Pharmacokinetics of Tranexamic Acid during Cardiopulmonary Bypass

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Abstract
Background: Tranexamic acid (TA) reduces blood loss and blood transfusion during heart surgery with cardiopulmonary bypass (CPB). TA dosing has been empiric because only limited pharmacokinetic studies have been reported, and CPB effects have not been characterized. We hypothesized that many of the published TA dosing techniques would prove, with pharmacokinetic modeling and simulation, to yield unstable TA concentrations. Methods: Thirty adult patients undergoing elective coronary artery bypass grafting, valve surgery, or repair of atrial septal defect received after induction of anesthesia: TA 50 mg/kg (n = 11), TA 100 mg/kg (n = 10), or TA 10 mg/kg (n = 10) over 15 min, with 1 mg x kg(-1) x hr(-1) maintenance infusion for 10 h. TA was measured in plasma using high performance liquid chromatography. Pharmacokinetic modeling was accomplished using a mixed effects technique. Models of increasing complexity were compared using Schwarz-Bayesian Criterion (SBC). Results: Tranexamic acid concentrations rapidly fell in all three groups. Data were well fit to a 2-compartment model, and adjustments for CPB were supported by SBC. Assuming a body weight of 80 kg, our model estimates V1 = 10.3 l before CPB and 11.9 l during and after CPB; V2 = 8.5 l before CPB and 9.8 l during and after CPB; Cl1 = 0.15 l/s before CPB, 0.11 l/s during CPB, and 0.17 l/s after CPB; and Cl2 = 0.18 l/s before CPB and 0.21 l/s during and after CPB. Based on simulation of previous studies of TA efficacy, we estimate that a 30-min loading dose of 12.5 mg/kg with a maintenance infusion of 6.5 mg x kg(-1) x hr(-1) and 1 mg/kg added to the pump prime will maintain TA concentration greater than 334 microm, and a higher dose based on 30 mg/kg loading dose plus 16 mg x kg(-1) x h(-1) continuous infusion and 2 mg/kg added to the pump prime would maintain TA concentrations greater than 800 microm. Conclusions: Tranexamic acid pharmacokinetics are influenced by CPB. Our TA pharmacokinetic model does not provide support for the wide range of TA dosing techniques that have been reported. Variation in TA efficacy from study to study and confusion about the optimal duration of TA treatment may be the result of dosing techniques that do not maintain stable, therapeutic TA concentrations.