Thrombolysis In Brain Ischemia Research Articles

Neurophysiologic Features Reflecting Brain Injury During Pediatric ECMO Support

BackgroundExtracorporeal membrane oxygenation (ECMO) provides lifesaving support to critically ill patients who experience refractory cardiopulmonary failure but carries a high risk for acute brain injury. We aimed to identify characteristics reflecting acute brain injury in children requiring ECMO support.MethodsThis is a prospective observational study from 2019 to 2022 of pediatric ECMO patients undergoing neuromonitoring, including continuous electroencephalography, cerebral oximetry, and transcranial Doppler ultrasound (TCD). The primary outcome was acute brain injury. Clinical and neuromonitoring characteristics were collected. Multivariate logistic regression was implemented to model odds ratios (ORs) and identify the combined characteristics that best discriminate risk of acute brain injury using the area under the receiver operating characteristic curve.ResultsSeventy-five pediatric patients requiring ECMO support were enrolled in this study, and 62 underwent neuroimaging or autopsy evaluations. Of these 62 patients, 19 experienced acute brain injury (30.6%), including seven (36.8%) with arterial ischemic stroke, four (21.1%) with hemorrhagic stroke, seven with hypoxic-ischemic brain injury (36.8%), and one (5.3%) with both arterial ischemic stroke and hypoxic-ischemic brain injury. A univariate analysis demonstrated acute brain injury to be associated with maximum hourly seizure burden (p = 0.021), electroencephalographic suppression percentage (p = 0.022), increased interhemispheric differences in electroencephalographic total power (p = 0.023) and amplitude (p = 0.017), and increased differences in TCD Thrombolysis in Brain Ischemia (TIBI) scores between bilateral middle cerebral arteries (p = 0.023). Best subset model selection identified increased seizure burden (OR = 2.07, partial R2 = 0.48, p = 0.013), increased quantitative electroencephalographic interhemispheric amplitude differences (OR = 2.41, partial R2 = 0.48, p = 0.013), and increased interhemispheric TCD TIBI score differences (OR = 4.66, partial R2 = 0.49, p = 0.006) to be independently associated with acute brain injury (area under the receiver operating characteristic curve = 0.92).ConclusionsIncreased seizure burden and increased interhemispheric differences in both quantitative electroencephalographic amplitude and TCD MCA TIBI scores are independently associated with acute brain injury in children undergoing ECMO support.

Abstract WP153: Abnormal Cerebral Blood Flow Determined By Transcranial Doppler In Patients With Anterior Circulation Large-vessel Occlusion Stroke And Successful Endovascular Recanalization

Background: Almost half of large-vessel occlusion (LVO) stroke patients have unfavorable outcomes despite successful endovascular revascularization. We aim to characterize post-revascularization cerebral blood flow (CBF) determined by transcranial Doppler (TCD) and explore whether abnormal CBF associates with in-hospital outcomes in this population. Methods: We analyzed 105 stroke patients with anterior circulation LVO who had successful endovascular revascularization (Thrombolysis in Cerebral Infarction 2b-3) and CBF assessment by TCD within 48 hours of recanalization. TCD parameters recorded at the ipsilateral middle cerebral artery included mean flow velocity, peak systolic velocity, pulsatility index (PI), and resistance index (RI). CBF was classified according to the Thrombolysis in Brain Ischemia (TIBI) score into dampened flow (score of 3), stenotic flow (score of 4), and normal flow (score of 5). We explored unadjusted associations between post-revascularization CBF and hospitalization outcomes including reduced disability at discharge (modified Rankin Score [mRS] 0-2), home disposition, and in-hospital mortality. Results: Table 1 summarizes study population characteristics. Overall, 62 (59.1%) individuals had normal CBF, 29 (27.6%) had stenotic flow, and 14 (13.3%) had dampened flow. Patients with abnormal CBF showed a trend towards lower likelihood of mRS 0-2 at discharge (32.1% vs. 44.2%; p=0.20) and home disposition (28.1% vs. 46.6%; p=0.08). TCD parameters were not associated with disability at discharge or home disposition. However, in-hospital mortality was significantly associated with elevated PI (1.3 ± 0.4 vs. 1.1 ± 0.5; p<0.01) and RI (0.7 ± 0.1 vs. 0.6 ± 0.1; p<0.01). Conclusion: A noteworthy fraction of anterior circulation LVO stroke patients had TCD-defined abnormal CBF despite successful revascularization. Abnormal CBF and increased vascular resistance may relate to unfavorable outcomes in this population.

Plasmin Generation Potential and Recanalization in Acute Ischaemic Stroke; an Observational Cohort Study of Stroke Biobank Samples.

