Effectiveness of lipid microbubbles and ultrasound in declotting thrombosis

doi:10.1016/j.ultrasmedbio.2005.03.008

Ultrasound in Medicine & Biology

Volume 31, Issue 7, July 2005, Pages 979-985

https://doi.org/10.1016/j.ultrasmedbio.2005.03.008 Get rights and content

Abstract

The objectives of this study were to determine the effectiveness of lipid-encapsulated microbubbles and ultrasound (US) in recanalizing arteriovenous graft thrombi and the effect that tissue attenuation has on the success rate. A total of 55 thrombotic occlusions were created in four canines. The thrombosed grafts were randomly treated with two different 1-MHz US intensities, low (0.4 to 0.6 W/cm²) and high (10 W/cm²). Intragraft microbubbles were compared with intragraft saline and with the same dose of microbubbles given IV. IV microbubbles were also given both in the presence and absence of a tissue-mimicking phantom. High-intensity US (10 W/cm²) with intragraft microbubbles produced significantly higher patency and flow scores than did US with saline (p < 0.01). US with IV microbubbles had higher success rates in recanalizing thrombosed grafts than did US alone at all intensities. Attenuation reduced the rate at which successful recanalization occurred at both low and high intensities. US and microbubbles are capable of recanalizing acute arteriovenous graft thromboses. Higher intensities may be needed in the presence of tissue attenuation.

Introduction

Intravenous microbubbles with ultrasound (US) have been shown in animal studies to be a potential alternative to fibrinolytic agents in recanalizing discrete peripheral intra-arterial thrombotic occlusions (Birnbaum et al. 1998). However, when larger intravascular thrombi are present, the quantity of microbubbles reaching the site after IV injection has been less effective than direct intragraft injections of the same number of microbubbles (Culp et al 2001, Culp et al 2003). Another problem with extrapolation of these animal studies into clinical practice is that the thrombi in the animal studies were relatively fresh (1 h) and there was minimal attenuation of US intensity along the path from the transducer to the thrombus (Culp et al. 2003).

Newer lipid-encapsulated microbubbles (LEMB) have been developed that are smaller, more resistant to US-induced destruction and achieve greater transpulmonary passage (Sonne et al. 2003; Rosenschein et al. 1997). Therefore, they may achieve higher concentrations within an arterial thrombus after venous injection. The purpose of this study was to determine the effectiveness of these LEMB in recanalizing older arteriovenous graft thrombi and to determine the effect of tissue attenuation on the success rate achieved with different US intensities and IV microbubbles.

Section snippets

Lipid microbubbles

The LEMB used in this study were lipid-encapsulated microbubbles (Definity^®) provided by ImaRx Therapeutics, Inc. (Tucson, AZ, USA). According to this manufacturer, the size of the microbubbles has been analyzed using a particle-sizing system model 770 (Particle Sizing Systems, Santa Barbara, CA, USA). This system permits the analysis of microbubbbles as small as 0.5 μm. The weighted mean size of six samples was 1.0 ± 0.1 μm, with less than 1% of the microbubbles being greater than 1.5 μm. The

Results

A total of 55 declotting procedures were performed in the four canines over the 13-month period (13 testing intragraft injections and 42 testing IV injections). Average duration of ligation was 3.9 ± 0.8 h. All four canines tolerated the repeated clotting procedures well. The RV function, as well as RV systolic pressures, did not change after any treatment (14 ± 6 mmHg before treatment and 14 ± 3 mmHg after treatment). Activated clotting times were not altered by the treatment. Despite a large

Discussion

Ultrasound has shown promise as a method of recanalizing thrombosed vessels. The success of US treatment improves when delivered in unattenuated conditions, such as directly through an intravascular catheter (Rosenschein et al. 1997). The mechanism for US enhancement has been attributed to improved clot exposure to adjuvant drugs, as well as to cavitation-mediated destruction.

Several preclinical studies have shown that US and IV microbubbles can dissolve an intra-arterial thrombus even without

Summary

Low-frequency US is capable of rapidly recanalizing large intravascular thromboses with IV LEMB. Higher intensities are the most effective, but have decreased effectiveness in the presence of tissue attenuation. The effects that we observed at the different intensities must be taken in the context of the fact that the duty cycles were different for these different intensities. Nonetheless, this indicates that loss of US energy in human tissue may limit the effectiveness of this treatment

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Original contributionEffectiveness of lipid microbubbles and ultrasound in declotting thrombosis

Abstract

Introduction

Section snippets

Lipid microbubbles

Results

Discussion

Summary

Ultrasound Med Biol

J Vasc Interv Radiol

Ultrasound Med Biol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Soc Echocardiogr

Original contribution
Effectiveness of lipid microbubbles and ultrasound in declotting thrombosis