First experience in using a novel operator-independent ultrasound device in stroke-free volunteers

Kristian Barlinn

Kristian Barlinn

As controversies exist concerning the effectiveness of sonothrombolysis and as to whether it can be broadly implemented as an adjunctive treatment approach for acute ischaemic stroke, a large clinical trial will add to the current body of evidence, write Kristian Barlinn, Andrew D Barreto and Andrei V Alexandrov.

Almost one in two acute ischaemic stroke patients remain permanently disabled or die despite treatment with intravenous tissue plasminogen activator (tPA). This is linked to the fact that the efficacy of tPA is strongly time dependent with an increasing number of patients needed to treat to achieve functional independence by one for every 20 minutes of delay in treatment initiation. Also, the ability of tPA to dissolve more proximal and larger intracranial thrombi is limited, decreasing the odds for good functional outcome and survival in stroke patients who fail to recanalise. Rapid arterial recanalisation and restoration of perfusion remain one of the main independent predictors of good functional outcome after acute ischaemic stroke.

The adjuvant exposure of an intracranial occlusive thrombus to high-frequency ultrasound has been shown to be a promising strategy to augment the reperfusion benefit of intravenous thrombolysis with tPA (ie. sonothrombolysis). Two recent meta-analyses found that sonothrombolysis using high-frequency ultrasound is safe, triples the likelihood of tPA induced recanalisation (odds ratio 2.99, 95% CI 1.70–5.25; p=0.0001) and doubles the odds of achieving functional independence after ischaemic stroke (odds ratio 2.09, 95% CI 1.17–3.71; p=0.01) when compared to intravenous tPA alone. These findings have been confirmed by a recent Cochrane review including five randomised clinical sonothrombolysis studies. In comparison to intravenous tPA alone, failure to recanalise (odds ratio 0.28, 95% CI 0.16–0.50) and risk for being functionally dependent or death at three months (odds ratio 0.50, 95% CI 0.27–0.91) were substantially lower in the sonothrombolysis group.

Although recommended as an integral part of comprehensive stroke centre capabilities, current transcranial Doppler technology still remains reserved to those formally trained in neurosonology techniques and its diagnostic utility greatly depends on the skills of the operator. The lack of trained and experienced ultrasound operators has not only limited the routine utilisation of transcranial Doppler in the acute management of ischaemic stroke, but also complicated the process of conducting pivotal blinded clinical trials for sonothrombolysis. Thus, a novel operator-independent ultrasound system has been developed that delivers ultrasound energy through the common transcranial acoustic windows (ie. temporal windows and the suboccipital window) via 18 separate transducers mounted on an adjustable head frame. This allows any healthcare professional to insonate the proximal intracranial arteries that most commonly contain thromboembolic occlusions in acute ischaemic stroke for therapeutic purposes. Acoustic output information and ultrasound energy exposure levels for this “hands-free” device were set to be comparable to those in commercially available 2MHz pulsed-wave transcranial Doppler units and that used in the operator-dependent hand-held CLOTBUST (Combined lysis of thrombus in brain ischemia using transcranial ultrasound and systemic tPA) trial. Meanwhile, the prototype of this operator-independent ultrasound device successfully passed through two National Institute of Health-sponsored clinical phase I/II safety studies.

The first study enrolled 15 non-stroke volunteers who underwent two hours of continuous insonation with varying transducer activation algorithms. Only one transducer was activated at any one time. None of the enrolled stroke-free volunteers experienced any dermatological adverse effects or neurological deficits during and after the ultrasound exposure. No disruption in the integrity of the blood brain barrier—a major safety concern in recent sonothrombolysis trials utilising low-frequency ultrasound—was found on any of the volunteers’ pre- and post-insonation multimodal magnetic resonance imaging (MRI) scans.

The subsequent, open-label study tested the safety of the operator-independent device in 20 patients with acute ischaemic stroke due to proximal intracranial arterial occlusions. All patients received the combination of standard dose (0.9mg/kg; 90mg maximum) intravenous tPA therapy and two hours of continuous ultrasound delivered by the operator-independent device. None of the patients experienced a symptomatic intracerebral haemorrhage or any other serious adverse events possibly related to the ultrasound device. Recanalisation rates after two hours of sonothrombolyis were comparable to those in the CLOTBUST trial and reported in the above mentioned meta-analyses.

Both of these pilot safety studies laid the groundwork for an ongoing multicentred phase III sonothrombolysis efficacy trial, CLOTBUST-ER (Combined lysis of thrombus using 2MHz PW ultrasound and systemic tPA for emergent revascularization) in patients with acute ischaemic stroke. This trial utilises a further developed proprietary operator-independent device (Cerevast Therapeutics) that contains 16 instead of 18 ultrasound transducers. Patients are considered eligible when having a pre-treatment vascular imaging confirmed or clinically presumed (NIHSS score ≥10 points) proximal intracranial arterial occlusion. All patients receive standard intravenous tPA therapy according to local regulatory authorities but no later than 4.5 hours from symptom onset and are randomised equally (1:1) either to two hours of continuous exposure to 2MHz pulsed-wave ultrasound or sham exposure. Safety is captured by the incidence of symptomatic intracerebral haemorrhage within 24 hours of treatment initiation and functional recovery by the modified Rankin Scale scores (primary end-point modified Rankin Scale 0–1) at three months. Additionally, a substudy will collect CT-angiography studies before and after the ultrasound and sham exposure in order to explore rates of arterial recanalisation.    

The operator-independent ultrasound device appears to be a safe alternative to commercially available transcranial Doppler systems and enables the possibility of performing a large-scale pivotal trial of sonothrombolysis in acute ischaemic stroke patients at centres experienced with tPA treatment and clinical trials, but which lack operators trained in neurosonology. As controversies exist concerning the effectiveness of sonothrombolysis and as to whether it can be broadly implemented as an adjunct treatment approach for acute ischaemic stroke, such a large clinical trial will add to the current body of evidence and possibly close the gap between clinical and experimental sonothrombolysis research. 

Kristian Barlinn is with the Dresden University Stroke Center, Department of Neurology and University of Technology Dresden, Dresden, Germany. Andrew D Barreto (Department of Neurology, Stroke Program, University of Texas-Health Science Center at Houston, Houston, Texas, USA) and Andrei V Alexandrov (Comprehensive Stroke Center, Department of Neurology and University of Alabama, Birmingham, USA) co-authored this article. Barlinn and Barreto were supported through National Institute of Neurological Disorders and Stroke (NINDS) grant, for project CLOTBUST hands Free, phase I/II studies of an operator-independent device for sonothrombolysis in stroke. Alexandrov serves as consultant to Cerevast Therapeutics and holds a USA patent “Therapeutic Method and Apparatus for Use of Sonication to Enhance Perfusion of Tissues,” assignee—Texas Board of Regent