A Pilot Randomized Clinical Safety Study of Sonothrombolysis Augmentation With Ultrasound-Activated Perflutren-Lipid Microspheres for Acute Ischemic Stroke

Abstract

Background and Purpose-Ultrasound transiently expands perflutren-lipid microspheres (S), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated S with systemic tissue plasminogen activator (tPA). Methods-Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPAϩTCD) or Target (tPAϩTCDϩ2.8 mL S). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by Ն4 NIHSS points within 72 hours. Results-Fifteen subjects were randomized 3:1 to Target, nϭ12 or Control, nϭ3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. S reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8Ϯ11.3 vs 28.8Ϯ13.8 cm/s, PϽ0.001. In 75% of subjects, S permeated to areas with no pretreatment residual flow, and in 83% residual flow velocity improved at a median of 30 minutes from start of S infusion (range 30 s to 120 minutes) by a median of 17 cm/s (118% above pretreatment values). To provide perspective, current study recanalization rates were compared with the tPA control arm of the CLOTBUST trial: complete recanalization 50% versus 18%, partial 33% versus 33%, none 17% versus 49%, Pϭ0.028. At 2 hours, sustained complete recanalization was 42% versus 13%, Pϭ0.003, and NIHSS scores 0 to 3 were reached by 17% versus 8%, Pϭ0.456. Conclusions-Perflutren S reached and permeated beyond intracranial occlusions with no increase in sICH after systemic thrombolysis suggesting feasibility of further S dose-escalation studies and development of drug delivery to tissues with compromised perfusion. (Stroke. 2008;39:1464-1469.)Key Words: microspheres Ⅲ thrombolysis Ⅲ stroke Ⅲ occlusion Ⅲ transcranial Doppler I ntravenous tissue plasminogen activator (tPA) remains the only approved therapy for acute ischemic stroke. 1 Successful thrombolysis depends on tPA delivery to the thrombus via residual flow around acute arterial obstruction. 2 Pulsed wave transcranial Doppler (TCD) can expose the thrombus-residual flow interface to a mechanical ultrasound pressure wave, and TCD monitoring can safely facilitate early recanalization in stroke subjects treated with systemic tPA. 3 In the CLOTBUST (Combined Lysis of Thrombus with 2 MHz transcranial Ultrasound and Systemic TPA) trial, TCD monitoring for 2 hours after tPA bolus with 1 hour tPA infusion tripled the chance of complete and sustained recanalization. 3 This early augmentation of reperfusion resulted in a trend toward favorable clinical recovery. Based on this trend, a pivotal trial to confirm efficacy of sonothrombolysis would require an estimated 600 subjects. 3 Because this is a large sample for an acute stroke trial, CLOTBUST investigators started to explore further ways to augment early reperfusion that could reduce the sample size of the pivotal ...

Ultrasound-Enhanced Thrombolysis in Acute Ischemic Stroke: Potential, Failures, and Safety

“…40 Several published studies have used different commercially available microspheres (TABLE 1). [43][44][45][46] Molina et al 43 pioneered this approach in stroke patients and reported the largest study to date that compared the CLOTBUST Target arm to the CLOTBUST Target insonation protocol (2 MHz continuous TCD-monitoring) combined with Levovist air microspheres (Schering, Berlin, Germany). Investigators demonstrated that at 2 hours after TPA bolus the TPA ϩ TCD ϩ Levovist group achieved a 55% sustained recanalization rate, compared with 38% in the TPA ϩ TCD group of the CLOTBUST trial.…”

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

“…3,4,15,16,20,23 Two studies were excluded (one consisted of a pilot study with 3 patients in the control arm, 3 and the other was published as an abstract 20 ). We did not find any randomized study addressing the effects of low-frequency transcranial ultrasound on thrombolysis.…”

“…17 In addition, 2-MHz ultrasound waves enhance tPA-thrombus dissolution by fluid streaming around the clot surface and disaggregation of fibrin fibers, which results in a greater amount of binding sites for tPA without heating or cavitation. 3 In stroke patients treated with tPA, intravenous infusion of microbubbles or microspheres has been proved to accelerate clot lysis during 2-MHz ultrasound monitoring, by transmitting energy momentum from an ultrasound wave to residual flow. 3,11,12,22,23 These mechanisms support the findings of sonothrombolysis in the clinical setting.…”

Current and future recanalization strategies for acute ischemic stroke

“…Augmentation of systemic tPA treatment can be accomplished with low power ultrasound and gaseous microspheres [39][40][41][42][43][44]. Since human application of frequencies below diagnostic range (i.e.…”

“…Molina et al pioneered the use of gaseous microspheres in combination with CLOTBUST monitoring methods and reported safety and recanalization rates with the first generation air-filled microspheres (Levovist, Schering AG) as well as newer diagnostic microspheres (Sonoview, Bracco) [39,41]. These microspheres were designed for diagnostic purposes to be given as boluses in order to enhance returned echoes and improve quality of ultrasound images.…”