急性缺血性脑卒中阿替普酶溶栓预后影响因素临床研究
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摘要
背景和目的
据国家卫生部第三次全国死亡原因调查显示,急性脑卒中已经成为中国人疾病死亡第一位死亡原因,首次超过了恶性肿瘤和心血管疾病。中国脑卒中年发病率超过200万,每年150万人因脑卒中死亡,死亡率已经是西方发达国家的4到5倍,是日本的3.5倍,未来国家第十二个五年计划,已经把降低脑卒中死亡率作为首要解决的重大科技攻关课题。急性脑卒中构成中,大约75%为缺血性卒中。中国城镇地区缺血性脑卒中死亡率约为38.7%,其中大部分患者死于发病一个月之后,但是国内关于缺血性脑卒中死亡原因尚未见到详尽的调查报告。组织型纤溶酶原激活剂(阿替普酶)是目前唯一被批准用于临床救治急性缺血性脑卒中的药物,国外大型、前瞻性、多中心临床试验已经证明了阿替普酶的安全性和有效性,但是该药在中国的使用尚不普及,据统计,发病3小时内到达医院,符合溶栓标准的超急性脑卒中患者,阿替普酶使用率仅为1.9%。西方国家的荟萃分析显示,随着溶栓时间窗的延迟超过4.5小时,脑卒中患者的死亡率轻微增加,但是死亡的增加与溶栓后出血性转化并无显著关系。这些证据表明,仍然有潜在的重要因素影响了脑卒中溶栓后的死亡率,比如年龄、性别、种族、卒中严重程度、并发症和某些临床变量。虽然阿替普酶已经被批准用于中国人群,但是到目前为止,尚没有大型的、安慰剂对照的临床研究,验证该药在国人中的有效性。影响溶栓后转归的决定因素,仍然缺乏有力的临床证据。本研究的目标,是分析脑卒中溶栓后预后的影响因素,特别是死亡这个明确的临床终点事件的影响因素,为今后的临床干预、减少脑卒中的死亡率做好前期工作。
对象和方法
病人的选择和测量方法：我们以国际疾病编码第十版中,出院诊断编码为I63-I67的患者为检索对象,查找了自2005年初至2011年4月连续登记在库的脑梗塞患者。由于急性缺血性脑卒中的定义缺乏统一的国际标准,我们在研究中将其定义为,由于脑部缺血快速出现的脑功能障碍,后期这种确切的损害可以被影像学证实,比如磁共振弥散成像、计算机断层扫描；或计算机断层血管成像、磁共振血管成像和数字减影血管成像技术。研究包含的“确切”脑卒中患者,发病时间均在72小时内,所有患者接受过组织型纤溶酶原激活剂(阿替普酶,德国勃林格殷格翰公司制造)。入选标准如下：(1)溶栓前美国国立卫生院卒中量表(NIHSS)评分4-26分；(2)阿替普酶静脉或动脉溶栓；(3)溶栓前脑部CT平扫或磁共振未见病灶形成,或低信号区域小于三分之一血管供血区域；排除标准与美国的NINDS试验类似,但是未排除即往有卒中史的患者,同时也未排除使用胰岛素控制血糖低于22.2mmol/L者,或使用了压宁定控制血压在185/11OmmHg以下的患者。另外凝血指标轻度异常和血小板异常患者也未排除。收集数据使用了Microsoft(?) Office Excel2003软件,并进行了双录入和数据核查。收集的变量包括最接近溶栓时刻前的年龄、性别和体重。实验室资料包括血肌钙蛋白、肌酐、尿素氮、肌酸肌酶、总胆固醇、高密度和低密度脂蛋白；谷丙转氨酶、总蛋白、总胆红素、血糖和碳酸氢盐；测量设备Automatic Test System-LX20。凝血酶原时间、部分凝血活酶时间、国际标准比值和纤维蛋白原,测量仪为Coagulation Analyzer-Sta-R。白细胞计数、中性粒细胞和淋巴细胞计数,红细胞计数、血球压积和血小板计数仪为Automatic Blood Cell Analyzer-LH755。溶栓前患者头部的影像学评价,由我院放射科工作人员回顾性进行评价,其中第一部分包括了重要指标----CT的大脑中动脉致密征,第二部分增加了CT溶栓后出血性转化和溶栓后血管再通TIM1分级的评价。心血管异常定义为任何以下发现之一：心电图发现的心房颤动、心房扑动、心律不齐和ST段的异常；或者超声心动图发现的中度以上瓣膜返流、附壁血栓或间隔缺陷。生命体征变量包括腋下体温、脉搏、血氧饱和度、收缩压和舒张压水平,均经由IntelliVue Information Center System监护系统获得。治疗时间窗定义为症状出现到治疗前的时间,程序性延误指患者达到医院至接受溶栓治疗的时间。阿替普酶的剂量和溶栓途径由医嘱单获得。静脉溶栓按照NINDS研究的流程执行,动脉溶栓在脑血管造影,发现责任血管后,导管内注入阿替普酶进行选择性溶栓。卒中严重程度评分,部分已由神经内科执业医师前瞻性地记录在病案中,其余分值由我科一名神经专科护师进行回顾性评定,该护师2009年曾作为访问学者,在香港威尔氏亲王医院获得了NIHSS评分的国际资格证书。患者重要的既往病史,如高血压、糖尿病、卒中史、房颤史、心衰史和家族卒中史,通过住院病历和门诊病历或服药记录得以确认。2011年7月前完成了电话随访、信访或登门造访。预后指标分为良好(改良的Rankin量表0-2分)和不良(改良的Rankin量表3-6分),同时登记和核实了患者的全因死亡。统计学分析：用线性回归法替代部分缺失的连续性变量。因为数连续型变量多为偏态分布,故以中位数加四分位间距或全距表示；定类变量以百分比表示。组间差异使用Mann-Whitney U检验、卡方检验或Fisher's精确概率检验。多因素分析过程时,分类变量采取两两比较方法。由于原始自变量较多,事先已经进行了变量筛选,目的在于挑选与预后变量有潜在相关的自变量,并检查自变量之间的共线性；自变量的共线性先用二元相关性检验,如果相关系数大于0.8,则通过专业知识,对相同或相近属性的自变量进行合并、替代或是删除,最终保持自变量之间相对的独立性,使相关性不再明显；例如,自变量“凝血酶原时间”和“国际标准比值”的相关系统为0.984,P=0.000,我们选择国际标准比值作为候选变量,因为两者都是凝血功能常用指标,但临床上最常用的指标是国际标准比值,不常用凝血酶原时间的绝对值。其后,利用逐步回归法进一步消除自变量共线性,筛选有意义的变量。二分类Logistic回归中,为了发现潜在对临床结局有独立影响的因素,并进一步排除自变量之间的共线性,从临床简便和实用性出发,纳入多因素回归分析的自变量,除组间有显著性差异者之外,同时校正了人口学变量、溶栓治疗中重要的时间窗、溶栓途径、用药剂量和临床常用的生命体征、生化指标等自变量。采取逐步后退法,最大似然比检验,步进入选和剔除标准分别为0.05和0.10,界值点设为0.5,最大迭代20次；同时检验了模型的意义和Hosmer-Lemeshow拟合优度。事后分析中,采用ROC曲线决定有意义自变量的界值,并与其他自变量进行Logistic回归分析,寻找可能的解释因素。Alpha值设定为0.05(双侧)。统计软件为IBM (?) SPSS(?) Statistics versionl9。
结果
第一部分共纳入了90名患者,1例失访,89例(98.9%)进行了单因素分析,但是7例(7.8%)患者缺失大脑中动脉致密征资料,4例(4.5%)缺失心脏异常资料,最后,一共82例(91.1%)患者进行了多因素分析。所有患者均是中国汉族,男性40名,占44.9%；女性49名,占55.1%；8例(8.9%)有既往脑卒中病史,但是mRs评分低于3分。自变量中,低密度脂蛋白、中性粒细胞计数和凝血酶原时间因为和其所属类别其他自变量的高度共线性,故予移除。年龄中位数为72岁,体重为59公斤,NIHSS评分13分,治疗时间窗4.42小时,阿替普酶用量为50毫克。60名患者(67.4%)接受了静脉溶栓治疗,而29名患者(32.6%)接受了动脉溶栓。一共16名患者三个月内死亡,而且所有病例均死于脑卒中后30天之内,死亡率为17.98%(16/73,n=89)。死亡组患者和生存组比较,NIHSS评分较严重,国际标准比值和白细胞水平均较高。另外,死亡组CT提示大脑中动脉致密征比例高于生存组,并且家族卒中史比例偏高,呈现出统计学边缘效应。二分类Logistic回归中,共纳入13个与溶栓后死亡结局可能有关的自变量：性别、年龄、NIHSS评分、白细胞计数、国际标准比值、大脑中动脉致密征、卒中家族史、时间窗、用药剂量、血糖水平、体温、收缩压和血氧饱和度。两个自变量在多因素、逐步回归后显示与死亡结局独立相关：NIHSS评分(P=0.001, OR1.48,95%C.I.1.18-1.86);体温(P=0.028, OR4.60,95%C.I.1.18-17.94);血氧饱和度(P=0.054, OR0.71,95%C.I.0.49-1.01)则显示了统计学有意义趋势。模型卡方为41.493(P=0.000); Nagelkerke R方为0.633,说明回归方程解释了影响因素的63.3%。Hosmer-Lemeshow卡方检验不显著(x2=0.927,P=0.999)。模型预测死亡的准确性达到89.0%。预测死亡概率C统计曲线下面积达到了0.939,P=0.000,95%C.I.0.889-0.990；估计个体死亡概率的方程为：y(?)=-31.280-0.349SPO2+1.526BT+0.395NIHSS+1.688HMCAS.另外,考虑到体温昼夜的生理波动,我们分析了这种变化对死亡的影响；根据体温生理波动规律,将时间段分为5-10点、11-18点和19-4点三段,卡方检验显示三个时间段内入院患者最后死亡结局无差异(,=1.164,P=0.559)。从临床实际意义考虑,急性缺血性脑卒中患者,基线时较高的NIHSS评分和较高的体温与溶栓后90天死亡独立相关,患者NIHSS评分每增加1分,溶栓后死亡可能性就增加1.48倍；体温每升高1摄氏度,死亡增加4.6倍。血氧饱和度低下也显示了对死亡有影响的趋势；事后分析中,体温变量ROC曲线下面积为0.620,血氧饱和度为0.608,体温变量分界值为36.9摄氏度,血氧饱和度分界值为96%。多因素分析一共纳入8个候选自变量(总胆固醇、血糖、糖尿病史、心功能不全、家族卒中史、年龄、体重和时间窗),与体温二分类变量进行Logistic回归。结果发现高血糖(P=0.008, OR,1.286,95%C.I.1.066-1.551)和家族卒中史(P=0.007, OR,9.191,95%C.I.1.827-46.241)与体温二分类相关。