Challenges in Perioperative. Coagulopathy in Elective and Urgent Cardiac Surgery

Transcription

1 Challenges in Perioperative Hemostasis: Managing Coagulopathy in Elective and Urgent Cardiac Surgery Ian J. Welsby, MD, MBBS, FRCA Assistant Professor Department of Anesthesiology and Critical Care Duke University Medical Center

2 Physiology of Hemostasis Response to traumatic or surgical injury Complex interaction between vascular wall, platelets, coagulation factors, and fibrinolysis Clotting is a complicated process Platelet-mediated primary hemostasis, explosive thrombin generation Conversion of fibrinogen to fibrin Stable fibrin and platelet network or clot produced Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64; Porte J, et al. Drugs. 2002;62: ; Sauaia A, et al. J Trauma. 1995;38:

3 Overview of Hemostasis Coagulation Cascade Fibrinolytic Cascade Plasminogen APC TAFIa Thrombin PC TAFI Thrombin Thrombomodulin Plasmin Fibrinogeni Fibrini FDPs FXIIIa Clot stabilizing factor Antifibrinolytic agents FDPs=fibrin degradation products. Adapted from Nesheim M. Chest. 2003;124:33S-39S. 3

4 Maintaining Hemostasis Hemostatic control depends on balance between procoagulant and anticoagulant factors 1 Coagulation Fibrinolysis Disorders in balance may result in severe bleeding or thrombotic complications 1 Hemostatic agents must maintain balance without causing adverse thrombotic effects of drug toxicity Challenge is to maintain patient physiology between balance of bleeding and clotting 2 1. Porte RJ, et al. Drugs. 2002;62: Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):

5 Preoperative Management of Elective Cardiac Patients Patient evaluation Medical history Bleeding from minor procedures Easy bruising Problems with previous surgeries Family members having had difficult surgeries Patient medications Platelet inhibitors, including ASA, clopidogrel, ticlopidine, disopyramide, vitamin E supplements Anticoagulants, including vitamin K antagonists For thienopyridines, such as clopidogrel, ACC/AHA and STS/SCA guidelines recommend 5- to 7-day drug holiday prior to surgery, if possible 1,2 For reversal of anticoagulants in emergent setting, can use vitamin K, FFP, PCC, or rfviia 3 1. Ferraris VA, et al. Ann Thorac Surg. 2005;79: ; 2. Braunwald E, et al. J Am Coll Cardiol. 2002;40: ; 3. Levy JH, et al. Semin Thromb Hemost. 2008;34:

6 Evaluation of Hemostasis Platelet count Antiplatelet drug effects Platelet function may only be detected by aggregometry; history PFA-100 may be more valuable TEG ROTEM Clopidogrel: reduced ADP aggregation PT/INR Aspirin: reduced AA aptt aggregation Fibrinogen level Eptifibatide (IIb/IIIa): reduced ADP, AA and collagen Cobas M. International Anesthesiology Clin. 2001;39:1-15; Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86; Disorders of hemostasis. In: Harrison s Internal Medicine. New York, NY: McGraw-Hill; 2007; Kalina U, et al. Blood Coagul Fibrinolysis. 2008;19:

7 Lab Values and Bleeding Association of Bleeding After CABG With Lab Values TEG MA PLT PT Fibrinogen R P value aue Association of Lab Values With TEG MA Parameter Platelet count Fibrinogen PT APTT R P value (<.001) (<.001) (.01) (<.001) The MA is a measure of clot strength. Welsby IJ, et al. J Cardiothorac Vasc Anesth. 2006;20:

8 Three Components of Hemostasis Fibrinogen FII prothrombin Fibrin IIa (α-thrombin) Prothrombinase complex FV FXa Platelet l plug at site of injury Primary Hemostasis vwf/collagen on subendothelium 8

