丁苯酞联合阿替普酶治疗缺血性卒中临床疗效的观察性研究

doi:10.3969/j.issn.1673-5765.2019.03.006

摘要/Abstract

摘要：

目的探讨丁苯酞联合阿替普酶静脉溶栓治疗缺血性卒中的临床疗效及安全性。方法回顾性分析青岛大学附属烟台毓璜顶医院急性缺血性卒中行静脉溶栓患者205例的队列，其中联合治疗组（阿替普酶+丁苯酞组）112例，阿替普酶组93例。分析两组患者溶栓后即刻及14 d后 NIHSS评分，90 d的mRS评分，并分析不同急性卒中治疗低分子肝素试验（Trial of Org 10 172 in Acute Stroke Treatment，TOAST）分型中的临床疗效。同时分析溶栓后14 d症状性颅内出血及死亡情况。结果 ①溶栓后两组NIHSS评分差异无统计学意义。溶栓后14 d联合治疗组NIHSS评分低于阿替普酶组，差异有统计学意义（[ 4.82±0.44）分 vs（6.40±0.66）分，P=0.041]。联合治疗组90 d预后良好率高于阿替普酶组，差异有统计学意义（72.3% vs 55.9%，P =0.014）；其中LAA亚型中联合治疗组患者NI HSS评分（P =0.023）及预后良好率（P =0.045）均高于阿替普酶组，差异有统计学意义。②治疗后90 d两组死亡率及14 d颅内出血率差异无统计学意义。③多因素回归分析结果显示丁苯酞是改善缺血性卒中溶栓患者预后的保护因素（OR 0.425，95%CI 0.216～0.835，P =0.013）；年龄＞60岁（OR 2.233，95%CI 1.047～4.766，P =0.038）、入院时收缩压＞160 mm Hg（OR 2.295，95%CI 1.126～4.679， P =0.022）、溶栓前NIHSS评分＞10分（OR 9.354，95%CI 4.049～21.610，P＜0.001）是预后的独立危险因素。结论丁苯酞联合阿替普酶静脉溶栓治疗缺血性卒中患者能改善90 d临床预后，对LAA患者可能更有效。

文章导读： 本文回顾性的在病例对照组中探讨了丁苯酞在急性缺血性患者溶栓是联合应用的安全性和有效性，结果发现丁苯酞可以进一步改善溶栓患者的神经功能，并改善溶栓后90 d预后。

关键词: 缺血性卒中; 溶栓; 预后; 出血转化; 丁苯酞

Abstract:

Objective To investigate the clinical effect of butylphthalide in ischemic stroke patients with intravenous thrombolysis. Methods A retrospective analysis of 205 ischemic stroke patients treated by intravenous thrombolysis from Yantai Yuhuangding Hospital Affiliated to Qingdao University was performed. The patients were divided into combination group (n =112, rt-PA+butylphthalide) and rt-PA group (n =93). Clinical efficacy was assessed by the NIHSS scores immediately after thrombolysis, the NIHSS scores at 14 days after thrombolysis and the mRS scores at 90 days after thrombolysis. The difference in clinical efficacy among different TOAST subtypes were also analyzed. The safety outcome was evaluated by intracranial hemorrhage within 14 days and mortality at 90 days. The difference of clinical efficacy and safety between the two groups were compared. Results (1) There was no statistical difference in the NIHSS score immediately after thrombolysis between two groups. The NIHSS score at 14 days in combination group significantly decreased than that in rt-PA group [(4.82±0.44) vs (6.40±0.66), P =0.041]. The good prognosis (mRS ≤2 score) rate at 90 days was higher in combination group than that in rt-PA group (72.3% vs 55.9%, P =0.014).Of all TOAST subgroups in combination group, the clinical efficacy (14-day NIHSS score and 90- day mRS score) in large-artery atherosclerosis (LAA) subgroup was best and significantly better than that in rt-PA group. (2) There were no statistical difference in safety outcome between the two groups. (3) Multiple-factor analysis showed butylphthalide was protective factor (OR 0.425, 95%CI 0.216-0.835, P =0.013) for prognosis in ischemic stroke patients, and age >60 years (OR 2.233, 95%CI 1.047-4.766, P =0.038), systolic blood pressure>160 mm Hg at admission (OR 2.295, 95%CI 1.126-4.679, P =0.022), and NIHSS score >10 before thrombolysis (OR 9.354, 95%CI 4.049- 21.610, P <0.01) were independent risk factors for prognosis in stroke patients with intravenous thrombolysis. Conclusions Butylphthalide injection used in ischemic stroke patients with intravenous thrombolysis can further improved short-term prognosis comparing with only intravenous thrombolysis, especially in LAA subgroup.

Key words: Ischemic stroke; Thrombolysis; Outcome; Hemorrhagic transformation;Butylphthalide

侯园园，梁志刚，孙旭文，杨绍婉，李冰，胡银宝. 丁苯酞联合阿替普酶治疗缺血性卒中临床疗效的观察性研究[J]. 中国卒中杂志, 2019, 14(03): 225-230.

HOU Yuan-Yuan, LIANG Zhi-Gang, SUN Xu-Wen, YANG Shao-Wan, LI Bing, HU Yin-Bao. The Effect of Butylphthalide Combined with Alteplase Thrombolysis in Patients with Ischemic Stroke[J]. Chinese Journal of Stroke, 2019, 14(03): 225-230.

参考文献

[1] 黄石，周峰，张颖冬. 替罗非班在急性缺血性卒中中

的研究进展[J]. 中国脑血管病杂志，2018，15（11）：

601-606.

[2] 卢桃利，张蓓. 1例脑梗死静脉溶栓病例的思考[J]. 中

国卒中杂志，2018，13（6）：612-615.

