Maher Saqqur

Site of Arterial Occlusion Identified by Transcranial Doppler Predicts the Response to Intravenous Thrombolysis for Stroke

Background and Purpose— The objective of this study was to examine clinical outcomes and recanalization rates in a multicenter cohort of stroke patients receiving intravenous tissue plasminogen activator by site of occlusion localized with bedside transcranial Doppler. Angiographic studies with intraarterial thrombolysis suggest more proximal occlusions carry greater thrombus burden and benefit less from local therapy. Methods— Using validated transcranial Doppler criteria for specific arterial occlusion (Thrombolysis in Brain Ischemia flow grades), we compared the rate of dramatic recovery (National Institutes of Health Stroke Scale score ≤2 at 24 hours) and favorable outcomes at 3 months (modified Rankin Scale ≤1) for each occlusion site. We determined the likelihood of recanalization at various occlusion sites and its predictors. Then, stepwise logistic regression was used to determine predictors of complete recanalization. Results— Three hundred thirty-five patients had a mean age 69±13 years and 48.5% were women (median baseline National Institutes of Health Stroke Scale score 16 [range, 3 to 32], mean time to transcranial Doppler 140±84 minutes, and mean time to intravenous tissue plasminogen activator 145±68 minutes). Distal middle cerebral artery occlusion had an OR of 2 for complete recanalization (50 of 113 [44.2%], 95% CI: 1.1 to 3.1, P=0.005), proximal middle cerebral artery 0.7 (49 of 163 [30%], 95% CI: 0.4 to 1.1, P=0.13), terminal internal carotid artery 0.1 (one of 17 [5.9%], 95% CI: 0.015 to 0.8, P=0.015), tandem cervical internal carotid artery/middle cerebral artery 0.7 (6 of 22 [27%], 95% CI: 0.3 to 1.9, P=0.5), and basilar artery 0.96 (3 of 10 [30%], 95% CI: 0.2 to 4, P=0.9). Prerecombinant tissue plasminogen activator National Institutes of Health Stroke Scale score, systolic blood pressure, glucose, and Thrombolysis in Brain Ischemia flow grade at the occlusion site were the negative independent predictors for complete recanalization in the final model. There were no associations among time to treatment, stroke mechanisms, or recanalization rate. Patients with no flow (Thrombolysis in Brain Ischemia 0) at the occlusion site had less probability of complete recanalization than patients with dampened flow (Thrombolysis in Brain Ischemia 3) (ORadj: 0.256, 95% CI: 0.11 to 0.595, P=0.002). Continuous transcranial Doppler monitoring (exposure to ultrasound) was a positive predictor for complete recanalization (ORadj: 3.02, 95% CI: 1.396 to 6.514, P=0.005). National Institutes of Health Stroke Scale score ≤2 at 24 hours was achieved in 66 of 305 patients (22%): distal middle cerebral artery 33% (35 of 107), tandem cervical internal carotid artery/middle cerebral artery 24% (5 of 21), proximal middle cerebral artery 16% (24 of 155), basilar artery 25% (2 of 8), and none of the patients with terminal internal carotid artery had dramatic recovery (0%, n=14; P=0.003). Modified Rankin Scale score ≤1 was achieved in 90 of 260 patients (35%): distal middle cerebral artery 52% (50 of 96), proximal middle cerebral artery 25% (33 of 131), tandem cervical internal carotid artery/middle cerebral artery 21% (3 of 14), terminal internal carotid artery 18% (2 of 11), and basilar artery 25% (2 of 8) (P<0.001). Patients with distal middle cerebral artery occlusion were twice as likely to have a good long-term outcome as patients with proximal middle cerebral artery (OR: 2.1, 95% CI: 1.1 to 4, P=0.025). Conclusions— Clinical response to thrombolysis is influenced by the site of occlusion. Patients with no detectable residual flow signals as well as those with terminal internal carotid artery occlusions are least likely to respond early or long term.