挑选9个自变量(药物剂量、时间窗、年龄、总蛋白、白细胞计数、血小板计数、收缩压、糖尿病史和心功能不全史)与血氧饱和度进行回归分析,也显示糖尿病(P=0.008, OR,0.182,95%C.I.0.052-0.634)与低血氧饱和度有关,同时血小板计数增高者,与低氧饱和度也有关(P=0.031, OR,0.990,95%C.I.0.981-0.999).糖尿病患者,发生急性缺血性脑中风时,更有可能在入院时表现出更高的体温和偏低的血氧饱和度；同样,有家族卒中史的患者,发病时也更容易出现体温上升。在第二部分中,数据库中追加了另外6名患者的资料,我们比较了中国人急性缺血性卒中阿替普酶静脉溶栓和动脉溶栓的安全性和有效性。入选标准和排除标准与第一部分相同。自变量中,重新评估了脑卒中的OCSP亚型和TOAST分型。预后指标中,加入了溶栓后出血性转化和责任血管的再通率。64名患者接受了静脉溶栓,32名接受了动脉溶栓。总的90天预后良好率达到了43.8%。单因素分析显示,动脉溶栓与静脉溶栓费用(47623.6VS.25699.8元)、院内程序性延误时间(3：10VS.1：44小时)、溶栓时间窗(5.54VS.3.58小时)、阿替普酶用量(20VS.50mg)有统计学差异。预后指标中,两种溶栓方式血管再通率(64.9%VS.53.8%)、出血性转化率(25%VS.31.3%)、预后良好率(45.3%VS.40.6%)和死亡率(22.2%VS.9.4%)均无显著性差异。溶栓途径对预后不良无独立影响(P=0.263, OR2.24,95%CI0.55-9.15)。但是血管的再通与否,与功能学预后独立相关(P=0.036, OR0.25,95%CI0.07-0.91)
结论
接受阿替普酶溶栓的急性缺血性脑卒中患者,治疗前较高的NIHSS评分、早期升高的体温和较低的血氧饱和度,可能与治疗后90天的死亡率有关。阿替普酶动脉溶栓和静脉溶栓90天预后良好比例、溶栓后出血转化率和死亡率无显著性差异。
Background and purpose
Stroke has ranked the first cause of death in China. The annual incidence of stroke exceeds2million and1.5million dead,4to5times higher than that of western countries, approximately75%are ischemic. The mortality of ischemic stroke in Chinese population is about38.7%in urban areas, most people died28days later after the ischemic attack, but the risk factors predicting death have not been fully elucidated. Although recombinant tissue plasminogen activator has been proved safe and effective in acute ischemic stroke therapy by large clinical trials, it is poorly used in China; only1.9%patients with acute ischemic stroke, who reached hospitals with symptoms onset within3hours, received thrombolysis. In western countries, pooled analysis have shown stroke mortality increased slightly with delay of thrombolysis of which onset-to-treatment time exceeded4.5hours and did not correlate with parenchymal hemorrhagic transformations, implying that there are still important factors such as age, gender, race, stroke severity, comobidities and clinical parameters that might affect death rate. Because of the lack of controlled clinical trials concerning thrombolysis in China, the truth is unclear. We aim to analyze predicting factors of mortality and hypothesize that some baseline clinical variables might also affect clinical outcome within90days after stroke in Chinese patients who have received tissue plasminogen activator therapy.
Subjects and methods
Patients'selection and measurements:we searched patients diagnosed with International Classification of Diseases10th edition163-167at discharge who were prospectively and consecutively registered in our database from January,2005to April,2011. Because of the lack of uniform international classification of acute ischemic stroke, we defined it as rapidly developing loss of brain functions due to cerebral ischemia in study cohort, which was definitely demonstrated later by neuro imaging such as diffusion weighted image, computed tomography; or computed tomography angiography, magnetic resonance angiography and digital subtraction angiography. Patients with documented "definite" stroke with symptoms onset within72hours, who received tissue plasminogen activator (Actilyse(?), Boehringer Ingelheim GmbH), were included in this analysis. Inclusion criteria were:(1) National Institutes of Health Stroke Scale4to26before treatment;(2) tissue plasminogen activator used either intravenously or intra-arterially;(3) routine brain CT or magnetic resonance image at baseline negative or hypo dense size less than1/3blood supply area; Exclusion criteria were similar to those of NINDS trial, except prior ischemic stroke, and occasional use of insulin to control glucose level under22.2mmol per liter, or urapidil to lower high blood pressure preceding thrombolysis, which exceeded185/110millimeters of mercury. Patients with abnormal prothrombin time, or activated partial thromboplastin time and abnormal platelet counts were not excluded. Patient's clinical variables, which nearest to the time point before thrombolysis, were collected using Microsoft Office Excel2003and were double entry and validated:age and gender, identified by resident card; body weight, obtained by self report or relatives or friends. Laboratory data:troponin, creatine kinase, blood urea nitrogen, creatinine, total cholesterol, high and low density