Magnetic resonance imaging characterization of hemorrhagic transformation of embolic stroke in the rat.

Intracranial hemorrhage is a critical factor when considering efficacy and safety of thrombolytic intervention after thromboembolic stroke. This study tested whether magnetic resonance imaging could identify tissue for hemorrhagic transformation after the onset of embolic stroke. Rats subjected to embolic stroke with and without recombinant tissue-type plasmogen activator (rt-PA) treatment were followed-up with magnetic resonance imaging using the inverse of the apparent forward transfer rate for magnetization transfer (k(inv)), gadolinium-chelate contrast-enhanced magnetic resonance imaging, and diffusion-, perfusion-, and T2-weighted imaging. Rats with embolic stroke either were treated with rt-PA 1 (n = 16) or 4 hours (n = 13) after stroke onset or were not treated (n = 15). From these groups, at total of 17 rats had intracerebral hemorrhage. Tissue progressing to hemorrhage and adjacent to the site of hemorrhage was analyzed to identify magnetic resonance imaging markers that characterize hemorrhagic transformation. The parameter maps of k(inv) and contrast-enhanced magnetic resonance imaging showed greater sensitivity in the detection of tissue destined for hemorrhagic transformation compared with the apparent diffusion coefficient of water (ADCw) and CBF. In tissue not destined to undergo hemorrhagic transformation, k(inv) maps and contrast-enhanced magnetic resonance imaging exhibited small increases in k(inv) and contrast-enhanced magnetic resonance imaging signal intensity in the area encompassing the territory supplied by the middle cerebral artery. In contrast, large increases in k(inv) and in signal intensity in the contrast-enhanced magnetic resonance images were detected in the region where gross hemorrhage was confirmed histologically. The values of k(inv), T2, and signal intensity in the contrast-enhanced magnetic resonance images were significantly higher in the region destined for hemorrhagic transformation (k(inv), P < or = 0.033 3-24 hours after embolization; T2, P < or = 0.037 24-48 hours; contrast-enhanced magnetic resonance imaging, P < 0.05 4-7 hours) compared with the nonhemorrhagic transformation ischemic region or in the contralateral homologous regions after onset of ischemia. Of these methods, k(inv) shows the most sensitivity in the detection of hemorrhagic transformation soon after embolization. The authors' data suggest that k(inv) and contrast-enhanced magnetic resonance imaging are potentially important methodologies for detecting tissue destined for hemorrhagic transformation.     

Magnetic resonance imaging indexes of therapeutic efficacy of recombinant tissue plasminogen activator treatment of rat at 1 and 4 hours after embolic stroke.

With use of magnetic resonance imaging (MRI), the effects of early and delayed treatment of embolic stroke in rat with recombinant tissue plasminogen activator (rt-PA) were investigated. Rats with embolic stroke were treated with rt-PA at 1 (n = 9) or 4 (n = 7) hours after stroke onset or were untreated (n = 15). Diffusion-weighted imaging, perfusion-weighted imaging, and T2-weighted imaging were performed before and after embolization from 1 hour to 7 days. No significant differences were detected in the relative areas with low cerebral blood flow (CBF), apparent diffusion coefficient of water (ADCw), and T2 between the 4-hour treated group and the untreated group. Significant decreases in the average relative areas with low CBF were detected in the 1-hour treated group from 4 to 48 hours after embolization as compared with the untreated group. The increase in T2 in the 1-hour treated group was significantly lower than in the untreated and 4-hour treated groups. A significant increase in ADCw was detected in the 1-hour treated group at 3 and 24 hours after embolization as compared with the untreated and 4-hour treated groups. Secondary embolization was detected by both MRI and laser scanning confocal microscopy. The data suggest that MRI can detect the efficacy of rt-PA treatment and secondary ischemic damage.     

Thrombolysis with reteplase, an unglycosylated plasminogen activator variant, in experimental embolic stroke.