9 Treatment of Coagulopathy: Blood Products Prophylactic transfusion not warranted; follow algorithms Define/identify coagulopathic bleeding first Platelet transfusion If <50 x10 9 /l Consider if x10 9 /l Consider if history of antiplatelet drugs Consider if known platelet dysfunction Plasma transfusion INR >2.0 PTT ratio >1.5 Cryoprecipitate transfusion If fibrinogen mg/dl Rarely indicated if >150 mg/dl Activated platelet ASA Current Practice Guidelines for Perioperative Transfusion. Anesthesiology. 2006;105:

10 Treatment of Refractory Coagulopathy: Off-Label Use of Factor Concentrates Recombinant activated factor VII (rfviia) FDA-approved for congenital FVII deficiency, hemophilia ACCP guidelines: for urgent coumadin reversal 1 bleeding, thrombotic events 2 Prothrombin complex concentrates (II, VII, IX, X, PC, PS) ACCP guidelines: for urgent coumadin reversal1 Some association with thrombosis Primarily apcc (FEIBA) 3,4 Purified/plasma-derived factor VIII/vWF complex Rarely described outside obstetric hemorrhage Purified/plasma-derived fibrinogen FDA-approved for congenital afibrinogenemia Low thrombogenicity in venous stasis animal models 5 1. Ansell J, et al. Chest. 2008;133(6 suppl)160s-198s; 2. Gill R, et al. Circulation. 2009;120:21-27; 3. Aledort LM. J Thromb Haemost. 2004;2: ; 4. Lusher JM. Semin Hematol. 1994;31:49-56; 5. Dickneite G, et al. Blood Coagul Fibrinolysis. 2009;20:

11 Restoration of Hemostasis Restoration of primary hemostasis DDAVP to increase vwf multimers Platelet transfusion Thrombocytopenia Platelet dysfunction Restoration of thrombin generation Coagulation factor replacement Restoration of stable fibrin clot formation Antifibrinolytic drugs Fibrinogen replacement FXIII replacement 11

12 Restoration of Primary Hemostasis Platelet transfusion DDAVP infusion Augments primary hemostasis Each apheresis unit or 6 pack concentrate dose contains 3x10 11 platelets in 250 ml plasma Assuming 4x10 11 platelets and a BAS of 2m2: 25 (+/-17) x10 9 /L typical response Reduced increment seen with: Men/higher body surface area DIC Sepsis Bleeding Mean Pla atelet Increment (x 10 3 /µl) hour hours Mean days to next transfusion ABO incompatible Platelet Transfusion Number BSA=body surface area; DIC=disseminated intravascular coagulation ays to Next Tra ansfusion Mean D Slichter SJ, et al. Blood. 2005;105:

13 Restoration of Hemostasis Restoration of primary hemostasis DDAVP to increase vwf multimers Platelet transfusion Thrombocytopenia Platelet dysfunction Restoration of thrombin generation Confirm full heparin reversal (protamine) Coagulation factor replacement Restoration of stable fibrin clot formation Antifibrinolytic drugs Fibrinogen replacement FXIII replacement 13

14 Restoration of Thrombin Generation (cont) Dosing of plasma (70-kg patient): 1 unit (250 ml) increases factor levels by 2.5% 4 units (1000 ml) increases levels l by 10% Less for FV, FVIII, vwf PT or PTT ratio >1.5 or INR >1.6 factor levels <30% What factor level is sufficient for hemostasis during surgery? In hemophilia, rfviia activity depends on FII 1 and FX 2 levels (II) (% normal) 1. Allen GA. Br J Haematol. 2006;134: Allen GA. Blood Coag Fibrinolysis. 2000;11(S1):S3-S7. 14

15 Restoration of Thrombin Generation FFP provides procoagulant factors Pro- and anticoagulant factors at normal levels l Thawed plasma FV 65% FVIII/vWF 40% normal (lower for Group O) PCCs replenish II (prothrombin), VII, IX and X, PC, PS Varying factor levels depending on product rfviia drives production of IXa and Xa Activation and propagation of coagulation Thrombin Tissue VIIa factor Tissue factor IX/X IXa VIIIa Xa Xa X Xa Va Prothrombin 15

