American Journal of Cardiovascular Drugs

, Volume 10, Issue 1, pp 5–10 | Cite as

Sonothrombolysis in the Management of Acute Ischemic Stroke

Leading Article


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.



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.


  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  5. 5.
    Leys D, Ringelstein EB, Kaste M, et al. Facilities available in European hospitals treating stroke patients. Stroke 2007; 38(11): 2985–91.PubMedCrossRefGoogle Scholar
  6. 6.
    Alexandrov AV. Ultrasound identification and lysis of clots. Stroke 2004; 35 (11 Suppl. 1): 2722–5.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  8. 8.
    Trubestein G, Engel C, Etzel F, et al. Thrombolysis by ultrasound. Clin Sci Mol Med Suppl 1976; 3: 697s–8s.PubMedGoogle Scholar
  9. 9.
    Tachibana K. Enhancement of fibrinolysis with ultrasound energy. J Vasc Interv Radiol 1992; 3(2): 299–303.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  12. 12.
    Tachibana K. Ultrasound therapy for stroke and regenerative medicine. Int Congr Ser 2004; 1274: 153–8.CrossRefGoogle Scholar
  13. 13.
    Polak JF. Ultrasound energy and the dissolution of thrombus. N Engl J Med 2004; 351(21): 2154–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Braaten JV, Goss RA, Francis CW. Ultrasound reversibly disaggregates fibrin fibers. Thromb Haemost 1997; 78(3): 1063–8.PubMedGoogle Scholar
  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.PubMedGoogle Scholar
  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.PubMedGoogle Scholar
  17. 17.
    Tachibana K, Tachibana S. Albumin microbubble echo-contrast material as an enhancer for ultrasound accelerated thrombolysis. Circulation 1995; 92(5): 1148–50.PubMedCrossRefGoogle Scholar
  18. 18.
    Luo H, Steffen W, Cercek B, et al. Enhancement of thrombolysis by external ultrasound. Am Heart J 1993; 125(6): 1564–9.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  22. 22.
    Suchkova V, Siddiqi FN, Carstensen EL, et al. Enhancement of fibrinolysis with 40-kHz ultrasound. Circulation 1998; 98(10): 1030–5.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  27. 27.
    IMARx. TUCSON trial [online]. Available from URL: [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.Google Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  31. 31.
    IMS II Trial Investigators. The Interventional Management of Stroke (IMS) II study. Stroke 2007; 38(7): 2127–35.CrossRefGoogle Scholar
  32. 32.
    Daffertshofer M, Hennerici M. Ultrasound in the treatment of ischaemic stroke. Lancet Neurol 2003; 2(5): 283–90.PubMedCrossRefGoogle Scholar
  33. 33.
    Tsivgoulis G, Culp WC, Alexandrov AV. Ultrasound enhanced thrombolysis in acute arterial ischemia. Ultrasonics 2008; 48(4): 303–11.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  35. 35.
    Tsivgoulis G, Alexandrov AV. Ultrasound-enhanced thrombolysis in acute ischemic stroke: potential, failures, and safety. Neurotherapeutics 2007; 4(3): 420–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Calliada F, Campani R, Bottinelli O, et al. Ultrasound contrast agents: basic principles. Eur J Radiol 1998; 27 Suppl. 2: S157–60.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  38. 38.
    Nanda NC, Schlief R, Goldberg BB. Advances in echo imaging using contrast enhancement. 2nd ed. Dordrecht: Kluwer Academic Publishers, 1997.CrossRefGoogle Scholar
  39. 39.
    Prokop AF, Soltani A, Roy RA. Cavitational mechanisms in ultrasound-accelerated fibrinolysis. Ultrasound Med Biol 2007; 33(6): 924–33.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar
  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.PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  1. 1.Comprehensive Stroke CenterUniversity of Alabama HospitalBirminghamUSA
  2. 2.Stroke Unit, Neurology DepartmentVall d’Hebron HospitalBarcelonaSpain

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