Patient case: Surgery-associated Bleeding J eremy D. Flynn, Pharm.D., BCPS
P R O G R A M F A C U L T Y Robert MacLaren, Pharm.D., FCCP, FCCM, Program Chair Associate Professor University of Colorado School of Pharmacy Denver, Colorado
Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM Associate Professor of Pharmacy and Neurosurgery Virginia Commonwealth University Medical College of Virginia Campus Richmond, Virginia
Jeremy D. Flynn, Pharm.D., BCPS Clinical Pharmacist Specialist UK HealthCare-Pharmacy Services Assistant Professor Department of Pharmacy Practice and Science University of Kentucky College of Pharmacy Lexington, Kentucky
1 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding
D I S C L O S U R E S T A T E M E N T In accordance with the Accreditation Council for Continuing Medical Educations and the Accreditation Council for Pharmacy Educations Standards for Commercial Support, ASHP Advantage requires that all individuals involved in the development of program content disclose their relevant financial relationships. A person has a relevant financial relationship if the individual or his or her spouse/partner has a financial relationship (e.g., employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose products or services may be discussed in the CME activity content over which the individual has control. The existence of these relationships is provided for the information of participants and should not be assumed to have an adverse impact on presentations.
All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP Advantage and required to disclose any relevant financial relationships with commercial interests. ASHP Advantage identifies and resolves conflicts of interest prior to an individuals participation in development of content for an educational activity.
The faculty and planners report the following relationships:
Robert MacLaren, Pharm.D., FCCP, FCCM, Program Chair
Dr. MacLaren reports that he has served as a consultant for Novo Nordisk.
Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM
Dr. Brophy reports that she has served as a consultant for and has received research grant funding from Novo Nordisk.
Jeremy D. Flynn, Pharm.D., BCPS
Dr. Flynn reports that he has served as a consultant for Novo Nordisk and The Medicines Company.
Kristi Hofer, Pharm.D.
Dr. Hofer reports no relationships pertinent to this activity. 2 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding
P R O G R A M O V E R V I E W The clinical and economic consequences of serious bleeding in critically ill patients are significant. Uncontrolled hemorrhage is considered the leading cause of preventable death in the United States. Because health system formularies include many agents to promote and inhibit blood coagulation, pharmacists need to know how to use them safely and appropriately.
Transfusion of blood products is often required to manage serious bleeding in critically ill patients; however, there are significant risks associated with transfusion of blood products. Consequently, pharmacologic strategies, including aminocaproic acid, tranexamic acid, desmopressin, and recombinant activated factor VIIa, are being investigated for controlling bleeding and reducing the need for transfusions. Pharmacists practicing in the acute care setting must keep abreast of this evolving body of knowledge to ensure that these agents continue to be used appropriately. Pharmacists involved in medication order review and approval, development and implementation of clinical guidelines and protocols, and formulary decision-making, as well as clinical specialists practicing in critical care, surgical, and emergency care settings need access to current information on agents used to manage bleeding in critically ill patients.
This educational activity will examine conditions that may lead to bleeding and strategies for managing bleeding, including both conventional treatments and emerging therapeutic alternatives. Using patient case examples and an automated audience response system, faculty will engage participants in the clinical decision-making process involved in managing patients with critical bleeding.
L E A R N I N G O B J E C T I V E S At the conclusion of this knowledge-based educational activity, participants should be able to: List the most common causes of bleeding in hospitalized patients. Analyze recently published data regarding the safety and efficacy of various agents used to control bleeding in critically ill patients. When presented with a patient case, suggest therapeutic options for managing bleeding in the perioperative and acute care settings. 3 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding
C O N T I N U I N G E D U C A T I O N A C C R E D I T A T I O N The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The program provides 2.0 hours (0.2 CEUs) of continuing education credit (program number 204-000-08- 455-H01P).
F O R M A T A N D M E T H O D S This is an online activity consisting of audio for three presentations, a post-test, and an activity evaluation tool. Participants must listen to all presentations, take the activity post-test, and complete the course evaluation to receive continuing education credit. A minimum score of 70% is required on the test for credit to be awarded, and participants may print their official statements of continuing education credit immediately. The estimated time to complete this activity is two hours. This activity is provided free of charge.
4 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding
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If you have any problems processing your CE, contact ASHP Advantage at support@ashpadvantage.com. 5 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding
Robert MacLaren, Pharm.D., FCCP, FCCM, Program Chair Associate Professor University of Colorado School of Pharmacy Denver, Colorado
Robert MacLaren, Pharm.D., FCCP, FCCM, is Associate Professor in the Department of Clinical Pharmacy at the University of Colorado Denver School of Pharmacy in Aurora, Colorado. In addition, he is a clinical pharmacist in the medical intensive care unit at the University of Colorado Hospital, which is also located on the Anschutz Medical Campus in Aurora. Dr. MacLaren also serves as co-director of the critical care residency at the University of Colorado.
After completing his undergraduate degree in pharmacy at the University of British Columbia in Vancouver, Canada, Dr. MacLaren earned his Doctor of Pharmacy degree at the University of Utah in Salt Lake City and completed a critical care specialty residency in Memphis at the University of Tennessee and Baptist Memorial Hospital. He worked for two years as a critical care specialist at the Queen Elizabeth II Health Sciences Centre in Halifax, Canada, before joining the faculty at the University of Colorado.
Dr. MacLaren is a fellow of the American College of Clinical Pharmacy and the Society of Critical Care Medicine. His clinical research interests include gastrointestinal motility dysfunction associated with critical illness and the use of intravenous glutamine as a supplement to parenteral nutrition. He conducts animal studies of acetaminophen toxicity and has been involved with outcomes research of pharmacologic therapies and the impact of pharmacists in the intensive care unit. He has authored several articles relating to the pharmacologic and nutritional therapies of critically ill patients and has been an invited speaker at national and international meetings. 6 Bleeding in Medical and Surgical Patients: Common Causes, Mechanisms, and Treatment Robert MacLaren, Pharm.D., FCCM, FCCP Associate Professor University of Colorado School of Pharmacy Denver, Colorado Case Scenario Jill is a 58-y.o. woman admitted with septic shock and oliguria. Her PMH is significant for PE 2 years ago (no longer requiring anticoagulation, but she takes aspirin 325 mg daily) Baseline labs show platelets 37 x 10 9 /L, Hct 24% (for which 2 units of RBCs are administered for early goal directed therapy of Hct >30%), INR 1.7, aPTT 48 seconds, BUN 85 mg/dL, ALT 2200 IU/L, and AST 3450 IU/L APACHE II score >25, so activated protein C is started She receives 8 L normal saline and norepinephrine 0.3 mcg/kg/min, is intubated, and renal support is started What risk factors does J ill have for hemorrhage? A. Anticoagulant use (activated protein C, aspirin) B. Baseline coagulopathy C. Thrombocytopenia D. Liver and renal dysfunction 7 What risk factors does J ill have for hemorrhage? A n tic o a g u la n t u s e (a c ... B a s e lin e c o a g u lo p a th y T h r o m b o c y to p e n ia L iv e r a n d r e n a l d y s fu ... 41% 25% 22% 12% A. Anticoagulant use (activated protein C, aspirin) B. Baseline coagulopathy C. Thrombocytopenia D. Liver and renal dysfunction How frequently is bleeding the primary reason for transfusion? A. < 25% B. 25-50% C. 50-75% D. > 75% How frequently is bleeding the primary reason for transfusion? < 2 5 % 2 5 -5 0 % 5 0 -7 5 % > 7 5 % 34% 16% 24% 26% A. < 25% B. 25-50% C. 50-75% D. > 75% 8 Reasons to Transfuse 0 25 50 75 100 L o w
