Ultrasound Enhanced Thrombolysis for Stroke

Abstract

Spontaneous arterial recanalization occurs at a rate of 6% per hour, and it can be doubled with intravenous tissue plasminogen activator (TPA) therapy since early dramatic clinical improvement, a substitute for early thrombus break-up, occurs in TPA-treated patients. TPA activity can be enhanced with ultrasound including 2-MHz transcranial Doppler (TCD). TCD identifies residual blood flow signals around thrombi, and, by delivering mechanical pressure waves, exposes more thrombus surface to circulating TPA. 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 compared with 8% who received TPA alone ( P = 0.02). Complete clearance of a thrombus and dramatic recovery of brain function during treatment are feasible goals for ultrasound-enhanced thrombolysis that can lead to sustained recovery. An early boost in brain perfusion seen in the Target CLOTBUST group resulted in a trend of 13% more patients achieving favorable outcome at 3 months, thus providing the rationale for a pivotal trial. The ability of TPA to break up thrombi can be further enhanced with harmless diagnostic ultrasound contrast agents. Current ongoing clinical trials include phase II studies of 2-MHz TCD with ultrasound contrast agents, or microbubbles: TCD+TPA+Levovist; TCD+TPA+MRX nano-platform (C 3 F 8 ImaRx). Intraarterial ultrasound-enhanced TPA delivery is tested in the Interventional Management of Stroke (IMS) clinical trial using 1.7- to 2.1-MHz pulsed-wave ultrasound catheter (EKOS). Dose escalation studies of microbubbles, ultrasound exposure, and the development of an operator-independent ultrasound device are currently underway.