DeNino Walter F, Carter Christopher B, Sievert Alicia, Goss Ashley, Toole John M, Mukherjee Rupak, Uber Walter E
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC, USA.
Perfusion Services, Medical University of South Carolina, Charleston, SC, USA.
Perfusion. 2016 Jul;31(5):424-30. doi: 10.1177/0267659115614640. Epub 2015 Oct 30.
Dabigatran etexilate is a direct thrombin inhibitor approved for use in patients with non-valvular atrial fibrillation. There is no currently available pharmacological therapy to reverse this renally cleared anticoagulant. Dabigatran has a low level of plasma protein binding and has been considered dialyzable. We used a pig model with renal artery ligation to exclude intrinsic drug excretion to examine the efficacy of ultrafiltration (UF) during cardiopulmonary bypass (CPB) for dabigatran removal.
Dabigatran was intravenously infused (20 mg) in Yorkshire pigs (male, n=7, 70±1 kg) following renal artery ligation. CPB with UF was initiated after heparinization and continued until a total volume of 6 liters of UF effluent was removed. Serial labs, including dabigatran concentration, activated coagulation times (ACT), hematocrit and creatinine were drawn at intervals before the start of CPB and then incrementally during UF (0, 2, 4 and 6 L removed). Hemodialysis (HD) was performed on one animal following UF.
Dabigatran concentration (ng/mL) rose from undetectable levels at baseline to 296±70 (p<0.05) at the conclusion of infusion, but dropped significantly upon administration of heparin (178±40, p<0.05). A further decrement in dabigatran concentration was observed from the administration of heparin to the start of CPB (to 135±28, p<0.05). Once on CPB, dabigatran remained stable, with the end UF (eUF) dabigatran concentration being 133±34. Dabigatran concentration in the UF effluent was measured in one animal and was 98.8, with 6 L of effluent having been removed. The total recovery of dabigatran was calculated to be less than 5%. Dabigatran concentrations also did not decrease appreciably with HD on CPB following UF.
UF in conjunction with CPB was ineffective at removing dabigatran. Heparin demonstrated a dabigatran-lowering effect, suggesting a possible drug interaction or assay impairment. Based on these findings, emergent cardiac surgery with UF on cardiopulmonary bypass to remove dabigatran is not advisable. Alternative forms of drug removal or reversal must be identified.
达比加群酯是一种已获批准用于非瓣膜性心房颤动患者的直接凝血酶抑制剂。目前尚无药理学疗法可逆转这种经肾脏清除的抗凝剂的作用。达比加群的血浆蛋白结合率较低，被认为是可透析的。我们使用肾动脉结扎的猪模型来排除药物的内在排泄，以研究体外循环（CPB）期间超滤（UF）清除达比加群的疗效。
在肾动脉结扎后，对约克夏猪（雄性，n = 7，70±1 kg）静脉输注达比加群（20 mg）。肝素化后开始进行伴有UF的CPB，并持续进行直至总共清除6升UF流出液。在CPB开始前定期采集系列实验室检测指标，包括达比加群浓度、活化凝血时间（ACT）、血细胞比容和肌酐，然后在UF期间（清除0、2、4和6升时）递增采集。在UF后对一只动物进行血液透析（HD）。
达比加群浓度（ng/mL）从基线时的不可检测水平升至输注结束时的296±70（p<0.05），但在给予肝素后显著下降（178±40，p<0.05）。从给予肝素到CPB开始，观察到达比加群浓度进一步下降（至135±28，p<0.05）。一旦开始CPB，达比加群浓度保持稳定，超滤结束时（eUF）达比加群浓度为133±34。在一只动物中测量了UF流出液中的达比加群浓度，为98.8，此时已清除6升流出液。计算得出达比加群的总回收率小于5%。在UF后的CPB上进行HD时，达比加群浓度也没有明显降低。
UF联合CPB清除达比加群无效。肝素显示出降低达比加群的作用，提示可能存在药物相互作用或检测干扰。基于这些发现，在CPB上进行UF以清除达比加群的急诊心脏手术不可取。必须确定其他形式的药物清除或逆转方法。