H g B le e d L o w
B P S u r g e r y I s c h e m i a O t h e r 25-30% of all transfusions are in the ICU Corwin HL et al. Crit Care Med. 2004;32:39-52. N=4892 patients from 284 ICUs Causes of Critical Bleeding Thrombocytopenia (<50 x 10 9 /L): 4- to 5-fold risk of hemorrhage Independent risk factor for mortality (OR = 1.9-4.2) Incidence is 21-41%, but only 5% <20 x 10 9 /L Coagulopathy: 4- to 5-fold risk of hemorrhage Independent risk factor for mortality (OR = 1.5-4.3) Incidence is 14-28% Levi Met al. Crit Care. 2006; 10:222. Mercer KWet al. Semin Respir Crit Care Med. 2006; 27:286-96. Thrombocytopenia General causes Decreased platelet production Congenital or acquired disorders of hematopoiesis Bone marrow suppression (drugs) Nutritional deficiencies (folate, vitamin B 12 ) Liver disease Distributional Massive blood transfusion Splenomegaly Increased platelet destruction Immunologic vs. non-immunologic mechanisms Specific causes in the ICU (<150 x 10 9 /L) Sepsis = 52% Disseminated intravascular coagulopathy (DIC) = 25% Drug (anticoagulant)-induced = 10% Massive blood loss = 8% Immune thrombocytopenia = 3% Thrombotic microangiography (e.g., TTP, HUS) = 1% Heparin-induced thrombocytopenia (HIT) = 1% Levi Met al. Crit Care. 2006; 10:222. TTP = thrombotic thrombocytopenic purpura, HUS = hemolytic uremic syndrome 9 Coagulopathy Reflected by prolonged prothrombin time (PT) or activated partial thromboplastin time (aPTT) of 1.5 times the upper limit of the normal range General causes: Test Result Likely Causes PT prolonged, aPTT normal Factor VII deficiency, mild vitamin K deficiency, mild liver dysfunction, vitamin K antagonists PT normal, aPTT prolonged Factor VIII, IX, XI deficiency, unfractionated heparin, antiphospholipid antibody Both prolonged Factor II, V, X deficiency, severe vitamin K deficiency, global clotting factor deficiency (lack of synthesis = liver failure, loss = massive bleeding, consumption = DIC) Levi Met al. Crit Care. 2006; 10:222. Thrombocytopenia/Coagulopathy Diagnosis in the ICU Platelet count: <100 x109/L or Drop >50 x109/L in 24 hours Normal Prolonged Present: DIC Absent: Sepsis Liver failure HIT antibody present with heparin exposure PT? D-dimer/ fibrin degradation products? Schistocytes present, then thrombotic microangiopathy Antiplatelet antibodies or medications Bone marrow suppression Levi Met al. Crit Care. 2006; 10:222. (Collagen) XII XIIa XI XIa IX Ca++ X IXa PF 3 Ca++ VIII Xa Ca++ PF 3 V X Factor III Ca++ VIIa VII XIII Fibrin (monomer/ polymer) Thrombin Prothrombin (II) Fibrinogen (I) XIIIa Stable Fibrin Polymer Monitoredby Prothrombin Time (PT, INR) Measures VII, X, V, II, I Monitoredby ActivatedPartial Thromboplastin Time (aPTT) Measures XII, XI, X, IX, VIII, V, II, I EXTRI NSI C SYSTEM I NTRI NSI C SYSTEM (Tissue Factor) The Clotting Cascade Adapted fromHirsh J et al. Circulation. 2007; 116:552-60. 10 Factors Contributing to Abnormal Coagulation Hypocalcemia Dilution Hypothermia Limits platelet activation and clotting factor function Mortality OR = 1.2 Dilution and hypothermia Hypothermia Acidosis Reduces clotting factor function (e.g., VII activity reduced 90% at pH of 7.20) due to altered protease activity and limited anion exposure of phospholipids Cohort analysis of recombinant factor VIIa showed pH <7.20 only predictor of bleeding cessation failure (OR = 0.21) Levi Met al. Crit Care. 2006; 10:222. Mercer KWet al. Semin Respir Crit Care Med. 2006; 27:286-96. Schreiber MA et al. Curr Opin Crit Care. 2005; 11:590-7. MacLaren R et al. Transfusion. 2005; 45:1434-42. Pathophysiology of Coagulopathy Inherited platelet/clotting factor dysfunction Liver failure DIC Massive blood loss Platelet dysfunction Drugs Microangiopathy Immune-mediated Anticoagulant-associated Liver Failure Defective coagulation Reduced levels of coagulation factors V, VII, IX, X, XI, prothrombin Defective vitamin K-dependent coagulation factors (II, VII, IX, X) Increased level of plasminogen activator Defective anticoagulation and fibrinolysis Reduced levels of thrombin activatable fibrinolysis inhibitor and endogenous anticoagulants (proteins C, S, Z; heparin cofactor II; Z-dependent protease inhibitor; and antithrombin) Increased levels of tissue plasminogen activator inhibitor and von Willebrand factor (vWf) Thrombocytopenia Hypersplenism, decreased thrombopoietin, vWf- induced clumping, uremia, immune-mediated (hepatitis C) Trotter J F. Clin Liver Dis. 2006; 10:665-78. Caldwell SH et al. Hepatology. 2006; 44:1039-46. Lisman T et al. Dig Surg. 2007;24:250-8. 11 DIC Common causes Sepsis, trauma/surgery/burns, malignancy (solid tumors, myeloproliferative, or lymphoproliferative), immunologic reactions (transplant rejection, transfusion, snake bites), obstetrical calamities, severe liver failure, pancreatitis, vascular abnormalities, cardio- pulmonary bypass Underlying themes = systemic inflammatory response and TF exposure Diagnosis Laboratory Test 0 Points 1 Point 2 Points 3 Points Platelet count (x 10 9 /L) >100 50-100 <50 Fibrin degradation products No increase Moderate increase Large increase Prolonged PT <3 seconds 3-6 seconds >6 seconds Fibrinogen (mg/dL) >100 <100 Cumulative score 5 suggests DIC if underlying condition also present Levi M. Crit Care Med. 2007; 35:2191-5. DIC Cascade Insult Inflammation Anti-inflam. Mediators Pro-inflam. Mediators Fibrinolysis PAI-1 t-PA TAFI inhibits stimulates or activates Endothelial Injury Coagulation TF Thrombin Thrombomodulin TAFI = thrombin activatable fibrinolysis inhibitor TF = tissue factor t-PA = tissue plasminogen activator PAI = plasminogen activator inhibitor Adapted fromLevi M. Crit Care Med. 2007; 35:2191-5. aProtein C Antithrombin DIC Cascade Insult Inflammation Anti-inflam. Mediators Pro-inflam. Mediators Fibrinolysis PAI-1 t-PA TAFI inhibits stimulates or activates Endothelial Injury Coagulation TF Thrombin Thrombomodulin TAFI = thrombin activatable fibrinolysis inhibitor TF = tissue factor t-PA = tissue plasminogen activator PAI = plasminogen activator inhibitor Adapted fromLevi M. Crit Care Med. 2007; 35:2191-5. aProtein C Antithrombin CONSUMPTION of FACTORS 12 The Importance of Exposed Tissue Factor Adapted fromLevi M. Crit Care Med. 2007; 35:2191-5. Massive Blood Loss/Transfusion Defined as hemorrhage requiring 10 units of RBCs in 24 hours Bleed causes loss and consumption of clotting factors, platelets, fibrinogen, etc. Hemodilution from saline resuscitation (room temperature and chloride-induced acidosis) Blood transfusions contain citrate, which binds calcium, and are acidic (pH 6.3-7) Napolitano LMet al. Crit Care Clin. 2004; 20:255-68. Hardy J F et al. Can J Anaesth. 2006; 53(6 Suppl):S40-58. Spahn DR et al. Br J Anaesth. 2005; 95:130-9. Storage of donor blood causes biochemical and corpuscular changes to RBC: Depletion of adenosine triphosphate and 2,3-DPG Activate platelets via thromboxane A 2 and adenosine diphosphate Membrane vesiculation and phospholipid exposure to activate thrombin Loss of cell deformability to induce endothelial damage and margination of platelets Increased time for pro-inflammatory cytokine production pH of stored blood ~ 6.3 Old Blood Napolitano LMet al. Crit Care Clin. 2004; 20:255-68. Hardy J F et al. Can J Anaesth. 2006; 53(6 Suppl):S40-58. Spahn DR et al. Br J Anaesth. 2005; 95:130-9. 13 Platelet Dysfunction Drugs: aspirin, NSAIDs, dipyridamole, clopidogrel, ticlopidine, glycoprotein IIb/IIIa inhibitors Microangiopathy TTP due to deficiency of protease that cleaves vWf to cause ultra-large vWf multimers that readily attach to endothelium and platelets HUS typical of E. coli O157:H7 that releases cytotoxin responsible for endothelial and platelet activation Immune-mediated HIT, drug- and non-drug-induced immune-mediated mechanisms Zimmerman LH. Pharmacotherapy. 2007; 27(9 Pt 2):45S-56S. J affer AK. J Thromb Thrombolysis. 2008; 25:85-90. (Collagen) XII XIIa XI XIa IX Ca++ X IXa PF 3 Ca++ VIII Xa Ca++ PF 3 V X Factor III Ca++ VIIa VII XIII Fibrin (monomer/ polymer) Thrombin Prothrombin (II) Fibrinogen (I) XIIIa Stable Fibrin Polymer EXTRI NSI C SYSTEM I NTRI NSI C SYSTEM (Tissue Factor) Mechanisms of Anticoagulants Adapted fromHirsh J et al. Circulation. 2007; 116:552-60. Heparin Fondaparinux DTI LMWH APC Fibrinolytics Goals of Therapy Stop or control hemorrhage Minimize blood product use Minimize adverse events Hgb of 7-8 g/dL, Hct of 21-24% INR <1.5, PT and aPTT <1.5 x upper limit of normal range, platelets 50 x 10 9 /L, normal activated clotting time pH 7.20, temperature 35 C, normal ionized calcium Dutton RP. Pharmacotherapy. 