[3] 刘昌亚，胡学斌，熊志勇，等. 丁苯酞注射液对动脉

瘤性蛛网膜下腔出血早期脑损伤的作用与机制探讨

[J]. 中国卒中杂志，2018，13（7）：692-695.

[4] YAN C，FENG Y. Effects of butylphthalide on

extracellular 6-keto-PGF1 alpha，TXB2 and 6-keto-

PGF1 alpha/TXB2 ratio in cultured rat cortical

neurons[J]. Yao Xue Xue Bao，1998，33（12）：881-

885.

[5] 杨绍婉，梁志刚，于国平. 缺血性卒中静脉溶栓后有

症状颅内出血：预测和治疗[J]. 国际脑血管病杂志，

2018，26（3）：201-206.

[6] 中华医学会神经病学分会脑血管病学组急性缺血性

脑卒中诊治指南撰写组. 中国急性缺血性脑卒中诊

治指南2010[J]. 中国全科医学，2011，14（35）：4013-

4017.

[7] POWERS W J，RABINSTEIN A A，ACKERSON

T，et al. 2018 guidelines for the early management of

patients with acute ischemic stroke：a guideline for

healthcare professionals from the American Heart

Association/American Stroke Association[J]. Stroke，

2018，49（3）：e46-e110.

[8] 胡火有，肖小华，雷志浩. 阿替普酶静脉溶栓联合丁

苯酞治疗超早期脑梗死的疗效观察[J]. 现代诊断与

治疗，2018，29（11）：1698-1700.

[9] 曹国军，张行丰，郑科达. 丁苯酞联合阿替普酶对急

性缺血性脑卒中患者神经保护作用及血清炎性标志

物的影响[J]. 浙江医学，2018，40（11）：1194-1198.

[10] LIU R Z，FAN C X，ZHANG Z L，et al. Effects of

Dl-3-n-butylphthalide on cerebral ischemia infarction

in rat model by mass spectrometry imaging[J/OL].

Int J Mol Sci，2017，18（11）：e2451. https：//doi.

org/10.3390/ijms18112451.

[11] 董高翔，冯亦璞. 丁基苯酞对局部脑缺血再灌注大

鼠脑线粒体ATPase，抗氧化酶活性和脂质过氧化的

影响[J]. 中国医学科学院学报，2002，24（1）：93-97.

[12] ZHAO Y，LEE J H，CHEN D，et al. DL-3-

n-butylphthalide induced neuroprotection，

regenerative repair，functional recovery and

psychological benefits following traumatic brain

injury in mice[J]. Neurochem Int，2017，17（111）：

82-92.

[13] 侯园园，梁志刚，孙旭文. 丁苯酞对缺血性脑卒中的

保护机制及治疗研究进展[J]. 医学综述，2018，

24（19）：103-108.

[14] YAN C，FENG Y. Protective effects of d-，l-，and

dl-3-n-butylphthalide on neuronal damage induced

by hypoxia/hypoglycemia in cultured rat cortical

neurons[J]. Yao Xue Xue Bao，1998，33（7）：486-

492.

[15] LI L，ZHANG B，TAO Y，et al. DL-3-nbutylphthalide

protects endothelial cells against

oxidative/nitrosative stress，mitochondrial damage

and subsequent cell death after oxygen glucose

deprivation in vitro[J]. Brain Res，2009，20（1290）：

91-101.

[16] 黄家星，林文华，刘丽萍，等. 缺血性卒中侧支循环

评估与干预中国专家共识[J]. 中国卒中杂志，2013，

8（4）：285-293.

[17] KONG S Y，LI Q F，YANG J，et al. The effect of

butylphthalide on expression of NGF and BDNF in

ischemia stroke tissue of rat cerebrum[J]. Sichuan

Da Xue Xue Bao Yi Xue Ban，2007，38（3）：400-

403，407.

[18] JIANG Y，SUN L，XUAN X，et al. Impacts of

N-Butylphthalide on expression of growth factors

in rats with focal cerebral ischemia[J]. Bosn J Basic

Med Sci，2016，16（2）：102-107.

[19] 徐皓亮，冯亦璞. 丁基苯酞对局灶性脑缺血大鼠软

脑膜微循环障碍的影响[J]. 药学学报，1999，34（3）：

13-16.

[20] XUE L X，ZHANG T，ZHAO Y W，et al. Efficacy

and safety comparison of DL-3-n-butylphthalide and

Cerebrolysin：Effects on neurological and behavioral

outcomes in acute ischemic stroke[J]. Exp Ther Med，

2016，11（5）：2015-2020.

[21] MOHR J P，CAPLAN L R，MELSKI J W，et al. The

Harvard Cooperative Stroke Registry：a prospective

registry[J]. Neurology，1978，28（8）：754-762.

[22] SACCO R L，ELLENBERG J H，MOHR J P，et al.

Infarcts of undetermined cause：the NINCDS Stroke

Data Bank[J]. Ann Neurol，1989，25（4）：382-390.

[23] VACLAVIK D，VILIONSKIS A，JATUZIS D，et

al. Clinical outcome of cardioembolic stroke treated

by intravenous thrombolysis[J]. Acta Neurol Scand，

2018，137（3）：347-355.

[24] DANOUN O，SACHAR P，RAJAMANI K.

Thrombolysis for Acute Ischemic Stroke After

Protamine Reversal of Heparin[J]. Am J Ther，

2018，25（5）：e552-e554. https：//doi.org/10.1097/

MJT.0000000000000634.

[25] YAGHI S，WILLEY J Z，CUCCHIARA B，et al. 急

性缺血性卒中静脉阿替普酶溶栓后出血转化的治疗

和结局：美国心脏协会/美国卒中协会科学声明[J].

中国脑血管病杂志，2018，15（7）：386-392.