Raquel Delgado-Mederos

Microbubble Administration Accelerates Clot Lysis During Continuous 2-MHz Ultrasound Monitoring in Stroke Patients Treated With Intravenous Tissue Plasminogen Activator

BACKGROUND AND PURPOSE We sought to evaluate the effects of administration of microbubbles (MBs) on the beginning, speed, and degree of middle cerebral artery (MCA) recanalization during systemic thrombolysis and continuous 2-MHz pulsed-wave transcranial Doppler (TCD) monitoring. METHODS We evaluated 111 patients with acute stroke attributable to MCA occlusion treated with intravenous tissue plasminogen activator (tPA). Thirty-eight patients were treated with tPA plus continuous 2-hour TCD monitoring plus 3 doses of 2.5 g (400 mg/mL) of galactose-based MBs given at 2, 20, and 40 minutes after tPA bolus (MB group). These patients were compared with 73 patients who were allocated to receive tPA plus continuous 2-hour TCD ultrasound (US) monitoring (tPA/US group) or tPA plus placebo monitoring (tPA group), most of whom were enrolled in a previous study of US-enhanced thrombolysis. The beginning, degree, and time to maximum completeness of recanalization during the first 2 hours of tPA bolus were recorded. RESULTS Median prebolus National Institutes of Health Stroke Scale (NIHSS) score was 18. Eighty patients (72%) had a proximal and 31 (28%) a distal MCA occlusion on TCD. Thirty-seven patients (33%) received tPA/US, 38 (34%) received tPA/US/MB, and 36 (32%) were treated with tPA alone. Stroke severity, time to treatment, location of MCA occlusion, and presence of carotid artery disease were similar among groups. Two-hour recanalization was seen in 14 (39%), 25 (68%), and 27 patients (71%) in the tPA, tPA/US, and tPA/US/MB groups, respectively (P=0.004). Two-hour complete recanalization rate was significantly (P=0.038) higher in the tPA/US/MB group (54.5%) compared with tPA/US (40.8%) and tPA (23.9%) groups. The time to beginning of recanalization after tPA bolus was 26+/-18 minutes in the tPA/US group and 19+/-12 minutes in the tPA/US/MB group (P=0.12). Four patients (3.6%) experienced symptomatic intracranial hemorrhage: 2 (5.5%), 1 (2.7%), and 1 patient (2.6%) who received tPA only, tPA/US, and tPA/US/MB, respectively, experienced symptomatic intracranial hemorrhage. At 24 hours, 31%, 41%, and 55% of tPA, tPA/US, and tPA/US/MB improved >4 points in the NIHSS score. CONCLUSIONS Administration of MBs induces further acceleration of US-enhanced thrombolysis in acute stroke, leading to a more complete recanalization and to a trend toward better short- and long-term outcome.

Tandem internal carotid artery/middle cerebral artery occlusion : An independent predictor of poor outcome after systemic thrombolysis

Background and Purpose— Although tandem internal carotid artery/middle cerebral artery (MCA; TIM) occlusion has been associated with low recanalization rate after IV tissue plasminogen activator (tPA), its independent contribution on stroke outcome remains unknown. Moreover, whether the relative resistance to thrombolysis in tandem lesions varies depending on the location of MCA clot remains uncertain. Methods— Two hundred and twenty-one consecutive stroke patients with an acute MCA occlusion treated with IV tPA were studied. Emergent carotid artery ultrasound and transcranial Doppler (TCD) examinations were performed in all patients before treatment. Recanalization was assessed on TCD at 2 hours of tPA bolus. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and after 24 hours. Modifed Rankin Scale score was used to assess outcome at 3 months. Results— Median prebolus NIHSS score was 16 points. On TCD, 156 (71.6%) patients had a proximal and 65 (29.4%) a distal MCA occlusion. TIM occlusion was identified in 44 (19.9%) patients. Eighteen (41.9%) patients with and 123 (69.5%) without TIM lesions achieved an MCA recanalization (P=0.01). In a logistic regression model, hyperglycemia >140 mg/dL (odds ratio [OR] 3.3, 95% CI, 1.6 to 6.8) and the presence of TIM occlusion (OR 2.8, 95% CI, 1.1 to 6.9) emerged as independent predictors of absence of recanalization. However, the independent contribution of TIM lesions on poor response to thrombolysis varied depending on the location of MCA occlusion. TIM occlusion independently predicted resistance to thrombolysis in patients with proximal (OR 4.63, 95% CI, 1.79 to 11.96), but not in those with distal MCA occlusion. Patients with TIM occlusion had worse short- (P<0.0001) and long-term (P<0.0001) clinical outcome. Conclusions— TIM occlusion independently predicts poor outcome after IV thrombolysis. However, its impact varies depending on the location of MCA clot. Therefore, emergent carotid ultrasound plus TCD examinations may improve the selection of patients for more aggressive reperfusion strategies.