lipoprotein, alanine aminotransferase, total protein, total bilirubin, blood glucose and bicarbonate were tested by Automatic Test System-LX20; prothrombin time, activated partial thromboplastin time, international normalized ratio and fibrinogen were tested by Coagulation Analyzer-Sta-R; white blood cell counts, neutrophil and lymphocyte counts, red blood cell counts, hematocrit and platelet counts were tested by Automatic Blood Cell Analyzer-LH755. Radiographic manifestations of brain CT, which was accomplished before treatment, were retrospectively assessed by radiologist who was unaware of the therapeutic regime, including hyper dense middle cerebral artery sign on CT in part1, hemorrhagic transformation and TIMI scale of re-canalization in part2. Cardiac abnormalities were defined as atrial fibrillation, atrial fluttering, arrhythmia and ST segment abnormalities verified by electrocardiograms or moderate to severe heart valve regurgitation, thrombus or septal defect by ultrasonography. Vital signs such as axilla body temperature, pulsation, and pulse oxygen saturation, systolic and diastolic blood pressure were collected through IntelliVue Information Center System. Onset to treatment time means the time loss after the symptoms onset until alteplase infusion, calculated automatically via Excel2003as onset and treatment time variables entered. Procedural delay indicates the preparation time loss before thrombolysis. Dosage of alteplase of each individual patient was obtained from the record of doctor's advice. Route of thrombolysis was the route of alteplase administration, which either intravenously as per NINDS protocol or intra-arterially after responsible brain vessel was affirmed by digital subtraction angiography. The stroke severity at admission had been evaluated by neurologists and physicians who were medical practitioners in our teaching hospital. Values of NIHSS were achieved in documentations and were reviewed by one of our staff members who had ever passed the NIHSS training course in2009at Hong Kong Prince Wales Hospital. Past history of patients'high blood pressure, diabetes mellitus, stroke, atrial fibrillation, cardiac insufficiency and family history of ischemic stroke were ascertained by corresponding medications or medical records in outpatient or previously hospitalized individuals. The prognostic outcome was defined as favorable (modified Rankin scale0-2) and unfavorable (modified Rankin scale3-6). All cause mortality within90days after thrombolysis were also recorded. Follow-ups were carried out through January to July,2011by structured telephone interviews or letters or home visit. Statistical analysis:for baseline independent variables, quantitative missing values were replaced by linear regression estimates and pairwise process undertaken for categorical variables in multivariate analysis. Binary correlations were used to test the collinearities of independent variables; if correlation coefficient r>=0.8and P<=0.05, variables were checked and combinations or reductions were made under professional considerations, until no obvious correlations between candidate variables were observed. Candidate continuous variables were presented with median plus interquartile range and qualitative data with proportion. Differences between groups were tested by Mann-Whitney U test for continuous variables because of skewed distribution, and Chi-square or Fisher's exact test was used for categorical variables. In multiple logistic regression process, important demographics and clinical variables such as onset to treatment and route of rtPA use were selected forcibly as candidates although some of them did not show differences in univariate analysis. Chi-square test was used for omnibus model coefficients; goodness of fit was assessed by Hosmer-Lemeshow test. The inclusion and exclusion criterion of stepping probability was0.05and0.10respectively. The cut point value was0.5and maximum iteration time was20, a=0.05(two sided) was considered significant. In Post hoc analysis, the cut value of predictor was determined by Receiver's Operating Curve, and possible factors associated with each predictor were regressed using logistic procedure mentioned above. Data were calculated by IBM(?) SPSS(?) Statistics version19.
