Sonothrombolysis In Acute Ischemic Stroke Research Articles

Abstract 106: Safety and Efficacy of Sonothrombolysis in Acute Ischemic Stroke Patients With Large Vessel Occlusion: International Collaborative Individual Patient Data Meta-Analysis

Introduction: Conflicting evidence has been published regarding the safety and efficacy of ultrasound-enhanced thrombolysis (sonothrombolysis) in acute ischemic stroke (AIS) patients with large vessel occlusion (LVO). Methods: We conducted an individual participant data meta-analysis of available randomized controlled trials (RCTs) comparing sonothrombolysis with or without addition of microspheres (treatment group) to intravenous thrombolysis alone (control group) in AIS patients with LVO. Results: We included 6 in total RCTs that enrolled 1077 AIS patients. A total of 138 and 134 confirmed LVO patients were randomized to treatment and control groups respectively (median age 68 years, 58% men, median baseline NIHSS score 16). Patients randomized to sonothrombolysis had increased odds of complete recanalization compared to patients receiving intravenous thrombolysis alone (40.3% vs. 22.4%; OR=2.30, 95%CI: 1.05-5.02; adjusted OR=2.33, 95%CI: 1.02-5.34). They also tended to have increased odds of any (complete or partial recanalization (66.4% vs. 53.0%; OR=1.78, 95%CI: 0.95-3.33; adjusted OR=1.85, 95%CI: 0.97-3.53). The likelihood of symptomatic intracranial hemorrhage did not differ between the two groups (7.3% vs. 3.7%, OR=2.52, 95%CI: 0.77-8.29; adjusted OR=2.55, 95%CI: 0.76-8.52). No differences in the likelihood of asymptomatic intracranial hemorrhage (adjusted OR: 1.30, 95%CI: 0.38-4.39), three-month mortality (adjusted OR: 1.23, 95%CI: 0.25-6.05), three-month favorable functional outcome (mRS-scores of 0-1; adjusted OR: 1.43, 95%CI: 0.64-3.19) and three-month functional independence (mRS-scores of 0-2; adjusted OR: 1.43, 95%CI: 0.77-2.64) were documented. Conclusion: Sonothrombolysis was associated with a two-fold increase in the odds of complete recanalization compared to intravenous thrombolysis alone in AIS patients with LVOs. Further study of the safety and efficacy of sonothrombolysis is warranted.

Sonothrombolysis in Acute Ischemic Stroke: Current Status

Transcranial Doppler (TCD) is an important tool in the armamentarium of stroke neurologists. This, bedsides modality, can help in establishing the presence, location, and severity of intracranial arterial occlusion in acute stroke cases. Various hemodynamic consequences of an acute arterial occlusion such as flow diversion and compensatory flow increase in other intracranial arteries can be monitored by TCD with reasonable accuracy. TCD monitoring during intravenous thrombolysis may demonstrate recanalization in real-time In addition, continuous ultrasound exposure during intravenous thrombolysis can enhance the rates of the recanalization of an acutely occluded intracranial artery. Therapeutic ultrasound or sonothrombolysis remains a widely debated application of TCD. We present the available evidence for sonothrombolysis as well as its current status in the hyperacute treatment of acute ischemic stroke.

Sonothrombolysis

It has been shown that the significant reduction in disability after acute ischemic stroke (AIS) depends on early recanalization. Recombinant tissue plasminogen activator given within 3 hours improves disability by 30% in 3 months. However, still there are a great number of stroke patients who remained signifcantly disabled with this acute intervention. Currently, numerous strategies are being tested to increase further the recanalization rate in AIS. Sonothrombolysis or adding microsphere, intra-arterial rTPA and mechanical thrombectomy have been tried to increase the recanalization rate hence significant improvement has been reported. The simultaneous ultrasound delivery while administering rTPA known as Sonothrombolysis will be discussed in this lecture. A recently concluded randomized, placebo controlled sonothrombolysis study, the CLOTBUST trial has shown significant recanalization rate as its primary outcome measure. However, long-term disability did not show significant difference against placebo. Another non-significant RCT was carried out utilizing “hands-free” TCD device to deliver ultrasound during thrombolysis. Following these results from several trials; a meta-analysis has shown some signals favoring sonothrombolysis in acute ischemic stroke.

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.

Endovascular Treatment versus Sonothrombolysis for Acute Ischemic Stroke

Background: Currently, there are 2 strategies to increase the effect of systemic thrombolysis with alteplase (rtPA) in acute major stroke: endovascular treatment via stent retrieval and ultrasound enhancement (sonothrombolysis). This study compares these 2 approaches in patients with proximal intracranial occlusion of the anterior circulation. Methods: Consecutive data on the treatment outcome of acute middle cerebral artery (M1) or carotid T occlusion were collected from 2 stroke centers: one center used rtPA plus endovascular stent retrieval as standard treatment and the other rtPA plus ultrasound (sonothrombolysis). The primary outcome was functional independence (modified Rankin scale (mRS) 0-2) after neurorehabilitation. Results: A total of 132 patients were assessed (n = 73 endovascular, n = 59 sonothrombolysis). The rate of functional independence was higher for endovascular treatment (adjusted OR 3.89 (95% CI 1.36-12.58)). Additionally, ordinal mRS analysis favored the endovascular strategy (adjusted common OR 1.70 (95% CI 0.88-3.31)). Subgroup analysis showed that endovascular treatment was superior for carotid T occlusion (adjusted common OR 5.61 (95% CI 1.60-20.93)), but not for middle cerebral artery occlusion (adjusted common OR 1.07 (95% CI 0.47-2.43)). Symptomatic intracerebral hemorrhage occurred in 3 patients from the endovascular group. Conclusions: This observational study suggests that endovascular treatment of acute major anterior circulation stroke is superior to sonothrombolysis in terms of functional outcome. This benefit seems to pertain primarily to patients with carotid T occlusion, whereas patients with M1 occlusion seem to profit in a similar way from both methods. (Clinical Trial Registration: URL: http://www.germanctr.de. Unique identifier: DRKS0000​5305.)

Sonothrombolysis: Is the story (t)old or just the beginning

Intravenous administration of recombinant tissue plasminogen activator, fastest and widely feasible treatment in acute ischemic stroke induces arterial recanalization, a prerequisite for neurological recovery. THE THERAPEUTIC ROLE OF ULTRASOUND AND POTENTIAL MECHANISM OF SONOTHROMBOLYSIS: Augmentation of recanalization can be achieved safely in combination with diagnostic transcranial Doppler by delivering mechanical pressure waves to the thrombus and exposing more thrombus surface to circulating drug. The addition of microspheres can further improve thrombolytic effect. International multicenter CLOTBUST trial showed that acute ischemic stroke patients treated with sonothrombolysis had higher rate of arterial recanalization and dramatic clinical recovery without increasing risk of symptomatic intracranial hemorrhage. A microsphere dose-escalation study called TUCSON showed that rates of recanalization and clinical recovery tended to be higher in target groups compared with controls. META-ANALYSIS OF CLINICAL TRIALS OF SONOTHROMBOLYSIS: Cochrane Stroke Group found that sonothrombolysis was likely to reduce death or dependency. A meta-analysis of sonothrombolysis showed that patients who received any form of sonothrombolysis had more than twofold higher likelihood of achieving complete arterial recanalization. PERSPECTIVES FOR SONOTHROMBOLYSIS - OPERATOR-INDEPENDENT DEVICE FOR SONOTHROMBOLYSIS: The collaborative group of the CLOTBUST trial designed multi-transducer assembly to cover conventional windows used for transcranial Doppler examinations. Operator-independent device can be quickly mounted by medical personnel with no prior experience in ultrasound. Sonothrombolysis for acute ischemic stroke is now tested in a pivotal efficacy multi-national trial called CLOTBUSTER. Ultrasound is a promising tool to enhance systemic thrombolysis.

The Role of Sonolysis and Sonothrombolysis in Acute Ischemic Stroke: A Systematic Review and Meta‐analysis of Randomized Controlled Trials and Case‐Control Studies

To assess the evidence on the safety and efficacy of sonothrombolysis in acute stroke. Electronic databases and grey literature were searched under different MeSH terms from 1970 to present. Randomized control trials (RCTs) and case control studies (CCSs) on sonolysis and sonothrombolysis alone or with microsphere in acute stroke patients (>18 old). Outcome measures included complete recanalization (CR) at 1-2 and 24 hours, 3 months modified Rankin Scale (mRS), and symptomatic intracerebral hemorrhage (sICH). Data was extracted to Review Manager software. Fifty-seven studies were retrieved and analyzed. Ten studies (7 RCTs and 3 CCSs) were included in our meta-analysis, which revealed that sonolysis and sonothrombolysis are safe (OR of sICH: 1.14; 95% confidence interval (CI): 0.56- 2.34;P=0.71) and effective (OR of CR at 1-2 hours: 2.95;95% CI: 1.81-4.81;P<0.00001) and have more than two-fold higher likelihood of favourable long-term outcome (3-month mRS 0-2; OR: 2.20; CI:1.52-3.19;P<0.0001). Further subgroup analysis based on the presence of microsphere revealed that it is safe (OR of sICH: 1.18; CI:0.433.24;P=0.75) and effective (OR of CR: 2.61; CI: 1.36-4.99;P=0.004). Subgroup analysis based on sonolysis revealed to be safe and effective. This novel treatment appears safe and effective. The evidence of microsphere as an enhancement of sonothrombolysis is evolving.

