Improved treatment of acute ischemic stroke with ultrasound and microbubbles in combination with thrombolytic drugs shows great promise, but the optimal techniques, indications, and contraindications have not yet been well defined. Moreover, details such as microbubble dosage, delivery, required thrombolytic drug dosage, and optimal ultrasound characteristics all remain uncertain. Recent results suggest that ultrasound and microbubbles may be effective in clot lysis of ischemic stroke without additional thrombolytic drugs. Moreover, targeting thrombus with specific immunobubbles may improve the efficacy of sonothrombolysis. Safety remains a major concern in the further development of ultrasound-enhanced thrombolysis and extensive animal work is required to define the most promising methods to translate into human application.

Keywords:
Ultrasound, Stroke, Thrombolysis, Microbubbles
1.
Sobbe A, Stumpff U, Trubestein G, Figge H, Kozuschek W: Die Ultraschall-Auflösung von Thromben. Klin Wochenschr 1974;52:1117–1121.
2.
Harpaz D, Chen X, Francis CW, Meltzer RS: Ultrasound accelerates urokinase-induced thrombolysis and reperfusion. Am Heart J 1994;127:1211–1219.
3.
Rosenschein U, Gaul G, Erbel R, Amann F, Velasguez D, Stoerger H, Simon R, Gomez G, Troster J, Bartorelli A, Pieper M, Kyriakides Z, Laniado S, Miller HI, Cribier A, Fajadet J: Percutaneous transluminal therapy of occluded saphenous vein grafts: can the challenge be met with ultrasound thrombolysis? Circulation 1999;99:26–29.
4.
Luo H, Birnbaum Y, Fishbein MC, Peterson TM, Nagai T, Nishioka T, Siegel RJ: Enhancement of thrombolysis in vivo without skin and soft tissue damage by transcutaneous ultrasound. Thromb Res 1998;89:171–177.
5.
Riggs PN, Francis CW, Bartos SR, Penney DP: Ultrasound enhancement of rabbit femoral artery thrombolysis. Cardiovasc Surg 1997;5:201–207.
6.
Hamm CW, Steffen W, Terres W, de Scheerder I, Reimers J, Cumberland D, Siegel RJ, Meinertz T: Intravascular therapeutic ultrasound thrombolysis in acute myocardial infarctions. Am J Cardiol 1997;80:200–204.
7.
Rosenschein U, Roth A, Rassin T, Basan S, Laniado S, Miller HI: Analysis of coronary ultrasound thrombolysis endpoints in acute myocardial infarction (ACUTE trial). Results of the feasibility phase. Circulation 1997;95:1411–1416.
8.
Yock PG, Fitzgerald PJ: Catheter-based ultrasound thrombolysis. Circulation 1997;95:1360–1362.
9.
Daffertshofer M, Hennerici M: Ultrasound in the treatment of ischaemic stroke. Lancet Neurol 2003;2:283–290.
10.
Luo H, Nishioka T, Fishbein MC, Cercek B, Forrester JS, Kim CJ, Berglund H, Siegel RJ: Transcutaneous ultrasound augments lysis of arterial thrombi in vivo. Circulation 1996;94:775–778.
11.
Siegel RJ, Atar S, Fishbein MC, Brasch AV, Peterson TM, Nagai T, Pal D, Nishioka T, Chae JS, Birnbaum Y, Zanelli C, Luo H: Noninvasive, transthoracic, low-frequency ultrasound augments thrombolysis in a canine model of acute myocardial infarction. Circulation 2000;101:2026–2029.
12.
Maxwell L, Collecutt T, Gledhill M, Sharma S, Edgar S, Gavin JB: The augmentation of leucocyte adhesion to endothelium by therapeutic ultrasound. Ultrasound Med Biol 1994;20:383–390.
13.
Daffertshofer M, Fatar M: Therapeutic ultrasound in ischemic stroke treatment: experimental evidence. Eur J Ultrasound 2002;16:121–130.
14.
Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, Montaner J, Saqqur M, Demchuk AM, Moye LA, Hill MD, Wojner AW: Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004;351:2170–2178.
