Ultrasound enhanced thrombolysis in acute arterial ischemia.
In vitro and animal studies have shown 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. Moreover, intravenous gaseous microspheres with ultrasound have been shown to be a potential alternative to fibrinolytic agents to recanalize discrete peripheral thrombotic arterial occlusions or acute arteriovenous graft thromboses. Small phase I-II randomized and non-randomized clinical trials have shown promising results concerning the potential applications of ultrasound-enhanced thrombolysis in the setting of acute cerebral ischemia. CLOTBUST was an international four-center phase II trial, which demonstrated that, in patients with acute ischemic stroke, transcranial Doppler (TCD) monitoring augments tPA-induced arterial recanalization (sustained complete recanalization rates: 38% vs. 13%) with a non-significant trend toward an increased rate of clinical recovery from stroke, as compared with placebo. The rates of symptomatic intracerebral hemorrhage (sICH) were similar in the active and placebo group (4.8% vs. 4.8%). Smaller single-center clinical trials using transcranial color-coded sonography (TCCD) reported recanalization rates ranging from 27% to 64% and sICH rates of 0-18%. A separate clinical trial evaluating the safety and efficacy of therapeutic low-frequency ultrasound was discontinued because of a concerning sICH rate of 36% in the active group. 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. Moreover, potential enhancement of intra-arterial tPA delivery is being clinically tested with 1.7-2.1 MHz pulsed wave ultrasound (EKOS catheter) in ongoing phase II-III clinical trials. Intravenous platelet-targeted microbubbles with low-frequency ultrasound are currently investigated as a rapid noninvasive technique to identify thrombosed intracranial and peripheral vessels. Multi-national dose escalation studies of microspheres and the development of an operator independent ultrasound device are underway.
Tsivgoulis
Georgios
G
Comprehensive Stroke Center, Department of Neurology, University of Alabama at Birmingham, Suite 226, RWUHM, 1719 6th Avenue South, Birmingham, AL 35294, USA.
Culp
William C
WC
Alexandrov
Andrei V
AV
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D004869:Equipment Safety; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D008863:Microspheres; D015912:Thrombolytic Therapy / Q000295:instrumentation*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D014464:Ultrasonic Therapy / Q000379:methods*; D017585:Ultrasonography, Doppler, Transcranial
D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator