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(Circulation. 1996;94:775-778.)
© 1996 American Heart Association, Inc.

Articles

Transcutaneous Ultrasound Augments Lysis of Arterial Thrombi In Vivo

Huai Luo, MD; Toshihiko Nishioka, MD; Michael C. Fishbein, MD; Bojan Cercek, MD; James S. Forrester, MD; Chong-Jin Kim, MD; Hans Berglund, MD; Robert J. Siegel, MD

the Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, Calif.

Correspondence to Robert J. Siegel, MD, Division of Cardiology, Rm 5335, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048.

	Abstract

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Background External ultrasound has a synergistic effect on thrombus disruption with thrombolytic agents in vitro. We hypothesized that transcutaneous ultrasound could augment thrombolysis in vivo.

Method and Results Thrombus formation was induced electrically in 48 pairs of iliofemoral arteries of 24 rabbits; arterial occlusions were documented angiographically. In 17 of 24 rabbits, 25 000 units/kg streptokinase was then administered intravenously. The pairs of iliofemoral arteries were randomized to receive ultrasound treatment or no ultrasound treatment. Low-frequency (26 kHz) ultrasound (continuous wave, 18 W/cm²) was applied transcutaneously over the area of occlusion. In 7 of 24 rabbits, 14 thrombotically occluded iliofemoral arteries were exposed to ultrasound alone without streptokinase. The results were evaluated through the use of angiography (TIMI grade flow) and histopathology. After 30±10 minutes of activated sonication combined with intravenous streptokinase, 10 of 17 iliofemoral arteries (59%) treated with transcutaneous ultrasound were widely patent angiographically, with TIMI grade 3 flow. Histologically, the patent arteries had only minimal focal mural thrombus. The angiographic patency rate was significantly lower in the control groups: 1 of 17 arteries (6%) treated with streptokinase alone (P=.0012) and 1 of 14 arteries (7%) treated with ultrasound alone (P=.0036).

Conclusions In vivo transcutaneous ultrasound significantly augments lysis of thrombi with streptokinase in rabbit iliofemoral arteries.

Key Words: ultrasound • thrombolysis • streptokinase

	Introduction

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Thrombolytic therapy reduces 30- to 35-day mortality by 25% in patients with acute myocardial infarction treated within 6 hours of the onset of symptoms.^{1 2 3} However, the mean time to reperfusion is 44 to 72 minutes, and at 90 minutes only 51% to 70% of the coronary arteries are patent.^{4 5} Consequently, there is a need for adjunctive treatment to enhance the rate of thrombolysis without increasing the incidence of hemorrhagic complications.^{6 7}

High-power intensity, low-frequency catheter-delivered ultrasound causes thrombus dissolution and has a synergistic effect with tissue-type plasminogen activator- or urokinase-induced thrombolysis.^{8 9 10 11} Catheter delivery systems, however, are limited by the time delay to intervention and by other technical, financial, and logistic factors.

In vitro, external ultrasound can enhance streptokinase, urokinase, or tissue-type plasminogen activator-induced thrombolysis. Enhancement is greatest in fresh thrombi with the use of low-frequency (25 to 50 kHz) and high-intensity ultrasound.^{12 13 14 15} We hypothesized that transcutaneous ultrasound might facilitate disruption of arterial thrombi with thrombolytic drugs. In the present study, we assessed the synergistic effect of transcutaneous ultrasound on thrombolysis with a dose of streptokinase previously shown not to be effective in this model.¹⁶

	Methods

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Ultrasound Device
We used an ultrasonic generator (model CU51-E-001, PIEZO System Inc) that operates in continuous mode at a frequency of 26 kHz. The dimensions of the transducer are 6.5-cm length and 2.0-cm diameter. The power output is 18 W/cm² at the tip of the transducer.

Thrombus Preparation: Induction of Thrombotic Occlusion
The American Physiological Society Guidelines for Animal Research were followed, which conform to the position of the American Heart Association on research animal use adopted in November 1984. Twenty-four adult New Zealand White rabbits weighing 3.5 to 4.5 kg were anesthetized and maintained with ketamine (20 mg/kg IV) and xylazine (3.0 mg/kg IV). A 5F arterial sheath was inserted through surgical cutdown technique into the right carotid artery.

