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阿替普酶静脉溶栓治疗轻型缺血性卒中的临床研究

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  [摘要] 目的 探討阿替普酶静脉溶栓治疗轻型缺血性卒中患者的安全性和90 d预后。 方法 选择2015年10月~2018年9月在北京市顺义区医院神经内科收治的110例轻型急性缺血性卒中患者,根据是否行阿替普酶静脉溶栓治疗分为溶栓组和非溶栓组,其中溶栓组42例,非溶栓组68例。比较两组溶栓后24 h美国国立卫生研究院卒中量表评分(NIHSS)、90 d改良Rankin评分及出血转化发生率。 结果 非溶栓组基线NIHSS评分为(1.86±0.55)分,溶栓组基线NIHSS评分为(1.94±0.58)分,差异无统计学意义(P>0.05)。非溶栓组24 h NIHSS评分为(1.69±0.32)分,溶栓组24 h NIHSS评分为(0.95±0.23)分。与非溶栓组患者相比,溶栓组患者24 h NIHSS评分更低,差异有统计学意义(P<0.05)。溶栓组中,与溶栓前NIHSS评分比较,溶栓后24 h NIHSS评分更低,差异有统计学意义(P<0.05)。溶栓组发生出血转化为2例(4.8%),非溶栓组发生出血转化为3例(4.4%),差异无统计学意义(P>0.05)。两组患者均未出现脑实质出血。溶栓组预后良好(mRS≤1分)的患者为38例(90.5%),预后不良(2≤mRS≤6分)的患者为4例(9.5%);非溶栓组预后良好的患者为51例(75.0%),预后不良患者为17例(25.0%),差异有统计学意义(P<0.05)。 结论 轻型急性缺血性卒中患者在发病4.5h内进行阿替普酶静脉溶栓有助于降低24 h NIHSS评分,改善90 d预后,并不增加出血转化。
  [关键词] 轻型缺血性卒中;阿替普酶;溶栓
  [中图分类号] R743.3          [文献标识码] B          [文章编号] 1673-9701(2019)09-0039-04
  [Abstract] Objective To explore the safety and 90-day prognosis of alteplase intravenous thrombolytic therapy in patients with minor ischemic stroke. Methods 110 patients with minor acute ischemic stroke admitted to our hospital from October 2015 to September 2018 were divided into thrombolytic group and non-thrombolytic group according to whether they were treated with alteplase intravenous thrombolytic therapy. There were 42 patients in the thrombolytic group and 68 patients in the non-thrombolytic group. The 24 hours National Institutes of Health Stroke Scale score(NIHSS), 90d modified Rankin score, and hemorrhagic transformation rate were compared after thrombolysis. Results The baseline NIHSS score of the non-thrombolytic group was(1.86±0.55) points, and the baseline NIHSS score of the thrombolytic group was(1.94±0.58) points. The difference was not statistically significant(P>0.05). The NIHSS score of the non-thrombolytic group was(1.69±0.32) points at 24 h, and the NIHSS score at the 24 h of the thrombolytic group was(0.95±0.23) points. Compared with patients in the non-thrombolytic group, the 24 h NIHSS score was lower in the thrombolytic group, and the difference was statistically significant(P<0.05). In the thrombolytic group, compared with the NIHSS score before thrombolysis, the NIHSS score was lower at 24 h after thrombolysis, and the difference was statistically significant(P<0.05). Hemorrhagic transformation occurred in 2 patients(4.8%) in