Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Sonothrombolysis in the Management of Acute Ischemic Stroke

Abstract

Multiple in vitro and animal models have demonstrated the efficacy of ultrasound to enhance fibrinolysis. Mechanical pressure waves produced by ultrasound energy improve the delivery and penetration of alteplase (recombinant tissue plasminogen activator [tPA]) inside the clot. In human stroke, the CLOTBUST phase II trial showed that the combination of alteplase plus 2 hours of continuous transcranial Doppler (TCD) increased recanalization rates, producing a trend toward better functional outcomes compared with alteplase alone. Other small clinical trials also showed an improvement in clot lysis when transcranial color-coded sonography was combined with alteplase. In contrast, low-frequency ultrasound increased the symptomatic intracranial hemorrhage rate in a clinical trial. Administration of microbubbles (MBs) may further enhance the effect of ultrasound on thrombolysis by lowering the ultrasound-energy threshold needed to induce acoustic cavitation. Initial clinical trials have been encouraging, and a multicenter international study, TUCSON, determined a dose of newly developed MBs that can be safely administered with alteplase and TCD. Even in the absence of alteplase, the ultrasound energy, with or without MBs, could increase intrinsic fibrinolysis. The intra-arterial administration of ultrasound with the EKOS NeuroWave® catheter is another ultrasound application for acute stroke that is currently being studied in the IMS III trial. Operator-independent devices, different MB-related techniques, and other ultrasound parameters for improving and spreading sonothrombolysis are being tested.

This is a preview of subscription content, log in to check access.

Table I

References

  1. 1.

    Molina CA, Saver JL. Extending reperfusion therapy for acute ischemic stroke: emerging pharmacological, mechanical, and imaging strategies. Stroke 2005; 36(10): 2311–20.

  2. 2.

    Higashida RT, Furlan AJ, Roberts H, et al. Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke 2003; 34(8): e109–37.

  3. 3.

    Adams Jr HP, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 2007; 38(5): 1655–711.

  4. 4.

    Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359(13): 1317–29.

  5. 5.

    Leys D, Ringelstein EB, Kaste M, et al. Facilities available in European hospitals treating stroke patients. Stroke 2007; 38(11): 2985–91.

  6. 6.

    Alexandrov AV. Ultrasound identification and lysis of clots. Stroke 2004; 35 (11 Suppl. 1): 2722–5.

  7. 7.

    Alexandrov AV, Molina CA, Grotta JC, et al. Ultrasound-enhanced systemic throm-bolysis for acute ischemic stroke. N Engl J Med 2004; 351(21): 2170–8.

  8. 8.

    Trubestein G, Engel C, Etzel F, et al. Thrombolysis by ultrasound. Clin Sci Mol Med Suppl 1976; 3: 697s–8s.

  9. 9.

    Tachibana K. Enhancement of fibrinolysis with ultrasound energy. J Vasc Interv Radiol 1992; 3(2): 299–303.

  10. 10.

    Lauer CG, Burge R, Tang DB, et al. Effect of ultrasound on tissue-type plasminogen activator-induced thrombolysis. Circulation 1992; 86(4): 1257–64.

  11. 11.

    Luo H, Nishioka T, Fishbein MC, et al. Transcutaneous ultrasound augments lysis of arterial thrombi in vivo. Circulation 1996; 94(4): 775–8.

  12. 12.

    Tachibana K. Ultrasound therapy for stroke and regenerative medicine. Int Congr Ser 2004; 1274: 153–8.

  13. 13.

    Polak JF. Ultrasound energy and the dissolution of thrombus. N Engl J Med 2004; 351(21): 2154–5.

  14. 14.

    Braaten JV, Goss RA, Francis CW. Ultrasound reversibly disaggregates fibrin fibers. Thromb Haemost 1997; 78(3): 1063–8.

  15. 15.

    Siddiqi F, Odrljin TM, Fay PJ, et al. Binding of tissue-plasminogen activator to fibrin: effect of ultrasound. Blood 1998; 91(6): 2019–25.

  16. 16.

    Devcic-Kuhar B, Pfaffenberger S, Gherardini L, et al. Ultrasound affects distribution of plasminogen and tissue-type plasminogen activator in whole blood clots in vitro. Thromb Haemost 2004; 92(5): 980–5.

  17. 17.

    Tachibana K, Tachibana S. Albumin microbubble echo-contrast material as an enhancer for ultrasound accelerated thrombolysis. Circulation 1995; 92(5): 1148–50.

  18. 18.

    Luo H, Steffen W, Cercek B, et al. Enhancement of thrombolysis by external ultrasound. Am Heart J 1993; 125(6): 1564–9.

  19. 19.

    Frenkel V, Oberoi J, Stone MJ, et al. Pulsed high-intensity focused ultrasound enhances thrombolysis in an in vitro model. Radiology 2006; 239(1): 86–93.

  20. 20.

    Schafer S, Kliner S, Klinghammer L, et al. Influence of ultrasound operating parameters on ultrasound-induced thrombolysis in vitro. Ultrasound Med Biol 2005; 31(6): 841–7.

  21. 21.

    Pfaffenberger S, Devcic-Kuhar B, Kollmann C, et al. Can a commercial diagnostic ultrasound device accelerate thrombolysis? An in vitro skull model. Stroke 2005; 36(1): 124–8.

  22. 22.

    Suchkova V, Siddiqi FN, Carstensen EL, et al. Enhancement of fibrinolysis with 40-kHz ultrasound. Circulation 1998; 98(10): 1030–5.

  23. 23.

    Daffertshofer M, Gass A, Ringleb P, et al. Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: results of a phase II clinical trial. Stroke 2005; 36(7): 1441–6.

  24. 24.

