Ultrasound-enhanced thrombolysis in acute ischemic stroke: potential, failures, and safety

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 + TCD (n = 63), compared with 8% of those who received TPA alone (n = 63, P = 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 mid-kilohertz (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.