Current Cardiology Reports

, Volume 12, Issue 1, pp 34–41

Ultrasound- and Microspheres-Enhanced Thrombolysis for Stroke Treatment: State of the Art



Intravenous administration of recombinant tissue-plasminogen activator (rt-PA) remains the fastest and widely feasible strategy to initiate treatment in acute ischemic stroke. Because it works by inducing recanalization of an occluded vessel, augmentation of this process is desirable and diagnostic transcranial Doppler (TCD) ultrasound can accomplish this safely. A 2-MHz pulsed-wave monitoring can at least double the chance of early complete arterial recanalization at no increase in the risk of symptomatic intracerebral hemorrhage. Gaseous microspheres, initially developed as ultrasound contrast agents, can further increase the effectiveness of rt-PA. A recent microsphere dose-escalation study called TUCSON showed sustained complete recanalization rates of 67% in patients receiving TCD monitoring with a 1.4-mL perflutren-lipid microsphere dose compared with controls receiving rt-PA alone with no increase in hemorrhage rate. In this article, we review the current and emerging applications of ultrasound and microspheres in stroke management including augmentation of systemic thrombolysis and implications for future reperfusion strategies.


Stroke Thrombolysis Ultrasound Reperfusion Outcome 

Clinical Trial Acronyms


Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic TPA


Interventional Management of Stroke


Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia


Transcranial Ultrasound in Clinical Sonothrombolysis


Papers of particular interest, published recently, have been highlighted as follows: • Of importance, ••Of major importance