Sonothrombolysis for acute ischemic stroke: a systematic review of randomized controlled trials

Sonothrombolysis has recently been considered an emerging modality for the treatment of stroke. The purpose of the present paper was to review randomized clinical studies concerning the effects of sonothrombolysis associated with tissue plasminogen activator (tPA) on acute ischemic stroke. Systematic searches for literature published between January 1996 and July 2011 were performed for studies regarding sonothrombolysis combined with tPA for acute ischemic stroke. Only randomized controlled trials were included. Data extraction was based on ultrasound variables, patient characteristics, and outcome variables (rate of intracranial hemorrhages and arterial recanalization). Four trials were included in this study; 2 trials evaluated the effect of transcranial Doppler (TCD) ultrasonography on sonothrombolysis, and 2 addressed transcranial color-coded duplex (TCCD) ultrasonography. The frequency of ultrasound waves varied from 1.8 to 2 MHz. The duration of thrombus exposure to ultrasound energy ranged from 60 to 120 minutes. Sample sizes were small, recanalization was evaluated at different time points (60 and 120 minutes), and inclusion criteria were heterogeneous. Sonothrombolysis combined with tPA did not lead to an increase in symptomatic intracranial hemorrhagic complications. Two studies demonstrated that patients treated with ultrasound combined with tPA had statistically significant higher rates of recanalization than patients treated with tPA alone. Despite the heterogeneity and the limitations of the reviewed studies, there is evidence that sonothrombolysis associated with tPA is a safe procedure and results in an increased rate of recanalization in the setting of acute ischemic stroke when wave frequencies and energy intensities of diagnostic ultrasound systems are used.

Potentiating intra-arterial sonothrombolysis for acute ischemic stroke by the addition of the ultrasound contrast agents (Optison™ &amp; SonoVue®)

Transcranial ultrasound in combination with intravenously administered ultrasound contrast agents (UCA) in the presence or absence of recombinant tissue plasminogen activator (rt-PA) has been widely evaluated as a new modality for treatment of ischemic stroke. Despite the successful demonstration of accelerated clot lysis there are inherent limitations associated with this modality such as inconsistency in temporal window thickness and/or potential serious cardiopulmonary reactions to intravenous administration of UCA that prevent broad application to ischemic stroke populations. As a complementary modality, we evaluated potential lysis enhancement by intra-arterial ultrasound with concurrent intra-clot delivery of UCA and rt-PA. To this end, clots were formed with average pore diameter similar to clinically retracted clots by adjusting the thrombin concentration. Physical characteristic and retention of UCA after delivery through the catheter as a function of clinically relevant flow rates of 6, 12, 18 ml/h were determined using a microscopic method. The ability of the UCA employed in this study, Optison and SonoVue, to penetrate into the clot was verified using ultrasound B-mode imaging. Clot lysis as a function of rt-PA concentration, 0.009 through 0.5 mg/ml, in the presence and absence of UCA diluted to 1:10, 1:100, and 1:200 v/v at two Peak rarefaction acoustic pressures of 1.3 and 2.1 MPa were evaluated using a weighing method. The study results suggest the addition of only 0.02 ml of 1:100 diluted UCA to rt-PA of 0.009, 0.05, 0.3, and 0.5 mg/ml can enhance the lysis rate by 3.9, 2.6, 1.9 and 1.8 fold in the presence of peak rarefaction acoustic pressure of 1.3 MPa and by 5.1, 3.4, 2.6, 3.1 in the presence of peak rarefaction acoustic pressure of 2.1 MPa, respectively. In addition, Optison and SonoVue demonstrated comparable effectiveness in enhancing the clot lysis rate. Addition of UCA to intra-arterial sonothrombolysis could be considered as a viable treatment option for ischemic stroke patients.

Sonothrombolysis for Acute Ischemic Stroke

Several studies have consistently demonstrated the capability of ultrasound to enhance the lysis of intra-arterial thrombi in acute ischemic stroke during systemic intravenous thrombolysis with tissue plasimogen activator (tPA), an intervention also called sonothrombolysis. ### Objectives 1. To quantify the potential benefits of sonothrombolysis in acute ischemic stroke. 2. To quantify the potential harms of sonothrombolysis. ### Types of Studies Randomized controlled trials with clear allocation concealment. ### Types of Participants Patients admitted to hospital with acute ischemic stroke. ### Types of Interventions Sonothrombolysis versus intravenous tPA therapy alone or …