Pharmacokinetic model of unfractionated heparin during and after cardiopulmonary bypass in cardiac surgery

Abstract

Background: Unfractionated heparin (UFH) is widely used as a reversible anti-coagulant in cardiopulmonary bypass (CPB). However, the pharmacokinetic characteristics of UFH in CPB surgeries remain unknown because of the lack of means to directly determine plasma UFH concentrations. The aim of this study was to establish a pharmacokinetic model to predict plasma UFH concentrations at the end of CPB for optimal neutralization with protamine sulfate.

Methods: Forty-one patients undergoing CPB during cardiac surgery were enrolled in this observational clinical study of UFH pharmacokinetics. Patients received intravenous injections of UFH, and plasma anti-FIIa activity was measured with commercial anti-FIIa assay kits. A population pharmacokinetic model was established by using nonlinear mixed-effects modeling (NONMEM) software and validated by visual predictive check and Bootstrap analyses. Estimated parameters in the final model were used to simulate additional protamine administration after cardiac surgery in order to eliminate heparin rebound. Plans for postoperative protamine intravenous injections and infusions were quantitatively compared and evaluated during the simulation.

Results: A two-compartment pharmacokinetic model with first-order elimination provided the best fit. Subsequent simulation of postoperative protamine administration suggested that a lower-dose protamine infusion over 24 h may provide better elimination and prevent heparin rebound than bolus injection and other infusion regimens that have higher infusion rates and shorter duration.

Conclusion: A two-compartment model accurately reflects the pharmacokinetics of UFH in Chinese patients during CPB and can be used to explain postoperative heparin rebound after protamine neutralization. Simulations suggest a 24-h protamine infusion is more effective for heparin rebound prevention than a 6-h protamine infusion.

Figure 1

Two-compartment model with intravenous injection and first-order elimination. X _UFH-C and X _UFH-P represent the amount of UFH in central and peripheral compartments respectively; V _UFH-C and V _UFH-P are the apparent volumes of distribution for the central and peripheral compartments respectively.

Figure 2

Anti-F _IIa activity vs . Time. A, Anti-F_IIa activity vs. time for blood samples obtained during CPB. B, anti-F_IIa activity vs. time for blood samples obtained no less than24 h after the end of CPB (n = 32). In both plots, the time at the start of CPB was set to 0.

Figure 3

Basic goodness-of-fit plots of the final population pharmacokinetic model. A: observed vs. population predicted concentrations. B: observed vs. individual predicted concentrations. C: conditional weighted residuals vs. population predicted concentrations. D: conditional weighted residuals vs. time after first dose. The red line represents the linear fit by the ordinary least square (OLS) method.

Figure 4

Distributions of the OFV and key parameters in bootstrap analyses. A: OFV; B: CL/F; C: V_UFH-C in Bootstrap analyses; D: Q/F; E: V_UFH-P.

Figure 5

VPC plots of the final model. A: before protamine neutralization; B: post-CPB VPC. Blue-colored areas are the 90% CI and pink-colored areas are the 50% CI for simulated concentrations. The red line represents the median of the observed concentration; the dashed lines represent the upper and lower 90% CI of observed concentrations.

Figure 6

Simulated plots of infusion times and a protamine infusion rate of 25 mg/h. A: 6-h infusion; B: 8-h infusion; C: 12-h infusion; D: 16-h infusion; E: 24-h infusion. Blue lines are simulated concentrations of UFH without follow-up protamine infusions or doses. Red lines denote simulated concentrations of UFH over different protamine infusion times.