出血对猪模型中氨甲环酸药代动力学的影响。
The effects of hemorrhage on the pharmacokinetics of tranexamic acid in a swine model.
机构信息
From the Madigan Army Medical Center (M.J.D., J.M.M., S.T.M., J.P.K., C.J.P., M.R.B., M.J.M., M.J.L.), Tacoma, Washington.
出版信息
J Trauma Acute Care Surg. 2018 Jul;85(1S Suppl 2):S44-S48. doi: 10.1097/TA.0000000000001861.
BACKGROUND
The early use of tranexamic acid (TXA) is strongly advocated in patients who are likely to require massive transfusion to decrease mortality. This study determines the influence of hemorrhage on the pharmacokinetics of TXA in a porcine model.
METHODS
The investigation was a prospective experimental study in Yucatan minipigs. First, in vitro plasma-cell partitioning of TXA was evaluated by inoculating whole blood with known aliquots, centrifuging, and measuring the supernatant with high-performance liquid chromatography with mass spectrometry (HPLC-MS). Then, using in vivo modeling, normovolemic and hypovolemic (35% reduction in blood volume) swine (n = 4 per group) received 1 g of intravenous TXA and had blood sampled at 14 time points over 4 hours to determine baseline clearance via HPLC-MS. Additional swine (n = 4) were hemorrhaged 35% of their blood volume, and TXA was administered as a 15 mg/kg infusion over 10 minutes followed by infusion of 1.875 mg/kg per hour to simulate massive hemorrhage scenario. During the first hour of TXA administration, one total blood volume was hemorrhaged and simultaneously replaced with TXA free blood. Serial blood samples and the hemorrhaged blood were analyzed by HPLC-MS to determine the percentage of dose lost via hemorrhage.
RESULTS
Clearance of TXA was diminished in the hypovolemic group compared with the normovolemic group (115 ± 4 vs 70 ± 7 mL/min). Percentage of dose lost via hemorrhage averaged 25%. The lowest measured plasma level during the exchange transfusion was 34 μg/mL.
CONCLUSION
Mean 25% of the present 2017 Joint Trauma System Clinical Practice Guideline dosing of TXA can be lost to hemorrhage if a blood volume is transfused within an hour of initiating therapy. In the case of TXA, which has limited distribution and is administered during active hemorrhage and massive blood transfusions, replacement strategies should be developed and tested to find simple methods of adjusting the current dosing guidelines to maintain therapeutic plasma concentrations.
LEVEL OF EVIDENCE
Therapeutic, level II.
背景
在可能需要大量输血以降低死亡率的患者中，强烈提倡早期使用氨甲环酸（TXA）。本研究旨在确定猪模型中出血对 TXA 药代动力学的影响。
方法
本研究是一项在尤卡坦小型猪中进行的前瞻性实验研究。首先，通过向全血中接种已知等分试样、离心并使用高效液相色谱-质谱联用（HPLC-MS）测量上清液来评估 TXA 的体外血浆细胞分配。然后，使用体内建模，接受 1 克静脉注射 TXA 的正常血容量和低血容量（血液体积减少 35%）猪（每组 4 只），并在 4 小时内采集 14 个时间点的血液，通过 HPLC-MS 确定基线清除率。另外 4 只猪（n = 4）出血 35%的血液量，并以 15mg/kg 的输注速度输注 TXA 10 分钟，然后以 1.875mg/kg/h 的速度输注以模拟大量出血情况。在 TXA 给药的第一小时内，总共损失一个全血容量，并同时用不含 TXA 的血液替代。通过 HPLC-MS 分析连续的血液样本和出血的血液，以确定通过出血损失的剂量百分比。
结果
与正常血容量组相比，低血容量组 TXA 的清除率降低（115 ± 4 与 70 ± 7 mL/min）。通过出血损失的剂量百分比平均为 25%。在交换输血过程中测量到的最低血浆水平为 34μg/mL。
结论
如果在开始治疗后 1 小时内输血，根据 2017 年联合创伤系统临床实践指南，目前 TXA 剂量的 25%可能会因出血而丢失。在 TXA 的情况下，其分布有限，并且在积极出血和大量输血期间给药，应开发和测试替代策略，以找到调整当前剂量指南以维持治疗性血浆浓度的简单方法。
证据水平
治疗，II 级。
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