The impact of heparin concentration and activated clotting time monitoring on blood conservation. A prospective, randomized evaluation in patients undergoing cardiac operation

A whole blood hemostasis system (Hepcon) provides both activated clotting time and accurate whole blood heparin concentration measurements via an automated protamine titration method. This study was designed to prospectively evaluate the impact of heparin and protamine administration using this system on the incidence and treatment of bleeding after cardiopulmonary bypass. Two hundred fifty-four patients requiring cardiopulmonary bypass were enrolled in this prospective study over a 7-month period. Patients treated with antifibrinolytic agents (aprotinin, ε-aminocaproic or tranexamic acid) were excluded. Patients were randomly assigned to either a control (n=127) or intervention (n=127) group. For control patients, the anticoagulation protocol consisted of an initial fixed dose of 250 U/kg of heparin, and additional 5000 U heparin doses were administered if the activated clotting time was less than 480 seconds. Heparin was neutralized with an initial fixed dose of protamine (0.8 mg protamine per milligram total heparin). For the intervention group, an initial dose of heparin was based on an automated heparin dose-response assay. Additional heparin doses were administered if the heparin concentration was less than the reference concentration or for an activated clotting time less than 480 seconds. The protamine dose was based on the residual heparin concentration. Treatment of excessive bleeding after cardiopulmonary bypass was based on an algorithm using point-of-care testing with whole blood prothrombin time, activated partial thromboplastin time, heparinase activated clotting time, and platelet count. No differences between the two treatment groups were identified in reference to demographic factors, preoperative anticoagulant medications, preoperative coagulation data, number of reoperations, or combined procedures and duration of cardiopulmonary bypass. Indirect evidence for coagulation factor consumption was demonstrated in control patients by more prolonged whole blood prothrombin time and activated partial thromboplastin time values after cardiopulmonary bypass when compared with values obtained in the intervention group. Patients in the intervention cohort received greater doses of heparin (intervention: 612±147, control: 462±114 U/kg, p<0.0001) and had lower protamine to heparin ratios (intervention: 0.70±0.64, control: 0.94±0.21, p=0.0001) compared with control patients. Patients in the intervention cohort received significantly fewer platelet (intervention: 1.7±3.6 U, control: 3.7±6.7 U, p=0.003), plasma (intervention: 0.4±1.3 U, control: 1.4±2.5 U, p=0.0001), and cryoprecipitate units (intervention: 0.0±0.0 U, control: 0.2±1.2 U, p=0.04) during the perioperative interval than control patients. A greater percentage of control patients required hemostatic transfusion (intervention: 17%, control: 33%, p=0.005) during the perioperative period. Control patients also required longer operative times for closure (intervention: 92±32, control: 102±34, p=0.02). Chest tube drainage in the first 24 postoperative hours was not different between treatment groups (intervention: 839±377, control: 924±520, p=0.14). In summary, maintenance of patient-specific heparin concentrations, based on heparin activated clotting time response, during cardiopulmonary bypass led to greater heparin doses and lower doses of protamine relative to heparin dose. Higher procine heparin doses were not associated with excessive postoperative bleeding. By facilitating maintenance of a therapeutic heparin concentration and determination of an appropriate protamine dose, point-of-care testing using the Hepcon system was associated with reduced blood product utilization. This difference may, in part, be due to better preservation of the coagulation system.