Acute Hyperglycemia State Is Associated With Lower tPA-Induced Recanalization Rates in Stroke Patients

Background and Purpose— Hyperglycemia (HG) has a deleterious effect in stroke patients by accelerating ischemic brain damage; moreover, its antifibrinolytic effect may also influence reperfusion. We aimed to study the effect of acute/chronic HG on tissue-type plasminogen activator (tPA)–induced recanalization. Methods— We studied 139 consecutive stroke patients with documented intracranial artery occlusion treated with intravenous tissue-type plasminogen activator (tPA). Admission glucose levels were recorded (in mg/dL). The existence of previous chronic HG was determined by plasma levels of glycosylated hemoglobin (HbA1c, %) and fructosamine (in &mgr;mol/L). Transcranial Doppler monitoring assessed complete recanalization 2 hours after tPA bolus. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 48 hours. Results— On admission, the median NIHSS score was 18 and mean glucose value was140±63 mg/dL. At 2 hours, 32% of patients(n=44) achieved complete recanalization. Patients who recanalized showed lower admission glucose levels (127 vs 146 mg/dL; P=0.039) but no differences in HbA1c (6.3% vs 6.3%; P=0.896) or fructosamine (292 vs 293 &mgr;mol/L; P=0.957) were observed. Other variables associated with recanalization were initial distal middle cerebral artery occlusion (P=0.011) and platelet count (P=0.015). Patients with an admission glucose level >158 mg/dL had lower recanalization rates (16% vs 36.1%; P=0.035) and a higher NIHSS score at 48 hours (7 vs 14.5; P=0.04). After adjustment for stroke etiology, age, and risk factors, the only independent predictors on admission of no recanalization were glucose value >158 mg/dL (odds ratio [OR], 7.3; 95% confidence interval [CI], 1.3 to 42.3; P=0.027), proximal middle cerebral artery occlusion (OR, 2.6; 95% CI, 1.1 to 6.5; P=0.034), and platelet count <219 000/mL (OR, 2.6; 95% CI, 1.1 to 6.1; P=0.029). Conclusions— In tPA-treated patients, the acute but not chronic HG state may hamper the fibrinolytic process, delaying reperfusion of the ischemic penumbra. Early measures to reduce HG may favor early recanalization.

Temporal Profile of Recanalization After Intravenous Tissue Plasminogen Activator Selecting Patients for Rescue Reperfusion Techniques