Results
In part one, a total of90patients met the inclusion criteria; one patient lost follow up at90days after discharge,89(98.9%) cases were included in univariate analysis except7(7.8%) patients lack the data of hyper-dense middle cerebral artery sign and4(4.5%) lack cardiac abnormality, finally,82(91.1%) cases were enrolled in multivariate analysis. All of them were ethnic Han Chinese,40(44.9%) males and49(55.1%) females,8(8.9%) with prior stroke but modified Rankin scale less than3. Independent variables including low density lipoprotein, neutrophil and prothrombin time were removed because of their high collinearities with others. The median of age was72years, body weight59kilograms, NIHSS13, onset to treatment time4.42hours and dose of alteplase50milligrams respectively. Sixty patients (67.4%) received intravenous thrombolytic therapy and29(32.6%) intra-arterially. Sixteen people had died when follow-up accomplished, all them died within30days after stroke, the mortality rate was17.98%(16/73, n=89). The deceased patients had relatively severe NIHSS, elevated international normalized ratio and white blood cell count than the survived. The proportion of hyper-dense middle cerebral artery sign in deceased group was significantly higher than that of survived, and that of family history of stroke was marginal. In multiple logistic regression,13independent variables were thought to be candidate factors:age; gender; dose of rtPA use; hyper-dense middle cerebral artery sign; family history of stroke; white blood cell count; NIHSS; body temperature; international normalized ratio; pulse oxygen saturation;; onset to treatment time; blood glucose level; systolic blood pressure; two variables were independently associated with mortality at the last step of backward stepwise logistic regression:NIHSS (P=0.001, OR1.48,95%C.I.1.18-1.86); body temperature (P=0.028, OR4.60,95%C.I.1.18-17.94). Pulse oxygen saturation showed a tendency of significance (P=0.054, OR0.71,95%C.I.0.49-1.01); other variables did not reach the significant level. The model chi-square was41.493and P=0.000; Nagelkerke R square was0.633. Hosmer-Lemeshow chi-square was0.927and P=0.999.The proportion of correctly predicted mortality by this model was89.0%. The likelihood of death for individual was y(?)=-31.
280-0.349SPO2+1.526BT+0.395NIHSS+1.688HMCAS. C statistic showed the area under the curve was0.939, P=0.000,95%C.I.0.889-0.990; Influence on mortality by diurnal variation of body temperature was explored, time point as per the time of thrombolysis; no differences were found in mortality. Acute ischemic stroke patients under thrombolysis, higher NIHSS scale and higher body temperature at baseline were significantly and independently correlated with90days mortality; Every1point increase in NIHSS scale will multiply the likelihood of death by1.48, every1℃increase of body temperature will increase death by4.6times. Drop of pulse oxygen saturation might also leads to increased mortality. In Post hoc analysis, the area under the curve was0.620for body temperature and0.608for pulse oxygen saturation respectively, and the cut value was36.9℃and96%. Multiple analysis included8candidate variables (total cholesterol, blood glucose, history of diabetes mellitus, cardiac insufficiency, family history of ischemic stroke, age, body weight and onset to treatment time) with body temperature, and9variables (dose, onset to treatment time, age, total protein, white blood cell counts, platelet counts, systolic blood pressure, history of diabetes mellitus, history of cardiac insufficiency) with pulse oxygen saturation. High glucose level (P=0.008, OR,1.286,95%C.I.1.066-1.551) and family history of stroke (P=0.007, OR,9.191,95%C.I.1.827-46.241) were significant for body temperature; whilst higher platelet count (P=0.031, OR,0.990,95%C.I.0.981-0.999) and history of diabetes mellitus (P=0.008, OR,0.182,95%C.I.0.052-0.634) for pulse oxygen saturation. Patients with diabetes mellitus, who undergo acute ischemic stroke, may have a greater opportunity to present higher body temperature and lower pulse oxygen saturation at admission, similarly, patients with family history of stroke are apt to have fever. In part two, additional6patients were enrolled in the dataset to compare the efficacy and safety of intravenous and intra-arterially thrombolysis in Chinese populations. The inclusion and exclusion criteria were the same as part one. Additional stroke OCSP subtypes, TOAST classification and outcome variables such as hemorrhagic transformation and re-canalization of responsible vessels were re-evaluated. Forty three were males and53females. Sixty four patients received intravenous and32with intra-arterial thrombolysis. Favorable outcome achieved43.8%at90days. Univariate analysis showed a higher cost in intra-arterial thrombolysis (47623.6VS.25699.8RMB), longer procedure delay (3:10VS.1:44hours) and time window (5.54VS.3.58hours); the dose of intra-arterial thrombolysis was lower (20VS.50mg). No differences were found in re-canalization of responsible vessels (64.9%VS.53.8%), hemorrhagic transformation (25%VS.31.3%), favorable outcome (45.3%VS.40.6%) and mortality (22.2%VS.9.4%). Route of thrombolysis did not predict unfavorable outcome (P=0.263, OR2.24,95%CI0.55-9.15). Re-canalization independently predicts functional outcome (P=0.036, OR0.25,95%CI0.07-0.91).
Conclusions
Pretreatment high NIHSS scale, early increase in body temperature and low pulse oxygen saturation might be associated with90-day mortality in Chinese stroke patients with thrombolysis of alteplase. The efficacy and safety were similar whether thrombolysis was manipulated intravenously or intra-arterially.
