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Hemostasis for the Anesthesiologist: Treatment Practices Richard P. Dutton, MD, MBA Associate Professor of Anesthesiology University of Maryland School of Medicine Director of Trauma Anesthesiology R Adams Cowley Shock Trauma Center Baltimore, Maryland “Keeping on Center”: Moving Toward Normal Hemostasis Topical Hemostatics Purified Factors, FFP, Cryo, PLTs Procoagulant Activity Bleeding Clotting Aminocaproic acid, Tranexamic acid, Aprotinin Antifibrinolytic Activity Normal Hemostasis Fibrinolytic Activity t-PA, SK, UPA FFP=fresh frozen plasma; Cryo=cryoprecipitate; PLTs=platelets; SK=streptokinase; UPA=urinary-type plasminogen activator; LMWH=low-molecular-weight heparin. Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64. Anticoagulant Activity Heparin, Warfarin LMWH, Argatroban 2 Challenges to Normal Hemostasis • Patient medications • Anatomic disruption by surgeons • Inflammatory by-products of surgery (eg, embolized bone marrow) • Hypothermia • Acidosis • Loss and dilution of clotting factors Levy JH. Transfusion. 2006;46:919-933. Dutton RP, et al. J Trauma. 2004;57:709-719. 3 The Cycle of Coagulopathy Tissue injury Hemorrhage Inflammation Loss, consumption, dilution Coagulopathy Acidosis Dysfunction Dysfunction Anticoagulants Genetics Hypothermia 4 The Basic Clinical Concept . . . Keeping Up (maintaining normal hemostasis) vs Catching Up (rescuing the coagulopathic patient) 5 Avoiding Coagulopathy: Basics • Stop all anticoagulant medications before surgery1,2: Heparins: 12 hours Aspirin: 5-7 days Clopidogrel: 5-7 days Warfarin: 5-6 days Herbal medications: 2 weeks3 • Plan the anesthetic to reduce estimated blood loss (EBL) Regional anesthesia if possible Deliberate hypotension 1. Pass SE, et al. Am J Health Syst Pharm. 2004;61:899-912; 2. Jaffer AK, et al. Cleve Clin J Med. 2006;73(suppl 1):S100-S105; 3. Ang-Lee MK, et al. JAMA. 2001;286:208-216. 6 Avoiding Coagulopathy: Basics (cont) • Conserve native blood Careful surgical technique Limit blood draws Cell salvage • Keep patient warm and well perfused • Have blood products ready • Have a plan to manage the actively bleeding patient 7 If Active Bleeding Occurs . . . • Expedite control of hemorrhage • Limit crystalloid infusion • Maintain anesthesia and paralysis • Keep BP low (80-100 systolic) • Resuscitate with blood: 1:1:1 RBC/plasma • Follow labs closely—especially calcium and pH Dutton RP. Pharmacotherapy. 2007;27(9 pt 2):85S–92S. 8 Resuscitation Vigorous fluid resuscitation Hemodilution increased bleeding Recurrent hypotension Dutton RP. Pharmacotherapy. 2007;27(9 pt 2):85S–92S. 9 Dilution Is Inevitable When Giving Blood Components Whole blood 500 mL (Hct 38%–50%; PLTs 150K–400K; Plasma coagulation activity 100%) 150 mL anticoagulant added; centrifuged 1 U PRBC (335 mL, Hct 55%) 1 U Plasma (275 mL, coagulation activity 80%) 1 U PLTs (50 mL, 5.5 x 1010 PLTs Patient Receives 650 mL fluid: Hct 29%, PLTs 88K, 65% coagulation activity Adapted from Dutton RP. Pharmacotherapy. 2007;27(9 pt 2):85S–92S. 10 Effect of FFP:RBC Ratio on Overall Mortality in 252 Massively Transfused Trauma Patients (long-term outcomes) 70 Chi Square RB: P=.006 RG: P<.001 BG: P=.034 65% 60 Mortality % 50 40 34% 30 20% 20 10 n=31 n=56 n=165 1:3.9 - 1:2.1 1:2 - 1:0.59 0 0:22 - 1:4 FFP:RBC Ratio Borgman MA, et al. J Trauma. 2007;63:805-813. 11 Guiding Principle Any fluid that does not clot or carry oxygen should be suspect. 