the thrombolytic group and 3 patients(4.4%) in the non-thrombolytic group. The difference was not statistically significant(P>0.05). No brain parenchymal hemorrhage occurred in either group. In the thrombolytic group, 38 patients(90.5%) had a good prognosis(mRS≤1), and 4 patients(9.5%) had a poor prognosis(2≤mRS≤6). The patients with good prognosis in the non-thrombolytic group were 51 patients(75.0%), and 17 patients(25.0%) had poor prognosis, and the difference was statistically significant(P<0.05). Conclusion Intravenous thrombolysis with alteplase within 4.5 hours of onset of minor acute ischemic stroke helps to reduce the 24 h NIHSS score, improve the 90 d prognosis, and does not increase hemorrhagic transformation.   [Key words] Minor ischemic stroke; Alteplase; Thrombolysis
  国外学者Von Weitzel-Mudersbach P等[1]报道小卒中及短暂性脑缺血发作占急性缺血性脑血管病事件的65%,且90 d卒中复发高达10%~15%[2,3]。1995年美国国立神经病与卒中研究院(National Institute of Neurological Disorders and Stroke,NINDS)[4]的研究首次证实符合适应证急性缺血性脑卒中(acute ischemic stroke,AIS)患者发病3 h内静脉阿替普酶溶栓是安全有效的,能显著增加生存及非残疾比例,2008年欧洲急性卒中协作组[5]研究将阿替普酶静脉溶栓时间窗扩大至4.5 h,目前已被国内外指南[6,7]推荐为静脉溶栓首选药物。国内指南将轻型缺血性卒中(minor ischemic stroke,MIS)列为相对禁忌证,但未接受溶栓治疗的轻型卒中患者的预后并不理想[8]。因此,本研究探讨轻型卒中患者阿替普酶静脉溶栓的安全性与有效性。
  1 资料与方法
  1.1一般资料
  选择2015年10月~2018年9月在北京市顺义区医院神经内科收治的首发急性轻型缺血性卒中患者110例,并根据是否进行阿替普酶静脉溶栓治疗分为溶栓组及非溶栓组。纳入标准:(1)有缺血性卒中导致的神经功能缺损症状;(2)症状出现<4.5 h;(3)年龄≥18岁;(4)患者或家属签署知情同意书;(5)美国国立卫生研究院卒中量表(National Institute of Health stroke scale,NIHSS)≤3分且每一单项均为0或1分,意识项为0分[4,9];(6)既往有卒中史。排除标准:(1)近3个月有重大头颅外伤史或卒中史;(2)可疑蛛网膜下腔出血;(3)近1周内有在不易压迫止血部位的动脉穿刺;(4)既往有颅内出血;(5)颅内肿瘤、动静脉畸形、动脉瘤;(6)近期有颅内或椎管内手术;(7)血压升高:收缩压≥180 mmHg,或舒张压≥100 mmHg;(8)活动性内出血;(9)急性出血倾向,包括血小板计数低于100×109/L或其他情况;(10)48 h内接受过肝素治疗(活化部分凝血活酶时间超出正常范围上限);(11)已口服抗凝剂者INR>1.7或PT>15 s;(12)目前正在使用凝血酶抑制剂或Xa因子抑制剂,各种敏感的实验室检查异常(如活化部分凝血活酶时间、国际标准化比值或恰当的Xa因子活性测定等);(13)血糖<2.7 mmol/L;(14)CT提示多脑叶梗死(低密度影>1/3大脑半球)。共收集急性轻型缺血性卒中患者110例,男73例,女37例,年龄37~77岁。其中溶栓组42例,男27例,女15例,年龄41~76岁,平均(58.10±11.01)岁;非溶栓组68例,男46例,女22例,年龄37~77岁,平均(56.75±11.88)岁。两组年龄、性别、发病至就诊时间、高血压病、2型糖尿病、高脂血症、吸烟史及饮酒史等资料差异无统计学意义(P>0.05),见表1。
  1.2 治疗方法
  静脉溶栓组:按照0.9 mg/kg计算患者需要的药物剂量,最大剂量不超过90 mg。应用药品自带的灭菌注射用水稀释,其中10%阿替普酶在1 min内静脉推注,剩余90%微量泵在1 h泵完,24 h后复查头颅CT,排除脑出血转化及脑出血后,给予阿司匹林肠溶片(拜耳医药保健有限公司生产)100 mg Qd至90 d。非溶栓组根据Wang Y等[9]的氯吡格雷联合阿司匹林治疗急性小卒中或短暂性脑缺血发作疗效(Clopidogrel with aspirin in acute minor stroke or transient ischemic attack,CHANCE),研究第1天给予阿司匹林100 mg及硫酸氢氯吡格雷(赛诺菲制药有限公司生产)300 mg,次日以后每日给予阿司匹林100 mg Qd及硫酸氢氯吡格雷75 mg Qd共20 d,随后给予阿司匹林100 mg Qd或硫酸氢氯吡格雷75 mg Qd至90 d。