Collateral blood vessels in acute ischaemic stroke: a potential therapeutic target

Ischaemic stroke results from acute arterial occlusion leading to focal hypoperfusion. Thrombolysis is the only proven treatment. Advanced neuroimaging techniques allow a detailed assessment of the cerebral circulation in patients with acute stroke, and provide information about the status of collateral vessels and collateral blood flow, which could attenuate the effects of arterial occlusion. Imaging of the brain and vessels has shown that collateral flow can sustain brain tissue for hours after the occlusion of major arteries to the brain, and the augmentation or maintenance of collateral flow is therefore a potential therapeutic target. Several interventions that might augment collateral blood flow are being investigated.

Improving the Predictive Accuracy of Recanalization on Stroke Outcome in Patients Treated With Tissue Plasminogen Activator

Background and Purpose— Although early recanalization is a powerful predictor of stroke outcome after thrombolysis, some stroke patients remain disabled despite tissue plasminogen activator (tPA)–induced recanalization. Therefore, we sought to investigate whether the predictive accuracy of early recanalization on stroke outcome is improved when combined with clinical and radiological information. Methods— We evaluated 177 patients with nonlacunar strokes in the middle cerebral artery (MCA) treated with intravenous tPA who were followed up during 3 months. Transcranial Doppler monitoring of recanalization was conducted during the first hours after tPA administration. The relative contribution of clinical, transcranial Doppler, and radiological information on stroke outcome was evaluated. We used logistic regression to derive a predictive model for good outcome (modified Rankin Scale score ≤2) after thrombolysis. Results— Median National Institutes of Health Stroke Scale (NIHSS) score before tPA was 16. At 3 months, 87 patients (49.2%) became functionally independent (modified Rankin Scale score ≤2). In a logistic regression model, degree of recanalization within 300 minutes (P <0.001), proximal MCA occlusion (P <0.001), baseline NIHSS score (P =0.0013), systolic blood pressure (P =0.0116), and early ischemic changes on CT (P =0.0253) independently predicted outcome at 3 months. A 5-item score was developed on the basis of the factors significantly associated with stroke outcome in the logistic regression (total score range, 0 to 7). The likelihood of good outcome at 3 months was 0.82 (95% CI, 0.72 to 0.92) in patients who scored 0 to 2, 0.51 (95% CI, 0.36 to 0.66) in those who scored 3 to 4, and 0.15 (95% CI, 0.05 to 0.25) in those who scored 5 to 7 points. Conclusions— The combination of clinical, radiological, and hemodynamic information predicts with a high accuracy long-term stroke outcome during or shortly after intravenous tPA administration.

Safety and Efficacy of Ultrasound-Enhanced Thrombolysis A Comprehensive Review and Meta-Analysis of Randomized and Nonrandomized Studies

Background and Purpose— Ultrasound-enhanced thrombolysis is a promising new approach to facilitate reperfusion therapies for acute ischemic stroke. So far, 3 different ultrasound technologies were used to increase the thrombolytic activity of tissue plasminogen activator (tPA), including transcranial Doppler (TCD), transcranial color-coded duplex (TCCD), and low-frequency ultrasound. We performed a meta-analysis to evaluate the safety and efficacy of ultrasound-enhanced thrombolysis compared to the current standard of care (intravenous tPA). Subjects and Methods— Through Medline, Embase, and Cochrane database search, we identified and abstracted all studies of ultrasound-enhanced thrombolysis in acute cerebral ischemia. Principal investigators were contacted if data not available through peer-reviewed publication were needed. Symptomatic intracerebral hemorrhage (sICH) and recanalization rates were compared between tPA, tPA+TCD±microspheres (&mgr;S), tPA+TCCD±&mgr;S, and tPA+low-frequency ultrasound. Results— A total of 6 randomized (n=224) and 3 nonrandomized (n=192) studies were identified. The rates of symptomatic intracerebral hemorrhage in randomized studies were as follows: tPA+TCD, 3.8% (95% CI, 0%–11.2%); tPA+TCCD, 11.1% (95% CI, 0%–28.9%); tPA+low-frequency ultrasound, 35.7% (95% CI, 16.2%– 61.4%); and tPA alone, 2.9% (95% CI, 0%–8.4%). Complete recanalization rates were higher in patients receiving combination of TCD with tPA 37.2% (95% CI, 26.5%– 47.9%) compared with patients treated with tPA alone 17.2% (95% CI, 9.5%–24.9%). In 8 trials of high-frequency (TCD/TCCD) ultrasound-enhanced thrombolysis, tPA+TCD/TCCD±&mgr;S was associated with a higher likelihood of complete recanalization (pooled OR, 2.99; 95% CI, 1.70–5.25; P=0.0001) when compared to tPA alone. High-frequency ultrasound-enhanced thrombolysis was not associated with an increased risk of symptomatic intracerebral hemorrhage (pooled OR, 1.26; 95% CI, 0.44–3.60; P=0.67). Conclusions— The present safety and signal-of-efficacy data of high-frequency ultrasound-enhanced thrombolysis should be taken into account in the design of future randomized controlled trials.