16 Restoration of Hemostasis Restoration of primary hemostasis DDAVP to increase vwf multimers Platelet transfusion Thrombocytopenia Platelet dysfunction Restoration of thrombin generation Coagulation factor replacement Restoration of stable fibrin clot formation Antifibrinolytic drugs FXIII replacement (in plasma) Fibrinogen replacement 16

17 Treatment of Coagulopathy: Fibrinogen Optimal level of plasma fibrinogen necessary to maintain perioperative hemostasis not fully understood 1 Boosting fibrinogen level (mean 3.6 g/l) can reduce transfusion of allogeneic blood products 1 Most transfusion algorithms do not treat levels unless they are < mg/dl 2 Higher than normal levels may be effective 1 Postoper rative Bleeding, ml Fibrinogen Level, ml Posted with permission from Ucar HI, et al. Heart Surg Forum. 2007;10:E392-E Rahe-Meyer N, et al. Br J Anaesth. 2009;102: ; 2. Nielsen VG, et al. Anesth Analg. 2007;105:

18 Treatment of Coagulopathy: Fibrinogen (cont) Plasma Normal levels of fibrinogen Increasing concentration difficult with plasma ml/kg increases fibrinogen by 40 mg/dl 30 ml/kg increases fibrinogen by 100 mg/dl Risk of volume overload Cryoprecipitate content (adult dose = 10 units or 100 ml) Fibrinogen (1.5-3 g) FXIII ( U) FVIII/vWF ( U) Albumin, fibronectin, IgG, IgM (less than FFP) One dose (10 units) of cryoprecipitate increases fibrinogen 60 mg/dl 18

19 Advantage of Factor Concentrates 4 units FFP Adult dose 10 pack CRYO 3g in 1000 ml mg/dl FIB CV = 5000 ml Total 7.5 g FIB 3.5 g in 100 ml Total 10.5 g FIB CV = 6000 ml 175 mg/dl FIB Total 11 g FIB CV = 5100 ml 215 mg/dl FIB 175 mg/dl FIB 215 mg/dl FIB 19

20 Drawbacks of Transfusable Factors TRALI risk (plasma > cryoprecipitate) Infection risk (10 donors for cryoprecipitate, 4 for plasma) Allergic reactions (plasma > cryoprecipitate) Volume overload/taco (plasma) Purified/plasma-derived or recombinant factors Possible alternative or adjunct to blood products Not currently FDA-approved for acquired deficiencies Use for refractory bleeding currently off-label Preliminary studies have been performed Studies to support FDA approval pending 20

21 Summary Presentation highlights: Explain the essential aspects of hemostasis, from primary hemostasis through thrombin generation, and cleavage of fibrinogen to formation of a stable fibrin i clot Evaluate the clinical utility of coagulation lab assays as markers for excessive perioperative bleeding and targeting hemostatic therapy Discuss current and emerging therapeutic options for restoring perioperative hemostasis in cardiac surgery patients 21

22 Challenges in Perioperative Hemostasis: Managing Coagulopathy in Elective and Urgent Cardiac Surgery Peter K. Smith, MD Professor and Chief Division of Cardiovascular and Thoracic Surgery Duke University Medical Center Durham, North Carolina

23 Perioperative Bleeding in Cardiac Surgery Cardiac surgery induces abnormalities of primary and secondary hemostasis resulting from Blood contact with nonendothelial surfaces of the extracorporeal circuit Release of TF (tissue factor) after surgical trauma Reinfusion of TF and activated coagulation factors Shear forces generated by cardiotomy suction Activation of the inflammatory system, generation of circulating thrombin Activation of platelets Ucar HI, et al. Heart Surg Forum. 2007;10:E392-E

