Optimising protamine dosing for heparin reversal after cardiopulmonary bypass: a population pharmacokinetic–pharmacodynamic study

Background Protamine is administered to reverse unfractionated heparin (UFH) after cardiopulmonary bypass (CPB), but dosing strategies—typically based on protamine-to-heparin (P:H) ratios—vary, and the minimal effective dose remains unclear. Reversal is commonly assessed using activated clotting time (ACT), which may not reliably reflect residual heparin activity. We used pharmacometric modeling to determine a minimal effective P:H ratio and to characterise the anti-factor Xa (anti-Xa) activity–ACT relationship. Methods In this prospective, single-centre study, 68 adults undergoing CPB-assisted cardiac surgery were enrolled. A total of 757 blood samples were collected intraoperatively and after UFH reversal to measure anti-Xa activity and ACT. A population pharmacokinetic–pharmacodynamic model was developed using a nonlinear mixed-effects approach to describe UFH neutralisation by protamine. This model was then used to perform Monte Carlo simulations estimating the probability of complete reversal (anti-Xa