Clinical Deterioration After Intravenous Recombinant Tissue Plasminogen Activator Treatment A Multicenter Transcranial Doppler Study

Background and Purpose— Patients may experience clinical deterioration (CD) after treatment with intravenous recombinant tissue plasminogen activator (rt-PA). We evaluated the ability of flow findings on transcranial Doppler to predict CD and outcomes on modified Rankin Scale. Methods— Patients with acute stroke received intravenous rt-PA within 3 hours of symptom onset at four academic centers. CD was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) score by 4 points or more within 24 hours. Poor long-term outcome was defined by modified Rankin Scale ≥2 at 3 months. Transcranial Doppler findings were interpreted using the Thrombolysis in Brain Ischemia flow grading system as persistent arterial occlusion, reocclusion, or complete recanalization. Multiple regression analysis was used to identify transcranial Doppler flow as a predictor for CD after controlling for age, sex, baseline NIHSS, hypertension, and glucose. Results— A total of 374 patients received intravenous rt-PA at 142±60 minutes (median pretreatment NIHSS score 16 points). At the end of intravenous rt-PA infusion, transcranial Doppler showed persistent arterial occlusion in 219 patients (59%), arterial reocclusion in 54 patients (14%), and complete recanalization in 101 patients (27%). CD occurred in 44 patients: 36 had persistent arterial occlusion or reocclusion (82%), 13 symptomatic intracerebral hemorrhage (29%), and both persistent occlusion/reocclusion and symptomatic intracerebral hemorrhage in 10 patients (23%). After adjustment, patient risk for CD with persistent occlusion was OR 1.7 (95% CI: 0.7 to 4) and with arterial reocclusion 4.9 (95% CI: 1.7 to 13) (P=0.002). Patient risk for poor long-term outcomes with persistent occlusion, partial recanalization, or reocclusion was OR 5.2 (95% CI: 2.7 to 9, P=0.001). Conclusions— Inability to achieve or sustain vessel patency at the end of rt-PA infusion correlates with the likelihood of clinical deterioration and poor long-term outcome. Early arterial reocclusion on transcranial Doppler is highly predictive of CD and poor outcome.

