/day, and the fat should not provide more than 30% of total
nonprotein calories.
Enzyme Treatment of Exocrine Pancreatic Insufficiency
Pancreatic exocrine insufficiency, endocrine insufficiency and pain are leading
manifestations of chronic pancreatitis.
2
Because of the large functional reserve of the
gland, steatorrhea secondary to incomplete digestion of ingested fats does not occur
in exocrine pancreatic insuf ficiency until approximately 90% of pancreatic secre-
tory function is lost, at which point exogenous pancreatic enzyme administration
becomes necessary for maintaining adequate digestion and absorption.
A variety of commercially available pancreatic enzyme preparations allow suc-
cessful supplemental or replacement therapy in exocrine pancreatic insufficiency or
failure. Pancreatin, which is derived from porcine or bovine pancreas, by alcohol
extraction, is a major source of these enzymes. Lipase-augmented pancreatin, known
generically as pancrelipase, may reduce steatorrhea more effectively than pancreatin
on an equal-weight basis.
31
In addition, a vegetable-derived form of pancreatin is
available for patients with sensitivities to porcine or bovine protein.
Based on normal pancreatic secretion after maximal stimulation with cerulein
and secretin, a secretory capacity of 10% corresponds approximately to 100,000
units of lipase activity.
46
Accordingly, effective control of steatorrhea will ordinarily
require the administration of at least 100,000 units of lipase per day. Therapeutic
success has been documented by a 50% reduction in stool fat with this dosage, and
a 70% reduction with a dosage of 200,000 units of lipase per day. Only rarely is
complete restoration of lipid hydrolysis possible, and as much as 100,000 units of
lipase are required per meal. Most pancreatic preparations containonly 3,500 to
10,000 units of lipase per dose,
32
requiring patients to take a large number of tablets
341
Nutritional Management of Chronic Pancreatitis
21
daily. However, a high potency enzyme tablet is now available that contains 22,500
units of lipase and 180,000 units each of protease and amylase, respectively.
Degradation in an acid environment is the major problem with these enzyme
preparations, especially lipase which is irreversibly denatured at a pH <4.33. Im-
proved digestive efficiency has been achieved by the simultaneous administration of
antacids or H
2
receptor blocking agents, thereby substantiating the clinical relevance
of acid degradation. Patients with refractory steatorrhea may benefit by the addition
of H
2
antagonists and proton pump inhibitors to their pancreatic enzyme replace-
ment therapy.
52
Enteric coated preparations that release the hydrolytic enzymes at a
pH above 5.5 have been developed and are currently available. The current recom-
mendations for using the ph-sensitive pancreatin microspheres are at a dose of 25,000
to 40,000 units per meal.47 Nonetheless, these preparations still lose much of their
activity along the gastrointestinal tract because only approximately 22% of trypsin
activity and 8% of lipase activity delivered by pancreatin have been found postpran-
dially past the ligament of Treitz.
34
In addition, because fiber has been shown to
inhibit pancreatic enzymes in vitro and in vivo, a fiber enriched diet should not be
given together with pancreatic enzymes.
12
Side effects of pancreatic enzymes may occur, but only rarely are of clinical sig-
nificance. Allergies to porcine preparations are possible and should be considered
following any immediate hypersensitivity reaction to powdered pancreatic extracts.
35
Oral pancreatic extracts can form insoluble complexes with folic acid and, by im-
pairing folate absorption
36
can affect iron absorption, especially in patients with
cystic fibrosis.
37
Hyperuricemia and hyperuricosuria can also occur in patients using
these preparations.
Most patients respond well to pancreatic enzymes. With failure of the patient to
respond to exogenous pancreatic enzymes, one must consider the patients noncom-
pliance, incorrect diagnosis (or overlooking other diseases or conditions ), incorrect
prescription of medication, or incorrect choice of pancreatic enzyme preparation.
38
Total elimination of steatorrhea may be prevented by the concomitant existence of
other factors and diseases that cause steatorrhea, such as celiac sprue, giardiasis, and
bacterial overgrowth; incomplete gastric emptying of the pancreatic enzyme prepa-
ration and food; low micellar concentrati on of bile salts; and susceptibility of lipase
to gastric acidity and chymotrypsin hydrolysis.
38
The Role of Exogenous Pancreatic Enzymes
in Pain Management
It has been hypothesized that enzyme preparations relieve pain accompanying
chronic pancreatitis.
39-41
The cause of this pain is poorly understood but is thought
to be secondary to multiple factors including ductal hypertension and obstruction,
recurrent auto-digestion, and increased nerve infiltration.
40
Alterations in
intaduodenal bile acids and plasma CCK concentrations may also be implicated in
the pathogenesis of pain.
54
In addition increased proliferation of peripheral mono-
nuclear cells and their demonstrated increase release of in vitro tumor necrosis fac-
tor-alpha and interleukin-10 have been hypothesized to contribute to pain
development.
55
In several controlled studies, most patients experienced a reduction in pain with
administration of pancreatic enzyme supplements that increased the levels of in-
traluminal proteases.
40-42
More profound effects of pain relief were noted with mod-
erate pancreatic insufficiency than with severe pancreatic insufficiency.
42
Greater
342
The Biology and Practice of Current Nutritional Support
21
relief of pain was achieved in patients who ingested the enzymes adlibitum in re-
sponse to the pain in addition to ingesting thei rprescribed standard doses of diges-
tive enzyme tablets.
41
The effect of acid-protected porcine pancreatic extracts on
pain was studied in a prospective placebo-controlled, double-blinded, multicenter
study.
43
In 43 patients with chronic pancreatitis, pain improved in most patients
irrespective of study group, thus the two treatment arms did not significantly differ.
Nonetheless, most authorities recommend that enzyme preparations, taken as re-
quired to relieve pain in patients with chronic pancreatitis, should be given at least a
two-month trial. If the pain does not decrease within that time, treatment should be
discontinued if analgesia rather than digestive enzyme replacement has been the
only reason for prescribing the medication.
The choice of enzyme replacement therapy depends on the dominant symptoms
present. If used for relief of pain only, enzymes high in protease are more desirable;
however, if used for amelioration of malabsorption, enzymes high in lipase and low
in protease should be used. In patients having both pain and malabsorption, prepa-
rations with high lipase and trypsin but without chymotrypsin should be used.
38
Antioxidant therapy with a complex of L-methionine, beta-carotene, vitamin C,
vitamin E, and organic selenium may also have a positive effect in patients who
suffer from pancreatic inflammatory pain.
50
Efforts to limit the stimulation of the exocrine pancreas by decreasing CCK
release through dietary modulation may be beneficial in relieving postparandial pain.
51
The Effect of Exogenous Enzymes
in Gastrointestinal Hormones
The effect of exogenous pancreatic enzymes on the enteropancreatic axis is com-
plete.
44
The feedback control of pancreatic secretion clearly depends on the dose
and the site of the administration of exogenous enzymes. Intraluminal duodenal
perfusion of pancreatic enzymes inhibits protease activity in patients with chronic
pancreatitis. This protease-mediated negative feed back of pancreatic secretion ap-
pears to be controlled largely by a duodenal mechanism. When infused into the
duodenum, exogenous pancreatic enzymes have no effect on gastrin release. On the
other hand, they do affect gastric inhibitory polypeptide (GIP) and following exog-
enous exocrine enzyme replacement in patients with chronic pancreatitis, increased
levels of GIP have been measured.
45-47
Conclusion
Chronic pancreatitis is a complex disorder induced by different causes, but mani-
fested by exocrine and endocrine insufficiency. Multiple nutritional and metabolic
derangements result from maldigestion and malabsorption, resulting in malnutri-
tion with severe weight loss. Persistent abdominal pain and potentially multiple
various complications requiring surgical intervention further diminish the patients
already compromised quality of life. Caring for this group of patients demands con-
scientious teamwork, persistence and dedication. Although very important, nutri-
tional support is only one aspect of comprehensive care. Nutritional management
ranges from simple dietary manipulation, with or without administration of
digestive enzymes, to enteral supplementation with modular or chemically defined
diets to total parenteral nutrition, depending on the stage, severity, manifestations
and complications of the disease.
343
Nutritional Management of Chronic Pancreatitis
21
Thus, close follow-up of patients with chronic pancreatitis is necessary and should
include:
25
1. individually tailored dietary counseling;
2. conscientious monitoring of glucose metabolism;
3. judicious administration of pancreatic enzyme supplements which must
be tailored to meet the need for adequate disease and possibly pain control;
4. control of gastric hyperacidity;
5. reduction of intestinal hypermotility;
6. definitive surgical management of biliary lithiasis; and
7. absolute abstinence from alcohol.
Even with all these measures, chronic pancreatitis can be a disabling disease. As
the pathophysiology of this complex process becomes better defined and under-
stood, new avenues for treatment likely to be developed. At the frontier, pancreatic
regeneration and autoislet transplantation are in their infancy but may prove prom-
ising for managing these chronically ill patients.
56,57
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28. Gossum AV, Memoyne M, Greig OD et al. Lipid-associated to total parenteral
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29. Davidoff F, Tishler S, Rosoff C. Marked hyperlipidemia and pancreatitis associ-
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31. Noseworthy J, Colodny AH, Erakalis AJ. Pancreatitis and intravenous fat: An as-
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32. Howard J M. Treatment of pancreatic malabsorption syndrome. In: Howard JM,
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33. Otte M, Ridder P, Pageforde J. In vitro Intersuchungen zur Pankreas-Enzym-sub-
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34. Heizer WD, Cleveland CR, Iber FL. Gastric inactivation of pancreatic enzyme
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35. DiMagno EP, Malagelada JR, Go VLW et al. Fate of orally ingested enzymes in
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36. Otte M, Riddler P, Gutowski HD. Substitutions Behandlung der Pankreas
Inaffinuffzienz mit Pankreatin-Fertigarz Neien. Inter Prax 1989; 29:185-189.
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38. Zempsky WT, Rosenstein BJ, Carrol JA et al. Effect of pancreatic enzyme supple-
ments on iron absorption. Am J Dis Child 1989; 143:969-972.
39. Lankisch PG. Enzyme treatment of exocrine pancreatic insufficiency in chronic
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40. Ihse I, Andersson R, Axelson J. Pancreatic pain: Is there a medical alternative to
surgery? Digestion 1993; 54(Suppl 2):30-34.
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44. Mossner J. Is there a place for pancreatic enzymes in the treatment of pain in
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49. Gansauge F, Gansauge S, Eh M et al. Distributional and functional alterations of
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50. De las Heras Castano G, Garcia de la Paz A, Fernandez MD et al. Use of antioxi-
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Lab Invest 2000 Aug; 80(8):1233-41.
CHAPTER 22
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Nutritional Support in Liver Failure and
Liver Transplantation
Rifat Latifi
Introduction
Liver transplantation (LT) has evolved into the most successful form of treat-
ment for end-stage liver disease (ESLD), with operative survival exceeding 90% for
the firstgraft, retransplant free survival greater than 85% at one year,
1,2
and pre-
dicted actuarial survival over 75%.
3
Although the indications for LT have become
more standardized (in adults as well as in children), 89% of adult patients undergo-
ing LT have advanced cirrhosis (secondary to primary cholestatic liver disease, alco-
holism, hepatitic C/non-A-non-B, autoimmune hepatitis, 0 or hepatitis B), followed
by fulminant hepatic failure (5.5% -7.0%), metabolic disease (4%), malignant and
benign neoplasms (3%-6% and 0.5% respectively), biliary atresia (0.5%), and other
miscellaneous indications (1.8%-2%).
3
On the other hand, the most common indi-
cations for LT in children are extrahepatic atresia (>50%) and alpha-1-antitrypsin
deficiency (9%-14%), followed by metabolic diseases (12%-13%), cirrhosis (7%)
and other indications.
4
Patients who have undergone LT, or are awaiting LT, represent the most complex
medical challenges. These patients are often plagued with multiple comorbid dis-
eases and require meticulous, well-planned and executed, highly individualized
medical care. Since the liver plays a major function in metabolic homeostasis, nutri-
tional and metabolic support becomes one of the most important therapeutic inter-
ventions. Malnutrition and its associated sequella are common features in patients
with chronic liver disease in general, and most patients awaiting LT are no excep-
tion. Malnutrition in this group of patients is a consequence of increased nutrient
requirements in the presence of hypermetabolism, anorexia and inadequate oral
intake, associated with concomitant impaired digestion, absorption, and assimila-
tion of nutrients.
Maintaining adequate nutrition represents a significant therapeutic challenge,
considering the profound metabolic alterations that impair the incorporation of
nutrient substrate into tissue. A vicious cycle then occurs, in which the patient is
profoundly hypoproteinemic, reflecting the depleted stores and synthetic activity of
the liver, and hypercatabolic, while at the same time provision of protein may result
in hyperammonemia and aggravation of existing encephalopathy. Although poor
nutritional status increases morbidity and mortality perioperatively, it is difficult to
correctly identify and quantify the impact of individual nutrient therapy on patients
with ESLD requiring LT.
347
Nutrition Support in Liver Failure and Liver Transplantation
22
Malnutrition in Patients with Chronic Liver Disease
The complex metabolic derangements that accompany liver failure reflect the
magnitude of the problems associated with liver failure (Table 22.1).
5
The frequency
and the degree of malnutrition varies among patients studied.
6
In one study, malnu-
trition was present in all 74 patients undergoing LT.
7
Patients with primary biliary
cirrhosis retained their hepatic synthetic function better than others despite extreme
wasting of muscle and fat.
8
Others
9
found malnutrition present less frequently (79%)
and no differences in nutritional status with regard to the etiology of chronic liver
disease. The etiologic factors of malnutrition in chronic liver disease are multiple
and synergistic in nature.
10
Among these factors, anorexia, nausea, vomiting, poor
dietary habits, malabsorption, frequent large volumes therapeutic paracenteses, and
inadequate protein and caloric intake are the most common. The mechanisms of
malnutrition varies and may include catabolism and altered hepatic metabolism of
key nutrients: carbohydrates, fat and protein.
10-12
The hepatocellular dysfunction that causes unique changes of protein, carbohy-
drate and fat metabolism becomes more prominent during the fasting state,
10,11
when a starvation type metabolism develops. Hepatic glycogen depletion occurs
rapidly (10-12 h instead of 36-48 h) resulting in accelerated and premature protein
catabolism.
Hepatic glucose production and peripheral glucose oxidation are significantly
decreased. This prevents fasting hypoglycemia. Serum free fatty acids are increased
secondary to increased peripheral lipolysis, which in turn stimulates ketogenesis.
12
Ketogenesis, however, ultimately fails with worsening of liver failure. In addition to
protein, fat, and carbohydrate metabolic abnormalities, impaired hepatic function
results in vitamin and mineral deficiencies. When patient condition deteriorates
and nutrient metabolism becomes insufficient to maintain body homeostasis, as in
the late stages of cirrhosis, or infulminant hepatic failure, liver transplantation be-
comes the only current, long-term live saving intervention.
Hepatic Encephalopathy
When the liver fails or blood is shunted past the liver, hyperammonemia results
and brain function deteriorates. This frequent complex syndrome in patients with
ESLD, known as hepatic encephalopathy, is manifested by varies signs and symp-
toms that range from rapidly developing delirium, convulsions and coma in acute
failure to more gradually impairment of intellect that eventually leads to stupor and
coma in chronic liver failure
13
(Table 22.2). Progression and severity depend on
whether the disease is in an acute or chronic stage and on the magnitude of the
insult to the liver. Although, the exact biochemical mechanisms and neurochemical
pathways of this complex condition are not known, one or more of several mechanisms
may adversely affect the brain function of patients with liver failure
14
(Table 22.3).
The blood-brain barrier (BBB) consists of tight junctions of endothelial cells in
the cerebral capillary bed. If substances are to affect the brain and tissues, they must
penetrate this barrier. Transport of substrates through the BBB is strictly regulated
and depends on their lipid solubility and on specific transport systems. For example,
amino acids and glucose have their own unique and distinct carrier systems for
transportation into the brain. The effectiveness of this physiologic barrier protects
the organisms from the potentially adverse effects of serious metabolic changes. In
HE, however, the BBB commonly breaks down, as demonstrated by the uptake of
substances that otherwise are not taken up by the brain.
15
In addition, hepatic
348
The Biology and Practice of Current Nutritional Support
22
encephalopathy significantly alters the BBB which affects specific transport systems
of neutral amino acids, glucose, ketone bodies, and basic amino acids. Transport of
neutral amino acids into the brain significantly increases, whereas the transport of
glucose, ketone bodies, and basic amino acids decreases.
16,17
On the other hand,
BBB alteration may be consequence of a generally nonspecific increased permeabil-
ity, which can expose the brain to a variety of neurotoxic substances circulating in
the blood and possibly cause cerebral edema.
Portal-systemic shunting of blood is associated with hyperammonemia, increased
glutamine concentration in the brain, an altered plasma neutral amino acid pattern,
and high levels of several large neutral amino acids in the brain. An altered amino
acid pattern is caused by liver disease as much as by portal-systemic shunting. The
amino acids of great importance in hepatic encephalopathy are tyrosine, phenylala-
nine, and tryptophan because they are involved in the synthesis of the catechola-
mines dopamine, noradrenaline, and serotonin and are potential precursors of false
neurotransmitters, such as octopamine or tryptamine.
18
These amino acids together
Table 22.1. Metabolic alterations in chronic liver disease*
Alteration Mechanism
Increased plasma glucagon Portosystemic shunting
Impaired hepatic degradation
Hyperammonemia
Increased plasma aromatic Hyperinsulinemia
amino acids Increased peripheral insulin resistance
Decreased effective insulin to glucagon ratio
Impaired hepatic function
Increased plasma epinephrine Impaired hepatic function
and cortisol
Decreased liver and muscle Accelarated glycogenolysis
carbohydrate Impaired glycogenesis
Accelarated gluconeogenesis Hyperglucagonemia
Hyperglycemia Portosystemic shunting
Increased glucose production
Decreased insulin-dependent glucose uptake
Decreased insulin-dependent hepatic glycolysis
Hyperammonemia Deamination and accelerated bacterial
degradation of protein in the colon
Increased plasma aromatic Decreased hepatic clearance
amino acids Increased release into circulation
Hypoalbuminemia, hyperbilirubinemia
Decreased incorporation of aromatic amino acids
into proteins
Increased plasma methionine, Decreased hepatic clearance
glutamine, asparagine, histidine
Decreased plasma Hyperinsulinemia
branched-chain amino acids Excessive uptake
Increased use of BCAA as energy source
*Adapted from Latifi R, Killam J, Dudrick SJ: Nutritional support in liver failure. Surg Cli
North Am 1991; 71:567-578.
349
Nutrition Support in Liver Failure and Liver Transplantation
22
with leucine, isoleucine, valine, methionine, threonine, and histidine compromise
the group of large neutral amino acids that have a common blood-brain transport
system. Other amino acids, such as glutamate, aspartate, taurine, and glycine, can
also act as neurotransmitters. Because some of these amino acids are precursors for
neurotransmitters and other potentially neuroactive substances, high central ner-
vous sytem levels of these amino acids may contribute to the development of en-
cephalopathy. Changes in the blood-to-brain transport of neutral and basic amino
acids, in part, may be caused by an increase in the V-max of the respective carrier
system, which is possible a consequence of hyperammonemia.
19
Amino Acids in Hepatic Encephalopathy
Hepatic encephalopathy is associated with increased plasma and brain concen-
trations of the aromatic amino acids (AAA): phenylalanine, tyrosine and tryptophan
(free form) and decreased concentrations of the branched-chain amino acids (BCAA):
valine, leucine and isoleucine.
18-23
Because large neutral amino acids share a com-
mon transport carrier in crossing the BBB, decreased BCAA concentrations in the
blood may in fact facilitate increased transport AAA into the brain.
23
High concen-
trations of the aromatic amino acids and methionine could limit the cerebral uptake
of BCAA because the higher AAA concentrations result in greater competition at
the BBB for the carrier-mediated transport system used by BCAA. When brains of
normal dogs were perfused with AAA a hepatic-like coma and an abnormal neu-
rotransmitter pattern were induced. These findings are, in part, responsible for the
false neurotransmitter-amino acid hypothesis of hepatic encephalopathy.
18
The
hepatic-like coma induced by AAA may be prevented when AAA and BCAA were
infused simultaneously.
24
During liver failure or diversion of the blood around the liver, amines and their
amino acid precursors accumulate in the circulation and enter the brain and
the peripheral autonomic nervous sytem, replacing the true neurotransmitter
Table 22.2. Clinical grading of hepatic encephalopathy
Grade Mental Status and Tremors EEG Findings
I. Prodome Euphoria, occasional depression; Usually no EEG
fluctuant, mild confusion; slowness changes
of mentation and affect; slurred
speech; disordered sleep rhythm;
tremor slight
II. Impending coma Accentuation of state I: Generalized
drowsiness; inappropriate behavior; slowing pattern,
inability to maintain sphincter control; abnormal
tremor present (easily elicited)
III. Stupor Asleep most of the time but can be Abnormal
roused; incoherent speech; marked
confusion; tremor usually present
(patient may not be able to cooperate)
IV. Deep cerebral coma May or may not respond to painful Abnormal
stimuli, and tremor usually absent
350
The Biology and Practice of Current Nutritional Support
22
norepinephrine with weak or false neurotransmitters, such as octopamine, tyrosine,
phenylethylamine, of phenylethanolamine. On the other hand, patients with liver
failure have increased levels of norepinephrine and the other catecholamines.
25
None-
theless, it is thought that this imbalance of neurotransmitters has serious conse-
quences which may be manifested as brain dysfuction and high cardiac output, low
peripheral vascular resistance states, as well as hepatorenal syndrome. Whether amino
acid imbalance precipitates encephalopathy, possibly, by promoting the synthesis of
toxic aromatic amines, is not clear, but attempts to correct this imbalance have been
the rationale for metabolic and nutritional therapy of patients with liver failure in
which the protein ration is enriched with BCAA and low in AAA is administered
(Tables 22.4,5).
The administration of BCAA to rats with portocaval shunts reduces the concen-
tration of tryptophan, serotonin, and 5-HIAA in brain indoles.
20
Formation of false
or weak adrenergic neurotransmitters may contribute to hepatic coma, pos-
sibly by displacing norepinephrine and dopamine from their storage granules
at nerve terminals.
Nutritional Assessment
Accurate assessment of nutrition status of patients with chronic liver disease is
very important, albeit characterized by many encumbrances to performing and in-
terpreting clinical and biochemical studies. Identifying and differentiating the im-
pact of malnutrition from the effects of liver disease and the therapy represent the
main predicament. Common methods of determining the nutritional status of these
patients have obvious practical limitations. Total body weight and measurements of
tricepts skinfold thickness and mid-arm circumference are influenced by ascites and
edema. Hypoalbuminemia is an important indicator of nutritional status and a good
index of hepatic functional reserve. The absolute rate of albumin synthesis is signifi-
cantly lower in patients with cirrhosis and correlates well with the Child-Turcotte
score and with its Pugh modification. However, when analyzed separately the rate of
albumin synthesis does not correlate with serum albumin concentration, intravas-
cular albumin mass, or with other clinical indexes of liver function or integrity.
Hypoalbuminemia decreases the colloid oncotic pressure, which contributes to the
Table 22.3. Mechanisms that may affect brain function in
hepatic encephalopathy
Mechanisms Consequences
Disruption of integrity of the Exposure of the brain to undesireable
brain-blood barrier neuroactive compounds
Alterations of specific transport systems Increased transport of neutral amino
acids
Decreased transport of glucose,
ketone bodies, and basic amino acids
Accumulation of neurotoxic substance Functional alterations of the brain
in the blood
Changes in the substrate supply Alterations and catabolism of normal
neurotransmitters in the brain
Lack of nutrients, e.g., glucose Impairment of brain energy metabolism
351
Nutrition Support in Liver Failure and Liver Transplantation
22
accumulation of ascites and edema, a persistent characteristic of decompensated
liver function. Close metabolic monitoring of these patients is of utmost impor-
tance. In addition to routine biochemical indices which include transferring,
prealbumin and retinol-binding protein, plasma levels of vitamins, trace elements
and apolipoprotein A-IV may be useful in a comprehensive nutritional assessment.
The new metabolic tool that is coming in the clinical practice is the measure-
ments of the hepatic mitochondrial redox potential,
26
but its role in CLD has not
been studied to date. The hepatic mitochondrial redox potential represents the ratio
of acetoacetate to -hydroxybutyrate and can be expressed and measured as the
arterial blood ketone body ratio (AKBR). The AKBR is not a specific measurement
of liver insufficiency, but does allow the severity of liver damage to be graded and
reflect the state of perfusion of splanchnic bed. Different clinical and biologic phe-
nomena are associated with a decrease in the AKBR, of which most prominent are
enhanced catabolism, impaired oxygen utilization, hypoperfusion and deterioration
of the immune response.
Protein malnutrition is a characteristic feature of patient with cirrhosis. More-
over, functional alterations and histologic abnormalities of the liver are known con-
sequences of malnutrition. Protein deprivation profoundly depletes liver protein
stores and adversely affects the breakdown and conversion of polysomes to free ribo-
somes. On the other hand, in chronic liver disease, alterations in visceral protein
synthesis, cellular immunity, and total lymphocyte count may be present indepen-
dently of protein malnutrition. Plasma protein levels correlate inversely with the
degree of liver damage and are its best indicators. Serum concentrations of AAA can
indicate the severity of chronic and acute liver disease as well. Furthermore, because
patients with hepatic encephalopathy have the lowest BCAA:AAA ratio, this deter-
mination may serve as an index of liver function impairment. Other markers such as
lean body mass and fat stores are not reliable indicators of structural liver damage.
Measurement of nitrogen balance has its limitation, because it is difficult to differ-
entiate impaired hepatic protein synthesis from accelerated breakdown of endog-
enous protein.
Standard tests of hepatic metabolic capacity and blood flow (aminopyxine breath
test, galactose elimination capacity and clearance of idiocyanine green) are less sen-
sitive indicators of prognosis than the Child-Pugh classification of liver disease.
7
The recognized, but less applied clinically prognostic nutritional index, which relies
mostly on plasma protein lacks the predictive value in patients with ESLD.
8
Table 22.4. Use of branched-chain amino acids in hepatic encephalopathy
When gluconeogenesis and ketogenesis are depressed, BCAAs* may furnish as much
as 30% of energy requirements for skeletal muscle, heart and brain.
The BCAAs may regulate the movement of other amino acids across the myocyte
membrane.
The BCAAs increase hepatic protein synthesis when given with glucose and decrease
aromatic amino acid concentrations.
Theoretically, BCAAs may improve peripheral catecholamine synthesis.
The BCAAs complete with aromatic amino acids for transport across the blood-brain
barrier.
*BCAA=Branched-chain amino acids
352
The Biology and Practice of Current Nutritional Support
22
Peritransplant Nutrition: Support
In a retrospective study of 160 adults with liver transplant, malnutrition score
was one of the six variables that highly correlated with patient survival. High malnu-
trition score was associated with increased postoperative morbidity and mortality.
27
The degree of postoperative malnutrition has been shown to predict the postopera-
tive morbidity and mortality in liver transplant patients.
9
This study demonstrated
a relationship between moderate to severe malnutrition and increased morbidity
(increased requirements for ventilatory support, and ICU and hospital stay) and
mortality.
9
Identifying the correct caloric and protein requirements in patients before and
after undergoing LT is not an easy task. In a prospective study of 16 adults patients
scheduled to undergo LT, nitrogen balance, 24-hour urinary cratinine, 3-methyl
histidine and resting energy expenditure (REE) were determined before transplan-
tation and on days 1,2,5,14 and 28 posttransplant.
28
Only 15% of patients in this
study achieved a positive balance, although parental nutrition (containing 1.29 gm/
protein/kg, 30% and 70% of calories were given as fat and dextrose respectively)
was started within 24 hours. Calculation of malnutritional needs on this study was
based on the Harris-Benedict equation, and parenteral feeds were continued until
solid oral intake reached 1200 calories in 24 hours in females and 1500 in males.
These investigators have suggested to use the Harris-Benedict formula for calcula-
tion of nutritional requirements and to add 20% more calories in order to provide
nutritional support in LT patients.
In another, most recent study,
29
150 patients with ESLD undergoing LT pro-
spectively were assessed and followed for an average of 46 months after LT. Body
composition analysis (24 hour urinary creatinine excretion, anthropometric mea-
surements and bioelectrical impedance analysis), changes of REE and other vari-
ables were analyzed. Patients with severe hypermetabolism (changes in REE >20%)
and reduced body cell mass (<35% of body weight) had reduced survival after LT.