2007; 27(9 Pt 2):85S-92S. 14 Therapeutic Options Treat the etiology! Blood products Red blood cells (RBCs) Whole blood Platelets (plts) Fresh frozen plasma (FFP) Prothrombin complex concentrate (PCC) Cryoprecipitate Cryosupernatant Pharmacologic agents Local hemostatic agents/sealants Vitamin K Recombinant activated factor VII (rFVIIa) Desmopressin (DDAVP) Conjugated estrogens Anti-fibrinolytic agents (aprotinin, aminocaproic acid, tranexamic acid) Others: recombinant activated factor VIII (rFVIIIa), recombinant activated factor IX (rFIXa), recombinant activated factor XI (rFXIa), vWf concentrate Shander A et al. Pharmacotherapy. 2007; 27(9 Pt 2):57S-68S. Voils S. Pharmacotherapy. 2007; 27(9 Pt 2):69S-84S. Blood Products Product Contents Indications and Dose Concerns* Platelets Thrombocytes in plasma Plts <50 x 10 9 /L (bleeding) Plts <20 x 10 9 /L (prevention) Stored at 20-24C Bacterial contamination ~1/2000 to 1/3000 units Worsens immune reactions FFP Coagulation factors and fibrinogen in variable amounts INR 1.5 15 mL/kg ~30% factor replacement Requires thawing Risk of hypervolemia PCC Factors II, VII, IX, X and prothrombin, proteins C, S, Z in variable amounts INR 1.5 25-50 IU/kg (based on factor IX) Variable amounts of factors May contain heparin Numerous donors Costly Cryo- precipitate Factors VIII, XIII, vWf, fibrinogen, fibronectin Fibrinogen <100 mg/dL 1 unit will fibrinogen ~ 5- 10 mg/dL vWf deficiency Cryo- supernatant Not factor VIII, vWf, and minimal fibrinogen TTP * All products are associated with thrombotic events, transfusion-related acute lung injury, transfusion-related immunomodulation, infection transmission, and febrile reactions. Shander A et al. Pharmacotherapy. 2007; 27(9 Pt 2):57S-68S. Voils S. Pharmacotherapy. 2007; 27(9 Pt 2):69S-84S. Pharmacologic Agents Product Contents or MOA Indications and Dose Concerns Local hemostatics A. Cellulose-based B. Fibrin (human or bovine) fibrinolytic inhibitor aprotonin thrombin C. Thrombin (human or bovine) D. Zeolite that causes exothermic reaction E. Chitason (chitin) that activates platelets and electrophysiologic endothelial attraction of RBCs F. Synthetics (PEGs or collagen-fibrin) A. May not adhere B. Immune reaction, infection transmission, aprotonin C. Immune reaction D. Heat-induced tissue damage E. May not adhere F. Immune reaction, costly Vitamin K Cofactor for activation of factors II, VII, IX, K INR 1.5 0.5-20 mg IV or PO Slow acting Variable SC absorption IV requires slow administration rFVIIa Activates platelets to augment thrombin burst Anticoagulant-induced hemorrhage, ICH, refractory hemorrhage (surgery, trauma) 10-90 mcg/kg IV Short-acting Thrombosis (<10%) Costly Desmopressin Selective V2 agonist to release factor VIII, vWf, and t-PA Platelet dysfunction 0.3 mcg/kg IV Short-acting Tachyphylaxis and bleeding risk with repeat doses Conjugated estrogen antithrombin and protein S while factors VII, VIII, IX, X, prothrombin Platelet dysfunction 25-50 mg IV Slow acting Slow offset Antifibrinolytics (aprotonin, EACA, TA) Inhibit plasminogen proteases and plasmin (aprotonin) and some anti- inflammation Prevention of surgical blood loss Refractory hemorrhage Aprotinin: 2 million units IV, then 0.5 million units/hr EACA: 150 mg/kg IV, then 15 mg/kg/hr TA: 10 mg/kg IV, then 1 mg/kg/hr Aprotinin: hypersensitivity (2.8%) with 9%mortality, renal dysfunction (OR~2), CVA (OR~2), MI (OR~1.55), 5- yr mortality (OR~1.48) Thrombosis, hypotension (TA) Mannucci PMet al. NEngl J Med. 2007; 356:2301-11. MacLaren R. Pharmacotherapy. 2007; 27(9 Pt 2):69S-102S. 15 Managing Anticoagulant-Induced Hemorrhage Anticoagulant Reversing Strategy Warfarin Vitamin K + FFP or PPC rFVIIa (low dose) Heparin Protamine Low molecular weight heparin Protamine (anti-IIa, ~60% anti-Xa) Fondaparinux, direct thrombin inhibitors PCC rFVIIa Fibrinolytics Antifibrinolytics + FFP or PCC rFVIIa Activated protein C FFP or PCC rFVIIa Antiplatelet agents Platelets + desmopressin Zimmerman LH. Pharmacotherapy. 2007; 27(9 Pt 2):45S-56S. J affer AK. J Thromb Thrombolysis. 2008; 25:85-90. Protocols and Targeted Therapy Several institution-specific protocols and guidelines directing therapy show similar patient outcomes while minimizing blood product use Targeted therapy based on point-of-care testing (PT, aPTT, plts fibrinogen thromboelastography) reduces procoagulant and blood product use while improving patient outcomes (shorter surgical time) Rebuck J A. Pharmacotherapy. 2007; 27(9 Pt 2):103S-9S. Despotis Get al. Transfusion. 2008; 48(1 Suppl):2S-30S. Thromboelastography Parameter Interpretation Therapy r (15-23 min) Quantity of clotting factors FFP K (5-10 min) Rate of clot formation Fibrinogen (cryoprecipitate) (22-38) Rate of clot formation Fibrinogen (cryoprecipitate) MA (47-58 mm) Strength of clot and platelet activation Platelets desmopressin rFVIIa A 60 (> 90%) Fibrinolysis Antifibrinolytics MacLaren R. Pharmacotherapy. 2007; 27(9 Pt 2):93S-102S. 16 Case Scenario Jill is a 58-y.o. woman admitted with septic shock and oliguria. Her PMH is significant for PE 2 years ago (no longer requiring anticoagulation, but she takes aspirin 325 mg daily) Baseline labs show platelets 37 x 10 9 /L, Hct 24% (for which 2 units of RBCs are administered for EGT of Hct >30%), INR 1.7, aPTT 48 seconds, BUN 45 mg/dL, ALT 2200 IU/L, and AST 3450 IU/L APACHE II score >25, so activated protein C is started She receives 8 L normal saline and norepinephrine 0.3 mcg/kg/min, is intubated, and renal support is started What additional information would you like to know to minimize J ills risk of hemorrhage? A. pH B. Fibrinogen C. Temperature D. Ionized calcium What additional information would you like to know to minimize J ills risk of hemorrhage? p H F ib rin o g e n T e m p e r a tu r e Io n iz e d c a lc iu m 41% 30% 7% 22% A. pH B. Fibrinogen C. Temperature D. Ionized calcium 17 Case Scenario The next day, Jills Hct and Hgb drop substantially. A retroperitoneal hematoma is suspected. Her blood pressure is tenuous and she is too unstable to go to the OR. Labs show platelets 24 x 10 9 /L, Hct 19% (for which 2 units of RBCs are administered), INR 2.2, aPTT 52 seconds, and fibrinogen 85 mg/dL Activated protein C is stopped Which of the following could be etiologies of J ills hemorrhage? A. Anticoagulant use (activated protein C, aspirin) B. Massive blood loss C. DIC D. Liver and renal dysfunction Which of the following could be etiologies of J ills hemorrhage? A n tic o a g u la n t u s e (a c ... M a s s iv e b lo o d lo s s D IC L iv e r a n d r e n a l d y s fu ... 0% 20% 20% 60% A. Anticoagulant use (activated protein C, aspirin) B. Massive blood loss C. DIC D. Liver and renal dysfunction 18 In addition to RBCs, what therapy would you recommend to treat J ills bleed? A. FFP for activated protein C use, liver dysfunction, and DIC B. Platelets for thrombocytopenia and aspirin use C. Cryoprecipitate for low fibrinogen D. Desmopressin for aspirin use E. rFVIIa for ??? In addition to RBCs, what therapy would you recommend to treat J ills bleed? F F P fo r a c tiv a te d p ro te .. P la te le ts fo r th ro m b o ... C r y o p r e c ip ita te fo r lo w ... D e s m o p r e s s in fo r a s p ... rF V IIa fo r ? ? ? 57% 20% 6% 8% 9% A. FFP for activated protein C use, liver dysfunction, and DIC B. Platelets for thrombocytopenia and aspirin use C. Cryoprecipitate for low fibrinogen D. Desmopressin for aspirin use E. rFVIIa for ??? You, the pharmacist, may help by? A. Correcting factors (e.g., pH, calcium) to maximize coagulation B. Realizing the benefits and limitations of procoagulant agents to optimize therapy C. Targeting therapy based on point-of-care testing D. Understanding the concerns associated with therapy to minimize adverse events 19 You, the pharmacist, may help by? C o r r e c tin g fa c to r s (e .... R e a liz in g th e b e n e fit... T a r g e tin g th e r a p y b a s .. U n d e rs ta n d in g th e c ... 19% 27% 18% 36% A. Correcting factors (e.g., pH, calcium) to maximize coagulation B. Realizing the benefits and limitations of procoagulant agents to optimize therapy C. Targeting therapy based on point-of-care testing D. Understanding the concerns associated with therapy to minimize adverse events 20 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding
S E L E C T E D R E F E R E N C E S - Presentation 1
Caldwell SH, Hoffman M, Lisman T et al. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management. Hepatology. 2006; 44:1039-46.
Corwin HL, Gettinger A, Pearl RG et al. The CRIT Study: anemia and blood transfusion in the critically ill--current clinical practice in the United States. Crit Care Med. 2004; 32:39-52.
