J Clin Neurol.  2007 Mar;3(1):1-8. 10.3988/jcn.2007.3.1.1.

Ultrasound Enhanced Thrombolysis: Applications in Acute Cerebral Ischemia

Affiliations
  • 1Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA. avalexandrov@att.net

Abstract

Intravenous tissue plasminogen activator (TPA) improves patient chances to recover from stroke by inducing mostly partial recanalization of large intracranial thrombi. TPA activity can be enhanced with ultrasound including 2 MHz transcranial Doppler (TCD). TCD identifies residual blood flow signals around thrombi, and, by delivering mechanical pressure waves, exposes more thrombus surface to circulating TPA. The international multi-center CLOTBUST trial showed that ultrasound enhances thrombolytic activity of a drug in humans thereby confirming multi-disciplinary experimental research conducted worldwide for the past 30 years. In the CLOTBUST trial, the dramatic clinical recovery from stroke coupled with complete recanalization within 2 hours after TPA bolus occurred in 25% of patients treated with TPA+TCD compared to 8% who received TPA alone (p=0.02). Complete clearance of a thrombus and dramatic recovery of brain functions during treatment are feasible goals for ultrasound-enhanced thrombolysis that can lead to sustained recovery. An early boost in brain perfusion seen in the Target CLOTBUST group resulted in a trend of 13% more patients achieving favorable outcome at 3 months, subject for a pivotal trial. However, different results were achieved in a small TRUMBI trial and another study that used Transcranial Color-Coded Duplex Sonography (TCCD). Adverse bio-effects of mid-KHz (300) ultrasound promote bleeding, including brain areas not-affected by ischemia while exposure to multi-frequency / multi-element duplex ultrasound resulted in a trend towards higher risk of hemorrhagic transformations. To further enhance the ability of TPA to break up thrombi, current ongoing clinical trials include phase II studies of a single beam 2 MHz TCD with perflutren-lipid microspheres. Enhancement of intra-arterial TPA delivery is being clinically tested with 1.7-2.1 MHz pulsed wave ultrasound (EKOS catheter). Multi-national dose escalation studies of microspheres and the development of an operator independent ultrasound device are underway.

Keyword

TPA; Transcranial Doppler; Stroke; Thrombolysis; Outcomes

MeSH Terms

Brain
Brain Ischemia*
Hemorrhage
Humans
Ischemia
Microspheres
Perfusion
Stroke
Thrombosis
Tissue Plasminogen Activator
Ultrasonography*
Tissue Plasminogen Activator

Figure

  • Figure 1 Reported controlled clinical trials of ultrasound-enhanced systemic thrombolysis for acute ischemic stroke.27,28,34 The Figure was reproduced with permission from Andrei Alexandrov (n; total number of patients enrolled in both control and target groups, Transducer; images of actual sources of ultrasound and their size relative to patient head, Tissues exposed; images of beam paths as ultrasound propagates through the brain, sICH; percent rates of symptomatic intracranial hemorrhages, CR; complete recanalization at the end of monitoring period, mRS 0-1; modified Rankin scores at 3 months follow-up (? -percent or actual number not reported in the original publication34).

  • Figure 2 PMD flow tracks showing individual and multiple perflutren-lipid microsphere permeation to areas with no detectable residual flow pre-treatment (white circles) and residual blood flow improvement following the administration of microspheres. The Figure was reproduced with permission from Andrei Alexandrov.


