Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada.
Ther Drug Monit. 2012 Feb;34(1):31-7. doi: 10.1097/FTD.0b013e3182400540.
The controversy still surrounds the optimal dosing regimen of tranexamic acid (TA), primary antifibrinolytic agent used in high-risk surgeries. This study compares the pharmacokinetics profile obtained from the group of patients undergoing heart surgery with the use of cardiopulmonary bypass (CPB) with the theoretical model currently used as an established dosing regimen of TA in cardiac surgery.
After induction of anesthesia, TA was administered intravenously as a bolus (30 mg/kg) infused over 15 minutes. Bolus was followed by an infusion of 16 mg·kg·h TA until the end of surgery (chest closure of the sternotomy wound). Before initiation of CPB, a bolus of 2 mg/kg was given to the pump prime. Blood samples were collected at baseline and at 30-minute time intervals during the surgery and after surgery. Automated solid-phase microextraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used for the determination of TA concentration. Blinded studies on monitoring of TA concentration were performed on 94 samples. Obtained results were compared with a previously described pharmacokinetic model of TA dosing.
The average concentration of TA during the use of CPB was 134 mcg/mL with the relative standard deviation 27%. The observed range of TA concentrations was 70-188 mcg/mL showing that individual patients can significantly exceed the recommended levels proposed by the theoretical model. lower limit of quantification of the proposed method was 1 mcg/mL. Intra- and interday accuracy was ±10% and precision was ≤12% at all concentration levels tested.
The suitability of automated solid-phase microextraction for high-throughput clinical analysis was established for the first time. The obtained pharmacokinetic profiles showed significant interpatient variation in the concentration of TA during heart surgery with the use of CPB, which confirms the need of the therapeutic monitoring of this antifibrinolytic agent.
氨甲环酸（TA）作为一种主要的抗纤维蛋白溶解剂，在高风险手术中被广泛应用。关于其最佳剂量方案仍存在争议。本研究比较了使用体外循环（CPB）的心脏手术患者组获得的药代动力学特征与目前作为心脏手术中 TA 既定剂量方案的理论模型。
麻醉诱导后，TA 静脉推注（30mg/kg），15 分钟内滴注完毕。推注后以 16mg·kg·h 的速度输注 TA，直至手术结束（胸骨切开术的胸部伤口闭合）。CPB 前，泵预充时给予 2mg/kg 的推注剂量。在手术期间和手术后，每隔 30 分钟采集基线和时间点的血样。采用自动化固相微萃取和液相色谱-串联质谱（LC-MS/MS）法测定 TA 浓度。对 94 份样本进行了 TA 浓度监测的盲法研究。将获得的结果与之前描述的 TA 剂量药代动力学模型进行了比较。
CPB 期间 TA 的平均浓度为 134 mcg/mL，相对标准偏差为 27%。观察到的 TA 浓度范围为 70-188 mcg/mL，表明个别患者的 TA 浓度可显著超过理论模型建议的推荐水平。该方法的定量下限为 1 mcg/mL。在所有测试浓度水平下，日内和日间准确度均为±10%，精密度均≤12%。
首次确立了自动化固相微萃取用于高通量临床分析的适用性。获得的药代动力学特征表明，在使用 CPB 的心脏手术中，TA 浓度存在显著的个体间差异，这证实了对这种抗纤维蛋白溶解剂进行治疗监测的必要性。