Rationale: More than half of patients who receive thrombolysis for acute ischaemic stroke fail to recanalize. Elucidating biological factors which predict recanalization could identify therapeutic targets for increasing thrombolysis success.Hypothesis: We hypothesize that individual patient plasmin potential, as measured by in vitro response to recombinant tissue-type plasminogen activator (rt-PA), is a biomarker of rt-PA response, and that patients with greater plasmin response are more likely to recanalize early.Methods: This study will use historical samples from the Barcelona Stroke Thrombolysis Biobank, comprised of 350 pre-thrombolysis plasma samples from ischaemic stroke patients who received serial transcranial-Doppler (TCD) measurements before and after thrombolysis. The plasmin potential of each patient will be measured using the level of plasmin-antiplasmin complex (PAP) generated after in-vitro addition of rt-PA. Levels of antiplasmin, plasminogen, t-PA activity, and PAI-1 activity will also be determined. Association between plasmin potential variables and time to recanalization [assessed on serial TCD using the thrombolysis in brain ischemia (TIBI) score] will be assessed using Cox proportional hazards models, adjusted for potential confounders.Outcomes: The primary outcome will be time to recanalization detected by TCD (defined as TIBI ≥4). Secondary outcomes will be recanalization within 6-h and recanalization and/or haemorrhagic transformation at 24-h. This analysis will utilize an expanded cohort including ~120 patients from the Targeting Optimal Thrombolysis Outcomes (TOTO) study.Discussion: If association between proteolytic response to rt-PA and recanalization is confirmed, future clinical treatment may customize thrombolytic therapy to maximize outcomes and minimize adverse effects for individual patients.

Toward automated classification of pathological transcranial Doppler waveform morphology via spectral clustering.

Cerebral Blood Flow Velocity waveforms acquired via Transcranial Doppler (TCD) can provide evidence for cerebrovascular occlusion and stenosis. Thrombolysis in Brain Ischemia (TIBI) flow grades are widely used for this purpose, but require subjective assessment by expert evaluators to be reliable. In this work we seek to determine whether TCD morphology can be objectively assessed using an unsupervised machine learning approach to waveform categorization. TCD beat waveforms were recorded at multiple depths from the Middle Cerebral Arteries of 106 subjects; 33 with Large Vessel Occlusion (LVO). From each waveform, three morphological features were extracted, quantifying onset of maximal velocity, systolic canopy length, and the number/prominence of peaks/troughs. Spectral clustering identified groups implicit in the resultant three-dimensional feature space, with gap statistic criteria establishing the optimal cluster number. We found that gap statistic disparity was maximized at four clusters, referred to as flow types I, II, III, and IV. Types I and II were primarily composed of control subject waveforms, whereas types III and IV derived mainly from LVO patients. Cluster morphologies for types I and IV aligned clearly with Normal and Blunted TIBI flows, respectively. Types II and III represented commonly observed flow-types not delineated by TIBI, which nonetheless deviate from normal and blunted flows. We conclude that important morphological variability exists beyond that currently quantified by TIBI in populations experiencing or at-risk for acute ischemic stroke, and posit that the observed flow-types provide the foundation for objective methods of real-time automated flow type classification.

Effect of Age on Arterial Recanalization and Clinical Outcome in Thrombolyzed Acute Ischemic Stroke in CLOTBUST Cohort.

Background and Aims:Despite the evidence from randomized clinical trials, the effectiveness of intravenous tissue recombinant plasminogen activator (IV-tPA) for elderly patients (≥80 yrs) with acute ischemic stroke (AIS) is often an important consideration in clinical practice. We evaluated the effect of older age on arterial recanalization, timing of recanalization and outcome in thrombolysed AIS patients.Methods:Consecutive AIS patients treated with IV-tPA and transcranial Doppler (TCD) examination within 3 hours of symptom-onset were included. Thrombolysis in Brain Ischemia (TIBI) flow-grading system was used to interpret TCD findings of persistent occlusion, re-occlusion and complete recanalization within 2 hours of IV-tPA bolus. Poor functional outcome was defined by modified Rankin score of 3 or more. Univariate and multiple logistic regression analyses were performed to assess the effect of age on clinical and TCD outcome measures.Results:The study included 361 patients (elderly = 85, <80 yrs = 276). Median age was 68 years (range 18-91 years). Compared to the elderly, younger patients (<80 years) were more females (63.5% versus 41.3%), had higher baseline National Institute of Health Stroke Scale score (17.5 versus 16.0 points) and shorter time from symptom-onset to IV-tPA bolus (median 136.6 versus 139.7 minutes). No significant differences were noted between the site of arterial occlusion, TCD outcome measures or time of complete recanalization between the 2 groups. More patients aged < 80 years achieved good functional outcome (51.9% versus 31.8% in the older age group; P = 0.004). IV-tPA induced recanalization and symptomatic intracranial hemorrhage were similar in the 2 groups. Multivariate logistic regression showed elderly age as an independent predictor of poor outcome (adjusted OR 2.5, 95%CI 1.26-4.95; P = 0.008).Conclusion:Elderly AIS patients achieve relatively poor functional outcome after IV-tPA despite similar rates of arterial recanalization. However, there is no increase in the hemorrhagic risk. Perhaps, decision for IV thrombolysis in elderly patients should be made cautiously.