据国家卫生部第三次全国死亡原因调查显示,急性脑卒中已经成为中国人疾病死亡第一位死亡原因,首次超过了恶性肿瘤和心血管疾病。中国脑卒中年发病率超过200万,每年150万人因脑卒中死亡,死亡率已经是西方发达国家的4到5倍,是日本的3.5倍,未来国家第十二个五年计划,已经把降低脑卒中死亡率作为首要解决的重大科技攻关课题。急性脑卒中构成中,大约75%为缺血性卒中。中国城镇地区缺血性脑卒中死亡率约为38.7%,其中大部分患者死于发病一个月之后,但是国内关于缺血性脑卒中死亡原因尚未见到详尽的调查报告。组织型纤溶酶原激活剂(阿替普酶)是目前唯一被批准用于临床救治急性缺血性脑卒中的药物,国外大型、前瞻性、多中心临床试验已经证明了阿替普酶的安全性和有效性,但是该药在中国的使用尚不普及,据统计,发病3小时内到达医院,符合溶栓标准的超急性脑卒中患者,阿替普酶使用率仅为1.9%。西方国家的荟萃分析显示,随着溶栓时间窗的延迟超过4.5小时,脑卒中患者的死亡率轻微增加,但是死亡的增加与溶栓后出血性转化并无显著关系。这些证据表明,仍然有潜在的重要因素影响了脑卒中溶栓后的死亡率,比如年龄、性别、种族、卒中严重程度、并发症和某些临床变量。虽然阿替普酶已经被批准用于中国人群,但是到目前为止,尚没有大型的、安慰剂对照的临床研究,验证该药在国人中的有效性。影响溶栓后转归的决定因素,仍然缺乏有力的临床证据。本研究的目标,是分析脑卒中溶栓后预后的影响因素,特别是死亡这个明确的临床终点事件的影响因素,为今后的临床干预、减少脑卒中的死亡率做好前期工作。
对象和方法
病人的选择和测量方法：我们以国际疾病编码第十版中,出院诊断编码为I63-I67的患者为检索对象,查找了自2005年初至2011年4月连续登记在库的脑梗塞患者。由于急性缺血性脑卒中的定义缺乏统一的国际标准,我们在研究中将其定义为,由于脑部缺血快速出现的脑功能障碍,后期这种确切的损害可以被影像学证实,比如磁共振弥散成像、计算机断层扫描；或计算机断层血管成像、磁共振血管成像和数字减影血管成像技术。研究包含的“确切”脑卒中患者,发病时间均在72小时内,所有患者接受过组织型纤溶酶原激活剂(阿替普酶,德国勃林格殷格翰公司制造)。入选标准如下：(1)溶栓前美国国立卫生院卒中量表(NIHSS)评分4-26分；(2)阿替普酶静脉或动脉溶栓；(3)溶栓前脑部CT平扫或磁共振未见病灶形成,或低信号区域小于三分之一血管供血区域；排除标准与美国的NINDS试验类似,但是未排除即往有卒中史的患者,同时也未排除使用胰岛素控制血糖低于22.2mmol/L者,或使用了压宁定控制血压在185/11OmmHg以下的患者。另外凝血指标轻度异常和血小板异常患者也未排除。收集数据使用了Microsoft(?) Office Excel2003软件,并进行了双录入和数据核查。收集的变量包括最接近溶栓时刻前的年龄、性别和体重。实验室资料包括血肌钙蛋白、肌酐、尿素氮、肌酸肌酶、总胆固醇、高密度和低密度脂蛋白；谷丙转氨酶、总蛋白、总胆红素、血糖和碳酸氢盐；测量设备Automatic Test System-LX20。凝血酶原时间、部分凝血活酶时间、国际标准比值和纤维蛋白原,测量仪为Coagulation Analyzer-Sta-R。白细胞计数、中性粒细胞和淋巴细胞计数,红细胞计数、血球压积和血小板计数仪为Automatic Blood Cell Analyzer-LH755。溶栓前患者头部的影像学评价,由我院放射科工作人员回顾性进行评价,其中第一部分包括了重要指标----CT的大脑中动脉致密征,第二部分增加了CT溶栓后出血性转化和溶栓后血管再通TIM1分级的评价。心血管异常定义为任何以下发现之一：心电图发现的心房颤动、心房扑动、心律不齐和ST段的异常；或者超声心动图发现的中度以上瓣膜返流、附壁血栓或间隔缺陷。生命体征变量包括腋下体温、脉搏、血氧饱和度、收缩压和舒张压水平,均经由IntelliVue Information Center System监护系统获得。治疗时间窗定义为症状出现到治疗前的时间,程序性延误指患者达到医院至接受溶栓治疗的时间。阿替普酶的剂量和溶栓途径由医嘱单获得。静脉溶栓按照NINDS研究的流程执行,动脉溶栓在脑血管造影,发现责任血管后,导管内注入阿替普酶进行选择性溶栓。卒中严重程度评分,部分已由神经内科执业医师前瞻性地记录在病案中,其余分值由我科一名神经专科护师进行回顾性评定,该护师2009年曾作为访问学者,在香港威尔氏亲王医院获得了NIHSS评分的国际资格证书。患者重要的既往病史,如高血压、糖尿病、卒中史、房颤史、心衰史和家族卒中史,通过住院病历和门诊病历或服药记录得以确认。2011年7月前完成了电话随访、信访或登门造访。预后指标分为良好(改良的Rankin量表0-2分)和不良(改良的Rankin量表3-6分),同时登记和核实了患者的全因死亡。统计学分析：用线性回归法替代部分缺失的连续性变量。因为数连续型变量多为偏态分布,故以中位数加四分位间距或全距表示；定类变量以百分比表示。组间差异使用Mann-Whitney U检验、卡方检验或Fisher's精确概率检验。多因素分析过程时,分类变量采取两两比较方法。由于原始自变量较多,事先已经进行了变量筛选,目的在于挑选与预后变量有潜在相关的自变量,并检查自变量之间的共线性；自变量的共线性先用二元相关性检验,如果相关系数大于0.8,则通过专业知识,对相同或相近属性的自变量进行合并、替代或是删除,最终保持自变量之间相对的独立性,使相关性不再明显；例如,自变量“凝血酶原时间”和“国际标准比值”的相关系统为0.984,P=0.000,我们选择国际标准比值作为候选变量,因为两者都是凝血功能常用指标,但临床上最常用的指标是国际标准比值,不常用凝血酶原时间的绝对值。其后,利用逐步回归法进一步消除自变量共线性,筛选有意义的变量。二分类Logistic回归中,为了发现潜在对临床结局有独立影响的因素,并进一步排除自变量之间的共线性,从临床简便和实用性出发,纳入多因素回归分析的自变量,除组间有显著性差异者之外,同时校正了人口学变量、溶栓治疗中重要的时间窗、溶栓途径、用药剂量和临床常用的生命体征、生化指标等自变量。采取逐步后退法,最大似然比检验,步进入选和剔除标准分别为0.05和0.10,界值点设为0.5,最大迭代20次；同时检验了模型的意义和Hosmer-Lemeshow拟合优度。事后分析中,采用ROC曲线决定有意义自变量的界值,并与其他自变量进行Logistic回归分析,寻找可能的解释因素。Alpha值设定为0.05(双侧)。统计软件为IBM (?) SPSS(?) Statistics versionl9。
结果
第一部分共纳入了90名患者,1例失访,89例(98.9%)进行了单因素分析,但是7例(7.8%)患者缺失大脑中动脉致密征资料,4例(4.5%)缺失心脏异常资料,最后,一共82例(91.1%)患者进行了多因素分析。所有患者均是中国汉族,男性40名,占44.9%；女性49名,占55.1%；8例(8.9%)有既往脑卒中病史,但是mRs评分低于3分。自变量中,低密度脂蛋白、中性粒细胞计数和凝血酶原时间因为和其所属类别其他自变量的高度共线性,故予移除。年龄中位数为72岁,体重为59公斤,NIHSS评分13分,治疗时间窗4.42小时,阿替普酶用量为50毫克。60名患者(67.4%)接受了静脉溶栓治疗,而29名患者(32.6%)接受了动脉溶栓。一共16名患者三个月内死亡,而且所有病例均死于脑卒中后30天之内,死亡率为17.98%(16/73,n=89)。死亡组患者和生存组比较,NIHSS评分较严重,国际标准比值和白细胞水平均较高。另外,死亡组CT提示大脑中动脉致密征比例高于生存组,并且家族卒中史比例偏高,呈现出统计学边缘效应。二分类Logistic回归中,共纳入13个与溶栓后死亡结局可能有关的自变量：性别、年龄、NIHSS评分、白细胞计数、国际标准比值、大脑中动脉致密征、卒中家族史、时间窗、用药剂量、血糖水平、体温、收缩压和血氧饱和度。两个自变量在多因素、逐步回归后显示与死亡结局独立相关：NIHSS评分(P=0.001, OR1.48,95%C.I.1.18-1.86);体温(P=0.028, OR4.60,95%C.I.1.18-17.94);血氧饱和度(P=0.054, OR0.71,95%C.I.0.49-1.01)则显示了统计学有意义趋势。模型卡方为41.493(P=0.000); Nagelkerke R方为0.633,说明回归方程解释了影响因素的63.3%。Hosmer-Lemeshow卡方检验不显著(x2=0.927,P=0.999)。模型预测死亡的准确性达到89.0%。预测死亡概率C统计曲线下面积达到了0.939,P=0.000,95%C.I.0.889-0.990；估计个体死亡概率的方程为：y(?)=-31.280-0.349SPO2+1.526BT+0.395NIHSS+1.688HMCAS.另外,考虑到体温昼夜的生理波动,我们分析了这种变化对死亡的影响；根据体温生理波动规律,将时间段分为5-10点、11-18点和19-4点三段,卡方检验显示三个时间段内入院患者最后死亡结局无差异(,=1.164,P=0.559)。从临床实际意义考虑,急性缺血性脑卒中患者,基线时较高的NIHSS评分和较高的体温与溶栓后90天死亡独立相关,患者NIHSS评分每增加1分,溶栓后死亡可能性就增加1.48倍；体温每升高1摄氏度,死亡增加4.6倍。血氧饱和度低下也显示了对死亡有影响的趋势；事后分析中,体温变量ROC曲线下面积为0.620,血氧饱和度为0.608,体温变量分界值为36.9摄氏度,血氧饱和度分界值为96%。多因素分析一共纳入8个候选自变量(总胆固醇、血糖、糖尿病史、心功能不全、家族卒中史、年龄、体重和时间窗),与体温二分类变量进行Logistic回归。结果发现高血糖(P=0.008, OR,1.286,95%C.I.1.066-1.551)和家族卒中史(P=0.007, OR,9.191,95%C.I.1.827-46.241)与体温二分类相关。