15.
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.
16.
Pfaffenberger S, Devcic-Kuhar B, Kollmann C, Kastl SP, Kaun C, Speidl WS, Weiss TW, Demyanets S, Ullrich R, Sochor H, Wober C, Zeitlhofer J, Huber K, Groschl M, Benes E, Maurer G, Wojta J, Gottsauner-Wolf M: Can a commercial diagnostic ultrasound device accelerate thrombolysis? An in vitro skull model. Stroke 2005;36:124–128.
17.
Meairs S, Dempfle CE: In vitro models for assessing transcranial ultrasound-enhanced thrombolysis. Stroke 2005;36:929–930.
18.
Baron C, Aubry J-F, Tanter M, Meairs S, Fink M: Simulation of intracranial acoustic fields in clinical trials of sonothrombolysis. Ultrasound Med Biol, in press.
19.
Eggers J, Seidel G, Koch B, Konig IR: Sonothrombolysis in acute ischemic stroke for patients ineligible for rt-PA. Neurology 2005;64:1052–1054.
20.
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 ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: results of a phase II clinical trial. Stroke 2005;36:1441–1446.
21.
Daffertshofer M, Huang Z, Fatar M, Popolo M, Schroeck H, Kuschinsky W, Moskowitz MA, Hennerici MG: Efficacy of sonothrombolysis in a rat model of embolic ischemic stroke. Neurosci Lett 2004;361:115–119.
22.
Reinhard M, Hetzel A, Kruger S, Kretzer S, Talazko J, Ziyeh S, Weber J, Els T: Blood-brain barrier disruption by low-frequency ultrasound. Stroke 2006;37:1546–1548.
23.
Wang Z, Moehring MA, Voie AH, Furuhata H: In vitro evaluation of dual mode ultrasonic thrombolysis method for transcranial application with an occlusive thrombosis model. Ultrasound Med Biol 2008;34:96–102.
24.
Everbach EC, Francis CW: Cavitational mechanisms in ultrasound-accelerated thrombolysis at 1 MHz. Ultrasound Med Biol 2000;26:1153–1160.
25.
Datta S, Coussios CC, Ammi AY, Mast TD, De Court, Holland CK: Ultrasound-enhanced thrombolysis using Definity as a cavitation nucleation agent. Ultrasound Med Biol 2008;34:1421–1433.
26.
Miller MW, Miller DL, Brayman AA: A review of in vitro bioeffects of inertial ultrasonic cavitation from a mechanistic perspective. Ultrasound Med Biol 1996;22:1131–1154.
27.
Datta S, Coussios CC, McAdory LE, Tan J, Porter T, De Court, Holland CK: Correlation of cavitation with ultrasound enhancement of thrombolysis. Ultrasound Med Biol 2006;32:1257–1267.
28.
Tachibana K, Tachibana S: Albumin microbubble echo-contrast material as an enhancer for ultrasound accelerated thrombolysis. Circulation 1995;92:1148–1150.
29.
Porter TR, LeVeen RF, Fox R, Kricsfeld A, Xie F: Thrombolytic enhancement with perfluorocarbon-exposed sonicated dextrose albumin microbubbles. Am Heart J 1996;132:964–968.
30.
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.
31.
Birnbaum Y, Luo H, Nagai T, Fishbein MC, Peterson TM, Li S, Kricsfeld D, Porter TR, Siegel RJ: Noninvasive in vivo clot dissolution without a thrombolytic drug: recanalization of thrombosed iliofemoral arteries by transcutaneous ultrasound combined with intravenous infusion of microbubbles. Circulation 1998;97:130–134.
32.
Tsivgoulis G, Alexandrov AV: Ultrasound-enhanced thrombolysis in acute ischemic stroke: potential, failures, and safety. Neurotherapeutics 2007;4:420–427.
33.
Stieger SM, Caskey CF, Adamson RH, Qin S, Curry FR, Wisner ER, Ferrara KW: Enhancement of vascular permeability with low-frequency contrast-enhanced ultrasound in the chorioallantoic membrane model. Radiology 2007;243:112–121.
