阿加曲班用于体外膜肺氧合支持患者的病例对照研究

Application of argatroban in patients receiving extracorporeal membrane oxygenation support: a case-control study

目的评估存在普通肝素(UFH)禁忌证并接受体外膜肺氧合(ECMO)支持危重症患者应用阿加曲班抗凝的安全性、有效性和抗凝剂量。方法收集2013年7月1日至2022年2月28日北京朝阳医院呼吸重症监护病房(RICU)收治的接受ECMO支持并应用阿加曲班抗凝的14例患者(阿加曲班组),其中2例初始应用阿加曲班抗凝,其余12例均为UFH抗凝后改用阿加曲班抗凝;根据人口学特征匹配应用UFH抗凝的28例患者(UFH组)。主要观察终点为ECMO相关血栓事件发生率。次要观察终点为血栓事件类型、ECMO相关出血事件发生率、出血部位、ICU病死率、ECMO使用期间病死率、肝肾功能、血栓弹力图、输血情况、阿加曲班使用剂量、阿加曲班抗凝治疗前4 d和治疗后7 d凝血指标的变化趋势。结果阿加曲班组和UFH组中,采用静脉-静脉ECMO(VV-ECMO)患者分别为8例和23例,采用静脉-动脉ECMO(VA-ECMO)患者分别为2例和3例,采用静脉-动脉-静脉ECMO(VAV-ECMO)患者分别为4例和2例。终点事件方面,阿加曲班组ECMO相关血栓事件发生率略高于UFH组(28.6%比21.4%),ECMO支持时间略长于UFH组〔d:16(7,21)比13(8,17)〕,ECMO相关出血事件发生率和ECMO期间病死率略低于UFH组(28.6%比32.1%,35.7%比46.4%),但两组间比较差异均无统计学意义(均P>0.05)。阿加曲班组血小板输注量显著高于UFH组〔U:7.7(0,10.0)比0.8(0,1.0)〕;血栓弹力图中凝血反应时间(R值)显著长于UFH组〔min:9.3(7.2,10.8)比8.8(6.3,9.7)〕,最大宽度值〔MA值,mm:48.4(40.7,57.9)比52.6(45.4,61.5)〕和血块生成率〔α角(°):54.1(45.4,62.0)比57.9(50.2,69.0)〕均显著低于UFH组(均P<0.05)。阿加曲班组患者从UFH更换为阿加曲班后APTT延长〔s:63.5(58.4,70.6)比56.7(53.1,60.9)〕,PLT水平在UFH抗凝治疗过程中呈降低趋势,更换为阿加曲班后逐渐升高;在更换阿加曲班抗凝时D-二聚体水平为19.1(7.0,28.7)mg/L,之后不再呈升高趋势;纤维蛋白原(FIB)水平在UFH抗凝治疗过程中呈降低趋势(最低为23.6 g/L),更换阿加曲班后波动在16.8~26.2 g/L。阿加曲班起始剂量为0.049(0.029,0.103)μg·kg-1·min-1,其中VV-ECMO患者的起始剂量最高〔0.092(0.049,0.165)μg·kg-1·min-1〕,VAV-ECMO患者起始剂量最低〔0.026(0.013,0.041)μg·kg-1·min-1〕,但比较差异无统计学意义(P>0.05);阿加曲班维持剂量为0.033(0.014,0.090)μg·kg-1·min-1,其中VV-ECMO患者维持剂量显著高于VA-ECMO和VAV-ECMO患者〔μg·kg-1·min-1:0.102(0.059,0.127)比0.036(0.026,0.060)、0.013(0.004,0.022),P<0.05〕。结论对存在UFH抗凝禁忌证的ECMO患者,应用阿加曲班可保持ECMO稳定运行,维持较为稳定的血小板水平,同时未增加血栓及出血事件发生率。