Effect of Hyperthermia on Prognosis After Acute Ischemic Stroke

Background and Purpose— Experimental studies have shown that hyperthermia is a determinant of poor outcome after ischemic stroke. Clinical studies evaluating the effect of temperature on poststroke outcome have, however, been limited by small sample sizes. We sought to evaluate the effect of temperature and timing of hyperthermia on outcome after ischemic stroke. Methods— Data of 5305 patients in acute stroke trials from the Virtual International Stroke Trials Archive (VISTA) data set were analyzed. Data for temperatures at baseline, eighth, 24th, 48th, and 72nd hours, and seventh day were assessed in relation to outcome (poor versus good) based on the modified Rankin Scale at 3 months. Hyperthermia was defined as temperature >37.2°C and poor outcome as 90-day modified Rankin Scale >2. Hazard ratios with 95% CIs were reported for hyperthermia in relation to the outcome. Logistic regression models, in relation to hyperthermia, were fitted for a set of preselected covariates at different time points to identify predictors/determinants of hyperthermia. Results— The average age of patients was 68.0±11.9 years, 2380 (44.9%) were females, and 42.3% (2233) received thrombolysis using recombinant tissue plasminogen activator. After adjustment, hyperthermia was a statistically significant predictor of poor outcome. The hazard ratios (95% CI) for poor outcome in relation to hyperthermia at different time points were: baseline 1.2 (1.0 to 1.4), eighth hour 1.7 (1.2 to 2.2), 24th hour 1.5 (1.2 to 1.9), 48th hour 2.0 (1.5 to 2.6), 72nd hour 2.2 (1.7 to 2.9), and seventh day 2.7 (2.0 to 3.8). Gender, stroke severity (National Institutes of Health Stroke Scale score >16), white blood cell count, and antibiotic use were significantly associated with hyperthermia (P≤0.01). Conclusions— Hyperthermia, in acute ischemic stroke, is associated with a poor clinical outcome. The later the hyperthermia occurs within the first week, the worse the prognosis. Severity of stroke and inflammation are important determinants of hyperthermia after ischemic stroke. In patients with acute ischemic stroke, aggressive measures to prevent and treat hyperthermia could improve the clinical outcomes.

Symptomatic intracerebral hemorrhage and recanalization after IV rt-PA A multicenter study

Background: Symptomatic intracerebral hemorrhage (sICH) is the most unfavorable complication after IV thrombolytic treatment. We aimed to determine the relationship between early recanalization and the risk of sICH. Methods: Patients with acute stroke received IV tissue plasminogen activator (rt-PA) within 3 hours of symptom onset with transcranial Doppler (TCD) monitoring at four academic centers. sICH was defined as parenchymal hemorrhage on CT in relation to neurologic worsening (NIH Stroke Scale [NIHSS] ≥4) within 72 hours after treatment. Poor outcome was defined as modified Rankin Scale 3-6 at 3 months. Early recanalization was graded with Thrombolysis in Brain Ischemia (TIBI) system. Multiple logistic regression analyses were used to identify predictors of sICH. Results: A total of 349 patients received rt-PA at median 134 ± 32 minutes (mean age 69 ± 13 years, 186 men [53%]). Median pretreatment NIHSS score was 16 points (interquartile range: 12-20). Median time to TCD was 130 ± 40 minutes. At the end of rt-PA infusion, 135 patients (38%) had no recanalization, 101 (29%) partial, and 113 (32%) complete recanalization. sICH occurred in 26 patients (7.4%). Of the 135 patients without early recanalization, 18 (13%) had sICH, as compared to 4 (4%) of the 109 subjects with partial recanalization and 4 (3.5%) of 113 with complete recanalization, p = 0.005. After adjustment for age, sex, baseline NIHSS score, glucose, blood pressure, and time to treatment, patients with persistent occlusion had sixfold higher risk of sICH (OR = 6, 95% CI 1.5-21.3, p = 0.01). Conclusion: The risk of tPA-related symptomatic intracerebral hemorrhage (sICH) is low after early and complete restoration of blood flow. Arterial occlusion persistent beyond tissue plasminogen activator infusion emerges as an independent predictor of higher risk of sICH in patients treated with systemic thrombolysis.