Based on the degree of hypermetabolism and malnutrition a prognostic risk profile
Table 22.5. General treatment of hepatic encephalopathy
Identify and treat other medical problems
Balance protein intake
Avoid antidepressants and hypnotics unless severe mania is present
Avoid extensive paracentesis or abrupt removal of fluids by dialysis
Avoid vigorous diuresis
Avoid use of acetazolamide
Slowly correct hyponatremia
Do not overhydrate
Monitor hemodynamic status and blood gases closely
Monitor arterial blood ketone body ratio
Avoid lumbar puncture if possible
Supplement vitamins
Avoid use of strong cathartics
353
Nutrition Support in Liver Failure and Liver Transplantation
22
predicted the survival. Patients with high risk profile had a 5-year survival of 88%
(P<.01). Others, have also found that nutritional status indices predict survival after
LT in children.
30
Although nutritional assessment in adult patients with ESLD is difficult and
complex, and the current indices cannot be applied optimally to all patients, it is
clear that hypermetabolism and malnutrition are present in a significant number of
patients undergoing LT and that perioperative nutritional and metabolic status of
these patients has great prognostic value.
Metabolic Changes
Hypermetabolism as a systemic manifestation of cirrhosis is closely related to
splanchnic hemodynamics and malnutrition.
31
Following LT patients are in a
hypercatabolic state, however their postoperative metabolic state (as measured by
REE) is a reflection of their preoperative state.
32,33
The degree of hemodynamic
abnormality, when studied intraoperatively, correlates with the stage of the disease.
34
LT does not reverse the existing splanchnic and systemic hemodynamic abnormali-
ties of ESLD completely.
31
The splanchnic hyperemia persists for at least two weeks,
and the closure of porto-collateral circulation occurs at a much slower rate, even
though the portal pressure returns to normal.
35
Total liver blood flow markedly
increases after LT, although the effects of persistent high liver blood flow on me-
tabolism are not known.
31
Immediately following LT (in the first 6 hours ) glucose utilization by the graft is
impaired until mitochondrial redox potential improves.
36
During this period, the
liver preferentially uses fatty acid oxidation for ATP generation. After 6 hours, if
transplanted liver have normal function, substrate utilization shifts from fat to glu-
cose. On the other hand, failing grafts will continue to utilize fat. These significant
metabolic changes may be followed by the serial measurements of arterial ketone
body ratio (acetoacetate/3-beta-hydroxybuturate) or AKBR. The AKBR reflects the
hepatic mitochondrial redox potential (oxidized nicotinamide adenine dinucleotide
(NAD)/reduced nicotinamide adenine dinucleotide (NADH). The ketone body ratio
reflects one of the most fundamental regulatory factors of energy production in the
liver. The AKBR changes may be used to predict the function of transplanted liver.
Low values of AKBR associated with low levels of ketone bodies should be regarded
as a strong indicator of graft failure.
37,38
Furthermore, fatty acid oxidation and keto-
genic pathways are accelerated to compensate for energy deficits immediately after
LT. Administration of small quantities of glucose in post operative period has been
suggested.
38
Glucose infusion may be increased as mitochondrial redox potential
recovers (AKBR >0.07). Low AKBR values (<0.07) have been associated with in-
creased mortality and morbidity.
39
Following LT low levels of some amino acids
such as glutamine, asparagine, citrulline and taurine have been reported.
40,41
All of the existing studies have involved patients undergoing standard cadaveric
donor LT. The use of partial liver grafts is becoming increasingly common, however.
These grafts are typically less than 50% of normal adult liver mass. The ability of
these organs to utilize nutrient substrates in the early postoperative period has
not been systematically studied and the optimal nutritional support for these
patients in unknown.
Nutrition Status of Donors
The nutritional status of donors has not received adequate attention, although it
has been suggested that the nutritional state of the donor may affect the outcome of
354
The Biology and Practice of Current Nutritional Support
22
LT.
42
Often times organ donors receive little, if any, nutritional support during their
hospitalization, and are subjected to acute starvation that may last for days in an
ICU. This period could substantially deplete the liver energy stores. The role of
acute nutritional repletion on the outcome of LT was examined experimentally.
42
Donor pigs were divided into three groups and pretreated for seven days before
harvesting their livers. Group I was given intravenous saline; Group II was fed orally
regular animal diet; and Group III was fasted, but given 20% glucose intravenously.
Harvested livers were stored for four hours in cold Euro-Collins solution before
transplantation. The glycogen content of the liver at harvesting was consumed com-
pletely in Group I, but was well preserved in Groups II and III. The ATP content of
the liver in all three groups were similar at harvesting and were markedly reduced
four hours after cold preservation. The amount of ATP recovered one hour after
reperfusion was 26% of that before preservation for Group I, and 48% and 73% for
Goups II and III, respectively. The mean survival for Group III was 37.2 days vs 5.8
0.7 days and 9.8 2.0 days in Group I and II (P<0.01). Other investigators,
43,44
have also shown that livers from nutritionally repleted animals have improved func-
tion when compared with livers from fasted animals after cold preservation. It has
been demonstrated that glycogen stores could be rapidly repleted in pigs by intraportal
infusion of glucose over 3 hours.
45
Studies in humans using this technique
46
have
shown that glycogen stores in human allograft are good and glycogen is needed
throughout the transplantation procedure. Futhermore, newly synthesized gly-
cogen is superior to preformed glycogen and glycogen repletion improves out-
come of liver transplantation in humans.
It appears that glucose infusions lower peak transaminase levels, and protects
against the effects of prolonged warm ischemia.
46
Rapid hepatic glycogenation was
shown to be beneficial in maintaining adenine nucleotide levels in a large animal
model.
47
Moreover, livers harvested from hyperglycemic donors receiving insulin
infusion during the procurement operation have significantly lower reperfusion hepa-
tocellular injury.
48
On the other hand, others have reported that livers from fasted
rats were more tolerant to long-term hypothermia than livers from fed donors.
49,50
More contrasting data were reported recently, were both extensive donor fasting and
glucose feeding enhanced outcome in LT.
51
Nonetheless, prevention of the nutritional status of the donor liver prior to har-
vesting may be a method to improve function of the livers for transplantation, as the
evidence suggests that nutritional status of organ donors matters. Furthermore, nu-
tritional modulation of hepatic reperfusion may have greater influence on liver pres-
ervation of LT, and nutritional supplementation may precondition the liver.
52
Until
a large human randomized clinical trial answers this question definitively, organ
doors should be treated principally the same as other critically ill patients: once fully
resuscitated, start the nutritional support, and when possible use the gastrointestinal
tract to deliver nutrition. Based on animal studies, during prolonged pretransplant
period, a higher percentage of glucose infusion may have theoritical advantage.
How to Feed Liver Transplant Patients
Attempts to reverse malnutrition in patients with advanced cirrhosis are very
complex and often are compounded by nutrient substrate intolerance and encepha-
lopathy requiring some protein restriction. The principle question to be answered is
not do these patients need to be fed, but rather how to do it and when to start? Until
recently TPN was the preferred form of postoperative nutritional support in LT as it
355
Nutrition Support in Liver Failure and Liver Transplantation
22
provides all the nutrients even in a face of significant gut dysfunction. In a random-
ized prospective, partially blinded, study, 28 patients were studied for seven days
following liver transplant.
53
Patients were randomized into three groups: Group I
(N=10) was given isotonic intravenous fluids with glucose; Group II (N=8) was
given standard TPN providing 1.5 g/protein/kg/day; and Group III (N=10) isoca-
loric isonitrogenous TPN fortified with 3.5% branched-chain amino acids. All pa-
tients were similar with regard to their disease stage, muscle wasting, albumin levels
and jaundice. Nitrogen balance was significantly improved in both TPN groups
(Group I vs Group II, P<0.0001; Group I vs Group III, P<0.0011). Furthermore,
both TPN groups were extubated earlier than the control and had a shorter ICU
stay (an average 2.4 days), although these differences did not achieve statistical sig-
nificance. This study
53
demonstrates that patients post LT can tolerate aggressive
nutritional support and protein load of 1.5 gm/kg/d without evidence of precipitat-
ing encephalopathy. Urea nitrogen and creatinine were also not effected by protein
intake. Achievement of nitrogen balance in patients with liver transplant has been
reported previously.
54,55
Since TPN has its inherent potential problems (metabolic, infectious, mechani-
cal) the provision of nutrients enterally when possible is an attractive concept. The
efficacy and the tolerance of early enteral feeding via a double-lumen nasojejunal
tube, placed at the time of transplant, was studied in 14 LT patients.
56
These pa-
tients were compared with 10 patients who received TPN as a main of provision of
nutritional support. Tube feeding was started within 18 hours after transplantation,
while TPN within 24 hours for most patients. These investigators concluded that
with early tube feeding after LT, the nutritional status can be maintained as effi-
ciently as with TPN, although nitrogen balance studies were not performed. All
patients in this study underwent studies of intestinal absorptive capacity and intes-
tinal permeability before and after transplant. These studies showed no significant
differences in intestinal permeability between the enterally and parenterally fed pa-
tients within the first seven days of provision of nutritional support.
56
This tech-
nique of provision of early enteral feeding may be difficult to achieve in cases when
choledocho-enteric biliary drainage is performed. In another study,
57
early enteral
feeding immediately after LT was shown to be safe but early postoperative feeding
did not effect the ICU or hospital stay, or ventilatory dependence. Thirty one (out
of 51) patients completed the study. Tube feeding was tolerated well by 14 patients
and these patients had a better nitrogen balance on post transplant day 4 than con-
trol (P<.03) and greater cumulative 12-day nutrient intake (P<0.002) and lower
viral infection rate (P<.05). The major deficiency of this study is that the control
group received no nutritional support until they were able to eat.
The means and technique of delivering enteral feedings has been a matter of
debate.
58
Because of associated discomfort of the nasojejunal tubes to the patient
and other technical difficulties, routine placement of feeding jejunostomies at the
same time of transplant has been recommended.
59
Many surgeons avoid this proce-
dure due to the high incidence of complications and infrequent need for prolonged
tube feeding. Although 15% of the patients had some type of complication related
to placement of J-tubes, placement of these tubes at the time of operation can be
done safely, with very low risk of serious complications and without adding signifi-
cant operative time. J-tubes may, however, be best reserved for those patients who
are at risk for prolonged postoperative malnutrition (i.e., prolonged ventilation).
356
The Biology and Practice of Current Nutritional Support
22
Naoenteric tubes are generally well tolerated in the short term and do not carry
potential the risk of J-tubes.
Based on these and other studies, enteral nutrition should be the primary mode
of nutrition support whenever possible. When to start the feeding is another ques-
tion. In general if the patients is fully resuscitated as documented by normal lactic
acid, base excess and gastric pHi (when measured) enteral nutrition support may be
started and advanced as tolerated. On the other hand, TPN should be reserved for
patients that cannot be fed enterally or their resuscitation is prolonged and/or com-
plicated by multiple returns to the operating room, for those with prolonged ileus,
abdominal distention, abdominal sepsis, or chylous ascites.
60
Conclusion
Malnutrition is very common in patients undergoing liver transplantation and
poor nutritional status is associated with increased morbidity and mortality. Correc-
tion and prevention of malnutrition and metabolic support of these patients in their
perioperative period is of utmost importance. Enteral feeding should be initiated as
soon as possible after LT. Enteral feeding should be used, even when all nutritional
needs cannot be met with this technique, and requires supplementation with TPN.
Use of specialized nutritional formulas need to be evaluated further, while individu-
alized dietary consult with the patient and the family is of great importance and
should be part of the therapeutic interventions.
61
The use of type and the amount of
lipids in nutrition support of patients with liver failure and transplant have not been
studied. It is clear, however that too much lipids, or when most of lipids are given in
a form of omega-6-fatty acids have deleterious effects on the immune status of the
critically ill patients. The nutritional therapeutic interventions should be oriented
toward reducing patient's protein catabolism and to provide sufficient nutrient sub-
strates in a form of amino acids and dextrose to improve nitrogen balance without
aggravating the hepatic encephalopathy.
7
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54. OKeefe S, Williams R, Calne R. Catabolic loss of body protein after human liver
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CHAPTER 23
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Nutritional Support in Renal Transplantation
Susan T. Crowley, Richard Formica and Antonio Cayco
Introduction
Because of the high prevalence and adverse impact of malnutrition in the
pretransplant end stage renal disease (ESRD) population, the effects of renal trans-
plantation on the nutritional state of the recipient is of interest. This Chapter re-
views the available published literature on selected aspects of nutrition in the kidney
transplant recipient (KTR). Because of their correlation with increased risk of mor-
bidity and mortality and their high prevalence among KTRs, the treatments of pro-
tein malnutrition and dyslipidemia are examined. The impact of vitamin
supplementation on modification of another potential cardiovascular risk factor in
the KTR, hyperhomocysteinemia is also considered. Finally, because serious mor-
bidity secondary to osteoporosis in the KTR has been recognized, bone metabolism
in the KTR is discussed.
Protein Malnutrition and Nitrogen Balance
The attributable impact of the restoration of renal function on nitrogen balance
in the KTR has been confounded by the requisite use of immunosuppressive therapy.
The latter has been well known to independently influence protein turnover. In
particular, glucocorticoids have been repeatedly shown to increase protein catabolic
rate (PCR) and result in negative nitrogen balance. Over a decade ago, multiple
investigators demonstrated that PCR doubled within 6-11 days post-renal trans-
plantation, independent of protein intake and in parallel with changes in steroid
dose. Studies reported that despite restoration of renal function and intake of at
least 1.2 gm protein/kg IBW/day, glucocorticoid therapy had a major impact on
PCR and was associated with dramatic nitrogen wasting.
Fortunately, it has been demonstrated that protein wasting is a not an invariable
consequence of glucocorticoid therapy. In nondiabetic renal transplant patients, in-
creased dietary protein intake (1.5 gm/kg/day) in the immediate postoperative pe-
riod diet accompanied by 30-35 kcal/kg/day of caloric intake is able to effect neutral
nitrogen balance, whereas more protein restricted patients develop negative nitro-
gen balance. Thus, dietary manipulation is effective in maintaining nitrogen bal-
ance, even in the immediate post-transplant period when high dose steroid therapy
is typically utilized.
More aggressive dietary protein supplementation has been shown to be a means
of further reducing negative nitrogen balance associated with high-dose steroids in
the early post-transplant period. In one study, isocaloric diets of approximately 30
kcal/kg/day, adjusted for the differences in the protein content of the diets, were
361
Nutrition Support in Renal Transplantation
23
consumed by 12 nondiabetics, randomized to either the control (1 gm/kg/day) or
experimental (3 gm/kg/day) diet. Over the study period of four weeks, both groups
lost a mean of 3 kg, yet a net increase of 4.5 kg of lean body mass was noted in the
experimental group. For both groups, nitrogen balance was directly proportional to
the nitrogen intake. Regression analysis of daily protein intake and nitrogen balance
suggested that neutral nitrogen balance was achieved at an intake of 1.3 gm protein/
kg/day. Thus, in the setting of adequate caloric intake, it is possible to improve
nitrogen balance by protein supplementation without suffering undue side effects
such as clinically significant hyperkalemia or azotemia.
Dietary protein intake recommendations in the long term KTR requires a bal-
ance between the potentially beneficial and the potentially detrimental effects of a
high protein diet. Diminished muscle mass, as evidenced by reduced forearm muscle
circumference, has been demonstrated in a significant proportion (38%) of diabetic
and nondiabetic patients even two years after successful renal transplantation, when
consuming 1 gm/kg/day protein and 25-35 kcal/kg/day. This occurs despite im-
provement in other nutritional parameters (weight, serum albumin) and minimal
steroid use.
It has also been shown, by computerized tomographic assessment of
mid-thigh muscle area, that marked muscle atrophy occurs in the otherwise stable
kidney transplant patient. Given the apparent extent of muscle wasting and protein
malnutrition in the stable KTR, dietary protein restriction for any reason would
appear questionable.
Some investigators however, have postulated that chronic rejection is a
forme-fruste of hyperfiltration induced vascular damage. Over the long term, there-
fore, a normal or high protein diet might potentially be detrimental to renal graft
survival by exacerbating hyperfiltration. A short-term study examining the effect of
a low protein (0.55 gm/kg/day) diet on a small cohort of KTRs revealed that urinary
protein excretion significantly diminished during low protein dietary intake, and
neutral nitrogen balance was achieved.
However, significant declines in serum total
protein, albumin, as well as transferrin occurred which would suggest that this was
too restrictive a diet to maintain overall protein balance.
Whether dietary protein restriction in the long term renal transplant recipient is
adequate to maintain nitrogen balance has been investigated by others as well.
Among
a small cohort of long term nondiabetic KTRs with moderate renal insufficiency
consuming a diet containing 0.6 gm protein/kg/day with a caloric intake of 30 kcal/
kg/day, no significant changes in inulin-measured glomerular filtration rate or sero-
logic nutritional parameters were noted over a four week follow-up period. While
nitrogen balance did not significantly change ( baseline = -0.88 1.14 gm/day; at
three weeks = -1.59 0.5 gm/day) nitrogen balance did correlate with protein in-
take (r=0.42, p< 0.05). Furthermore, caloric intake was positively correlated with
nitrogen balance, with near-neutral nitrogen balance being achieved in subjects con-
suming greater than 25 kcal/kg/day, regardless of protein intake. Thus, there ap-
pears to be a threshold for caloric intake (28 kcal/kg/day) which must be met to
maintain weight and neutral nitrogen balance.
Because it appears difficult to achieve a protein-restricted diet without compro-
mising essential caloric intake, protein restriction should probably be avoided in the
renal transplant recipient. A diet containing at least 1 gm/kg/day of protein and
25-35 kcal/kg/day appears to be the best compromise in the stable, long term renal
allograft recipient (Table 23.1).
362
The Biology and Practice of Current Nutritional Support
23
Dyslipidemia
Cardiovascular disease remains a leading cause of death in renal transplant re-
cipients. In Europe, among long term KTRs, coronary artery disease is responsible
for 32% of deaths, approximately equivalent to the number of deaths caused by
infection.
In the United States, 18% of all long-term KTRs die of coronary artery
disease. Despite these findings, there are few studies elucidating the risk factors for
cardiovascular disease in the kidney transplant patient.
A recent retrospective review of 54 long term KTRs demonstrated significantly
greater LDL and TC levels in KTRs vs. normal controls. Furthermore, blood lipid
levels in KTRs with coronary artery disease were significantly greater than in KTRs
without coronary disease suggesting an association between blood lipids and athero-
genesis in the transplant population, analogous to their relationship in the general
population. In another study, a Cox proportional hazard analysis of vascular disease
risk factors for a large cohort of both cyclosporine and non-cyclosporine treated
KTRs, determined that low serum high density lipoprotein (HDL) level was an
independent relative risk factor for ischemic heart disease. Thus, in addition to other
traditional risk factors for coronary artery disease, such as diabetes mellitus and
hypertension that KTRs may have, it seems reasonable to conclude that elevated
serum lipids place these patients at increased risk of cardiovascular disease and that
lipid lowering strategies may be beneficial (Table 23.2).
The incidence of hyperlipidemia post transplantation is high; approximating
40% in one large study of over 500 subjects. The cause of hyerlipidemia in the KTR
has multiple factors (Table 23.3). Diabetes mellitus, insulin resistance and weight
gain all play a role. Additionally, immunosuppressive medications have a role. Pred-
nisone has been shown to increase serum lipids in patients with systemic lupus
erythematosis in a dose-related fashion. For each 10 mg increase in dose, prednisone
increased TC by 7.5 mg/dl. In KTRs, prednisone has also been shown to increase
LDL and TC while reducing HDL.
Blood lipids are also affected by cyclosporine. In a trial evaluating the effective-
ness of cyclosporine in treating psoriasis, TC and triglycerides were significantly
increased during cyclosporine treatment and diminished after discontinuation of
cyclosporine. Studies in KTRs have shown cyclosporine treatment to be associated
with a significant increase in serum lipids. However, because of concomitant use of
prednisone, the attributable effect of cyclosporine on blood lipids in these studies
could not be independently assessed.
With regard to treatment of dyslipidemias, it has been well established that reduc-
tion of TC and LDL in hypercholesterolemic patients in the general population signifi-
cantly reduces the number of coronary events and coronary deaths. This has been
Table 13.1. Suggested dietary protein intake in the KTR
Time Period
Postoperative Long-Term
Protein 1.5 gm/kg/d 1 gm/kg/d
Calories 30-35 kcal/kg/d 25-35 kcal/kg/d
363
Nutrition Support in Renal Transplantation
23
shown in both primary and secondary prevention trials. It has also been established
that reduction of TC and LDL in patients in the general population who have coro-
nary artery disease but, whose cholesterol is in the normal range by western stan-
dards, also reduces coronary artery disease endpoints. In all of these trials success
was achieved through the combined use of dietary modification and HMG CoA
reductase inhibitors.
The use of the HMG CoA reductase inhibitors, lovastatin and fluvastatin, has
been shown to be safe and effective in reducing TC and LDL, and in raising HDL in
KTRs receiving azathioprine and/or cyclosporine and prednisone. Of note, in pa-
tients being treated with cyclosporine, HMG CoA reductase inhibitors did not change
cyclosporine blood levels.
Side effects such as muscle aches, frank myositis or labora-
tory abnormalities in creatinine phosphokinase, AST or ALT were minimized by
reducing the maximum dose of the statin in KTRs to 20 mg per day.
It should be
pointed out that although these medications have been shown to be safe and effec-
tive in lowering TC and LDL as well as in raising HDL in KTRs, long-term efficacy
and a survival benefit have not yet been demonstrated in this population. It is still a
reasonable assumption however, that serum lipid lowering therapy in the hyperlipi-
demic KTR is beneficial because there is no evidence to suggest that elevated serum
lipids in the KTR behave differently than in the general population.
There is limited published research concerning the use of alternative lipid lower-
ing agents in the renal transplant population (Table 23.4). A second line agent that
has been shown to be very effective at reducing TC, LDL, and triglycerides, and can
raise HDL in cyclosporine and noncyclosporine treated KTRs is nicotinic acid.
While
most patients in one study tolerated the dose of 1 gm twice a day without undue side
effects, conclusions about safety must be limited due to the small number of subjects.
Similarly, experience with the use of the bile acid sequestrant cholestyramine, is
limited. Bile acid sequestrants significantly reduce TC and LDL in hypercholester-
olemic patients but, there has been concern about impairment of cyclosporine ab-
sorption by the sequestrants. In one small study in KTRs, cholestyramine taken as a
single 4 gm dose at least 4 hours after the last dose of cyclosporine did not affect the
absorption of cyclosporine from the gastrointestinal tract. However, no information
Table 13.2. Cardiovascular risk factors in the KTR
Hypertension
Dyslipidemialow HDL
Diabetes Mellitus
Hyperhomocysteinemia?
Table 13.3. Causes of hyperlipidemia in the KTR
Medications:
Prednisone, Cyclosporine
Diabetes Mellitus
Insulin Resistance
Obesity
364
The Biology and Practice of Current Nutritional Support
23
on efficacy of lipid lowering was provided. The strict compliance required to prop-
erly use cholestyramine, the large amount needed, the somewhat unpleasant taste,
and the constipation associated with its use diminish enthusiasm to evaluate this
agent further.
Based on epidemiological evidence from the Greenland Eskimo population, who
have a very low rate of CAD and a fish-rich diet, fish oil tablets have also been used
in an effort to reduce blood lipids.
In one study conducted in KTRs however, the
administration of fish oil tablets had no effect on TC, LDL, or HDL.
Fish oil did
significantly reduce serum triglycerides and decrease platelet adhesion in response to
ADP which may be beneficial in reducing atheromatous plaque thrombus forma-
tion. The only significant side effect from fish oil consumption was fishy eruction,
which, overtime, the participants in the study reportedly grew accustomed to.
Vitamin Supplementation
In addition to lipid lowering agents, vitamin supplementation has been pro-
posed as an intervention to lower the risk of coronary artery disease in patients at
risk. Folic acid supplementation, in particular, has been the subject of considerable
investigation. Folic acid is a requisite factor in one of the metabolic pathways of the
sulfur-containing amino acid, homocysteine (HCY), which was first linked with
accelerated atherosclerosis nearly three decades ago. In vitro evidence suggests that
HCY can both directly and indirectly, via enhancement of lipid peroxidation, pro-
duce endothelial injury. Epidemiological investigations have demonstrated a strong
correlation between elevated plasma HCY levels (hyperhomocysteinemia) and the
frequency of vascular disease. In fact, hyperhomocysteinemia has been shown to be
an independent risk factor for primary as well as secondary cardiovascular disease in
the general population.
Increased levels of plasma HCY have been demonstrated in a variety of acquired
disease states including folate deficiency and renal insufficiency. Present in 75% of
Table 13.4. Treatment of hyperlipidemia*
Agent Note
HMG Co-A r.i.s Preferred agent
(ex. lovastatin, fluvastatin) Reduces TC, LDL
No change in CYA level
Myositis
Max dose of statin 20 mg qd
Nicotinic Acid Reduces TC, LDL, TG
Increases HDL
Safety?
Cholestyramine Reduces TC, LDL
Impaired CYA absorption?
Compliance?
Fish oil Reduces TG
Decreases platelet adhesion
Fishy eruction
* in addition to dietary fat reduction
365
Nutrition Support in Renal Transplantation
23
ESRD patients in one study, hyperhomocysteinemia was 33 times more common in
ESRD patients than in controls, and was far more common (2- to 15-fold) than
traditional risk factors for cardiovascular disease.
Longitudinal follow up to
determine if HCY levels correlate with incident cardiovascular disease rates in
ESRD is ongoing.
The effect of restoration of renal function through transplantation and of the
administration of folic acid supplements on homocysteine metabolism in the KTR
has been recently examined. In 27 long-term, non-cyclosporine treated KTRs with
creatinines ranging from normal to 0.5 mmol/l, plasma HCY level in the KTR was
inversely proportional to renal clearance.
In addition, it was possible to reduce HCY
levels via folate supplementation (1-5 mg/day) as similarly demonstrated in normal
patients, dialysis patients, and in patients with renal insufficiency.
Immunosuppressive therapy may have an independent effect on HCY metabo-
lism. Specifically, cyclosporine therapy can raise plasma HCY independently of re-
nal function and may abrogate the HCY lowering effect of folic acid via interference
with the folate dependent metabolism of homocysteine.
Despite the aforementioned studies, the clinical relevance of hyper-
homocysteinemia to cardiovascular disease in the KTR population is unclear. In a
previous multivariate analysis of cardiovascular risk factors in stable long-term renal
transplant patients, HCY levels were not considered. Past cross-sectional compari-
son of HCY levels in KTRs with and without cardiovascular disease demonstrated
significantly greater HCY levels in transplant patients with cardiovascular disease
compared to patients without it. Since comparisons were uncontrolled for differ-
ences in time at which sampling of plasma HCY and the cardiovascular event oc-
curred, and lacked matching for other cardiovascular risk factors, conclusions about
causality could not be firmly drawn. Hence, the contributory role of
hyperhomocysteinemia in the development of cardiovascular disease in the KTR
requires further investigation.
Vitamin supplementation with alpha tocopherol, vitamin E, as a means of re-
ducing cardiovascular disease risk has also been a subject of considerable investiga-
tion in the general population. In vitro, vitamin E supplementation increases the
resistance of LDL to oxidation which may result in improved endothelial cell va-
sodilator function, decreased foam cell formation, and decreased chemotactic sig-
nals for monocytesall proposed mechanisms which contribute to the atherogenic
process. In addition, growing epidemiological evidence suggests that vitamin E supple-
mentation reduces the risk of myocardial events and possibly reduces the risk of
death from myocardial infarction in the general population. However, no data cur-
rently exists to support the efficacy or safety of supplemental vitamin E in the kid-
ney transplant population.
Bone Metabolism
Kidney transplantation is the second most frequently used modality of renal
replacement therapy in the United States, serving the needs of 27.1% of the end-stage
renal disease population. As KTRs live longer, long term complications, such as post
transplantation bone disease start to impact on patient morbidity.
Osteoporosis is a condition wherein bone density is reduced such that fracture
risk is dramatically increased. Significant declines in vertebral bone mineral density
(BMD) have been observed not only during the first years after kidney transplantation,
but continuously for rates up to -1.7% per year for several years post transplantation.
