Dowd Noreen P, Karski Jacek M, Cheng Davy C, Carroll Jo A, Lin Yonggu, James Robert L, Butterworth John
Division of Cardiac Anesthesia and Intensive Care, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Anesthesiology. 2002 Aug;97(2):390-9. doi: 10.1097/00000542-200208000-00016.
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.
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).
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.
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.
氨甲环酸（TA）可减少体外循环（CPB）心脏手术中的失血和输血。由于仅有有限的药代动力学研究报道，且CPB的影响尚未明确，TA的给药一直是凭经验进行。我们推测，通过药代动力学建模和模拟，许多已发表的TA给药技术将被证明会产生不稳定的TA浓度。
30例接受择期冠状动脉搭桥术、瓣膜手术或房间隔缺损修复术的成年患者在麻醉诱导后接受：TA 50 mg/kg（n = 11）、TA 100 mg/kg（n = 10）或TA 10 mg/kg（n = 10），静脉输注15分钟，随后以1 mg·kg⁻¹·h⁻¹持续输注10小时。使用高效液相色谱法测定血浆中的TA。采用混合效应技术进行药代动力学建模。使用施瓦茨-贝叶斯准则（SBC）比较复杂度不断增加的模型。
所有三组的氨甲环酸浓度均迅速下降。数据与二室模型拟合良好，SBC支持对CPB进行校正。假设体重为80 kg，我们的模型估计CPB前V1 = 10.3 L，CPB期间及CPB后为11.9 L；CPB前V2 = 8.5 L，CPB期间及CPB后为9.8 L；CPB前Cl1 = 0.15 L/s，CPB期间为0.11 L/s，CPB后为0.17 L/s；CPB前Cl2 = 0.18 L/s，CPB期间及CPB后为0.21 L/s。基于对既往TA疗效研究的模拟，我们估计，30分钟负荷剂量为12.5 mg/kg，维持输注为6.5 mg·kg⁻¹·h⁻¹，并在预充液中添加1 mg/kg，将使TA浓度维持在大于334 μmol/L，基于30 mg/kg负荷剂量加16 mg·kg⁻¹·h⁻¹持续输注并在预充液中添加2 mg/kg的更高剂量将使TA浓度维持在大于800 μmol/L。
氨甲环酸的药代动力学受CPB影响。我们的TA药代动力学模型不支持已报道的广泛的TA给药技术。不同研究中TA疗效的差异以及对TA最佳治疗持续时间的困惑可能是由于未能维持稳定的治疗性TA浓度的给药技术所致。
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