第二军医大学学报  2021, Vol. 42 Issue (2): 146-152   PDF    
急性缺血性脑卒中血管内治疗常见不良事件和预后分析
邢鹏飞, 沈芳, 李子付, 张磊, 张永鑫, 张小曦, 花伟龙, 张永巍, 杨鹏飞, 刘建民     
海军军医大学(第二军医大学)长海医院脑血管病中心, 上海 200433
摘要: 目的 探讨急性缺血性脑卒中患者血管内治疗术中及术后常见不良事件的发生率、发生原因及其对预后的影响。方法 回顾性连续纳入2013年9月至2018年5月在我院接受血管内治疗的急性缺血性脑卒中患者513例,根据术中及术后是否发生不良事件分为研究组(发生1种或几种不良事件,230例)和对照组(无不良事件,283例)。分析入组患者不良事件的发生率和原因,对比分析两组患者基线资料、血管成功再通率、良好预后率、病死率等,并采用多因素logistic回归分析探讨不良事件与临床预后的关系。结果 513例患者不良事件总发生率为44.8%(230/513),包括任何类型颅内出血(22.0%,113例)、症状性颅内出血(9.6%,49例)、进展性缺血性脑卒中(23.4%,120例)、新血管流域栓塞(6.2%,32例)、动脉夹层(1.4%,7例)、支架内血栓形成(1.9%,10例)和血管再闭塞(4.5%,23例)等。导致不良事件的原因有再灌注损伤、无效再灌注、机械损伤(支架、导管、导丝)和药物等。与对照组相比,研究组患者年龄偏大(t=2.298,P < 0.05),男性患者占比低(χ2=9.614,P < 0.01),术前美国国立卫生研究院卒中量表(NIHSS)评分较高、美国神经介入和治疗神经放射学会/介入放射学会侧支循环分级系统(ASITN/SIRs)评分较低(Z=34.378、13.311,P均 < 0.01)。研究组取栓次数多于对照组(Z=22.677,P < 0.01),但血管成功再通(改良脑梗死溶栓2b/3级)率和术后90 d预后良好(改良Rankin量表评分为0~2分)率均低于对照组(χ2=19.903、180.191,P均 < 0.01),术后90 d病死率高于对照组(χ2=52.818,P < 0.01)。多因素logistic回归分析表明,症状性颅内出血和进展性缺血性脑卒中是急性缺血性脑卒中患者血管内治疗后预后不良的独立危险因素(P均 < 0.01)。结论 急性缺血性脑卒中血管内治疗术中及术后不良事件会影响90 d预后,症状性颅内出血和进展性缺血性脑卒中是预后不良的独立预测因素。
关键词: 缺血性脑卒中    血管内治疗    不良事件    预后    症状性颅内出血    进展性缺血性脑卒中    
Analysis of common adverse events and prognosis of endovascular treatment for acute ischemic stroke
XING Peng-fei, SHEN Fang, LI Zi-fu, ZHANG Lei, ZHANG Yong-xin, ZHANG Xiao-xi, HUA Wei-long, ZHANG Yong-wei, YANG Peng-fei, LIU Jian-min     
Stroke Center, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China
Abstract: Objective To explore the incidence and causes of common adverse events of acute ischemic stroke patients during and after endovascular treatment, and to analyze their effects on prognosis. Methods A total of 513 consecutive patients with acute ischemic stroke, who received endovascular treatment in our hospital from Sep. 2013 to May 2018, were included retrospectively. The patients with 1 or more adverse events (n=230) were included in study group, and those without adverse events (n=283) were included in control group. The incidence and etiology of adverse events were analyzed in both groups. The baseline data, successful recanalization rate, good prognosis rate and mortality in the two groups were compared and analyzed. The relationship between adverse events and clinical prognosis was explored by multivariate logistic regression analysis. Results The total incidence of adverse events was 44.8% (230/513), including intracranial hemorrhage (22.0%, 113 cases), symptomatic intracranial hemorrhage (9.6%, 49 cases), progressive ischemic stroke (23.4%, 120 cases), new territory embolism (6.2%, 32 cases), arterial dissection (1.4%, 7 cases), stent thrombosis (1.9%, 10 cases), reocclusion (4.5%, 23 cases) and so on. Reperfusion injury, futile reperfusion, mechanical injury (caused by stent, catheter or wire) and drugs were responsible for the development of the adverse events. Compared with the control group, the age and the pre-procedural score of National Institutes of Health stroke scale (NIHSS) were significantly higher (t=2.298, P < 0.05, and Z=34.378, P < 0.01), and the proportion of males and the pre-procedural score of American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology scale (ASITN/SIRs) were significantly lower (χ2=9.614, P < 0.01, and Z=13.311, P < 0.01) in the study group. Although more passes were significantly performed to achieve successful recanalization in the study group compared with the control group (Z=22.677, P < 0.05), the rates of successful recanalization (modified thrombolysis in cerebral infarction graded 2b/3) and good prognosis (modified Rankin scale scored 0-2) 90 d after operation were significantly lower in the study group (χ2=19.903 and 180.191, both P < 0.01), but with a significantly higher mortality 90 d after operation (χ2=52.818, P < 0.01). The results of the multivariate logistic regression analysis indicated that symptomatic intracranial hemorrhage and progressive ischemic stroke were independent risk factors of poor prognosis of acute ischemic stroke patients after endovascular treatment (both P < 0.01). Conclusion Adverse events of acute ischemic stroke patients during and after endovascular treatment can affect the 90-d prognosis. Symptomatic intracranial hemorrhage and progressive ischemic stroke are independent predictors of poor prognosis.
Key words: ischemic stroke    endovascular treatment    adverse events    prognosis    symptomatic intracranial hemorrhage    progressive ischemic stroke    