24 Perioperative Impairment of Hemostasis Bleeding following cardiac surgery is often multifactorial Inhibition of hemostasis or platelets Hypothermia Mechanical or inflammatory injury Heparin or protamine Preoperative drug therapies Extrinsic pathway activation Tissue or vascular injury Reperfusion of ischemic tissues Local thrombin generation Dilutional coagulopathy Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27 S86; Disorders of hemostasis. In: Harrison s Internal Medicine. New York, NY: Mc-Graw Hill; Available at: accessmedicine.com/resourcetoc.aspx?resourceid=4. 24

25 Predictors of Postoperative Bleeding in Cardiac Surgery Advanced age Small body size or preoperative anemia (low RBC volume) Antiplatelet, antithrombotic drugs Prolonged operation CPB time high h correlation with surgery type Low preoperative fibrinogen level Emergency surgery Other comorbidities CHF COPD Hypertension PVD Renal failure RBC=red blood cell; CPB=cardiopulmonary bypass; CHF=congestive heart failure; COPD=chronic obstructive pulmonary disease; PVD=peripheral vascular disease. Ferraris VA, et al. Ann Thorac Surg. 2005;79: ; Ferraris VA, et al. Ann Surg. 2002;235: ; Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86; Karlsson M, et al. Transfusion. 2008;48: ; Ucar HI, et al. Heart Surg Forum. 2007;10:E392-E

26 Frequently Encountered Complications of Cardiac Surgery Hemostatic imbalance often occurs after prolonged cardiopulmonary bypass Platelet dysfunction 1 Depletion of coagulation factors 1,2 Hemodilution Cell saver Fibrinolysis Hypothermia 1 Residual anticoagulants 1 1. Tanaka KA, et al. Anesth Analg. 2008;106: Beckmann SR, et al. J Extra Corpor Technol. 2007;39:

27 Frequently Encountered Complications of Cardiac Surgery (cont) Major bleeding and hemorrhage a major challenge after surgery Prevalence 5%-7% 1 Surgical reexploration for bleeding occurs after 2%-6% of CABG procedures 2 More likely in urgent or emergency setting 3 Significant multivariate predictor of increased morbidity and mortality 3 Associated with prolonged LOS 4 Increased cost after surgery 4 1. Despotis GJ, et al. Anesth Analg. 1996;82:13-21; 2. Dacey LJ, et al. Arch Surg. 1998;133: ; 3. Moulton MJ, et al. J Thorac Cardiovasc Surg. 1996;111: ; 4. Ucar HI, et al. Heart Surg Forum. 2007;10:E392-E

28 Patient Case: Harold C. History: 72-year-old white man undergoing g urgent aortic valve replacement for aortic stenosis and LIMA to LAD with cardiopulmonary bypass; prior myocardial infarction (MI); heart failure; history of hypertension No prior history of excessive bleeding Family history of coronary artery disease (father had fatal MI at age 58) Current medications: Lisinopril 40 mg/d Clopidogrel 75 mg/d Aspirin 81 mg/d 28

29 Harold C.: Preoperative Status Vital signs BP 110/75 mm Hg HR 72 BPM Echocardiogram findings: Pulmonary artery pressure 45/26 mm Hg Pulmonary artery occlusion pressure (wedge) 15 mm Hg Decompensation of left ventricle Ejection fraction 30% Preoperative labs: HCT 42%; Hb 14 g/dl; PLT 210K; PT 13 sec; aptt 37.5 sec; fibrinogen 90 mg/dl 29

30 Harold C.: Intraoperative Status After intubation 1 g tranexamic acid given over 30 min Heparin administered at loading dose of 300 IU/kg of body weight Additional heparin doses given during CPB Careful sternotomy and dissection Left internal mammery artery (IMA) taken down Aortic cannulation AVR with porcine tissue valve LIMA to LAD bypass graft 30

31 Harold C.: Intraoperative Status (cont) Aortic clamp time: 72 min CPB time: 108 min Following weaning from CPB, persistent and diffuse bleeding observed Surgeon determines that this is coagulopathic bleeding after careful survey of operative field Intraoperative labs: HCT 25%; Hb 7 g/dl; PLT 103K; PT 30 sec; aptt 50 sec; fibrinogen 70 mg/dl Transfusion of allogeneic blood products FFP Platelet concentrate Cryoprecipitate Treatment of acquired von Willebrand disease Cryoprecipitate DDAVP 31