Reference

1. del Zoppo GJ, Poeck K, Pessin MS, Wolpert SM, Furlan AJ, Ferbert A, et al. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol. 1992. 32:78–86.
Article
2. Brott TG, Haley EC, Levy DE, Sheppard GL, Wong MC, Kongable GL, et al. Urgent therapy for stroke. Part I pilot study of tissue plasminogen activator administered within 90 minutes. Stroke. 1992. 23:632–640.
Article
3. Haley EC, Levy DE, Brott TG, Barsan W, Broderick J, Sheppard GL, et al. Urgent therapy for stroke. Part II pilot study of tissue plasminogen activator administered 91-180 minutes from onset. Stroke. 1992. 23:641–645.
Article
4. The National Institutes of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995. 333:1581–1587.
5. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke: the European Cooperative Acute Stroke Study. JAMA. 1995. 274:1017–1025.
Article
6. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II): Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998. 352:1245–1251.
Article
7. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, et al. ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004. 363:768–774.
8. Haley EC, Lewandowski C, Tilley BC. Myths regarding NINDS rt-PA Stroke Trial: setting the record straight. Ann Emerg Med. 1997. 30:676–682.
9. Demchuk AM, Felberg RA, Alexandrov AV. Clinical recovery from acute ischemic stroke after early reperfusion of the brain with intravenous thrombolysis. N Engl J Med. 1999. 340:894–895.
Article
10. Grotta JC, Alexandrov AV. TPA-associated reperfusion in acute ischemic stroke demonstrated by SPECT. Stroke. 1998. 29:429–432.
Article
11. Heiss W-D, Grond M, Thiel A, von Stockhausen H-M, Rudolf J, Ghaemi M, et al. Tissue at risk of infarction rescued by early reperfusion: a positron emission tomography study in systemic recombinant tissue plasminogen activator thrombolysis of acute stroke. J Cereb Blood Flow Metab. 1998. 18:1298–1307.
Article
12. Ringelstein EB, Biniek R, Weiller C, Ammeling B, Nolte PN, Thron A. Type and extent of hemispheric brain infarctions and clinical outcome in early and delayed middle cerebral artery recanalization. Neurology. 1992. 42:289–298.
Article
13. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007. 38:967–973.
Article
14. Trubestein R, Bernard HR, Etzel F, Sobbe A, Cremer A, Stumpff U. Thrombolysis by ultrasound. Clin Sci Mol Med. 1976. 51:697–698.
15. Tachibana K, Tachibana S. Ultrasonic vibration for boosting fibrinolytic effects of urokinase in vivo. Thromb Haemost. 1981. 46:211. [abstract].
16. Lauer CG, Burge R, Tang DB, Bass BG, Gomez ER, Alving BM. Effect of ultrasound on tissue-type plasminogen activator-induced thrombolysis. Circulation. 1992. 86:1257–1264.
Article
17. 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.
Article
18. Akiyama M, Ishibashi T, Yamada T, Furuhata H. Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro. Neurosurgery. 1998. 43:828–832.
Article
19. Suchkova V, Siddiqi FN, Carstensen EL, Dalecki D, Child S, Francis CW. Enhancement of fibrinolysis with 40 kHz ultrasound. Circulation. 1998. 98:1030–1035.
20. 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.
Article
21. Spengos K, Behrens S, Daffertshofer M, Dempfle CE, Hennerici M. Acceleration of thrombolysis with ultrasound through the cranium in a flow model. Ultrasound Med Biol. 2000. 26:889–895.
Article
22. Behrens S, Spengos K, Daffertshofer M, Schroeck H, Dempfle CE, Hennerici M. Transcranial ultrasound-improved thrombolysis: diagnostic vs. therapeutic ultrasound. Ultrasound Med Biol. 2001. 27:1683–1689.
Article
23. Blinc A, Francis CW, Trudnowski JL, Carstensen EL. Characterization of ultrasound-potentiated fibrinolysis in vitro. Blood. 1993. 81:2636–2643.
24. Alexandrov AV, Demchuk AM, Felberg RA, Christou I, Barber PA, Burgin WS, 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.
Article
25. Chernyshev OY, Garami Z, Calleja S, Song J, Campbell MS, Noser EA, et al. The yield and accuracy of urgent combined carotid-transcranial ultrasound testing in acute cerebral ischemia. Stroke. 2005. 36:32–37.
Article
26. Tsivgoulis G, Sharma VK, Lao AY, Malkoff MD, Alexandrov AV. Validation of Transcranial Doppler With Computed Tomography Angiography in Acute Cerebral Ischemia. Stroke. 2007. 38:[Epub ahead of print].
Article
27. Kim YS, Meyer JS, Garami Z, Molina CA, Pavlovic AM, Alexandrov AV. Flow diversion in transcranial Doppler ultrasound is associated with better improvement in patients with acute middle cerebral artery occlusion. Cerebrovasc Dis. 2006. 21:74–78.
Article
28. Kim YS, Garami Z, Mikulik R, Molina CA, Alexandrov AV. 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.
Article
29. Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med. 2004. 351:2170–2178.
Article
30. 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.
Article
31. Eggers J, Seidel G, Koch B, Konig IR. Sonothrombolysis in acute ischemic stroke for patients ineligible for rt-PA. Neurology. 2005. 64:1052–1054.
Article
32. 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.
Article
33. Skoloudik D, Bar M, Hradilek P, Vaclavik D, Skoda O. Safety and efficacy of thrombotripsy - acceleration of thrombolysis by TCCS. CD-ROM Proceedings of the NSRG 2003 Meeting. Germany.
34. The IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: The Interventional Management of Stroke Study. Stroke. 2004. 35:904–912.
35. Daffertshoffer M, Hennerici M. Ultrasound in the treatment of ischaemic stroke. Lancet Neurology. 2003. 2:283–290.
Article
36. Daffertshofer M, Gass A, Ringleb P, Sitzer M, Sliwka U, Els T, et al. Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator. Stroke. 2005. 36:1441–1446.
Article
37. Unger EC, Porter T, Culp W, Labell R, Matsunaga T, Zutshi R. Therapeutic applications of lipd-coated microbubbles. Adv Drug Deliv Rev. 2004. 56:1291–1314.
38. Culp WC, Porter TR, McCowan TC, Robertson PK, James CA, Matchett WJ, et al. Microbubble-augmented ultrasound declotting of thrombosed arteriovenous dialysis grafts in dogs. J Vasc Interv Radiol. 2003. 14:343–347.
Article
39. Culp WC, Porter TR, Lowery J, Xie F, Roberson PK, Marky L. Intracranial clot lysis with intravenous microbubbles and transcranial ultrasound in swine. Stroke. 2004. 35:2407–2411.
Article
40. Molina CA, Ribo M, Arenillas J, Rubiera M, Montaner J, Santamarina E, et al. Microbubbles administration accelerates clot lysis during continuous 2 MHz ultrasound monitoring in stroke patients treated with intravenous tPA. Stroke. 2005. 37:425–429.
Article
41. Alexandrov AV, Mikulik R, Ribo M, Sharma VK, Lao AY, Tsivgoulis G, et al. A Pilot Randomized Clinical Safety Study of Thrombolysis Augmentation with Ultrasound-Activated Perflutren Lipid Microspheres. Stroke. 2007. 38:LBP4.
42. Perren F, Loulidi J, Poglia D, Landis T, Sztajzel R. Microbubble potentiated transcranial duplex ultrasound enhances IV thrombolysis in acute stroke. Cerebrovasc Dis. 2007. 23:[epub ahead of print].
Article
43. Larrue V, Viguier A, Arnaud C, Cognard C, Petit R, Rigal M, et al. Trancranial Ultrasound Combined with Intravenous Microbubbles and Tissue Plasminogen Activator for Acute Ischemic Stroke: A Randomized Controlled Study. Stroke. 2007. 38:472.
44. The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke. 1997. 28:2109–2118.
45. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et al. For the second European-Australasian Acute Stroke Study investigators. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998. 352:1245–1251.
Article
Full Text Links
  • JCN
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr