Department of Anesthesiology and Perioperative Medicine, Medical University of South Carolina, Charleston, SC 29403, USA.
Anesth Analg. 2010 Mar 1;110(3):694-701. doi: 10.1213/ANE.0b013e3181c7eb27.
A major complication associated with cardiac surgery is excessive and prolonged bleeding in the perioperative period. Improving coagulation by inhibiting fibrinolysis, primarily through inhibition of plasmin activity (PLact) with antifibrinolytics such as tranexamic acid (TXA), has been a pharmacological mainstay in cardiac surgical patients. Despite its almost ubiquitous use, the temporal and regional modulation of PLact profiles by TXA remains unexplored. Accordingly, we developed a fluorogenic-microdialysis system to measure in vivo dynamic changes in PLact after TXA administration in a large animal model.
Pigs (25-35 kg) were randomly assigned to receive TXA (30 mg/kg, diluted into 50 mL normal saline; n = 9) or vehicle (50 mL normal saline; n = 7). Microdialysis probes were placed in the liver, myocardium, kidney, and quadriceps muscle compartments. The microdialysate infusion contained a validated plasmin-specific fluorogenic peptide. The fluorescence emission (standard fluorogenic units [SFU]) of the interstitial fluid collected from the microdialysis probes, which directly reflects PLact, was determined at steady-state baseline and 30, 60, 90, and 120 min after TXA/vehicle infusion. Plasma PLact was determined at the same time points using the same fluorogenic substrate approach.
TXA reduced plasma PLact at 30 min after infusion by >110 SFU compared with vehicle values (P < 0.05). Specifically, there was a decrease in liver PLact at 90 and 120 min after TXA infusion of >150 SFU (P < 0.05) and 175 SFU (P < 0.05), respectively. The decrease in liver PLact occurred 60 min after the maximal decrease in plasma PLact. In contrast, kidney, heart, and quadriceps PLact transiently increased followed by an overall decrease at 120 min.
Using a large animal model and in vivo microdialysis measurements of PLact, the unique findings from this study were 2-fold. First, TXA induced temporally distinct PLact profiles within the plasma and selected interstitial compartments. Second, TXA caused region-specific changes in PLact profiles. These temporal and regional differences in the effects of TXA may have important therapeutic considerations when managing fibrinolysis in the perioperative period.
心脏手术相关的一个主要并发症是围手术期内出血过多和时间延长。通过抑制纤维蛋白溶解来改善凝血，主要是通过使用氨甲环酸（TXA）等抗纤维蛋白溶酶剂抑制纤溶酶活性（PLact），这一直是心脏外科患者的药理学基础。尽管 TXA 被广泛应用，但 TXA 对 PLact 谱的时间和区域调节仍未得到探索。因此，我们开发了一种荧光微透析系统，以在大型动物模型中测量 TXA 给药后 PLact 的体内动态变化。
猪（25-35 公斤）随机分为 TXA 组（30mg/kg，稀释至 50ml 生理盐水；n=9）或对照组（50ml 生理盐水；n=7）。微透析探针分别置于肝脏、心肌、肾脏和股四头肌隔室。微透析液输注物中含有经过验证的纤溶酶特异性荧光肽。从微透析探针收集的间质液的荧光发射（标准荧光单位 [SFU]）在稳定状态基线和 TXA/载体输注后 30、60、90 和 120 分钟时进行测定。同时使用相同的荧光底物方法测定血浆 PLact。
与对照组相比，TXA 输注后 30 分钟时 PLact 降低了 >110SFU（P<0.05）。具体来说，TXA 输注后 90 和 120 分钟时，肝脏 PLact 分别降低了 >150SFU（P<0.05）和 >175SFU（P<0.05）。肝脏 PLact 的下降发生在血浆 PLact 最大下降后 60 分钟。相比之下，肾脏、心脏和股四头肌的 PLact 先短暂增加，然后在 120 分钟时整体下降。
使用大型动物模型和体内 PLact 荧光微透析测量，本研究的独特发现有两个方面。首先，TXA 在血浆和选定的间质隔室内诱导了时间上不同的 PLact 谱。其次，TXA 导致 PLact 谱在特定区域发生变化。TXA 作用的这些时间和区域差异在围手术期管理纤溶时可能具有重要的治疗意义。