We incorporated diffusion-weighted magnetic resonance imaging (MRI) (DWI) and perfusion-weighted MRI (PWI) to evaluate the efficacy of thrombolysis in experimental embolic stroke using a plasminogen activator, reteplase. Reteplase (rPA) is an unglycosylated plasminogen activator with enhanced fibrinolytic potency. Right internal carotid arteries of 34 rabbits were embolized using aged heterologous thrombi. Baseline DWI and PWI scans 0.5 hours after embolization confirmed successful embolization among 32. Intravenous treatment with rPA (n=11; 1 mg/kg bolus), recombinant tissue plasminogen activator (rt-PA) (n=11; 6 mg/kg bolus over 1 hour), or placebo (n=10) commenced 1 hour after stroke induction. MRIs were performed at 1.75, 3, and 5 hours after embolization. Six hours after embolization, brains were harvested and examined for hemorrhage. Posttreatment areas of diffusion abnormality and perfusion delay were graded using both a semiquantitative scale and percent areas expressed as a ratio of the baseline values. Improved perfusion was seen among the rt-PA, and rPA-treated groups compared with placebo, using a semiquantitative scale (P<.01 rt-PA v controls, P<.05, rPA v controls). DWI scans, however, were not improved with thrombolysis. Cerebral hemorrhage was not increased with thrombolytic treatment, although the incidence of wound site hemorrhage was higher with either rPA or rt-PA. One fatal systemic hemorrhage was observed in each of the thrombolytic-treated groups. Cerebral perfusion was equally improved with either rt-PA or rPA without causing excess cerebral hemorrhage. An advantage of rPA is single-bolus dosing rather than continuous infusion. Use of rPA for stroke treatment should be further explored.     

Prediction of hemorrhagic transformation following acute stroke: role of diffusion- and perfusion-weighted magnetic resonance imaging

BACKGROUND: Acute diffusion-weighted (DWI) and perfusion-weighted (PWI) magnetic resonance imaging (MRI) findings may correlate with secondary hemorrhagic transformation (HT) risk in patients with stroke. This information could be of value, particularly in individuals being considered for thrombolytic therapy. OBJECTIVE: To determine the relationship between DWI and PWI findings and the risk of secondary HT in patients with acute stroke. DESIGN: Retrospective case series. SETTING: Academic medical center. PATIENTS: Twenty-seven patients with acute stroke capable of being evaluated with DWI/PWI 8 hours or less after symptom onset. MAIN OUTCOME MEASURES: Apparent diffusion coefficient values, perfusion delay measurements, and subsequent MRI or computed tomographic scans detected HT. RESULTS: The mean +/- SD apparent diffusion coefficient of ischemic regions that experienced HT was significantly lower than the overall mean +/- SD apparent diffusion coefficient of all ischemic areas analyzed (0.510 +/- 0.140 x 10(-3) mm(2)/s vs 623 +/- 0.113 x 10(-3) mm(2)/s; P =.004). This difference remained significant when comparing the HT-destined ischemic areas with the non-HT-destined areas within the same ischemic lesion (P =.02). Patients receiving recombinant tissue-type plasminogen activator (rt-PA) experienced HT significantly earlier than patients not receiving rt-PA (P =.002). Moreover, a persistent perfusion deficit in the area of subsequent hemorrhage at 3 to 6 hours after the initial MRI scan was identified in significantly more patients who experienced HT than in those who did not (83% vs 30%; P =.03). CONCLUSION: Both DWI and PWI scans detect abnormalities that are associated with HT. These findings support a role for MRI in identifying patients who are at increased risk for secondary HT following acute ischemic stroke.     

MRI evaluation of treatment of embolic stroke in rat with intra-arterial and intravenous rt-PA

Using magnetic resonance imaging (MRI), we investigated treatment of a rat model of embolic stroke with rt-PA via intra-arterial (IA) and intravenous (IV) routes of administration. Rats were treated with rt-PA by either IA (n = 13) or IV (n = 13) routes at 3 h after stroke induction. Diffusion, perfusion, T2, and magnetization transfer MRI were performed prior to and at 1-3 and at 24 h after embolization. The IA treated group exhibited smaller lesion volumes than the IV treated group (p = 0.02). The relative areas with low ADCW and cerebral blood flow (CBF) after IA rt-PA intervention were significantly (p < or = 0.03) smaller than those in the IV treated group at 24 h after embolization. Significant differences (p < 0.02) between IA and IV treated groups in the relative area with high T2 and inverse of the apparent forward transfer rate of magnetization (kINV) in the ipsilateral hemisphere were also detected at 24 h after embolization. The IA treated group exhibited less intracerebral hemorrhage (27%) than the IV treated (64%) groups. Our data suggest that the beneficial effects of IA rt-PA treatment can be detected by changes in CBF, ADCW, T2, and kINV.     