34.
Molina CA, Ribo M, Rubiera M, Montaner J, Santamarina E, Delgado-Mederos R, Arenillas JF, Huertas R, Purroy F, Delgado P, Alvarez-Sabin J: 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.
35.
Alexandrov AV, Mikulik R, Ribo M, Sharma VK, Lao AY, Tsivgoulis G, Sugg RM, Barreto A, Sierzenski P, Malkoff MD, Grotta JC: A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke. Stroke 2008;39:1464–1469.
36.
Perren F, Loulidi J, Poglia D, Landis T, Sztajzel R: Microbubble potentiated transcranial duplex ultrasound enhances IV thrombolysis in acute stroke. J Thromb Thrombolysis 2008;25:219–223.
37.
Pagola J, Ribo M, Alvarez-Sabin J, Lange M, Rubiera M, Molina CA: Timing of recanalization after microbubble-enhanced intravenous thrombolysis in basilar artery occlusion. Stroke 2007;38:2931–2934.
38.
Porter TR, Kricsfeld D, Lof J, Everbach EC, Xie F: Effectiveness of transcranial and transthoracic ultrasound and microbubbles in dissolving intravascular thrombi. J Ultrasound Med 2001;20:1313–1325.
39.
Culp WC, Porter TR, Xie F, Goertzen TC, McCowan TC, Vonk BN, Baxter BT: Microbubble potentiated ultrasound as a method of declotting thrombosed dialysis grafts: experimental study in dogs. Cardiovasc Intervent Radiol 2001;24:407–412.
40.
Culp WC, Porter TR, McCowan TC, Roberson PK, James CA, Matchett WJ, Moursi M: Microbubble-augmented ultrasound declotting of thrombosed arteriovenous dialysis grafts in dogs. J Vasc Interv Radiol 2003;14:343–347.
41.
Culp WC, Erdem E, Roberson PK, Husain MM: Microbubble potentiated ultrasound as a method of stroke therapy in a pig model: preliminary findings. J Vasc Interv Radiol 2003;14:1433–1436.
42.
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.
43.
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.
44.
Korninger C, Collen D: Studies on the specific fibrinolytic effect of human extrinsic (tissue-type) plasminogen activator in human blood and in various animal species in vitro. Thromb Haemost 1981;46:561–565.
45.
Donnan GA: The 2007 Feinberg lecture: a new road map for neuroprotection. Stroke 2008;39:242.
46.
Alonso A, Della Martina A, Stroick M, Fatar M, Griebe M, Pochon S, Schneider M, Hennerici M, Allemann E, Meairs S: Molecular imaging of human thrombus with novel abciximab immunobubbles and ultrasound. Stroke 2007;38:1508–1514.
47.
Alonso A, Dempfle CE, Della Martina A, Stroick M, Fatar M, Zohsel K, Allemann E, Hennerici M, Meairs S: In vivo clot lysis of human thrombous with intravenous abciximab immunobubbles and ultrasound. Thromb Res, in press.
48.
Culp WC, McLafferty RP, Uflacker CH, Danielson T, Matsunaga T, Unger EC: Microbubble-augmented sonothrombolysis of occluded dialysis grants: initial human experience. J Vasc Interv Radiol 2005;16:S36.
49.
Nguyen PD, O’Rear EA, Johnson AE, Lu R, Fung BM: Thrombolysis using liposomal-encapsulated streptokinase: an in vitro study. Proc Soc Exp Biol Med 1989;192:261–269.
50.
Heeremans JL, Prevost R, Bekkers ME, Los P, Emeis JJ, Kluft C, Crommelin DJ: Thrombolytic treatment with tissue-type plasminogen activator (t-PA) containing liposomes in rabbits: a comparison with free t-PA. Thromb Haemost 1995;73:488–494.
51.
Perkins WR, Vaughan DE, Plavin SR, Daley WL, Rauch J, Lee L, Janoff AS: Streptokinase entrapment in interdigitation-fusion liposomes improves thrombolysis in an experimental rabbit model. Thromb Haemost 1997;77:1174–1178.