12 “Citrate Intoxication” • Occurs in any patient receiving a rapid transfusion (>2 U/hr) • Caused by citrate in the transfused blood chelating circulating calcium • serum ionized calcium leads to coagulopathy, cardiac performance • Treated with calcium administration Dutton RP. Anesthesiology Clin. 2007;25:23-24. 13 The Basic Clinical Concept . . . Keeping Up (maintaining normal hemostasis) vs Catching Up (rescuing the coagulopathic patient) 14 “Jump-starting” Coagulation • Active bleeding in the coagulopathic patient • Concentrated clotting factors: Cryoprecipitate (fibrinogen) Platelets Recombinant factor VIIa (rVIIa) • Bicarbonate/THAM? THAM=tris-hydroxymethyl aminomethane. Dutton RP. Pharmacotherapy. 2007;27(9 pt 2):85S–92S. 15 The Ideal Hemostatic Agent • Will clot inappropriate hemorrhage • Will not clot working vessels • Will not have side effects • Will be easy to store and use • Will be free 16 Recombinant Factor VIIa • Recombinant human product1 • Facilitates cell-based coagulation, triggering thrombin burst on platelet surface2 • In large doses, requires only factor I (fibrinogen), II (thrombin), and platelets to produce clotting1,2 • Licensed only for use in hemophiliacs with inhibitors to factor VIII or IX1 1. Mannucci PM, et al. N Engl J Med. 2007;356:2301-2311. 2. Dutton RP, et al. J Trauma. 2004;57:709-719. 17 Recombinant Factor VIIa: Packaging 18 Recombinant Factor VIIa: Mechanism of Action 19 Recombinant Factor VIIa: Procedure for Use, STC • “Off-label” use requested by attending physician • Gatekeeper approval required Life-threatening hemorrhage Coagulopathy Failure of conventional therapy Non-futile • Periodic data analysis approved by the IRB STC=R Adams Cowley Shock Trauma Center. Dutton RP, et al. J Trauma. 2004;57:709-719. Thomas GO, et al. J Trauma. 2007;62:564-569. 20 400 Patients to Date • Acute hemorrhagic shock • Traumatic brain injury • Warfarin, clopidogrel • Sepsis, ICU coagulopathy • Cirrhosis • FVII deficiency 21 Dosing of Recombinant Factor VIIa • 100 mcg/kg1 Shock Rapid bleeding • 1.2 mg (smallest possible dose)2 No shock Slow or no bleeding 1. Dutton RP, et al. J Trauma. 2004;57:709-719. 2. Dutton RP. Pharmacotherapy. 2007;27(9 pt 2):85S–92S. 22 Hemostasis • 10% no response (futile) Massive hemorrhage Profound shock • 90% response rate Dutton RP. Pharmacotherapy. 2007;27(9 pt 2):85S–92S. 23 Survival • Overall survival about 65% • Causes of death: Overwhelming shock Severe brain injury Multisystem failure Dutton RP. Pharmacotherapy. 2007;27(9 pt 2):85S–92S. 24 Change in Prothrombin Time Prothrombin Time (sec) 28 24 20 16 12 8 Pre PT Dutton RP, et al. J Trauma. 2004;57:709-719. Post PT 25 Thromboelastogram Before and After Recombinant Factor VIIa Reprinted with permission from Dutton RP, et al. J Trauma. 2004;57:709-719. ©2004 Lippincott Williams & Wilkins http://lww.com 26 Safety of Recombinant Factor VIIa • 9% thromboembolic complications Mostly arterial Occur in the region of surgery/trauma • 3% highly associated with rVIIa • 1% highly associated with rVIIa and lethal Thomas GO, et al. J Trauma. 2007;62:564-569. 27 Thromboembolic Complications • rVIIa is a potent procoagulant • Thrombotic complications will be highly patient-dependent Unstable atherosclerotic disease Blunt vascular injury (carotid, mesenteric arteries) Extracorporeal circulation Other procoagulants? • Probably not dose-dependent Thomas GO, et al. J Trauma. 2007;62:564-569. 28 29 Summary • The anesthesiologist can contribute substantially to hemostasis • Planning should begin pre-op; the best approach is to prevent coagulopathy from ever occurring • If the patient does become coagulopathic, catching up is difficult, but not impossible • rVIIa may be a useful option 30