急性脑梗死患者多模式CT指导下的静脉溶栓治疗

目的 对发病3～9 h内的急性脑梗死患者,应用多模式CT指导下静脉rt-PA溶栓治疗,研究其疗效.方法 2007年8月至2009年5月于我院就诊,经多模式CT筛选出符合溶栓的患者27例.分为＞3～6 h组及7～9 h组,记录溶栓前、后的NIHSS、mRS及BI评分,症状性出血率和病死率.结果 27例样本中20例(74.1%)患者溶栓治疗有效,11例(40.7%)临床结局良好,5例(18.5%)血管完全再通,症状性出血1例(3.7%).其中＞3～6 h组有效率为92.3%(12/13,χ~2=4.34,P=0.037),血管冉通率38.5%(5/13,χ~2=6.608,P=0.010).结论 多模式CT指导下＞3～9 h溶栓是超过常规溶栓时间窗患者的一种可选择的治疗方法.     

Multiparametric ISODATA analysis of embolic stroke and rt-PA intervention in rat

To increase the sensitivity of MRI parameters to detect tissue damage of ischemic stroke, an unsupervised analysis method, Iterative Self-Organizing Data Analysis Technique Algorithm (ISODATA), was applied to analyze the temporal evolution of ischemic damage in a focal embolic cerebral ischemia model in rat with and without recombinant tissue plasminogen activator (rt-PA) treatment. Male Wistar rats subjected to embolic stroke were investigated using a 7-T MRI system. Rats were randomized into control (n=9) and treated (n=9) groups. The treated rats received rt-PA via a femoral vein at 4 h after onset of embolic ischemia. ISODATA analysis employed parametric maps or weighted images (T1, T2, and diffusion). ISODATA results with parametric maps are superior to ISODATA with weighted images, and both of them were highly correlated with the infarction size measured from the corresponding histological section. At 24 h after embolic stroke, the average map ISODATA lesion sizes were 37.7+/-7.0 and 39.2+/-5.6 mm2 for the treated and the control group, respectively. Average histological infarction areas were 37.9+/-7.4 mm2 for treated rats and 39.4+/-6.1 mm2 for controls. The R2 values of the linear correlation between map ISODATA and histological data were 0.98 and 0.96 for treated and control rats, respectively. Both histological and map ISODATA data suggest that there is no significant difference in infarction area between non-treated and rt-PA-treated rats when treatment was administered 4 h after the onset of embolic stroke. The ISODATA lesion size analysis was also sensitive to changes of lesion size during acute and subacute stages of stroke. Our data demonstrate that the multiparameter map ISODATA approach provides a more sensitive quantitation of the ischemic lesion at all time points than image ISODATA and single MRI parametric analysis using T1, T2 or ADCw.     

The application of fast multiparametric protocol MRI-based thrombolysis with rt-PA hyperacute cerebral infarction

OBJECTIVE: To investigate the value of fast multiparametric protocol magnetic resonance imaging (MRI)-based thrombolysis in hyperacute cerebral infarction. METHODS: Seventy-seven patients with acute ischemic stroke were examined by multiparametric protocol MRI and among them, 12 patients with hyperacute cerebral infarction were treated by recombinant tissue plasminogen activator (rt-PA) and followed up periodically by MRI. RESULTS: The 12 patients selected by FMPMRI to receive thrombolysis demonstrated clinical improvement, with 90 day modified Rankin scale scores (mRs) < or = 2 and life quality Barthel index (BI) of 80-100. The only complication involved one patient (8.3%) who developed an asymptomatic intracranial hemorrhage 3 weeks after receiving thrombolytics. CONCLUSION: Multiparametric protocols have significant clinical potential for the treatment of hyperacute stroke patients who are candidates for receiving intravenous thrombolytic therapy. Our data suggest that patients suffering from hyperacute ischemic cerebral infarction that are strong candidates for intravenous thrombolytic therapy can be identified by multiparametric protocol MRI, especially to those whose time windows were undefined or beyond 3 hours after symptom onset.     

