ISCHEMIC STROKE / ACUTE THERAPY

Sonothrombolysis

Created 09/09/2022, last revision 09/09/2022

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]

Methods

Sonothrombolysis

  • 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   CLOTBUST trial    [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   Schematic representation of the effect of microbubbles
  • 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
  • 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)
Metaanalysis of sonothrombolytic trials (ESO 2021)

Endovascular sonothrombolysis

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

Sonolysis

  • 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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