Safety and Efficacy of Ultrasound-Enhanced Thrombolysis

Abstract

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, tPAϩTCDϮmicrospheres (S), tPAϩTCCDϮS, and tPAϩlow-frequency ultrasound. Results-A total of 6 randomized (nϭ224) and 3 nonrandomized (nϭ192) studies were identified. The rates of symptomatic intracerebral hemorrhage in randomized studies were as follows: tPAϩTCD, 3.8% (95% CI, 0%-11.2%); tPAϩTCCD, 11.1% (95% CI, 0%-28.9%); tPAϩlow-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, tPAϩTCD/TCCDϮS was associated with a higher likelihood of complete recanalization (pooled OR, 2.99; 95% CI, 1.70 -5.25; Pϭ0.0001) 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; Pϭ0.67). 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. (Stroke. 2010;41:280-287.)

Thrombolytic Recanalization of Carotid Arteries Is Highly Dependent on Degree of Stenosis, Despite Sonothrombolysis

“…In this study, we used the standard ultrasound parameters used for transcranial sonothrombolysis;5, 12 however, even in the absence of skull attenuation, there did not appear to be a large additive benefit over tPA alone. Ultrasound power is attenuated through the skull by as much as 99%,13, 14 yet evidence that higher power increases clot lysis15 indicates that power attenuation likely limits the efficacy of intracranial sonothrombolysis.…”

“…Given the low efficacy of tPA in carotid athero‐thrombotic occlusion, approaches to enhance its effect are required. Ultrasound+tPA (sonothrombolysis) appears promising for improving intracranial recanalization,5 but has not been tested in extracranial carotid artery occlusion. Therefore, our primary aim was to determine whether the degree of carotid stenosis affected rates of sustained recanalization with thrombolysis at 4.5 hours postocclusion.…”

Acute Ischemic Stroke Management: Medical Management

“…41 A meta-analysis of 6 randomized and 3 nonrandomized studies confirmed higher complete recanalization rates in patients receiving combined transcranial ultrasound and rtPA compared with patients receiving rtPA alone (37.2% vs. 17.2%). 42 The systematic review found that sonothrombolysis was not associated with an increased risk of symptomatic intracranial hemorrhage. As with other ultrasound techniques, transcranial Doppler is operator-dependent and blood-flow velocities measured with this technique are not corrected for the angle of insonation.…”

“…42,43 Clinical studies have demonstrated poorer outcomes after stroke in patients with hyperglycemia or diabetes, including patients treated with IV thrombolysis. 44,45 The mechanisms underlying neurologic worsening associated with hyperglycemia are likely multifactorial, and include tissue acidosis, free radical formation, blood-brain barrier disruption, and augmentation of cerebral edema formation.…”

Real-time two-dimensional imaging of microbubble cavitation

“…In the context of stroke, the addition of US and MBs to standard tPA thombolytic therapy has been shown to accelerate thrombus dissolution in humans [3]. However, MB cavitation also has the potential for detrimental side effects under certain circumstances.…”