This prospective study of 68 cardiac surgery patients used pharmacometric modeling to determine optimal protamine dosing for reversing unfractionated heparin after cardiopulmonary bypass. Researchers found that a protamine-to-heparin ratio of 0.625:1 achieved complete reversal in 95% of patients, lower than the commonly used 1:1 ratio. The study also revealed that activated clotting time (ACT) unreliably reflects residual heparin, suggesting fixed low-ratio dosing may be a practical alternative requiring validation.