Thrombotic occlusion of the iliofemoral artery was induced with the use of electricity, as we described previously.⁸ A 3.5F coronary Tracker catheter over a 0.014-in coronary guide wire was inserted through the carotid arterial sheath to the iliofemoral artery. The guide wire, connected to the positive electrode of a 3-V battery, was advanced 1 cm beyond the tip of the Tracker catheter. The negative pole of the battery was connected to the rabbit's skin. Electrical interference on the ECG monitor indicated that an electric current was established.

Experimental Protocol
Angiography confirmed that all 48 iliofemoral arteries of 24 rabbits were occluded (Thrombolysis in Myocardial Infarction [TIMI] grade 0 flow) at an average of 33±7 minutes (range, 30 to 45 minutes) after the beginning of electrical induction.

There were three experimental protocols. In 17 of 24 rabbits (34 iliofemoral arteries), after a thrombotic occlusion formed on one side of the pair of iliofemoral arteries, the guide wire and the Tracker catheter were pulled back into the abdominal aorta and then advanced to the contralateral vessel for subsequent induction of a thrombotic occlusion. Streptokinase was then administered at a dose of 25 000 units/kg through intravenous injection in the marginal ear vein. One side of the 17 iliofemoral arteries received ultrasound treatment (with streptokinase), whereas the other side of 17 iliofemoral arteries served as a control group with streptokinase treatment alone. Because thrombus was induced sequentially in both iliofemoral arteries and thrombotic occlusions were not carried out simultaneously, the left or right iliofemoral arteries with "new" or "old" thrombus (age difference, 33±7 minutes) were randomized to receive ultrasound energy. In the third group (7 rabbits), 14 iliofemoral thrombi were induced. However, in these rabbits, ultrasound exposure was applied within 10 minutes of unilateral thrombotic occlusion of the iliofemoral artery. Subsequently, a thrombus was induced in the contralateral iliofemoral artery, and ultrasound exposure was then applied within 10 minutes to this site.

The 26-kHz, 18-W/cm² ultrasound transducer was applied transcutaneously over the area of the thrombotically occluded artery. To establish that ultrasound energy reached the target site, an echocardiographic contrast agent (EchoGen, Bothell) was injected into the aorta in two of the treated rabbits at the end of the monitoring period before the animals were killed. During activation of the 26-kHz ultrasound probe, simultaneous echocardiographic imaging demonstrated a contrast effect of the EchoGen in the artery at the target site. This contrast effect was present only when the ultrasound probe was activated. To reduce thermal damage to the skin, ultrasound energy was applied in 5-minute intervals followed by 2 minutes of no ultrasound exposure. Cooled gel (17°C) was placed between the transducer and skin.

The results of thrombolysis were evaluated through the use of angiography with the TIMI ordinal scale used for arterial blood flow.¹⁷

Angiographic Protocol for Iliofemoral Arteries
We used Omnipaque contrast by hand injection (Sanofi Winthrop Pharmaceuticals). From 1 to 2 mL of contrast was injected for each angiogram. All studies were recorded with both 35-mm cine film at a rate of 30 frames per second and digital acquisition with a posteroanterior projection. Serial bilateral angiograms were performed every 15 minutes to assess blood flow and arterial occlusions from baseline and then for 1 hour after the induction of the occlusion. The angiographic monitoring of iliofemoral flow was terminated after 60 minutes of treatment in cases with a persistent occlusion. The cases in which the arteries were patent after ultrasound were monitored angiographically for an additional 30 minutes after recanalization. Analysis of the angiograms was based on the consensus of four investigators regarding the presence or absence of an occlusion, TIMI grade flow, vessel spasm, and distal or side branch embolization.

Pathological Studies
After the experiments, all rabbits were killed by an injection of sodium pentobarbital (120 mg/kg IV, Deimarva Laboratories, Inc). The iliofemoral arteries, ultrasound exposed skin, and soft tissues were excised, examined grossly, and then fixed in 10% neutral buffered formalin for 24 to 72 hours. The iliofemoral arteries were then cut transversely every 2 mm for the length of the vessel. Samples were dehydrated in graded alcohol, cleared in Hemo-De, and embedded in paraffin. Sections 4 to 5 µm thick were cut, mounted on glass slides, and stained with hematoxylin and eosin.

Statistical Analysis
Data are given as mean±SD. The ² test was performed to compare the angiographic patency rate among arteries treated with streptokinase and ultrasound, streptokinase alone, and ultrasound alone. Fisher's exact test was used for subsequent comparison between two treatment groups. A value of P.05 was considered statistically significant.