血管内治疗可明显提高闭塞大血管的再通率和改善临床预后,已成为伴有大血管闭塞的急性缺血性脑卒中的首选治疗策略,并得到国内外指南的一致推荐[1-2]。然而,即使及时接受血管内治疗,仍有50.4%的患者预后不良[3]。血管内治疗术中和术后不良事件,尤其是症状性颅内出血(symptomatic intracranial hemorrhage,sICH)等的发生会降低临床良好预后率[4]。然而,有关不良事件发生的原因及各因素导致的不良事件发生率的研究报道较少。本研究回顾我院急性缺血性脑卒中患者血管内治疗过程中的常见不良事件,分析不良事件发生的原因、发生率及其与预后的关系,以期为临床操作和预后判断提供依据。

1 资料和方法 1.1 研究对象与分组

回顾性分析2013年9月至2018年5月我院收治的688例行脑血管数字减影血管造影(digital subtraction angiography,DSA)检查的急性缺血性脑卒中患者资料。纳入标准:因前循环近端大血管(颈内动脉、大脑中动脉M1段和大脑中动脉M2段近端)闭塞和/或远端血管(大脑中动脉M2段远端和M3段、大脑前动脉A1至A3段)闭塞,或后循环大血管(椎动脉和基底动脉)闭塞和/或远端血管(大脑后动脉P1段)闭塞行血管内治疗的患者。排除标准:(1)脑血管造影提示有血管内治疗指征但未接受治疗;(2)大动脉炎急性期;(3)血管内治疗前闭塞血管自发再通;(4)血栓向远端移位不能行血管内治疗;(5)无90 d随访记录。根据血管内治疗术中及术后有无不良事件,将入组患者分为研究组(发生1种或几种不良事件)和对照组(无不良事件)。

1.2 研究方法 1.2.1 手术方法

血管内治疗方法包括中间导管辅助的支架取栓器取栓(Solumbra技术)[5]和应用抽吸导管直接抽吸取栓(ADAPT技术)。若采用Solumbra技术在同一闭塞部位连续取栓3次血管未再通时,更换ADAPT技术取栓;反之亦然。常规取栓操作失败时的补救策略包括双支架取栓、血管成形术(单纯球囊扩张或支架植入)、静脉应用糖蛋白Ⅱb/Ⅲa受体拮抗剂和动脉溶栓等。