Background and Purpose— Intravenous thrombolysis in stroke achieves arterial recanalization in ≈50% of cases. Determining temporal profile of recanalization may address patient selection and potential benefits of further rescue reperfusion techniques. Methods— We studied 179 consecutive intravenous tissue plasminogen activator (t-PA)–treated patients with intracranial artery occlusion. Continuous transcranial Doppler assessed recanalization (none-partial-complete) at 60 minutes (early), 120 minutes (delayed) after t-PA bolus, and 6 hours (late) from symptom onset. Outcomes were determined: National Institutes of Health Stroke Scale (NIHSS; 48-hour NIHSS) and 3-month modified Rankin Scale (mRS). Results— On admission, 68% of patients presented proximal middle cerebral artery occlusion, median NIHSS 17. Early recanalization was complete for 30 patients (17%), partial for 50 (28%), and none for 99 (55%). Delayed recanalization was complete for 56 patients (31%), partial for 39 (22%), and none for 84 (47%). Although early flow improvement was observed in up to 45% of patients, only 19% of patients with persistent occlusion (11% of total) presented delayed recanalization (odds ratio [OR] delayed/early recanalization, 0.16; 95% CI, 0.085 to 0.304; P<0.001). Among patients with persistent occlusion at 2 hours, only 13 (7% of total) presented late flow improvement (OR late/early recanalization, 0.09; 95% CI, 0.043 to 0.196; P<0.001). The few patients with late recanalization presented comparable median 48-hour NIHSS to those with early/delayed recanalization (3 versus 4.5; P=0.9) and much lower than those with persistent occlusion after 6 hours (3 versus 15; P=0.005). At 3 months, the rate of mRS ≤2 was not statistically different between patients with early/delayed versus late recanalization (55% versus 86%; P=0.12) but was lower if occlusion persisted 6 hours after onset (22%; P<0.001). Conclusion— The majority of t-PA-induced recanalizations occur during the first hour after treatment. Recanalizations during the following hours are rare but still related to clinical improvement if achieved within 6 hours from onset. Rescue reperfusion techniques should be considered if flow improvement is not observed 60 minutes after t-PA bolus.

Hyperglycemia during ischemia rapidly accelerates brain damage in stroke patients treated with tPA.

To evaluate impact of glucose burden on diffusion-weighted imaging (DWI)-lesion evolution according to ischemia duration in stroke. We studied 47 patients with transcranial Doppler (TCD)-documented artery occlusion treated with intravenous tissue plasminogen activator. Hyperglycemia (HG) was defined as glucose > 140 mg/dL. A subcutaneous device continuously monitored glucose during 24 h. Magnetic resonance imaging was performed pretreatment (1) and at 24 to 36 h (2) in 30 patients. We measured initial PWI lesion (PW1) and DWI growth: DW2–DW1 (DWg). Serial TCD during 24 h determined occlusion time (OT). National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 48 h. Poor short-term clinical course defined as <50% recovery of initial NIHSS. Baseline NIHSS was 18. On admission 10 patients (21.3%) were hyperglycemic and presented similar NIHSS, DW1, and PW1 lesion extension as those without HG. During monitoring 24 patients (51%) had HG, 21 (45%) of them during OT (median OT 12 h). Median 48 h-NIHSS was 10; 15 patients presented poor outcome. 48 h-NIHSS was higher in patients with HG during OT (15 versus 3; P < 0.001). Patients with favorable outcome had shorter OT (8.4 versus 17.4 h; P < 0.001). However, the only independent predictor of poor outcome was HG during OT (OR: 20.3; 95% CI: 3.77 to 108.8; P < 0.001). At 24 h mean DWg was 52 cm3. A receiver operating characteristic curve identified DWg > 14 cm3 best predictor of poor outcome (sensitivity, 85.7%; specificity, 75%). Total OT (P = 0.007) and HG during OT (P = 0.01) showed the strongest correlation with DWg. DWI lesion grew 2.7 times faster in patients with HG than without HG during OT (1.73 versus 4.63 cm3/h of occlusion; P = 0.07). In a regression model the only independent predictor of DWg was HG during OT (OR: 10.83; 95% CI: 1.96 to 59.83; P = 0.006). Hyperglycemia, especially during OT, has a powerful deleterious effect after stroke accelerating brain damage.