MRI of combination treatment of embolic stroke in rat with rtPA and atorvastatin

To test the hypothesis that combination treatment of embolic stroke with rtPA and statins improves the efficacy of thrombolytic therapy in rats. Rats subjected to embolic MCA occlusion (MCAo) were randomized into control (n = 10) and treatment (n = 9) groups. Four hours after MCAo, a combination of rtPA and atorvastatin (treatment) or saline (control) was administered. MRI measurements were performed on all animals at 2 h, 24 h and 48 h after MCAo. The patency of cerebral microvessels was examined using fluorescent microscopy. MRI images showed complete blockage of the right MCA and a reduction of CBF in the territory supplied by the MCA 2 h after MCAo for all animals. By 48 h after stroke, MRI showed that the decreased lesion size, elevated CBF and increased incidence of recanalization were found in treated rats compared with the control rats. The combination treatment significantly increased microvascular patency (16.3 +/- 5.5% vs. 12.4 +/- 3.5%, of field-of-view) and reduced the infarct volume (23.1 +/- 9.6% vs. 38.8 +/- 13.3%, of hemisphere). These data demonstrate that the co-administration of rtPA and atorvastatin 4 h after ischemia is efficacious and is reflected by the MRI indices of recanalization of the MCA, reduction of secondary microvascular perfusion deficits and reduction of the ischemic lesion.     

Combined X-ray angiography and diffusion-perfusion MRI for studying stroke evolution after rt-PA treatment in rats

Clinical studies on rt-PA (recombinant tissue-type plasminogen activator) treatment of stroke showed a favorable outcome. However, there are reports of harmful effects of t-PA via the potentiation of excitotoxic injury. We used combined X-ray angiography and MRI imaging to study the balance between the beneficial effect of reperfusion and secondary detrimental effects of rt-PA. Therefore, rats (n=15) were assigned to three groups according to recanalization or lack thereof of the middle cerebral artery (MCA) and rt-PA or saline treatment in an embolic stroke model. Diffusion and perfusion MRI showed that animals had significantly improved perfusion values and final infarct size when recanalization was successful. However, final infarct volumes at 6 h post stroke onset were greater in the rt-PA group compared to controls at comparable perfusion values when the MCA did not recanalize after treatment (67.4+/-5.4 versus 47.7+/-17.9% of ipsilateral hemisphere, P=0.042). Our results demonstrate that the combination of angiography and MR-imaging is useful to further evaluate rt-PA treatment of thromboembolic stroke.     

不同剂量rt-PA静脉治疗急性缺血性卒中临床分析

目的 重组组织型纤溶酶原激活剂（reconstructive tissue plasminogen activator,rt-PA）在静脉溶栓治疗急性缺血性卒中时,美国食品药品管理局（food and drug administration,FDA）批准剂量为0.9mg/kg（总量≤90mg）,国内亦有应用剂量0.6～0.8mg/kg（总量50mg）。本试验拟探讨两种剂量rt-PA的疗效及安全性。方法 纳入急性缺血性卒中患者30例,美国国立卫生研究院卒中量表（N ati o n a l I n sti tu te s of Health Stroke Scale NIHSS）评分2～26分,发病时间0.5～6h,无溶栓禁忌证。随机分为两组：rt-PA0.6～0.8mg/kg（总量50mg）组（A组）和0.9mg/kg组（B组）。比较两组治疗前、治疗后24h及14d的NIHSS评分改善率（≥4分）及颅内出血率、死亡率。结果 两组治疗前的基本资料无统计学差异,NIHSS评分平均为10.17分。B组治疗后14d NIHSS评分改善率明显优于A组（86.67% vs 53.3%,P <0.05）。两组发生颅内出血的比例均为6%。两组死亡病例均为非出血性病变,A组死亡率略高于B组,但无统计学差异（26.67% vs 20%,P =0.67）。结论 rt-PA 0.9mg/kg剂量疗效优于0.6～0.8mg/kg剂量,并未增加颅内出血并发症及死亡率,该溶栓剂量同样适用于国人。     

