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. Author manuscript; available in PMC: 2014 Sep 6.
Published in final edited form as: Stroke. 2013 Apr 18;44(6):1641–1646. doi: 10.1161/STROKEAHA.113.001122

CLOTBUST-Hands Free

Initial Safety Testing of a Novel Operator-Independent Ultrasound Device in Stroke-Free Volunteers

Kristian Barlinn 1, Andrew D Barreto 1, April Sisson 1, David S Liebeskind 1, Mark E Schafer 1, John Alleman 1, Limin Zhao 1, Loren Shen 1, Luis F Cava 1, Mohammad H Rahbar 1, James C Grotta 1, Andrei V Alexandrov 1
PMCID: PMC4156594  NIHMSID: NIHMS508714  PMID: 23598523

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

Ultrasound energy at diagnostic frequencies safely enhances intravenous tissue-type plasminogen activator (tPA)–induced arterial recanalization and this combined approach is associated with a 2-fold likelihood of complete recanalization and a trend toward a better functional outcome compared with intravenous tPA alone.1 However, recent phase II sonothrombolysis trials were conducted at centers where expert ultrasound operators were always available, providing considerable expertise with vessel identification, lesion localization, and interpretation of certain findings associated with acute thromboembolic ischemic stroke.2,3 The major limitation of current transcranial Doppler (TCD) ultrasound technology is its operator dependency. Thus, the paucity of trained and experienced operators has limited TCD use in the clinical management of acute ischemic stroke and has hindered the process of conducting pivotal sonothrombolysis clinical trials. A novel operator-independent ultrasound system has been developed to deliver ultrasound energy exposure levels comparable with those administered in the Combined Lysis of Thrombus in Brain Ischemia using Transcranial Ultrasound and Systemic tPA (CLOTBUST) trial.2 The aim of this phase I study was to assess the safety of this device applied to stroke-free volunteers. Replacing the operator-dependent TCD with a simple-to-apply device would allow any emergency room to provide therapeutic ultrasound as needed, and create an opportunity to conduct double-blinded sonothrombolysis stroke trials.

Methods

Operator-Independent Ultrasound Device

A novel operator-independent transcranial ultrasound unit was developed by our collaborative group, including Cerevast Therapeutics, Inc, Redmond, WA, Sonic Tech Inc, Philadelphia, PA, and the University of Texas (holder of the US patent #6,733,450). The operator-independent device was designed to allow healthcare professionals without training in ultrasound to insonate traditional cranial windows effectively. The device was designed to deliver ultrasound energy for therapeutic purposes, and its exposure characteristics were set to emulate those of the commercially available 2-MHz pulsed-wave TCD ultrasound systems used in the CLOTBUST trial.4 As a safety measure, the device was designed to never exceed the US Food and Drug Administration–mandated ultrasound intensity limits for diagnostic ultrasound systems (derated Spatial Peak Temporal Average Intensity, ISPTA <720 mW/cm2; the ISPTA represents the maximum intensity within the ultrasound field, averaged over the exposure time. For a fixed focus system, such as the 1 described here, it correlates to tissue heating effects). Additionally, the device itself does not provide any diagnostic information about the insonated vessels.

To cover the entire area of each temporal and the suboccipital windows, the operator-independent device consisted of 18 transducers that were fitted on an adjustable headframe (Cerevast Therapeutics, Inc, Redmond, WA; Figure 1A). For this study, the insonating frequency of each transducer was set to 2.0 MHz, with a pulse repetition frequency (PRF) of 8.3 kHz (which is typical for conventional TCD location of the middle cerebral arteries used in the CLOTBUST trial)2; the carrier frequency exactly matched existing FDA-approved TCD equipment, and the PRF was the highest that allowed unambiguous detection of the ultrasound pulse traveling across the skull from a transmitter on 1 side to a receiver on the other (Figure 1B). Only 1 transducer was active at any moment in time, so that even though the beams from several transducers may have overlapped in a given volume of tissue, the insonated tissue was never exposed to 2 beams simultaneously as they never overlapped in time, thus avoiding exposure to energy levels above the FDA limit. This approach also avoids any incidence of transducer beam constructive interference (summation). Each transducer was pulsed in an identical manner. Furthermore, all transducers had been individually calibrated so that the ultrasound exposure from each would be known.