Translational research: May transplantation of human umbilical cord blood mononuclear cells become an adjuvant therapy for delayed thrombolysis in brain ischemia?

Translational research: May transplantation of human umbilical cord blood mononuclear cells become an adjuvant therapy for delayed thrombolysis in brain ischemia?

EFFECT OF CONTINUOUS TRANSCRANIAL DOPPLER ON THROMBOLYSIS IN ISCHEMIC STROKE DUE TO ACUTE MIDDLE CEREBRAL ARTERY OCCLUSION

Purpose: Recombinant tissue plasminogen activator (rtPA) activity may be enhanced with ultrasound, 2 MHz transcranial Doppler (TCD). We performed the trial to determine the efficacy of ultrasound-enhanced thrombolysis compared to the current standard of care (intravenous rtPA). Subjects and methods: We treated 80 patients who had acute ischemic stroke due to occlusion of the middle cerebral artery with intravenous rtPA within 4.5 hours after the onset of symptoms. The patients were randomly assigned to receive continuous 2-MHz transcranial Doppler ultrasonography (the target group) or placebo (the control group). The primary combined end point was complete recanalization as assessed by transcranial Doppler ultrasonography and dramatic clinical recovery at 2 hours. Complete recanalization was defined as thrombolysis in brain ischemia (TIBI) flow grades 4-5. Secondary end points included recovery at 24 hours, a favorable outcome at three months. Results: A total of 80 patients were randomly assigned to receive continuous ultrasonography (40 patients) or placebo (40 patients). Complete recanalization and dramatic clinical recovery within two hours after the administration of a rtPA bolus occurred in 13 patients in the target group (32,5%), as compared with 8 patients in the control group (20%) (P=0.038). At three months, 22 patients in the target group who were eligible for follow-up analysis (55%) and 13 in the control group (32,5%) had favorable outcomes (as indicated by a score of 0 to 1 on the modified Rankin scale) (P=0.012). Intracerebral hemorrhage occurred in five patients in the target group and in four in the control group. Conclusion: In patients with acute ischemic stroke due to occlusion of the middle cerebral artery, continuous transcranial Doppler augments rtPA-induced arterial recanalization, with an increased rate of recovery from stroke, as compared with placebo. Continuous 2-MHz transcranial Doppler ultrasonography for 2 hours is safe. Key words: Stroke, transcranial Doppler, tissue plasminogen activator

THE RELATIONSHIP BETWEEN TIMING OF RECANALIZATION AND CLINICAL OUTCOME OF ISCHEMIC STROKE DUE TO ACUTE MIDDLE CEREBRAL ARTERY OCCLUSION AFTER ULTRASOUND-ENHANCED THROMBOLYSIS

Purpose: The relationship between arterial recanalization after use of intravenous recombinant tissue plasminogen activator (rtPA) and outcome is still uncertain. The aim of our study was to evaluate the association between the timing and impact of recanalization on functional outcomes in ischemic stroke patients due to acute middle cerebral artery occlusion. Subjects and methods: Nonrandomized 40 stroke patients with proximal middle arterial occlusion on a prebolus TCD receiving intravenously 0.6 mg/kg rtPA within 4.5 hours after stroke onset were monitored with portable diagnostic TCD equipment and a standard headframe. Complete recanalization was defined as thrombolysis in brain ischemia (TIBI) flow grades 4-5. Results: 40 patients (mean age 67±14 years, NIH Stroke Scale [NIHSS] 16.15±8.6 points) were treated at 180±80 minutes from symptom onset. TCD was monitored continously for 120 minutes. Complete recanalization on TCD within 2 hours after bolus was found in 13 patients (32.5%). In this group, NIHSS decreased quickly at 2 hours and 24 hours. Modified Rankins 0-1point was seen in 92.3% of patients with complete recanalization compared to 37.0% of patients with uncomplete recanalization at 90 days. Non-symptomatic intracranial hemorrhage was seen in 1 patient in the group of complete recanalization. Conclusions: Complete recanalization of middle cerebral arteries within 2 hours after IV rtPA treatment plays a role in predicting the good functional and clinical outcomes after ultrasound-enhanced thrombolysis in acute ischemic stroke patients due to acute middle cerebral artery occlusion. Key words: stroke, recombinant tissue plasminogen activator, transcranial Doppler sonography

Sonothrombolysis for acute ischemic stroke - Break on through to the other side.

