Can sound waves be used to break up a clot, specifically in the treatment of acute ischemic stroke?

Ultrasound for Clot Lysis in Acute Ischemic Stroke

Sonothrombolysis (ultrasound-enhanced thrombolysis) shows potential for improving recanalization rates in acute ischemic stroke but is not currently recommended as standard treatment due to insufficient evidence of clinical benefit.

Mechanism and Approaches

Sonothrombolysis refers to the use of ultrasound waves to enhance clot breakdown, which can be delivered in several ways:

1. Transcranial Doppler (TCD) ultrasonography - diagnostic ultrasound probe positioned at the site of occlusion
2. Transcranial color-coded duplex (TCCD) ultrasonography
3. Unfocused low-frequency ultrasound without imaging guidance
4. Intra-arterial or intraclot delivery via catheter (e.g., EKOS technology) 1

The proposed mechanism involves ultrasound's ability to:

• Increase exposure of the clot to thrombolytic agents
• Enhance fibrinolysis through non-thermal mechanical effects
• Potentially break up clots even without thrombolytic drugs 2

Evidence on Efficacy

Clinical Trials and Outcomes

The CLOTBUST trial showed promising early results:

• 83% of patients achieved some recanalization with intravenous rtPA plus TCD versus 50% with rtPA alone
• Complete recanalization rates were 46% versus 17%, respectively
• Symptomatic intracranial hemorrhage (sICH) rates were similar at 3.8% in both groups 1

However, larger subsequent trials have not confirmed clinical benefit:

1. CLOTBUST-ER (2019) - a multicenter, double-blind phase 3 trial:

   • Found no significant improvement in functional outcomes at 90 days
   • Was stopped early for futility
   • Demonstrated safety but no clinical benefit 3

2. NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study):

   • Randomized 183 patients receiving either alteplase or tenecteplase
   • Found no statistically significant difference in neurological improvement at 24 hours or functional outcome at 90 days
   • No significant difference in sICH rates 1, 4

Current Guidelines

The 2018 AHA/ASA guidelines explicitly state:

• "The use of sonothrombolysis as adjuvant therapy with IV thrombolysis is not recommended" (Class III: No Benefit; Level of Evidence B-R) 1

This recommendation is based on the lack of randomized controlled trial data supporting additional clinical benefit of sonothrombolysis as adjuvant therapy for IV thrombolysis.

Technical Considerations and Limitations

Several technical factors affect the efficacy and safety of sonothrombolysis:

1. Frequency of ultrasound waves (typically 1.8-2 MHz for diagnostic ultrasound)

2. Duration of thrombus exposure (ranging from 60-120 minutes in trials)

3. Skull transmittance variability:

   • Substantial fluctuation of ultrasound transmittance through human skulls
   • Fluctuation ratios between maximum and minimum transmittance can reach 3:1
   • This variability represents a potential risk factor for treatment 5

4. Operator dependence and technical expertise requirements 1

Safety Considerations

Safety concerns include:

1. Risk of symptomatic intracranial hemorrhage:

   • Higher-frequency diagnostic ultrasound appears relatively safe
   • Low-frequency ultrasound has been associated with increased bleeding rates 1

2. The TRUMBI study (Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia) indicated increased risk of hemorrhage with low-frequency ultrasound 1

Current Treatment Approach

For acute ischemic stroke, the current evidence-based approach is:

1. IV alteplase (tPA) remains the only FDA-approved pharmacological therapy for patients who can be treated within the appropriate time window 1

2. For patients with large vessel occlusions, mechanical thrombectomy is recommended:

   • Patients eligible for IV alteplase should receive it even if mechanical thrombectomy is being considered (Class I, Level A) 1
   • Observation after IV alteplase to assess for clinical response before proceeding to thrombectomy should not be performed (Class III: Harm) 1

Future Directions

Despite current limitations, sonothrombolysis remains an area of ongoing research:

• May have potential in settings where endovascular reperfusion therapies are not immediately available
• Could be valuable in regions where advanced stroke treatments are limited
• Modulated ultrasound waves might reduce the risk of transmittance fluctuation 5

Conclusion

While sonothrombolysis has shown promise in enhancing clot lysis in laboratory and small clinical studies, current guidelines do not support its use outside clinical trials due to lack of demonstrated clinical benefit in larger randomized controlled trials.