32 Strategies for Reversing Perioperative Bleeding Multifaceted approach Correction of hypothermia and acidosis Resuscitation with crystalloids or colloids Infusion of RBCs, FFP, platelets, and cryoprecipitate Antifibrinolytic therapy Fenger-Eriksen C, et al. Br J Anaesth. 2008;101:

33 Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery Transfuse patients on CPB with Hb 6 g/dl Transfusion justified when Hb 7 g/dl in patients older than 65 years and patients with chronic CVD or respiratory disease Benefit unclear for stable patients with Hb between 7 and 10 g/dl Transfusion recommended for patients with acute blood loss >1500 ml or >30% of blood volume Evidence of rapid blood loss without immediate control warrants transfusion STS/SCA=Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists. 33 Adapted from Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.

34 Benefits and Risks of Blood Transfusion Benefits: Blood volume replacement Transport of O 2 and CO 2 Coagulation factors Risks: TACO TRALI Disease transmission (especially platelets) TRIM Transfusion errors Evidence: Not enough data about benefits TACO=transfusion-associated circulatory overload; TRALI=transfusion-related acute lung injury; TRIM=transfusion-related immunomodulation. Adapted from Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86. 34

35 Harold C.: Assessing Intraoperative Developments 35

36 Harold C.: Additional Complications Active bleeding continues Second round of intraoperative labs reveals the following: HCT 30%; Hb 10 g/dl; PLT 110K; PT 20 sec; aptt 45 sec Fibrinogen level drops to 65 mg/dl Fibrin split products indicate intravascular consumption 36

37 Harold C.: Surgical Decisions Harold C. has received two rounds of blood products, including cryoprecipitate, FFP, and platelets. He has required ed 10 units of RBCs and continues to have major hemorrhage without an identifiable surgical source. The patient is becoming difficult to ventilate, and is becoming hypoxic despite an Fi02 of 1.0. The surgeon determines that it is not safe to close, and that the degree of bleeding is life threatening and not amenable to conventional therapy. What would be your next step at this juncture? 37

38 Harold C.: Surgical Decisions Administration of additional blood products, including cryoprecipitate and platelets? Close and autotransfuse shed mediastinal blood? Administration of rviia? 1,2 Prothrombin complex concentrates t (II, VII, IX, X, PC, PS)? 1,3,4,5 Fibrinogen replacement therapy? Ansell J, et al Chest. 2008;133(6 suppl):160s-198s; 2. Gill R, et al. Circulation. 2009;120:21-27; 3. Pabinger I, et al. Thromb Haemost. 2008;6: ; Aledort LM. J Thromb Haemost. 2004;2: ; Lusher JM. Seminars in Hematology. 1994;31:49-52; 6. Karlsson M, et al. Transfusion. 2008;48: ; 7. Ucar HI, et al. Heart Surg Forum. 2007;10:E392-E396; 8. Levy JH, et al. Semin Thromb Hemost. 2008;34:

39 Postoperative Status of Harold C. Resolution of intraoperative bleeding complications Lab values postop day 3 HCT 31% Hb 10 g/dl PLT 220K PT 16 sec aptt 36 sec Fibrinogen 200 mg/dl Transesophageal echocardiography on postop day 3 is unremarkable Aspirin started at 81 mg/d 39

40 Harold C. Conclusions This patient s case has demonstrated the following: Cardiopulmonary bypass is often a cause of hemostatic imbalance It is essential to normalize clotting factor levels and platelet function, and to inhibit fibrinolysis to achieve hemostasis Controlling perioperative bleeding necessitates the employment of a multifactorial approach Massive uncontrollable coagulopathic bleeding occurs with currently approved therapies and may not respond to normal measures 40

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