	Results

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Fig 1 shows the angiogram of a rabbit's left iliofemoral artery at baseline, during and after induction of a thrombus, at thrombotic occlusion, and after a 30-minute treatment with ultrasound plus streptokinase. The vessel is widely patent after combined streptokinase and ultrasound treatment.

View larger version (123K): [in this window] [in a new window]   Figure 1. Example of left iliofemoral artery treated with transcutaneous ultrasound and streptokinase. a, Baseline angiogram. b, Guide wire-assisted electrical induction of a thrombotic occlusion. c, Angiographic thrombotic occlusion. d, Angiogram of the widely patent artery after 30 minutes of treatment.

As shown in the Table, the difference in angiographic patency rates among the three groups was statistically significant (P=.0003). The combination of streptokinase and ultrasound was different from ultrasound alone (P=.0036) or streptokinase alone (P=.0012), whereas the effects of the ultrasound alone and streptokinase alone did not differ.

View this table: [in this window] [in a new window]   Table 1. Artery Patency Among the Three Rabbit Treatment Groups

In 17 iliofemoral arteries treated with the combination of ultrasound and low dose of streptokinase, angiography revealed that after 30±10 minutes, 10 of 17 arteries (59%) were widely patent, with TIMI grade 3 flow, and 7 remained occluded at the end of the intervention. There were no angiographic reocclusions in the 30-minute serial angiographic observation period after the initial recanalization. In 17 contralateral arteries without ultrasound treatment, 1 artery (6%) had angiographic TIMI grade 3 flow 30 minutes after injection of intravenous streptokinase. The other 16 arteries were still occluded (TIMI grade 0) at 60 minutes. Fourteen thrombotic iliofemoral arteries (7 of 24 rabbits) were exposed to transcutaneous ultrasound alone without streptokinase administration. Angiography showed that 1 of the 14 (7%) arteries was patent 30 minutes after ultrasound energy was activated, and the remaining 13 arteries were still occluded after 60 minutes of energy exposure.

Histopathology revealed that arteries that were patent according to angiographic examination were also patent according to microscopic examination, with only focal residual mural thrombus. Fig 2A is an example of a thrombotic occlusion in an iliofemoral artery. Fig 2B and 2C shows that the patent vessel has only minimal residual focal mural thrombus (arrow) after ultrasound and streptokinase treatment.

View larger version (86K): [in this window] [in a new window]   Figure 2. Histological examples of rabbit iliofemoral arteries. a, Thrombotic occlusion in an iliofemoral artery (hematoxylin and eosin stain; original magnification, x10). b and c, Rabbit iliofemoral artery that was angiographically patent after 30 minutes of treatment with transcutaneous ultrasound and streptokinase; the patent artery has a focal residual thrombus in the lumen (arrow) without evidence of vessel wall damage (hematoxylin and eosin stain; original magnification, b: x10; c: x50).

In the arteries that remained occluded despite ultrasound and streptokinase treatment for 60 minutes (n=7), microscopy revealed mural thrombus. Small areas of focal necrosis were found in all vessels studied. The magnitude of vessel injury was the same in the arteries that received ultrasound and those that received streptokinase alone (without ultrasound exposure). The rabbit dermis at the sites of ultrasound exposure revealed thermal injury characterized by variable degrees of coagulation and focal hemorrhage consistent with thermal injury. The degree of cutaneous tissue injury varied in direct relation to ultrasound exposure time.

	Discussion

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This is the first study to show that in vivo transcutaneous high-intensity, low-frequency ultrasound significantly augments lysis of arterial thrombi with streptokinase. The luminal patency rate was 7% with ultrasound irradiation alone (1 of 14), 6% with intravenous streptokinase injection alone (1 of 17), and 59% with ultrasound and streptokinase (10 of 17; P=.0003). There was no specific histological evidence of ultrasound-mediated damage to the arterial wall in the patent arteries. The transcutaneous application of ultrasound, however, was associated with a variable extent of thermal injury to the rabbit dermis.

Thrombus Induction and Streptokinase Dose
The major causes of vessel thrombosis in humans are intimal disruption, reduced blood flow, and altered systemic coagulation. In our study, the thrombus was initiated by electrical injury to the intima and perhaps by restricted blood flow caused by the 3.5F Tracker catheter. This method caused iliofemoral artery occlusion after 33±7 minutes. The electrical induction of thrombus results in a platelet-rich thrombus, histologically similar to those that occur during acute thrombosis in humans, although the vessels in our study were not atherosclerotic. Rabbit thrombi are resistant to 10 times the streptokinase dose used clinically in humans.¹⁶ We chose a dose of 25 000 units/kg because it has been shown to be ineffective in lysing rabbit thromboses.