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The Biology and Practice of Current Nutritional Support
23
In a recently conducted cross-sectional study among long-term KTRs, the preva-
lence of osteoporosis at the hip or spine was 42%. Osteoporosis has been reported
not only in KTRs but in heart and liver transplant recipients as well. These findings
suggest that the loss of bone is quite prevalent and may be attributed not entirely to
previous renal osteodystrophy but to transplantation itself.
Various mechanisms have been proposed to explain the pathogenesis of bone
loss in KTRs (Table 23.5). Bone mass is governed by the two dynamic and opposing
forces of bone resorption and bone formation. Previously, bone loss during the first
year post transplantation, was attributed to a decrease in bone formation rate, or a
low bone turnover state, as a result of corticosteroid therapy. Recently however,
long-term KTRs more than a year after transplantation were found to have a high
bone resorption and turnover state. Furthermore, their high bone resorption rate
was correlated with reduced BMDs. The etiology of this accelerated resorption of
bone tissue remains unknown. Despite the restoration of normal renal function and
calcium homeostasis by a functioning allograft, a hyperplastic parathyroid gland
could occasionally fail to involute and lead to persistent hyperparathyroidism. This
residual hyperparathyroidism could cause the high bone resorption and turnover
which would eventually lead to bone loss. The immunosuppressive drugs, cyclosporine
and FK506, have also been shown to cause a high turnover bone loss. Vitamin D
deficiency does not appear to be a major cause of reduced bone mass in KTRs with
decent allograft function. Several studies have consistently shown adequate stores of
25(OH)-Vitamin D and 1,25 (OH)2-Vitamin D in KTRs even in those with re-
duced BMD.
Several treatment regimens have been evaluated to reduce the high turnover bone
loss associated with transplantation. The agents, calcitonin (40 IU IM daily) or
disodium etidronate (400 mg/day p.o. for 15 days every three months), increased
vertebral BMD in liver transplant patients compared to the untreated historical
control group. In a randomized study, a regimen consisting of 40 g of 25(OH)
-Vitamin D3 and 3 grams of calcium taken daily significantly minimized the reduc-
tion in the lumbar, femoral and total body BMD in KTRs. However, these studies
are limited by their relatively short duration of follow up. Further studies are needed
to evaluate and compare the long-term efficacy and safety of these different regi-
mens in the prevention and treatment of post transplant bone disease.
Summary
Malnutrition is highly prevalent in the pretransplant ESRD population and is
associated with increased morbidity and mortality. Hence, attention to nutritional
prescription in the perioperative period is particularly important to avoid compound-
ing an already compromised nutritional state. The well known protein catabolic
effect of glucocorticoid therapy can be abrogated by ensuring adequate caloric and
dietary protein intake. Optimally, the protein and caloric intake in the perioperative
period should be at least 1.5 gm protein/kg/day and 30-35 kcal/kg/day.
The optimal long-term dietary prescription of the KTR is controversial. Mainte-
nance of nitrogen balance needs to be balanced by the theoretical risk of hyperfiltration
induced by dietary protein loading. In summary, because it appears difficult to achieve
a protein restricted diet without compromising essential caloric intake, protein re-
striction should probably be avoided in the long term renal transplant recipient. A
diet containing 1 gm/kg/day and 25-35 kcal/day appears to be the best compromise
in the stable renal allograft recipient.
367
Nutrition Support in Renal Transplantation
23
A major cause of mortality in the KTR remains cardiovascular disease which has
been linked to markers of malnutrition in other populations, specifically to alter-
ations in lipid metabolism. In conjunction with a low fat diet, careful pharmaco-
logical therapy with HMG CoA reductase inhibitors appears to be safe and effective
in the short-term treatment of dyslipidemias in the transplant patient. Since there is
currently no evidence to suggest that lipids in the KTR behave differently than in
the general population, it is reasonable to assume that KTRs will benefit from serum
lipid reduction until a treatment outcomes study suggests otherwise.
An alternate nutritional parameter that may be associated with enhanced cardio-
vascular disease risk in the KTR, hyperhomocysteinemia, should also be considered.
In non-cyclosporine treated KTRs, hyperhomocysteinemia can be modified by nu-
tritional supplementation with folic acid. Since folate supplementation is relatively
innocuous, modest repletion (5 mg/day) should be considered in this group. The
utility of folate supplementation in the vitamin-replete cyclosporine treated KTR is
less clear.
Bone disease remains a significant cause of morbidity in the long-term renal
allograft recipient. Further studies are needed to evaluate and compare the long-term
efficacy and safety of different regimens in the prevention and treatment of post
transplant bone disease. Several therapeutic interventions hold promise for attenu-
ating the debilitating bone-associated side effects of immunosuppressive medications.
Because of limited original research concerning nutrition in the KTR, the true
impact of altered nutrition in the KTR is poorly understood. Additional investiga-
tions correlating measures of nutrition to specific renal transplant patient and al-
lograft outcomes are needed.
Selected References
1. Ikizler TA, Hakim RM. Nutrition in end-stage renal disease. Kidney Intl 1996;
50:343-357.
2. Cogan MA, Sargent JA, Yarbrough SG et al. Prevention of prednisone-induced
negative nitrogen balance:effect of dietary modification on urea generation rate in
patients on hemodialysis receiving high-dose glucocorticoids. Ann Int Med 1981;
95:158-161.
3. Whittier FC, Evans DH, Dutton S et al. Nutrition in renal transplantation. Am J
of Kidney Dis 1985; 6(6):405-411.
4. Miller DG, Levine SE, DElia JA et al. Nutritional status of diabetic and nondia-
betic patients after renal transplantation. Am J Clin Nutr 1986; 44:66-69.
5. Horber FF, Zurcher RM, Herren H et al. Altered body fat distribution in patients
with glucocorticoid treatment and in patients on long-term dialysis. Am J Clin
Nutrition 1986; 43:758-769.
6. Salahudeen AK, Hostetter TH, Raatz SK et al. Effects of dietary protein in pa-
tients with chronic renal transplant rejection. Kidney Intl 1992; 41;183-190.
Table 13.5. Causes of bone loss in the KTR
Residual Hyperparathyroidism
Medications
Corticosteroids
Cyclosporine
FK506
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23
7. Windus DW, Lacson S, Delmez JA. The short-term effects of a low-protein diet in
stable renal transplant recipients. Am J Kidney Dis 1991; 17(6): 693-699.
8. Kasiske BL, Guijarro C, Massy ZA et al. Cardiovascular disease after renal trans-
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9. Hilbrands LB, Demacker PNM, Hoitsma AJ et al. The effects of cyclosporine and
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10. Goldberg R, Roth D. Evaluation of fluvastatin in the treatmentof hypercholester-
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11. Lal SM, Hewett JE, Petroski GF et al. Effects of nicotinic acid and lovastatin in
renal transplant patients: A prospective, randomized, open-labeled crossover trial.
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12. Jensen RA, Lal SM, Diaz-Arias A et al. Does cholestyramine interfere with
cyclosporine absorption? A prospective study in renal transplant patients. ASAIO
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13. Urakaze M, Hamazaki T, Yano S et al. Effect of fish oil concentrate on risk factors
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14. Nygard O, Nordrehaug JE, Refsum H et al. Plasma homocysteine levels and mor-
tality in patients with coronary artery disease. New Engl J Med 1997; 337:230-236.
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treated renal transplant recipients. Transplantation 1996; 61(3):509-512.
16. Kirkman RL, Strom TB, Weir MR et al. Late mortality and morbidity in recipi-
ents of long-term renal allografts. Transplantation 1982; 34:347-351.
17. Pichette V, Bonnardeaux A, Prudhomme L et al. Long-term bone loss in kidney
transplant recipients: A cross-sectional and longitudinal study. Am J Kidney Dis
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18. Cayco AV, Wysolmerski J, Simpson C et al. Posttransplant bone disease: Evidence
for a high bone resorption state. J Am Soc Nephrol 1997; 8:549A.
19. Valero MA, Lonaz C, Larrodera L et al. Calcium and biphosphonates in bone loss
after liver transplantation. Calcif Tissue Int 1995; 57:15-19.
20. Talalaj M, Gradowska L, Marcinowska-Suchowierska E et al. Efficiency of preven-
tive treatment of glucocorticoid-induced osteoporosis with 25-hydroxyvitamin D
3
and calcium in kidney transplant recipients. Transplant Proc 1996; 28:3485-3487.
CHAPTER 1
CHAPTER 24
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Biology of Nutrition Support
in the Critically Ill Patient
Rifat Latifi, Selman Uranes
Introduction
The vocabulary and the practice of nutrition support of critically ill patients
have changed significantly in recent years, and new era of nutri-pharmaceutics has
become integral part of patients care. The question to be answered is not any longer
should critically ill patients be fed or not, but rather when to feed and what to feed
them. The benefit of early institution of enteral or parenteral nutrition in the overall
management of critically ill patients has been well established. Following injury,
energy requirements are greatly increased to sustain the increased metabolism and
wound repair. Similarly protein requirements are also greatly increased to provide
substrate for protein synthesis. In this situation, provision of calories and nitrogen
in a ratio of 150:1 has been shown to be most efficacious in achieving a positive
balance. However it is not yet completely understood whether improved nitrogen
balance in patients receiving TPN is achieved by an increase in protein synthesis or
a decrease in protein (muscle) catabolism. Irrespective of these results, it is
well established that TPN is associated with improved nitrogen balance in criti-
cally ill patients.
In general, the optimal route of providing nutrition in critically ill patients has
been established: use the gastrointestinal tract whenever possible. If, on the other
hand, a patient will not receive all needed nutrient substrates and calories enterally,
then nutrition should be provided parenterally. Because of recent advances, in iden-
tifying and recognizing fundamental metabolic changes of key nutrient substrates in
critically ill patients, nutritional formulas are being designed to overcome these
changes and support the organism during critical illness, infection, trauma or severe
sepsis. Example of such approach to nutritional support of critically ill patients is
the provision of immune-enhancing formulas (IEF) that have been shown to im-
prove immune response in laboratory animals and in critically ill patients. These
enteral formulas contain increased amounts of peptides, arginine, glutamine, vita-
mins E, A, and C, nucleotides and nucleosides, branched- chain amino acids and
omega 3-fatty acids. It is suggested that these key nutrients can modulate and affect
a variety of inflammatory, metabolic, and immune processes if given in doses higher
than those recommended. Based on current evidence derived from randomized pro-
spective controlled trials, early provision of nutrition in critically ill patients is a
Level I recommendation,
1
however the controversy exists on what type of nutrition
formula should be used.
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The Biology and Practice of Current Nutritional Support
24
Protein and Nitrogen Metabolism in Critically Ill Patients
Severely injured and critically ill patients characteristically demonstrate signifi-
cant muscle losses and consequently are in negative nitrogen balance. During criti-
cal illness, dietary amino acid requirements are increased two to three times as a
result of hypercatabolism and inefficient reutilization of endogenous nitrogen. Fur-
thermore, amino acids are redistributed from peripheral tissues to splanchnic organs
to maintain protein synthesis in the gut mucosa and immune system. Although
different tissues have varies rates of protein synthesis and, respond differently to
stress and trauma, both muscle protein and albumin synthesis rate correlate with the
metabolic status and severity of the disease. A brief period of accentuated proteoly-
sis, ureagenesis and negative nitrogen balance is tolerated by the stressed, but
well-nourished patient. If the patient is malnourished prior to injury or surgery, or
develops a complication that precludes adequate oral intake or if a patient sustain a
prolonged catabolic phase, then special nutritional support is indicated.
Metabolic response to injury is the striking increase in protein catabolism along
with a marked increase in urinary losses of nitrogen, phosphorus, sulfur, potassium,
magnesium, and creatinine. Skeletal muscle and nitrogen losses following injury
may occur secondary to actual destruction of tissue by injury, blood loss, and exu-
dates from wounds, and muscle wasting secondary to atrophy. The process of in-
creased nitrogen losses is complex and correlates with increased metabolic rate, which
peaks several days after injury and gradually returns towards normal over several
weeks.
1-5
This phenomenon occurs consistently following major fractures or major
blunt injury, burns, sepsis and various other injuries.
6-10
The mechanism for net
protein increase is not entirely clear, although hormonal effect of insulin resistance,
cortisol effects, and proinflammatory cytokines activity have synergistic effects. Di-
minished activity of antioxidants such as gluthatione may effect protein stability
within the cell it self. Metabolic response to severe surgical illness is associated with
mobilization and utilization of nutrient substrates such as fatty acids, amino acids
and glucose. Although, there is a well orchestrated redistribution of body protein
from carcass to visceral organs, the rates of tissue protein synthesis varies with differ-
ent trauma, but correlates with clinical status and overall metabolic indices and is
clearly exacerbated during criticall illness and directly is influenced by the illness it
self, the PO
2
, pH, and hemoglobin.
11
An increased muscle protein catabolism fol-
lowing injury has been demonstrated by measuring the excretion of 3-methyhistidine,
which serves as an index of muscle protein catabolism.
9
As protein is broken down,
3-methylhistidine is released and excreted unchanged by the kidneys especially fol-
lowing critical injury, burns, post- operative trauma, infections and other critical
illness.
10
The primary origin of the 3-methylhistidine is skeletal muscle, but some of
it is derived from the smooth muscle of the gastrointestinal tract. During periods of
starvation and bowel rest, the intestine may become the source for large portion
muscle losses and increased amount of excreted 3-methylhistidine.
Amino Acid Metabolism
Although plasma amino acid levels have been measured in critically ill and in-
jured patients in an effort to identify specific changes related to the catabolic re-
sponse, the results have been inconsistent.
12
The mobilization of amino acids from
muscle protein leads to an irretrievable loss of nitrogen from the body in the form of
urea, ammonia, uric acid, creatinine and other excreted compounds. If left uncor-
rected, the adverse consequences for the critically ill patient are a rapid loss of muscle
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Biology of Nutrition Support in the Critically Ill Patient
24
mass and subsequent marked debility. All amino acids are required for optimal pro-
tein synthesis; however, alanine and glutamine are the major carriers of nitrogen
from muscle, constituting as much as 70% of the amino acids released from skeletal
muscle following injury.
13
Alanine is a major substrate for production of glucose by
the liver, and during that conversion, the nitrogen released is incorporated into urea.
This represents the final breakdown step of the protein and results in an irreversible
loss of nitrogen from the bodys metabolic pool. Glutamine, a nonessential amino
acid, serves as an important respiratory substrate for the enterocytes and other rap-
idly dividing cells, including the bone marrow, endothelial cells, and proliferating
cells in wounds and areas of inflammation.
14,15
Following surgical interventions, glutamine consumption by the gastrointestinal
tract is greatly increased.
16,17
Glutamine has been identified as primary fuel for
enterocytes, and for other rapidly dividing masses of cells where it is converted to
alanine The utilization of glutamine by the intestine as an oxidative fuel has a spar-
ing effect on glucose. During the sepsis, glutamine depletion is even more severe
and lasts longer than that associated with the hypercatabolism following injury. In
sepsis, the lung and the kidney, in addition to the skeletal muscle, becomes an organ
of net glutamine release.
18,19
Furthermore, during the sepsis the liver has increased
glutamine uptake, and becomes the primary organ for glutamine utilization.
19
In
the presence of endotoxemia, glutamine may be used in the liver for gluconeogen-
esis, ureagenesis and synthesis of proteins, nucleotides, and glutathione.
20,21
Following surgery, severe injury or sepsis, the rapid fall in the concentration of
glutamine in the plasma and in the intracellular pool is greater than that of any
other amino acid and is inversely correlated with the severity of the underlying in-
sult. It is reversed only late in the course of recovery.
21
This marked decline in
glutamine concentrations in blood and tissues during critical illness indicates that
glutamine is being consumed at a greater rate than endogenous synthesis. Thus, it
has been hypothesized that glutamine is a conditionally essential nutrient, especially
following injury. Glutamine supplementation has been shown to exert trophic ef-
fects on intestinal mucosa. TPN solutions enriched with glutamine
22
increase jeju-
nal mucosal weight, nitrogen and DNA content, and significantly decrease atrophy
of the villi. Furthermore, glutamine prevents deterioration of gut permeability,
23
and has been proven beneficial for patients with intestinal mucosal injury secondary
to chemotherapy and radiation.
24,25
Reduction of hepatic steatosis,
26
pancreatic at-
rophy
27
and in bacterial translocation from the gut,
28
associated with standard TPN
solutions have been reported with the use of glutamine supplemented TPN solutions.
Glutamine also improves the nitrogen balance and reduces the skeletal muscle glutamine
loss in patients following elective cholecystectomy
29
and other major surgeries. Admin-
istration of glutamine in TPN as glutamine-containing dipeptides has decreased the
incidence of infections in bone marrow transplant patient.
31
Arginine is considered a nonessential amino acid in the diet of healthy adults
because the endogenous synthetic pathways provide adequate amounts of this amino
acid. Arginine stimulates release of growth hormone and prolactin, and also induces
a marked release of insulin.
32
Supplementing the diet with arginine has been shown
to improve weight gain, increase nitrogen retention, and accelerate wound healing
in animals and in human beings.
33
The trophic effects of arginine on the immune
system in human beings have also been demonstrated.
34
In both animals and human
beings, plasma arginine levels decreases significantly following a burn injury.
35
Ex-
perimentally, arginine and glutamine as well as dehydroepiandrosterone reversed
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The Biology and Practice of Current Nutritional Support
24
the susceptibility to infections caused by prednisone and may be useful agents for
preventing infections in patients treated with steroids.
36
Branched-Chain Amino Acids (BCAA)
Following injury and sepsis, an energy deficit that may develop in skeletal muscle
is met by an oxidation of the BCAA. BCAA oxidation is increased after trauma and
sepsis, and evidence indicates that skeletal muscle is the major site of BCAA degra-
dation.
37-41
Most recent study has demonstrated that when critically ill patients,
unable to be fed enterally, were given total parenteral nutrition fortified with BCAA
of 23% and 45% respectively, as compared with standard TPN which provided 1.5
g/kg/day of protein, they had significantly lower morbidity and mortality (42). The
decrease in mortality correlated with higher doses of BCAA to or > 0.5 g/kg/day).
Furthermore, BCAA rich parenteral nutrition formulas have been shown to correct
the plasma amino acids imbalance that consistently exist in critically ill patients, and
improves plasma concentrations of pre-albumin and retinol binding protein
in septic patients.
In a series of trauma patients, nitrogen retention, transferrin level and lympho-
cyte counts were all improved with BCAA supplementation. Since the concentra-
tion of BCAA is low in septic patients, probably as a result of over utilization,
supplementation of feeding regimen with BCAA may be beneficial.
Nucleotides and Nucleic Acids in Nutritional Support
Nucleotides, as building blocks of DNA and RNA, are essential to genetic mecha-
nism, protein synthesis, regulation and structure. These low molecular weight, highly
biological compounds, are involved in virtually all biochemical processes.
43-61
They consist of a nitrogenous base, a 5-carbon sugar, and at least one phosphate
group. RNA and DNA are high-molecular-weight compounds that are made up of
long chains of nucleotides. They form the genetic code and are essential for protein
synthesis. They function as an energy source in cellular metabolism and as interme-
diates in biosynthetic and oxidative pathways. The synthesis of nucleotides is a ma-
jor activity of the cell. Next to protein synthesis, nucleotide synthesis consumes
more amino acids than any other biologic activity. Nucleotides contain either pu-
rine or pyrimidine bases. Adenine, inosine, and guanine, are purine bases, while
thymidine, cytosine and uracil are pyramidine bases. Purine nucleotides are
synthesi zed de novo from gl utami ne, gl yci ne, aspar tate, CO2, and
phosophoribosylpyrophosphate (PRPP), while pyrimidines are synthesized from
aspartate or glutamine, NH
3
, and CO
2
. Purine nucleotides, with their high-energy
phosphate side chains are fundamental to cellular energy metabolism and are inter-
mediaries in biosynthetic and oxidative pathways. Purine nucleotide biosynthesis
produces inosine monophosphate (IMP). IMP is synthesized by the de novo path-
way of purine biosynthesis from glycine and is then converted to AMP and GMP.
The three main sources of nucleotides are: dietary nucleotides, salvage of nucle-
otides released by intracellular metabolism, de novo synthesis from amino acids and
sugars. The addition of a pentose sugar to a nitrogen base produces a nucleoside.
Depending on which sugar is added to the nitrogen base, a nucleoside can be ribo-
nucleoside or a deoxyribonucleoside. Nucleosides are produced by intracellular
metabolism and are used for purine biosynthesis via the salvage pathway. The most
common pathway is the resynthesis of IMP from inosine, which is a product of
adenosine nucleotide metabolism.
373
Biology of Nutrition Support in the Critically Ill Patient
24
The adenosine monophosphate (AMP), adenosine diphosphate (ADP) and ad-
enosine triphosphate (ATP), are energy sources and participants in carbohydrate,
protein, and lipid synthesis. Nucleotides are required in all cells undergoing prolif-
eration, but they are especially important in tissues with rapid cell proliferation such
as intestine, liver, and lymphoid tissue. T lymphocytes require nucleotides to main-
tain a normal cellular immune response. Various tissues in the body, such as liver,
are capable of synthesizing nucleotides de novo. When tissues are unable to synthe-
size purine nucleotides, purines are transported from another tissue. For example,
adenosine is released from the liver and taken up by the lung in large amounts.
The small intestinal mucosa requires a constant supply of nucleotides to produce
DNA and RNA. In these rapidly proliferating cells, the content of DNA and RNA
must double for cell division to occur. However, in these cells, the enterocyte has a
limited capacity for de novo biosynthesis. The small intestine must rely on the sal-
vage pathway to synthesize nucleotides from nucleosides. The nucleosidesinosine,
adenosine, and so on, come either from the blood, or from luminal nucleosides. The
latter may come from the diet, and the sloughing of enterocytes, or from bacterial
breakdown. In addition, nucleotides themselves can be absorbed from the in-
testinal lumen.
It is clear that the small intestinal mucosa relies partially on intestinal nucle-
otides and nucleosides to meet synthetic demands. There are at least two significant
implications. The first is that diets that contain no nucleotides or nucleosides may
not offer sufficient support to the intestinal diets that contain no nucleotides or
nucleosides may not offer sufficient support to the intestinal mucosa in some cir-
cumstances. This includes many enteral diets, especially elemental diets, and in-
cludes all varieties of total parenteral nutrition (TPN). The second implication is
that nucleotide or nucleoside supplementation could be beneficial to critically ill
patients. This type of supplementation has been implemented clinically in certain
enteral products. Nucleotides exert multiple protective actions on the intestinal
mucosa and facilitate repair of injured mucosa. Experimental rats receiving TPN
supplemented with nucleotides showed higher protein and DNA content in intesti-
nal mucosa, increased maltase activity, higher villous height, and more proliferative
activity in crypt cells compared with rats receiving nucleotide-free TPN. In mice,
intraperitoneal and oral administration of a mixture of nucleotides and nucleosides
reduced bacterial translocation and improved repair of mucosal injuries.
Clinically, the frequency of diarrhea in children was reduced from 68% to 52%
when milk formulas were supplemented with nucleotides. While the basis for this
protective action is unclear, although it is known that dietary nucleotides enhance
intestinal epithelial proliferation and differentiation.
The metabolic fate of any exogenously administered nucleotide depends on its
entry position in the overall pathway of purine metabolism. Nucleic acids undergo
partial hydrolysis in the stomach, after which they are subjected to pancreatic nu-
clease to yield nucleotides. Phosphodiesterases and alkaline phosphatases cleave phos-
phate groups to form nucleosides. The presence of charged phosphates in nucleotides
impedes their transport across cell membranes. Phosphates remove the charged phos-
phates and together with nucleotidase facilitate transport across the cell membrane.
Dietary nucleotides converge in the cell cytoplasm in the form of nucleosides, which
are then used in the salvage pathway to reform nucleotides. Nucleotides may be
supplied either enterally or parenterally. Parenterally administered purine and py-
rimidine derivatives are effectively used throughout the salvage pathway. TPN
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The Biology and Practice of Current Nutritional Support
24
formulas supplemented with a mixture of nucleotides and nucleosides can promote
ulcer healing in rats by restoring villous architecture and accelerating cell prolifera-
tion. TPN supplemented with a mixture of nucleotides and nucleosides in animals
undergoing massive intestinal resection resulted in significantly higher residual jeju-
nal total mucosa weight, protein, DNA, RNA, and the ratio of proliferating cells per
crypt a compared with a standard TPN formula. The clinical use of nucleotides in
liver disease has been suggested in order to improve healing of the liver. Experimen-
tal studies have suggested beneficial effects. A mixture of nucleotides and nucleo-
sides given subcutaneously prevented ethionine-induced liver injury by suppressing
the accumulation of triglycerides in the liver, reducing the increase of liver enzymes,
and preventing the decrease of hepatic ATP concentration. In rats undergoing a
70% hepatectomy, supplementation of TPN regimens with nucleotides and nucleo-
sides improved both nitrogen balance and whole body protein turnover. Nucleotide
supplementation was beneficial in galactosamine induced liver injury by reducing
the extent of injury histologically and by improving clinical biochemical liver indi-
ces. Currently, nucleotides are not included in standard TPN solutions, however
there are now enteral formulas fortified with nucleotide (in addition to arginine,
omega-3 fatty acids, and glutamine) that are intended to enhance the immune sys-
tem in patients receiving them.
The immunologic role of nucleotides has been studied mainly in experiments
with nucleotide-free diets. In the early 1980s it was observed that renal transplant
patients receiving standard nucleotide-free TPN had better graft function with few
rejection episodes and required lower doses of immunosuppressants. Once on a
regular diet, these patients required increased doses of immunosuppressants to main-
tain graft function and prevent rejection. Clearly, the patients were immunosup-
pressed on TPN.
It was postulated that lack of preformed nucleotides in TPN was a cause of this
immunosuppression. Animal studies have demonstrated the effects of nucleotide-free
diets. Such diets diminish T cell mediated immune responses such a delayed-type
cutaneous hypersensitivity to various antigens, decreased mitogenic response, and
reduced interleukin-2 production. There is also evidence of decreased survival from
systemic infections caused by Staphylococcus aureus and Candida albicans in ani-
mal fed a nucleotide-free diet. The increased susceptibility to systemic infections has
been shown to reverse with RNA supplementation. Furthermore, nucleotide defi-
ciency reduces splenic stem cell proliferation. This can be reversed with RNA supple-
mentation. Dietary nucleotides modulate T helper cell mediated antibody
production and have a preferential effect on antigen-driven T helper cell-mediated
immune response. Nucleotides and nucleosides are major and essential components
of all cells. The metabolic rate of nucleotides is accelerated in hypermetabolic condi-
tions such as sepsis, trauma, or surgical stress. Substantial evidence suggests that
these nutrients are conditionally essential for normal stress responses. The condi-
tions that increase nucleotide requirements are rapid cellular proliferation and
include hepatic injury or resection, intestinal development and adaptation fol-
lowing massive intestinal resection, and other nonspecific challenges to the
host immune system.
Nucleotides are a component of several immune-enhancing formulas that also
contain glutamine, arginine, and omega 3-fatty acids. These formulas have been
shown to be beneficial in multiple clinical trials. Glutamine, arginine, nucleic acid,
and omega 3-fatty acid supplemental enteral feeding in severe trauma patients
375
Biology of Nutrition Support in the Critically Ill Patient
24
reduced major infection rate, decreased the use of antibiotics, and shortened hospi-
tal stays, In a prospective, randomized, placebo-controlled, double-blinded,
multicenter trial of patients in the surgical intensive care unit, early enteral feeding
supplemented with arginine, nucleotides, and omega 3-fatty acids was shown to
reduce postoperative and wound complications. Septic patients fed early enterally
with the same supplemented diet (in another double blinded multi-center study)
had a substantial reduction in the hospital stay. No clinical study has examined the
beneficial effect of isolated nucleotide supplementation in enteral feeding formulas
critically ill or trauma patients. However, as a component of an immune-enhancing
formula, nucleotides have a role in nutritional support of the critically ill. Nucle-
otides should not be administered as a calorie source, only as a promoter of protein
synthesis and cellular immunity. It seems likely that nucleotides will become an
essential component of nutri-pharmacologic intervention in critically ill and trauma
patients. Published studies have used different terms to describe various nucle-
otide supplementation regimens including nucleotides, polynucleotides,
nucleotide-nucleoside mixtures, RNA, and purines and pyrimidines
Purine nucleotides with their high-energy phosphate chains are fundamental to
cellular energy metabolism and are intermediaries in biosynthetic and oxidative path-
way. Nucleotides exert multiple protective actions on intestinal mucosa and facili-
tate repair of injured mucosa. They prevent ethionine-induced liver injury by
suppressing accumulation of triglycerides in the liver, reducing the increase of liver
enzymes, and preventing the decrease of hepatic ATP concentration. In rats under-
going a 70% hepatectomy, supplementation of TPN with nucleotides and nucleo-
sides improved both nitrogen balance and whole body protein turnover. Furthermore,
nucleotide supplementation was beneficial in galactosamine-induced liver injury by
reducing the extent of injury histologically and by improving clinical biochemical
indices. The turnover rate of nucleotides is accelerated in hypermetabolic condi-
tions such as sepsis, trauma or surgical stress. Substantial evidence suggests that
these nutrients are conditionally essential for normal stress response.