    Eggers J, Koch B, Meyer K, et al. Effect of ultrasound on thrombolysis of middle cerebral artery occlusion. Ann Neurol 2003; 53(6): 797–800.

  25. 25.

    Molina CA, Ribo M, Rubiera M, et al. Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke 2006; 37(2): 425–9.

  26. 26.

    Alexandrov AV, Mikulik R, Ribo M, et al. A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke. Stroke 2008; 39(5): 1464–9.

  27. 27.

    IMARx. TUCSON trial [online]. Available from URL: http://www.imarx.com/ImaRx/clinical_trials5_0 [Accessed 2009 Sep 28].

  28. 28.

    Larrue AV, Arnaud C. Trancranial ultrasound combined with intravenous micro-bubbles and tissue plasminogen activator for acute ischemic stroke: a randomized controlled study [abstract]. Stroke 2007; 38: 472.

  29. 29.

    Perren F, Loulidi J, Poglia D, et al. Microbubble potentiated transcranial duplex ultrasound enhances IV thrombolysis in acute stroke. J Thromb Thrombolysis 2008; 25: 219–23.

  30. 30.

    Eggers J, Seidel G, Koch B, et al. Sonothrombolysis in acute ischemic stroke for patients ineligible for rt-PA. Neurology 2005; 64(6): 1052–4.

  31. 31.

    IMS II Trial Investigators. The Interventional Management of Stroke (IMS) II study. Stroke 2007; 38(7): 2127–35.

  32. 32.

    Daffertshofer M, Hennerici M. Ultrasound in the treatment of ischaemic stroke. Lancet Neurol 2003; 2(5): 283–90.

  33. 33.

    Tsivgoulis G, Culp WC, Alexandrov AV. Ultrasound enhanced thrombolysis in acute arterial ischemia. Ultrasonics 2008; 48(4): 303–11.

  34. 34.

    Saqqur M, Tsivgoulis G, Molina CA, et al. Design of a PROspective multi-national CLOTBUST collaboration on reperfusion therapies for stroke (CLOTBUST-PRO). Int J Stroke 2008; 3(1): 66–72.

  35. 35.

    Tsivgoulis G, Alexandrov AV. Ultrasound-enhanced thrombolysis in acute ischemic stroke: potential, failures, and safety. Neurotherapeutics 2007; 4(3): 420–7.

  36. 36.

    Calliada F, Campani R, Bottinelli O, et al. Ultrasound contrast agents: basic principles. Eur J Radiol 1998; 27 Suppl. 2: S157–60.

  37. 37.

    Holland CK, Apfel RE. Thresholds for transient cavitation produced by pulsed ultrasound in a controlled nuclei environment. J Acoust Soc Am 1990; 88(5): 2059–69.

  38. 38.

    Nanda NC, Schlief R, Goldberg BB. Advances in echo imaging using contrast enhancement. 2nd ed. Dordrecht: Kluwer Academic Publishers, 1997.

  39. 39.

    Prokop AF, Soltani A, Roy RA. Cavitational mechanisms in ultrasound-accelerated fibrinolysis. Ultrasound Med Biol 2007; 33(6): 924–33.

  40. 40.

    Dijkmans PA, Juffermans LJ, Musters RJ, et al. Microbubbles and ultrasound: from diagnosis to therapy. Eur J Echocardiogr 2004; 5(4): 245–56.

  41. 41.

    Nishioka T, Luo H, Fishbein MC, et al. Dissolution of thrombotic arterial occlusion by high intensity, low frequency ultrasound and dodecafluoropentane emulsion: an in vitro and in vivo study. J Am Coll Cardiol 1997; 30(2): 561–8.

  42. 42.

    Culp WC, Porter TR, McCowan TC, et al. Microbubble-augmented ultrasound declotting of thrombosed arteriovenous dialysis grafts in dogs. J Vasc Interv Radiol 2003; 14(3): 343–7.

  43. 43.

    Culp WC, Porter TR, Lowery J, et al. Intracranial clot lysis with intravenous micro-bubbles and transcranial ultrasound in swine. Stroke 2004; 35(10): 2407–11.

  44. 44.

    Mizushige K, Kondo I, Ohmori K, et al. Enhancement of ultrasound-accelerated thrombolysis by echo contrast agents: dependence on microbubble structure. Ultrasound Med Biol 1999; 25(9): 1431–7.

  45. 45.

    Rubiera M, Ribo M, Delgado-Mederos R, et al. Do bubble characteristics affect recanalization in stroke patients treated with microbubble-enhanced sonothrombolysis? Ultrasound Med Biol 2008; 34(10): 1573–7.

  46. 46.

    Xie F, Tsutsui JM, Lof J, et al. Effectiveness of lipid microbubbles and ultrasound in declotting thrombosis. Ultrasound Med Biol 2005; 31(7): 979–85.

  47. 47.

    Atar S, Luo H, Nagai T, et al. Ultrasonic thrombolysis: catheter-delivered and trans-cutaneous applications. Eur J Ultrasound 1999; 9(1): 39–54.

Download references

Acknowledgments

No sources of funding were used to assist in the preparation of this article. Dr Alexandrov has been a consultant for ImaRx Therapeutics and has received honoraria from Genentech Inc. Dr Rubiera has no conflicts of interest that are relevant to the content of this article.

Author information

Correspondence to Marta Rubiera MD.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rubiera, M., Alexandrov, A.V. Sonothrombolysis in the Management of Acute Ischemic Stroke. Am J Cardiovasc Drugs 10, 5–10 (2010). https://doi.org/10.2165/11316850-000000000-00000

Download citation

Keywords

  • Middle Cerebral Artery Occlusion
  • Alteplase
  • Ultrasound Energy
  • Complete Recanalization
  • Transcranial Ultrasound