Figure 1.

Figure 1

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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.

To expose reliably all regions of the proximal intracranial occlusion locations detectable by TCD,5,6 the transducers covered the areas of standard acoustic TCD windows for the location of the M1-proximal M2 middle cerebral, terminal internal carotid, A1 anterior cerebral arteries and P1-proximal P2 posterior cerebral, terminal vertebral, and basilar arteries (Figure 2A and 2B).7 Six transducers covered each temporal window, specifically its anterior (ie, distal M1 and proximal M2 middle cerebral artery), middle (ie, proximal M1 and terminal internal carotid artery), and posterior (ie, P1-proximal P2 posterior cerebral artery) aspects. Six transducers covered the suboccipital window including 4 transducers for the midline position aiming just above and below the projected bridge of the nose line (aimed at the proximal and distal parts of the basilar artery), and 2 transducers each covering lateral aspects of the suboccipital window aimed at the terminal vertebral arteries with slightly upward and midline angulation.

Figure 2.

Figure 2

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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).

Because the system was designed for use by those not formally trained as sonographers, it is important to make sure that ultrasound energy is successfully transmitted through the temporal bone window. To address this requirement, a unique approach was used in which transducers on the contralateral side from the active transducer were used as ultrasound receivers. Each transducer on 1 side was activated sequentially, whereas the received signals on the opposite side were monitored. By sequencing through all transmitter/receiver pairs, it was possible to determine the transducer that produced the highest ultrasound transmission through the skull in a particular subject. The pair of transducers (transmitter/receiver) that generated the strongest pulse transcranially was designated as the best pair (Figure 1B). Finally, the system allowed any transducer to be connected to a separate commercial TCD system for Doppler processing. This was done to determine if spectral Doppler waveforms could be obtained during therapeutic exposure to show feasibility of concurrent reperfusion monitoring with future generations of operator-independent systems.

Stroke-Free Volunteers

Stroke-free volunteers were recruited by flyers distributed at the University of Alabama (UAB) campus and the outpatient headache clinic. Inclusion criteria were (1) age ≥18 years; (2) presence of temporal windows as measured first by an FDA-approved diagnostic TCD device, and (3) signed informed consent. Exclusion criteria were as follows: (1) history of cerebrovascular disease; (2) any neurological structural disease affecting the central nervous system; (3) lack of temporal windows; (4) history of renal disease or glomerular filtration rate <60 mL/min per 1.73 m2; (5) contraindication to MRI (eg, pacemaker, spinal cord stimulator, severe claustrophobia). Written informed consent was obtained from all participants before performing any protocol-specific procedures. The study was approved by the UAB Institutional Review Board.

All volunteers underwent physical examination for skin integrity and complete neurological examination to exclude any neurological deficits before ultrasound insonation. The neurological examinations comprised assessments of mental status and orientation, cranial nerve examination, muscle strength and tone, deep tendon reflexes, sensory testing, coordination and gait. We also obtained the National Institutes of Health Stroke Scale (NIHSS) score at baseline and after the exposure to ultrasound.

Imaging

Serial multimodal MRI of the brain was acquired immediately before and after ultrasound insonation, including an identical protocol with diffusion-weighted imaging/apparent diffusion coefficient, fluid attenuated inversion recovery, gradient recalled echo, pre- and postgadolinium T1-weighted images and dynamic susceptibility-weighted perfusion imaging. All MRI studies were acquired on a Philips Ingenia 3.0 T scanner (Philips Medical Systems, Cincinnati, OH) with this standard protocol. Primary MRI safety analyses used permeability maps generated from the perfusion sequence source images to assess for any blood brain barrier (BBB) disruption, using a previously published algorithm.8,9 In brief, the signal intensity decreases at the terminal phase of perfusion sequence acquisition after contrast bolus passage is used to discern any potential accumulation of contrast within tissue parenchyma caused by BBB disruption. BBB compromise would manifest as gadolinium extravasation from the vasculature into surrounding tissue, causing a T2* decrease and resultant abnormality on the calculated permeability maps. Such potential disruption of the BBB as a risk factor for hemorrhagic transformation in stroke patients8 was assessed by an experienced investigator blinded to pre- and postinsonation MRI scans and to any results of the pre- and postinsonation clinical assessments.

