J Clin Neurol.  2007 Mar;3(1):1-8. 10.3988/jcn.2007.3.1.1.

Ultrasound Enhanced Thrombolysis: Applications in Acute Cerebral Ischemia

• Tsivgoulis G
• Alexandrov AV

• KMID: 1700680
• DOI: http://doi.org/10.3988/jcn.2007.3.1.1

Abstract

Intravenous tissue plasminogen activator (TPA) improves patient chances to recover from stroke by inducing mostly partial recanalization of large intracranial thrombi. 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. The international multi-center CLOTBUST trial showed that ultrasound enhances thrombolytic activity of a drug in humans thereby confirming multi-disciplinary experimental research conducted worldwide for the past 30 years. 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 to 8% who received TPA alone (p=0.02). Complete clearance of a thrombus and dramatic recovery of brain functions 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, subject for a pivotal trial. However, different results were achieved in a small TRUMBI trial and another study that used Transcranial Color-Coded Duplex Sonography (TCCD). Adverse bio-effects of mid-KHz (300) ultrasound promote bleeding, including brain areas not-affected by ischemia while exposure to multi-frequency / multi-element duplex ultrasound resulted in a trend towards higher risk of hemorrhagic transformations. 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). Multi-national dose escalation studies of microspheres and the development of an operator independent ultrasound device are underway.

Keyword

TPA; Transcranial Doppler; Stroke; Thrombolysis; Outcomes

MeSH Terms

Brain
Brain Ischemia*
Hemorrhage
Humans
Ischemia
Microspheres
Perfusion
Stroke
Thrombosis
Tissue Plasminogen Activator
Ultrasonography*
Tissue Plasminogen Activator

Figure

• 

  Figure 1 Reported controlled clinical trials of ultrasound-enhanced systemic thrombolysis for acute ischemic stroke.27,28,34 The Figure was reproduced with permission from Andrei Alexandrov (n; total number of patients enrolled in both control and target groups, Transducer; images of actual sources of ultrasound and their size relative to patient head, Tissues exposed; images of beam paths as ultrasound propagates through the brain, sICH; percent rates of symptomatic intracranial hemorrhages, CR; complete recanalization at the end of monitoring period, mRS 0-1; modified Rankin scores at 3 months follow-up (? -percent or actual number not reported in the original publication34).

• 

  Figure 2 PMD flow tracks showing individual and multiple perflutren-lipid microsphere permeation to areas with no detectable residual flow pre-treatment (white circles) and residual blood flow improvement following the administration of microspheres. The Figure was reproduced with permission from Andrei Alexandrov.

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