PROGNOSTIC SIGNIFICANCE OF BLOOD PRESSURE VARIABILITY AFTER THROMBOLYSIS IN ACUTE STROKE

Objective: To evaluate the impact of early blood pressure (BP) changes on diffusion-weighted imaging (DWI) lesion evolution and clinical outcome in patients with stroke treated with IV tissue plasminogen activator (tPA). Methods: We prospectively evaluated 80 patients with stroke with a documented middle cerebral artery occlusion treated with IV tPA. Multiple repeated systolic (SBP) and diastolic (DBP) BP measurements were obtained during 24 hours after admission. All patients underwent DWI, perfusion-weighted imaging, and magnetic resonance angiography before and 36–48 hours after thrombolysis. Recanalization was assessed on transcranial Doppler at 6 hours of stroke onset. NIH Stroke Scale scores were recorded at baseline and 24 hours. Modified Rankin Scale was used to assess 3-month outcome. Results: Recanalization occurred in 44 (55%) patients. BP variability, estimated as the SD of the mean, was associated with DWI lesion growth (r = 0.46, p = 0.0003 for SBP and r = 0.26, p = 0.02 for DBP), early clinical course (p = 0.06 for SBP and p = 0.01 for DBP), and 3-month outcome (p = 0.002 for SBP and 0.07 for DBP). However, the prognostic significance of BP changes differed depending on the presence of recanalization. SBP variability emerged as an independent predictor of DWI lesion growth (β: 6.9; 95% CI, 3.2 to 10.7, p = 0.003) and worse stroke outcome (OR: 11; 95% CI: 2.2 to 56.1; p = 0.004) in patients without recanalization, but not in recanalized patients. Conclusion: Blood pressure variability is associated with greater diffusion-weighted imaging lesion growth and worse clinical course in patients with stroke treated with IV tissue plasminogen activator. However, its impact varies depending on the occurrence of early recanalization after thrombolysis.

Speed of tPA-Induced Clot Lysis Predicts DWI Lesion Evolution in Acute Stroke

Background and Purpose— We sought to evaluate the impact of the speed of recanalization on the evolution of diffusion- weighted imaging (DWI) lesions and outcome in stroke patients treated with tissue-type plasminogen activator (tPA). Methods— We evaluated 113 consecutive stroke patients with a middle cerebral artery occlusion who were treated with intravenous tPA. All patients underwent multiparametric magnetic resonance imaging studies, including DWI and perfusion-weighted imaging before and 36 to 48 hours after administration of a tPA bolus. Patients were continuously monitored with transcranial Doppler during the first 2 hours after tPA administration. The pattern of recanalization on transcranial Doppler was defined as sudden (<1 minute), stepwise (1 to 29 minutes), or slow (>30 minutes). Results— During transcranial Doppler monitoring, 13 (12.3%) patients recanalized suddenly, 32 (30.2%) recanalized in a stepwise manner, and 18 (17%) recanalized slowly. Baseline clinical and imaging parameters were similar among recanalization subgroups. At 36 to 48 hours, DWI lesion growth was significantly (P=0.001) smaller after sudden (3.23±10.5 cm3) compared with stepwise (24.9±37 cm3), slow (46.3±38 cm3), and no (51.7±34 cm3) recanalization. The slow pattern was associated with greater DWI growth (P=0.003), lesser degree of clinical improvement (P=0.021), worse 3-month outcome (P=0.032), and higher mortality (P=0.003). Conclusions— The speed of tPA-induced clot lysis predicts DWI lesion evolution and clinical outcome. Unlike sudden and stepwise patterns, slow recanalization is associated with greater DWI lesion growth and poorer short- and long-term outcomes.

Outcomes of a contemporary cohort of 536 consecutive patients with acute ischemic stroke treated with endovascular therapy.

Background and Purpose— We sought to assess outcomes after endovascular treatment/therapy of acute ischemic stroke, overall and by subgroups, and looked for predictors of outcome. Methods— We used data from a mandatory, population-based registry that includes external monitoring of completeness, which assesses reperfusion therapies for consecutive patients with acute ischemic stroke since 2011. We described outcomes overall and by subgroups (age ⩽ or >80 years; onset-to-groin puncture ⩽ or >6 hours; anterior or posterior strokes; previous IV recombinant tissue-type plasminogen activator or isolated endovascular treatment/therapy; revascularization or no revascularization), and determined independent predictors of good outcome (modified Rankin Scale score ⩽2) and mortality at 3 months by multivariate modeling. Results— We analyzed 536 patients, of whom 285 received previous IV recombinant tissue-type plasminogen activator. Overall, revascularization (modified Thrombolysis In Cerebral Infarction scores, 2b and 3) occurred in 73.9%, 5.6% developed symptomatic intracerebral hemorrhages, 43.3% achieved good functional outcome, and 22.2% were dead at 90 days. Adjusted comparisons by subgroups systematically favored revascularization (lower proportion of symptomatic intracerebral hemorrhages and death rates and higher proportion of good outcome). Multivariate analyses confirmed the independent protective effect of revascularization. Additionally, age >80 years, stroke severity, hypertension (deleterious), atrial fibrillation, and onset-to-groin puncture ⩽6 hours (protective) also predicted good outcome, whereas lack of previous disability and anterior circulation strokes (protective) as well as and hypertension (deleterious) independently predicted mortality. Conclusions— This study reinforces the role of revascularization and time to treatment to achieve enhanced functional outcomes and identifies other clinical features that independently predict good/fatal outcome after endovascular treatment/therapy.