  1.3 观察指标
  1.3.1 一般资料  由神经内科专科医师登记所有入组患者的临床资料,包括基线NIHSS评分、24 h NIHSS评分,记录患者年龄、性别、高血压、糖尿病、高血脂、吸烟史、饮酒史等。
  1.3.2 出血转化评价  依据欧洲协作组急性卒中研究[10]分为以下两型:①出血性梗死(Hemorrhagic infraction,HI):梗死灶边缘少量渗血或梗死范围内片状出血,但无占位效应;②脑实质出血(Parenchymal Hemorrhage,PH):血肿形成并伴有占位效应,或者出现在梗死灶远隔部位的出血。溶栓组24 h后复查头颅CT,两组临床症状加重时均急查头颅CT。
  1.3.3 预后及复发评价标准  90 d预后评价:用改良Rankin量表(modified Rankin scale,mRS)对患者预后进行评估,国内外大型临床研究[4,9]均设定mRS评分≤1分为预后良好,2~6分為预后不良,本文也采用上述标准。
  1.3.4 神经系统缺损症状  采用美国国立卫生研究院卒中量表[11](National Institute of Health stroke scale,NIHSS),共15项,包含意识水平、意识水平提问、意识水平指令、凝视、视野、面瘫、上下肢运动、肢体共济失调、感觉、语言(命名、阅读测试)、构音障碍、忽视,总分42分,分数越高,病情越重。
  1.4 统计学方法
  采用SPSS18.0统计软件进行数据分析。计量资料用(x±s)表示,计量资料比较采用t检验,计数资料用绝对数和百分数表示,计数资料组间比较采用χ2检验。等级资料采用秩和检验,以P<0.05为差异有统计学意义。   2 结果
  2.1 两组基线NIHSS评分及24 h NIHSS评分比较
  非溶栓组基线NIHSS评分为(1.86±0.55)分,溶栓组基线NIHSS评分为(1.94±0.58)分,差异无统计学意义(P>0.05),见表2。非溶栓组24 h NIHSS评分为(1.69±0.32)分,溶栓组24 h NIHSS评分为(0.95±0.23)分。与非溶栓组相比,溶栓组24 h NIHSS评分更低,差异有统计学意义(P<0.05)。溶栓组溶栓前后NIHSS评分比较,溶栓后24 h NIHSS评分更低,差异有统计学意义(P<0.05)。
  2.2 两组出血转化比较
  溶栓组发生出血转化2例,比例为4.8%,非溶栓组发生出血转化3例,比例为4.4%,差异无统计学意义(P>0.05)。两组患者均未出现脑实质出血。
  2.3 两组90 d mRS比较
  溶栓组预后良好的患者为38例,比例为90.5%,预后不良的患者为4例,比例为9.5%;非溶栓组预后良好的患者为51例,比例为75.0%,预后不良患者为17例,比例为25.0%,差异有统计学意义(P<0.05),见表3。
  3 讨论
  目前MIS的定义并没有统一标准,Park TH等[12]研究將NIHSS≤1分定义为MIS,而美国国立神经病与卒中研究院[13]在2005年将轻型缺血性卒中定义为≤6分,但NINDS[4]研究及CHANCE研究[9]均将轻型缺血性卒中定义为≤3分,且NIHSS≤3分是临床研究中常用的轻型缺血性卒中定义标准,故本研究入组设定为NIHSS≤3分患者。
  尽管一些患者表现为非致残性轻型缺血性卒中,但这些患者中有40%发展为致残性卒中[14]。Smith EE等[15]研究收集1092家医院在2 h内到达医院的近3万例急性轻型缺血性卒中和快速缓解的缺血性卒中未进行静脉溶栓治疗患者,这些患者中有高达28.5%患者在出院时需要借助帮助才能行走,3个月仍有致残可能。轻型缺血性卒中目前是否进行静脉溶栓仍有争议,有研究[15-18]显示轻型缺血性卒中静脉溶栓是安全有效的,但也有研究[4,18,19]显示轻型缺血性卒中静脉溶栓并未获益。
  本研究中溶栓组患者24 h时NIHSS评分低于基线NIHSS评分及低于非溶栓组患者,差异有统计学意义,说明4.5 h内阿替普酶静脉溶栓治疗能改善短期神经功能,与Logallo N等[20]研究结果一致。目前静脉溶栓在血管再通的同时,容易出现出血转化及脑实质出血等严重的并发症。本研究中溶栓组发生出血转化为2例,出血转化率为4.8%,于若梅等[21]的研究出血转化发生率为6%,略高于本研究,考虑与于若梅的研究入组患者NIHSS≤5分、临床症状更重有关。本研究溶栓组未出现脑实质出血,与急性缺血性卒中溶栓治疗的第三国际卒中试验亚组分析[22]及于若梅等[21]的研究一致。
  本研究中溶栓组预后良好的患者比例为90.5%,非溶栓组预后良好的患者为75.0%,差异有统计学意义,提示阿替普酶静脉溶栓治疗能改善轻型卒中患者的90 d预后。Frank B等[23]研究发现轻型缺血性卒中患者静脉溶栓并未获益,Huisa BN等[24]研究发现溶栓组与非溶栓组患者90 d预后良好率差异无统计学意义。这些与本研究的结论不同,考虑与纳入标准、种族差异有关。卒中溶栓安全实施-国际卒中溶栓登记研究[24,25]显示轻型卒中患者静脉溶栓90 d预后良好的比例高,与本研究相似。
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  (收稿日期:2018-12-12)
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