Supplementary Material for: Symptomatic Intracranial Hemorrhage following Intravenous Thrombolysis for Acute Ischemic Stroke: A Critical Review of Case Definitions

<b><i>Background:</i></b> Symptomatic intracranial hemorrhage (SICH) is a devastating complication of intravenous thrombolysis treatment that is associated with high mortality. Clinical trials, stroke registries and cohort studies employ different case definitions to identify stroke patients with SICH following intravenous thrombolysis. We systematically reviewed the reported rates of SICH following intravenous thrombolysis and compared their consistency with mortality outcomes. <b><i>Methods:</i></b> Studies were identified from the PubMed and Embase databases from January 1994 to July 2011 by cross-referencing the following MeSH terms: ‘thrombolysis’, ‘recombinant tissue plasminogen activator’, ‘rtPA’, ‘hemorrhagic stroke’, ‘cerebral hemorrhage’, ‘hematoma’ and ‘ischemic stroke’. Demographic information, baseline National Institute of Health Stroke Scale (NIHSS) scores, time from stroke onset to intravenous thrombolysis, SICH and mortality rates were derived from published data in 7 randomized controlled trials, 7 stroke registries and 10 cohort studies (4 multicenter and 6 single center) with more than 200 consecutively recruited patients. Mortality rates were considered as the percentage of patients treated with intravenous thrombolysis who died within 90 days after stroke. <b><i>Results:</i></b> The mean age of patients included in this analysis was 68.8 years (standard deviation, SD 2.9, range 63–75), of whom 56.3% (SD 4.5, range 45–63) were men. They presented with a mean baseline NIHSS of 12.5 (SD 1.4, range 9–15) and received intravenous thrombolysis 175 min (SD 62, range 120–328) from stroke onset. The overall mean SICH and mortality rates of patients treated with intravenous thrombolysis were 5.6% (SD 2.3) and 14.7% (SD 4.8), respectively. A moderate correlation was observed between the incidence of SICH and mortality in patients treated with intravenous thrombolysis (r = 0.401, p = 0.050). The variation in SICH rates was highest across studies that reported SICH rates using the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria compared with the European Cooperative Acute Stroke Study and National Institute of Neurological Disorders and Stroke (NINDS) criteria. Studies that defined SICH as parenchymal hemorrhage with a neurological decline NIHSS ≥4 occurring within 36 h of intravenous thrombolysis reported a higher consistency between SICH and mortality rates (correlation coefficient 0.631). <b><i>Conclusions:</i></b> SICH rates vary considerably between studies and these differences may relate to the differences in the criteria used to define SICH. Until a case definition with high interrater agreement and good correlation with stroke outcomes becomes available, detailed information on the type of bleeding, the extent of NIHSS deterioration, neuroimaging features and the time from thrombolysis to diagnosis of hemorrhage should be reported to permit a correct interpretation of SICH rates.

**<i>背景：</i>** 症状性颅内出血（Symptomatic intracranial hemorrhage, SICH）是静脉溶栓（intravenous thrombolysis）治疗的致命并发症，且与高死亡率密切相关。当前临床试验、卒中登记研究及队列研究均采用不同的病例定义，以识别接受静脉溶栓治疗后出现SICH的卒中患者。本研究对静脉溶栓后SICH的报道发生率进行了系统综述，并对比其与死亡率结局的一致性。**<i>方法：</i>** 本研究检索1994年1月至2011年7月期间PubMed和Embase数据库中的文献，以以下医学主题词（MeSH terms）进行交叉检索：溶栓治疗（thrombolysis）、重组组织型纤溶酶原激活剂（recombinant tissue plasminogen activator, rtPA）、出血性卒中（hemorrhagic stroke）、脑出血（cerebral hemorrhage）、血肿（hematoma）及缺血性卒中（ischemic stroke）。本研究从7项随机对照试验、7项卒中登记研究及10项队列研究（其中4项为多中心研究、6项为单中心研究，均连续入组超过200例患者）的已发表数据中提取以下信息：人口统计学资料、基线美国国立卫生研究院卒中量表（National Institute of Health Stroke Scale, NIHSS）评分、卒中发病至静脉溶栓的时间、SICH发生率及死亡率。本研究将死亡率定义为：接受静脉溶栓治疗的患者中，卒中发病后90天内死亡的患者占比。**<i>结果：</i>** 本分析纳入患者的平均年龄为68.8岁（标准差（standard deviation, SD）=2.9，范围63~75岁），其中男性占比56.3%（SD=4.5，范围45%~63%）。患者基线平均NIHSS评分为12.5分（SD=1.4，范围9~15分），且于卒中发病后平均175分钟（SD=62，范围120~328分钟）接受静脉溶栓治疗。接受静脉溶栓治疗的患者总体平均SICH发生率为5.6%（SD=2.3），总体平均死亡率为14.7%（SD=4.8）。在接受静脉溶栓治疗的患者中，SICH发生率与死亡率呈中等程度相关（r=0.401，P=0.050）。与采用欧洲急性卒中协作研究（European Cooperative Acute Stroke Study）及美国国立神经病学与卒中研究所（National Institute of Neurological Disorders and Stroke, NINDS）标准的研究相比，采用卒中溶栓安全实施-监测研究（Safe Implementation of Thrombolysis in Stroke-Monitoring Study, SITS-MOST）标准报告SICH发生率的研究，其SICH发生率的组间差异最大。当将SICH定义为“静脉溶栓后36小时内出现脑实质出血且NIHSS评分下降≥4分的神经功能恶化”时，相关研究报告的SICH发生率与死亡率之间的一致性更高（相关系数r=0.631）。**<i>结论：</i>** 不同研究间的SICH发生率存在显著差异，此类差异可能与SICH定义标准的不同有关。在获得具有高评定者间一致性且与卒中结局相关性良好的统一病例定义之前，应报告出血类型、NIHSS恶化程度、神经影像学特征及从溶栓治疗到出血诊断的时间等详细信息，以确保能够正确解读SICH发生率。