ISCHEMIC STROKE / ACUTE THERAPY

Sonothrombolysis

Created 09/09/2022, last revision 03/10/2022

Introduction

diagnostic ultrasound at high frequency (~2 MHz) and low intensity leads to acceleration of enzymatic processes induced by thrombolytics (sonothrombolysis) and can be applied externally using commercial transcranial and duplex Doppler devices
it provides:
- improved penetration of fibrinolytic drugs into the thrombus
- direct activation of the fibrinolytic system
- change in thrombus microstructure and improved binding of thrombolytics to fibrin [Braaten 1997]
low-frequency ultrasound (300 kHz) transcranial ultrasound was also tested to accelerate thrombolysis; the TRUMBI trial was terminated prematurely due to high rates of IC bleeding [Daffertshoffer, 2007]

the CLOTBUST trial demonstrated a higher rate of complete recanalization in patients treated with IVT in combination with 2-hour TCD monitoring (2MHz probe) compared to IVT alone [Alexandrov, 2004]]
according to several in vitro and human clinical studies, the use of echo contrast during sonothrombolysis further increases the recanalization potential of sonothrombolysis (DEFINITI, TUCSON )
- modified microbubbles are tested, which are more stable in solution and smaller (1-2 μm) than the diagnostic ones
a significant obstacle to the further development of sonotrombolysis and to the conduct of a large clinical trial that would have the power to demonstrate the expected clinical effect was the unavailability of experienced sonographers
thus automated device that does not require the presence of a skilled operator (operator-independent) was developed
- the CLOTBUST-HF was a pilot trial with the CLOTBUST-ER device from Cerevast [Barreto, 2013]
- in 2015, the multicenter phase 3 CLOTBUST-ER trial was terminated early due to negative results [Alexandrov, 2019]

a meta-analysis of 5 RCTs demonstrated no benefit (mRS score 0-1/3 months) of sonothrombolysis over TL alone
sonothrombolysis is currently not recommended beyond clinical trials (ESO guidelines 2021) (AHA/ASA 2019 III/A)

direct endovascular insonation of the thrombus using endovascular probes attached to the end of the catheter (e.g., EKOS system) was tested
- the IMS3 trial was terminated early in 2012 – no significant clinical benefit of combination therapy over IVT alone was demonstrated (Broderick, 2013)

small trials testing the effect of sole insonation without tPA (sonolysis) during interventional procedures (CEA, CAS) to reduce the risk of thromboembolism show promising results → here

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