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

Abstract

Summary:Experimental and pilot clinical evidence shows that thrombolysis with intravenous tissue plasminogen activator (TPA) can be enhanced with ultrasound. Ultrasound delivers mechanical pressure waves to the clot, thus exposing more thrombus surface to circulating drug. The international multicenter phase II CLOTBUST trial showed that, in patients with acute ischemic stroke, transcranial Doppler (TCD) monitoring augments TPA-induced arterial recanalization, with a nonsignificant trend toward an increased rate of recovery from stroke, compared with placebo. In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 hours after TPA bolus occurred in 25% of patients treated with TPA ϩ TCD (n ϭ 63), compared with 8% of those who received TPA alone (n ϭ 63, P ϭ 0.02). Different results were achieved in smaller studies that used transcranial color-coded duplex sonography (TCCD) and a nonimaging therapeutic ultrasound system. The findings of the TRUMBI trial (26 patients) underscored the adverse bioeffects of midkilohertz (300 kHz) ultrasound, such as promotion of bleeding in brain areas both affected and unaffected by ischemia. Exposure to multifrequency, multielement duplex ultrasound resulted in a trend toward a higher risk of hemorrhagic transformation. To further enhance the ability of TPA to break up thrombi, current ongoing clinical trials include phase II studies of a single-beam, 2-MHz TCD with perflutren lipid microspheres. Enhancement of intra-arterial TPA delivery is being clinically tested with 1.7-2.1 MHz pulsed-wave ultrasound (EKOS catheter). Multinational dose escalation studies of microspheres and the development of an operator-independent ultrasound device are underway.

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

“…The following 3 different ultrasound modalities were used to increase the thrombolytic activity of tPA: TCD ultrasonography, TCCD ultrasonography, and therapeutic transcranial low-frequency ultrasonography. 27,28 These devices generate ultrasound beams that differ greatly in acoustic properties, such as frequency, mechanical index, and the amount of brain tissue included in the beam (that is, areas of the brain exposed to ultrasound energy). Transcranial Doppler ultrasonography equipped with a 2-MHz transducer has been widely used for evaluating patients with acute ischemic stroke, 27,28 traumatic brain injury, 9,10 and aneurysmal subarachnoid hemorrhage.…”

“…7 This nonimaging and hand-held ultrasound examination device provides real-time blood flow velocity from cerebral arteries that can indicate arterial occlusion or recanalization, embolization, functional status of collateral circulatory pathways, and blood steal phenomenon. 27,28 For diagnostic purposes, the emitted-power output is usually set at the maximal achievable level below the allowed limit of 720 mW with selected insonation deaths, and the sample volumes, or gates of insonation, are set at 3-6 mm for power motion Doppler devices and 10-15 mm for other single channel devices. 27,28 While using TCD ultrasonography to monitor tPA thrombolysis, Alexandrov et al 2 incidentally suspected the ability of TCD ultrasonography to facilitate arterial recanalization in patients with acute ischemic stroke treated with intravenous tPA, a phenomenon confirmed afterward by the CLOTBUST (Combined Lysis of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic tPA) trial.…”

“…27,28 For diagnostic purposes, the emitted-power output is usually set at the maximal achievable level below the allowed limit of 720 mW with selected insonation deaths, and the sample volumes, or gates of insonation, are set at 3-6 mm for power motion Doppler devices and 10-15 mm for other single channel devices. 27,28 While using TCD ultrasonography to monitor tPA thrombolysis, Alexandrov et al 2 incidentally suspected the ability of TCD ultrasonography to facilitate arterial recanalization in patients with acute ischemic stroke treated with intravenous tPA, a phenomenon confirmed afterward by the CLOTBUST (Combined Lysis of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic tPA) trial. When signs of arterial occlusion are detected, the TCD ultrasound beam can be continu- ously focused at the presumed thrombus location, allowing both sonothrombolysis and continuous monitoring of the recanalization process.…”

“…It is unrealistic to expect that an unskilled TCD ultrasonography clinician can develop skills for a rapid and accurate location of cerebral arterial occlusions. 4,27,28 Transcranial color-coded duplex is another ultrasound method that, like TCD ultrasonography, provides real-time blood flow dynamics of cerebral arteries. However, unlike TCD technology, TCCD transducers generate multiple small ultrasound beams at dual emitting frequencies, one for gray scale imaging and another for Doppler imaging; hence, besides assessment of cerebral hemodynamics, this technology can also afford both arterial location on color flow imaging and imaging of the brain on B-mode ultrasonography.…”

“…However, unlike TCD technology, TCCD transducers generate multiple small ultrasound beams at dual emitting frequencies, one for gray scale imaging and another for Doppler imaging; hence, besides assessment of cerebral hemodynamics, this technology can also afford both arterial location on color flow imaging and imaging of the brain on B-mode ultrasonography. 5,8,27,28 The TCCD ultrasound beam includes a larger brain area (a greater amount of brain tissue is exposed to ultrasound energy) compared with the more focal TCD ultrasound beam. Among the limitations of TCCD ultrasonography, there are no head frames for transducer fixation (recanalization monitoring is carried out using handheld probes), the mechanical index (an indicator of the likelihood of mechanical biological effects, that is, streaming and cavitation) of the TCCD ultrasonography is higher than that for TCD ultrasonography, and no dose escalation study has been performed to determine the levels of ultrasound intensity needed to enhance thrombolysis without risks.…”