1.2.2 围手术期用药

发病4.5 h内、符合静脉溶栓指征的患者予标准剂量(0.9 mg/kg)阿替普酶静脉溶栓[1]。血管成形术前5 min开始静脉注射糖蛋白Ⅱb/Ⅲa受体拮抗剂替罗非班[5 mg/100 mL,远大医药(中国)有限公司]0.4 μg•kg-1•min-1,持续30 min,总剂量不超过1 mg[6],之后继续静脉泵入0.1 μg•kg-1•min-1维持24~36 h至口服抗血小板药起效;合并静脉溶栓治疗者,替罗非班使用剂量为2/3推荐剂量。其余患者围手术期用药均按美国心脏协会/美国卒中协会2018年发布的急性缺血性脑卒中早期管理指南[1]执行。

1.2.3 不良事件类型

本研究关注的不良事件主要包括任何类型的颅内出血、sICH[美国国立卫生研究院卒中量表(National Institutes of Health stroke scale,NIHSS)评分较术前增加≥4分[7]]、新血管流域栓塞、进展性缺血性脑卒中(24 h NIHSS评分较术前增加或出现脑水肿、脑疝等)、症状无缓解(24 h NIHSS评分无变化,且无出血转化及脑水肿、脑疝等)、动脉夹层、支架内血栓形成和血管再闭塞(原闭塞血管再通后由于各种原因导致的再闭塞)等。

1.2.4 评价指标

记录并分析不良事件类型及导致不良事件发生的原因。对比分析两组患者基线NIHSS评分、术前美国神经介入和治疗神经放射学会/介入放射学会侧支循环分级系统(American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology scale,ASITN/SIRs)评分[8]、取栓次数、术后DSA提示血管再通达到改良脑梗死溶栓(modified thrombolysis in cerebral infarction,mTICI)分级[9]2b/3级(血管成功再通)的百分比、术中支架植入率、发病至血管再通时间、术后90 d时改良Rankin量表(modified Rankin scale,mRS)评分为0~2分的百分比和术后90 d内的病死率。

1.3 统计学处理

应用SPSS 22.0软件进行统计学分析。符合正态分布的计量资料以x±s表示,两组间比较采用两样本t检验;非正态分布计量资料以中位数(下四分位数,上四分位数)表示,两组间比较采用Mann-Whitney U检验;计数资料以例数和百分数表示,两组间比较采用Pearson χ2检验或连续校正χ2检验。采用单因素分析探讨研究组患者各不良事件对预后的影响,对其中P<0.15的变量进行多因素logistic回归分析。检验水准(α)为0.05。

2 结果 2.1 不良事件和病因分析

共513例患者入组,总体不良事件发生率为44.8%(230/513),任何类型颅内出血的发生率为22.0%(113/513),sICH发生率为9.6%(49/513),24 h症状无缓解率为6.8%(35/513),进展性缺血性脑卒中的发生率为23.4%(120/513),新血管流域栓塞的发生率为6.2%(32/513),动脉夹层的发生率为1.4%(7/513),支架内血栓形成的发生率为1.9%(10/513),血管再闭塞的发生率为4.5%(23/513)。术后90 d全因死亡率为12.9%(66/513),其中86.4%(57/66)死于脑血管疾病。导致不良事件发生的原因包括再灌注损伤、无效再灌注、机械损伤(支架、导管、导丝)及药物(包括静脉溶栓药和抗血小板药)相关损伤等(表 1);其中,静脉溶栓药主要引起颅内出血和血栓碎解向远端移位导致的新血管流域栓塞。

表 1 513例急性缺血性脑卒中患者血管内治疗术中、术后不良事件病因分析 Tab 1 Causes of intra- and post-procedural adverse events in 513 acute ischemic stroke patients receiving endovascular treatment 

2.2 两组患者基线资料

研究组患者230例,年龄为29~88岁,平均年龄为(68.0±12.4)岁;男133例,女97例;接受静脉溶栓患者73例;前循环血管闭塞186例,后循环血管闭塞44例;术前NIHSS评分为20(14,23)分,ASITN/SIRs评分为2(1,2)分。对照组患者283例,年龄为26~88岁,平均年龄为(66.0±12.5)岁;男194例,女89例;接受静脉溶栓患者73例;前循环血管闭塞219例,后循环血管闭塞64例;术前NIHSS评分为14(8,20)分,ASITN/SIRs评分为2(1,3)分。与对照组相比,研究组患者年龄偏大(t=2.298,P<0.05),男性患者占比较低(χ2=9.614,P<0.01),术前NIHSS评分较高、ASITN/SIRs评分较低(Z=34.378、13.311,P均<0.01)。研究组急性脑卒中治疗Org 10172试验(trial of Org 10172 in acute stroke treatment,TOAST)分型中大动脉粥样硬化型患者占比低于对照组(χ2=4.587,P<0.05),其余分型比较差异均无统计学意义(P均>0.05);两组静脉溶栓率差异无统计学意义(P>0.05)。见表 2

表 2 两组血管内治疗急性缺血性脑卒中患者基线资料比较 Tab 2 Comparison of baseline characteristics of acute ischemic stroke patients receiving endovascular treatment between two groups

2.3 两组患者术后临床资料

研究组患者血管内治疗后血管成功再通(mTICI 2b/3级)率为88.3%(203/230),低于对照组[98.2%(278/283),χ2=19.903,P<0.01]。研究组取栓次数为2(1,3)次,多于对照组的2(1,2)次(Z=22.677,P<0.01);两组急诊支架植入患者占比、发病至血管再通时间差异均无统计学意义(P均>0.05)。随访结果显示,研究组术后90 d时预后良好(mRS评分为0~2分)率低于对照组(χ2=180.191,P<0.01),术后90 d内病死率高于对照组(χ2=52.818,P<0.01)。见表 3

表 3 两组急性缺血性脑卒中患者血管内治疗术后资料比较 Tab 3 Comparison of post-procedure indicators of acute ischemic stroke patients receiving endovascular treatment between two groups

2.4 不良事件与血管内治疗急性缺血性脑卒中患者临床预后多因素分析

多因素logistic回归分析结果显示,sICH、进展性缺血性脑卒中是急性缺血性脑卒中患者血管内治疗术后预后不良(mRS评分≥3分)的独立危险因素(P均<0.01),动脉夹层、血管再闭塞、支架内血栓形成、新血管流域栓塞均不会直接导致预后不良(P均>0.05)。见表 4

表 4 不良事件对血管内治疗急性缺血性脑卒中患者预后影响的多因素logisitic回归分析 Tab 4 Multivariate logistic regression analysis for effect of adverse events on prognosis of acute ischemic stroke patients receiving endovascular treatment

3 讨论

本研究结果表明对于急性缺血性脑卒中患者,血管内治疗在提高闭塞血管再通率及改善临床预后的同时会导致较高比例的不良事件。不良事件的发生与再灌注损伤、无效再灌注、机械损伤及药物使用等有关,且会降低临床良好预后率。多因素logistic回归分析表明,sICH、进展性缺血性脑卒中是急性缺血性脑卒中患者血管内治疗后预后不良的独立危险因素。

血管内治疗后伴有大血管和/或远端血管闭塞的急性缺血性脑卒中患者的血管再通率达71%~78%,预后良好率为46.0%~62.0%,但也会导致较高比例的不良事件[3, 10]。本组病例血管内治疗总体不良事件发生率为44.8%(230/513),与MR CLEAN研究中不良事件发生率相仿(42.3%~47.2%)[11]。MR CLEAN研究中sICH发生率为7.7%,动脉夹层为1.7%,新血管流域栓塞为8.6%,进展性缺血性脑卒中为19.7%[11]。EXTEND IA研究[12]在选择病例时限定了术前核心坏死体积,因而该研究中术后良好预后率(72%)明显高于MR CLEAN研究(32.6%)[11]。远端血管闭塞能否行血管内治疗目前仍存在争议,但系统综述结果表明,大脑中动脉M2段及以远血管闭塞患者血管内治疗术后良好预后率为62%,sICH发生率为5%[10]。虽然后循环大血管闭塞机械取栓治疗缺乏多中心随机对照研究结果,但单中心数据结果表明血管内治疗能提高后循环闭塞大血管的再通率并改善预后,同时也存在手术相关不良事件,包括颅内出血、再闭塞、新血管流域栓塞和无效再灌注等[13-15]。因此,急性缺血性脑卒中患者行血管内治疗的获益与风险同时存在。

