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Individual aspects of heparin or protamine dosing have been better controlled than previously as useful tests have become available. Although many variables including drug potency, drug source, and individual patient response have been separately identified, there has not been an attempt to integrate them into a single management strategy. This study was undertaken to learn whether more precise control of drug variables and patient response would affect blood loss and transfusion requirements. Adult patients having primary cardiac operations were prospectively randomized into two groups. A control group received heparin and protamine by conventional methods. The test group received heparin and protamine according to in vitro predictive tests integrating drugs, tests, and patient response. Supplemental protamine was given in this group only if heparin was specifically found by testing. Anticoagulation in all patients was maintained at an activated coagulation time greater than 400 seconds, and any other treatment for bleeding was at the discretion of the clinical team caring for the patients. Testing and treatment for both groups followed routine practice after patient arrival in the intensive care unit. Test patients received slightly more heparin and a markedly lower dose of protamine than the control patients. Testing identified patients with decreased heparin sensitivity (preoperative heparin therapy) and correctly predicted the effective heparin dose. Supplemental protamine was given twice as often to control patients and frequently when no heparin was detectable (retrospectively). Test patients exhibited less 24-hour chest tube drainage (671 ml versus 1298 ml) and fewer patients received transfusion (9/22 versus 18/24) with fewer donor exposures (22/22 versus 101/24). The management strategy used for heparin and protamine added accuracy and precision, which was associated with improved hemostasis. Although the observation is valid, the mechanism or mechanisms are not completely clear. Nevertheless, it is reasonable to apply basic pharmacologic principles and establishment of consistent, predictable protocols that are beneficial. It is against this background that the efficacy of additional drugs or equipment should be assessed. It is quite possible that only marginal if any improvement in hemostasis may be found in patients having primary, uncomplicated cardiac operation with the addition of more costly drugs or equipment.