挑选9个自变量(药物剂量、时间窗、年龄、总蛋白、白细胞计数、血小板计数、收缩压、糖尿病史和心功能不全史)与血氧饱和度进行回归分析,也显示糖尿病(P=0.008, OR,0.182,95%C.I.0.052-0.634)与低血氧饱和度有关,同时血小板计数增高者,与低氧饱和度也有关(P=0.031, OR,0.990,95%C.I.0.981-0.999).糖尿病患者,发生急性缺血性脑中风时,更有可能在入院时表现出更高的体温和偏低的血氧饱和度；同样,有家族卒中史的患者,发病时也更容易出现体温上升。在第二部分中,数据库中追加了另外6名患者的资料,我们比较了中国人急性缺血性卒中阿替普酶静脉溶栓和动脉溶栓的安全性和有效性。入选标准和排除标准与第一部分相同。自变量中,重新评估了脑卒中的OCSP亚型和TOAST分型。预后指标中,加入了溶栓后出血性转化和责任血管的再通率。64名患者接受了静脉溶栓,32名接受了动脉溶栓。总的90天预后良好率达到了43.8%。单因素分析显示,动脉溶栓与静脉溶栓费用(47623.6VS.25699.8元)、院内程序性延误时间(3：10VS.1：44小时)、溶栓时间窗(5.54VS.3.58小时)、阿替普酶用量(20VS.50mg)有统计学差异。预后指标中,两种溶栓方式血管再通率(64.9%VS.53.8%)、出血性转化率(25%VS.31.3%)、预后良好率(45.3%VS.40.6%)和死亡率(22.2%VS.9.4%)均无显著性差异。溶栓途径对预后不良无独立影响(P=0.263, OR2.24,95%CI0.55-9.15)。但是血管的再通与否,与功能学预后独立相关(P=0.036, OR0.25,95%CI0.07-0.91)
结论
接受阿替普酶溶栓的急性缺血性脑卒中患者,治疗前较高的NIHSS评分、早期升高的体温和较低的血氧饱和度,可能与治疗后90天的死亡率有关。阿替普酶动脉溶栓和静脉溶栓90天预后良好比例、溶栓后出血转化率和死亡率无显著性差异。
Background and purpose
Stroke has ranked the first cause of death in China. The annual incidence of stroke exceeds2million and1.5million dead,4to5times higher than that of western countries, approximately75%are ischemic. The mortality of ischemic stroke in Chinese population is about38.7%in urban areas, most people died28days later after the ischemic attack, but the risk factors predicting death have not been fully elucidated. Although recombinant tissue plasminogen activator has been proved safe and effective in acute ischemic stroke therapy by large clinical trials, it is poorly used in China; only1.9%patients with acute ischemic stroke, who reached hospitals with symptoms onset within3hours, received thrombolysis. In western countries, pooled analysis have shown stroke mortality increased slightly with delay of thrombolysis of which onset-to-treatment time exceeded4.5hours and did not correlate with parenchymal hemorrhagic transformations, implying that there are still important factors such as age, gender, race, stroke severity, comobidities and clinical parameters that might affect death rate. Because of the lack of controlled clinical trials concerning thrombolysis in China, the truth is unclear. We aim to analyze predicting factors of mortality and hypothesize that some baseline clinical variables might also affect clinical outcome within90days after stroke in Chinese patients who have received tissue plasminogen activator therapy.
Subjects and methods
Patients'selection and measurements:we searched patients diagnosed with International Classification of Diseases10th edition163-167at discharge who were prospectively and consecutively registered in our database from January,2005to April,2011. Because of the lack of uniform international classification of acute ischemic stroke, we defined it as rapidly developing loss of brain functions due to cerebral ischemia in study cohort, which was definitely demonstrated later by neuro imaging such as diffusion weighted image, computed tomography; or computed tomography angiography, magnetic resonance angiography and digital subtraction angiography. Patients with documented "definite" stroke with symptoms onset within72hours, who received tissue plasminogen activator (Actilyse(?), Boehringer Ingelheim GmbH), were included in this analysis. Inclusion criteria were:(1) National Institutes of Health Stroke Scale4to26before treatment;(2) tissue plasminogen activator used either intravenously or intra-arterially;(3) routine brain CT or magnetic resonance image at baseline negative or hypo dense size less than1/3blood supply area; Exclusion criteria were similar to those of NINDS trial, except prior ischemic stroke, and occasional use of insulin to control glucose level under22.2mmol per liter, or urapidil to lower high blood pressure preceding thrombolysis, which exceeded185/110millimeters of mercury. Patients with abnormal prothrombin time, or activated partial thromboplastin time and abnormal platelet counts were not excluded. Patient's clinical variables, which nearest to the time point before thrombolysis, were collected using Microsoft Office Excel2003and were double entry and validated:age and gender, identified by resident card; body weight, obtained by self report or relatives or friends. Laboratory data:troponin, creatine kinase, blood urea nitrogen, creatinine, total cholesterol, high and low density lipoprotein, alanine