Despotis G, Eby C, Lublin DM. A review of transfusion risks and optimal management of perioperative bleeding with cardiac surgery. Transfusion. 2008; 48(1 Suppl):2S-30S.
Dutton RP. Goals of therapy in common bleeding emergencies. Pharmacotherapy. 2007; 27(9 Pt 2):85S-92S.
Hardy JF, de Moerloose P, Samama CM et al. Massive transfusion and coagulopathy: pathophysiology and implications for clinical management. Can J Anaesth. 2006; 53(6 Suppl):S40-58.
Hirsh J, ODonnell M, Eikelboom JW. Beyond unfractionated heparin and warfarin: current and future advances. Circulation. 2007; 116:552-60.
Levi M. Disseminated intravascular coagulation. Crit Care Med. 2007; 35:2191-5.
Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care. 2006; 10:222.
Lisman T, Leebeek FW. Hemostatic alterations in liver disease: a review on pathophysiology, clinical consequences, and treatment. Dig Surg. 2007; 24:250-8.
MacLaren R, Weber LA, Brake H et al. A multicenter assessment of recombinant factor VIIa off-label usage: clinical experiences and associated outcomes. Transfusion. 2005; 45:1434-42.
MacLaren R. Key concepts in the management of difficult hemorrhagic cases. Pharmacotherapy. 2007; 27(9 Pt 2):93S-102S.
Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med. 2007; 356:2301-11.
Mercer KW, Gail Macik B, Williams ME. Hematologic disorders in critically ill patients. Semin Respir Crit Care Med. 2006; 27:286-96.
Napolitano LM, Corwin HL. Efficacy of red blood cell transfusion in the critically ill. Crit Care Clin. 2004; 20:255-68.
21 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding
Rebuck JA. Practical considerations when developing guidelines for managing critical bleeding. Pharmacotherapy. 2007; 27(9 Pt 2):103S-9S.
Schreiber MA. Coagulopathy in the trauma patient. Curr Opin Crit Care. 2005; 11:590-7.
Shander A, Goodnough LT. Update on transfusion medicine. Pharmacotherapy. 2007; 27(9 Pt 2):57S-68S.
Spahn DR, Rossaint R. Coagulopathy and blood component transfusion in trauma. Br J Anaesth. 2005; 95:130-9.
Trotter JF. Coagulation abnormalities in patients who have liver disease. Clin Liver Dis. 2006; 10:665-78.
Voils S. Pharmacologic interventions for the management of critical bleeding. Pharmacotherapy. 2007; 27(9 Pt 2):69S-84S.
Zimmerman LH. Causes and consequences of critical bleeding and mechanisms of blood coagulation. Pharmacotherapy. 2007; 27(9 Pt 2):45S-56S.
22 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding
Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM Associate Professor of Pharmacy and Neurosurgery Virginia Commonwealth University Medical College of Virginia Campus Richmond, Virginia
Gretchen M. Brophy Pharm.D., BCPS, FCCP, FCCM, is Associate Professor of Pharmacy and Neurosurgery at Virginia Commonwealth University (VCU) in Richmond, Virginia. In addition, she is the critical care pharmacist in the Neuroscience Intensive Care Unit (NSICU) at VCU Health System, Medical College of Virginia Campus.
After earning her Doctor of Pharmacy degree at the University of Arizona, Dr. Brophy completed pharmacy practice and critical care residencies at the University of Kentucky. She is a Board Certified Pharmacotherapy Specialist and fellow of the American College of Critical Care Medicine and the American College of Clinical Pharmacy.
Dr. Brophy is currently a co-investigator in traumatic brain injury biomarker studies sponsored by the National Institutes of Health and Department of Defense. Her research interests include neuroprotection, intracranial hemorrhage, acute ischemic stroke, and biokinetics. 23 Anticoagulant-Associated Intracerebral Hemorrhage: Conventional and Emerging Therapeutic Strategies Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM Associate Professor of Pharmacy and Neurosurgery Virginia Commonwealth University Medical College of Virginia Richmond, Virginia Objectives Identify pharmacologic options for hemostasis in the patient with intracerebral hemorrhage (ICH) Review the evidence for use of hemostatic agents in patients with anticoagulant-associated ICH Discuss strategies and guidelines for treatment of life- threatening ICH Determine the best therapeutic strategy for a patient who presents with anticoagulant-associated ICH Clinical Case J C is a 72-y.o. African American man who presents with ICH HPI: he was found downby his wife after she made a 5- minute trip to the mailbox He is currently unconscious, and was intubated for airway protection CT scan: left-sided ICH and subdural hematoma Vitals: BP 184/89 mm Hg; HR 99 bpm; temp 99.8F; height 61; weight 87 kg Neuro: Glasgow coma scale score of 6 PMH: atrial fibrillation, hypertension, hypercholesterolemia Home meds: warfarin 5 mg daily, amlodipine 10 mg daily, atorvastatin 20 mg daily at bedtime Labs: INR 3.1 J C was admitted to the neuroscience ICU 2 hours after symptom onset and needs emergent neurosurgical intervention 24 Anticoagulant-Associated Intracerebral Hemorrhage (ICH) ICH accounts for 10-15% of all strokes, and anticoagulant-associated ICH accounts for ~20% of all ICH 1,2 Hematoma expansion is an independent risk factor for poor outcomes and high mortality 3 Warfarin use is a risk factor for hematoma expansion and almost doubles ICH mortality 2,4 Rapid INR reversal decreases the risk of hematoma growth and may decrease time to emergent surgery 1 FlahertyML et al. Neurology. 2006; 66:1182-6. 3 Davis SM et al. Neurology. 2006; 66:1175-81. 2 Rosand J et al. Arch Intern Med. 2004;164:880-4. 4 Flibotte J J et al. Neurology. 2004; 63:1059-64. What pharmacologic treatment options does J C have for anticoagulant-associated ICH? Vitamin K Promotes liver synthesis of clotting factors: II, VII, IX, X Fresh frozen plasma (FFP) Coagulation factors and fibrinogen in variable amounts Prothrombin complex concentrate (PCC) Factors II, VII, IX, and X and prothrombin, proteins C, S, & Z in variable amounts Recombinant activated factor VII (rFVIIa) rFVIIa only Liu-DeRyke X et al. Pharmacotherapy. 2008;28:485-95. Warfarin Reversal Studies and Case Reports 25 Guidelines for Managing Elevated INR or Bleeding in Patients Receiving Warfarin Condition Intervention Serious bleeding at anyelevation of INR Withhold warfarin therapyand give vitamin K (10 mg by slow IV infusion), supplemented with FFP, PCC, or rFVIIa, depending on the urgencyof the situation; vitamin K can be repeated every12 hr (Grade 1C) Life-threatening bleeding Withhold warfarin therapyand give FFP, PCC, or rFVIIa supplemented with vitamin K (10 mg by slowIV infusion). Repeat, if necessary, depending on INR (Grade 1C) Warfarin-associated ICH Vitamin K IV +clotting factor replacement (Class I, B). PCC, rFVIIa, factor IX complex concentrate to normalize INR very rapidly with smaller volumes than FFP but risk of thromboembolism FFP is a potential choice but requires large volumes and much longer infusion times (Class IIb, B) Ansell J et al Chest. 2008; 133(6 Suppl):160S-98S. Ansell J et al. Chest. 2008; 133(6 Suppl):160S-98S. Broderick J et al. Stroke. 2007; 38:2001-23. Which of the following is the best initial treatment option for J C after stopping warfarin? A. Vitamin K and FFP B. FFP and PCC C. PCC and vitamin K D. Vitamin K, FFP, and rFVIIa Which of the following is the best initial treatment option for J C after stopping warfarin? V ita m i n K a n d F F P F F P a n d P C C P C C a n d v ita m in K V ita m i n K , F F P , a n d r ... 52% 32% 12% 3% A. Vitamin K and FFP B. FFP and PCC C. PCC and vitamin K D. Vitamin K, FFP, and rFVIIa 26 Emergency Management of Coagulopathic ICH Patients Scenari o Agent Dose Comments Warfarin FFP or PCC and Vitamin K 15 mL/kg IV 1530 IU/kg IV 10 mg IV Typically 4-6 units (200 mL) given Faster than FFP 1 mg/min max Warfarin and emergency neurosurgical intervention Above PLUS rFVIIa 20-80 mcg/kg IV Contraindicated in acute thromboembolic disease Mayer SA et al. Lancet Neurol. 2005; 4:662-72. Which agent has the fastest time to INR reversal? A. Vitamin K B. FFP C. PCC D. rFVIIa Which agent has the fastest time to INR reversal? V ita m i n K F F P
P C C