Is it Time to Reassess the SITS-MOST Criteria for Thrombolysis? A Comparison of Patients With and Without SITS-MOST Exclusion Criteria

Background and Purpose— The Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) established guidelines to increase safety in acute stroke thrombolysis, but precluding treatment in an important proportion of patients. We aimed to assess safety/efficacy of thrombolysis in patients with SITS-MOST exclusion criteria. Methods— 369 nonlacunar tPA-treated patients were studied. Patients were classified as SITS-MOST (SM) or non–SITS-MOST (NSM) according to SITS-MOST–criteria fulfilling. Clinical evaluation was assessed by NIHSS and functional outcome by mRS at 3 months (functional independency=mRS ≤2). Results— Baseline NIHSS was 17. 169 (45.8%) patients were SM and 200 (54.1%) NSM. Recanalization (47.6%/50.3%, P=0.36), 24-hour-improvement (55.6%/49.5%, P=0.114), and SICH were similar (4.8%/5.1%, P=0.554). At discharge, clinical improvement in SM-group was higher (66.7%/55.7%, P=0.024). NSM tended to higher mortality (10.5%/16.1%, P=0.084) and lower functional independence (48.7%/39.6%, P=0.082). Conclusion— Thrombolysis may be safe in patients not fulfilling SITS-MOST criteria. Testing thrombolysis in patients outside SITS-MOST could be considered in the future.

Do bubble characteristics affect recanalization in stroke patients treated with microbubble-enhanced sonothrombolysis?

Administration of microbubbles (MB) may augment the effect of ultrasound-enhanced systemic thrombolysis in acute stroke. Bubble structural characteristics may influence the effect of MB on sonothrombolysis. We aimed to compare the effects of galactose-based air-filled MB (Levovist) and sulphur hexafluoride-filled MB (Sonovue) on recanalization and clinical outcome. One hundred thirty-eight i.v. recombinant tissue plasminogen activator-(tPA-) treated patients with middle cerebral artery (MCA) occlusion were studied. Presence and location of arterial occlusion and recanalization (RE) were assessed using the thrombolysis in brain ischemia (TIBI) flow grading system. Patients underwent 2 h of continuous transcranial Doppler (TCD) monitoring and received three bolus of MB after 2, 20 and 40 min of tPA bolus. Ninety-one patients received Levovist (LV) and 47 received Sonovue (SV). NIHSS scores were obtained at baseline and after 24 h. Modified Rankin Scale (mRS) score was used to assess outcome at 3 mo. Median admission NIHSS was 17. On TCD, 96 (69.6%) patients had a proximal and 42 (30.4%) a distal MCA occlusion. Age, baseline NIHSS, clot location, stroke subtypes and time to treatment were similar between LV and SV groups. Recanalization rates after 1 h (32.2%/35.6%), 2 h (50.0%/46.7%) and 6 h (63.8%/54.5%) were similar in LV/SV groups (p > 0.3). Clinical improvement (NIHSS decrease >or= 4 points) at 24 h was similar in both groups (54.9%/51.1%, p = 0.400), as well as symptomatic intracranial haemorrhage rate (3.3%/2.1%, p = 0.580) and in-hospital mortality (8.1%/9.3%, p = 0.531). Similarly, the type of MB administered did not affect long-term outcome after sonothrombolysis. Forty-four percent of patients in the LV group and 48.5% in the SV group achieved functional independence (mRS <or= 2) at 3 mo (p = 0.440). MB administration during sonothrombolysis is associated with a high RE rate. However, RE rates, clinical course and long-term outcome are comparable when administering galactose-based air-filled MB (Levovist) or sulphur hexafluoride-filled MB (Sonovue).