  1. 1.
    Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group [no authors listed]. N Engl J Med 1995, 333:1581–1587.Google Scholar
  2. 2.
    •• 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, 359:1317–1329. This is the second positive phase 3 trial of intravenous rt-PA. It showed that intravenous rt-PA between 3 to 4.5 hours after symptom onset improves clinical outcomes in acute ischemic stroke at a small risk of sICH. Time window expansion for rt-PA is now endorsed by the US and European guidelines.CrossRefPubMedGoogle Scholar
  3. 3.
    Del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr: Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke 2009 40:2945–2948.CrossRefPubMedGoogle Scholar
  4. 4.
    European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee: Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008, 25:457–507.CrossRefGoogle Scholar
  5. 5.
    Furlan A, Higashida R, Wechsler L, et al.: Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999, 282:2003–2011.CrossRefPubMedGoogle Scholar
  6. 6.
    Smith WS, Sung G, Starkman S, et al.: Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke 2005, 36:1432–1438.CrossRefPubMedGoogle Scholar
  7. 7.
    Smith WS: Safety of mechanical thrombectomy and intravenous tissue plasminogen activator in acute ischemic stroke. Results of the multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial, part I. AJNR Am J Neuroradiol 2006, 27:1177–1182.PubMedGoogle Scholar
  8. 8.
    Bose A, Henkes H, Alfke K, et al.: The Penumbra System: a mechanical device for the treatment of acute stroke due to thromboembolism. AJNR Am J Neuroradiol. 2008, 29:1409–1413.CrossRefPubMedGoogle Scholar
  9. 9.
    Alexandrov AV, Demchuk AM, Felberg RA, et al.: High rate of complete recanalization and dramatic clinical recovery during TPA infusion when continuously monitored by 2 MHz transcranial Doppler monitoring. Stroke 2000, 31:610–614.PubMedGoogle Scholar
  10. 10.
    Alexandrov AV, Burgin WS, Demchuk AM, et al.: Speed of intracranial clot lysis with intravenous TPA therapy: sonographic classification and short term improvement. Circulation 2001, 103:2897–2902.PubMedGoogle Scholar
  11. 11.
    Alexandrov AV, Molina CA, Grotta JC, et al.: Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004, 351:2170–2178.CrossRefPubMedGoogle Scholar
  12. 12.
    Rha JH, Saver JL: The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 2007, 38:967–973.CrossRefPubMedGoogle Scholar
  13. 13.
    • De Silva DA, Fink JN, Christensen S, et al.: Assessing reperfusion and recanalization as markers of clinical outcomes after intravenous thrombolysis in the echoplanar imaging thrombolytic evaluation trial (EPITHET). Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) Investigators. Stroke 2009, 40:2872–2874. The EPITHET was a prospective, randomized, placebo-controlled trial of intravenous tissue plasminogen activator in the 3- to 6-hour window. It showed that reperfusion and recanalization with intravenous tissue plasminogen activator were strongly correlated. Reperfusion was associated with improved clinical outcome independent of whether recanalization occurred.CrossRefPubMedGoogle Scholar
  14. 14.
    Tsivgoulis G, Sharma VK, Lao AY, et al.: Validation of transcranial Doppler with computed tomography angiography in acute cerebral ischemia. Stroke 2007, 38:1245–1249.CrossRefPubMedGoogle Scholar
  15. 15.
    Alexandrov AV, Grotta JC: Arterial re-occlusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology 2002, 59:862–867.CrossRefPubMedGoogle Scholar
  16. 16.
    • Alexandrov AV, Sharma VK, Lao AY, et al.: Reversed Robin Hood syndrome in acute ischemic stroke patients. Stroke 2007, 38:3045–3048. This descriptive study suggested the possibility to detect and quantify the cerebral steal phenomenon in real time by TCD with important therapeutic implications: confirming the steal as the cause of neurologic worsening, rRHS may identify a target group for testing blood pressure augmentation and noninvasive ventilatory correction in stroke patients.CrossRefPubMedGoogle Scholar
  17. 17.
    Francis CW: Ultrasound-enhanced thrombolysis. Echocardiography 2001, 18:239–246.CrossRefPubMedGoogle Scholar
  18. 18.
    Kimura M, Iijima S. Kobayashi K, Furuhata H: Evaluation of the thrombolytic effect of tissue-type plasminogen activator with ultrasound irradiation: in vitro experiment involving assay of the fibrin degradation products from the clot. Biol Pharm Bull 1994, 17:126–130.Google Scholar
  19. 19.