Association of Pretreatment Blood Pressure With Tissue Plasminogen Activator-Induced Arterial Recanalization in Acute Ischemic Stroke

Background and Purpose— Elevated systolic blood pressure (SBP) and lack of early vessel recanalization are predictors of poor outcome among patients with stroke treated with systemic tissue plasminogen activator (tPA). We aimed to evaluate the potential relationship between pretreatment SBP and tPA-induced recanalization. Methods— Consecutive patients with acute ischemic stroke resulting from intracranial artery occlusion were treated with standard intravenous tPA and assessed with 2-MHz transcranial Doppler for arterial recanalization. Early arterial recanalization was determined with previously validated Thrombolysis in Brain Ischemia flow grading system at 120 minutes after tPA bolus. Functional outcome at 3 months was evaluated using the modified Rankin Scale. Results— A total of 351 patients received intravenous tPA (mean age: 68.7±13.4 years, median National Institutes of Health Stroke Scale score 16.5). Patients with complete recanalization (n=94) had lower mean pretreatment SBP values (152±23 mm Hg) than patients with incomplete or absent recanalization (n=257, 160±22 mm Hg, P=0.010). Pretreatment SBP levels were inversely associated with complete recanalization (OR per 10-mm Hg increase: 0.85; 95% CI: 0.74 to 0.98, P=0.022) after adjustment for demographics, risk factors, stroke severity, pretreatment Thrombolysis in Brain Ischemia grades, and continuous versus intermittent exposure to transcranial Doppler. Although patients with poor functional 3-month outcomes (modified Rankin Scale >2) had higher pretreatment SBP values (160±25 mm Hg) than functionally independent patients (154±20 mm Hg, P=0.027), pretreatment SBP levels were not independently associated with functional outcome on multivariable analysis. Age, complete recanalization, baseline National Institutes of Health Stroke Scale score, and time from symptom onset to tPA bolus were independent (P<0.05) predictors of 3-month outcome. Conclusion— Higher pretreatment SBP levels are associated with poor recanalization in patients with acute stroke treated with intravenous tPA.

Prevalence and Predictors of Paroxysmal Atrial Fibrillation on Holter Monitor in Patients With Stroke or Transient Ischemic Attack

Background and Purpose— Our aims were to quantify the yield of Holter monitor for detection of paroxysmal atrial fibrillation (PAF) in patients with stroke and TIA, and to determine potential predictors of PAF to allow more focused testing. Methods— We reviewed records of 1128 consecutive patients attending a university stroke clinic from September 2005 to September 2006 and identified 426 patients with definite TIA or stroke. We abstracted clinical, cardiac imaging, and neuroimaging data. Logistic regression analysis was performed to determine independent predictors of PAF on Holter monitor. Results— Overall, 413 of 426 patients (65±15 years; male, 49.8%) with a definite TIA (53%) or stroke (47%) underwent Holter monitoring for a mean of 22.6 hours. PAF occurred in 39 patients (9.2%) all older than age 55 years. PAF lasting >30 seconds was evident in 11 patients (2.5%). The other 28 patients had PAF <30 seconds (6.5%). In multivariate analyses, number of acute (odds ratio [OR], 1.7 for each 1 lesion increase; 95% confidence interval [CI], 1.2–2.6; P=0.0047) and chronic (OR, 1.6 for each 1 lesion increase; 95% CI, 1.2–2.3; P=0.0001) infarcts on brain CT, number of chronic infarcts on MRI (OR, 3.0 for each 1 lesion increase; 95% CI, 1.7–5.1; P<0.0001), and any acute cortical infarct on imaging (OR, 5.8; 95% CI, 1.9–17.8; P=0.0023) were associated with PAF. Conclusions— PAF is present in 9.2% of patients with definite stroke or TIA. Age older than 55 years and presence of acute or chronic brain infarcts on neuroimaging are strongly associated with PAF.

Role of transcranial Doppler in neurocritical care.

Transcranial Doppler has several practical applications in neurocritical care. It has its main application in the diagnosis and monitoring of vasospasm in patients with subarachnoid hemorrhage. In addition, it holds promise for the detection of critical elevations of intracranial pressure. Its ability to measure CO2 reactivity and autoregulation may ultimately allow intensivists to optimize cerebral perfusion pressure and ventilatory therapy for the individual patient. Transcranial Doppler findings of brain death are well described and can be useful as a screening tool.