In the last few years, several studies have improved our knowledge and understanding of the dynamic nature of the recanalization process during stroke thrombolysis. Transcranial Doppler ultrasound provides a unique opportunity to assess several aspects of clot dissolution by means of continuous monitoring of recanalization during and after administration of tissue plasminogen activator. This approach allows us to evaluate at the patient’s bedside and in real time the beginning, timing, speed and degree of artery reopening, as well as to document reocclusion after successful recanalization. Moreover, the simultaneous clinical assessment during transcranial Doppler monitoring allows correlation of the hemodynamic changes with the clinical course and outcome. Experimental studies have shown that ultrasound (US)-accelerated thrombolysis may be further enhanced by administration of microbubbles (MBs). Low-frequency US with high power has been demonstrated to produce cavitation and fluid motion in the thrombus. The MBs, by acting as cavitation nuclei, lower the amount of energy needed for cavitation. Application of high-acoustic-pressure US has been shown to induce nonlinear oscillations of MBs, leading to a continuous absorption of energy until the bubbles explode, releasing the absorbed energy. A multicenter randomized phase II trial of MB-enhanced thrombolysis in acute stroke is under way.

Molina CA, Alexandrov AV, Demchuk AM, Saqqur M, Uchino K, Alvarez-Sabin J, CLOTBUST Investigators: Improving the predictive accuracy of recanalization on stroke outcome in patients treated with tissue plasminogen activator. Stroke 2004;35:151–156.
Demchuk AM, Burgin WS, Christou I, Felberg RA, Barber PA, Hill MD, Alexandrov AV: Thrombolysis in Brain Ischemia (TIBI) transcranial Doppler flow grades predict clinical severity, early recovery, and mortality in patients treated with intravenous tissue plasminogen activator. Stroke 2001;32:89–93.
Burgin WS, Malkoff M, Demchuk AM, Felberg RA, Christou I, Grota JC, Alexandrov AV: Transcranial Doppler ultrasound criteria for recanalization after thrombolysis for middle cerebral artery stroke. Stroke 2000;31:1128–1132.
Alexandrov AV, Burgin SW, Demchuk AM, El-Mitwalli A, Grotta JC: Speed of intracranial clot lysis with intravenous tissue plasminogen activator therapy: sonographic classification and short-term improvement. Circulation 2001;103:2897–2902.
Christou I, Alexandrov AV, Burgin WS, Wojner AW, Felberg RA, Malkoff M, Grotta JC: Timing of recanalization after tissue plasminogen activator therapy determined by transcranial Doppler correlates with clinical recovery from ischemic stroke. Stroke 2000;31:1812–1816.
Blinc A, Planinsic G, Keber D, Jarh O, Lahajnar G, Zidansek A, Demsar F: Dependence of blood clot lysis on the mode of transport of urokinase into the clot: a magnetic resonance imaging study in vitro. Thromb Haemost 1991;65:549–552.
Blinc A, Keber D, Lahajnar G, Stegnar M, Zidansek A, Demsar F: Lysing patterns of retracted blood clots with diffusion or bulk flow transport of plasma with urokinase into clots: a magnetic resonance imaging study in vitro. Thromb Haemost 1992;68:667–671.
Blinc A, Francis CW: Transport processes in fibrinolysis and fibrinolytic therapy. Thromb Haemost 1996;76:481–491.
Linfante I, Llinas RH, Selim M, Chaves C, Kumar S, Parker RA, Caplan LR, Schlaug G: Clinical and vascular outcome in internal carotid artery versus middle cerebral artery occlusions after intravenous tissue plasminogen activator. Stroke 2002;33:2066–2071.
Molina CA, Montaner J, Arenillas JF, Ribó M, Rubiera M, Alvarez-Sabín J: Differential pattern of tPA-induced proximal MCA recanalization among stroke subtypes. Stroke 2004;35:486–490.
Ribo M, Alvarez-Sabin J, Montaner J, Romero F, Delgado P, Rubiera M, Delgado-Mederos R, Molina CA: Temporal profil of recanalization after intravenous tissue plasminogen activator. Selecting patients for rescue reperfusion techniques. Stroke 2006;37:1000–1004.
Delgado-Mederos R, Ribó M, Alvarez-Sabín J, Rovira A, Munuera J, Rubiera M, Santamarina E, Maisterra O, Delgado P, Montaner J, Molina CA: Speed of tPA-induced clot lysis predicts DWI lesion evolution in acute stroke. Stroke 2007;38:955–960.
Higashida RT, Furlan AJ: Trial design and reporting standards for intra-arterial thrombolysis for acute ischemic stroke. Stroke 2003;34:e109–e137.