Intravenous (IV) tissue plasminogen activator (tPA) infusion combined with transcranial low-frequency ultrasound waves targeted on the occluded arterial segment (sonothrombolysis) can increase recanalization in large artery-acute ischemic stroke (LA-AIS). To evaluate the benefits of sonothrombolysis in LA-AIS. An open-labeled observational study done in a quaternary care teaching hospital. Patients with LA-AIS within the window period (<4.5 h) with no contraindications for IV-recombinant tPA were sonothrombolysed. Recanalization was monitored and graded using the transcranial Doppler thrombolysis in brain ischemia (TIBI) flow criteria and also by time of flight magnetic resonance angiography using a modified thrombolysis in myocardial infarction score. Parenchymal changes were assessed using computed tomography (CT) or diffusion-weighted imaging-Alberta Stroke Programme Early CT Score. National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) were used to assess the outcome. Eighteen patients underwent sonothrombolysis and the mean onset to needle time was 138 min (range 65-256). TIBI residual flow grade of ≥2 was seen in 15 of 18 patients (83%). Immediate dramatic improvement (NIHSS score ≤3 points or improvement by ≥10 points) was seen in 6 of 18 patients (30%) and in 9 of 18 patients (50%) within the next 24 h. Two patients (one with TIBI 0, another with re-occlusion) underwent mechanical thrombectomy post-sonothrombolysis. Symptomatic hemorrhage occurred in 5.5% of the patients. At 6 months, 2 of 18 patients (11%) died and 10 of 16 patients (63%) achieved mRS ≤2. Sonothrombolysis appears to be a safe way to augment the effect of tPA without increasing the door to needle time with the added advantage of observing flow through the occluded artery in real time.

Accuracy of National Institutes of Health Stroke Scale Score in Predicting the Site of Arterial Occlusion in Acute Stroke: A Transcranial Doppler Study

In acute stroke, it is crucial to assess for intracranial large-vessel occlusion and site of occlusion. The National Institutes of Health Stroke Scale score (NIHSSS) is the frequently used clinical tool to predict the site of arterial occlusion. In this study we aimed to determine the following: (1) if there is a correlation between the site of occlusion and the NIHSSS at presentation (bNIHSSS); and (2) if there is a bNIHSSS cutoff which can distinguish proximal occlusions (PO) from distal occlusions (DO). Up to 313 patients from CLOTBUST data bank with demonstrable intracranial arterial occlusion and having received intravenous recombinant tissue plasminogen activator (rt-PA) were included. Occlusions were classified as PO (terminal internal carotid artery, M1 segment of middle cerebral artery [M1 MCA], and basilar artery) or DO (M2 MCA, anterior cerebral artery, posterior cerebral artery, and vertebral artery). By univariate analysis, bNIHSSS, thrombolysis in brain ischemia (TIBI) flow grade before rt-PA, degree of recanalization after rt-PA, and modified Rankin Scale score at 3 months were significantly different between various sites of occlusion. By univariate analysis, a higher bNIHSSS, lower TIBI flow grade, and lower ASPECTS (Alberta Stroke Program Early CT Score) differentiated PO from DO. Lower TIBI flow grade and higher bNIHSSS differentiated PO from DO by logistic regression analysis. No single NIHSSS cutoff with acceptable sensitivity and specificity could be derived to differentiate PO from DO. Although NIHSSS are higher in PO, there is no satisfactory NIHSSS cutoff which differentiates PO from DO. A vascular imaging or transcranial doppler should be obtained to determine the site of arterial occlusion in acute stroke.

The Combination of Clinical Features, Transcranial Doppler, and Alberta Stroke Program Early Computed Tomography Score (Computed Tomography Angiography) in Predicting Outcome in Intravenous Recombinant Tissue Plasminogen Activator-Treated Patients