aminotransferase, total protein, total bilirubin, blood glucose and bicarbonate were tested by Automatic Test System-LX20; prothrombin time, activated partial thromboplastin time, international normalized ratio and fibrinogen were tested by Coagulation Analyzer-Sta-R; white blood cell counts, neutrophil and lymphocyte counts, red blood cell counts, hematocrit and platelet counts were tested by Automatic Blood Cell Analyzer-LH755. Radiographic manifestations of brain CT, which was accomplished before treatment, were retrospectively assessed by radiologist who was unaware of the therapeutic regime, including hyper dense middle cerebral artery sign on CT in part1, hemorrhagic transformation and TIMI scale of re-canalization in part2. Cardiac abnormalities were defined as atrial fibrillation, atrial fluttering, arrhythmia and ST segment abnormalities verified by electrocardiograms or moderate to severe heart valve regurgitation, thrombus or septal defect by ultrasonography. Vital signs such as axilla body temperature, pulsation, and pulse oxygen saturation, systolic and diastolic blood pressure were collected through IntelliVue Information Center System. Onset to treatment time means the time loss after the symptoms onset until alteplase infusion, calculated automatically via Excel2003as onset and treatment time variables entered. Procedural delay indicates the preparation time loss before thrombolysis. Dosage of alteplase of each individual patient was obtained from the record of doctor's advice. Route of thrombolysis was the route of alteplase administration, which either intravenously as per NINDS protocol or intra-arterially after responsible brain vessel was affirmed by digital subtraction angiography. The stroke severity at admission had been evaluated by neurologists and physicians who were medical practitioners in our teaching hospital. Values of NIHSS were achieved in documentations and were reviewed by one of our staff members who had ever passed the NIHSS training course in2009at Hong Kong Prince Wales Hospital. Past history of patients'high blood pressure, diabetes mellitus, stroke, atrial fibrillation, cardiac insufficiency and family history of ischemic stroke were ascertained by corresponding medications or medical records in outpatient or previously hospitalized individuals. The prognostic outcome was defined as favorable (modified Rankin scale0-2) and unfavorable (modified Rankin scale3-6). All cause mortality within90days after thrombolysis were also recorded. Follow-ups were carried out through January to July,2011by structured telephone interviews or letters or home visit. Statistical analysis:for baseline independent variables, quantitative missing values were replaced by linear regression estimates and pairwise process undertaken for categorical variables in multivariate analysis. Binary correlations were used to test the collinearities of independent variables; if correlation coefficient r>=0.8and P<=0.05, variables were checked and combinations or reductions were made under professional considerations, until no obvious correlations between candidate variables were observed. Candidate continuous variables were presented with median plus interquartile range and qualitative data with proportion. Differences between groups were tested by Mann-Whitney U test for continuous variables because of skewed distribution, and Chi-square or Fisher's exact test was used for categorical variables. In multiple logistic regression process, important demographics and clinical variables such as onset to treatment and route of rtPA use were selected forcibly as candidates although some of them did not show differences in univariate analysis. Chi-square test was used for omnibus model coefficients; goodness of fit was assessed by Hosmer-Lemeshow test. The inclusion and exclusion criterion of stepping probability was0.05and0.10respectively. The cut point value was0.5and maximum iteration time was20, a=0.05(two sided) was considered significant. In Post hoc analysis, the cut value of predictor was determined by Receiver's Operating Curve, and possible factors associated with each predictor were regressed using logistic procedure mentioned above. Data were calculated by IBM(?) SPSS(?) Statistics version19.