Exposure to Ultrasound

To confirm that the operator-independent device placement covered the conventional TCD windows and achieved successful energy transmission, stroke-free volunteers underwent hand-held diagnostic TCD (Multigon Industries, Inc, Yonkers, NY) examination of the 12 intracranial proximal arterial segments using a standardized scanning protocol.7 Once the window of insonation was established by experienced and certified sonographers using TCD, the hands-free device was placed on the volunteer’s head using anatomic landmarks only (ie, above eye-brows, midline atop bridge of the nose) and pulse transmission through the skull was assessed as described above. Subsequently, each temporal and suboccipital transducers of the operator-independent device were individually connected to the hand-held TCD system to detect and receive spectral Doppler waveforms of the anterior and posterior cerebral arteries, as well as to validate correct positioning of the transducers. Once the successful ultrasound transmission through the skull was achieved, the volunteers were exposed to 2 hours of pulsed-wave 2-MHz ultrasound (at 8.3-kHz PRF with a pulse duration of 5 μs) with transducer activation one at a time.

The first 5 of 15 volunteers underwent 2 hours of ultrasound exposure through the temporal window that had been found to produce the best ultrasound transmission condition (via the best pair transducers). The next 5 volunteers underwent 2 hours of exposure through the suboccipital window. The last 5 volunteers received 2 hours of sequential exposure through all 3 windows (the left and right temporal windows and the suboccipital window). Subjects’ exposure to the total ultrasound emitted energy dose was essentially equivalent in all 3 groups. The rationale for the final mode of exposure was to insonate all proximal intracranial arterial segments that may contain occlusions. This approach would be particularly useful for those situations in which occlusion localization with computed tomography angiography or MR angiography is not feasible in a hyperacute stroke patient eligible for the standard of care tPA therapy.

All participating volunteers were monitored by a study nurse during exposure and any complaints were documented. A neurological examination, including NIHSS score, was performed after 1 hour of ultrasound exposure (without interrupting the treatment) and right after the 2-hour exposure period. The areas of skin exposed to ultrasound were also examined after the exposure. Once the 2-hour insonation period was completed, volunteers underwent a follow-up MRI of the brain that included the same sequences obtained preinsonation and BBB permeability was compared with pre-exposure imaging as described above. The stroke-free volunteers underwent a final neurological examination at 24 hours after insonation to monitor for any adverse events.

The ultrasound system generated a log file, which recorded the exposure parameters of each transducer in real time, allowing the overall exposure to be determined for each patient. The estimation of the rarefactional pressure level in situ was based on the recorded log files and a multilayer attenuation model that incorporates energy loss through bone, acoustic impedance mismatch at the bone–brain interface, and energy loss through brain tissue as described elesewhere.10 For the temporal bone thickness measurement, each pretreatment axial MRI scan was reviewed for the thinnest portion of the temporal bone anterior to the upper part of the helix—the site most commonly used for successful transtemporal insonation and monitoring (midtemporal TCD window). Temporal bone thickness was measured with an internal digital caliper by an experienced investigator independently of clinical data. Measurements were taken in volunteers who received the insonation via the best pair temporal transducers.

Results

A total of 15 volunteers agreed to participate: 6 were patients from the UAB Headache Treatment and Research Program; 9 were UAB employees or relatives of UAB employees but not directly used with or related to study personnel. They all were free of cerebrovascular disease (40% men; 49±16 years; 27% black, NIHSS scores 0). All subjects had successful hand-held TCD examinations of all 3 windows showing normal blood flow velocity measurements in all 12 intracranial arterial segments for each participant. Successful transcranial ultrasound pulse transmission was confirmed by the hands-free–activated best pair temporal transducers in 14/15 volunteers (93%). Spectral Doppler waveforms were detectable by at least 1 hands-free transducer in 13/15 volunteers (87%) for the right temporal, in 12/15 (80%) for the left temporal, and in 7/15 (47%) for the suboccipital arrays.

