What is ultrasound augmentation of intravenous (IV) thrombolysis in acute ischemic stroke?

Ultrasound Augmentation of Intravenous Thrombolysis in Stroke

Ultrasound augmentation of IV thrombolysis is a technique where continuous transcranial Doppler (TCD) ultrasound is applied to the occluded cerebral artery during IV tissue plasminogen activator (tPA) administration to mechanically enhance clot breakdown and accelerate recanalization. 1

Mechanism of Action

Ultrasound delivers mechanical pressure waves directly to the thrombus, which:

• Exposes more thrombus surface area to circulating tPA 2, 3
• Accelerates enzymatic thrombolysis through physical disruption 4
• Can be performed at the safer energy levels used in diagnostic ultrasound (2 MHz) rather than requiring high-intensity therapeutic ultrasound 4

Methods of Delivery

There are three primary approaches to ultrasound-enhanced thrombolysis 1:

1. Transcranial Doppler (TCD) monitoring - A sonographic operator actively positions a diagnostic Doppler probe over the occluded vessel 1
2. Unfocused low-frequency ultrasound - Sonicates vessels and brain tissue without imaging guidance 1
3. Intra-arterial catheter delivery - Such as the EKOS catheter system that delivers ultrasound directly at the clot site 1

Clinical Evidence: The CLOTBUST Trial

The landmark CLOTBUST (Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic rtPA) trial demonstrated significant benefits 1:

• Complete recanalization: 49% with TCD + IV tPA versus 30% with IV tPA alone 1
• Any recanalization: 83% (46% complete, 27% partial) with TCD + IV tPA versus 50% (17% complete, 33% partial) with IV tPA alone within 2 hours 1
• Dramatic clinical recovery with complete recanalization: 25% in the TCD group versus 8% in the control group (P=0.02) 2
• Safety profile: Symptomatic intracranial hemorrhage rate was identical at 3.8% in both groups 1

The trial was underpowered to detect significant final clinical improvement despite the recanalization benefits 1

Critical Safety Considerations

Low-frequency ultrasound (kilohertz range) is contraindicated due to unacceptable hemorrhage risk. 1

The TRUMBI (Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia) trial demonstrated:

• 36% symptomatic intracranial hemorrhage rate with 300 kHz ultrasound 2, 3
• Bleeding occurred in both ischemic and non-ischemic brain areas 2
• The trial was discontinued for safety concerns 1

Only diagnostic-range ultrasound (2 MHz megahertz frequency) has demonstrated acceptable safety. 1

Current Clinical Status

While the evidence shows enhanced recanalization, ultrasound augmentation remains investigational 1:

• Trials of diagnostic ultrasound enhancement are ongoing 1
• Phase II studies are evaluating 2 MHz TCD with perflutren-lipid microspheres (ultrasound contrast agents) 2, 3
• Operator-independent ultrasound devices are under development 2, 3
• The technique requires appropriate temporal bone windows for TCD penetration 1

Practical Limitations

Several factors limit widespread implementation 1:

• Temporal bone window adequacy - Not all patients have adequate acoustic windows for TCD 1
• Operator dependence - Requires skilled sonographer to maintain continuous monitoring 1
• Vessel visualization - Limited to vessels capable of TCD visualization; not useful for posterior circulation 1
• Technical expertise - Accuracy depends on technician and interpreter experience 1

Integration with Other Therapies

Ultrasound augmentation can be combined with other approaches 1:

• May be used alongside reduced-dose IV tPA followed by intra-arterial therapy 1
• The IMS II study evaluated ultrasonic EKOS catheter for intra-arterial delivery after reduced-dose IV tPA 1
• Can provide real-time monitoring of recanalization timing and detect reocclusion 1

Common Pitfalls to Avoid

• Never use low-frequency (kilohertz) ultrasound - This dramatically increases hemorrhage risk 1, 2
• Do not delay IV tPA administration to arrange for ultrasound augmentation - Time to treatment is paramount 5
• Recognize bone window limitations - Not all patients are candidates due to skull thickness 1
• Avoid multifrequency duplex ultrasound - This showed a trend toward higher hemorrhagic transformation risk 2