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Pharmacological Methods to Reduce Blood Loss in Surgery

Pharmacological Methods to Reduce Blood Loss in Surgery. George Despotis, MD Associate Professor of Anesthesiology, Pathology and Immunology Department of Anesthesiology and Blood Bank Washington University School of Medicine St. Louis, Missouri.

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Pharmacological Methods to Reduce Blood Loss in Surgery

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  1. Pharmacological Methods to Reduce Blood Loss in Surgery George Despotis, MDAssociate Professor of Anesthesiology, Pathology and Immunology Department of Anesthesiology and Blood Bank Washington University School of Medicine St. Louis, Missouri

  2. Reexploration for Bleeding: Risk Factors and Outcomes Unsworth et al (n=2221) Moulton et al (n=6015) Dacey et al (n=8586) Reexploration for bleeding 4.2% 3.6% 3.8% CPB time  time  time Procedure Non-coronary OP  # grafts Valve/Repeat Other factors  Age,  Cr  Age,  BSA  x4 Mortality  x4  x3  Renal Failure  x18   Mech vent support / ALI  x5   Sepsis / arrhythmias / IABP  x2   x6 Hospitalization interval   x2 Dacey LJ et al, Arch Surg 1998; 133: 442-7 Moulton MJ et al, J Thorac Cardiovasc Surg 1996; 111: 1037-46 Unsworth-White et al, Ann Thorac Surg 1995; 59: 664-7 Risk Factors Adverse Outcomes

  3. Pathophysiology of CPB-Related Hemostatic Abnormalities HEMODILUTION ACTIVATION CONSUMPTION Contact activation • XIIa, KallikreinTissue Factor activation •Tissue Injury• Monocyte-related• Pericardial bloodActivation of fibrinolysis • Increased tPA via: -endothelial cells -pericardial cavity• Intrinsic activation • Heparin or Protamine Thrombin-mediated Plasmin-mediatedInflammation-mediated:• Elastase• Complement• Leukocyte-platelet complexes Mechanical (ECC): oxygenator, cardiotomy suction, roller/centrifugal pump, filter CPB prime (crystalloid/colloid) Cardioplegia volumeExtensive use of cell salvage systems (loss of platelets/ coagulation factors) Despotis GJ et al, Anesthesiology 1999; 91: 1122-51

  4. Non-Bleeders (n=31) Bleeders (n=42) * CPB Time 121 min 200 min * CTD 24 hrs 1051±509 mL 1594±1440 mL * Postop TDE 1.9±4.2 U 8.2±11.1 U 0 FIX 122 * p < 0.05 FVIII 137 FIX 98 -20 % Decrease FVII 58 FXII 53 FVII 48 FIB 196 -40 FVIII 90 FX 53 FXII 40 * PLT 118 FX 36 * FV 42 * FIB 170 -60 PLT 83 * FV 26 * pre-CPB post-CPB * -80 Despotis GJ et al, J Thorac Cardiovasc Surg 1994;107:271-79

  5. OPERATIVE PREDICTORS OF MICROVASCULAR BLEEDING Single Combined 37/248 (0.15) 25/61 (0.41) [0.14] [0.44] [0.44] 1.0 PrimaryOperation 0.5 Incidence of MVB 0 12/42 (0.29) 9/10 (0.9) [0.33] [0.71] 1.0 Reoperation 0.5 0 Despotis GJ et al, J Thorac Cardiovasc Surg 1994;107:271-79 Single vs Combined Procedures Operative History

  6. PHARMACOLOGIC PRESERVATION OF THE HEMOSTATIC SYSTEM • Platelet inhibition: - Dipyridamole - Prostacyclin (PGI2), PGE1 - IIb/IIIa receptor inhibition: Abxcimab, integrelin • Broad-spectrum inhibition: Aprotinin • Plasmin inhibition: Tranexamic Acid, EACA • Thrombin and Factor Xa inhibition: - Heparin: LMWH (Xa) vs UFH (Xa/IIa) - Heparin Adjuncts: AT III, HCF II (Dermatan Sulfate) - Warfarin - Direct Thrombin Inhibitors

