Coagulation during and after cardiopulmonary bypass with focus on heparin, protamine, aprotinin and platelet function

Abstract

Background: Heparin and protamine dosing for anticoagulation during cardiopulmonary bypass (CPB) and its reversal after CPB, respectively, is usually given according to body weight. Excess protamine may impair coagulation. The HeProCalc algorithm calculates heparin and protamine doses during the procedure. Platelets play a crucial role in coagulation and haemostasis after cardiac surgery and platelet malfunction may explain excessive bleeding after CPB. Patients on clopidogrel and aspirin undergoing coronary surgery with CPB risk excessive bleeding. Between 2008-2012, the European Medicines Agency (EMA) suspended the marketing authorization of aprotinin, but Swedish hospitals received permission to continue its use.

Aims: To investigate whether the HeProCalc algorithm affects heparin and protamine dosing, postoperative blood loss, and transfusion rate (Study I+II), whether ROTEM®platelet provides additional information to ROTEM® analysis in guiding platelet transfusions after cardiac surgery and identifying factors triggering platelet administration (Study III), and to compare aprotinin use in coronary surgery during 2006‒2007 vs. 2008‒2014, before and after the EMA suspension (Study IV).

Methods: In Study I and II 40 and 210 patients, respectively, undergoing cardiac surgery with CPB were randomized to heparin and protamine dosage based on body weight only or the HeProCalc algorithm. In Study III ROTEM® and ROTEM®platelet were analysed before anaesthesia (T0, n=23), after CPB (T1, n=23) and after platelet transfusion (T2, n=10). In Study IV consecutive patients on clopidogrel and aspirin undergoing coronary surgery with CPB and received aprotinin 2006-2014 were included.

Results: Study I: Equal doses of heparin were given in both groups, but there were lower mean doses of protamine in the HeProCalc vs. the control group (211±56 vs. 330±61mg, p<0.001). Postoperative bleeding was less in the HeProCalc group (280±229 vs. 649±279mL, p=0.074). Study II: Total protamine dose was 210mg (interquartile range [IQR] 190-240) in the HeProCalc group vs. 350mg (IQR 300-380, p<0.001) in the control group. The ratio of total protamine to initial dose of heparin in the HeProCalc group was 0.62 vs. 1.0 (p<0.001). Bleeding after 12 hours was 320mL (IQR 250-460) in the HeProCalc group vs. 350mL (IQR 250-450, p=0.754) in the control group. Transfusion rate did not differ sign. between groups. Study III: ROTEM® and ROTEM®platelet tests were all significantly reduced between T0 and T1. ROTEM® parameters improved sign. after platelet transfusion. Only ROTEM®platelet TRAPTEM increased between T1 and T2 (p=0.008). Factors triggering platelet transfusion were long duration of surgery and time on CPB. Study IV: After 2007, aprotinin was restricted to patients on clopidogrel with platelet aggregation <85% on day of surgery. Use of aprotinin decreased from 113 patients/year 2006‒2007 to 6 patients/year 2008‒2014. Mean EuroSCORE I and mean CPB time were sign. higher in the second period, indicating greater operative and bleeding risk. No sign. differences were observed regarding mortality, complications, bleeding and transfusion rates between the two periods.

Conclusions: Study I: HeProCalc-based dosage of heparin and protamine allowed for reduced protamine use after CPB compared with conventional calculations. Furthermore, HeProCalcbased regimen for heparin reversal suggested less postoperative bleeding, although the difference between the groups was not statistically significant. Study II: Use of the HeProCalc algorithm reduced protamine dosage and the protamine/heparin ratio after cardiopulmonary bypass compared with conventional dosage based on weight without significant effect on postoperative blood loss or the transfusion rate. Study III: ROTEM®platelet TRAPTEM improvement indicated that platelet transfusion may reverse CPB induced platelet dysfunction. Study IV: Aprotinin use decreased sign. after 2007. Despite a higher operative risk and longer CPB duration, patients given aprotinin between 2008 and 2014 did not differ sign. in outcomes and transfusion rates compared with those treated with aprotinin during the prior 2 years.