Alvarez-Sabin J, Molina CA, Ribo M, Arenillas JF, Montaner J, Huertas R, Santamarina E, Rubiera M: Impact of admission hyperglycemia on stroke outcome after thrombolysis: risk stratification in relation to time to reperfusion. Stroke 2004;35:2493–2498.
Burgin WS, Alexandrov AV: Deterioration following improvement with tPA therapy: carotid thrombosis and reocclusion. Neurology 2001;56:568–570.
Grotta JC, Welch KM, Fagan SC, Lu M, Frankel MR, Brott T, Levine SR, Lyden PD: Clinical deterioration following improvement in the NINDS rt-PA Stroke Trial. Stroke 2001;32:661–668.
Alexandrov AV, Grotta JC: Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology 2002;59:862–867.
Rubiera M, Alvarez-Sabin J, Ribo M, Montaner J, Santamarina E, Arenillas JF, Huertas R, Delgado P, Purroy F, Molina CA: Predictors of early arterial reocclusion after tissue plasminogen activator-induced recanalization in acute ischemic stroke. Stroke 2005;36:1452–1456.
El-Mitwalli A, Saad M, Christou I, Malkoff M, Alexandrov AV: Clinical and sonographic pattern of tandem internal carotid artery/middle cerebral artery occlusion in tissue plasminogen activator-treated patients. Stroke 2002;33:99–102.
Christou I, Felberg RA, Demchuk AM, Burgin WS, Malkoff M, Grotta JC, Alexandrov AV: Intravenous tissue plasminogen activator and flow improvement in acute ischemic stroke patients with internal carotid artery occlusion. J Neuroimaging 2002;12:119–123.
Kim YS, Garami Z, Mikulik R, Molina CA, Alexandrov AV, for the CLOTBUST Collaborators: Early recanalization rates and clinical outcomes in patients with tandem internal carotid artery/middle cerebral artery occlusion and isolated middle cerebral artery occlusion. Stroke 2005;36:869–871.
Rubiera M, Ribo M, Delgado-Mederos R, Santamarina E, Delgado P, Montaner J, Alvarez-Sabin J, Molina CA: Tandem internal carotid artery/middle cerebral artery occlusion: an independent predictor of poor outcome after systemic thrombolysis. Stroke 2006;37:2301–2305.
Daffertshofer M, Hennerici M: Ultrasound in the treatment of ischemic stroke. Lancet Neurol 2003;2:283–290.
Eggers J, Koch B, Meyer K, Konig I, Seidel G: Effect of ultrasound on thrombolysis of middle cerebral artery occlusion. Ann Neurol 2003;53:797–800.
Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, Montaner J, Saqqur M, Demchuk AM, Moyé LA, Hill MD, Wojner AW, for the CLOTBUST Investigators: Ultrasound-enhanced thrombolysis for acute ischemic stroke. N Engl J Med 2004;351:2170–2178.
Daffertshofer M, Gass A, Ringleb P, Sitzer M, Sliwka U, Els T, Sedlaczek O, Koroshetz WJ, Hennerici MG: Transcranial low-frequency ultrasound-mediated thrombolysis in brain: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator. Stroke 2005;36:1441–1446.
Dijkmans PA, Juffermans LJM, Musters RJP, van Wamel A, ten Cate FJ, van Gilst W, Vis-ser CA, de Jong N, Kamp O: Microbubbles and ultrasound: from diagnosis to therapy. Eur J Echocardiography 2004;5:245–256.
Tachibana K, Tachibana S: Albumin microbubble echo-contrast material as an enhancer for ultrasound accelerated thrombolysis. Circulation 1995;92:1148–1150.
Culp WC, Porter TR, Lowery J, Xie F, Robertson PK, Marky L: Intracranial clot lysis with intravenous microbubbles and trans-cranial ultrasound in swine. Stroke 2004;35:2407–2411.
Xie F, Tsutsui JM, Lof J, Unger EC, Johanning J, Culp WC, Matsunaga T, Porter TR: Effectiveness of lipid microbubbles and ultrasound in declotting thrombosis. Ultrasound Med Biol 2005;31:979–985.
Unger EC, Matsunaga TO, McCreery T, Schumann P, Sweitzer R, Quigley R: Therapeutic applications of microbubbles. Eur J Radiol 2002;42:160–168.
Cintas P, Nguyen F, Boneu B, Larrue V: Enhancement of enzymatic fibrinolysis with 2-MHz ultrasound and microbubbles. J Thromb Haemost 2004;2:1163–1166.
Molina CA, Ribo M, Rubiera M, Montaner J, Santamarina E, Delgado-Mederos R, Arenillas JF, Purroy F, Delgado P, Alvarez-Sabín J: Microbubbles administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tPA. Stroke 2006;37:425–429.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.