Little data exist on using combined baseline clinical neuroimaging and transcranial Doppler (TCD) information in predicting clinical outcome in stroke patients treated with intravenous (IV) thrombolysis. Stroke patients received IV recombinant tissue plasminogen activator (rt-PA) and had diagnostic TCD within 3 hours of symptom onset. The TCD result was interpreted using the thrombolysis in brain ischemia (TIBI) flow grading system. Following multiple regression analysis, a grading system was created with 1 point for each of the following: National Institutes of Health Stroke Scale (NIHSS) score of 16 or higher, TIBI score of 1 or lower, and Alberta Stroke Program Early CT Score (ASPECTS) of 6 or lower. The patients' scores were compared to modified Rankin Scale (mRS) scores at 90 days. A total of 349 patients were included. In unvaried analysis, age of 80 years or older (P = .002), an ASPECTS of 6 or lower (P < .001), an NIHSS score of 16 or higher (P < .001), a TIBI score of 1 or lower (P < .001), and a glucose level ≥ 200 mg/dl (P = .04) were associated with poor outcome (mRS score > 2). In the multiple regression analysis, age of 80 years or older, an ASPECTS of 6 or lower, an NIHSS score of 16 or higher, and hyperglycemia were predictors of poor outcome (P < .05). Based on our scoring system, the patients' odds ratios for poor outcome were 7 (95% confidence interval [CI]: 2-23, P = .003), 8 (95% CI: 3-25, P < .001), and 24 (95% CI: 4-151, P = .001) for scores of 1, 2, and 3, respectively, after adjustment for common stroke risk factors. The mean time to recanalization increased as the score increased (score of 0: 160 ± 45 minutes versus score of 3: 186 ± 38 (P = .70). A multimodal grading system is useful in predicting outcome in patients treated with IV rt-PA. Those withhigher scores might be candidates for interventional therapy.

Abstract 189: ADAMTS13 Activity Predicts Response to Thrombolysis in the Acute Stroke Setting

INTRODUCTION: Biological markers predicting tPA response in acute stroke could be used for dose adjustments or early selection of patients for endovascular procedures. ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) inactivates Von Willebrand Factor by cleaving it, and its deficiency may generate prothrombotic diseases such as thrombotic thrombocytopenic purpura. We aimed to analyze ADAMTS13 activity in acute stroke patients and its relation to vessel patency among those treated with intravenous tPA. METHODS: Acute ischemic stroke patients (n=104) with documented arterial occlusion by transcranial Doppler (TCD), who received tPA within the first 4.5 hours after symptoms onset were recruited and compared with 38 age-matched healthy subjects. Samples were collected at baseline, before thrombolytic treatment, and ADAMTS13 activity was measured by ELISA and expressed as %. A temporal profile of ADAMTS13 activity was determined at 24 hours and 3 months in a subset of 10 patients. Recanalization was assessed 2 hours after tPA bolus by TCD, using thrombolysis in brain ischemia (TIBI) flow grading system. Logistic regression analysis was conducted to determine independent predictors of 2-hour recanalization in patients with proximal arterial occlusions. RESULTS: ADAMTS13 activity was consistently lower in stroke patients than in healthy controls (p&lt;0.001), and remained lower at 24 hours and 3 months. For those patients who presented arterial recanalization at 2 hours, higher baseline ADAMTS13 activity (p=0.032) was noted. In logistic regression analysis from 72 patients with proximal MCA occlusion, ADAMTS13 activity &gt;74.72% was an independent predictor of recanalization [OR=5.148 (1.463-18.111), p=0.011], together with early ischemic signs at baseline neuroimaging [OR=0.065 (0.006-0.712), p=0.025] and OCSP classification (TACI vs. PACI) [OR=0.072 (0.011-0.45), p=0.005]. CONCLUSIONS: In stroke patients treated with tPA, ADAMTS13 activity may be used to monitor the treatment as well as to make decisions regarding more aggressive reperfusion therapies when the absence of a response to intravenous tPA is anticipated.

Does the sex of acute stroke patients influence the effectiveness of rt-PA?

BackgroundWomen have been reported to show more frequent recanalization and better recovery after intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment for acute stroke compared with men. To investigate this we studied a series of stroke patients receiving IV rt-PA and undergoing acute transcranial doppler (TCD) examination.MethodsAcute stroke patients received IV rt-PA and had acute TCD examination within 4 hours of symptom onset at 4 major stroke centers. TCD findings were interpreted using the Thrombolysis in Brain Ischemia (TIBI) flow grading system. The recanalization rates, and poor 3-month outcomes (modified Rankin scale >2) of men and women were compared using the chi-square test. Multiple regression analysis was used to assess sex as a predictor of recanalization and poor 3-month outcome after controlling for age, baseline NIH Stroke Scale (NIHSS), time to treatment, hypertension, and blood glucose.Results369 patients had TCD examinations before or during IV rt-PA treatment. The 199 (53.9%) men and 170 (46.1%) women had mean ages of 67 ± 13 and 70 ± 14 years, respectively. The sexes did not differ significantly in baseline stroke severity, time to TCD examination, or time to thrombolysis. Of the men, 68 (34.2%) had complete recanalization, 58 (29.1%) had partial recanalization, and 73 (36.6%) had no recanalization. Of the women, 53 (31.2%) had complete recanalization, 46 (27%) had partial recanalization, and 71 (41.8%) had no recanalization (p = 0.6). Multiple regression analyses showed no difference between the sexes in recanalization rate, time to recanalization, or clinical outcome at 3 months.ConclusionsIn our study; sex is not a significant predictor of recanalization rate, time to recanalization or 3-month outcome in stroke patients following IV rt-PA.Trial registrationData from CLOTBUST trial Clinicaltrails.gov Identifier: NCT01240356.