    Trubestein R, Bernard HR, Etzel F, et al.: Thrombolysis by ultrasound. Clin Sci Mol Med 1976, 51:697–698.Google Scholar
  20. 20.
    Akiyama M, Ishibashi T, Yamada T, Furuhata H: Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro. Neurosurgery 1998, 43:828–832.CrossRefPubMedGoogle Scholar
  21. 21.
    Suchkova V, Siddiqi FN, Carstensen EL, et al.: Enhancement of fibrinolysis with 40-kHz ultrasound. Circulation 1998, 98:1030–1035.PubMedGoogle Scholar
  22. 22.
    Behrens S, Daffertshoffer M, Spiegel D, Hennerici M: Low-frequency, low-intensity ultrasound accelerates thrombolysis through the skull. Ultrasound Med Biol 1999, 25:269–273.CrossRefPubMedGoogle Scholar
  23. 23.
    Polak JF: Ultrasound energy and the dissolution of thrombus. N Engl J Med 2004, 351:2154–2155.CrossRefPubMedGoogle Scholar
  24. 24.
    Francis CW, Blinc A, Lee S, Cox C: Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots. Ultrasound Med Biol 1995, 21:419–424.CrossRefPubMedGoogle Scholar
  25. 25.
    Sakharov DV, Barrertt-Bergshoeff M, Hekkenberg RT, Rijken DC: Fibrin-specificity of a plasminogen activator affects the efficiency of fibrinolysis and responsiveness to ultrasound: comparison of nine plasminogen activators in vitro. Thromb Haemost 1999, 81:605–612.PubMedGoogle Scholar
  26. 26.
    Cintas P, Le Traon AP, Larrue V: High rate of recanalization of middle cerebral artery occlusion during 2-MHz transcranial color-coded Doppler continuous monitoring without thrombolytic drug. Stroke 2002, 33:626–628.CrossRefPubMedGoogle Scholar
  27. 27.
    Blinc A, Francis CW, Trudnowski JL, Carstensen EL: Characterization of ultrasound-potentiated fibrinolysis in vitro. Blood 1993, 81:2636–2643.PubMedGoogle Scholar
  28. 28.
    Eggers J, Koch B, Meyer K, et al.: Effect of ultrasound on thrombolysis of middle cerebral artery occlusion. Ann Neurol 2003, 53:797–800.CrossRefPubMedGoogle Scholar
  29. 29.
    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, 36:1441–1446.CrossRefPubMedGoogle Scholar
  30. 30.
    Daffertshofer M, Huang Z, Fatar M, et al.: Efficacy of sonothrombolysis in a rat model of embolic ischemic stroke. Neurosci Lett 2004, 361:115–119.CrossRefPubMedGoogle Scholar
  31. 31.
    Reinhard M, Hetzel A, Kruger S, et al.: Blood-brain barrier disruption by low-frequency ultrasound. Stroke 2006, 37:1546–1548.CrossRefPubMedGoogle Scholar
  32. 32.
    • Tsivgoulis G, Molina CA, Eggers J, et al.: Safety and efficacy of ultrasound-enhanced thrombolysis: a meta-analysis of randomized and non-randomized studies. Stroke 2008, 39:593–594. This meta-analysis of six randomized and three nonrandomized clinical studies of sonothrombolysis showed that any diagnostic ultrasound monitoring can at least double the chance of early complete arterial recanalization at no increase in the risk of symptomatic intracerebral hemorrhage.Google Scholar
  33. 33.
    Demchuk AM, Burgin WS, Christou I, et al.: Thrombolysis in brain ischemia (TIBI) transcranial Doppler flow grades predict clinical severity, early recovery and mortality in intravenous TPA treated patients. Stroke 2001, 32:89–93.PubMedGoogle Scholar
  34. 34.
    Alexandrov A, Schafer M: Operator-independent device for sonothrombolysis. Cerebrovasc Dis 2008, 26(Suppl 1):6.Google Scholar
  35. 35.
    Alonso A, Della Martina A, Stroick M, et al.: Molecular imaging of human thrombus with novel abciximab immunobubbles and ultrasound. Stroke 2007, 38:1508–1514.CrossRefPubMedGoogle Scholar
  36. 36.
    Vignon F, Arnal B, Shi W, et al.: Mapping the acoustical transparency of the skull. Cerebrovasc Dis 2008, 26(Suppl 1):13.Google Scholar
  37. 37.
    Tanter M, Couture O, Fink M: Time reversal of acoustic waves in the nonlinear regime: basic physics and application to ultrasound contrast imaging. J Acoust Soc Am 2008, 123:3830.CrossRefGoogle Scholar
  38. 38.
    Hoelscher T, Tu E, Ackley D: Development of an acoustically active TPA drug carrier: experiences with a first prototype. Cerebrovasc Dis 2008, 26(Suppl1):15–16.Google Scholar
  39. 39.
    Harnof S, Schiff G, Hananel A, et al.: Trans-skull clot lysis—proof of concept. Cerebrovas Dis 2008, 26(Suppl 1):12.Google Scholar
  40. 40.
    Tomsick T, Broderick J, Carrozella J, et al. Revascularization results in the Interventional Management of Stroke II trial. AJNR Am J Neuroradiol 2008, 29:582–587.CrossRefPubMedGoogle Scholar
  41. 41.
    Mahon BR, Nesbit GM, Barnwell SL, et al.: North American clinical experience with the EKOS MicroLysUS infusion catheter for the treatment of embolic stroke. AJNR Am J Neuroradiol 2003, 24:534–538.PubMedGoogle Scholar