Other External Ultrasound Studies in Animal Models
Our study is the only angiographic/histopathological study in which transcutaneous ultrasound was used in an intact animal model with thrombotic arterial occlusion. Kudo¹⁸ treated surgically exposed canine femoral arteries with combined tissue plasminogen activator and 200-kHz ultrasound irradiation delivered at a distance of 5 cm. Recanalization time, determined with the use of a flowmeter, was reduced by 75% compared with treatment with the tissue-type plasminogen activator. Lauer et al¹⁹ treated thrombosed rabbit jugular veins with combined pulsed ultrasound (1 MHz, 1.75 W/cm²) and tissue plasminogen activator (1 mg). With the use of ¹²⁵I-labeled fibrinogen, they found that after 100 minutes of sonication, the percent clot lysis (55%) was greater than that with tissue plasminogen activator alone (33%).

After recanalization, results have been contradictory. Yoshizawa²⁰ found that ultrasound prevented acute reocclusion for 2 hours after initial thrombolysis in an isolated dog femoral artery thrombosis model. In contrast, Kornowski et al,²¹ who monitored rabbit occlusion for 2 hours, found that ultrasound irradiation was associated with more frequent reocclusion after initial recanalization. In the present study, no acute reocclusion was detected within 30 minutes after arterial recanalization. These differences may reflect variations of thrombus induction, the thrombolysis protocol, and the frequency and intensity of ultrasound.

Mechanism of Enhanced Efficacy With Combined Ultrasound and Low-Dose Streptokinase on Lysis of Arterial Thrombi
Acoustic cavitation is the most likely mechanism by which ultrasound causes clot lysis. When ultrasound waves pass through a liquid with an alternating pressure, acoustic cavitation results in the formation of microbubbles. These bubbles grow from cycle to cycle and then collapse instantly and violently at resonant size. Both the vibration of microbubbles and their rapid collapse in the acoustic field result in local pressures of up to 20 000 atm.²² This mechanical shock of bubble collapse is felt at a distance of a few microns, resulting in intense shear stress that could break fibrin bonds of thrombi and induce thrombus fragmentation, exposing more fibrin sites to streptokinase. The size of microbubbles generated by ultrasound during cavitation is inversely proportional to ultrasound frequency. The large bubbles produced by low-frequency ultrasound are thought to produce greater force during their vibration and implosion than the smaller bubbles that are produced at high ultrasound frequency. As ultrasound frequency is increased, more power is necessary to produce cavitation. The intensity of the collapsing force is greatly diminished at >1 MHz, and cavitation cannot be produced at all at >2.5 MHz.²³ Other factors that may contribute to clot disruption include microstreaming, heating effects, and direct vibration. These disruptive effects on the clot structure are presumed to enhance the efficacy of the thrombolytic agent.

Study Limitations
Direct particle size measurements in our previous in vitro study showed that particulates ranged from 2.8 to 3.8 µm.²⁴ Nevertheless, we cannot exclude the possibility of occlusive distal embolization to very small distal arterial branches after ultrasound treatment, despite negative angiographic evaluation. In addition, we did not assess the long-term patency or potential for reocclusion beyond 30 minutes after initial recanalization. The effective use of ultrasound in our study was accompanied by cutaneous thermal injury, which would be unacceptable in clinical use. Future studies must be directed to develop (1) methods for cutaneous cooling and (2) methods for focusing the ultrasound energy. Furthermore, for application to coronary thromboses, there are potential problems of more dense tissue to penetrate, greater transducer-to-target distances, and a moving vascular target.

Conclusions
Transcutaneous low-frequency, high-intensity ultrasound is effective in augmenting streptokinase-induced lysis of thrombi in rabbit iliofemoral arteries. This effect may be due to acoustic cavitation, which enhances the exposure of thrombus to streptokinase. Our study suggests that further development of a focused ultrasound system for localized energy delivery in combination with a low dose of a thrombolytic drug has the potential for clinical application in patients with acute arterial thrombosis.

	Acknowledgments

 
This work was supported in part by the Lee E. Siegel, MD, Memorial Fund; Herbert Stein, MD, Research Fund; Japan Self Defense Forces Central Hospital; Swedish Society of Medicine and Wenner-Gren Center Foundation, Sweden; and Western Cardiac Research Fund.

Received December 28, 1995; revision received February 12, 1996; accepted February 17, 1996.

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