rF V IIa 7% 66% 13% 13% A. Vitamin K B. FFP C. PCC D. rFVIIa 27 Time to Reversal Aguilar MI et al. Mayo Clin Proc. 2007; 82:82-92. Mathews M et al. Neurocrit Care. 2006; 5:141-52 Rapid Rapid Fast Prompt Slow Huttner HB et al. Stroke. 2006; 37:1465-70. PCC Usual dose: 15-50 IU/kg Dosed based on factor IX content Individualize therapy based on INR levels: Dose =actual body weight (kg) X (target % plasma activity current % plasma activity) Yasaka M et al. Thromb Res. 2005; 115:455-9. Aguilar MI et al. Mayo Clin Proc. 2007; 82:82-92. MacLaren R.Pharmacotherapy. 2007; 27(9 Pt 2):93S-102S. Preston FE et al. Br J Haematol. 2002; 116:619-24. Infusion rate: 2 mL/min (Bebulin VH); 3-10 mL/min (Profilnine SD) Reports of infusions as short as 2-10 minutes for Profilnine SD Expensive INR Target <1.3 28 PCC Aguilar MI et al. Mayo Clin Proc. 2007; 82:82-92. Factor VIIa: Mechanism of Action 1. INITIATION: Tissue Factor/FVIIa interaction leads to thrombin generation 2. AMPLIFICATION/ PROPAGATION: rFVIIa activates factor X on the surface of activated platelets, leading to an enhanced thrombin burst at the site of injury 3. FIBRIN CLOT FORMATION: Thrombin converts fibrinogen into fibrin, producing a stable clot Hoffman M et al. Thromb Haemost. 2001;85:958-65. 29 rFVIIa Concentration needed for normal hemostasis: 0.075 to 0.125 mcg/mL (congenital FVII deficiency data) 70-kg patient, 3 L plasma volume: needs 3 to 5 mcg/kg to secure hemostasis (assuming 100% recovery) PK Onset: 10 minutes or less Half-life: 2.3 hours (range 1.7-2.7) Duration (INR <1.5): 2 to 6 hours (dose dependent) No good test for clinical efficacy! Dose Warfarin reversal: 5-50 mcg/kg/dose reported NEW (Aug 2008) roomtemperature stable formulation in 1-mg, 2-mg, and 5- mg vials Interference with clinical efficacy Platelet count: 20,000-50,000 needed Acidosis and hypothermia decrease efficacy COST ~U.S. $1 per mcg (AWP) Kawaguchi C et al. Thromb Haemost. 2002;88:768-72. NovoSeven prescribing information, 2008. Dutton RP et al. J Trauma. 2004; 57:709-18. Erhardtsen E et al. Blood Coagul Fibrinolysis. 1998; 9:741-8. rFVIIa for Acute ICH: Phase IIb study rFVIIa: 40, 80 and 160 mcg/kg in spontaneous ICH Dose given within 4 hours of symptom onset Excluded patients with thrombotic or vaso-occlusive disease Outcomes: Significantly reduced hematoma growth in a dose-dependent fashion Significantly reduced mortality and significantly improved global functional outcome (mRS and Barthel Index) at 90 days Was associated with a small increase in the risk of acute thromboembolic events (7% vs. 2%, arterial 5% vs. 0%, p=0.01) Mayer SA et al. N Engl J Med. 2005; 352:777-85. FAST: Phase III Study Placebo, rFVIIa 20 mcg/kg and rFVIIa 80 mcg/kg in spontaneous ICH Included patients with vascular risk factors Primary endpoint mRS at 3 months Outcomes Reduced hematoma growth (p=0.001) No improvement in survival or functional outcome after ICH More ADRs in higher rFVIIa dose group vs. placebo (arterial - 8% vs. 4%, p=0.04) Study limitations Confounding factors may have limited the treatment effect Target population for rFVIIa administration Age <70 yr Time to dose <3 hours Baseline volume of ICH <60 mL Baseline intraventricular hemorrhage volume <5 mL Mayer SA et al. N Eng J Med. 2008; 358:2127-37. 30 Clinical Case Repeat CT scan 2 hours after admission shows no further growth of ICH INR is now 1.4 J C was rushed to surgery for evacuation of the hematoma and is doing well postoperatively Repeat CT at 24 hours shows no hematoma growth On day 2, you notice J C has a right facial droop and right-sided weakness He is diagnosed with acute ischemic stroke (AIS) What should be recommended at this time? A. Consider t-PA treatment for the AIS B. Consider rFVIIa and PCC as a potential cause of the AIS C. Consider further INR corrections with vitamin K and FFP D. Consider starting heparin anticoagulation What should be recommended at this time? C o n s id e r t-P A t r e a tm e .. C o n s id e r r F V IIa a n d P .. C o n s id e r fu rth e r IN R ... C o n s id e r s ta r ti n g h e p ... 20% 24% 3% 53% A. Consider t-PA treatment for the AIS B. Consider rFVIIa and PCC as a potential cause of the AIS C. Consider further INR corrections with vitamin K and FFP D. Consider starting heparin anticoagulation 31 Treatment Overview Vitamin K Delayed onset: 1-2 hours Correction of INR: 6-24 hours (INR <1.5) FFP Rate of reversal unpredictable and extended Large volumes and long infusion time PCC Short duration of action Risk of thrombosis and disseminated intravascular coagulopathy Limited availability Expensive rFVIIa Short duration of action (dose dependent) Risk of thrombosis Expensive Clinical Case On day 5, J C is awake and oriented with slight weakness on the right side He is transferred out of the ICU The resident asks your recommendations for J Cs long-term anticoagulation therapy What is the best recommendation regarding J Cs home warfarin therapy? A. Do not restart warfarin in J C B. Restart warfarin therapy today C. Consider restarting warfarin in 1 week D. Change to antiplatelet therapy 32 What is the best recommendation regarding J Cs home warfarin therapy? D o n o t r e s ta r t w a r fa ri ... R e s t a r t w a r fa r i n th e r... C o n s id e r r e s ta rt i n g w ... C h a n g e to a n tip la te l e t... 5% 40% 35% 21% A. Do not restart warfarin in J C B. Restart warfarin therapy today C. Consider restarting warfarin in 1 week D. Change to antiplatelet therapy What if J C was receiving warfarin for deep vein thrombosis treatment (week 8) instead of for atrial fibrillation? A. Do not restart warfarin in J C B. Restart warfarin therapy today C. Consider restarting warfarin in 1 week D. Insert an inferior vena cava filter What if J C was receiving warfarin for deep vein thrombosis treatment (week 8) instead of for atrial fibrillation? D o n o t r e s ta r t w a r fa ri ... R e s ta r t w a r fa r i n th e r... C o n s id e r r e s ta rti n g ... In s e rt a n in fe r io r v e n ... 8% 57% 24% 11% A. Do not restart warfarin in J C B. Restart warfarin therapy today C. Consider restarting warfarin in 1 week D. Insert an inferior vena cava filter 33 Restarting Anticoagulation??? Who? Benefit >risk Prosthetic cardiac valves (AIS risk at least 4%) Secondary prevention in atrial fibrillation (AIS risk 12%) Risk >benefit Primary prevention in nonvalvular atrial fibrillation (AIS risk 5%) When? No large, prospective trials in ICH patients Data suggest a low risk of thromboembolic complications 7-14 days after reversal in patients with prosthetic valves Clinical practice: delay for 1-6 weeks after ICH Eckman E et al. Stroke. 2003;34:1710-6. Aguilar MI et al. Mayo Clin Proc. 2007; 82:82-92. Broderick J et al. Stroke. 2007; 38:2001-23. AHA/ ASA Guideline: Recommendations for Management of ICH Related to Coagulation Decision to restart antithrombotic therapy depends on the risk of subsequent arterial or venous thromboembolism, the risk of recurrent ICH, and the overall state of the patient Comparatively lower risk of cerebral infarction (e.g., atrial fibrillation without prior ischemic stroke) and a higher risk of amyloid angiopathy or verypoor overall neurological function Antiplatelet agent maybe an overall better choice for prevention of ischemic stroke than warfarin Veryhigh risk of thromboembolismin whomrestarting warfarin is considered Warfarin therapymaybe restarted at 7 to 10 days after onset of the original ICH (Class IIb, Level of Evidence B). Treatment of patients with ICH related to thrombolytic therapy includes urgent empirical therapies to replace clotting factors (cryoprecipitate that contains factor VIII) and platelets (6-8 units) (Class IIb, Level of Evidence B) Broderick J et al. Stroke. 2007; 38:2001-23. 34 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding
S E L E C T E D R E F E R E N C E S - Presentation 2
Aguilar MI, Hart RG, Kase CS et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc. 2007; 82:82-92.
Ansell J, Hirsh J, Hylek E et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008; 133(6 Suppl):160S-98S.
Broderick J, Connolly S, Feldmann E et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke. 2007; 38:2001-23.
Davis SM, Broderick J, Hennerici M et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006; 66:1175-81.
Dutton RP, McCunn M, Hyder M et al. Factor VIIa for correction of traumatic coagulopathy. J Trauma. 2004; 57:709-18.
Eckman MH, Rosand J, Knudsen KA et al. Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis. Stroke. 2003; 34:1710-6.
Erhardtsen E, Nony P, Dechavanne M et al. The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an international normalized ratio above 2.0. Blood Coagul Fibrinolysis. 1998; 9:741-8.
Flaherty ML, Haverbusch M, Sekar P et al. Long-term mortality after intracerebral hemorrhage. Neurology. 2006; 66:1182-6.
Flibotte JJ, Hagan N, ODonnell J et al. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology. 2004; 63:1059-64.
Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. 2001; 85:958-65.
Huttner HB, Schellinger PD, Hartmann M et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke. 2006; 37:1465-70.