Abstract W MP24: Modified Tibi (Thrombolysis in Brain Ischemia) Grading System for Assessment of Abnormal Residual Flow at Site of Intracranial Occlusion in Acute Ischemic Stroke

Background and purpose: The intracranial blood flow at the site of arterial occlusion in acute ischemic stroke can be measured with Transracial Doppler (TCD) using the Thrombolysis in Brain Ischemia (TIBI) grading system. The TIBI ranges from 0 to 5, where 0 no flow and 5 normal flow. Our study’s aim is to modify the TIBI grading system in order to make it simple to implement in an acute stroke setting. METHODS: We classified Modified TIBI grading as: Grade 0- no flow, Grade 1- Bad flow: there is systolic flow but no diastolic flow or systolic flow with delayed acceleration and diastolic flow, Grade 2-Good flow: normal upstroke systolic flow and diastolic flow with decreased mean flow velocity compared to contralateral vessel by 30 %. We used the clotbust database to evaluate the modified TIBI scoring system. Poor long-term outcome was defined as modified rankin scale (MRS) score &gt; 2. RESULTS: Total of 369 patients with acute ischemic stroke and intracranial arterial occlusion received IV r TPA. Median age was 71 years (IQ range: 58.7-79), Sex: women: 170(46.1%). Median NIHSS was 16 (IQ range: 12.7-2), 17/98 (17.3%) patients with modified TIBI 0, 73/205(35.6%) with modified TIBI 1 and 31/66( 47%) with modified TIBI 2 had achieved complete recanalization ( p value=0001). The multiple logistic regression model revealed Baseline higher NIHSS, systolic BP, glucose and modified TIBI grade 0 were independent negative predictor of complete recanalization. Patients with modified TIBI 3 had high probability of complete recanalization compared to TIBI 0(OR 3.14, CI 95%: 1.4-6.8, P=0.004).Poor outcome at 3 months (MRS&gt;2) was found in 46/75(61.3%) patients with modified TIBI 0, 94/170(55.3%) with modified TIBI 1 and 19/38(33.3%) with modified TIBI 2(P value &lt;0.004). On logistic model age, baseline NIHSS, glucose and TIBI 0 were independent negative predictors of good outcome.Although statistically insignificant but patients with modified TIBI 3 had a trend towards high probability of good functional outcome (OR: 1.73, CI 95%:0.73-4.12, p=0.20). CONCLUSION: Modified TIBI grading system is simplified version of TIBI grading and is easy to understand and apply clinically. It also predicts reliably the recanalization and functional outcome.

Comparative study of transcranial Doppler ultrasonography and magnetic resonance angiography on recanalization of intravenous thrombolysis with alteplase in acute ischemic stroke patients

Objective To evaluate the accuracy and clinical diagnostic values of thrombolysis in brain ischemia (TIBI) grade system of transcranial Doppler ultrasomography (TCD) in assessing the situation of recanalization after thrombolytic therapy with modified thrombolysis in cerebral infarction (m-TICI) grade system of MRA as reference. Methods Select 61 acute ischemic stroke patients with middle cerebral artery (MCA), basilar artery (BA) stenosis or occlusion receiving thrombolytic therapy with alteplase. The patients underwent MRA and TCD examination before and after 24 h thrombolysis. Use m-TICI and TIBI grade system to evaluate the rate of occlusion and recanalization of target artery and test the consistency of two systems on recanalization evaluation. Results Before thrombolytic therapy, m-TICI grade showed artery occlusion in 49 cases (80.33% ) and TIBI grade displayed artery occlusion in 45 cases (73.77% ), indicating high consistency statistically (κ = 0.816, P = 0.000). Twenty-four hours after thrombolytic therapy, m-TICI and TIBI grade showed complete recanalization in 9 cases (14.75%) and 11 cases (18.03%), partial recanalization in 18 cases (29.51% ) and 17 cases (27.87% ) respectively, showing high statistical consistency. The comprehensive evaluation of m-TICI and TIBI grade system revealed total recanalization in 27 cases (44.26%) and 28 cases (45.90%), showing high statistical consistency (κ = 0.917, P = 0.000). Conclusion The TIBI grade system of TCD has high consistency in diagnosing artery stenosis or occlusion and evaluating vascular recanalization in acute ischemic stroke patients with thrombolytic therapy compared with m-TICI grade system of MRA examination. TCD examination is flexible, convenient, economical, repeatable and can give bedside long monitoring, so it is worthy of further in-depth research, in order to promote its application in thrombolytic treatment process. doi：10.3969/j.issn.1672-6731.2013.12.010

