Comparisons of these three methods suggest that ACT-based measurements of re- sidual heparin effect are the least accurate means of detecting residual heparin effect [84, 85]. Methods of heparin reversal are several and contro- versy exists regarding the optimal strategy. Traditional methods administer heparin based on body weight and protamine based on the amount of heparin administered. Certain methods of protamine administration depend on titration of protamine to neutralize heparin in blood samples at the end of CPB. The literature comparisons of these methods are mixed, with most reports [86 88] but not all [89, 90] favoring titration methods. A meta-analysis of standard weight-based versus titrated protamine dosing favors titrated dose protamine for heparin reversal because of less postoperative blood loss and decreased packed red blood cell transfusion [91]. Two studies suggest that viscoelastic measurements are useful indicators of adequate titrated heparin reversal [92, 93]. These studies found that individualized heparin-protamine titration decreased the protamine- to-heparin ratio, improved post-CPB thromboelasto- metric hemostatic factors, and reduced the incidence of severe blood loss compared with an ACT-based strat- egy. In addition, evidence supports the use of sequential heparin and protamine titrations after CPB to further limit blood loss and to provide adequate protamine reversal [86]. Class IIa Recommendation  Protamine overdose: It is reasonable to limit the ratio of protamine/heparin to less than 2.6 mg protamine per 100 units heparin because total doses above this ratio inhibit platelet function, prolong ACT, and in- crease the risk of bleeding. (Level of Evidence C) It is possible to overdose patients with protamine. Excess protamine inhibits platelet function and prolongs the ACT after CPB. Two studies provide convincing evi- dence that when the ratio of protamine to heparin (protamine mg per 100 units heparin) is above 5:1, platelet aggregation and function are impaired [94, 95]. 