Diffusion-Weighted Magnetic Resonance Imaging Characteristics of Hemorrhagic Transformation in Experimental Embolic Stroke

Diffusion-weighted magnetic resonance imaging (MRI) can detect ischemia within minutes of onset, but its ability to reliably detect hyperacute cerebral hemorrhage is unknown. The present study characterized diffusion-weighted, T2-weighted, and contrast-enhanced T1-weighted MRI appearances of hemorrhagic transformation within 5 hours of onset in experimental embolic stroke. Apparent diffusion coefficients and MRI signal characteristics were noted within corresponding regions of hemorrhage observed on gross pathology. Apparent diffusion coefficients were significantly increased within hemorrhagic lesions, but were still within the expected range for bland ischemia. The appearance of the hemorrhagic lesions on diffusion-weighted MRI was also very heterogeneous and not very useful for clinical screening. Other MRI modalities should be investigated, but computed tomography remains the only widely available clinical method of reliably detecting cerebral hemorrhage.     

Antiactin-targeted immunoliposomes ameliorate tissue plasminogen activator-induced hemorrhage after focal embolic stroke.

Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by serious risks of intracerebral hemorrhage. In this study, the authors show that a novel antiactin-targeted immunoliposome significantly reduced tPA-induced hemorrhage in an established rat model of embolic focal stroke. Spontaneously hypertensive rats were subjected to focal ischemia using homologous blood clot emboli. Delayed administration of tPA (10 mg/kg, 6 hours after ischemia) induced intracerebral hemorrhage at 24 hours. In control rats treated with tPA plus vehicle, hemorrhage volumes were 9.0 +/- 2.4 uL (n = 7). In rats treated with tPA plus antiactin immunoliposomes, hemorrhage volumes were significantly reduced to 4.8 +/- 2.7 uL (n = 8, P < 0.05). No significant effects were seen when rats were treated with tPA plus a nontargeted liposome (7.8 +/- 2.1 uL, n = 9). Fluorescent immunohistochemistry showed that rhodamine-labeled targeted liposomes colocalized with vascular structures in ischemic brain that stained positive for endothelial barrier antigen, a marker of cerebral endothelial cells. These data suggest that immunoliposomes may ameliorate vascular membrane damage and reduce hemorrhagic transformation after thrombolytic therapy in cerebral ischemia.     

Detection of BBB disruption and hemorrhage by Gd-DTPA enhanced MRI after embolic stroke in rat

Thrombolytic therapy with rtPA increases the risk of hemorrhagic transformation (HT) after cerebral ischemia. We employed contrast enhancement MRI with Gd-DTPA to detect HT in a rat model of embolic stroke treated with rtPA and a glycoprotein IIb/IIIa receptor antagonist, 7E3 F(ab')2, at 4 h after embolic stroke. Male Wistar rats were subjected to embolic stroke and treated with the combination of rtPA and 7E3 F(ab')2 (n=12) or with saline (n=10) at 4 h after onset of stroke. MRI studies were performed immediately and at 24 h after embolization using a 7-T system. Histological measurements were obtained at 48 h. With Gd-DTPA, T1WI images and permeability related MRI parameters (the blood-to-brain transfer constant, Ki, and the distribution volume of mobile protons, Vp) of 15 out of 18 animals showed hyperintensity regions in gross or microscopic HT areas at 24 h, confirmed histologically at 48 h post stroke. Contrast enhancement MRI detected six of seven (86%) animals with gross HT and nine of eleven (82%) animals with microscopic HT at 24 h after ischemia. Two of eighteen animals with HT, had MRI indices of hemorrhage at 3 h post stroke. However, compared to HT data measured histologically at 48 h in embolic stroke rats, the enhanced areas by Gd-DTPA at 24 h were larger, and the patterns (time, intensity and region) did not directly correlate to the subtypes of HT, i.e., gross or microscopic hemorrhage. Contrast enhancement MRI using Gd-DTPA provides a method to detect gross and microscopic HT after stroke in rats.     