Kawaguchi C, Takahashi Y, Hanesaka Y et al. The in vitro analysis of the coagulation mechanism of activated factor VII using thrombelastogram. Thromb Haemost. 2002; 88:768-72.
Liu-DeRyke X, Rhoney D. Hemostatic therapy for the treatment of intracranial hemorrhage. Pharmacotherapy. 2008; 28:485-95.
35 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding
MacLaren R. Key concepts in the management of difficult hemorrhagic cases. Pharmacotherapy. 2007; 27(9 Pt 2):93S-102S.
Mathews M, Newman R, Chappell ET. Management of coagulopathy in the setting of acute neurosurgical disease and injury. Neurocrit Care. 2006; 5:141-52.
Mayer SA, Brun NC, Begtrup K et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005; 352:777-85.
Mayer SA, Rincon F. Treatment of intracerebral haemorrhage. Lancet Neurol. 2005; 4:662-72.
Mayer SA, Brun NC, Begtrup K et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008; 358: 2127-37.
NovoSeven prescribing information. Novo Nordisk Inc: Princeton, NJ; 2008.
Preston FE, Laidlaw ST, Sampson B et al. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. Br J Haematol. 2002; 116:619-24.
Rosand J, Eckman MH, Knudsen KA et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004; 164:880-4.
Yasaka M, Sakata T, Naritomi H et al. Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res. 2005; 115:455-9.
36 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding
Jeremy D. Flynn, Pharm.D., BCPS Clinical Pharmacist Specialist UK HealthCare-Pharmacy Services Assistant Professor Department of Pharmacy Practice and Science University of Kentucky College of Pharmacy Lexington, Kentucky
J eremy D. Flynn, Pharm.D., BCPS, is Assistant Adjunct Professor of Pharmacy at the University of Kentucky (UK) College of Pharmacy Department of Pharmacy Practice in Lexington, Kentucky. He is also Assistant Adjunct Professor of Surgery at the UK College of Medicine. Dr. Flynn is a clinical pharmacy specialist in cardiothoracic surgery and critical care at the University of Kentucky Chandler Medical Center. He is actively involved with the critical care residency program at UKHealthcare.
Following completion of pharmacy practice and critical care residencies at UK, Dr. Flynn completed an ACCP Critical Care fellowship under the guidance of W. Scott Akers. Dr. Flynn has been active in the field of cardiovascular and critical care pharmacotherapy. His teaching, research, and patient care activities focus on the pharmacotherapeutic management of the cardiothoracic surgery and heart / lung transplant populations. Recent areas of research include an evaluation of antifibrinolytic therapy in cardiac surgery patients and the treatment and prevention of atrial arrhythmias following thoracic surgery. Dr. Flynn serves as a journal referee for Pharmacotherapy, The Annals of Pharmacotherapy, and Critical Care Medicine. 37 Surgery-Associated Bleeding: A Cardiac Surgery Case J eremy Flynn, Pharm.D., BCPS Clinical Pharmacist Specialist, Cardiothoracic Surgery Assistant Professor University of Kentucky College of Pharmacy Department of Pharmacy Practice and Science Lexington, Kentucky Objectives List the most common risk factors for bleeding associated with cardiac surgery Describe the preoperative interventions commonly employed to reduce bleeding, including the available pharmacologic agents for prophylaxis Explain the therapeutic options available for the treatment of bleeding in the cardiac surgical patient Apply the information discussed to a patient case and select appropriate therapy Patient Case AB is a 70-y.o. woman who presents with chest pain (found to be NSTEMI) and is taken for PCI UFH started, 600-mg clopidogrel loading dose given before catheterization (ACC/AHA Class IA recommendation) Catheterization shows 3-vessel CAD w/60% left main coronary artery occlusion Lesions not amenable to angioplasty/stenting Ongoing chest pain not relieved by IABP (Intra-aortic balloon pump) PMH: CAD, HTN, chronic renal insufficiency (SCr 2.0 mg/dL), DM, aortic valve replacement in 1998 Hct 34%; BSA 1.5 m 2 It is determined that the patient will need CABG Anderson JL et al. J Am Coll Cardiol. 2007; 50:e1-157. 38 Which of the following is NOT a risk factor associated with increased bleeding with cardiac surgery? A. Advanced age B. Urgent/emergent operation C. Obesity D. Use of antiplatelet/ antithrombotic agents E. Redo sternotomy Which of the following is NOT a risk factor associated with increased bleeding with cardiac surgery? A d v a n c e d a g e U r g e n t/e m e rg e n t o p e ... O b e s ity U s e o f a n tip la te le t/ a n ... R e d o s te r n o to m y 3% 23% 16% 2% 55% A. Advanced age B. Urgent/emergent operation C. Obesity D. Use of antiplatelet/ antithrombotic agents E. Redo sternotomy Predictors of Postoperative Bleeding 1) Advanced age 2) Small body size or preoperative anemia (low RBC volume) 3) Prolonged operation (cardiopulmonary bypass time) high correlation with type of surgery 4) Emergency operation 5) Other comorbidities (e.g., CHF, COPD, HTN, peripheral vascular disease, renal failure) 6) Use of antiplatelet & antithrombotic drugs Redo sternotomy can also increase risk Ferraris VA et al. Ann Thorac Surg. 2007; 83(5 Suppl):S27-86. Ferraris VA et al. Ann Surg. 2002; 235:820-7. 10-20% of patients consume 80% of blood products 39 Critical Stages of Cardiac Surgery Preoperative Risk factor assessment Medications Prophylaxis strategy Intraoperative Type and length of procedure Cardiopulmonary bypass (CPB) Anticoagulation strategy Postoperative Monitoring Coagulopathy What do we need to know to continually assess bleeding risk, severity of bleed, and/or treatment options? What is the best option for prophylaxis to minimize the bleeding risk for this patient? A. Aprotinin loading dose and infusion B. Wait 5 days prior to proceeding with CABG C. Give platelet transfusion prior to surgery D. -aminocaproic acid (EACA) E. Desmopressin (DDAVP) What is the best option for prophylaxis to minimize the bleeding risk for this patient? A p r o tin in lo a d in g d o s ... W a it 5 d a y s p r io r to ... G iv e p la te le t tr a n s fu s ... D e s m o p r e s s in (D D A V P ) 12% 16% 19% 18% 34% A. Aprotinin loading dose and infusion B. Wait 5 days prior to proceeding with CABG C. Give platelet transfusion prior to surgery D. -aminocaproic acid (EACA) E. Desmopressin (DDAVP) 40 Preoperative/Prophylactic Treatment Anticoagulation discontinuation/reversal Heparin, LMWH, warfarin, fondaparinux Blood products Platelet transfusions for clopidogrel exposure? Antifibrinolytics Lysine analogues -aminocaproic acid (EACA) Tranexamic acid (TXA) Aprotinin No longer available in U.S. due to safety concerns Antifibrinolytic DataMeta-Analysis Total of 19 trials randomizing 2430 subjects 10 aprotinin vs. TXA -- 3 TXA vs. EACA 6 aprotinin vs. EACA Aprotinin vs. TXA (1707 patients) Aprotinin vs. EACA (399 patients) Blood Loss Aprotinin superior 106 mL (37-176) Aprotinin superior 184 mL (134-235) Transfusion (rate and total) ND ND Re-operation ND Insufficient data Mortality, MI, and stroke No trends observed favoring any of the agents No differences found between TXA and EACA Carless PA et al. BMC Cardiovasc Disord. 2005; 5:19. Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) Study Compared the three antifibrinolytic products Similar demographics, risk profiles, and operative data Modest reduction in massive bleeding with aprotinin Mortality? Fergusson DA et al. N Engl J Med. 2008; 358:2319-31. Number needed to harm: 50 patients Doubling of death from cardiac causes 41 BART Study - Efficacy Aprotinin (%) TXA (%) EACA (%) Aprotinin vs. TXA (RR 95% CI) Aprotinin vs. EACA (RR 95% CI) Bleeding from chest tubes 5.3 7.5 8.3 0.70 (0.47-1.03) 0.63 (0.43-0.92) Massive transfusion 2.1 2.2 2.8 0.93 (0.47-1.83) 0.73 (0.38-1.37) Death due to hemorrhage 1.4 1.0 0.5 1.36 (0.55-3.36) 2.75 (0.88-8.60) Re-operation 5.5 8.1 8.2 0.68 (0.47-1.00) 0.67 (0.46-0.98) Any massive bleeding 9.5 12.1 12.1 0.79 (0.59-1.05) 0.79 (0.59-1.05) Fergusson DA et al. N Engl J Med. 2008; 358:2319-31. No differences identified in major adverse effects: Stroke, MI, DVT, PE, or renal failure AB proceeded to urgent CABG and was given appropriate doses of -aminocaproic acid for prophylaxis. Patient Case The patient experienced significant generalized oozing after separation from CPB and reversal of heparin, leading to significant blood loss and pooling of blood in the thoracic cavity Unable to close until bleeding is corrected Time on CPB X-clamp time 220 minutes 160 minutes Anticoagulation Monitoring Reversal Heparin 300 units/kg bolus ACT (POC) Goal >550 sec Protamine 3 mg/kg Total dose 550 units/kg Packed RBC (PRBC) transfusions Total of 4 units through the case to maintain Hct 26-28% What is the first intervention you would make to correct the bleeding? A. Send coagulation labs and hemogram B. Transfuse blood products (e.g., packed RBCs, platelets, fresh frozen plasma, fibrinogen) C. Check activated clotting time (ACT)/point-of-care (POC) testing D. Give desmopressin E. Give recombinant factor VIIa (rFVIIa) 42 What is the first intervention you would make to correct the bleeding? S e n d c o a g u la tio n la b ... T r a n s fu s e b lo o d p r o ... C h e c k a c tiv a te d c lo tti.. G iv e d e s m o p r e s s in G iv e re c o m b in a n t fa c t.. 11% 30% 31% 11% 17% A. Send coagulation labs and hemogram B. Transfuse blood products (e.g., packed RBCs, platelets, fresh frozen plasma, fibrinogen) C. Check activated clotting time (ACT)/point-of-care (POC) testing D. Give desmopressin E. Give recombinant factor VIIa (rFVIIa) Bleeding and Cardiac Surgery Surgically correctable (<3% cases) Associated with brisk hemorrhage (>200 mL/hr) Normal coagulation studies Clotting in mediastinal drainage tubes Coagulopathy related (generalized oozing) Common occurrence after exposure to extracorporeal circulation (severity related to duration of CPB) Related to abnormal: Clotting parameters Platelet quantity and quality Fibrinogen levels Residual drug effect Sabiston DC J r, Spencer F, eds. Surgery of the chest. 6 th ed. Philadelphia, PA: W.B. Saunders; 1995. Evidence from Randomized Trials for Massive Hemorrhage in the Cardiac Surgery Patient Some of the issues are addressed in the clinical practice guideline from the Society of Thoracic Surgeons and Society of Cardiovascular Anesthesiologists: Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery Ferraris VA et al. Ann Thorac Surg. 2007; 83(5 Suppl):S27-86. 43 Key Points to Consider Planning is essential Identify high-risk patients Have treatment options immediately available Protocols Massive transfusion protocol or service-specific bleeding protocol Monitoring strategy Anticoagulation strategy Complete reversal of heparin Residual heparin or rebound effect Goals of Therapy Stop or control hemorrhage Minimize blood product use Minimize adverse events Correct coagulation tests and blood counts pH 7.20, temperature 35C, normal ionized calcium Avoid re-exploration for bleeding Ferraris VA et al. Ann Thorac Surg. 2007; 83(5 Suppl):S27-86. Dutton RP. Pharmacotherapy. 2007; 27(9 Pt 2):85S-92S. Monitoring Point-of-care vs. central laboratory? Point-of-care preferred ACT monitoring Platelet function Thromboelastography (TEG) Timing of treatment Do NOT wait for test results from lab Use visual cues in the OR 44 Transfusion Therapy Primary means of treating/controlling acute intraoperative bleeding Product Contents Indications and Dose Concerns PRBC Maintain target Hgb/Hct Platelets Thrombocytes in plasma Plts <50 x 10 9 /L (bleeding) Plts <20 x 10 9 /L (prevention) Stored at 20-24C Bacterial contamination ~1/2000 to 1/3000 units Worsens immune reactions FFP Coagulation factors and fibrinogen in variable amounts INR 1.5 15 mL/kg ~ 30% factor replacement Requires thawing Risk of hypervolemia Cryo- precipitate Factors VIII, XIII, vWf, fibrinogen, fibronectin Fibrinogen <100 mg/dL 1 unit will fibrinogen ~5-10 mg/dL vWf deficiency Mannucci PMet al. NEngl J Med. 2007; 356:2301-11. MacLaren R. Pharmacotherapy. 2007; 27(9 Pt 2):93S-102S. Voils S. Pharmacotherapy. 2007; 27(9 Pt 2):69S-84S. Pharmacologic Agents Product Contents or MOA Indications and Dose Concerns Local hemostatics A. Cellulose-based B. Fibrin (human or bovine) fibrinolytic inhibitor aprotonin thrombin C. Thrombin (human or bovine) D. Zeolite that causes exothermic reaction E. Chitason (chitin) that activates platelets and electrophysiologic endothelial attraction of RBCs F. Synthetics (PEGs or collagen-fibrin) A. May not adhere B. Immune reaction, infection transmission, aprotonin C. Immune reaction D. Heat-induced tissue damage E. May not adhere F. Immune reaction, costly Vitamin K Cofactor for activation of factors II, VII, IX, K INR 1.5 0.5-20 mg Slow acting Variable SC absorption IV requires slow administration rFVIIa Activates platelets to augment thrombin burst Anticoagulant-induced hemorrhage, ICH, refractory hemorrhage (surgery, trauma) 10-90 mcg/kg IV Short-acting Thrombosis (<10%) Costly Desmopressin Selective V2 agonist to release factor VIII, vWf, and t- PA Platelet dysfunction 0.3 mcg/kg IV Short-acting Tachyphylaxis and bleeding risk with repeat doses Conjugated estrogen antithrombin and protein S while factors VII, VIII, IX, X, prothrombin Platelet dysfunction 25-50 mg iv Slow acting Slow offset Antifibrinolytics (aprotonin, EACA, TXA) Inhibit plasminogen proteases and plasmin (aprotonin) and some anti- inflammation Prevention of surgical blood loss Refractory hemorrhage Aprotinin: 2 million units IV, then 0.5 million units/hr EACA: 150 mg/kg IV, then 15 mg/kg/hr TXA: 10 mg/kg IV, then 1 mg/kg/hr Aprotinin: hypersensitivity (2.8%) with 9%mortality, renal dysfunction (OR~2), CVA (OR~2), MI (OR~1.55), 5- yr mortality (OR~1.48) Thrombosis, hypotension (TXA) Mannucci PMet al. NEngl J Med. 2007; 356:2301-11. MacLaren R. Pharmacotherapy. 2007; 27(9 Pt 2):69S-102S. Pharmacologic Agents Product Contents or MOA Indications and Dose Concerns Local hemostatics A. Cellulose-based B. Fibrin (human or bovine) fibrinolytic inhibitor aprotonin thrombin C. Thrombin (human or bovine) D. Zeolite that causes exothermic reaction E. Chitason (chitin) that activates platelets and electrophysiologic endothelial attraction of RBCs F. Synthetics (PEGs or collagen-fibrin) A. May not adhere B. Immune reaction, infection transmission, aprotonin C. Immune reaction D. Heat-induced tissue damage E. May not adhere F. Immune reaction, costly Vitamin K Cofactor for activation of factors II, VII, IX, K INR 1.5 0.5-20 mg Slow acting Variable SC absorption IV requires slow administration rFVIIa Activates platelets to augment thrombin burst Anticoagulant-induced hemorrhage, ICH, refractory hemorrhage (surgery, trauma) 10-90 mcg/kg IV Short-acting Thrombosis (<10%) Costly Desmopressin Selective V2 agonist to release factor VIII, vWf, and t- PA Platelet dysfunction 0.3 mcg/kg IV Short-acting Tachyphylaxis and bleeding risk with repeat doses Conjugated estrogen antithrombin and protein S while factors VII, VIII, IX, X, prothrombin Platelet dysfunction 25-50 mg iv Slow acting Slow offset Antifibrinolytics (aprotonin, EACA, TXA) Inhibit plasminogen proteases and plasmin (aprotonin) and some anti- inflammation Maybe Some data with EACAfor treatment of hemorrhage. Continue infusion for 6 hours post-op. Mannucci PMet al. NEngl J Med. 2007; 356:2301-11. MacLarenR. Pharmacotherapy. 2007; 27(9Pt 2):69S-102S. 45 Desmopressin Use of desmopressin acetate (DDAVP) is not unreasonable to attenuate excessive bleeding and transfusion in certain patients with demonstrable and specific platelet dysfunction known to respond to this agent (Class IIb, Level of evidence B) Uremic or CPB-induced platelet dysfunction Type I von Willebrand disease Not shown to be effective as prophylaxis Typical dose 0.3 mcg/kg IV Laupacis A et al. Anesth Analg. 1997; 85:1258-67. Ferraris VA et al. Ann Thorac Surg. 2007; 83(5 Suppl):S27-86. Recombinant Factor VIIa Use of recombinant factor VIIa concentrate is not unreasonable for the management of intractable nonsurgical bleeding that is unresponsive to routine hemostatic therapy after cardiac procedures using CPB (Class IIb, level of evidence B) Issues to consider pH, temperature, platelet count Place in therapy? Early, prerequisite blood products, salvage Patient-specific risk CVA, PVD, PE, mechanical valve, VAD, etc. Dose? Round to nearest vial size, dose cap, multiple doses? Ferraris VA et al. Ann Thorac Surg. 2007; 83(5 Suppl):S27-86. VAD = ventricular assist device The team has decided to give AB rFVIIa after an inadequate response to blood products (8 PRBCs, 6 FFP, 4 Plts, and 1 Cryo) What is the most appropriate dose? A. 1 mg B. 30 mcg/kg C. 90 mcg/kg D. 120 mcg/kg 46 The team has decided to give AB rFVIIa after an inadequate response to blood products (8 PRBCs, 6 FFP, 4 Plts, and 1 Cryo) What is the most appropriate dose? 1 m g 3 0 m c g /k g 9 0 m c g /k g 1 2 0 m c g /k g 43% 3% 24% 30% A. 1 mg B. 30 mcg/kg C. 90 mcg/kg D. 120 mcg/kg rFVIIa Dosing No published randomized, controlled trials to guide dosing Should consider Severity of bleeding (urgency) Patient risk factors Ease of evaluating response Doses reported in the literature for cardiac surgery 11 to 180 mcg/kg Trend toward smaller doses Warren O et al. Ann Thorac Surg. 2007; 83:707-15. Karkouti K et al. Can J Anaesth. 