  7. Reduction in Blood Loss and Transfusion by Aprotinin Alderman 1998 n=870 Lemmer 1996 n=317 (704) Levy 1995n=126 (278) Lemmer 1994 n=216 Primary Primary Repeat Both 15 2000 5% 3% 3% 4% 12 1600 9 1200 Mean Total Donor Exposures (U) Blood Loss: CTD (mL) 0 1% 0 1.6% 6 800 3 400 0 0 P A P A P A P A

  8. Efficacy of Aprotinin Based on Dose and Operative Risk Lemmer 1996n=704 primary Levy 1995n=278 repeat 12 1600 9 1200 Blood Loss: CTD (mL) Mean Total Donor Exposures (U) 6 800 3 400 ASA No ASA 0 0 P PO LD HD P PO LD HD

  9. Reduction in Blood Loss & Transfusion: Aprotinin vs EACA EACA: 9 studies (n = 932) Aprotinin: 4 studies (n = 1529) 15 15 2000 4.0% 12 12 1600 p=0.006 9 9 1200 Mean Total Donor Exposures (U) Blood Loss: CTD (mL) 27% in PRBC Tx 1.6%% 6 6 800 3 3 400 0 0 0 P P A E

  10. Mechanisms of Action: Aprotinin vs Antifibrinolytic Agents Aprotinin EACA / TA Yes Yes Preservation of Fibrinogen, Factors V, VIII Yes Yes Preservation of Platelet GP 1b receptors Yes Yes Reduced Platelet Inhibition via FDPs Yes* No Inhibition of Contact Activation Probable* No Inhibition of Tissue Factor Activation Yes* No Inhibition of Platelet Activation / Consumption Yes* No Antiinflammatory Properties Yes** No Inhibition of Protein C Activity Antifibrinolytic Actions: Effect on Hemostatic System Activation: *200 KIU/mL ** > 250-300 KIU/mL

  11. CHALLENGES TO HEMOSTATIC SYSTEM BALANCE DURING CPB GOAL: EFFECTIVE HEMOSTASIS HEMORRHAGE THROMBOSIS ADEQUATE AND REVERSIBLE ANTICOAGULATION Pre-existing HYPERCOAGULABILITY:ATIII/Protein C/S, FV Leiden, LA/ACLAbs,  homocysteine, HIT, h/o thromboembolism, h/o CHF, hypoperfusion INHIBITION OF FIBRINOLYSIS (e.g. EACA) or PROTEIN C (e.g. >300 KIU/mL Aprotinin) INCREASED PROCOAGULANTS DDAVP (e.g. vWF), Tx (e.g. platelets, FEIBA)  INADEQUATE SUPPRESSION OF HEMOSTATIC ACTIVATION DURING CPB  DECREASED PROCOAGULANTS CPB hemodilution, consumption INHIBITION OF HEMOSTASIS - Antibodies to platelets, coag proteins - Xa/IIa inhibitors (e.g. LMWH, r-hirudin) - Platelet inhibitors (e.g Plavix, ? Reopro) - Heparin rebound, FFP Tx (i.e., ATIII)

  12. Summary for Bleeding Complications Perioperative Bleeding Complications: Can lead to adverse outcomes related to complications associated with reexploration, transfusion and CNS injury Patients at high-risk include those: with congenital defects, on long-acting anti-thrombotic agents, with trauma, or patients who require complex cardiac procedures (CPB) Prevention  When compared to EACA/TA, aprotinin (full-dose regimen): - is probably more effective in reducing bleeding, transfusion and reexploration in high-risk patients - and has an extensive safety record Optimal Anticoagulation results in preservation of the hemostatic system especially with prolonged CPB which leads to reduced blood loss / transfusion and possibly thrombotic complications

  13. Summary for Bleeding Complications Optimal Management of excessive bleeding: Although laboratory-based tests may be helpful, the history and physical exam should preoperatively identify patients at risk who require further laboratory evaluation  Use of POC diagnostic tests along with a standardized transfusion approach (e.g. algorithm) can optimize perioperative transfusion/pharmacologic (e.g. DDAVP) management  Although factor concentrates used as a rescue therapy can be life-saving, thrombotic risk and cost preclude routine use

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