Noninvasive In Vivo Clot Dissolution Without a Thrombolytic Drug

Birnbaum, Yochai; Luo, Hao; Nagai, Tomoo; Fishbein, Michael C.; Peterson, Thomas; Li, Shouping; Kricsfeld, David; Porter, Thomas R.; Siegel, Robert J.

doi:10.1161/01.cir.97.2.130

Cited by 156 publications

(27 citation statements)

References 6 publications

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“…In vitro and in vivo studies have confirmed this on several scales ranging from tiny to large clots [27, 30, 31,38,39,40,41,42,43]. In vitro examples show a predominately mechanical effect of the bubble encountering the clot and eroding it when activated by ultrasound [27, 30, 38].…”

Section: Clot Lysis With Ultrasound and Microbubbles Without Thrombolmentioning

confidence: 92%

“…Moreover, optimal microbubble dosage, delivery, required thrombolytic drug dosage, and optimal ultrasound characteristics all remain uncertain [28,29,30,31,32]. Microbubbles that have been used for thrombolysis include lipid, albumin, or galactose spheres ranging in size from 0.5 to about 5 µm surrounding a gas or air bubble.…”

Section: Microbubble-enhanced Thrombolysis With Tissue Plasminogen Acmentioning

confidence: 99%

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Microbubbles for Thrombolysis of Acute Ischemic Stroke

Meairs

Culp

2009

Cerebrovasc Dis

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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.

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Section: Clot Lysis With Ultrasound and Microbubbles Without Thrombolmentioning

confidence: 92%

Section: Microbubble-enhanced Thrombolysis With Tissue Plasminogen Acmentioning

confidence: 99%

Microbubbles for Thrombolysis of Acute Ischemic Stroke

Meairs

Culp

2009

Cerebrovasc Dis

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“…Thrombolytic efficacy is dependent on intensity and on duration of exposure [5]. Combination with an ultrasound contrast agent may further enhance the therapeutic effect [6,7,8,9]. There are reports on clinical studies that have shown an improvement of recanalisation rates and clinical outcome of stroke patients treated with rt-PA when diagnostic ultrasound was applied simultaneously [10,11,12].…”

Section: Introductionmentioning

confidence: 99%

“…This effect is used in catheter-based ultrasound thrombolysis [16]. Effective clot dissolution also occurs when ultrasound is applied over a distance, with a more pronounced effect in the presence of an echo contrast agent [4,5,6, 17]. This opens up the possibility of external, i.e., non-invasive application of therapeutic ultrasound without a thrombolytic drug in acute vessel occlusion.…”

Section: Introductionmentioning

confidence: 99%

Ultrasound-Induced Blood Clot Dissolution without a Thrombolytic Drug Is More Effective with Lower Frequencies

Nedelmann¹,

Brandt²,

Schneider³

et al. 2005

Cerebrovasc Dis

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Background and Purpose: Therapeutic ultrasound as stand-alone therapy or in combination with rt-PA has proven to be an effective measure for recanalisation of acute vessel occlusion in different in vitro and in vivo studies. Uncertainty still exists concerning the optimal frequency and intensity with regard to the thrombolytic efficacy of ultrasound. The purpose of this study was a direct comparison of different ultrasound frequencies, when otherwise using identical measurement settings and parameters. Methods: Ultrasound-induced dissolution of fresh human blood clots was studied in a flow system using low-frequency continuous wave ultrasound of 20, 40 and 60 kHz. After calibration of each ultrasound probe, blood clots were exposed to local time average intensities of either 0.12 or 0.2 W/cm². Exposure time of the clots to ultrasound was 10 min, the number of treated clots in each experimental group was 12. Results: As tested with 0.2 W/cm², we found the most pronounced thrombolytic effect with the 20-kHz probe (weight loss of blood clots: 52.4%) and the 40-kHz probe (49.4%), as compared to the 60-kHz probe (21.4%) and the control group (18.5%). The difference between the 20- and 60-kHz probes was statistically significant (p < 0.001). The treatment effect was clearly intensity dependent with a less pronounced, but still significant treatment effect at 0.12 W/cm² (24.5% at 20 kHz; p < 0.001 compared to 0.2 W/cm²; p = 0.045 compared to controls). Conclusions: These data show that therapeutic efficacy of ultrasound, in absence of a thrombolytic drug, is frequency and intensity dependent with best results at low frequencies. With continuous wave transmission, the benefit may be limited to the very low frequency range. The results are a basis for further evaluation in animal models.

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“…6 Multiple animal studies, including intracranial clot lysis in pigs, have confirmed this concept. [7][8][9][10][11] Cavitation has been theorized to cause mechanical stress on the surface of the thrombus leading to its destabilization. 12 Microbubble administration dramatically lowers the threshold for cavitation and increases the lytic activity of ultrasound.…”

mentioning

confidence: 99%

Intracranial Clot Lysis With Intravenous Microbubbles and Transcranial Ultrasound in Swine

Culp

Porter

Lowery

et al. 2004

Stroke

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100

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Background and Purpose-Destruction of microbubbles by transcutaneous low-frequency ultrasound (LFUS) has been used to lyse adjacent clot and recanalize acutely thrombosed vessels. LFUS with intraarterial microbubbles has been shown to lyse cerebral clot rapidly in pigs without thrombolytic drugs. We hypothesized that intravenous platelettargeted microbubbles with LFUS may be a rapid noninvasive technique to recanalize thrombosed intracerebral vessels. Methods-After angiography, 0.5 cc of autogenous thrombus was injected into 1 ascending pharyngeal artery of a pig, occluding it and the rete mirabile. These vessels connect the carotid to the internal carotid and are the main cerebral blood supply. Saline control or intravenous decafluorobutane-sonicated dextrose albumin microbubbles tagged with a subtherapeutic quantity of glycoprotein 2b/3a receptor inhibitor eptifibatide (75 U/kg plus 12 cc of microbubbles administered over 21 minutes), or eptifibatide control, was given with transcutaneous temporal LFUS (1 MHz at 2.0 W/cm 2 ) for 24 minutes. Angiography followed with scoring of declotting and flow. The same protocol was repeated on the contralateral side with the other test fluid so each animal received a saline control and either tagged microbubble or eptifibatide alone. Results-Fifteen pigs completed the protocol with a mean clot age of 4.6 hours. Using tagged microbubbles, 6 of 8 achieved success compared with 0 of 7 receiving eptifibatide alone (Pϭ0.007) and 1 of 15 receiving saline alone (Pϭ0.02). Conclusions-Intravenous

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Noninvasive In Vivo Clot Dissolution Without a Thrombolytic Drug

Abstract: In vivo arterial clot dissolution can be achieved with intravenous microbubbles and transcutaneous ultrasound delivery alone. This technique has potential for clinical application in patients with acute arterial and venous thrombotic occlusions.

Cited by 156 publications

References 6 publications

Microbubbles for Thrombolysis of Acute Ischemic Stroke

Microbubbles for Thrombolysis of Acute Ischemic Stroke

Ultrasound-Induced Blood Clot Dissolution without a Thrombolytic Drug Is More Effective with Lower Frequencies

Intracranial Clot Lysis With Intravenous Microbubbles and Transcranial Ultrasound in Swine

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