Results
In part one, a total of90patients met the inclusion criteria; one patient lost follow up at90days after discharge,89(98.9%) cases were included in univariate analysis except7(7.8%) patients lack the data of hyper-dense middle cerebral artery sign and4(4.5%) lack cardiac abnormality, finally,82(91.1%) cases were enrolled in multivariate analysis. All of them were ethnic Han Chinese,40(44.9%) males and49(55.1%) females,8(8.9%) with prior stroke but modified Rankin scale less than3. Independent variables including low density lipoprotein, neutrophil and prothrombin time were removed because of their high collinearities with others. The median of age was72years, body weight59kilograms, NIHSS13, onset to treatment time4.42hours and dose of alteplase50milligrams respectively. Sixty patients (67.4%) received intravenous thrombolytic therapy and29(32.6%) intra-arterially. Sixteen people had died when follow-up accomplished, all them died within30days after stroke, the mortality rate was17.98%(16/73, n=89). The deceased patients had relatively severe NIHSS, elevated international normalized ratio and white blood cell count than the survived. The proportion of hyper-dense middle cerebral artery sign in deceased group was significantly higher than that of survived, and that of family history of stroke was marginal. In multiple logistic regression,13independent variables were thought to be candidate factors:age; gender; dose of rtPA use; hyper-dense middle cerebral artery sign; family history of stroke; white blood cell count; NIHSS; body temperature; international normalized ratio; pulse oxygen saturation;; onset to treatment time; blood glucose level; systolic blood pressure; two variables were independently associated with mortality at the last step of backward stepwise logistic regression:NIHSS (P=0.001, OR1.48,95%C.I.1.18-1.86); body temperature (P=0.028, OR4.60,95%C.I.1.18-17.94). Pulse oxygen saturation showed a tendency of significance (P=0.054, OR0.71,95%C.I.0.49-1.01); other variables did not reach the significant level. The model chi-square was41.493and P=0.000; Nagelkerke R square was0.633. Hosmer-Lemeshow chi-square was0.927and P=0.999.The proportion of correctly predicted mortality by this model was89.0%. The likelihood of death for individual was y(?)=-31.
280-0.349SPO2+1.526BT+0.395NIHSS+1.688HMCAS. C statistic showed the area under the curve was0.939, P=0.000,95%C.I.0.889-0.990; Influence on mortality by diurnal variation of body temperature was explored, time point as per the time of thrombolysis; no differences were found in mortality. Acute ischemic stroke patients under thrombolysis, higher NIHSS scale and higher body temperature at baseline were significantly and independently correlated with90days mortality; Every1point increase in NIHSS scale will multiply the likelihood of death by1.48, every1℃increase of body temperature will increase death by4.6times. Drop of pulse oxygen saturation might also leads to increased mortality. In Post hoc analysis, the area under the curve was0.620for body temperature and0.608for pulse oxygen saturation respectively, and the cut value was36.9℃and96%. Multiple analysis included8candidate variables (total cholesterol, blood glucose, history of diabetes mellitus, cardiac insufficiency, family history of ischemic stroke, age, body weight and onset to treatment time) with body temperature, and9variables (dose, onset to treatment time, age, total protein, white blood cell counts, platelet counts, systolic blood pressure, history of diabetes mellitus, history of cardiac insufficiency) with pulse oxygen saturation. High glucose level (P=0.008, OR,1.286,95%C.I.1.066-1.551) and family history of stroke (P=0.007, OR,9.191,95%C.I.1.827-46.241) were significant for body temperature; whilst higher platelet count (P=0.031, OR,0.990,95%C.I.0.981-0.999) and history of diabetes mellitus (P=0.008, OR,0.182,95%C.I.0.052-0.634) for pulse oxygen saturation. Patients with diabetes mellitus, who undergo acute ischemic stroke, may have a greater opportunity to present higher body temperature and lower pulse oxygen saturation at admission, similarly, patients with family history of stroke are apt to have fever. In part two, additional6patients were enrolled in the dataset to compare the efficacy and safety of intravenous and intra-arterially thrombolysis in Chinese populations. The inclusion and exclusion criteria were the same as part one. Additional stroke OCSP subtypes, TOAST classification and outcome variables such as hemorrhagic transformation and re-canalization of responsible vessels were re-evaluated. Forty three were males and53females. Sixty four patients received intravenous and32with intra-arterial thrombolysis. Favorable outcome achieved43.8%at90days. Univariate analysis showed a higher cost in intra-arterial thrombolysis (47623.6VS.25699.8RMB), longer procedure delay (3:10VS.1:44hours) and time window (5.54VS.3.58hours); the dose of intra-arterial thrombolysis was lower (20VS.50mg). No differences were found in re-canalization of responsible vessels (64.9%VS.53.8%), hemorrhagic transformation (25%VS.31.3%), favorable outcome (45.3%VS.40.6%) and mortality (22.2%VS.9.4%). Route of thrombolysis did not predict unfavorable outcome (P=0.263, OR2.24,95%CI0.55-9.15). Re-canalization independently predicts functional outcome (P=0.036, OR0.25,95%CI0.07-0.91).
Conclusions
Pretreatment high NIHSS scale, early increase in body temperature and low pulse oxygen saturation might be associated with90-day mortality in Chinese stroke patients with thrombolysis of alteplase. The efficacy and safety were similar whether thrombolysis was manipulated intravenously or intra-arterially.
引文
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