Pharmacokinetic/pharmacodynamic model for unfractionated heparin dosing during cardiopulmonary bypass

Abstract

BackgroundHigh-dose heparin is used during cardiopulmonary bypass (CPB) to prevent thrombosis in the circuits used for extracorporeal circulation. The aim of this study was, initially, to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to assess the variability of PK/PD parameters and their correlation with the results of the routine haemostatic test activated clotting time (ACT) and thereafter to develop a Bayesian estimator enabling an individualized dosing strategy. MethodsFifty consecutive patients undergoing cardiac surgery with CPB were included in the study. Heparin was administered as an initial bolus of 300 IU kg−1 followed by additional boluses of 5000 IU to maintain ACT <400 s. In total, 361 blood samples were collected. The PK and PD data were analysed using a non-linear mixed effect model. ResultsA two-compartment model with a linear elimination link to an Emax model best described heparin anti-factor Xa activities and ACT. Covariate analysis showed that body weight was positively correlated with clearance and central compartment volume. Inclusion of body weight with these parameters decreased their variability by 11 and 15%, respectively. The Bayesian estimator performed well in predicting individual parameters in an independent group of patients. ConclusionsA population PK/PD analysis of heparin during CPB, using a routine haemostatic test, shows that Bayesian estimation might help to predict ACT on the basis of only one or two blood samples.