<![CDATA[Protamine sulfate remains the standard agent for reversing unfractionated heparin following cardiopulmonary bypass (CPB). Conventional reversal is typically based on a fixed protamine-to-heparin ratio of 1 mg per 100 IU of heparin. However, increasing evidence indicates that this empirical approach may not accurately reflect residual circulating heparin levels at the end of CPB and may result in either inadequate reversal or protamine overdose. Excess protamine administration has been associated with platelet dysfunction, impaired thrombin generation, coagulopathy, and increased postoperative bleeding. This narrative review summarizes current evidence on individualized protamine dosing and discusses major controversies and future directions in precision anticoagulation reversal. A literature search was conducted in PubMed/MEDLINE, Embase, and the Cochrane Library for English-language studies published between 2021 and 2026, with earlier landmark studies included when relevant. Priority was given to randomized controlled trials, pharmacokinetic–pharmacodynamic studies, systematic reviews, and meta-analyses.Current evidence consistently demonstrates that individualized protamine dosing reduces total protamine exposure compared with conventional fixed-ratio protocols while maintaining effective heparin neutralization. Heparin concentration-guided strategies and low-dose protamine protocols have achieved comparable reversal outcomes without increasing postoperative bleeding or transfusion requirements. Pharmacokinetic–pharmacodynamic modeling suggests that a protamine-to-heparin ratio of approximately 0.625:1 may be adequate for most patients, substantially lower than traditional recommendations. Meta-analytic evidence further indicates improved coagulation-related outcomes and fewer bleeding complications with concentration-guided management, although definitive benefits regarding mortality, re-exploration for bleeding, and thrombotic events remain uncertain. Individualized protamine dosing represents a promising approach to optimizing anticoagulation reversal after CPB. Nevertheless, further large, multicenter randomized trials evaluating patient-centered outcomes are required before individualized dosing strategies can be recommended as the universal standard of care.]]>