Omega 3-Fatty Acids
The ability of omega 3-fatty acids to incorporate into a cell membrane and their
use during the inflammatory process, as well as their ability to modify the inflam-
matory response, is the rationale for their use in dietary formula in critically ill
patients.
62
Omega 3-fatty acids affect cytokine production, decrease both tumor
necrosis factor (TNF ) and IL-1 synthesis and significantly modulate the inflam-
matory response in adult respiratory distress syndrome (ARDS).
63
Growth Hormone
Growth hormone has been shown to attenuate the protein catabolic response
after major surgery, induce nitrogen retention in patients undergoing gastrointesti-
nal surgery with epidural anesthesia and TPN, and attenuate forearm glutamine,
alanine, 3-methylhistidine and total amino acid efflux. Moreover, growth hormone
has been shown to preserve both muscle protein synthesis and the decrease in
muscle-free glutamine, and improve the whole-body nitrogen economy after sur-
gery.
64
In addition, growth hormone has been shown to reduce skeletal muscle re-
lease of glutamine. Most recently growth hormone and insulin-like growth factor 1
was shown to promote intestinal uptake and hepatic release of glutamine in sepsis.
65
Use of growth hormone in critically ill patients, however, has become controversial
66-74
376
The Biology and Practice of Current Nutritional Support
24
While GH administration was shown to accelerate protein gain in stable adult pa-
tients receiving aggressive nutritional support, and attenuate the catabolic response
to injury, surgery, and sepsis, more recently
GH treatment in critically ill patients has been associated with increased mortal-
ity and morbidity. In a prospective, multi-center, double blind, randomized
placebo-controlled trial, patients treated with high dose GH (0.1 mg/kg body weight)
had higher mortality rate then patients who did not receive GH (p<0.001).
66
Be-
cause of conflicting results of studies, administration of high dose GH is not recom-
mended in critically ill patients.
Immune-Enhancing Enteral Nutrition: Clinical Evidence
Enteral formulas fortified with immune-enhancing substrates are associated with
significant reduction in the risk of infectious complications as well as reduction of
overall hospital stay. Providing adequate standard enteral or parenteral nutrition
support does not necessarily protect critically ill patients from developing nosoco-
mial infections. Since most critically ill patients are immuno-commpromized modu-
lating or enhancing their immune status with nutrient substrates has great
potential.
75-80
It has been demonstrated that certain nutrients can modulate inflam-
matory, metabolic and immune processes. Amino acids such as arginine and
glutamine, improve body defenses, tumor cell metabolism, increase wound healing
and reduce nitrogen losses. RNA and omega 3-fatty acids also modulate the im-
mune function. To this end, supplementation of enteral diets in critically ill patients
with specific immuno-nutrients such as arginine, glutamine, nucleotides, nucleo-
sides, and omega 3-fatty acids in critically ill patients have been shown to be clini-
cally beneficial. These immune-enhancing formulas improve immune response
experimentally as well as clinically. Studies performed in burn, trauma, or surgical
patients have shown outcome advantages with reduction in infections, total compli-
cations, or length of stay. The majority of the prospective, randomized, clinical trials
published to date used formula fortified with arginine, RNA, omega-3 and omega-6
fatty acids. Although various formulas are used they all were associated with im-
proved outcome. The mortality rate however, has not been reduced by the use of
these immune-enhancing formulas.
The effect of the first immune-enhancing formula on the length of hospital stay
and complication rate of critically ill and septic patients was studied in a multi-center
study of 296 traumas, post-surgery and septic patients.
75
The patients in this study
had entry requirements of an APACHE II score greater then 10 and therapeutic
intervention score (TIS) greater than 20, and were stratified by age (less than 60 or
greater than 60 years) and whether they had sepsis or systemic inflammatory re-
sponse syndrome (SIRS), highlighted by fever and leukocytosis. One hundred
sixty-eight patients were randomized to receive the fortified formula, while 158 were
fed with isonitrogenous enteral diet. Both groups tolerated early feeding well, had a
low tube-feeding related complication rate, and achieved similar nitrogen balance.
Patients receiving diet supplemented with arginine, nucleotide and fish oil had higher
levels of plasma arginine and ornithine concentration. Furthermore, their plasma
fatty-acids profiles demonstrated higher concentration of linoleic acid in patients
with common formula (control group) while patients receiving immune-enhancing
formula had higher concentrations of eicosapentaenoic acid and docosahexaenoic
acid. There were no differences in mortality between the groups, however both groups
had overall lower than expected mortality. Moreover, patients who received at least
377
Biology of Nutrition Support in the Critically Ill Patient
24
821 mL/day of enteral diet had an average length of hospital stay reduced by 8.1
days. Most beneficial effects were demonstrated in severely and septic patients with
reduction of length of hospital stay by 10 predicted days along with a major reduc-
tion in frequency of acquired infections (p< 0.01). In a subgroup of septic patients
in whom early enteral feeding goals were achieved, the median length of stay was
reduced by 11.5 days. In a group that was stratified as SIRS, there were no statistical
differences in benefits between the groups. These investigators concluded that early
enteral feeding in severely ill patients is safe and is associated with significant ben-
efits, especially if patients were septic.
75
Another immune-enhancing enteral diet containing glutamine reduced septic
complications in patients with severe trauma.
76
This study, unlike the previous study,
had an isonitrogenous (INIC) control not receiving the immune enhancing diet
(IEF). In a prospective, blinded study 35 severely injured patients with abdominal
trauma supplemented with glutamine, arginine, nucleotides, and omega-3 fatty ac-
ids, or INIC diet (N=18). Nineteen other patients without enteral access served as a
control. Significantly fewer major infections complications (6%) developed in pa-
tients that received IEF than in patients receiving INIC diet (41%, p = 0.02) or the
control group (58%, p = 0.002). The hospital stay, antibiotic use, and the develop-
ment of intra-abdominal infections were significantly lower in IEF group. Patients
that were not fed had the highest rate of complications.
In another prospective, randomized, placebo, double blind, multicenter study of
surgical intensive care patents that underwent upper gastrointestinal surgery, clini-
cal outcome and costs were compared.
77
Early enteral feeding with arginine, dietary
nucleotides, and omega-3 fatty acids was associated with significant reduction in the
frequency rate of late post-operative infection and wound complications. Further-
more, the treatment cost was substantially reduced in the immune-nutrition group
as compared with the control group. Immuno-nutrition (Impact, Novartis Nutri-
tion, Minneapolis, MN) was given to 77 patients, while an isocaloric and
isonitrogenous diet was given to 77 patients. Enteral feeding was initiated within
12-24 hours after surgery and advanced to a target volume of 80 mL/hr by
post-operative day 5. There were no differences in early post-operative complica-
tions between the groups: however, there were significantly fewer late complications
were significantly fewer in immune-nutrition group.
Achieving nutritional goals early in critically ill patients with immune-enhancing
enteral diet has been shown to greatly reduce morbidity and shorten time on me-
chanical ventilation.
78
These investigators studies 390 critically ill surgical and medical
patients. Of the 101 patients achieving early enteral nutrition (within 72 hours), 50
patients fed with Impact had a significant reduction in requirements for mechanical
ventilation compared with controls. There was also an associated reduction in the
length of hospital stay. The administration of immune-enhancing enteral nutrition
had no clear benefits over standard high-protein enteral diets in burn patients, and
was even found to increase the incidence of adult respiratory distress syndrome.
41
Recent prospective double- blind, randomized trial of patients with major burns
(>50% body surface) demonstrated that supplemental intravenous glutamine in-
fused continuously over 24 hours was significantly better than just isonitrogenous
amino acid solutions. In this study, 26 severely burned patients (20%-90% were
randomized to either intravenous glutamine (0.57 g/kg/body weight) or
isonitrogenous amino acid solutions (to give patients 0.57 g/kg/body weight, with-
out glutamine) administered continuously in addition to enteral nutrition support,
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The Biology and Practice of Current Nutritional Support
24
or enteral and parenteral nutrition, for those patients unable to achieve nutritional
goals with enteral nutrition alone. The study group receiving glutamine had lower
incidence of Gram-negative bacteremia (8% vs 43%; p=<0.04), and significant im-
provements in serum transferrin and prealbumin at 14 days after the injury (p<0.01
and 0.04, respectively). Furthermore, there was a trend toward lower mortality, de-
creased bacteremia incidence, and antibiotic usage in glutamine group.
79
Other studies
have shown similar results in multiple trauma patients, where use of glutamine was
associated with significant reduction in the incidence of bacteremia, septic episodes,
and pneumonia.
80
Patients treated with glutamine, had no episodes of Gram- nega-
tive bacteremia, where as the 54% of all bacteremia and 63% of sepsis were caused
by Gram-negative bacteria. Although the mechanism is not entirely clear, it appears
from both these studies that glutamine protects from Gram- negative bacteria in
these most critically ill patients.
Meta-analysis of 11 randomized controlled clinical trials of enteral nutrition with
immune-enhancing formula) that included 1009 patients,
81
concluded that nutri-
tional support supplemented with key nutrients (arginine, glutamine, branched-chain
amino acids, nucleotides, and omega-3 fatty acids) results in a significant reduction
in the risk of developing infectious complications and reduces the overall hospital
stay in critically ill patients and in patients with gastrointestinal cancer.
Although multiple studies have shown beneficial effect of IED, non- the less
their use is not wide spread yet. A consensus panel from a recent conference on
immune-enhancing enteral therapy,
82
recommend the use of IED in the following
patients: a) severely malnourished patients (albumin <3.5 g/dL) undergoing upper
GI surgery, or patients with albumin <2.8 g/dL, undergoing lower GI surgery; b)
patients with blunt or penetrating torso trauma with an ISS of >18/or or abdominal
trauma index >20. Although there are insufficient data to recommend use of IED,
non the less patients undergoing elective aortic surgery with preexisting chronic
pulmonary disease, or those undergoing major head and neck surgery with preexist-
ing malnutrition, severe head injury patients (GCS <8 with an abnormal CT scan),
burns patients (>30%, third degree) and ventilatory dependent patients at risk of
subsequent infections may benefit from early IED use.
Summary
The biology of nutrition support has become much better understood, although
we far from knowing all we need to know in this complex field. Amino acids are a
key component of the nutritional and metabolic management of critically ill pa-
tients. As our current knowledge of the altered regulation of amino acid metabolism
in critically ill patients increases, the formulation and administration of more effec-
tive parenteral and enteral therapeutic feeding regimens will inevitably evolve. The
use of specific amino acids in pharmacological doses and in special combinations
and ratios is likely to be beneficial to critically ill patients. A working knowledge of
the multiple and complex functions of amino acids is essential to the competent and
efficacious practice of medicine. Because derangements in amino acid metabolism
are common in pathologic states and are detrimental to optimal metabolic function,
reversal of these path physiologic alterations by optimal nutritional support will be
obligatory if the outcome of critically ill patients is to be significantly improved.
Metabolic changes of amino acid pool and milieu simply cannot be ignored any
more, and will need to be taken in account when creating new formulation of nutri-
ent formulas, enteral as well as parenteral. Standardization of methodology of
379
Biology of Nutrition Support in the Critically Ill Patient
24
studying end points of nutrition support, clinical criteria for specialized nutrient
substrate such as those fortified with BCAA, patients selection and other variables
will resolve the contradictory findings of future clinical studies. The main difficulty
in obtaining evidence-based data in surgical nutrition support, when different nu-
trient substrates are used, lie the patients selection criteria and study end point, as
well as multiple other variables. The use of specific immune-enhancing formulas
with amino acids in higher pharmacological doses and in special combinations and
ratios is beneficial to critically ill patients.
One should compare nutrition support and advances that need to be made with
other fields such as management of anemia in critically ill patients. Today one can
manage anemia virtually without transfusing blood using genetically created recom-
binant erythropoietin (Procrit
- Ortho Biotech).
83
So, just as we can support ane-
mic patient with substrates that will stimulate bone marrow to produce blood and
blood products, without transfusing blood, we should strive to use in the future
genetically altered nutrient substrates that will mimic, or better off, substitute the
perfect nutrient substrates for most critically ill patients and correct exactly the cel-
lular imbalances caused by the injury, severe sepsis or other disorders. Derangement
in amino acid metabolism, nucleotides, vitamins and trace elements are common in
critically ill patients. Reversal of these pathophysiologic alterations by optimal nu-
tritional support with immune-enhancing formulas is obligatory if the outcomes of
critically ill patients are to be significantly improved. Ideally the formula used for
nutrition and metabolic support in critically ill patients should contain high doses
of arginine, glutamine, taurine, BCAA, nucleotide and nucleoside, omega 3-fatty
acids, zinc, selenium, and vitamins A, E, C. It is also important for this formula to
be inexpensive and should be available in the enteral as well parenteral form.
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53. Sukumar P, Loo A, Magur E et al. Dietary supplementation of nucleotides and
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CHAPTER 25
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Nutrition Support in Patients
with Pulmonary Failure and ARDS
Vanessa Fuchs, A.K. Malhotra and Rifat Latifi
Malnutrition and Lung Functions
Malnutrition is a leading cause of impaired respiratory muscle strength, endur-
ance and contractility, as well as lung function and their dynamics. In addition,
malnutrition causes deleterious changes in the structure and function of the dia-
phragm muscle mass and thickness which are reduced in proportion to the reduc-
tion in body weight. While the diseases associated with somatic wasting cause atrophy
of the respiratory muscles, respiratory muscle strength and endurance are reduced
more dramatically than the weight loss. Patients suffering from chronic obstructive
pulmonary disease (COPD) frequently exhibit profound malnutrition both as a
consequence of and result of their disease. Patients with acute respiratory failure,
secondary to sepsis, trauma, or intrinsic lung disease, may rapidly progress to a state
of nutritional embarrassment due to multiple factors. Furthermore, patients with
ARDS, or those sufferings from conditions rendering them susceptible to develop
ARDS, similar to other critically ill patients, have increased caloric requirement, are
hyperglycemic and have triglyceride intolerance, and overall net increase in protein
catabolism. Subsequently most patients with pulmonary failure have an attendant
compromise in nutrition status. Malnutrition may precede or follow respiratory
failure and if nutritional status is not preserved or malnutrition reversed with ag-
gressive nutritional support, the condition will progress into severe malnutrition
with significant clinical deterioration.
1
Malnutrition can adversely affect lung func-
tion and the adverse effects of such malnutrition include: decreased ventilatory drive,
decreased respiratory muscle function, alterations of lung parenchyma and depressed
lung defense mechanism. The incidence of post-operative pneumonia or atelectasis
is higher in protein-depleted patients as compared with well-nourished patients.
2,3
Anatomy of Respiratory Failure
Three categories of pulmonary failure are of special clinical interest: acute respi-
ratory failure (ARF) or acute respiratory distress syndrome (ARDS) and chronic
obstructive pulmonary disease (COPD), and post operative
Acute Respiratory Failure
Acute respiratory failure (ARF) occurs when the respiratory system is no longer
capable of providing sufficient oxygenation or is unable to eliminate enough CO
2
.
Several disorders including alveolar edema, fungal infections, lung cancer, tuberculosis
385
Nutrition Support in Patients with Pulmonary Failure and ARDS
25
and COPD may cause acute respiratory failure, which is classified in three types.
Type I respiratory failure is hypoxemic, caused mostly by shunting, thus is unre-
sponsive to supplemental oxygen therapy. Alveoli are basically flooded with puru-
lent material such is in pneumonia, blood in lung contusion, or edema in ARDS
caused by sepsis, aspiration, massive transfusion, shock, severe pancreatitis, fat em-
boli syndrome or amniotic fluid emboli. While many scoring systems have been
used in an attempt to define the severity of ARF, the PaO
2
/FiO
2
(P/F) ratio is most
useful. When this ratio is between 300 and 200 there is acute lung injury, and when
this ratio drops below 200, then this is considered ARDS. If, on the other hand, the
P/F ratio is <100, this is considered to be a severe ARDS. Because Type I respiratory
failure causes significant respiratory dysfunction with decreased lung compliance,
and dramatic increase in work of breathing, the majority of patients with ARF re-
quire some form of mechanical ventilation. Chronic pulmonary failure is character-
ized by abnormal expiratory flow that does not change markedly over several months.
Because expiration is obstructed, breathing requires more effort and more energy.
Type II of respiratory failure is characterized by elevation of CO
2
which is caused by
hypoventilation as a result of loss of respiratory drive, impaired mechanics of breathing
or simply excessive work load. Type III respiratory failure occurs mainly in the post-
operative patients, and is typically associated with hypoxemia and hypoventilation.
While this type of ARF is considered to be mainly from atelectasis and decreased
movement of diaphragm, which could progress in to pneumonia, the weakness of
diaphragmatic muscle secondary to perioperative malnutrition should be strongly
considered.
Chronic Respiratory Failure
Two major causes of COPD are chronic bronchitis and emphysema. Often this
type of respiratory failure is termed acute on chronic respiratory failure, when a
patient with relatively compensated respiratory failure experiences an insult such as
trauma or infection and deteriorates in full respiratory failure requiring mechanical
ventilatory support. This group of patients is at increased risk for significant malnu-
trition since increased metabolic demands and reduction of nutrient substrate in-
take result in a malnutrition state.
1,4,5
Chronic obstructive pulmonary disease (COPD) is associated with a variety of
nutritional and metabolic abnormalities. These abnormalities include protein and
caloric malnutrition, associated muscular atrophy, alteration in carbohydrate me-
tabolism, and altered respiratory drive. In addition, COPD is often associated with
hypermetabolism that is caused by an increase in the work of breathing. During
pulmonary failure, superimposed starvation may rapidly lead to worsening of respi-
ratory muscle function and inability to wean mechanical ventilatory support. It has
been demonstrated that during the period of acute illness and starvation, that muscle
degradation occurs primarily as a result of decreased protein synthesis and increases
muscle protein catabolism.
6,7
It has been also shown that malnutrition and immu-
nity may play a very important role in the pathogenesis of COPD. Furthermore,
malnourished patients have lower cellular immune function, although their humoral
immune function was similar to healthy subjects.
8
Acute Respiratory Distress Syndrome (ARDS)
ARDS is a common, devastating syndrome of lung injury affecting both surgical
and medical patients. It is estimated that approximately 75 per 100,000 populations
386
The Biology and Practice of Current Nutritional Support
25
will suffer from ARDS. Although ARDS was described for the first time in 1967, it
was not until 1994 that a new definitions was created by the American-European
Consensus Conference Committee, that defined ARDS as a syndrome occurring
particularly in subset of patients with severe of acute lung injury (ALI), character-
ized by a constellation of clinical, radiological, and physiologic abnormalities that
cannot be explained by, but may coexist with left arterial or pulmonary capillary
hypertension. In particular, this syndrome must have acute onset, bilateral infil-
trates on chest radiography, pulmonary- artery wedge <18 mm Hg, and P/F ratio
less than 200.
9-11
There are numerous predisposing factors and clinical disorders associated with
development of the ARDS, including direct acute lung injury (aspiration, pneumo-
nia or inhalation injury), and indirect causes such as sepsis, severe multiple traumas,
shock, massive blood transfusion, and pancreatitis. Other less common causes of
ARDS are pulmonary contusion, fat emboli, near- drowning, and reperfusion pul-
monary edema after lung transplantation or pulmonary embolectomy, cardiopul-
monary bypass and drug overdose.
11
Overall mortality from ARDS is typically
reported to be greater than 50%, mainly because of underlying predisposing illness,
sepsis, or multiple organ dysfunctions. The primary reason for high mortality is
multiple organ system failure and sepsis, rather than primary respiratory causes,
although death may be related to the lung injury with high tidal volumes therapy.
12
The long-term consequences of ARDS are often very serious, although full return of
pulmonary function in a patient who survives ARDS is seen, with pulmonary func-
tion returning to normal within 6-12 months. If on the other hand, patient had
suffered long period of ventilatory support, sepsis, then the residual impairment of
lung function is present although may be asymptomatic. Currently patients with
ARDS are supported with mechanical ventilation and other supportive measures
directed at reducing and reversing the lung injury, such as low tidal volumes, pres-
sure control ventilation with or without inverse ratio ventilation and other tech-
niques such as prone positioning of the patients and aggressive pulmonary toilet.
Failure of standard advanced therapeutic measures to resolve ARDS have prompted
the use of other techniques such as tracheal gas insufflations, inhaled nitric oxide,
extra corporeal membrane oxygenation (ECMO) or partial liquid ventilation. Most
impressive progress in ventilatory support of patients with ARDS was reported re-
cently.
12
In an randomized, multicenter trial patients with acute lung injury and
ARDS, mechanical ventilation with lower tidal volume than traditionally used low
tidal volumes decreased mortality rate and decreased ventilatory days. Patient with
ALI and ARDS, were enrolled in a study that compared ventilatory support involv-
ing high tidal volume (12 ml per kg body weight) with low tidal volume (6 ml per
kg). The primary outcomes were the death before discharge home and breathing
without assistance. The trial of 861 patients was stopped because patients with lower
tidal volumes had significantly lower mortality rate (31% vs 39.8%; p=0.007) as
well as had fewer days in the ventilator (12+/-11 vs 10+/-11;P=0.007), than those
with high tidal volume. Most of these techniques, however, do not address the main
issue in ARDS: the molecular basis for the condition and, as such are supportive
only. Until such treatment becomes available, we will continue to support these
patients with multiple modalities, hoping to reduce effectively high morbidity and
mortality of ARDS.
387
Nutrition Support in Patients with Pulmonary Failure and ARDS
25
Nutritional Assessment
Respiratory Quotient
In the process of converting the macronutrients such as protein, fat and carbo-
hydrates to energy, oxygen is consumed and carbon dioxide is produced.
13,14
Utiliza-
tion of caloric sources is estimated from the respiratory quotient (RQ), which is the
ratio of carbon dioxide produced to oxygen consumed. The RQs produced from
carbohydrate, fat, and protein is 1.0, 0.7, and 0.8, respectively. For a given amount
of oxygen consumed, more carbon dioxide is produced from metabolism of carbo-
hydrates then from fat or protein. Metabolism of fat yields the lowest RQ (0.7). The
RQ of a typical mixed diet is 0.85.
Since patients with COPD and respiratory failure suffer from carbon dioxide
retention and oxygen depletion in the blood, the goal of therapy is to decrease the
blood level of carbon dioxide. Administration of a diet with and increased propor-
tion of fat calories and decreased carbohydrate calories can reduce carbon dioxide
production and RQ, thus diminishing ventilatory requirements. The end result is
desirable both for the patient with COPD, for whom hypercapnia may lead to res-
piratory failure, and for patient with respiratory failure who must be weaned from
mechanical ventilation.
Although providing sufficient protein for anabolism is important, the overfeed-
ing of protein should be avoided. Protein intake has little effect on carbon dioxide
production but has been demonstrated to augment the ventilatory drive mecha-
nism. High protein diets will stimulate ventilatory drive and minute ventilation in
normal persons. An increase in respiratory drive can be beneficial for patients able to
respond to stimulus. However, for patients unable to increase minute ventilation,
the stimulus can increase the work of breathing and cause dyspnea.
15,16
Excess nutrient administration in patients on mechanical ventilation could ag-
gravate respiratory failure by augmenting CO
2
production.
17-19
Thus, provision of
caloric intake that exceeds metabolic requirements can lead to net lipogenesis with
associated RQ >1. At the same token, estimation of energy requirements of patients
with respiratory disease can be difficult.
20-23
In normal subjects only a small fraction
of REE is devoted to supporting the metabolic activity of respiratory muscles. Both
COPD patients and patient with respiratory failure of various causes have increased
work of breathing. Therefore, commonly used prediction models for estimation of
metabolic requirements, which typically use parameters attempting to estimate the
lean tissue mass, may have limited accuracy in the patient with pulmonary disease.
While indirect calorimetry can be used as an assessment of energy expenditure to
predict metabolic needs more accurately, there is a specific equation to predict en-
ergy requirements for COPD patients.
Men (11.5 x weight (kg) + 952
Women (14.1 x weight (kg) + 515
Energy requirement may be estimated based on indirect calorimetry. However,
the most accurate method for determination of estimated caloric requirements is
the indirect measurement of actual energy expenditure with a metabolic chart, al-
though these devices are subject to significant error because of short sampling time,
usually 10 to 15 minutes.
The goals of nutritional support and nitrogen requirements of patients with
pulmonary disease are not significantly different from other patients. The optimal
support entail establishing neutral or positive nitrogen balance. This is usually
388
The Biology and Practice of Current Nutritional Support
25
accomplished by giving 0.16 to 0.24 g of nitrogen per kilogram per day for mild to
moderate stress and 0.32 g/kg per day for marked stress. The composition of nutri-
ent substrates however should be directed to the individual disease process, in order
to address the basic molecular needs as well as derangement at the molecular level.
The goal of nutritional assessment is to identify those patients at high risk for an
adverse outcome. Once identified, the nutritional assessment parameters can be
used to identify the response of selected patients to an intervention program. Effec-
tive screening tools must be safe, cost effective, wildly applicable, an accurate in
predicting adverse sequale.
Anthropometrical measurements are limited by the assumption of uniform dis-
tribution of total body fat. However, they remain useful in patients with end stage
pulmonary disease (ESPD) because they identify an adverse nutritional effect that is
not evident with the monitoring of body weight alone. Weight gain in patients with
ESPD may be interpreted as favorable, but weight gain of primarily fat mass is
unlikely to be beneficial. The use of anthropometrical assessment can provide valu-
able insight into the patients progress during a rehabilitation program if measured
and interpreted correctly.
Hepatic secretory proteins such as albumin, prealbumin, transferrin, and
retinol-binding protein are often measured as part of a comprehensible nutritional
assessment program as indicators of visceral protein stores. Malnourished ESPD
patients generally do not present with decrements in these parameters, based on a
number of clinical trials of nutritional support in COPD patients, and routine se-
rum measurements are probably not indicated.
An alternative approach to nutritional assessment involves a more functional
assessment. Examples of these are adductor policis muscle for a functional nutri-
tional assessment owing the ready accessibility of the ulnar nerve for neural stimula-
tion. The respiratory muscles demonstrate similar neurophysiologic properties to
peripheral muscles during electrical stimulation; a simpler, less precise alternative to
neurophysiologic testing is the use of voluntary tests of maximal muscle strength,
such as handgrip dynamometry or respiratory muscle pressure. Handgrip dynamom-
etry provides an inexpensive and simple method of assessing muscle function and is
easily obtained in the output setting; it can be incorporated into an initial assess-
ment with little difficulty and used serially to confirm strength changes by nutrition
and exercise. Muscle mass is a difficult parameter to assess in ESPD patients. A
standard index is the 24-hour collection of urinary creatinine. This measurement
requires a controlled diet and meticulous collection of the urine sample, making it
impractical in the outpatient setting. When the more practical indices of muscle
mass such as body weight or arm muscle circumference are compared with urinary
index, the correlation is poor.
Another functional assessment tool is a measurement of immune function. Un-
dernourished COPD patients demonstrate abnormalities in these markers that ap-
pear to improve following the institution of nutritional support. Although useful,
this test may be affected by multiple factors such as such as aging, corticosteroid use,
chronic infection, and malnutrition, all of which are typically present in the patient
with ESPD. This relationship limits the ability of these functional assessment tools
to identify patients at nutritional risk, although the tools are still valuable for assess-
ing the response to a nutritional intervention program. All physiological and his-
torical findings are used to identify the specific nutritional problems of the individual
patient and to develop a comprehensive care plan.
13-20
Patients with obstructive disease
389
Nutrition Support in Patients with Pulmonary Failure and ARDS
25
(COPD) and those who suffer from adult respiratory distress syndrome (ARDS) are
at high nutritional risk.
16,21
Merely providing adequate calories to the severely ill
ventilated patient is not sufficient. Specialized nutrition support regimens for pa-
tients with respiratory disease should include carbohydrate doses below the maxi-
mal oxidative rates for glucose and omega 3-fatty acid fat emulsions as a daily
continuous infusion.