Stroke-free volunteers were continuously insonated for 2 hours with the operator-independent device at a transmit frequency of 2 MHz. The maximum derated ISPTA level was 207 mW/cm2, far below the FDA guideline limit. Assuming a typical distance of 45 mm from the transducer to the anatomic region of interest (eg, M1/proximal M2 middle cerebral artery occlusion), and the measured temporal bone thickness (median, 2.3 mm; range, 1.5–3.0 mm) of the respective subjects, the estimated rarefactional pressure level in situ was between 40 and 100 kPa (in water values 325–455 kPa). A complete list of the ultrasound exposure parameters are given in Table 1.

Table 1.

Acoustic Parameters for the Operator-Independent Ultrasound Device11

Ultrasound Parameters Value (Unit)
Frequency, and any modulation 2 MHz (pulsed)
Derated ISPTA intensity (for comparison to FDA limits) 207 mW/cm2 max
Total power 32 mW average
Pulse duration 5 μs (10 cycles)
Pulse repetition frequency 8.3 kHz
Beam width, −6 dB, min and at region of interest 4.5 mm at 27 mm
6 mm at 45 mm
Aperture size and shape 10 mm, circular
Focal distance (or unfocused) 30 mm
Distance from transducer to region of interest 45 mm
Max peak rarefactional pressure (in water /in situ) 455 kPa/100 kPa
Mechanical/thermal index, max 0.23 MI, 0.81 TIC
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FDA indicates Food and Drug Administration; ISPTA Spatial Peak Temporal Average Intensity; MI, mechanical index; TIC, thermal index for cranial bone.

All subjects tolerated tight headframe fixation without complaints or adverse events. All volunteers were safely insonated with no adverse effects as indicated by the neurological examinations during, immediately after the exposure, and at 24 hours after treatment (NIHSS 0 points, respectively). No breaks in the skin or skin irritation were observed at 2 hours and at 24 hours after the exposure to the operator-independent device. The time delay between the end of the ultrasound exposure and the repeat MRI for BBB leakage detection was 27.2±21.0 minutes. No breach of the BBB was found on any MRIs.

Discussion

Our novel operator-independent ultrasound device was well tolerated by the stroke-free volunteers and did not cause any neurological dysfunction nor did it affect the integrity of the BBB. The latter constitutes an important safety measure in sonothrombolysis trials because a recent trial produced excessive bleeding complications likely caused by BBB disruption in acute ischemic stroke patients.12,13 However, it should be mentioned that this trial used ultrasound at a much lower frequency (in the kilohertz range) coadministered with intravenous tPA, whereas no BBB disruption has ever been reported in human subjects when the ultrasound frequency was >1 MHz and below the FDA guideline limits on derated ISPTA. In our study, successful ultrasound transmission was confirmed for almost all best pair temporal transducers used, on the basis of the received signals on the contralateral side of the head. Because no transducers were operated simultaneously, the ultrasound intensity delivered to the brain never exceeded the FDA guideline limits.

Faster recanalization of an occluded vessel constitutes 1 of the major determinants of the therapeutic success for revascularization therapies in acute ischemic stroke.14–16 However, although recent endovascular approaches produced recanalization rates >80%, corresponding improvements in functional outcomes have been modest.17 Even with the recent and promising results of the Solitaire with the Intention for Thrombectomy and Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke trials,18,19 endovascular therapies may not become the front-line treatment for stroke because of logistic challenges and patient access to neuroendovascular specialists. This emphasizes the need for adjuvant therapeutic approaches to systemic tPA,20 which remains the only effective and approved therapy for ischemic stroke.15,21 Adjuvant treatment with diagnostic TCD frequency has been shown to double recanalization rates when compared with systemic tPA alone,1 and a device capable of creating comparable levels of ultrasound exposure in emergency situations is needed in order for sonothrombolysis to be tested in a phase III trial. The major obstacle to the adoption of ultrasound-enhanced treatment methods has been the need for highly trained physicians or sonographers, who are not typically available on an emergency basis at most stroke centers. Although comprehensive stroke centers are recommended to have diagnostic TCD equipment available for the management of acute stroke patients,22 only a few stroke centers and even fewer emergency departments not affiliated with a stroke center have access to TCD. This limitation of current TCD equipment can be overcome by an operator-independent ultrasound technology that could be used by any health professional, even those without any prior training in ultrasound. This now opens the possibility of conducting a large-scale pivotal trial of sonothrombolysis at centers experienced with tPA treatment and clinical trials but which lack trained sonographers on call. Our study reported the first step in the development of a safe device for the next phase of clinical trials.

Our phase I clinical study has limitations. Our results are limited by a relatively small number of volunteers. Also, although we excluded volunteers who had any history of cerebrovascular disease, some of the participants had chronic headache (mostly migraine) and chronic tension-type headache, which could have biased our results because these patients may be oversensitive to external stimulation. However, none of the volunteers experienced any discomfort caused by the study-related procedures, indicating that our operator-independent ultrasound device was well tolerated. Another limitation is related to the fact that we did not confirm successful Doppler visualization of intracranial blood flow waveforms with all activated transducers during exposure and instead relied on a limited sampling pre-exposure and on the time-of-flight and amplitude measurements to indicate successful ultrasound transmission during the exposure. Even if such a blind application introduces some targeting error, the ultrasound beam broadens as it travels through the temporal bone and widens further as it propagates past the focal point (Figure 2C). Thus, each beam covers a significant volume of tissue. We were able to confirm that our blind or unguided transmission through the temporal window did occur by the novel technique of contralateral reception. Although our model-based estimates of in situ pressure levels have its limitations, it is not practical to take actual in situ measurements. Finally, our choice of relatively low-intensity levels, such as those achieved with standard TCD, may be debatable. However, data from our prior clinical trials, as well as others using similar approaches, indicate that low power 2-MHz ultrasound intensity levels offer a safe exposure compared with other approaches.1,23 Distributing the delivered energy of 1 TCD beam between 18 transducers further reduces the exposure of any 1 tissue volume. TCD is designed to sample blood flow velocities in real time, and the PRF is generally not adjusted for therapeutic purposes. In the design of our device, we hypothesized that even though the total energy delivered from 18 transducers equaled that from the 1 transducer used for 2 hours in the CLOTBUST trial,2 and thus any given thrombus location would receive lower effective PRF, this would not necessarily result in decreased efficiency of sonothrombolysis. On the contrary, ultrasound exposure at a lower pulse rate is less likely to create hot spots of energy overlap and summation,24 and this would better address the safety issues on hands-free exposure. In developing therapeutic ultrasound, 1 must choose among many parameters, among these being transmit mode (pulsed versus continuous wave), frequency of operation (megahertz versus kilohertz), and estimate peak rarefaction pressure generated at the thrombus.10,23 The pressure level at the thrombus is independent of how often 1 exposes thrombus to ultrasound (ie, PRF). Rather, the beam characteristics become of paramount importance in properly exposing the thrombus to sufficient ultrasound energy.

Conclusions

Our novel operator-independent device seems safe when used with stroke-free volunteers. The safety and efficacy of the device in acute ischemic stroke patients receiving intravenous tPA are currently being tested in phase II and III clinical trials.25,26

Acknowledgments

Sources of Funding

This study was supported by grant P50NS044227 from the National Institute of Neurological Disorders and Stroke and the Center for Clinical and Translational Sciences, which is funded by National Institutes of Health (NIH) Clinical and Translational Award UL1 RR024148 (TL1 RR024147 for the T32 program; KL2 RR024149 for the K12 program) from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the NIH.

Footnotes

Disclosures

Dr Barlinn and Dr Barreto were supported through National Institute of Neurological Disorders and Stroke (NINDS) Specialized Programs of Translational Research in Acute Stroke (SPOTRIAS) grant (PI—James Grotta, MD, University of Texas-Houston), project CLOTBUST-Hands Free, phase I/II studies of an operator-independent device for sonothrombolysis in stroke. Dr Liebeskind serves as consultant to Concentric Medical, Inc. and CoAxia, Inc. Dr Alexandrov serves as consultant to Cerevast Therapeutics, Inc and holds a US patent 6733450 “Therapeutic Method and Apparatus for Use of Sonication to Enhance Perfusion of Tissues,” assignee—Texas Board of Regents. Dr Alexandrov’s role in the studies sponsored by the NINDS SPOTRIAS grant has been approved by the University of Alabama Centralized Institutional Review Board (CIRB) and independent Data Management and Data Safety Monitoring Boards were overseeing data analysis. Dr Schafer serves as consultant to Cerevast Therapeutics, Inc. J. Alleman is the Vice President of Operations at Cerevast Therapeutics, Inc. The other authors have no conflicts to report.

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