不同时间窗重组组织型纤溶酶原激活剂静脉溶栓治疗椎-基底动脉系统脑梗死的疗效

目的探讨不同时间窗重组组织型纤溶酶原激活剂(rt-PA)静脉溶栓治疗椎-基底动脉系统脑梗死的疗效。方法对26例经多模式MRI证实的椎-基底动脉系统脑梗死患者行rt-PA静脉溶栓治疗,治疗时间窗<4.5 h组和4.5～9 h组各13例。患者在治疗前及治疗后24 h、14 d、90 d进行美国国立卫生研究院卒中量表(NIHSS)评分,90 d时行Bathel指数(BI)、改良Rankin量表(mRs)评分,比较两组的疗效;观察溶栓后有无脑出血发生。结果 <4.5 h组与4.5～9 h组各时间点NIHSS、BI及mRs评分差异无统计学意义。<4.5 h组与4.5～9 h组各有1例非症状性脑出血。90 d时,<4.5 h组mRS评分预后良好7例(53.85%);4.5～9 h组6例(46.15%),两组预后良好率的差异无统计学意义。结论椎-基底动脉系统脑梗死静脉rt-PA溶栓治疗4.5 h时间窗和适当延长治疗时间窗均安全有效。     

Infarct prediction and treatment assessment with MRI-based algorithms in experimental stroke models.

There is increasing interest in using algorithms combining multiple magnetic resonance imaging (MRI) modalities to predict tissue infarction in acute human stroke. We developed and tested a voxel-based generalized linear model (GLM) algorithm to predict tissue infarction in an animal stroke model in order to directly compare predicted outcome with the tissue's histologic outcome, and to evaluate the potential for assessing therapeutic efficacy using these multiparametric algorithms. With acute MRI acquired after unilateral embolic stroke in rats (n=8), a GLM was developed and used to predict infarction on a voxel-wise basis for saline (n=6) and recombinant tissue plasminogen activator (rt-PA) treatment (n=7) arms of a trial of delayed thrombolytic therapy in rats. Pretreatment predicted outcome compared with post-treatment histology was highly accurate in saline-treated rats (0.92+/-0.05). Accuracy was significantly reduced (P=0.04) in rt-PA-treated animals (0.86+/-0.08), although no significant difference was detected when comparing histologic lesion volumes. Animals that reperfused had significantly lower (P<0.01) GLM-predicted infarction risk (0.73+/-0.03) than nonreperfused animals (0.81+/-0.05), possibly reflecting less severe initial ischemic injury and therefore tissue likely more amenable to therapy. Our results show that acute MRI-based algorithms can predict tissue infarction with high accuracy in animals not receiving thrombolytic therapy. Furthermore, alterations in disease progression due to treatment were more sensitively monitored with our voxel-based analysis techniques than with volumetric approaches. Our study shows that predictive algorithms are promising metrics for diagnosis, prognosis and therapeutic evaluation after acute stroke that can translate readily from preclinical to clinical settings.     

Systemische Thrombolysetherapie mit rt-PA beim akuten Mediaterritorialinfarkt Erfahrungen aus der klinischen Routine

BACKGROUND AND PURPOSE: Only a few clinical reports about the routine use of intravenous rt-PA for the treatment of acute ischemic stroke have been published. Wether the perfusion of the extracranial parts of the internal carotid artery influences the outcome of the patients is still unknown, because the two major studies about systemic thrombolytic therapy with rt-PA in stroke (ECASS and NINDS) did not formally assess the status of the extracranial vessels. METHODS: 56 Patients were treated with intravenous rt-PA within 6 h of acute ischemic stroke between January 1995 and May 1998. Before and within 24 h after the thrombolytic therapy usually a neurovascular diagnostic with extra- und transcranial Doppler-ultrasound or CT-angiography was performed. Occlusions of the intracranial parts of the internal carotid artery (Carotid-T) were excluded from thrombolytic therapy. The outcome was assessed using the Rankin-scale at least 3 month after the therapy. RESULTS: The average time from stroke onset to administration of treatment was 3.7 h.A parenchymal hemorrhage with clinical deterioration was found in four patients (7.1%). Eight patients died until the follow-up (14.3%), four within 14 days. 39 patients showed a clinical improvement. Outcome and recanalization rate of the medial cerebral artery was not influenced by stenoses or occlusions of the extracranial internal carotid artery. CONCLUSIONS: Routine intravenous use of rt-PA for acute ischemic stroke shows safety comparable to the results of the NINDS study even in 6 h time window. The outcome and recanalization rate depends not on the perfusion of the extracranial parts of the internal carotid artery.     

不同剂量重组组织型纤溶酶原激活剂静脉溶栓治疗对超早期急性脑梗死预后的影响

目的 通过对超早期脑梗死患者接受不同剂量重组组织型纤溶酶原激活剂（rt-PA）静脉溶栓治疗的分析，探讨使用rt-PA对超早期脑梗死预后的影响。方法 超早期脑梗死患者308例，根据家属的意愿及是否签署溶栓治疗知情同意书分别给予溶栓治疗和非溶栓治疗。溶栓组221例，接受rt-PA静脉溶栓，其中92例给予rt-PA 0.9 mg/kg，发病在3 h内68例，>3～≤4 h内9例，>4～≤6 h内15例。129例给予rt-PA0.6～0.8 mg/kg，发病在3 h内72例，>3～≤4 h内24例，>4～≤6 h内33例。对照组87例，未应用rt-PA治疗。记录各组在基线、治疗24 h、发病90 dNIHSS评分、Barthel指数。预后良好定义为发病90 d Barthel指数≥95；颅内出血分为症状性颅内出血和非症状性颅内出血。同时记录随访期间的血管性死亡事件和卒中再发事件。应用logistic多因素分析预后的独立相关因素。结果 预后良好的独立相关因素为患者接受治疗前NIHSS评分（OR＝2.067，95%CI 1.201～3.556，P =0.009），冠心病史（OR =1.942，95%CI 1.040～3.625，P =0.037）和溶栓治疗（rtPA 0.9 mg/kg时，OR =0.414，95%CI 0.207～0.826，P =0.012；rtPA 0.6～0.8 mg/kg时，OR =0.261，95%CI 0.137～0.497，P＜0.01）。症状性颅内出血发生率在rtPA 0.9 mg/kg溶栓组与rtPA 0.6～0.8 mg/kg溶栓组分别为3.3%（3/92）和4.7%（6/129），差别无统计学意义。结论 静脉应用r t - PA溶栓治疗超早期急性脑梗死可获得较好的预后，不同剂量 r t - PA（0.6～0.8 mg/kg vs 0.9 mg/kg）对预后的影响无统计学差异，伴有心房颤动、糖尿病史将可能影响预后。     

Analysis of combined treatment of embolic stroke in rat with r-tPA and a GPIIb/IIIa inhibitor.

Suppression of platelet activation improves the efficacy of thrombolytic therapy for stroke. Thus, combination treatment with recombinant tissue plasminogen activator (r-tPA) and 7E3 F(ab')2, a GPIIb/IIIa inhibitor that binds the platelet to fibrin, may improve the efficacy of thrombolytic therapy in embolic stroke. Magnetic resonance imaging (MRI) was used to monitor treatment response in rats subjected to embolic middle cerebral artery (MCA) occlusion (MCAo). Animals were randomized into treated (n=12) and control (n=10) groups and received intravenous combination therapy or saline, respectively, 4 hours after MCAo. Magnetic resonance imaging (MRI) measurements performed 1 hour after MCAo showed no difference between groups. However, an increased incidence (50%) of MCA recanalization was found in the treated group at 24 hours compared with 20% in the control group. The area of low cerebral blood flow at 24 and 48 hours was significantly smaller in the combination treatment group, and the lesion size, as indicated from the T2 and T1 maps, differed significantly between groups. Fluorescence microscopy measurements of cerebral microvessels perfused with fluorescein isothiocyanate-dextran and measurements of infarct volume revealed that the combination treatment significantly increased microvascular patency and reduced infarct volume, respectively, compared with the control rats. The efficacy of combination treatment 4 hours after ischemia is reflected by MRI indices of tissue perfusion, MCA recanalization, and reduction of lesion volume. The treatment also reduced secondary microvascular perfusion deficits.