  42. 42.
    Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the interventional management of stroke study. The IMS Study Investigators [no authors listed]. Stroke 2004, 35:904–912.Google Scholar
  43. 43.
    The interventional management of stroke (IMS) II study. IMS II Trial Investigators [no authors listed]. Stroke 2007, 38:2127–2135.CrossRefGoogle Scholar
  44. 44.
    Gramiak R, Shah PM: Echocardiography of the aortic root. Invest Radiol 1968, 3:356–366.CrossRefPubMedGoogle Scholar
  45. 45.
    Ferrara K, Pollard R, Borden M: Ultrasound microbubble contrast agents: fundamentals and application to gene and drug delivery. Annu Rev Biomed Eng 2007, 9:415–447.CrossRefPubMedGoogle Scholar
  46. 46.
    Meairs S: Contrast-enhanced ultrasound perfusion imaging in acute stroke patients. Eur Neurol 2008, 59:17–26.CrossRefPubMedGoogle Scholar
  47. 47.
    Bleeker H, Shung K, Barnhart J: On the application of ultrasonic contrast agents for blood flowmetry and assessment of cardiac perfusion. J Ultrasound Med 1990, 9:461–471.PubMedGoogle Scholar
  48. 48.
    Kaufmann BA, Lindner JR: Molecular imaging with targeted contrast ultrasound. Curr Opin Biotechnol 2007, 18:11–16.CrossRefPubMedGoogle Scholar
  49. 49.
    Schneider M: Molecular imaging and ultrasound-assisted drug delivery. J Endourol 2008;22:795–801.CrossRefPubMedGoogle Scholar
  50. 50.
    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, 37:425–429.CrossRefPubMedGoogle Scholar
  51. 51.
    Culp WC, Porter TR, Lowery J, et al.: Intracranial clot lysis with intravenous microbubbles and transcranial ultrasound in swine. Stroke 2004, 35:2407–2411.CrossRefPubMedGoogle Scholar
  52. 52.
    Unger EC, Porter T, Culp W, et al.: Therapeutic applications of lipid-coated microbubbles. Adv Drug Deliv Rev 2004, 56:1291–1314.CrossRefPubMedGoogle Scholar
  53. 53.
    Dayton PA, Morgan KE, Klibanov AL, et al.: Optical and acoustical observations of the effects of ultrasound on contrast agents. IEEE Trans Ultrason Ferroelectr Freq Control 1999, 46:220–232.CrossRefPubMedGoogle Scholar
  54. 54.
    Sharma VK, Tsivgoulis G, Lao AY, et al.: Quantification of microspheres (µS) appearance in brain vessels: implications for residual flow velocity measurements, dose calculations and potential drug delivery. Stroke 2008, 39:1476–1481.CrossRefPubMedGoogle Scholar
  55. 55.
    Xie F, Tsutsui JM, Lof J, et al.: Effectiveness of lipid microbubbles and ultrasound in declotting thrombosis. Ultrasound Med Biol 2005, 31:979–985.CrossRefPubMedGoogle Scholar
  56. 56.
    Fatar M, Stroick M, Griebe M, et al.: Effect of combined ultrasound and microbubbles treatment in an experimental model of cerebral ischemia. Ultrasound Med Biol 2008, 34:1414–1420.CrossRefPubMedGoogle Scholar
  57. 57.
    Alexandrov AV, Strong R, Wojner-Alexandrov AW, Aronowski J: Low-power 2 MHz transcranial ultrasound reduces ischemic brain damage in rat. Stroke 2006, 37:680.CrossRefGoogle Scholar
  58. 58.
    Alexandrov AV, Mikulik R, Ribo M, et al.: A pilot randomized clinical safety study of thrombolysis augmentation with ultrasound-activated perflutren lipid microspheres. Stroke 2008, 39:1464–1469.CrossRefPubMedGoogle Scholar
  59. 59.
    Perren F, Loulidi J, Poglia D, et al.: Microbubble potentiated transcranial duplex ultrasound enhances IV thrombolysis in acute stroke. Cerebrovasc Dis 2007, 25:219–223.Google Scholar
  60. 60.
    Larrue V, Viguier A, Arnaud C, et al.: Transcranial ultrasound combined with intravenous microbubbles and tissue plasminogen activator for acute ischemic stroke: a randomized controlled study. Stroke 2007, 38:472.Google Scholar
  61. 61.
    Ribo M, Molina CA, Alvarez B, et al.: Intra-arterial administration of microbubbles and continuous 2-MHz ultrasound insonation to enhance intra-arterial thrombolysis. J Neuroimaging 2009 Feb 13 (Epub ahead of print).Google Scholar
  62. 62.
    •• Molina CA, Barreto AD, Tsivgoulis G, et al.: Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial. Ann Neurol 2009, 66:28–38. This randomized, multicenter, phase 2 trial of microsphere dose escalation with systemic thrombolysis showed that perflutren-lipid microspheres can be safely combined with systemic rt-PA and ultrasound at a dose of 1.4 mL, reporting a trend toward higher early recanalization and clinical recovery rates compared with standard intravenous tissue plasminogen activator therapy.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Comprehensive Stroke CenterUniversity of Alabama HospitalBirminghamUSA

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