Objective To evaluate the safety and efficacy of argatroban applied as alternative anticoagulant in critical illness patients underwent extracorporeal membrane oxygenation(ECMO)with contraindications of unfractionated heparin(UFH),and to further explore the effective dose of argatroban.Methods From July 1,2013 to February 28,2022,there were 14 patients who admitted in the respiratory intensive care unit(RICU)of Beijing Chao-Yang Hospital received ECMO and used argatroban for anticoagulation(argatroban group).Two of them received argatroban as the initial anticoagulant.The remaining 12 patients used UFH at first,and then switched to argatroban.UFH group included 28 patients who received UFH for anticoagulation after matching the demographic characteristics.Primary endpoint was the prevalence of ECMO-related thrombotic events.Secondary endpoints included the type of thrombotic events,prevalence of ECMO-related major bleeding events,bleeding sites,ICU mortality,mortality during ECMO,liver and kidney function,thrombelastogram,blood transfusion,dosage of argatroban,the dynamic changes of coagulation variables 4 days before and 7 days after argatroban treatment.Results In argatroban group,there were 8 patients received veno-venous ECMO(VV-ECMO),2 patients with veno-arterial ECMO(VA-ECMO),and 4 patients with veno-arterio-venous ECMO(VAV-ECMO).In UFH group,VV-ECMO was applied in 23 patients,VA-ECMO and VAV ECMO was established in 3 patients and 2 patients,respectively.In endpoint events,the incidence of ECMO related thrombotic events in argatroban group was slightly higher than that in UFH group(28.6%vs.21.4%).The ECMO running time in argatroban group was slightly longer than that in UFH group[days:16(7,21)vs.13(8,17)].The incidence of ECMO-related bleeding events(28.6%vs.32.1%)and mortality during ECMO(35.7%vs.46.4%)in argatroban group were slightly lower than those in UFH group.However,the differences were not statistically significant(all P<0.05).The platelet transfusion in argatroban group was significantly higher than that in UFH group[U:7.7(0,10.0)vs.0.8(0,1.0)].The coagulation reaction time(R value)in thrombelastography in argatroban group was significantly longer than that in UFH group[minutes:9.3(7.2,10.8)vs.8.8(6.3,9.7)].The maximum width value[MA value,mm:48.4(40.7,57.9)vs.52.6(45.4,61.5)]and blood clot generation rate[α-Angle(deg):54.1(45.4,62.0)vs.57.9(50.2,69.0)]in the argatroban group were significantly lower than those in the UFH group(all P<0.05).The activated partial thromboplastin time(APTT)was prolonged after changing from UFH to argatroban in the argatroban group[seconds:63.5(58.4,70.6)vs.56.7(53.1,60.9)].The PLT level showed a decreasing trend during UFH anticoagulation therapy,and gradually increased after changing to argatroban.D-dimer level was 19.1(7.0,28.7)mg/L after switching to argatroban,and then no longer showed an increasing trend.The level of fibrinogen(FIB)showed a decreasing trend during the anticoagulant therapy of UFH(the lowest was 23.6 g/L),and fluctuated between 16.8 and 26.2 g/L after changing to argatroban.The median initial dose of argatroban was 0.049(0.029,0.103)μg·kg-1·min-1,which the highest dose was in VV-ECMO patients of[0.092(0.049,0.165)μg·kg-1·min-1].The initial dose of VAV-ECMO was the lowest[0.026(0.013,0.041)μg·kg-1·min-1],but without significant difference(P>0.05).The maintenance dose of argatroban was 0.033(0.014,0.090)μg·kg-1·min-1,VV-ECMO patients was significantly higher than those in VA-ECMO and VAV-ECMO patients[μg·kg-1·min-1:0.102(0.059,0.127)vs.0.036(0.026,0.060),0.013(0.004,0.022),both P<0.05].Conclusion Argatroban appears to be a feasible,effective and safety alternative anticoagulant for patients with contraindications to UFH who undergoing ECMO support.