本研究结果显示,不良事件的发生主要与围手术期用药、术中机械损伤和术后再灌注损伤等有关。本组单纯阿替普酶静脉溶栓导致的颅内出血发生率为1.8%(2/113),低于文献报道的4.3%[3];5例(15.6%)新血管流域栓塞的发生与静脉溶栓后血栓碎解、移位相关;8例支架内血栓形成为缺血性脑卒中急性期支架植入术后患者对抗血小板药物不敏感所致。本研究中因取栓装置机械损伤导致的不良事件(病因)包括动脉夹层(支架/导管损伤等)、新血管流域栓塞(取栓时血栓被切割、移位或微导管通过闭塞部位时血栓被推挤到远端等)、颅内出血(导管/导丝穿破血管等)和再闭塞(局部内皮损伤致血栓形成等)等,严重时导致患者死亡。动物实验研究表明,任何取栓器械都会导致血管内皮损伤且程度不一,其中以抽吸取栓损伤最严重[16]。内皮损伤会导致血管痉挛、动脉夹层、原位血栓形成或再闭塞、血管破裂出血。再灌注损伤是导致血管内治疗术后出血转化、脑卒中进展(脑水肿或脑疝等)等不良事件的最重要原因[17]。本研究不良事件发生原因分析结果显示,78.8%(89例)的颅内出血、79.6%(39例)的sICH和40.8%(49例)的进展性缺血性脑卒中均为再灌注损伤所致。术前大面积核心坏死被认为是导致术后再灌注损伤发生和预后不良的重要因素[18];而EXTEND IA研究[12]在选择病例时限定了术前核心坏死体积,故术后无sICH发生。DAWN[19]和DEFUSE 3[20]研究通过对超时间窗患者术前核心坏死体积进行限制,术后90 d mRS评分为0~2分的患者占比(44%~49%)均高于标准药物治疗组,且不良事件未明显增加(sICH发生率为6%~7%,进展性缺血性脑卒中发生率为9%~14%)。本组研究对象术后90 d全因死亡率为12.9%,低于HERMES协作组的汇总分析结果(15.3%)[3]

根据不良事件发生与否进行分组,相比对照组,研究组中位取栓次数多,血管成功再通率和90 d良好预后率低、术后90 d病死率高。文献报道高龄、重度卒中和侧支循环代偿差等是导致急性缺血性脑卒中患者不良预后的危险因素[21-24]。因此,研究组患者年龄偏大、术前NIHSS评分高且ASITN/SIRs评分低等可能是导致术中及术后发生不良事件和预后不良的重要因素。

进一步多因素logistic回归分析结果显示,sICH及进展性缺血性脑卒中与不良预后相关,是预测不良预后的独立危险因素。研究表明,与无sICH患者相比,sICH患者术后90 d良好预后率明显下降、病死率明显增加[21, 24],且多次取栓、侧支循环代偿较差与sICH发生相关[24]。本研究中,研究组的取栓次数多且侧支循环代偿较差(P均<0.01),可能是不良事件中sICH占比较高的原因。本研究中进展性缺血性脑卒中主要表现为无效再灌注或再灌注损伤等导致的脑水肿或脑疝;而脑水肿、脑疝是脑卒中加重和预后不良的影响因素[25-26]。与对照组相比,研究组术前NIHSS评分高、术后血管成功再通率低,这可能导致研究组术后脑水肿、脑卒中进展发生率高,最终引起预后不良[26]

本研究存在以下不足之处:(1)纳入病例时间跨度大、评估手段存在差异与介入材料应用不等,这些均可能导致病例选择和手术操作存在偏差。(2)本组中2017年1月以后的病例虽然采用了RAPID软件评估术前核心坏死体积,但未严格限定血管内治疗前核心坏死体积,部分术前RAPID成像提示大面积核心坏死的患者亦接受了血管内治疗。(3)本组病例行血管内治疗时未严格限定年龄、治疗时间窗(24 h睡眠卒中、串联病变且发病超过24 h但症状突然加重的缺血性脑卒中等)、闭塞部位(前循环远端血管、后循环大血管等)等,可能对结果有一定影响。

综上所述,急性缺血性脑卒中患者进行血管内治疗时术中、术后不良事件的发生会影响术后90 d预后,sICH和进展性缺血性脑卒中是预测不良预后的危险因素。

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