21
Early enteral feeding is clearly most beneficial.
Molecular Basis Nutritional Management
In order to help patients with ARDS as well as those with COPD, we must
understand the pathophysiology of this complexes disease process, especially in pa-
tients with ARDS. The molecular basis of inflammatory process and lung injury has
been advanced significantly in recent years.
10,11
While the issue is far from being
resolved, the evidence of neutrophil predominance in the pulmonary edema fluid
and bronchoalveolar lavage obtained from patients with ARDS and animal models
has been accumulated, although ARDS may develop in neutropenic patients as well.
10
At the same time, a complex cadre of prroinflammatory cytokines is activated lo-
cally or systemically and initiate or exacerbate the inflammatory response in ALI
and ARDS. Most important though is the balance between the pro-inflammatory
and anti-inflammatory cytokines. If this process can be reversed effectively or pre-
vented than one will expect that ARDS will not progress into fibrosing alveolitis or
fibrotic lung injury, as this finding clearly corresponds with increased mortality.
Interleukin-1 (IL-1) is known to promote the development of fibrosing alveolitis,
and procollagen III peptide, a precursor of collagen synthesis that is elevated very
early in the course of disease process. The strategies to improve the resolution of
ARDS should be closely related to arrest the inflammatory process of lung injury.
Fluid and hemodynamic support of these patients, surfactant therapy, use of in-
haled nitric oxide and other vasodilators and glucocorticoids as well as use of other
anti-inflammatory agents are part of the current pharmacological armamentarium
in the treatment of ARDS. However, the concept that we may feed patients with a
specially formulated diet, that will maintain optimal nutritional status, prevent or
reverse malnutrition, and at the same time reverse effectively or arrest the inflamma-
tory process of sepsis or other causes induced acute lung injury is certainly
very appealing.
For practical purposes we will separate nutritional management of patients with
COPD and those with ARDS. Although most patients with COPD, except those
with acute on chronic respiratory failure do not require special dietary measure-
ment. While nocturnal nasoenteric feeds are well tolerated by most patients and
results in weight gain, the termogenic effect of a large meal may include significant
metabolic demand and ventilatory workload due to excess CO
2
production and
could precipitate acute respiratory failure.
22
In COPD patients with acute respira-
tory failure, a hyper caloric nutrition may induce complications that result mainly
from an excessive CO
2
production. The use of a specially formulated lipid enriched
diet has been recently proposed in these patients to facilitate weaning from ventila-
tory support. Nutritional regimen providing optimal calorie and protein is associ-
ated with weight gain, nitrogen retention, and improvement in muscle.
physiologic parameters.
On the other hand, for the patient with severe pulmonary disease or requiring
mechanical ventilation, the over-provision of carbohydrate may have serious
theoretical sequale, although practically this is not very common. As part of the
390
The Biology and Practice of Current Nutritional Support
25
conversion of excess carbohydrate to fat, additional CO
2
is produced. To maintain
acid-base balance, the excess CO
2
must be eliminated, thus increasing the amount
of respiratory work. This process has been shown to increase VO
2
, VCO
2
, VE, REE,
and ventilatory response to hypoxia, hypercapnea, and respiratory work.
23
In order
to avoid this, the optimal amount of carbohydrate utilization has been determined.
It has been shown that patients do not oxidize more than 5 to 7 mg glucose/kg body
weight/min given intravenously. Higher rates of administration can lead to fat stor-
age. In septic patients, the maximal amount of glucose oxidized may even be lower.
Initially, the excess glucose is used to replete glycogen stores in the liver. Because this
is a finite pool of glucose, it is quickly replenished and the body converts all excess
glucose into triglyceride. Therefore, in most circumstances, the rate of infusion should
not exceed 4 to 5 mg/kg/min. In average size patient, daily provision should not be
greater than 300 to 400 g/day.
23
Another interesting point of nutritional therapy in
pulmonary failure is the achievement of most accurate combination and proportion
of nutrients.
22
When nutrient substrates provision in both enteral and parenteral
formulas is properly calculated and provided, caloric goals can be achieved with less
potential for carbohydrate overfeeding. To avoid the provision of all non-protein
calories as carbohydrate, approximately 30% of caloric requirements are usually sup-
plied as lipids. The provision of lipids, traditionally as long chain triglycerides, has
been associated with immunological abnormalities including reticuloendothelial
system dysfunction, impaired phagocytosis, increased gram-positive bacterial sur-
vive and depression of cardiac function.
While the lipids are useful to prevent essential fatty acids deficiency, the amount
and the type of fatty acids provided is very important element of nutritional support
of patient with respiratory failure. This may be true for other critically ill patient as
well. A recent study compared hemodynamic and gas exchange alterations in septic
patients with ARDS receiving long-chain triglycerides (LCT) versus medium chain
triglycerides (MCT). The results showed that, in septic patients with respiratory
failure, LCT administration was associated with more significant changes of Qva/
Qt, MPAP and P/F ratio compared to an infusion of an LCT/MCT 1:1 emulsion.
Clinically, these transient alterations might cause serious problems in patients with
marginal arterial oxygenation and cardio-respiratory impairment.
14
High fat, low
carbohydrate enteral feeds appeared to be beneficial in patients with acute respira-
tory failure requiring ventilatory support.
24
Furthermore, there have been experimental studies in which it was demonstrated
that supplementation of parenteral nutrition with -linolenic acid increased dihomo
-linolenic acid, and prostaglandin E, increased the plasma arachidonic acid ratio,
and favorably reduced the ratio of thromboxane B
2
and 6-ketoprostaglandin F 1
in injured rats. These reflect the potential capacity of -linolenic acid enriched emul-
sions to increase dihomo -linolenic, fatty acid precursor of anti-inflammatory
eicosanoids, prostaglandin E
1
; and to modulate arachidonic acid-deviated prostag-
landin after injury.
25
In another study, the researches demonstrated that dietary fish
oil and borage oil suppressed intrapulmonary proinflamatory eicosanoid biosynthe-
sis and attenuates pulmonary neutrophil accumulation in endotoxic rats. Fish oil
and fish and borage oil when compared with corn oil may ameliorate
endotoxin-induced acute lung injury by suppressing the levels of proinflammatory
eicosanoids (but not TNF or MIP-2) in broncho-alveolar lavage fluid and reduc-
ing pulmonary neutrophil accumulation.
26
In addition dietary fish oil and borage
oil significantly alter the fatty acid composition of lung phospholipids by decreasing
391
Nutrition Support in Patients with Pulmonary Failure and ARDS
25
arachidonic acid and increasing eicosapentanoic acid (EPA) with fish oil and in-
creasing dihomo-gama-linolenic acid when fish oil and borage oil were used in com-
bination.
26
These changes are consistent with suppression of eicosanoids associated
with SIRS. There is evidence that incorporation of EPA into phospholipids shifts
eicosanoid metabolism to the less biologically actively 3-series prostaglandins and
5-series leukotrienes.
27-29
Others have shown that following enteral feeds, as short as only three days; there
is significant incorporation of EPA and GLA with displacement of arachidonic acid
in lung alveolar macrophage phospholipids.
30
Leukotrienes are considered to be the
mediators in lung inflammation and have also been found to be in high concentra-
tions in the bronchoalveolar lavage fluid of patients with ARDS. Inhibition of
leukotriene B
4
formation significantly reduces lung microvascular permeability and
edema formation in experimental animals. Fish oil and borage oil diet was shown to
reduce the synthesis of B
4
leukotriene. Lower levels of leukotriene B
4
reduces the
effect of neutrophils and increased microvascular protein permeability in endotoxic
rats. Most importantly animals fed with this diet, did not mount the expected re-
sponse in eicosanoid production when challenged with endotoxins.
26
Entirely specialized diets enriched in eicosapentanoic acid (EPA) and -linolenic
acid, precursors of trienoic and monoenoic eicosanoids, respectively, have proven to
attenuate cardiopulmonary dysfunction during acute injury in pigs. These diets
improve gas exchange and O
2
delivery, presumably in part through a modification
of thromboxane B
2
(TxB
2
) production with decrease in pulmonary vascular resis-
tance and an increase in cardiac index, and acute lung injury (ALI).
31
Using this
background,
24-32
a prospective, multicenter, double-blind, randomized controlled
trial was reported recently.
33
One hundred and forty-six patients with ARDS were
randomized to receiving enteral tube feeds with either eicosapentaenoic acid (EPA)
and gamma- linolenic acid (GLA) or isonitrogenous isocaloric standard diet for at
least 4-7 days. Patients who were fed with EPA+GLA had significantly lower neu-
trophils in the bronchoalveolar lavage, significantly improved in the P/F oxygen-
ation ratio, had lower ventilatory variables (Fio2, PEEP, minute ventilation) than
controls. Furthermore, patients fed with EPA and GLA had fewer days in a ventila-
tor support and a decreased stay in the ICU. In addition, only 8% of patients with
ARDS fed EPA+GLA developed multiple organ system failure when compared to
28% of the controlled group. The beneficial effects of the EPA+GLA diet on neu-
trophil recruitment, gas exchange, requirement for mechanical ventilation, ICU stay
and reduction in development of multiple organ system failure were clearly demon-
strated. Specialized diet with EPA+GLA and antioxidants modulates neutrophil
mediated lung injury, and it is thought the mechanism of action is anti-inflammatory
and vasodilator properties of EPA and GLA.
Chronic Obstructive Pulmonary Disease (COPD)
The occurrence of weight loss in obstructive lung disease has been described in
50% of COPD patients who require hospitalization. Positive energy balance in weight
losing COPD patients is associated with nitrogen retention and weight gain. These
finding distinguishes the patient with COPD from other diseases models associated
with hypercatabolism, such as sepsis or trauma, in which positive balance does not
produce nitrogen retention. Studies associated with positive energy and nitrogen
balance have produced improvements in measured muscle strength parameters, as
well as walking distance, dyspnea, and quality of life.
21,23,34
COPD flares are often
392
The Biology and Practice of Current Nutritional Support
25
associated with increased respiratory muscle metabolism, inactivity, limited caloric
intake, systemic inflammation, and frequent steroid use. When approaching the
patient with ESPD and ongoing weight loss, the contribution of these individual
factors must be addressed and appropriate solutions incorporated into the treat-
ment plan. Nutrition counseling to address the planning, preparation and the use of
nutritionally adequate meal plan, food supply at home, the use of nutritional supple-
ments, and other details is essential to the success of any intervention program. The
benefits of altering fat-to-carbohydrate ratios in the provision of non-protein calo-
ries in ambulatory COPD patients remain to be proven. However, there are studies
that attempt to surpass daily caloric requirement with nutritional manipulation in
favor of a low carbohydrate, high fat diet may be an important consideration for
patients with COPD. When compared to standard liquid diets, a diet with a high
percentage of fat results in decrease carbon dioxide production and retention. In
another study in which it was study the effects of refeeding a high fat enteral diet
versus a high carbohydrate one in patients with COPD, the authors showed that the
high fat diet resulted in lower oxygen consumption and carbon dioxide production
than the high-carbohydrate formula. They concluded that metabolic response to
each regimen was primarily related to dietary content and composition. These func-
tional changes were primarily related to feeding duration.
24
Nutrition intervention for COPD patients should be viewed as complementary
to the other components of a comprehensive rehabilitation program. There is strong
evidence that the onset of weight loss is a poor prognostic indicator, and that mod-
est weight gain facilitated improves in muscle function. Excessive weight gain, espe-
cially of body fat, would likely have deleterious effect in these patients and should be
avoided. Investigations that address the mechanisms of weight loss in an effort to
better understand the decline of patients with severe emphysema are indicated.
Summary
General goals of nutritional therapy in the patient with respiratory failure in-
clude maintenance of lean body mass and positive nitrogen balance. Weight gain
should be reserved for more protracted phase of respiration failure, such as malnour-
ished patients requiring long-term ventilatory support. The key for the treatment of
those patients is mainly not to overfeed them, especially with carbohydrates, and to
reassess them as frequent as possible in order to adjust their diet according to their
nutritional requirements depending on their disease and state. Nutrition therapy is
an important part of the treatment of patients with pulmonary failure and should be
taken into consideration since the onset of the disease, and should be monitored
throw the evolution of these patients.
Selected References
1. Pinard B, Geller E. Nutritional support during pulmonary failure. Crit Care Clin
1995; 11(3):705-15.
2. Dureuil B, Matuszczak Y. Alteration in nutritional status and diaphragm muscle
function. Reprod Nutr Dev 1998; 38(2):175-80.
3. Ferrari-Baliviera E, Pierdominici S. Effects of nutritional status on respiratory sys-
tem. Minerva Anestesiol 1989; 55(11):443-50.
4. Grant J. Nutrition Care of patients with acute and chronic respiratory failure.
NCP 1994; 9:11-17
5. Blair G, Sharpe L. Nutrition support in Respiratory Disorders. NCP
1989.4:173-175
393
Nutrition Support in Patients with Pulmonary Failure and ARDS
25
6. Ireton-Jones C, Borman K, Turner W. Nutrition considerations in management of
ventilator-dependent patients. NCP 1993; 8:60-64
7. Branson R, Hurst J. Nutrition and respiratory function: Food for thought. Resp
Care 1988; 33(2):89-92.
8. Song Y, Kang XM, Xia XR. The nutritional status and immune function of pa-
tients with chronic obstructive pulmonary disease. Chung Hua Nei Ko Tsa Chih
1993; 32(1):33-6.
9. Bernard GR, Artigas A, Brigham KL et al. The American-European consensus
conference on ARDS: Definitions, mechanism, relevant outcomes and clinical trial
coordination. Am J Respir Crit Care Med 1994; 149:818-24
10. Ware BL, Matthay M. The acute respiratory distress syndrome. NEJM 2000;
342:1334-1349.
11. Tobin MJ. Culmination of an era in research on the acute respiratory distress syn-
drome. NEJM 2000; 342:1360-1361
12. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal
volumes as compared with traditional tidal volumes for acute lung injury and the
acute respiratory distress syndrome. NEJM 2000; 342;1301-1308.
13. Pingleton S, Harmon G. Nutritional management in acute respiratory failure. JAMA
1987; 257(22):3094-3099.
14. Smirniotis V, Kostopanagiotou G, Vassiliou J et al. Long chain versus medium
chain lipids in patients with ARDS: Effect on pulmonary homodynamic and gas
exchange. Intensive Care Med 1998; 24(10):1029-33.
15. Azkenazi J, Weissman C, Rosenbaum H et al. Nutrition and respiratory system.
Crit. Care Med 1982; 10(3):163-72.
16. Blair G, Sharpe L. Nutrition support in respiratory disorders. Nutr Clin Prac 1989;
4:173-175
17. Cerra FB, Hypermetabolism, organ failure and metabolic support- clinical review.
Surgery 1987; 101:1-14
18. Clemmer TP, Orme JF. Nutritional support in the adult respiratory distress syn-
drome. Clin Chest Med 1982; 3:101-8.
19. Spector N. Nutritional Support of the ventilator dependent-patient. Nurs Clin
North Am. 1989; 24:2
20. Glodstien SA, Thomashow B, Azkenazi J. Functional changes during nutritional
repletion in patients with lung disease. Clin Chest Med 1986; 7(1):141-151.
21. Mowatt-Larssen CA, Brown RO. Specialized nutrition support in respiratory dis-
ease. Clin Pharm 1993; 12(4):276-92
22. Ryan CF, Road JD, Buckley PA et al. Energy balance in stable malnourished pa-
tients with chronic obstructive pulmonary disease. Chest 1993; 103(4):1038-44.
23. Donahue M. Nutritional aspects of lung disease. Resp Care Clin North America.
1998; 4(1):85-111.
24. Al-Saady NM, Blackmore CM, Bennet ED. High fat, low carbohydrate, enteral
feeding lowers PaCO
2
and reduces the period of ventilation in artificially venti-
lated patients. Int Care Med 1989; 15:290-295.
25. Karlstad M, DeMichelle S. Effects of intravenous lipid emulsions enriched with
-linolenic acid on plasma n-6 fatty acids and prostaglandin biosynthesis after
burn and endotoxin injury in rats. Crit Care Med 1993; 21(2):1740-49.
26. Mancusco P, Whelan J. Dietary fish oil and fish and borage oil suppress intrapul-
monary proinflammatory eicosanoid biosynthesis and attenuate pulmonary neu-
trophil accumulation in endotoxic rats. Crit Care Med 1997; 25:1198-1206.
27. Lee TH, Mencia-Huerta J, Shih C, et al: Characterization and biologic properties
of 5,12-dihydroxy derivatives of eicosapentaenoic acid including leukotriene B
5
and double lipoxygenase product. J Biol Chem 1984; 259:2383-2389
28. Fischer S. Weber PC. Prostaglandin I
3
is formed in vivo in man after dietary
eicosapentaenoic acid. Nature 1984; 307:165-168
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29. Needleman P, Raz A, Minkes MS et al. Triene prostagladins: Prostacyclin and throm-
boxane biosynthesis and unique biological properties. Proc Natl Acad Sci USA
1979; 76:944-948
30. Palombo JD, DeMichele SJ, Lyndon E et al. Rapid modulation of lung and liver
macrophage phospholipids fatty acids in endotoxemic rats by continuous enteral
feeding with n-3 and gamma-linolenic acids. Am J Clin Nutr 1996; 63:208-219.
31. Mancusco P, Whelan J, DeMichele SJ et al. Effects of eicosapentaenoic acid and
gamma-linolenic acid on lung permeability and alveolar macrophage eicosanoid
synthesis in endotoxic rats. Crit Care Med 1997; 25:523-532
32. Murray M, Kumar M, Gregory TJ et al. Enteral diet enriched with eicosapentaenoic
acid and gamma-linolenic acid attenuate cardiopulmonary dysfunction in a por-
cine model of acute lung injury. Am J Physiol 1995; 269:H2090-H20997.
33. Gadeck JE, DeMichele SJ, Karlstad MD et al. Effect of enteral feeding with
eicosapentaenoic acid, -linolenic acid, and antioxidants in patients with acute
respiratory distress syndrome. CCM 1999; 27:1409-1420
34. Shikora S, Benotti P. Nutritional support for the mechanically ventilated patient.
Resp Care Clin North Am 1997; 3(1):69-91.
CHAPTER 1
CHAPTER 26
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Nutritional Support for the Burned Patient
G.J.P Williams, Michael J. Muller and David N. Herndon
Introduction
Weight loss of 30% was common among burned patients prior to the advent of
adequate nutritional support and was partly responsible for high mortality rates
associated with moderate or large size burns.
1
Metabolic rates of burn patients can
be double that of normal individuals. This can cause marked wasting of lean body
mass within a few weeks of injury and failure to satisfy the increased energy and
protein requirement results in impaired wound healing, cellular dysfunction, de-
creased resistance to infection and, ultimately, death.
In 1949, a 49% TBSA burn caused 50% mortality in patients aged 0-14years.
2
Modern techniques of immediate total burn excision, rapid wound closure, and
adequate early enteral feeding have made a great impact on mortality. Today, a 98%
TBSA burn has a 50% mortality in the same age group.
4
The hypermetabolic re-
sponse to the burn injury is driven by a series of interconnecting physiologic and
biochemical changes that are themselves promoted by the presence of the wound.
This chapter will describe the hypermetabolic response and then the hormonal and
metabolic responses that drive hypermetabolism. An approach to the estimation of
the nutritional requirements of burn patients and some of the practical issues in-
volved in delivery of nutritional support will be outlined. Recent advances in phar-
macological support will also be summarized.
Hypermetabolism in Burns
The response to burn injury is similar to the stress response provoked by any
critical illness or severe injury. However, its extended duration is unique. Burned
patients pass through an ebb phase immediately after injury that lasts two or three
days. During this time, metabolic rate and cardiac output are decreased. After the
ebb phase comes the flow or hypermetabolic phase. This may last up to twelve
months (Fig. 26.1)
4
and can be associated with a rise in resting metabolic rate to
200% of normal values.
5
Hypermetabolism, hyperdynamic circulatory response,
marked protein catabolism, nitrogen wasting, amino acid mobilization, accelerated
lipolysis, fluid retention, insulin resistance, hyperglycemia, hyperthermia,
immunodepression and poor wound healing are characteristic of this phase.
6
Early investigators believed that post-burn hypermetabolism was due to energy
generated to offset heat loss due to evaporation through the water-permeable eschar.
Evaporative water loss can be as high as 3,500cc m
2
of body surface area burned per
hour.
7
Since the heat of water evaporation is 0.576 kcal/ml, this represents a consid-
erable amount of energy. When evaporative water loss was prevented through the
396
The Biology and Practice of Current Nutritional Support
26
use of a water-impermeable membrane, burned patients remained hypermetabolic.
8
Furthermore, burned patients remain hypermetabolic at an environmental tempera-
ture of 33C, at which point the energy of evaporation comes from the environ-
ment.
9,10
Nursing patients in rooms heated to this temperature reduced the degree
of hypermetabolism, but did not abolish it.
11,12
Local and systemic infection will increase hypermetabolism. More effective antimi-
crobial therapy, early burn wound excision and wound closure with skin substitutes in
cases where autograft is unavailable reduces burn wound sepsis. This undoubtedly
has the added benefit of reducing energy requirements for many patients.
Figure 26.1. Indirect calorimetry was used to measure energy expenditure in a resting state
at admission, full healing, and 6, 9, and 12 months after burn. At all time points, the energy
expenditure was higher than the basal metabolic rate predicted for age-, sex-, weight-, and
height-matched individuals by the Harris-Benedict equation. Error bars represent 95%
confidence intervals.
397
Nutritional Support for the Burned Patient
26
The central nervous system plays a key role in the initiation and maintenance of
the hypermetabolic state. Hyperpyrexia is a result of an upward reset of the tempera-
ture control centre in the hypothalamus.
13
Large wounds, such as those seen with
burn injury, induce activated leukocytes to elaborate mediators such as histamine,
cytokines and thromboxanes in sufficient quantity to produce measurable serum
levels.
14,15
It is well recognized that inflammatory mediators such as bacterial endo-
toxin and various cytokines, such as interleukin-1 and tumor necrosis factor-a, stimu-
late the hypothalamus directly.
16-20
They increase the thermoregulatory set-point and
alter endocrine function.
21,22
The importance of the central nervous system in stimu-
lating the stress response to burn injury is demonstrated in individuals with a con-
comitant head injury or who are unconscious due to barbiturates or alcohol
intoxication when they develop an attenuated stress response consequent to their
neurological impairment.
13,23,24
Physiologic Responses to Burn Injury
Hormonal Response
Cortisol, glucagon and the catecholamines are characterized as counter-regula-
tory, anti-insulin or stress hormones. After injury, they are all elevated and all have
synergistic effects.
25
Catecholamines are thought to be the mediators of hyperme-
tabolism and their production following thermal injury is under hypothalamic con-
trol.
26
Norepinephrine levels are raised two- to ten-fold in proportion to burn size.
27
A close correlation exists between the increase in plasma catecholamines and meta-
bolic rate.
11,28
Catecholamine levels remain elevated until wound repair is complete.
Catecholamines cause increased glycogenolysis, hepatic gluconeogenesis and
glucogenic precursor mobilization, promote lipolysis, peripheral insulin resistance
and inhibit insulin release.
29
Glucagon production by pancreatic a cells is elevated in
burned individuals.
30
Insulin and hyperglycemia decrease glucagon secretion.
31
The
effect of glucagon on glucose production depends on changes in the molar ratio of
glucagon to insulin. Injury results in adrenergic stimulation of glucagon release.
This results in mobilization of glycogen stores and enhancement of gluconeogen-
esis. Continued adrenergic stimulation of glucagon prevents suppression of its re-
lease during hyperglycemia. Glucagon may substitute for thyroid hormone during
the period of postburn hypermetabolism.
32
Glucagon increases hepatocyte cyclic
adenine monophosphate (cAMP) and promotes gluconeogenesis, glycogenolysis,
lipolysis and ketogenesis in the liver.
Cortisol production can rise 10-fold in severely burned patients. Following burn
injury, the amplitude of the circadian rhythm of plasma cortisol levels is diminished
and sometimes absent.
32
Cortisol stimulates gluconeogenesis, increases proteolysis
and alanine production, sensitizes adipocytes to the action of lipolytic hormones
(catecholamines) and has an anti-inflammatory action. It also causes insulin resis-
tance. Cortisol facilitates the action of catecholamines and helps maintain cardio-
vascular stability during stress.
33
Cortisol synergizes with catecholamines and glucagon
to divert glucose utilization from skeletal muscle to central organs, such as the brain.
The mechanisms of synergy of cortisol, glucagon and catecholamines are varied.
Cortisol may induce inhibition of catechol-o-methyl transferase and block re-up-
take of catecholamines by the sympathetic nerve ends.
34
Cortisol also increases b-
receptors.
35
Glucagon increases intracellular cyclic AMP levels by a non-b-receptor
mechanism and catecholamines are adrenoreceptor agonists. The net effect is to
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The Biology and Practice of Current Nutritional Support
26
increase the availability of the substrates required for gluconeogenesis (glycerol,
pytuvate, lactate, alanine) and maintain blood glucose levels at or above fasting lev-
els until recovery.
36
Metabolic Response to Burn
Substrate cycling may exist when opposing, non-equilibrium reactions, catalyzed
by different enzymes, are active simultaneously.
37
It involves the use of high-energy
phosphate bonds in ATP, with the net result being heat production. There is no
change in the amount of the substrate or the products, but energy expenditure is
increased in order to resynthesize the ATP. This process is therefore known as fu-
tile or wasteful substrate cycling. One such example is a glucose-lactate-glucose
metabolic sequence known as the Cori cycle.
Burned extremities metabolize a large amount of glucose to lactate and pytuvate.
38
The inflammatory cells in burn wounds (leukocytes and fibroblasts) primarily me-
tabolize glucose in an anaerobic fashion.
39
The anaerobic metabolites of glucose
(lactate and pytuvate) are then returned to the liver along with gluconeogenic amino
acids released from muscle tissue for the synthesis of additional glucose. Burned
patients have a significant rate of hepatic uptake of lactate and pytuvate, which are
generated from anerobic metabolism of glucose peripherally. The liver synthesizes
glucose from these substrates which is then reutilized as an energy source by the
leukocytes and fibroblasts in the wound.
38,40
Thus, burned patients have an acceler-
ated Cori cycle in which glucose is synthesized by the liver and metabolized through
anaerobic metabolism by the various cells present in the burn wound. Not surpris-
ingly, the hyperglycemia that follows burn injury is usually proportional to burn size.
41,42
Glucose is an important energy source for burned patients, and large amounts of
glucose are required to avoid excessive protein catabolism. Unfortunately, there are
limits to the amount of glucose which burned patients can metabolize. They begin
to develop difficulties when the rate of infusion exceeds 4 mg/kg/min. Lipids and
proteins are then utilized to meet the remaining metabolic requirements.
43,44
The stress response causes increased lipolytic activity and results in elevated se-
rum levels of free fatty acids and glycerol and a decreased rate of ketogenesis.
45-47
Since ketone bodies are one of the primary energy sources utilized to decrease pro-
tein catabolism, this would indicate that burned patients may require increased
amounts of carbohydrate and protein in their diet in order to prevent protein ca-
tabolism and achieve positive nitrogen balance.
48
The metabolism of fatty acids by
the cyclooxygenase enzyme system is significantly increased in burned patients.
Protein breakdown and synthesis rates are both elevated following burn injury,
but the rate of protein breakdown is elevated in excess of protein synthesis, resulting
in net protein/nitrogen loss.
49
There is increased efflux of amino acids, especially alanine, glutamine and phe-
nylalanine, from muscle following burn injury.
50,51
Plasma levels of all amino acids
are decreased, except for phenylalanine. This was felt to be due to a disproportionate
rate of release by muscle tissue. Alanine efflux occurs from muscle tissue distant
from the site of burn injury indicating a generalized response.
50
The branched-chain
amino acids (valine, leucine and isoleucine) supply nitrogen for transamination of
pytuvate to produce alanine, which is subsequently utilized for glucose production.
Glutamate is converted to glutamine by the action of glutamine synthetase before
conversion to alanine and ammonia in the gut mucosa. Alanine is transported to the
liver for gluconeogenesis, and ammonia is converted to urea and subsequently ex-
creted in the urine.
48,52
399
Nutritional Support for the Burned Patient
26
In summary, the wound releases a variety of mediators which stimulates a hor-
monal response which in turn drives biochemical processes to produce glucose, waste
energy, and cannibalise skeletal muscle. Grossly emaciated, weak patients whose
wounds are slow to heal is the end result. Immediate institution of adequate nutri-
tional support is vital to ameliorate this process.
