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

Abstract

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. 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 <0.10 IU ml^-1) at various P:H ratios, based on cumulative intraoperative UFH dose. Patients received a mean total dose of 30 250 IU UFH and 200 mg protamine i.v. Measured anti-Xa activity decreased to <0.10 IU ml^-1 in all patients within 10 min of protamine initiation, indicating rapid reversal. Model-based simulations predicted that a P:H ratio of 0.625:1 would achieve complete reversal in 95% of patients. Although ACT and anti-Xa activity were positively associated, ACT values varied widely at low anti-Xa concentrations. A P:H ratio of 0.625:1 provided adequate UFH reversal. Given the imprecision of ACT, fixed low-ratio dosing without routine monitoring could be a practical alternative but requires prospective validation. EudraCT (2019-000859-14); www. gov (NCT04092868).