Sonothrombolysis in Stroke
The current state of play in hyper-acute stroke care mirrors the evolution of acute STEMI care over a decade ago. There is now beginning a very slow and gradual transition from systemic thrombolysis to neuro-interventional, catheter directed therapies. Whilst this is a wonderful thing, there remains significant barriers to accessing clot retrieval for most patients. Further, both primary percutaneous coronary intervention (pPCI) and clot retrieval are not just currently inaccessible to the majority of the world’s population, but, due to cost and expertise, will likely remain so for decades to come.
Could ultrasound hold the key to future low-cost interventional therapies?
Trans-Cranial Ultrasound, as its name suggests, involves placing the probe over the thinnest portion of the temple and scanning through the skull to visualise the brain.
Trans-Cranial Ultrasound can allow visualisation of various aspects of the brain, particularly the circle of Willis (most importantly the Mid- Cerebral Artery (MCA)) using Doppler, as well the ventricles, in B-mode. This technology has been around for a while and is finally starting to gain rapid traction as a diagnostic modality (1).
While its diagnostic use continues to grow, another avenue of possibility has opened up. Through exploring the effects of focussed ultrasound technology on tissues, ultrasound as an interventional modality is undergoing an evolution. The impact of sound waves on tissue causes rarefaction and compression; a kind of expansion and contraction. This vibration (movement) also causes some heat and has traditionally been viewed in a negative light; being the reason the ALARA (As Low As Reasonably Achievable) principle was introduced, and MI (Mechanical Index) and TI (Thermal Index) values are displayed on all machines. Interventional ultrasound is harnessing this effect to target lesions; and in the case of endovascular pathology, to target clots.
Roughly 80-90% of the population have skulls thin enough for Transcranial Doppler to penetrate them; however in the remaining 10-20% of people (2,3), a microbubble contrast is required for visualisation. This microbubble contrast is a non-reactive substance of micro-gas particles trapped in a synthetic fatty-fluid, and a critical component to only excellent visualisation, but also intervention.
When microbubbles are exposed to an ultrasound beam, they alter the attenuation of sound through the fluid inside a vessel. An effect known as Inertial Cavitation occurs(4) (i.e. the formation and violent collapse of gas-filled bubbles in a fluid) which causes short lived micro-jetting of surrounding fluid, structurally weakening the clot(5). Stable cavitation also causes microstreaming, which enlarges the size of the microbubbles and might compress the thrombus against the vessel wall, creating small pores in its surface(3).
By focussing the ultrasound beam on the thrombosed vessel for between 30-60 minutes, preliminary research is suggesting that rarefaction and compression work to affect a combination of an acoustic radiation force, stable cavitation, and inertial cavitation, of the microbubble contrast. We still don’t know which effect is most important, nonetheless, combined they effectively “shake up” and dislodge the fibrin structures of the clot, causing it’s proximal edges to weaken and degrade(3). This then paves the way for either the body’s endogenous lytic process, or an introduced lytic agent, to begin further disintegrating the thrombus.
Already three separate observational studies suggest that Trans-Cranial Doppler might accelerate vessel recanalization in combination with r-tPa (recombinant tissue plasminogen activator) (6–10).
Sonothrombolysis might also be effective in occlusive myocardial infarction, and initial trials are underway at the University of Alberta to test the effect of pre-pPCI microbubble contrast sonothrombolysis (NCT03092089)(11).
It sounds rather magical and far-fetched, and frankly the science still has a way to go, but sonothrombolysis is pitching to hit serious research soon, and when it does, it’s going to make waves.
Images Credit (12,13)
1. Lau VI, Arntfield RT. Point ‑ of ‑ care transcranial Doppler by intensivists. Critical Ultrasound Journal. 2017;
2. Bahner DP, Blickendorf JM, Bockbrader M, Adkins E, Vira A, Boulger C, et al. Language of Transducer Manipulation. Journal of Ultrasound in Medicine [Internet]. 2016 Jan;35(1):183–8. Available from: http://doi.wiley.com/10.7863/ultra.15.02036
3. Bader KB, Bouchoux G, Holland CK. Sonothrombolysis. Adv Exp Med Biol. 2016;339–62.
4. Everbach EC, Francis CW. Cavitational mechanisms in ultrasound-accelerated thrombolysis at 1 MHz. Ultrasound in medicine & biology [Internet]. 2000 Sep;26(7):1153–60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11053750
5. Meairs S. Sonothrombolysis. Translational Neurosonology. 2015;36:83–93.
6. Eggers J. Sonothrombolysis for treatment of acute ischemic stroke: Current evidence and new developments. Perspectives in Medicine [Internet]. 2012 Sep;1(1–12):14–20. Available from: http://linkinghub.elsevier.com/retrieve/pii/S2211968X12000290
7. Rubiera M, Alexandrov A V. Sonothrombolysis in the Management of Acute Ischemic Stroke. American Journal Cardiovascular Drugs [Internet]. 2010 Feb;10(1):5–10. Available from: http://link.springer.com/10.2165/11316850-000000000-00000
8. Lu Y, Wang J, Huang R, Chen G, Zhong L, Shen S, et al. Microbubble-Mediated Sonothrombolysis Improves Outcome After Thrombotic Microembolism-Induced Acute Ischemic Stroke. Stroke [Internet]. 2016 May;47(5):1344–53. Available from: http://stroke.ahajournals.org/lookup/doi/10.1161/STROKEAHA.115.012056
9. Ricci S, Dinia L, Sette M Del, Anzola GP, Mazzoli T, Cenciarelli S, et al. Sonothrombolysis for Acute Ischemic Stroke. Stroke. 2013;6–8.
10. Controlled R, Sonothrombolysis C. NOR-SASS ( Norwegian Sonothrombolysis in Acute. Stroke. 2017;1–8.
11. Becher H. Clinical Trials: Sonothrombolysis in Patients With STEMI [Internet]. NCT. 2017 [cited 2018 Jun 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT03092089
12. Phillips. Microbuble Cavitation [Image] [Internet]. 2017. Available from: http://thefutureofthings.com/3805-ultrasound-activated-microbubbles-fight-cancer/
13. Radiologykey.com. Use of transcranial Doppler ultrasonography in the pediatric intensive care unit [Internet]. radiologykey.com; 2016. p. 1. Available from: https://radiologykey.com/use-of-transcranial-Doppler-ultrasonography-in-the-pediatric-intensive-care-unit-consultant-level-examination
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