Nutritional Support
Caloric Requirements
Caloric needs can be estimated using formulae created by the retrospective analysis
of maintenance of body weight or by measurement of metabolic rate using indirect
calorimetry. Accurate provision of calories is important. Overfeeding leads to respi-
ratory failure from excess CO
2
production, hepatomegaly from fatty infiltration and
increased blood urea nitrogen. Underfeeding causes increased loss of lean body mass,
muscle wasting, poor wound healing and increased susceptibility to infection.
Total energy expenditure (TEE) is made up of basal metabolism, diet-induced
thermogenesis and energy consumed by muscular activity. In burned patients, futile
substrate cycling, shivering, anxiety and pain all increase total energy expenditure.
Direct calorimetry measures actual heat elaborated when the subject is placed in a
sealed, insulated chamber. Indirect calorimetry uses the stoichiometric relationship
between oxygen consumption and carbon dioxide production during respiratory
gas exchange analysis. This can be done as a bedside procedure with a mobile meta-
bolic cart, which measures the concentration of oxygen and carbon dioxide in the
inspired and expired gas, and the volume of gas exchanged.
53
The oxygen consump-
tion and carbon dioxide production are determined and equations used to calculate
the energy expenditure.
54
These measurements should be performed in the resting
state (at least one hour following activity) and in the same absorptive state. If per-
formed in a fasting state, basal metabolic rate or basal energy expenditure is mea-
sured. As many burned patients undergo continuous feeding, a measurement taken
during this process also accounts for the thermic effect of food and is known as
measured resting energy expenditure (REE). Metabolism of different substrates yields
known ratios of carbon dioxide production to oxygen consumption. These ratios
are known as the respiratory quotient (RQ). Fat oxidation produces an RQ of 0.7
while glucose oxidation gives an RQ of 1.0. A respiratory quotient of greater than
1.0 indicates net fat synthesis. This can occur with overnutrition and may lead to
hepatic steatosis.
55
Alternatively, low RQ readings indicate inadequate nutrition.
56
Extrapolation of measured resting energy expenditure to total energy expendi-
ture over 24 hours requires multiplication by an activity factor. Total energy expen-
diture can be quantified with infusion of two stable isotopes of water, H
2
18
O and
2
H
2
O and is known as the doubly-labeled water technique.
2
H
2
O is lost from the
body at a rate proportional to water flux alone while H
2
18
O is lost in water and in
CO
2
during rapid equilibration through carbonic anhydrase. The difference in turn-
over rates gives total CO
2
production, and total energy expenditure can be calcu-
lated if dietary intake is known. Application of this technique in severely burned
children during convalescence revealed total energy expenditure exceeded measured
resting energy expenditure by a factor of 1.18 0.17.
57
Analysis of the determinants of measured resting energy expenditure has shown
that the predicted basal energy expenditure (PBEE) based on the Harris-Benedict
equation (Table 26.1),
58
total body surface area and body weight correlated signifi-
cantly with REE. Burn size and time after burn only accounted for 24% and 21%
400
The Biology and Practice of Current Nutritional Support
26
respectively, of the variation in the elevation in REE above PBEE.
The following
equation will predict the energy required to ensure that 95% of burned children will
receive sufficient calories to reach a state of energy balance: TEE = (1.55 x PBEE) +
(2.39 x PBEE
0.75
). In most cases, this is close to: TEE = 2 x PBEE. Therefore, 2 x
PBEE is probably a reasonable starting point.
59
The Harris-Benedict equation may be inaccurate in burned patients as it is based
on body weight, which is difficult to accurately assess following burn. When using
indirect calorimetry, two factors should be considered: energy expenditure may be
less than energy requirement if malabsorption or diarrhea is present and indirect
calorimetry loses accuracy at FiO
2
> 60 torr or if a gas leak occurs. If performed
accurately and in a similar state, indirect calorimetry represents the most reliable
method of estimating energy requirements. Measured resting energy expenditure
multiplied by an activity factor of 1.2-1.35 will provide the total energy expenditure
appropriately for the majority of patients.
60
Although mobile metabolic carts are the ideal, they require a sizeable financial
outlay initially and a trained technician to use and maintain them. Therefore, many
units will depend on feeding formulae to calculate requirements (Table 26.2 for
adults and Table 26.3 for children).
The Curreri formula is based on only nine pa-
tients over the first 20 days of recovery.
61
In fact, the only patient in the group who
lost weight received only 20% of requirements while weight was maintained in the
other patients whose energy intake was significantly less than that prescribed by the
formula. The pediatric formulae have been derived from retrospective analyses of
Table 26.3. Galveston formula to estimate caloric requirements for children
with burns
Age Maintenance Plus Burn
< 1 year 2100 Kcal/m
2
TBSA/day + 1000 Kcal/m
2
TBSAB/day
1-12 years 1800 Kcal/m
2
TBSA/day + 1300 Kcal/m
2
TBSAB/day
12-18 years 1500 Kcal/m
2
TBSA/day + 1500 Kcal/m
2
TBSAB/day
TBSA = Total Body Surface Area; TBSAB = Total Body Surface Area Burned
Table 26.2. Curreri formula to estimate caloric requirements for adults
with burns
Age Maintenance Plus Burn
16- 60 years 25 Kcal/Kg + 40 Kcal/% burn
> 60 years 25 Kcal/Kg + 65 Kcal/% burn
Table 26.1. Harris Benedict equation for predicted basal energy expenditure
Males BMR = 66.47 + (13.75 x W) + (5.0 x H) - (6.76 x A)
Females DMR = 655.10 + (9.56 x W) + (1.85 x H) - (4.6% x A)
W = Weight in Kg; H = Height in CM; A = Age in years
401
Nutritional Support for the Burned Patient
26
dietary intake, which was associated with maintenance of body weight average over
hospital stay.
62-67
It has been shown that resting energy expenditure rarely exceeds predicted basal
metabolic rate by more than 50%, in patients with burns > 45%, if treated with
modern techniques.
68
This means that adult patients will rarely require more than
3,500 Kcal/day.
Dietary Composition
Carbohydrates
The major source of calories for thermally injured patients should be carbohy-
drates. However, glucose intolerance can be a significant problem. Plasma insulin
levels are usually elevated in burned patients but they are overshadowed by eleva-
tions of glucagon and cortisol producing the so-called diabetes of injury. In addi-
tion, the patients caloric requirements may exceed the bodys ability to assimilate
glucose. This is estimated at approximately 7gm/kg/day or 2,240 kcal for an 80kg
man.
68
Patients often require significant amounts of exogenous insulin to improve
glucose absorption but refractory hyperglycemia may sometimes force reduction of
administered calories.
Protein
Protein availability is essential to adequate wound healing. Protein malnutrition
is associated with decreased rates in gain of strength of the skin, abdominal wounds
and intestinal anastomoses. More specifically, a shortage of protein blunts fibroblas-
tic proliferation, neoangiogenesis, collagen synthesis and wound remodeling.
70,71
It
is therefore essential that negative nitrogen balance be avoided. The ideal amount of
protein which should be provided in the diet of burned patients has not yet been
determined. Increasing protein intake in burned patients from 1.4 g protein/kg/day
to 2.2g protein/kg/day did not alter nitrogen balance.
72
Another study showed that
increasing the percentage of protein in the diet of burned patients resulted in a
number of immunologic benefits. They compared patients receiving 16.5% of their
calories as protein to those receiving 23% of their calories as protein. Although
neither group was able to achieve the desired caloric intake, the group receiving the
higher protein content was found to have significantly higher serum levels of IgG,
transferrin, and complement factor 3. More importantly, they experienced fewer
bacteremic days and had a significantly lower mortality rate.
73
However, protein
should not be given primarily as an energy source. Calculated energy requirements
must be supplied as non-protein calories. Current recommendations call for 1.5-2.0
gm protein/kg/day in adults and up to 3.0 gm protein/kg/day in children.
74,75
This
should result in a calorie:nitrogen ratio of 100:1 or less.
Amino Acids
Arginine is an integral substrate of the urea cycle and is not considered an essen-
tial amino acid, but under periods of severe stress it is thought to become an essen-
tial dietary nutrient. An experimental deficiency in arginine in the traumatized rat
produced decreased collagen deposition and decreased wound breaking strength.
76
Arginine is not only important to wound healing in deficiency, it also appears to
promote wound healing when given as a supplement. High arginine levels were
shown to improve wound healing in rats as demonstrated by increased collagen
deposition. In healthy humans, it was shown to increase the deposition of total
402
The Biology and Practice of Current Nutritional Support
26
protein and hydroxyproline (an indicator of collagen content) into wound cylin-
ders. Supplemental arginine has also been shown to decrease skin weight loss under
stress, therefore, retaining more dermal protein for wound healing. It also promotes
retention of nitrogenous calories and decreased protein catabolism. Arginine ap-
pears to achieve most of its stimulatory action secondarily via the hypothalamic-
pituitary axis as a secretagogue of insulin, glucagon, prolactin and growth hormone
because these effects are absent in hypophysectomized rats. In support of these mecha-
nisms, arginine supplementation appears to be most effective in the first three days
of wound healing, the period of inflammation and fibroblast migration and activa-
tion. On the cellular level, there has been demonstrated an altered metabolism of
arginine in wounded tissue. Although arginase is present in fibroblasts only in very
low levels, its presence is significant in macrophages and in extracellular wound
fluid, presumably released from dying macrophages. Arginase catalyzes the conver-
sion of arginine to ornithine, which is a precursor of proline. Arginine supplemen-
tation in an experimental burn model
77
and in post surgical cancer patients
78
improved indices of immune function of a collagen precursor. In this fashion, supple-
mental arginine may directly enhance collagen production in the wound.
79-84
Glutamine is also an amino acid thought to play an integral role in wound heal-
ing. It is known that it is utilized in substantial amounts by macrophage metabo-
lism.
85
Glutamine is considered to be a major fuel of rapidly dividing cells, such as
fibroblasts, enterocytes and stimulated lymphocytes.
86,87
Cultures of fibroblasts re-
quire more glutamine to survive than any other amino acid, and the glutamine
metabolized is primarily oxidized to carbon dioxide to provide a source of energy.
Fibroblasts may even derive more energy from glutamine metabolism than from
glucose.
Glutamine is also important in the production of collagen because glutamate,
a primary metabolite of glutamine, is the primary precusor to proline in pure fibro-
blast cultures. Glutamine is the preferred fuel of the small bowel enterocyte.
89
Sepsis
has been shown to decrease glutamine uptake by the small bowel enterocyte, which
may result in barrier failure,
90
and the addition of gultamine to the nutritional regi-
men has been theorized to improve barrier function.
Methionine and cysteine have important roles in antioxidant production. Sulf-
hydryl group produced directly from cysteine, or indirectly from methionine, act as
oxygen free radical scavengers. Cysteine and glutamine form glutathione, which is a
strong sulfhydryl-reducing substance and is required in the synthesis of the
leukotrienes. Their presence is, therefore, required to limit lipid penoxidation.
91
Lipids
The hormonal environment of the burned patient limits the extent to which
lipids can be utilized as energy. Peripheral lipolysis, mediated through the catabolic
hormones, is a principal component of the metabolic response to injury. Released
free fatty acids circulate to the liver where they are oxidized for energy and re-esteri-
fied to triglyceride. They are either deposited in the liver or further packaged for
transport to other tissues. In the burned patient processing of lipid by the liver can
be overwhelmed by the increasing amounts of circulating fat leading to fatty depo-
sition. This may be further complicated by overfeeding which can contribute to
hepatomegaly. Cyclooxygenase activity leads to an increased rate of production of
the physiologically active prostaglandins that have immunosuppressive activity. One
means of limiting this effect is to supply dietary lipids such as Omega-3 fatty acids,
which are metabolized by the cyclooxygenase enzyme system to yield PGE
3
. The
403
Nutritional Support for the Burned Patient
26
more common dietary fatty acids are of the Omega-6 group and are metabolized to
yield PGE
1
and PGE
2
PGE
1
and
PGE
2
have been reported to have significant immu-
nosuppressive properties while PGE
3
has been reported to be immunologically in-
ert. It has, therefore, been hypothesized that by replacing the Omega-6 fatty acids
obtained from standard vegetable and animal oils with the Omega-3 fatty acids
from fish oil, postburn immunosuppression might be avoided or reversed.
92
Vitamins
Vitamin C
Vitamins and trace minerals play a part in polymorphonuclear and macrophage
chemotaxis during inflammation.
93
Macrophage function is impaired by ascorbic
acid deficiency.
94
During the proliferative and maturation phases of wound healing,
vitamin C acts as a necessary electron donor in the hydroxylation of proline and
lysine residues in the collagen precursor procollagen. Scurvy is characterized by weak-
ening and dehiscence of previously healed wounds. Collagen in scar tissue is in a
continuous process of revision with reabsorption and manufacture of new collagen.
Ascorbic acid deficiency leads to defective cross-linking, thus weakening the scar.
Supplemental ascorbic acid delivery has been demonstrated to have two comple-
mentary effects on healing. Within the first 24 hours, there is a reduction in the
degradation of intracellular collagen and after 24 hours, supplementation increases the
synthesis of collagen protein and favors its release into the extracellular medium.
95,96
Vitamin A
Vitamin A is usually stored in the liver in large amounts, however, it is known to
be the most commonly depleted vitamin. Vitamin A has been shown to affect cell
morphology, and its influence on epithelial cell differentiation and mucus produc-
tion may be humoral. Vitamin A binds to specific intracellular receptor protein
which carry the vitamin to the nucleus where it affects the gene expression of
glycosyltransterases, fibronectin and perhaps even transglutaminases.
97
It also ap-
pears necessary as a cofactor in collagen synthesis and cross-linking. T lymphocyte
function is enhanced by Vitamin A.
98
Supplemental Vitamin A also increases fi-
broplasia and collagen accumulation in wounds and increases the differentiation rate
of fibroblasts.
99
Vitamin E
Vitamin E is an antioxidant and free radical scavenger, which appears to act in
preventing the oxidation of cell membrane polyunsaturated phospholipids.
100,101
It
is a promising means of counteracting the oxidative changes induced by injury.
Cutaneous burn wounds have increased xanthine oxidase activity which produces
damaging oxygen radicals and hydrogen peroxide. In turn, hydroxyl ion release leads
to distant organ lipid peroxidation and systemic inflammation. These changes can
be limited experimentally with xanthine oxidase, thromboxane synthetase inhibi-
tors and prostaglandin antagonists.
102
Malondialdehyde levels, an indicator of lipid
peroxidation, are increased in the wound, serum and lung in burns.
103
Levels of
naturally occurring antioxidants such as vitamin E are decreased, due to consump-
tion by both regional and systemic inflammation.
104
404
The Biology and Practice of Current Nutritional Support
26
Vitamin B Group
The B vitamin group is central to the metabolism of all cells because they are
coenzymes in reactions necessary for energy metabolism. Riboflavin is a coenzyme
in the oxidation-reduction reactions involved in fatty acid synthesis and oxidation,
amino acid oxidation, electron transport, xanthine oxidase function and glutathione
reductase function.
105
Pantothenic acid functions as part of coenzyme-A, and
phosphopantetheine is involved in the Krebs cycle as well as in -oxidation of fatty
acids. It also appears to play an important role in collagen production by the wound.
Alone, it has been shown to increase skin strength and the fibroblastic content of
scar tissue.
106
Minerals
Iron
Iron plays an important role in the oxygen-carrying proteins hemoglobin and
myoglobin. It also acts as a cofactor for a number of important enzymes. Burn
patients are susceptible to iron deficiency although blood transfusions do deliver a
significant amount of iron.
Zinc
Zinc has been known to be an essential element of the mammalian diet since the
early decades of this century.
107,108
Zinc oxide has been used in surgical dressings for
a long time. Zinc deficiency impairs the rate of epithelialization and lessens the gain
in wound strength through impaired amino acid utilization.
109
A hypercatabolic
state induces hyperzincuria, which can progress to zinc depletion.
110,111
In addition
to substantial urinary loss, a redistribution of zinc occurs after tissue injury and
surgical stress. Zinc uptake is increased in the wound, liver, spleen and lung while
zinc levels decrease in plasma and skin.
112,113
Zinc supplementation has not been
shown to accelerate wound healing in non-burned, normal subjects.
114
Burned pa-
tients have substantial sequestration in the wound and high urinary loss and should
benefit from zinc supplementation.
Selenium
Selenium has an influence on wound healing through its presence in selenium-
dependent glutathione peroxidase.
115
This enzyme protects the cell from oxidative
damage by catalyzing the reduction of hydrogen peroxide. Selenium deficiency may
also affect wound healing by altering macrophage and polymorphonuclear cell func-
tion. A state of selenium deficiency often occurs in burned patients and is thought
to be secondary to topical silver preparation.
116
Route of Administration
Enteral Nutrition
The route of delivery of nutrients is almost as important as their composition.
Ischemic mucosal erosions in the stomach and duodenum are seen within hours of
significant burn injury and are most likely present throughout.
117
Ileus results from
ischemia that is reversed by reperfusion and is obviously dependent upon adequate
fluid resuscitation. A pernasal, transgastric jejunal tube advanced past the ligament
of Treitz allows enteral feeding to commence well before gastroduodenal function is
restored. This seems to diminish the extent and duration of ileus.
118
Furthermore
405
Nutritional Support for the Burned Patient
26
when used in combination with a nasogastric tube to ensure gastric emptying, there
is no reason to subject the patient to preoperative periods of fasting.
Experimental models have shown attenuation of catecholamine elaboration and
maintenance of gut mucosal integrity with immediate enteral, but not parenteral,
nutrition. Immediate enteral feeding in a clinical trial was associated with a 3%
daily incidence of vomiting, no aspiration pneumonia and delivery of calculated
needs by the third postburn day.
119
Other studies have shown that when continuous
enteral tube feeding were started immediately following burn injury, the postburn
hypermetabolic response was prevented, and elevations of serum glucagon, cortisol
and catecholamines failed to develop.
120,121
Intestinal permeability, as assessed by lactulose mannitol absorption
122
and poly-
ethylene glycol,
123
is increased in a burn size-dependent fashion early after injury.
Thereafter, infection will induce increased intestinal permeability.
124,125
Passage of
these macromolecules implies that bacterial translocation or leak of endotoxin can
occur.
126,127
Burn size-dependent increases in levels of circulating endotoxin and
cytokines, such as IL-1, TNF, and IL-6 occur post-burn,
128-130
and may originate for
the gut. Animals who receive immediate enteral feeding do not develop gut mucosa
atrophy, while they do develop it when enteral feeding is delayed. Gut mucosa atro-
phy allows translocation of bacteria and endotoxin into the portal circulation.
131
Postburn ileus affects the stomach and colon, sparing the small bowel.
132
Therefore,
duodenal or jejunal tube feeding can be commenced early in the postburn period,
and preferably within the first six hours.
Parenteral Nutrition
Enteral feeding is far preferable to total parenteral nutrition in the critically ill
patient.
133
Parenteral nutrition in burned patients increases mortality three-fold and
decreases the amount of enteral calories tolerated.
134,135
Therefore, total parenteral
nutrition is indicated only if there is an absolute contraindication to enteral feeding,
such as pancreatitis or ischemic enterocolitis.
The same rationale for calorie, protein, carbohydrate and lipid composition of
enteral diet can be applied to parenteral nutrition. Obviously, vitamins and trace
elements need to be added as appropriate. Carbohydrate is usually provided as dex-
trose (glucose) which gives 3.4 Kcal/g. Free amino acids, to a concentration of around
5%, which includes all essential amino acids, provide the protein requirement. Supple-
mentation with arginine, glutamine (as di-peptide) and branched chain amino acids
(leucine, isoleucine and valine) is theoretically inviting. Essential fatty acid defi-
ciency can be avoided by providing 10% of daily calories as lipid.
Rigid compliance with aseptic principals for handling lines and insertion sites is
mandatory. If complications, such as bacterial endocarditis and pyogenic throm-
bophlebitis, are to be avoided, lines must be changed every 72 hours.
Assessment of Nutritional Support
Assessment of pre-morbid nutritional state is an essential step and provides baseline
information. Heavier, more muscular subjects, and subjects whose definitive surgi-
cal treatment is delayed are at the greatest risk for excess catabolism after burn.
Sepsis and excessive hypermetabolism are also associated with protein catabolism.
136
Daily intake of total calories and macronutrients, regular weighing and routine labo-
ratory tests, such as electrolytes, glucose and protein, provide most information re-
quired. Further laboratory assessment such as prealbumin or retinol-binding protein
and total lymphocyte count can be added.
137
A total lymphocyte count less than
406
The Biology and Practice of Current Nutritional Support
26
1,800/ml indicates malnutrition, but is unreliable in the presence of infection or
during the early resuscitation phase.
138
Nitrogen balance assessments are cumber-
some and require fastidious performance to eliminate inaccuracies. As such, they are
more often a research tool. Static measurements of serum concentrations of markers
of nutritional status, such as prealbumin, albumin, transferrin, cholesterol, triglyc-
eride, calcium and ascorbic acid, are not as reliable as functional testing
139
and often
indicate a poor nutritional state when none exists. Having a dedicated dietician as
part of the burns team who is responsible for monitoring daily dietary intake and
weight trends is essential. As the patient recovers and has changing needs, weekly
measurements of resting energy expenditure using metabolic carts will allow for
adjustments in administered calories. New techniques for measuring body composi-
tion, such as Dual energy x-ray absorptiometry scanning, enables accurate determi-
nation of body composition and will be a useful adjunct in the future.
Hormonal Manipulation of Burn Hypermetabolism
The metabolic response to burn injury is produced by increased levels of cata-
bolic hormones including catecholamines, cortisol and glucagon. Attempts to re-
duce hypermetabolism have focused on agents that block or counteract their effects.
These anabolic agents can be divided into three groups. The first group includes
anabolic proteins such as growth hormone, insulin and insulin-like growth factor.
The second group includes anabolic steroids such as oxandrolone. The third group
includes antagonists of the mediators of hypermetabolism such as propranolol and
glucocorticoid blockers. Whilst some of these agents have shown promising results
in clinical trials, the hormonal milieu that accompanies the burn injury is complex
and further research is needed to confirm the efficacy and safety of these drugs.
Growth Hormone and Insulin-Like Growth Factor
Hyperaminoacidemia is a major stimulus to net protein synthesis in normal sub-
jects.
140
In burned patients, however, hyperaminoacidemia fails to completely re-
verse net protein catabolism, possibly because of defective trans-membrane amino
acid transport.
141
This may be the result of decreased growth hormone (GH) and
insulin-like growth factor 1 (IGF-1) levels following burn injury.
142
GH promotes protein synthesis by increasing the cellular uptake of amino acids
and accelerating nucleic acid and accelerating nucleic acid translation and transcrip-
tion, thereby enhancing cell proliferation. Fatty acids are released from the hydroly-
sis of fat for conversion to acetyl Co-A, an essential energy-producing molecule for
the tricarboxylic acid cycle. Through the preferential use of adipose tissue for energy
production, there is a decrease in body fat with the result that protein is spared from
catabolism.
143-144
Recombinant GH and IGF-1 have been shown to increase trans-membrane amino
acid transport in-vitro,
145
reverse diet-induced protein catabolism,
146
attenuate post-
surgical amino acid efflux from skeletal muscle
147
and accelerate skin graft donor site
wound healing by 25% in severely burned children. GH was shown to reduce the
healing time of the second and third donor site compared with a placebo group as
well. The significance of these results is that massively burned children can be taken
to the operating room for further skin grafting about two days earlier if treated with
GH. The use of GH results in a significant decrease in time required to close a burn
wound. When adjusted for percentage of total body surface area burned (% TBSA),
the treated group took 0.54 0.04 days/% TBSA, (mean 3 SEM), and the placebo
group took 0.80 0.09 days/% TBSA to achieve total wound closure. This represents
407
Nutritional Support for the Burned Patient
26
a decrease from 46 to 32 days to achieve total wound closure for a patient with a
burn size of 60% TBSA.
148
Donor sites healed faster in the growth hormone-treated group perhaps due to
the resultant three-fold increase in 1GF-1 levels. GH treatment also accelerates wound
healing in adults, in infants aged less than two years, and in very severely burned
children who present late for treatment and are consequently in an advanced state of
emaciation.
149,150
Studies in severely burned subjects indicated that those receiving
GH had an increased protein turnover with elevation of both protein synthesis and
breakdown, but with synthesis exceeding breakdown. This resulted in a net reduc-
tion in protein loss of 50% compared with controls.
151
Children who are not in their growth-spurt years have a decrease in their height-
velocity growth curves for more than two years following severe burns. However,
recent studies have shown that children with severe burns treated with growth hor-
mone (0.2mg/kg/day) during the acute phase of their management continued to
have normal growth curves following their injury.
152
Furthermore, following severe burns, administration of growth hormone in low
doses (0.05mg/kg/day subcutaneously) for one year after hospital discharge increased
total body weight, linear growth, lean body mass and bone mineral content com-
pared to an equivalent group receiving placebo (Fig. 26.2, Fig. 26.3).
153
Insulin
Insulin has been shown to promote muscle anabolism in healthy volunteers by
either stimulating protein synthesis,
154,155
or inhibiting protein breakdown.
156
In
burned patients it has been shown that over short periods of time, submaximal
insulin administration also produces muscle anabolism via net muscle protein syn-
thesis. This is achieved with normal feeding by efficient reuse of intracellular amino
acids.
157
Currently, clinical studies are underway using exogenous insulin infusions
to produce euglycemic hyperinsulinemia for the duration of hospital stay in an at-
tempt to reduce muscle breakdown. Whenever exogenous insulin is administered, careful
monitoring is required to minimize the potential for precipitating hypoglycemia.
Oxandrolone
Oxandrolone is an oral synthetic testosterone analogue. Compared with test-
osterone, it has minimal virilizing activity and little hepatotoxicity.
158,159
Oxandrolone
has been used in acute and rehabilitating adult burn patients with promising results
in terms of weight gain and urinary nitrogen balance.
160,161
Recently it has been
shown to improve net muscle protein synthesis in children malnourished due to
delay in burn treatment.
162
Current clinical trials are underway investigating its use
during the acute phase of burn treatment. Whilst growth hormone can produce
hyperglycemia and insulin can induce hypoglycemia, oxandrolone has minimal side
effects and has the additional advantage of being given as a tablet. These features are
sure to encourage further study.
-Blockade
Elevated catecholamine levels in burn patients have been implicated in myocar-
dial dysfunction similar to that seen with pheochromocytoma, myocarditis, cardi-
omyopathy and focal myocardial necrosis. Children who succumb to burn injuries
often have hepatomegaly with marked fatty change from catecholamine-induced
lipolysis.
163
The modulation of these potentially harmful effects has been attempted
with blockers.
408
The Biology and Practice of Current Nutritional Support
26
and -adrenergic blockade has been shown to decrease the metabolic rate of
burned patients. Selective -2 blockade with clenbuterol increases skeletal muscle
mass experimentally.
Selective -1 blockade with metoprolol (2 mg/kg/day) signifi-
cantly reduced cardiac work but did not affect protein or lipid metabolism.
164
Propranolol, a nonselective blocker, decreased myocardial oxygen requirements
without affecting cardiac output or whole-body oxygen delivery or consumption
when administered to massively burned patients.
165
Patients were noted to be calmer
when on this treatment.
166
Doses of 1-2 mg/kg/day are required to achieve a 25%
reduction of the elevated heart rate. The patients were still able to respond appropri-
ately to cold stress and to an isoproterenol challenge, which supported the conten-
tion that limited -blockade causes decreased myocardial work while cardiovascular
responsiveness to stress was retained.
167
Propranolol administration decreased lipolysis but also resulted in increased urea
production in fasted patients. This was partially reduced by feeding.
166
This effect
was thought to be due to increased protein catabolism to provide substrate for glu-
coneogenesis as -1 receptor blockade of adipocytes decreased lipolysis and led to
decreased glycerol and free fatty acid availability. Further research is needed to deter-
mine the effect of propranolol on muscle protein in the acute phase of burn treatment.
Figure 26.2. Changes in bone mineral content from baseline at discharge.
409
Nutritional Support for the Burned Patient
26
Glucocortioid Blockers
Glucocorticoids can be blocked either by decreasing production with agents such
as Ketoconazole or by competitive inhibition with agents such as RU-486. Studies
are currently in progress to determine if glucocorticoid levels can be decreased with
Ketoconazole to the extent that metabolism is altered but current regulatory diffi-
culties with the availability of RU-486 have hampered the investigation of this agent
in modifying hypermetabolism.
Summary
Burn patients have increased nutritional requirements due to hypermetabolism.
Enteral feeding initiated as early as possible after injury, decreases mortality. Total
calorie requirements for hypermetabolic patients are best estimated by indirect calo-
rimetry to find the resting energy expenditure (REE). Total energy expenditure (TEE)
is then calculated by multiplying the REE by 1.35. If REE measurements are not
available, an activity factor of 1.55 on the predicted basal energy expenditure (PBEE)
from the Harris and Benedict equation should provide adequate calories for virtu-
ally all burned patients without excessive overfeeding.
Figure 26.3. Change in lean body mass from baseline at discharge.
410
The Biology and Practice of Current Nutritional Support
26
Most standard formulae used to estimate calorie requirement overestimate needs
for large burns. The Curreri formula provides a good guide for burned adults but
not for children. Retrospective analyses of total calorie intake, daily calorie intake
and lowest weight loss in burned children have produced a series of formulae based
on age and body surface area. Application of these formulae has resulted in mainte-
nance of body weight to within 5% of pre-injury weight.
Feeding should be started as early as possible in the post burn period. Nutrition
should be delivered enterally via the nasojejunal route until the patient is able to
tolerate the required calorie intake orally. Parenteral feeding should be avoided if
possible. Calculated energy requirements should be given as non-protein calories
but protein requirements may be as great as 3 gm/kg/day in children. Continuous
reassessment of nutritional status is essential.
Appropriate nutritional support of the burned patient has resulted in increased
survival, improved immune status and improved rehabilitation. Recent innovations
in dietary components such as o 3 fatty acids, specific trauma essential amino
acids and vitamin and mineral supplements have contributed to this. In children,
therapies such as growth hormone which have been shown to improve growth fol-
lowing severe burns should be continued following discharge from hospital. Future
advances in hormonal manipulation of post burn hypermetabolism will further
improve outcome.
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gery attenuated forearm glutamine, alanine, 3-methyhistidine and total parenteral
nutrition. Ann Surg 1993; 217:413-22.
148. Herndon DN, Barrow RE, Kunkel KR et al. Effects of recombinant human growth
hormone on donor-site healing in severely burned children. Ann Surg 1990;
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149. Sherman SK, Demling RH, Lalonde C et al. Growth hormone enhances re-epi-
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150. Gilpin DA, Barrow RE, Rutan RL et al. Recombinant human growth hormone
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151. Gore DC, Honeycutt D, Jahoor F et al. Effect of exogenous growth hormone on
whole-body and isolated-limb protein kinetics in burned patients. Arch Surg 1991;
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233(6):827-834.
154. Bennet WM, Connacher AA, Scrimgeour CM et al. Euglycemic hyperinsulinemia
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tein synthesis and enhances transport of selected amino acids in human skeletal
muscle. J Clin Invest 1995; 95:811-819.
156. Fryburg DA, Jahn LA, Hill SA et al. Insulin and insulin-like growth factor-1 en-
hance human skeletal muscle protein anabolism during hyperaminoacidemia by
different mechanisms. J Clin Invest 1995; 96:1722-1729.
417
Nutritional Support for the Burned Patient
26
157. Ferrando AA, Chinkes DL, Wolf SE et al. A submaximal dose of insulin promotes
net skeletal muscle protein synthesis in patients with severe burns. Ann Surg 1999;
229(1):11-18.
158. Fox M, Minor A et al. Oxandrolone: A potent anabolic steroid. J Clin Endocrinol
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160. Demling RH, Desanti L. Oxandrolone, an anabolic steroid, significantly increases
the rate of weight gain in the recovery phase after major burns. J Trauma 1997;
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161. Demling RH. Comparison of the anabolic effects and complications of human
growth hormone and the testosterone analog, oxandrolone, after severe burn in-
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162. Hart DW, Wolf SE, Ramzy PI et al. Anabolic effects of oxandrolone following
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CHAPTER 27
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Nutritional Support
after Small Bowel Transplantation
S. Janes, S.V. Beath
Introduction
Small bowel transplantation has been attempted since the 1950s but with sur-
vival times of less than two weeks in dogs and human subjects. It did not become
established until the development of more effective immunosuppression regimes in
the 1980s and 1990s.
1-6
In the meantime, patients with chronic intestinal failure
have been managed with parenteral nutrition (PN) which has developed to the point
where 75% of patients can expect to survive 10 years.
7
There are 33 centers carrying
out small bowel transplantation world wide (communication Dr. D Grant, 5th In-
ternational Symposium on Intestinal Transplantation, Cambridge 1997), but only
patients who are experiencing complications with parenteral nutrition or feel that
their quality of life is intolerable are selected as candidates for intestinal transplanta-
tion.
8-10
In the UK, around 250 patients are identified as being on home PN which
equates to 4 per million and 50% of these could be considered potential recipients
for intestinal transplantation.
11-13
The reason successful intestinal transplantation has been hard to achieve is be-
cause of several unique characteristics: the great mass of lymphoid tissue in the gut
renders it highly immunogenic; accurate identification of rejection episodes in the
gut is difficult because of the presence of large numbers of lymphocytes under nor-
mal circumstances and the patchy nature of rejection; and the gut is continually
exposed to bacteria, fungi and food antigens resulting in high rates of sepsis when
gut integrity is damaged (as during rejection).
14
Furthermore, the newly engrafted
bowel seems to take longer than other organs to recover from the effects of ischemia
and hypoxia incurred during harvesting and preservation, and intestinal function
may take many months to stabilize (compared with an average of 2-3 weeks after
liver transplantation). The current 5-year survival after intestinal transplantation is
50%, although there is a center effect with the large North American centers achiev-
ing better figures than this and smaller centers with less than 10 patients achieving
less (personal communication Dr. David Grant, 5th International Symposium on
Intestinal Transplantation, Cambridge 1997).
The postoperative care of intestinal transplant recipients centers on fluid bal-
ance, meticulous attention to immunosuppression and a transfer from parenteral to
enteral feeding.
15
The fact that only patients experiencing significant morbidity are
selected for transplantation means that nutritional support after transplantation must
ensure good patient rehabilitation and stimulate graft adaptation simultaneously.
The goal of small bowel transplantation is to achieve independence of parenteral
419
Nutritional Support after Small Bowel Transplantation
27
nutrition and enhance quality of life for the patient and normal growth velocity for
pediatric patients.
16
This chapter will concentrate on nutritional support for small
bowel transplantation which can be split into three phases:
1. Recovery from the effects of ischemia, preservation and implantation.
2. Weaning from parenteral nutrition and establishment of enteral nutrition.
3. Establishment of oral intake of a wide range of foods including whole pro-
tein, lactose and long chain triglyceride.
Recovery from Ischemia and Preservation
4 (Post-Op Day 0-14)
The technique used for harvesting small bowel is similar to other abdominal
organs in that the graft is mobilized ready for excision and then perfused with a
preservation solution at 4
o
C which flushes out all blood.
17
The graft is kept on ice
until re-implantation 6-12 hours later. Even with rapid cooling and the use of a
preservation solution high in glucose and lactate, changes secondary to ischemia
occur. The production of free radicals from hypoxic tissue induces polymorph mar-
gination from capillaries into the lamina propria which becomes congested with a
mixed inflammatory infiltrate which produces yet more biochemical changes in-
cluding elevated phospholipase A2.
18
This process occurs slowly at 4C, but after 12
hours there is a risk that excessive inflammation may be associated with severe graft
dysfunction, sloughing of the mucosa and hyperacute rejection. This is in contrast
to liver and kidney tissue which are stable in preservation solution at 4
o
C for 24 and
48 hours, respectively. Therefore, transplant teams arrange to harvest the intestinal
graft and reimplant as soon as possible, even so some loss of villi occurs especially at
the apices where the effects of hypoxia are initially manifested. Preservation solu-
tions are an area of very active research with solutions being developed which neu-
tralize chemotactic molecules produced in hypoxic tissue. However, the solution
currently used in human intestinal transplantation is generally University of Wis-
consin solution which is able to preserve small bowel allografts isolated from the
circulation for up to 12 hours maximum.
Early intestinal dysfunction is, therefore, inevitable and takes the form of a para-
lytic ileus as a result of the surgical handling, lasting 2-5 days. From day 5-15 a
secretory diarrhea related to mucosal damage regeneration, develops. The secretory
diarrhea is usually mild (10-30 ml/kg/day) and self-limiting.
5,6
Occasionally, espe-
cially with end ileostomies a severe secretory diarrhea develops (greater than 100 ml/
kg/day) which requires treatment with octreotide (e.g., Sandostatin Sandoz, 1-3 g
per kg per hour intravenously or 50 g subcutaneously 2-4 times a day), although
long-term treatment should be avoided because of reports of hepatic dysfunction.
As soon as bowel sounds are heard or the ileostomy is seen to peristalse, dioralyte
solution 10-20 mls/hour is introduced. It is not usually possible to introduce feed
until there is evidence of absorption of dioralyte (i.e., ileostomy output is less than
enteral intake) which may occur anytime from day 5 postoperatively depending on
the speed of recovery from graft preservation and implantation. The principles used
in initiating enteral feeding after small bowel transplantation are similar to those in
rehabilitation of patients after major intestinal resection.
19
Nutrients are introduced
separately and in small increments so that tolerance and adequate absorption are
confirmed before adding more nutrients to the feed. This approach, which is called
modular feeding, has been useful in enhancing rapid adaptation of the newly en-
grafted bowel and is also important in enabling quicker identification of rejection
420
The Biology and Practice of Current Nutritional Support
27
episodes which are manifested by malabsorption of the feed, which might otherwise
be attributed to changes in the feed. Table 27.1 shows details of the introduction of
enteral feeding for pediatric patients at our unit. Our initial modular feed provided
0.2 kcal/ml and 233 mosmol/kg, containing protein, carbohydrate and electrolytes,
with lipid omitted. The concentration is increased by adjusting one ingredient at a
time, adding fat during the third week of feeding and gradually progressing towards
an energy density of 1 kcal/ml and osmolality of 440 mosmol/kg (Fig. 27.1).
Weaning off Parenteral Nutrition
(Post-Op Day 15-40)
From day 15, the calorie density of the enteral feed is steadily increased to ap-
proximately 0.8 kcal/ml. In order to achieve this, medium chain triglyceride
20
and
disacharides are introduced individually with increments every 24-48 hours.
19
The
volume of the feed is usually kept low (i.e., 10-20 ml/kg per day) whilst the feed is
gradually built up. However, once the energy density of the feed is comparable to
the energy density of the PN, the latter is reduced while the feed is increased by the
same volume. This allows a smooth change over from PN and maintains the patients
nutritional parameters.
16
Fluid balance usually remains a problem especially with
end ileostomies and intravenous dextrose saline (i.e., 25-50 ml/kg/day) may still be
required at night for some months.
21
This system allows total flexibility and enables
the addition of chosen nutrients at the optimal time with respect to evolving recov-
ery and function of the graft. For details of the types of nutrients used please see
Table 27.2.
Components of Postoperative Enteral Feed
Protein
The initial protein source used in our unit is hydrolysed whey (hydrolysed whey
protein maltodextrin mixtureHWPMM, SHS), which is well absorbed even
in the presence of exocrine pancreatic dysfunction (common in enteral
understimulation
22
). The HWPMM provides 55 g protein per 100 g and some
carbohydrate. Increased intestinal permeability is also common in the first few weeks
after transplantation, so the hydrolysed protein is useful, with 28% of the peptides
having a molecular weight of greater than 1000 Daltons.
23
Hydrolysed protein is as
trophic to gut mucosa as whole protein,
24
which is an advantage after intestinal
transplant. In pediatric cases, we aim to provide greater than the reference nutrient
intake for protein, based on estimated requirements for sick children,
25
i.e., 3 g/kg
for infants and 2 g/kg for children.
Carbohydrate
Glucose polymer (Super Soluble Maxijul, SHS) is the principal source of carbo-
hydrate, as it is well tolerated due to its ease of absorption and low osmolality. When
the limit of tolerance of glucose polymer is reached (usually between 8-12 g per 100
ml feed), disaccharides (i.e., sucrose and lactose) may be incorporated to utilize al-
ternative channels of absorption which increases energy density of the feed.
19
Lipid
During retrieval and re-implantation, the lacteals are interrupted so that long
chain triglyceride (LCT) malabsorption is inevitable postoperatively. In the rat model
421
Nutritional Support after Small Bowel Transplantation
27
reconnection of lacteals can be demonstrated after 4 weeks,
26
but this appears to be
delayed for at least 3 months in humans,
27
where the coefficient of fat absorption on
a mixed diet is rarely greater than 80% before six months postoperatively. Thus,
medium chain triglyceride (MCT) emulsion (Liquigen, SHS) is the main lipid used
in initial feeds because it is absorbed directly into the portal vein and provides an
excellent alternative energy source.
28
Three to five grams of fat per 100 mls of feed
was introduced from the third week. However, restricting long chain triglyceride
(LCT) is likely to induce essential fatty acid deficiency which are important bioactive
molecules especially in the central nervous system and intercellular signalling in the
immune system.
29
Intralipid contains high concentrations of linoleic and linolenic
acid which can be given intermittently (i.e., 500 mg/kg intralipid once per
week) intravenously, until lacteal drainage is reestablished at about six months
postoperatively.
Substances Promoting Adaptation
Two novel substances were included in the feed used in our Unit: glutamine and
pectin. Glutamine is a preferred fuel source for enterocytes and is important in
maintaining mucosal integrity and preventing bacterial translocation.
22,30,31
Ani-
mal models with short bowel have shown increased mucosal weight and length of
villi when fed glutamine. Glutamine provided 25% of the protein within our modular
feed.
Ornithine alpha-ketoglutarate is a precursor of glutamine and may also have a
useful role in promoting adaptation of the intestinal graft. Rats fed enterally for 7
days with feed enriched with ornithine alpha-ketoglutarate demonstrated an in-
crease villus height and protein turnover in the tibialis muscle after extensive small
bowel resection (poster presentation Dr. F. Dumas et al, 5th International Sympo-
sium on Intestinal Transplantation, Cambridge 1997). A human study evaluating
the effect of 15 g ornithine alpha-ketoglutarate added to parenteral nutrition and
Table 27.1. Nutrient content of enteral feeds in early post-operative period
Post-Op Day
Gram per 100 ml of Feed 9 12 15 18 21 24
Carbohydrate (Total) 4.0 5.0 6.0 7.0 7.0 10.0
As glucose polymer 4.0 5.0 6.0 6.0 6.0 8.0
As lactose 0 0 0 0 0 0
As sucrose 0 0 0 1.0 1.0 2.0
Protein (Total) 1.1 1.1 1.1 2.2 2.2 2.2
As hydrolysed whey (75%) 0.83 0.83 0.83 1.65 1.65 1.65
As glutamine (25%) 0.28 0.28 0.28 0.55 0.55 0.55
Fat 0 0 0 1.0 3.0 3.0
As medium chain 0 0 0 1.0 3.0 3.0
triglyceride
As long chain triglyceride 0 0 0 0 0 0
Energy (kilocalories per ml) 0.21 0.25 0.29 0.46 0.64 0.77
422
The Biology and Practice of Current Nutritional Support
27
administered to children with growth failure, showed an increase in glutamine,
glutamate, IGF-1 and height velocity (3.8 cm/yr to 6.5 cm/yr).
32
Pectin is a source of fermentable dietary fiber, which is thought to increase mu-
cosal hyperplasia and increase height of villi through the trophic action of the short
chain fatty acids derived from bacterial metabolism of pectin.
33,34
An additional
role of pectin is to prolong intestinal transit time, which enhances nutrient absorp-
tion in a similar way to loperamide.
35
One gram of powdered pectin was added per
100 ml of feed.
Electrolytes
To optimize feed absorption, electrolytes are included at similar concentrations
as in oral rehydration solutions
36
and are then adjusted to meet individual require-
ments. Sodium requirements may be as high as 10 mmol/kg/day at first when the
ileostomy output is high and sodium enriched. A comprehensive vitamin and min-
eral supplement (Pediatric Seravit, SHS) is added to the feed to meet the dietary
reference values for each patient.
37
Proprietary Feeds
There is no suitable single feed which meets all these requirements; however
examples of proprietary feeds that are used in children post small bowel transplant
are Pregestimil (Mead Johnson) and Neocate (Scientific Hospital Supplies UK Lim-
ited). Pregestimil is a semi-elemental infant formula, comprised of hydrolysed casein,
glucose polymer and both medium- and long-chain fats (55%MCT: 45%LCT).
Neocate is an elemental formula comprised of amino acids glucose polymer and
long chain fat. Whichever feed is chosen, it is commenced at low concentration and
osmolality, e.g., half strength (0.33 kcal/ml) and the density gradually increased,
according to tolerance, before advancing the volume of feed given. It is our practice
Fig. 27.1. Sequential additions of nutrients to enteral feed for child under 5 years of age
weeks 1-6 post small bowel transplant.
423
Nutritional Support after Small Bowel Transplantation
27
to change from a modular feed to MCT Pepdite between two and six months as
most children remain dependent on tube feeding for at least six months, and a
proprietary feed is easier to manage in the home environment. Adults are usually
able to progress onto a normal diet within 6 months if graft function is good, be-
cause they do not usually exhibit food aversion. However, adults who require calorie
supplementation may receive Nutrison (Nutricia Clinical Foods Limited) or some
other complete feed overnight.
Motility
The gut smooth muscle normally functions as an electrical syncytium with spe-
cialized cells in the stomach and proximal duodenum acting as a pacemaker for the
migrating myoelectric complexes (MMC) which sweep through the length of the
gastrointestinal tract. Since extrinsic denervation of the transplanted bowel is inevi-
table, motility depends on the intrinsic nervous system of the gut
38
and the trans-
planted gut develops its own contractile pattern which is independent of the native
gut. There have been few studies in man, but MMC activity appears to be absent,
and the transit of intestinal content seems to depend on local intestinal contractions
which are peristaltic for 10 cm or less.
39
There is some evidence in the canine model,
that reconnection of the native enteric nervous system with the donor enteric ner-
vous system occurs after 12-20 months and that MMCs reappear, but it is not
known if this occurs in man.
40
Thus motility of the transplanted intestine is sensi-
tive to local factors such as luminal distension and nutrient content, rather than
vagally mediated postprandial patterns of inhibition. Clinically, we have found that
patients have satisfactory gastric emptying followed by rapid transit (1-2 hours) as
the chyme passes along the transplanted intestine to the distal stoma. In our center,
this pattern of motility appears to be established two weeks postoperatively.
The transit time can be slowed using loperamide (50 mg/kg per dose
35
), but
care must be taken in the dose regimen to avoid inducing a paralytic ileus
Table 27.2. Types of nutrients used in nutritional support after small bowel
transplantation
Component Name Supplier
Carbohydrate
glucose polymer Maxijul super soluble SHS*
lactose Lactose BP Thornton & Ross
sucrose sugar supermarket
Protein
hydrolysed whey Hydrolysed whey protein SHS*
maltodextrin mixture
glutamine L-Glutamine SHS*
Fat
medium chain triglyceride Liquigen SHS*
long chain triglyceride Calogen SHS*
Vitamins & Minerals Pediatric seravit SHS*
Pectin Citrus pectin powder Citrus Colloid Limited
*Scientific Hospital Supplies
424
The Biology and Practice of Current Nutritional Support
27
(unpublished observations). Transit time is conveniently measured using carmine
red dye taken orally, and transit times of less than 4 hours are treated with increasing
doses of loperamide to a maximum of 200 mg/kg/day.
Establishment of Normal Diet
4 (Post-Op 2-12 Months)
A low fat, cows milk protein free diet is allowed as soon as the patient requests it
(in practice usually at least one week postoperatively), but the majority of calories
will be derived from the modular feed. A cows milk protein diet is adopted as there
is increased intestinal permeability within the first few weeks posttransplantation. A
feed using protein hydrolysates is somewhat unpalatable and older children and
adults usually require administration nasogastrically, but babies will often drink it.
Many small bowel transplant recipients have poorly developed feeding skills and
may be afraid to swallow food.
14
These children may take 12-18 months to learn to
be confident about eating and the input of a multi-disciplinary including dietitian,
speech therapist and clinical psychologist is crucial,
41
beginning even before trans-
plantation.
12,20
Of 30 pediatric patients from Pittsburgh, 22% required tube feeds
at 1-3 years post-transplant, 20% at 3-5 years and two of three patients at 5-7 years
posttransplant (poster presentation B Kosmach et al, 5th International Symposium
on Intestinal Transplantation, Cambridge 1997). The speed at which a normal diet
is adopted is dependent on several factors: patient preference, graft function includ-
ing motility, fat absorption and type of ileostomy. Patients with a history of
pseudo-obstruction and infants tend to remain on specialized feeds longer. How-
ever, older children and adults may be able to take a normal diet from three months,
although fat malabsorption may cause high stomal output, which has to be com-
pensated for by increased oral intake or overnight intravenous dextrose and saline.
By six months the coefficient fat absorption is much improved with approximately
85-90% of conventional long chain fat being absorbed in dogs,
42
but there are only
limited studies in man.
27
Some patients, particularly those with an end ileostomy,
have a continuing requirement for intravenous fluids, after PN has been stopped,
owing to large volumes of fluid and electrolytes lost from the ileostomy. Of 22
patients from Pittsburgh, one third required intravenous fluid overnight at one year
posttransplant.
21
However, even end ileostomies achieve better sodium and water
reabsorption after 1-2 years.
43
Monitoring
Even before the patient is fully weaned from PN, close monitoring of graft func-
tion and nutritional support is essential. The daily volume of ileostomy output and
presence or not of reducing substances is extremely useful in early detection of rejec-
tion and other complications such as cytomegalovirus (CMV) enteritis and other
systemic infections, as well as determining changes to the feed
21
(see Fig. 27.2).
Provided good graft function is present (defined as when the ileostomy output does
not exceed input and there are no more than 1% reducing substances
16
), then the
energy density and volume of the feed can be increased.
In addition to anthropometric indices, biochemical markers of intestinal func-
tion such as albumin, essential fatty acids and trace elements should be assessed
regularly (see Table 27.3). At one year post transplant, 22 pediatric patients from
Pittsburgh, who were off PN, had increased their height centiles, were appropriate
weight for height and had maintained both muscle and fat stores (poster presentation
425
Nutritional Support after Small Bowel Transplantation
27
Dr. GM Rovera et al, 5
th
International Symposium on Intestinal Transplantation,
Cambridge 1997). Specific markers of intestinal function such as permeability may
be assessed by the differential absorption of lactulose and mannitol
44
or chromium
labelled EDTA
45
and differential fat absorption by extraction of lipids from ileal
output.
46
Disaccharidase activity in the transplanted small bowel is normal with two
weeks of operation (unpublished observations) although during severe rejection
disacharidase activity may be reduced.
47
Endoscopy and mucosal biopsies are taken
frequently (once or twice a week) to monitor for rejection which occurs at some
stage in over 75% patients.
3,5,14
Eosinophilic infiltration of the small bowel lamina
propria has also been reported to occur in over 50% of patients in the first four months
after transplant and in the absence of rejection may represent food sensitization.
48
Complications after Intestinal Transplant and Implications
for Nutritional Support
The main complications of small bowel transplantation are rejection and the
consequences of heavy immune suppression required to prevent it (see Table 27.4).
Rejection is most likely to occur in the first month and is manifested by malabsorp-
tion of enteral feeding. Patients are usually still receiving some PN which can be
increased to prevent weight loss, while the rejection episode is treated with methyl-
prednisolone.
15
Severe secretory diarrhea is uncommon fortunately, because it is life
threatening and may require octreotide to control it. However, a low grade secretory
state may be present at first manifested by sodium rich ileal output (sodium >100
mmol/L), which is important to recognize as the patient will require sodium supple-
ments. Cytomegalovirus (CMV) enteritis has been a major problem especially in
adult small bowel transplant recipients that some transplant centers will not use
CMV positive donors. CMV produces multiple ulcers in the graft which often bleed
Fig 27.2. Diagram illustrating major complications and effect on absorption of enteral feed in
a pediatric patient.
426
The Biology and Practice of Current Nutritional Support
27
and may perforate. Although, CMV responds to hyperimmune globulin and
ganciclovir, it is liable to recur and a temporary return to PN may be needed for a
few weeks during treatment. The frequency of infections after intestinal transplan-
tation is directly related to the intensity of immune suppression and high levels of
tacrolimus (trough level greater than 30 ng/mL) are associated with opportunist
infections such as pneumocystis, and ultimately lymphoma triggered by Epstein-
Barr virus (EBV).
49,50
With increasing experience it has been realized that satisfac-
tory gut function can be achieved using lower exposure to tacrolimus (trough levels
of approximately 15 ng/mL after 3 months). Paradoxically, insufficient immune
suppression is also associated with infection in the form of septicaemia related to
translocation of enteric organisms through the leaky mucosa of rejecting bowel.
Conclusion
Small bowel transplantation is an alternative to patients on parenteral nutrition
with irreversible intestinal failure, but the necessity to use intense immune suppres-
sion and the susceptibility of the transplanted intestine to functional instability causing
malabsorption of drugs, fluids and food means that this is far from being a routine
operation and requires sophisticated nutritional support. However, in well prepared
patients supported by an experienced multidisciplinary team of surgeons, physi-
cians, nurses, dietitians, play specialists, feeding psychologist and liason staff this
operation achieves around 65% four-year survival
51
and is now a viable option for
patients with chronic intestinal failure.
Acknowledgment
We are grateful to colleagues in the Liver Unit and Gastroenterology Depart-
ment especially Dr. D.A. Kelly and Prof. I.W. Booth for their support, to Mrs. Rosie
Jones for much of the original dietetic protocol, and to Mrs. Anita MacDonald for
reviewing the manuscript.
Table 27.3. Nutritional monitoring after small bowel transplantation
Daily Weekly Monthly
plasma electrolytes zinc copper, selenium, manganese
ileostomy output (mls) magnesium essential fatty acids
reducing substances liver function viral serology, polymerase
in ileal fluid chain reaction e.g. EBV [44]
enteral intake (mls) coagulation
intestinal permeability
e.g. lactulose:mannitol
coefficient of fat absorption
weight triceps skin-fold
mid-arm circumference
height
ileoscopy*
* gastroscopy and ileoscopy are done every three months to screen for
lymphoproliferative disease.
427
Nutritional Support after Small Bowel Transplantation
27
Selected References
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Lancet 1990; 335:181-4.
2. Kelly DA, Buckels JAC. The future of small bowel transplantation. Arch Dis Child
1995; 72:447-451.
3. Grant D. Current results of intestinal transplantation. Lancet 1996; 347:1801-3.
4. Beath SV and Mayer AD. Small bowel transplantation. Hospital Update
1996:27-31.
5. Kocoshis SA. Small bowel transplantation in infants and children. Gastroenterol-
ogy Clinics of North America 1994; 23:727-42.
6. Goulet O, Jan D, Brousse N et al. Intestinal transplantation. J Ped Gastroenterol
Nutr 1997; 25:1-11.
7. Messing B, Crenn P, Beau P et al. Long-term survival and parenteral
nutrition-dependency of adult patients with nonmalignant short bowel. Trans-
plant Proc 1998; in Press.
8. Colomb V, Goulet O, De Potter S et al. Liver disease associated with long-term
parenteral nutrition in children. Transplant Proc1 1994; 26:1467.
9. Dollery CM, Sullivan ID, Bauraind O et al. Thrombosis and embolism in long
term central venous access for parenteral nutrition. Lancet 1994; 344:1043-45.
10. Beath SV, Needham SJ, Kelly DA et al. Clinical features and prognosis of children
assessed for isolated small bowel (ISBTx) or combined small bowel and liver trans-
plantation (CSBLTx). J Pediatr Surg 1997; 32:459-61.
11. Ingham Clark CL, Lear PA, Wood S et al. Potential candidates for small bowel
transplantation. Br J Surg 1992; 79:676-9.
12. Beath SV, Booth IW, Murphy MS et al. Nutritional care and candidates for
small-bowel transplantation. Arch Dis in Child 1995; 73:348-50.
13. Beath SV, Brook GA, Buckels JAC et al. Demand for paediatric small bowel trans-
plantation in the United Kingdom. Transplant Proc 1998; in press.
14. Tzakis AG, Todo S, Reyes J et al. Clinical intestinal transplantation: focus on com-
plications. Transplant Proc 1992; 24:1238-40.