2007; 54:573-82. The Safety and Efficacy of Recombinant Factor VII for the Treatment of Bleeding following Cardiac Surgery: A Multinational, Randomized, Placebo-controlled Trial 172 patients randomized to 1 of 3 groups (single bolus in ICU) Placebo (n=68) rFVIIa 40 mcg/kg (n=35) rFVIIa 80 mcg/kg (n=69) Primary Outcome Critical serious adverse events at 30 days Death Acute MI Cerebral infarction Clinical symptomatic PE or other thromboembolic events Secondary endpoints Rates of re-operation, blood loss volumes, and transfusion ClinicalTrials.gov Identifier: NCT00154427; Ravi G et al. Presented at AHA Scientific Sessions. New Orleans, LA; 2008 Nov 9. 47 Authors cautiously concluded that rFVIIa is probably safe and may be beneficial to treat bleeding after cardiac surgery. Outcome Placebo rFVIIa 40 mcg/kg rFVIIa 80 mcg/kg Critical Serious Adverse Events 7% 14% (p=0.25) 12% (p=0.43) Re-operation 25% 14% (p=0.21) 12% (p=0.04) Allogeneic Blood Transfusion volumes 825 ml 640 ml (p=0.047) 500 ml (p=0.042) Median Drainage Rate (4 hours after drug) 51 ml/hr 35 ml/hr (p=0.763) 24 ml/hr (p=0.018) Age, CPB time, and type of surgery (emergent/urgent) predicted cSAEs (critical, serious adverse events) The Safety and Efficacy of Recombinant Factor VII for the Treatment of Bleeding following Cardiac Surgery: A Multinational, Randomized, Placebo-controlled Trial Ravi G et al. Presented at AHA Scientific Sessions. New Orleans, LA; 2008 Nov 9. Authors cautiously concluded that rFVIIa is probably safe and may be beneficial to treat bleeding after cardiac surgery. Outcome Placebo rFVIIa 40 mcg/kg rFVIIa 80 mcg/kg Critical Serious Adverse Events 7% 14% (p=0.25) 12% (p=0.43) Re-operation 25% 14% (p=0.21) 12% (p=0.04) Allogeneic Blood Transfusion volumes 825 ml 640 ml (p=0.047) 500 ml (p=0.042) Median Drainage Rate (4 hours after drug) 51 ml/hr 35 ml/hr (p=0.763) 24 ml/hr (p=0.018) Age, CPB time, and type of surgery (emergent/urgent) predicted cSAEs (critical, serious adverse events) The Safety and Efficacy of Recombinant Factor VII for the Treatment of Bleeding following Cardiac Surgery: A Multinational, Randomized, Placebo-controlled Trial Ravi G et al. Presented at AHA Scientific Sessions. New Orleans, LA; 2008 Nov 9. ICU Management of Hemorrhage following Cardiac Surgery Patient evaluation Hemodynamically stable or not Surgical bleed or generalized oozing Rebound of anticoagulation (heparin) Monitoring? Chest tube drainage Lab values (CBC, PT/INR, aPTT, fibrinogen, etc) Treatment strategies? Return to OR (if unstable or unresponsive to treatment) Directed by lab values for stable patients Correct coagulopathy (blood products and drugs) 48 What If Scenarios What if AB had a recent history of HIT and was anticoagulated for CPB with bivalirudin? What if the hospital routinely used TEG monitoring for cardiac surgery and the tracing suggested? Abnormal TEG Segment Blood Product Indicated Increased r-time (start of clot formation) FFP Decreased MA (overall clot strength) Platelets Decreased angle (speed of clot formation) Cryoprecipitate Luddington RJ. Clin Lab Haematol. 2005; 27:81-90. 49 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding
S E L E C T E D R E F E R E N C E S - Presentation 3
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Clinicaltrials.gov. Identifier NCT00154427. Use of activated recombinant human factor VII in cardiac surgery. http://clinicaltrials.gov/ct2/show/NCT00154427 (accessed 2008 Nov 6).
Dutton RP. Goals of therapy in common bleeding emergencies. Pharmacotherapy. 2007; 27(9 Pt 2):85S-92S.
Fergusson DA, Hbert PC, Mazer CD et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008; 358:2319-31.
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Ferraris VA, Ferraris SP, Saha SP et al. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007; 83(5 Suppl):S27-86.
Karkouti K, Beattie WS, Crowther MA et al. The role of recombinant factor VIIa in on- pump cardiac surgery: proceedings of the Canadian Consensus Conference. Can J Anaesth. 2007; 54:573-82.
Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. The International Study of Peri-operative Transfusion (ISPOT) Investigators. Anesth Analg. 1997; 85:1258-67.
MacLaren R. Key concepts in the management of difficult hemorrhagic cases. Pharmacotherapy. 2007; 27(9 Pt 2):93S-102S.
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50 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding
Voils S. Pharmacologic interventions for the management of critical bleeding. Pharmacotherapy. 2007; 27(9 Pt 2):69S-84S.
Warren O, Mandal K, Hadjianastassiou V et al. Recombinant activated factor VII in cardiac surgery: a systematic review. Ann Thorac Surg. 2007; 83:707-14.
51 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding Table 1. Blood Products Product Contents Indications and Dose Concerns* Platelets Thrombocytes in plasma Plts <50 x 10 9 /L (bleeding) Plts <20 x 10 9 /L (prevention) Stored at 20-24C Bacterial contamination ~1/2000 to 1/3000 units Worsens immune reactions FFP Coagulation factors and fibrinogen in variable amounts INR 1.5 15 mL/kg ~30% factor replacement Requires thawing Risk of hypervolemia PCC Factors II, VII, IX, X and prothrombin, proteins C, S, Z in variable amounts INR 1.5 25-50 IU/kg (based on factor IX) Variable amounts of factors May contain heparin Numerous donors Costly Cryo- precipitate Factors VIII, XIII, vWf, fibrinogen, fibronectin Fibrinogen <100 mg/dL 1 unit will fibrinogen ~ 5- 10 mg/dL vWf deficiency Cryo- supernatant Not factor VIII, vWf, and minimal fibrinogen TTP * All products are associated with thrombotic events, transfusion-related acute lung injury, transfusion-related immunomodulation, infection transmission, and febrile reactions. Shander A et al. Pharmacotherapy. 2007; 27(9 Pt 2):57S-68S. Voils S. Pharmacotherapy. 2007; 27(9 Pt 2):69S-84S. 52 Acute Care Update: Causes, Consequences, and Strategies for Managing Critical Bleeding Table 2. Pharmacologic Agents Product Contents or MOA Indications and Dose Concerns Local hemostatics A. Cellulose-based B. Fibrin (human or bovine) fibrinolytic inhibitor aprotonin thrombin C. Thrombin (human or bovine) D. Zeolite that causes exothermic reaction E. Chitason (chitin) that activates platelets and electrophysiologic endothelial attraction of RBCs F. Synthetics (PEGs or collagen-fibrin) A. May not adhere B. Immune reaction, infection transmission, aprotonin C. Immune reaction D. Heat-induced tissue damage E. May not adhere F. Immune reaction, costly Vitamin K Cofactor for activation of factors II, VII, IX, K INR 1.5 0.5-20 mg IV or PO Slow acting Variable SC absorption IV requires slow administration rFVIIa Activates platelets to augment thrombin burst Anticoagulant-induced hemorrhage, ICH, refractory hemorrhage (surgery, trauma) 10-90 mcg/kg IV Short-acting Thrombosis (<10%) Costly Desmopressin Selective V2 agonist to release factor VIII, vWf, and t-PA Platelet dysfunction 0.3 mcg/kg IV Short-acting Tachyphylaxis and bleeding risk with repeat doses Conjugated estrogen antithrombin and protein S while factors VII, VIII, IX, X, prothrombin Platelet dysfunction 25-50 mg IV Slow acting Slow offset Antifibrinolytics (aprotonin, EACA, TA) Inhibit plasminogen proteases and plasmin (aprotonin) and some anti- inflammation Prevention of surgical blood loss Refractory hemorrhage Aprotinin: 2 million units IV, then 0.5 million units/hr EACA: 150 mg/kg IV, then 15 mg/kg/hr TA: 10 mg/kg IV, then 1 mg/kg/hr Aprotinin: hypersensitivity (2.8%) with 9% mortality, renal dysfunction (OR~2), CVA (OR~2), MI (OR~1.55), 5- yr mortality (OR~1.48) Thrombosis, hypotension (TA) Mannucci PMet al. N Engl J Med. 2007; 356:2301-11. MacLaren R. Pharmacotherapy. 2007; 27(9 Pt 2):69S-102S. 53