Clinical Deterioration Following Middle Cerebral Artery Hemodynamic Changes after Intravenous Thrombolysis for Acute Ischemic Stroke

Little information exists regarding what occurs in the affected artery in the days after acute ischemic stroke and its impact in the outcome. We sought to determine the hemodynamic evolution and correlated this evoution with clinical outcome in stroke patients treated with intravenous thrombolysis. Using serial transcranial Doppler ultrasound (TCD) on days 1 (TCD1), 3 to 6 (TCD2), and 7 to 10 (TCD3) after stroke, we determined the hemodynamics in the affected artery by means of the thrombolysis in brain ischemia (TIBI) score and compared this with clinical outcome (National Institutes of Health Stroke Scale [NIHSS] score) and functional outcome (modified Rankin Scale score) at discharge and at 3 months. Thirty-four patients were studied. There were 24 men with a mean (± SD) age of 72.9 ± 16.2 years. The mean time from stroke onset to the administration of intravenous tissue plasminogen activator was 181 ± 54.4 minutes, and the mean NIHSS score at admission was 16.9 ± 9. Hemodynamic changes were observed in 23 (68%) patients, including improvement in 17 (50%) patients and worsening in 6 (18%) patients within the first 10 days poststroke. Clinical deterioration (NIHSS ≥4 points) was timely associated with hemodynamic deterioration in 3 cases. Patients achieving full recanalization at TCD3 had better mRS scores at 3 months (4 v 3; P = .02). Hemodynamic changes in the affected artery occurred in about two-thirds of patients within the first 10 days after receiving intravenous thrombolysis; 18% had hemodynamic deterioration, which was associated with clinical worsening in half of these cases.

Real-time Validation of Transcranial Doppler Criteria in Assessing Recanalization During Intra-arterial Procedures for Acute Ischemic Stroke An International, Multicenter Study

We sought to evaluate the diagnostic accuracy of ultrasound criteria for recanalization during real-time transcranial Doppler monitoring of intra-arterial reperfusion procedures in acute ischemic stroke patients in an international, multicenter study. Consecutive acute ischemic stroke patients with proximal intracranial occlusions underwent intra-arterial reperfusion procedures with simultaneous real-time transcranial Doppler monitoring at 3 tertiary-care stroke centers. Residual flow signals at the site of angiographically confirmed occlusions were monitored at a constant transtemporal insonation angle using a standard head-frame. Recanalization was assessed simultaneously by digital subtraction angiography and ultrasound using thrombolysis in myocardial infarction and thrombolysis in brain ischemia (TIBI) criteria, respectively. Independent readers blinded to digital subtraction angiography performed validation of TIBI flow grades. The interrater reliability for assessment of TIBI grades was investigated. We evaluated time-linked real-time digital subtraction angiography transcranial Doppler images from 96 diagnostic digital subtraction angiography runs during intra-arterial reperfusion procedures in 62 acute ischemic stroke patients (mean age, 59 ± 17 years; 58% men; median baseline National Institutes of Health Stroke Scale score, 18 [interquartile range 12-21]; median time from symptom onset to intra-arterial procedure initiation, 240 minutes [interquartile range 163-308]). The interrater reliability for evaluation of TIBI grades and assessment of recanalization was good (Cohen κ: 0.838 and 0.874, respectively; P<0.001). Compared with angiography, transcranial Doppler had the following accuracy parameters for detection of complete recanalization (TIBI 4 and 5 versus thrombolysis in myocardial infarction 3, flow grades): sensitivity, 88% (95% confidence interval, 72%-96%); specificity, 89% (79%-95%); positive predictive value, 81% (65%-91%); negative predictive value, 93% (84%-98%); and overall accuracy 89% (80%-94%). At laboratories with high-interrater reliability, TIBI criteria can accurately predict brain recanalization in real time as compared with thrombolysis in myocardial infarction angiographic scores.

Circadian Rhythms in the Efficacy of Intravenous Alteplase in Patients With Acute Ischemic Stroke and Middle Cerebral Artery Occlusion