15. Beath SV, Kelly DA, Booth IWB et al. Post operative care of children undergoing
combined small bowel and liver transplantation. Brit J Int Care 1994; 4:302-8.
16. Janes S, Beath SV, Jones R et al. Enteral feeding after intestinal transplantation: the
Birmingham experience. Transplant Proc 1997; 29:1855-6.
17. Casavilla A, Selby R, Abu-Elmagd K et al. Logistics and technique for combined
hepatic-intestinal retrieval. Ann Surg 1992; 216:605-9.
18. Sonnino RE, Wong L, Franson RC. Early secretory events during intestinal graft
preservation. Transplant Proc 1998; in press.
Table 27.4. Complications after intestinal transplantation
Typical Time of
Complication Onset Post-Op Day
Rejection 7-10
Secretory diarrhea 5-20
CMV enteritis 40
GI infections* e.g.rotavirus any time, often adenovirus after discharge
Lymphoproliferative disease 180 days
* may be severe leading to loss of graft
428
The Biology and Practice of Current Nutritional Support
27
19. Warner BW, Ziegler MM. Management of the Short Bowel Syndrome in the Pedi-
atric Population. Pediatric Clinics of North America 1993; 40(6):1335-1350.
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nal allograft recipients. Transplant Proc 1998; in press.
22. Vanderhoof JA, Langnas AN, Pinch LW et al. Short Bowel SyndromeA Review.
J Pediatr Gastroenterol Nutr 1992; 14:359-370.
23. MacDonald A. Which formula in cows milk protein intolerance? The dietitians
dilemma. Euro J Clin Nutr 1995; 49,Suppl 1:S56-S63.
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hydrolysate on mucosal adaptation following massive bowel resection in growing
rats. J Pediatr Gastroenterol Nutr 1983; 2:617-21.
25. Shaw V, Lawson M. Principles of paediatric dietetics. In: Shaw V and Lawson M,
eds. Clinical Paediatric Dietetics. 1st ed.Oxford:Blackwell Science Lim-
ited,1994:3-12.
26. Liu H, Teraoka S, Ota K et al. Successful lymphangiographic investigation of me-
senteric lymphatic regeneration after orthoptopic intestinal transplantation in the
rat. Transplant Proc 1992; 24:1113-14.
27. Mousa H, Bueno J, Griffith J et al. Intestinal motility in children after small bowel
transplantation. Transplant Proc 1998; in press.
28. Senior JR. Medium chain triglycerides. Philadelphia: University Pennsylva-
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29. Sanders TAB. Essential and Trans-fatty acids in nutrition. Nutrition Research Re-
views. 1988; 1:57-78.
30. Hambridge KM, Krebs NF, Sokol RJ. Energy and Nutrient Requirements. In: Roy
CR, Silverman A and Alagille D, eds. Pediatric Clinical Gastroenterology. 4th ed.
Missouri: MosbyYear Book, Inc., 1995; 1005-1019.
31. McAnena OJ, Moore FA, Moore EE et al. Selective Uptake of Glutamine in the
Gastrointestinal Tract: Confirmation in a Human Study. Brit J Surgery 1991;
78:480-2.
32. Moukarzel AA, Goulet O, Salas JS et al. Growth retardation in children receiving
long-term parenteral nutrition: Effects of ornithine alpha-ketoglutrate. Am J Clin
Nutrition 1994; 60:408-13.
33. Allard JP, Jeejeebhoy KN. Nutritional Support and Therapy in the Short Bowel
Syndrome. Gastroenterology Clinics of North America 1989; 18:3,589-601.
34. Thompson JS. Management of the Short Bowel Syndrome. Gastroenterology Clin-
ics of North America 1994; 23(2):403-420.
35. Sandhu BK, Tripp JH, Milla PJ et al. Loperamide in severe protracted diarrhea.
Arch Dis Child 1983; 58:39-43.
36. Greenough III WB. Oral rehydration therapy: An epithelial transport success story.
Arch Dis Child 1989; 64:419-22.
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reference values for food energy and nutrients for the United Kingdom. Lon-
don: HMSO, 1991.
38. Sarr MG, Kelly KA. Myoelectric activity of the autotransplanted canine
jejuno-ileum. Gastroenterol 1981; 81:303-10.
39. Sarr M, Hakim N. Motility of the transplanted gut. In: Enteric Physiology of the
transplanted intestine. Austin: RG Landes, 1994; 5:28-54.
40. Quigley EMM, Spanta AD, Rose SG et al. Long-term effects of jejunoileal au-
totransplantation on myoelectric activity in canine small intestine. Dig Dis Sci
1990; 35:1505-17.
41. Harris G, Booth IW. Feeding problems and eating disorders in children and ado-
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Reading: Harwood Academic Publishers, 1992; 5:61-84.
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42. Thompson JS, Rose SG, Spanta Ad et al. The long-term effect of jejunoileal au-
totransplantation on intestinal function. Surgery 1991; 111:62-8.
43. Ein SH. The pediatric ostomy. In: Walker WA, Durie PR, Hamilton JR et al, eds.
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44. Lim et al. HIV and permeability. Scand J Gastroenterology 1993; 28:573-80.
45. Grant D, Hurlbut D, Zhong R et al. Intestinal permeability and bacterial translo-
cation following small bowel transplantation in the rat. Transplantation 1992;
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46. Beath SV, Willis KD, Hooley I et al. New method for determining faecal fat excre-
tion in infancy. Arch Dis Child 1993; 69:138-40.
47. Akhtar K, Deardon D, Pemberton PW et al. Study of mucosal brush border en-
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28:2556-7.
48. Putnam PE, Bueno J, Kocoshis SA et al. Tissue eosinophilia after small bowel
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Epstein-Barr viral infection and post-transplant lymphoproliferative disease after
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tinal transplantation in infants and children. Transplant Proc 1996; 28:2752.
CHAPTER 28
The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi
and Stanley J. Dudrick. 2003 Landes Bioscience.
Nutritional Support in Patients
with Head and Neck Cancer
Matthew E. Cohen, Rosemarie L. Fisher
Introduction
Patients with head and neck cancer share many nutritional support issues en-
countered in most patients with cancer, yet possess unique nutritional challenges
due to the location of their cancers in the proximal digestive tract. In this chapter,
the following topics are reviewed:
1. risk factors for malnutrition;
2. the relationship between malnutrition and clinical outcome;
3. the impact of enteral and parenteral nutritional support around the time of
surgery, radiotherapy or chemotherapy; and
4. methods of delivering enteral nutritional support.
Most studies of nutritional support have been retrospective, and many have suf-
fered from inadequate experimental design, heterogeneous or small groups of pa-
tients, or inappropriate endpoints.
1
In addition, many nutritional studies performed
in patients with head and neck cancer were descriptive without statistical analyses.
Thus, comparisons of studies are, at times, limited.
Risk Factors for Malnutrition
Forty-
2
to sixty-percent
3
of patients with head and neck cancer are malnourished
at presentation. There are many possible reasons for this high prevalence of malnu-
trition, including advanced age, alcohol or tobacco abuse, or dysphagia from the
tumor site, as well as psychosocial factors such as concomitant depression or inad-
equate social support. Data in patients with head and neck cancer are mixed, how-
ever, regarding the contribution of these characteristics to the risk of developing
malnutrition (Table 28.1).
While some researchers have found a trend toward age being an independent
risk factor for malnutrition,
4
others have not.
3,5
Despite the widely held assumption
that many patients maintain a marginal nutritional status at baseline because of
their unhealthy habits, smoking and alcohol consumption failed to correlate with
worse nutritional status in at least two studies.
3,4
A third study found a correlation
between pack-years of smoking and better nutritional status, but the implications of
this relationship are not known.
5
Psychosocial factors may play a role in the nutritional status of patients with
head and neck cancer. For example, depression may be more common in patients
with malnutrition than in those without malnutrition. Westin
6
performed nutri-
tional assessments and psychopathological ratings on 53 patients with various head
431
Nutrition Support in Patients with Head and Neck Cancer
28
and neck tumor sites, stages, therapeutic modalities and points in oncologic therapy.
While no well-nourished patient was depressed, 30% of the 16 malnourished pa-
tients were depressed, which was a statistically significant difference. The five de-
pressed patients had completed their therapies more than one year previously and
were admitted because of suspected or known cancer recurrence. The presence or
absence of a spouse is another psychosocial variable that may influence the nutri-
tional status of patients with head and neck cancer. In patients less than 60 years old
with head and neck cancer, being married decreased the risk of malnutrition, while
in those over 60 years of age, being married increased the risk of malnutrition.
5
The
source of this discrepancy was not discussed.
Another possible reason for malnutrition in patients with head and neck cancer
is the location of the tumor. Oropharyngeal cancer may cause anorexia, nausea,
inadequate mastication, xerostomia, dysgeusia, dysphagia or odynophagia.
7
Dimin-
ished oral intake and avoidance of firm solids correlated with malnutrition.
4
Main-
tained oral intake, however, did not prevent weight loss in all cases,
4
perhaps due to
tumor-induced metabolic alterations which favor tumor growth at the hosts ex-
pense.
8
Some studies of patients with head and neck cancer noted that tumors lo-
cated within the upper digestive tract (but not in the upper respiratory tract) pre-
dicted malnutrition (Table 28.1). As with tumor site, tumor stage may correlate
with malnutrition (Table 28.1). Other studies, in contrast, found that neither tu-
mor site nor stage predicted nutritional status.
9
Matthews, however, did find a cor-
relation between tumor stage and weight loss, which has predicted poor nutritional
status in some
5
(but not other
10
) studies.
Depressed cellular immune response is often attributed at least in part to malnu-
trition in patients with cancer. However, age (which affects immune response
5
) and
nutritional status were not investigated in most studies. In one study which did
compare well-nourished to malnourished patients with head and neck cancer, an-
ergy to all seven skin tests and a suppressed in vitro purified lymphocyte response to
Table 28.1. Possible risk factors for malnutrition in patients with head and
neck cancer
Variable Risk Factor?
Age Trend
4
No
3, 5
Depression Yes
6
Marriage Yes (if patient >= 60 years old)
5
No (if patient < 60 years old)
5
Smoking No
3-5
Tobacco No
3-5
Tumor Site Yes Oral cavity/oropharynx/hypopharynx
cervical esophagus >larynx/
nasopharynx/paranasal sinuses
2
Yes Oropharynx/hypopharynx > larynx
3
No
9
Tumor stage Yes
4
Trend
3
No
9
432
The Biology and Practice of Current Nutritional Support
28
one of the stimulants (concanavalin A) correlated with malnutrition.
5
In another
study, patients with localized head and neck cancer were skin-tested sequentially
with DNCB and four common antigens.
11
DNCB reactivity correlated significantly
with disease-free survival at six months, one year and four years. In contrast, skin
test antigen reactivity did not correlate with clinical course. Any impairment in the
immune response was thought to be from deficits other than nutritional, however,
since all of the study subjects were outpatients and none had extreme cachexia.
11
In conclusion, about one-half of patients with head and neck cancer present
malnourished, which likely results more from tumor-induced metabolic alterations
than from any preexisting malnutrition from tobacco or alcohol abuse. In general,
both advanced head and neck cancer and location of tumor within the digestive
(versus respiratory) tract appear to increase the risk of malnutrition. Depressed de-
layed hypersensitivity responses reflect poor nutritional status, but may be as depen-
dent on advanced tumor burden. It is unclear if depression among patients with
head and neck cancer causes malnutrition or simply correlates with recurrent disease.
Malnutrition and Clinical Outcome
Some studies of patients with head and neck cancer have found correlations
between malnutrition and increased postoperative morbidity,
5,12,13
mortality,
5,13
length of hospitalization,
5
and decreased survival at two years.
2
Others have found
no independent correlation between any nutritional parameter and incidence of
postoperative complications or death.
9
Hooley
12
prospectively calculated the Prognostic Nutritional Index (Table 28.2)
in 29 patients with head and neck cancer 48 hours before surgery. All patients had
completed preoperative high-dose radiotherapy. The more malnourished patients
had a greater apparent risk of a major postoperative complications. No consider-
ation was given to the site of the head and neck cancer or to patient comorbidity.
Linn
5
prospectively evaluated 79 men who had surgery for head and neck can-
cer, using his Protein Energy Malnutrition Scale (Table 28.2).
14
Malnourished eld-
erly patients had the worst surgical outcomes. Potential reservations about the study
included the existence of significant differences between the cancer types in the
malnourished versus well-nourished groups and uncontrolled preoperative nutri-
tional support (given in 60% of younger malnourished patients and 20% of older
malnourished patients).
Goodwin
13
retrospectively studied 50 consecutive patients with stage III, IV or
recurrent squamous cell carcinoma of the head and neck, 47 of whom had a variety
of treatments, including induction chemotherapy, surgery, and/or radiation.
Treatment-related complications in the 14 patients with severe malnutrition based
on the Prognostic Nutritional Index were always major and more frequent, com-
pared to the 36 patients with no or mild malnutrition. Statistical analysis was re-
ported only for the 38 patients having surgery, nine of whom were severely mal-
nourished and suffered significantly more morbidity and mortality. There was no
attempt, however, to demonstrate a risk of malnutrition independent of tumor or
treatment variables.
Brookes
2
prospectively followed 114 patients with untreated squamous cell can-
cer of the head and neck, and found that a General Nutritional Status (Table 28.2)
of less than -10% (undernutrition) correlated with poorer survival, where a life table
analysis excluding those patients who received intensive nutritional support showed
a 58% survival rate of the adequately nourished patients at two years compared to
433
Nutrition Support in Patients with Head and Neck Cancer
28
Table 28.2. Nutritional indexes used to assess patients with head and neck cancer
Protein Energy Malnutrition Scale
14
Note that the score of each item ranges along a geometric scale.
Score 1 2 4 8
Clinical History
Inadequate nutrient intake None Mild Moderate Severe
Excessive nutrient losses None Mild Moderate Severe
Increased metabolic needs None Mild Moderate Severe
Anti-nutrient or catabolic None Mild Moderate Severe
medications
Physical Examination
Cachexia None Mild Moderate Severe
Hair easily pluckable or None Mild Moderate Severe
nails brittle/ridged
Hepatomegaly or ascites None Mild Moderate Severe
Muscle atrophy None Mild Moderate Severe
Generalized edema None Mild Moderate Severe
Dry skin, scaling skin, or None Mild Moderate Severe
skin lesions
Anthropometric
Relation to ideal body weight (%) >=90 85-89 80-84 <80
Weight loss from usual weight (%) <=5 6-12 13-19 >=20
Triceps skin fold (mm)
MEN >=9.0 7.0-8.9 5.0-6.9 <5.0
WOMEN >=16.0 11.0-15.9 6.0-10.9 <6
Mid-arm muscle circumference (mm)
MEN >=243 216-242.9 189-215.9 <189
WOMEN >=192 170-191.9 148-169.9 <148
Laboratory
Albumin (gm/dL) >=3.5 2.8-3.4 2.1-2.7 <2.1
Hemoglobin (gm/dL) >=14.0 13.9-12.0 11.9-10.0 <10.0
Delayed hypersensitivity >=2>5mm 1>5mm 1<5mm Anergy
skin tests (of four)
Lymphocytes (cells/mL) >=1500 1200-1500 1000-1200 <1000
Creatinine excretion >=80 60-79 40-59 <40
index (%standard)
Transferrin (mg/dL) >=200 150-199 100-149 <100
Retinol-binding protein (mg/dL) >=3.0 2.5-2.9 2.0-2.4 <2.0
Pre-albumin (mg/dl) >=15 12.5-14.9 10.0-12.4 <10.0
Negative nitrogen balance (g/day) <=5.0 5.1-10.0 10.1-15.0 >15.0
Prognostic Nutritional Index (PNI)
12
PNI% = 158% - 16.6(ALB) - 0.78 (TSF) - 0.2(TFN) -5.8(DH)
ALB = albumin (g/dL); TSF = average of three triceps skin fold measurements (mm); TFN =
serum transferrin (mg/dL); DH = number of positive delayed hypersensitivity responses
measured at 24 and 48 hours after intradermal injection of five antigens (Candida albicans,
mumps, tuberculin purified protein derivative, Trichophyton, and streptokinase-strep-
todornase). Major post-operative complications occurred in patients with a PNI > 20.
12
In
another study, a PNI > 40 indicated a high risk of developing a post-operative infection.
64
continued on next page
434
The Biology and Practice of Current Nutritional Support
28
an 8% survival rate among the undernourished patients. The authors claimed that
this correlation was irrespective of tumor site, stage, histology or age, although sta-
tistical analyses of these data were not presented.
Matthews
9
prospectively studied 42 patients with newly diagnosed upper
aerodigestive squamous cell carcinoma (31 of whom had cancer of the oral cavity,
oropharynx, or hypopharynx) who subsequently had surgery with or without radia-
tion therapy. There was a 38% incidence of minor complications, and a 10% inci-
dence of major complications. The study was limited by incomplete compilation of
data in the Subjective Global Assessment of Nutritional Status (Table 28.2), varied
tumor sites and non-standardized surgical procedures.
In summary, although data conflict and analyses are imperfect, most studies
support the conclusion that malnutrition predicts increased perioperaive morbidity
and mortality, and decreased long-term survival.
Surgery, Nutritional Support and Clinical Outcome
Data on the effect of preoperative enteral supplementation on postoperative
outcome in malnourished patients with head and neck cancer are mixed.
13,15
Flynn
15
prospectively studied 61 patients with squamous cell cancer of the upper aerodigestive
tract who were candidates for operative resection (Fig. 28.1). Malnourished patients
receiving nutritional supplementation were provided with specific recommenda-
tions to meet their individual nutrient requirements and an unspecified number
were given nutritional supplements. Additionally, these patients were contacted as
necessary during the 10-21 days between counseling and hospital admission to
Table 28.2. (cont'd)
General Nutrition Status (GNS)
2
GNS = P% + I% + A
3
P% = percentage weight change from pre-morbid weight; I% = percentage of ideal weight;
A% = percentage arm muscle circumference (AMC) change; AMC = mid-point non-dominant
upper arm circumference - ( x triceps skin fold {mm})
GNS > -10% Adequate nutrition
< -10% to 20% Under-nutrition
< -20% to 30% Malnutrition
<-30% Severe malnutrition
Subjective Global Assessment of Nutritional Status (SGA)
65
A routine history and physical examination is utilized for clinical assessment.
History includes Physical examination
inquiry about weight loss includes inspection for
Edema Cheilosis
Anorexia Glossitis
Vomiting Subcutaneous fat loss
Diarrhea Muscle wasting
Decreased or unusual food intake Edema
Chronic illness
Based on a global assessment of nutritional status, the examiner classifies a patient as:
A = NORMAL NUTRITIONAL STATUS B = MILD MALNUTRITION C = SEVERE MALNUTRITION
The SGA had a better combination of sensitivity (0.82) and specificity (0.72) in predicting post-
operative infection than the PNI or individual measures of creatinine-height index, percentage
body fat, serum transferrin, serum albumin, or delayed cutaneous hypersensitivity.
64
435
Nutrition Support in Patients with Head and Neck Cancer
28
determine their nutritional status and to encourage them to comply with their nu-
tritional programs. The malnourished unsupplemented group received only nutri-
tional counseling, suggestions on ways to cope with eating problems, and no follow-up
until hospital admission. Seven of the 25 well-nourished patients (26%) and 23 of
F
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.
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8
.
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.
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436
The Biology and Practice of Current Nutritional Support
28
the 36 malnourished patients (63%) had received prior radiotherapy. Postopera-
tively, patients received oral, tube and/or parenteral nutrition. Compared to the
malnourished unsupplemented group, the malnourished supplemented patients were
younger, had a greater prevalance of advanced disease (68% prevalence versus 35%,
respectively), a greater likelihood of prior radiotherapy and a higher rate of extensive
resection (26% versus 0%). Yet, the supplemented group had fewer complications
and a shorter average hospital stay. The three-day decrease in average hospital stay
saved an average of $2,298 per patient. Limitations of the study included small
study size, nonstandardized treatment within the supplemented group, differences
of stage, prior irradiation and extent of surgery between compared groups, and de-
scriptive nonstatistical analysis.
Goodwin
13
included in their study six patients with severe malnutrition who
had an average of 14 days of preoperative enteral and parenteral nutrition, of whom
five had major complications. The three severely malnourished patients who under-
went surgery without preoperative nutritional support all suffered major complica-
tions. Despite the disappointing results, albeit on a small number of patients,
Goodwin advocated nearly a decade later one to two weeks of preoperative nutri-
tional support in those patients who have a 15% weight loss, decreased general
strength, or low serum proteins.
16
Data pertaining to altered clinical outcome with perioperative parenteral nutri-
tion are as rare as those addressing the role of enteral nutrition. Shortly after parenteral
nutrition became widely available in the 1970s, researchers noted that perioperative
parenteral nutrition improved some nutritional parameters. Yet, the majority of pa-
tients appeared to possess sufficient nutrient reserves to survive the catabolic and
semistarvation recovery period without the need for parenteral nutritional support.
Although researchers have argued against its use in the majority of patients due to its
high cost,
8
parenteral nutrition has been advocated for selected patients with head
and neck cancer, such as those who cannot tolerate enteral nutrition or require rapid
repletion of nutritional stores in order to qualify for timely oncologic therapy.
17
Copeland
17
reported an uncontrolled trial of perioperative (as well as
periradiotherapy and convalescent) parenteral nutrition in 23 patients with head
and neck cancer who had lost at least 20 pounds and who were severely cachectic or
intolerant of nasogastric feeding. Seven of the eight patients who received preopera-
tive parenteral nutrition suffered no postoperative complications. Weight gain, wound
healing and recovery were achieved in 20 patients, while only three patients suffered
intravenous catheter-related complications. Many patients who previously were in-
tolerant of enteral feeding regained their ability to tolerate enteral nutrition follow-
ing parenteral nutritional support.
Sako
18
studied 69 patients with head and neck cancer who had no better than a
moderate prognosis, stratified them based on nutritional status and prognosis, and
randomized them to receive either parenteral or enteral postoperative nutrition (Fig.
28.2). Eight of the 35 patients in the parenteral group received preoperative parenteral
nutrition for at least eight days as well. Thirty of the 35 patients received the postop-
erative parenteral nutrition for at least 12 days. Postoperative wound complications
and recurrence of cancer were similar in the two groups. Survival curves were signifi-
cantly worse in the patients receiving postoperative parenteral versus enteral nutri-
tion in all strata of malnutrition. Parenteral nutrition was superior to enteral nutri-
tion only in maintaining nitrogen balance and weight, and the stable weight was
thought to be secondary to fluid retention rather than from preserved tissue mass.
4
3
7
N
u
t
r
i
t
i
o
n
S
u
p
p
o
r
t
i
n
P
a
t
i
e
n
t
s
w
i
t
h
H
e
a
d
a
n
d
N
e
c
k
C
a
n
c
e
r
2
8
Fig. 28.2. Effect of parenteral hyperlimentation in surgical patients with head and neck cancer. Adapted from Sako and colleagues.
18
438
The Biology and Practice of Current Nutritional Support
28
Although the decreased survival among those patients receiving parenteral nutri-
tion in Sakos
18
study was not a result of catheter-related sepsis, this complication is
more common in patients treated for head and neck cancer than in patients with
any other site of cancer.
19
Contamination of central venous catheters in patients
with head and neck cancer may be more frequent due to pharyngostomy or tracheo-
stomy secretions, or from skin compromise secondary to local radiotherapy.
19
Changes in reimbursement policies may limit flexibility in providing periopera-
tive nutritional support. When 61 patients who were admitted for radical resections
of head and neck cancer after the implementation of diagnosis-related group
(DRG)-based reimbursement were compared with 59 similar patients admitted be-
fore DRGs were used, complications rates had more than doubled in malnourished
patients.
20
Comparing the post-DRG with the pre-DRG groups, nutritional status
determined by the Protein Energy Malnutrition Scale was similar at admission, but
the time from admission to surgery and nutritional status at surgery both decreased
in the post-DRG group. Linn
20
concluded that the higher complication rate in the
post-DRG patients was attributed to the DRG-driven pressure to limit preoperative
hospital stay and nutritional interventions. Although comparisons using historical
controls must be interpreted with caution, the study design usually favors the popu-
lation treated most recently (not the historical control).
In patients undergoing immediate mandibular reconstruction for oral cavity or
oropharyngeal cancer, decreased length of hospital stay was achieved by using a
coordinated care plan including oral feeding with speech and swallowing therapy
beginning on the first or second postoperative day. The ultimate ability to tolerate
regular food was influenced positively by the presence of teeth and tumor originat-
ing from the gingiva or retromolar trigone as opposed to the floor of the mouth or
the tongue.
21
In a study of 44 patients with dysphagia following head and neck
surgery who were enrolled in a comprehensive swallowing rehabilitation program,
the severity of impairment was related to the extent of surgical resection, and the
number of swallowing phases that were impaired (oral, pharyngeal or esophageal).
Severity of the residual swallowing impairment correlated with the magnitude of
initial impairment. The ability to compensate for residual impairment varied widely.
22
Copeland
19
advocated the use of parenteral nutrition during swallowing reha-
bilitation, after concluding that the lack of a nasogastric tube psychologically facili-
tated jaw function rehabilitation in five poorly motivated patients and after witness-
ing a return of competent swallowing function in three patients on parenteral nutrition
as general strength returned. Alternative routes of enteral nutrition delivery were
not considered, and it is unclear to what degree, if any, the positive outcome in these
patients was due to the parenteral nutrition. In the absence of a controlled trial,
parenteral nutrition cannot be recommended routinely for swallowing rehabilitation.
Although parenteral nutrition has not been demonstrated to be better than en-
teral nutrition (and may be worse
18
), relative indications for parenteral nutritional
support include a persistent pharyngocutaneous fistula
17
or chylous fistula.
23
Sus-
pending enteral nutrition decreases salivary and mucosal secretions. If the fistula
fails to heal spontaneously, surgical closure may be successful after parenteral
nutritional support even if a prior attempt at surgical correction was unsuccessful.
19
It appears reasonable to advocate preoperative coordinated nutritional counsel-
ing, enteral nutritional supplementation in severely malnourished patients, and avoid-
ance of preoperative parenteral nutrition. Following surgery, aggressive speech and
swallowing therapy should be implemented, as well as enteral tube feeding in those
439
Nutrition Support in Patients with Head and Neck Cancer
28
patients with a protracted recovery of deglutition. If one wishes to avoid a nasogastric
tube, enteral feeding via a gastrostomy tube (placed prior to surgical resection) is
preferable to parenteral nutrition. Parenteral nutrition can be recommended only in
patients who cannot tolerate enteral feeding or who have persistent enteric fistulas.
Radiotherapy, Nutritional Support and Clinical Outcome
Radiotherapy is provided commonly to patients with head and neck cancer, but
may adversely affect nutritional status by causing mucositis, stomatitis, increased
xerostomia, dysgeusia, anorexia or dental defects. Radiotherapy may also affect nu-
tritional status by causing a preference for carbohydrates at the expense of protein,
24,25
perhaps as a result of relative sparing of sweet taste perception.
26
Radiotherapy-
induced dental lesions similar to caries may appear as early as one month after the
initiation of radiotherapy when the salivary glands are in the radiation field, likely
due to alterations in the oral milieu resulting from inadequate salivation.
27
Some
degree of anorexia, dysphagia, or dysgeusia may persist for several months.
28
Of note, zinc may prevent hypogeusia when administered at varying doses prior
to the initiation of radiotherapy.
29
Additionally, zinc therapy may improve hypogeusia
in patients receiving radiotherapy to the head and neck.
26
One recommended regi-
men is zinc sulfate 110 mg (elemental zinc 25 mg) orally four times a day during or
after meals (to decrease gastrointestinal toxicity).
29
To address the risk of malnutrition, 31 patients with newly-diagnosed localized
head and neck cancer treated with radical external beam radiotherapy for cure were
followed for six months.
10
In this descriptive study, weight loss averaging 10% cor-
related with the size of the radiation field when the oral cavity or oropharynx was
included within the field (assuming that the table correlating weight loss with the
radiation field only when located outside of the oral cavity was the result of a typo-
graphical error). Weight loss did not correlate with pretreatment dietary habits, an-
thropometric or biochemical measures. Two patients received enteral tube feeding
during the last week of four weeks of therapy, and none received parenteral nutrition.
In order to investigate the potential impact of nutritional supplements on nutri-
tional status, Nayel
25
prospectively randomized 11 patients to receive enteral supple-
mentation (Ensure