Sonothrombolysis in the Management of Acute Ischemic Stroke
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Multiple in vitro and animal models have demonstrated the efficacy of ultrasound to enhance fibrinolysis. Mechanical pressure waves produced by ultrasound energy improve the delivery and penetration of alteplase (recombinant tissue plasminogen activator [tPA]) inside the clot. In human stroke, the CLOTBUST phase II trial showed that the combination of alteplase plus 2 hours of continuous transcranial Doppler (TCD) increased recanalization rates, producing a trend toward better functional outcomes compared with alteplase alone. Other small clinical trials also showed an improvement in clot lysis when transcranial color-coded sonography was combined with alteplase. In contrast, low-frequency ultrasound increased the symptomatic intracranial hemorrhage rate in a clinical trial. Administration of microbubbles (MBs) may further enhance the effect of ultrasound on thrombolysis by lowering the ultrasound-energy threshold needed to induce acoustic cavitation. Initial clinical trials have been encouraging, and a multicenter international study, TUCSON, determined a dose of newly developed MBs that can be safely administered with alteplase and TCD. Even in the absence of alteplase, the ultrasound energy, with or without MBs, could increase intrinsic fibrinolysis. The intra-arterial administration of ultrasound with the EKOS NeuroWave® catheter is another ultrasound application for acute stroke that is currently being studied in the IMS III trial. Operator-independent devices, different MB-related techniques, and other ultrasound parameters for improving and spreading sonothrombolysis are being tested.