Circadian rhythm interactions of hemostatic factors can modify tissue plasminogen activator (tPA) effects. We assess the relationship of the time frame of intravenous tPA administration with the outcome of patients with acute ischemic stroke (AIS). We studied 135 consecutive patients with AIS and transcranial duplex documented middle cerebral artery (MCA) occlusion treated with intravenous tPA. Complete recanalization was defined as total improvement on thrombolysis in brain ischemia (TIBI) grades 2 h after tPA infusion. Clinical response was evaluated by the modified Rankin scale at 90 days. We determined plasminogen activator inhibitor-1 (PAI-1) levels in 33 patients with available plasma samples before treatment. Our results are follows: 92 (68.1%) patients were treated in the diurnal (9:00–21:00) and 43 (31.8%) in the nocturnal period (21:00–9:00). Complete recanalization was recorded in 52/135 (38.5%) patients. Both the rate of complete recanalization (45.6% vs. 23.2%; p = .01) and good clinical outcome (64.1% vs. 44.2%; p = .02) were significantly higher in the group of diurnal tPA administration compared with those treated in the nocturnal period. The adjusted odds ratio (OR) of diurnal tPA treatment for complete MCA recanalization was 2.37 (95% confidence interval [CI], 1.02–5.52; p = .045). Diurnal tPA infusion significantly improved the overall distribution of scores on the modified Rankin scale, as compared with nocturnal treatment (OR, 2.07; 95% CI, 1.16–4.64 by ordinal regression analysis). Low PAI-1 levels were associated with complete recanalization but did not significantly differ between the two time frames. In conclusion, diurnal administration of tPA is associated with complete MCA recanalization and better functional outcome at 90 days in patients with AIS. (Author correspondence: mgomis.germanstrias@gencat.cat, meritxellgomis@gmail.com)

Progress in Sonothrombolysis for the Treatment of Stroke

In 1974, Sobbe et al1 applied 26.5-kHz ultrasound (US) to recanalize thrombosed iliofemoral arteries in dogs with minimal complications. These pioneer efforts were followed by studies showing that catheter-based or transcutaneous US can enhance the effect of fibrinolytic agents in recanalizing thrombosed arteries,2–8 thus paving the way for first clinical studies evaluating the adjunct effect of US in treating patients with ischemic stroke. ### Mechanisms #### US Thrombolysis Despite numerous studies documenting a thrombolytic effect of US, the mechanisms remain poorly understood. Inertial cavitation (ie, the formation and violent collapse of gas-filled bubbles in a fluid exposed to US) gave rise to transient microjets that disintegrate thrombus mechanically.9 Stable cavitation (ie, sustainable nonlinear periodic contraction or expansion of a gas body or bubble) may be more effective than inertial cavitation in clot lysis.10 US also facilitates penetration of fibrinolytic drugs into the thrombus and binding to fibrin.11 This is because US promotes the motion of fluids around the clot surface through a process called microstreaming. Moreover, pressure waves may increase the permeation of tissue-type plasminogen activator (tPA) into the interior of the fibrin network.12 Heating is uniformly present in tissue exposed to US but has been deemed too mild to explain thrombolytic effects. #### Microbubble-Enhanced Thrombolysis With tPA Significant amplification of lysis occurs with the addition of microbubbles to the combination of thrombolytic drug and US.13–15 Microbubbles, composed of lipid, albumin, or galactose shells and ranging in size from 0.5 to 5 μm, lower the threshold for thrombolysis by providing a pre-existing bubble that easily can be made to cavitate by US. Stable cavitation can produce microstreaming in the area and dramatically enlarge the bubble momentarily. This will cause localized mechanical stress on the adjacent clot. The surface of the clot will erode, and even penetration and numerous microscopic …

Evaluation of very early recanalization after tPA administration monitoring by transcranial color-coded sonography

Summary Background/aims Cerebrovascular ultrasonography was useful clinically for evaluating cerebral hemodynamics rapidly and in real-time for patients with acute ischemic stroke. We analyzed if the patients had early recanalization or not using transcranial color-coded sonography (TCCS) in order to evaluate the usefulness of real-time monitoring in systemic thrombolysis. Methods Subjects were patients who had acute ischemic stroke with intravenous tissue plasminogen activator (tPA) within 3 h from onset. We evaluated occlusion of intracranial arteries from transtemporal or suboccipital window by TC-CFI with Thrombolysis in Brain Ischemia (TIBI) flow-grading system and monitored residual flow in real-time every 15 min until 120 min after the t-PA bolus. Results We could monitor residual flow in 5 patients who had good echo windows (4 male, mean age; 60.8 ± 6.4 years). Two patients had proximal occlusion of the middle cerebral artery (MCA), one patient had distal occlusion of MCA, one patient had M2 occlusion and one patient had distal occlusion of unilateral vertebral artery. Four patients had early complete recanalization within 60 min after the t-PA bolus (two patients within 60 min and other two patients within 30 min), however, occlusion persisted during 120 min monitoring in one patient with proximal occlusion of MCA. NIH Stroke Scale of two patients with very early recanalization was 0 at the end of the treatment. There was no symptomatic and asymptomatic intracranial hemorrhage in 4 patients except for the patients without recanalization. Conclusions It is anticipated that real-time ultrasound monitoring is useful for evaluating a very early thrombolytic effect of tPA connected with early clinical recovery.