CLOTBUST-hands free: initial safety testing of a novel operator-independent ultrasound device in stroke-free volunteers

Abstract

Background and purpose: We aimed to evaluate safety and tolerability of a novel operator-independent ultrasound device among stroke-free volunteers.

Methods: A headframe containing 18 ultrasound transducers (each operating at 2 MHz, pulsed-wave) was used to expose both temporal windows and the suboccipital window. The transmission characteristics were set to emulate the acoustic characteristics of the exposure levels in the Combined Lysis of Thrombus in Brain Ischemia using Transcranial Ultrasound and Systemic tPA (CLOTBUST) trial and to never exceed Food and Drug Administration mandated diagnostic ultrasound exposure limits. Volunteers underwent 2 hours of insonation with transducer activation one at a time. Safety was captured using serial neurological examinations and pre- and postinsonation MRI for detection of the blood brain barrier permeability.

Results: A total of 15 volunteers (40% men; 49 ± 16 years; 27% black; all pre-exposure National Institutes of Health Stroke Scale scores 0) were enrolled. Five volunteers received pulsed-wave ultrasound via the best pair temporal transducers, 5 via sequential activation of the suboccipital transducers, and 5 via sequential activation of all bilateral temporal and suboccipital transducers. All subjects were safely insonated with no adverse effects as indicated by the neurological examinations during, immediately after the exposure, and at 24 hours, and no abnormality of the blood brain barrier was found on any of the MRIs.

Conclusions: Our novel device was well tolerated by stroke-free volunteers and did not cause any neurological dysfunction nor did it affect blood brain barrier integrity. The safety and efficacy of the device are now being tested in stroke patients receiving intravenous tissue-type plasminogen activator in phase II-III clinical trials.

Keywords: CLOTBUST; ischemic stroke; operator-independent device; reperfusion therapy.

Figures

Figure 1

A, Operator-independent ultrasound device. B, The graph shows received voltage amplitude (V) versus time (μs). The voltage displayed at the far left of the graph display is system noise detected when the transmitter is putting out energy during each pulse. The portion of the signal shown at the right of the graph display is the actual received energy at the receive transducer. In this case, the data take about 100 μs to travel from the left transmitter to the right receiver. This time delay multiplied by the speed of sound through the head (1560 m/s) is approximately equal to the contralateral distance between the 2 best pair transducers, in this case ≈160 mm.

Figure 2

A schematic illustration showing the various beams (A, diagonal view; B, plan view) penetrating the skull, their special (but not temporary) overlap, and the theoretical migration (depending of the angulation of the transducers) of the ultrasound burst to the various proximal intracranial arterial segments using the example of the right transtemporal array. C, Ultrasound beam with its typical profile originating from a single transducer. Notice that the beam broadens progressively as it propagates past the focal zone (smallest diameter of the beam).