52.
Leach JK, O’Rear EA, Patterson E, Miao Y, Johnson AE: Accelerated thrombolysis in a rabbit model of carotid artery thrombosis with liposome-encapsulated and microencapsulated streptokinase. Thromb Haemost 2003;90:64–70.
53.
Wang SS, Chou NK, Chung TW: The t-PA-encapsulated PLGA nanoparticles shelled with CS or CS-GRGD alter both permeation through and dissolving patterns of blood clots compared with t-PA solution: an in vitro thrombolysis study. J Biomed Mater Res A 2008; Epub ahead of print.
54.
Xi X, Yang F, Chen D, Luo Y, Zhang D, Gu N, Wu J: A targeting drug-delivery model via interactions among cells and liposomes under ultrasonic excitation. Phys Med Biol 2008;53:3251–3265.
55.
Vandenbroucke RE, Lentacker I, Demeester J, De Smedt SC, Sanders NN: Ultrasound assisted siRNA delivery using PEG-siPlex loaded microbubbles. J Control Release 2008;126:265–273.
56.
Lentacker I, Vandenbroucke RE, Lucas B, Demeester J, De Smedt SC, Sanders NN: New strategies for nucleic acid delivery to conquer cellular and nuclear membranes. J Control Release 2008, Epub ahead of print.
57.
Marsh JN, Senpan A, Hu G, Scott MJ, Gaffney PJ, Wickline SA, Lanza GM: Fibrin- targeted perfluorocarbon nanoparticles for targeted thrombolysis. Nanomed 2007;2:533–543.
58.
Fatar M, Stroick M, Griebe M, Alonso A, Kreisel S, Kern R, Hennerici M, Meairs S: Effect of combined ultrasound and microbubbles treatment in an experimental model of cerebral ischemia. Ultrasound Med Biol 2008;34:1414–1420.
59.
Dirnagl U, Iadecola C, Moskowitz MA: Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999;22:391–397.
60.
Porter TR, Xie F: Ultrasound, microbubbles, and thrombolysis. Prog Cardiovasc Dis 2001;44:101–110.
61.
Altland OD, Dalecki D, Suchkova VN, Francis CW: Low-intensity ultrasound increases endothelial cell nitric oxide synthase activity and nitric oxide synthesis. J Thromb Haemost 2004;2:637–643.
62.
Flores R, Lowery J, Brown AT, Atherton ME, Hennings L, Culp WC: Severity of stroke in a rabbit model: effects of ultrasound augmentation of thrombolysis. J Vasc Interv Radiol 2008;19:S19–S19.
63.
Skyba DM, Price RJ, Linka AZ, Skalak TC, Kaul S: Direct in vivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue. Circulation 1998;98:290–293.
64.
Hynynen K, McDannold N, Martin H, Jolesz FA, Vykhodtseva N: The threshold for brain damage in rabbits induced by bursts of ultrasound in the presence of an ultrasound contrast agent (Optison). Ultrasound Med Biol 2003;29:473–481.
65.
Rosenberg GA, Mun-Bryce S, Wesley M, Kornfeld M: Collagenase-induced intracerebral hemorrhage in rats. Stroke 1990;21:801–807.
66.
Culp WC, Brown AT, Hennings L, Lowery J, Culp BC, Erdem E, Roberson PK, Matsunaga T: Safety of microbubbles and transcranial ultrasound in rabbits. AIP Conf Proc 2007;911:542–546.
67.
Larrue V, Viguier A, Armaud C, Cognard C, Petit R, Rigal M, Cristini C: Transcranial ultrasound combined with intravenous microbubbles and tissue plasminogen activator for acute ischemic stroke: a randomized controlled study. Stroke 2007;38:472.
68.
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 ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: results of a phase II clinical trial. Stroke 2005;36:1441–1446.
69.
Eggers J, Konig IR, Koch B, Handler G, Seidel G: Sonothrombolysis with transcranial color-coded sonography and recombinant tissue-type plasminogen activator in acute middle cerebral artery main stem occlusion: results from a randomized study. Stroke 2008;39:1470–1475.
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