Microbubble mediated thrombus dissolution with diagnostic ultrasound for the treatment of chronic venous thrombi.

BACKGROUND: Central venous catheter (CVC) thrombi result in significant morbidity in children, and currently available treatments are associated with significant risk. We sought to investigate the therapeutic efficacy of microbubble (MB) enhanced sonothrombolysis for aged CVC associated thrombi in vivo. METHODS AND RESULTS: A model of chronic indwelling CVC in the low superior vena cava with thrombus in situ was established after feasibility and safety testing in 7 pigs; and subsequently applied for repeated, sonothrombolytic treatments in 9 pigs (total 24 treatments). Baseline intracardiac echocardiography (ICE, 10.5F, Siemens), fluoroscopy and saline flushing confirmed the absence of any pre-existing CVC thrombus. A thrombus was then allowed to form and age over 24 hours. The created thrombus was localized and measured by ICE, and transthoracic image guided high mechanical index (MI) two-dimensional US treatments (1.1-1.7 MI; iE33, Philips) applied intermittently whenever intravenously infused MBs (3% MRX-801; NuVox) were visualized near the thrombus (n = 10; Group A). Control pigs (n = 10; Group B) received US without MB. All treatments were randomized. Post-treatment thrombus area by ICE planimetry was compared with pre-treatment measurements. Thrombus area measurements before and after treatment were 0.22 and 0.10 cm(2) respectively in Group A; compared to 0.24 and 0.21 cm(2) in Group B (p  = 0.0003). Effectiveness of longer duration US and MB thrombolytic treatments were studied (n = 4), which suggested that near complete thrombus dissolution is possible. No pulmonary emboli, alterations in oxygen saturation, or hemodynamics occurred with either treatment. CONCLUSIONS: Guided high MI diagnostic US+systemic MB facilitates reduction of aged CVC associated thrombi in vivo. MB enhanced sonothrombolytic therapy may be a non-invasive safe alternative to thrombolytic agents in treating thrombotic CVC occlusions.

Effects of attenuation and thrombus age on the success of ultrasound and microbubble-mediated thrombus dissolution.

The purpose of this study was to examine the effects of applied mechanical index, incident angle, attenuation and thrombus age on the ability of 2-D vs. 3-D diagnostic ultrasound and microbubbles to dissolve thrombi. A total of 180 occlusive porcine arterial thrombi of varying age (3 or 6 h) were examined in a flow system. A tissue-mimicking phantom of varying thickness (5 to 10 cm) was placed over the thrombosed vessel and the 2-D or 3-D diagnostic transducer aligned with the thrombosed vessel using a positioning system. Diluted lipid-encapsulated microbubbles were infused during ultrasound application. Percent thrombus dissolution (%TD) was calculated by comparison of clot mass before and after treatment. Both 2-D and 3-D-guided ultrasound increased %TD compared with microbubbles alone, but %TD achieved with 6-h-old thrombi was significantly less than 3-h-old thrombi. Thrombus dissolution was achieved at 10 cm tissue-mimicking depths, even without inertial cavitation. In conclusion, diagnostic 2-D or 3-D ultrasound can dissolve thrombi with intravenous nontargeted microbubbles, even at tissue attenuation distances of up to 10 cm. This treatment modality is less effective, however, for older aged thrombi.

Sonothrombolysis of intra-catheter aged venous thrombi using microbubble enhancement and guided three-dimensional ultrasound pulses.

BACKGROUND: Central venous and arterial catheters are a major source of thromboembolic disease in children. The investigators hypothesized that guided high-mechanical index (MI) impulses from diagnostic three-dimensional (3D) ultrasound during an intravenous microbubble infusion could dissolve these thrombi. METHODS: An in vitro system simulating intracatheter thrombi was created and then treated with guided high-MI impulses from 3D ultrasound, using low-MI microbubble sensitive imaging pulse sequence schemes to detect the microbubbles. Ten aged thrombi >24 hours old were tested using 3D ultrasound coupled with a continuous diluted microbubble infusion (group A) and 10 with 3D ultrasound alone (group B). RESULTS: The mean thrombus age was 28.6 hours (range, 26.6-30.3 hours). Group A exhibited a 55 +/- 19% reduction in venous thrombus size compared with 31 +/- 10% in group B (P = .008). Feasibility testing was performed in four pigs, establishing an in vivo model to investigate further the efficacy of this approach. CONCLUSIONS: Sonothrombolysis of aged intracatheter venous thrombi can be achieved with commercially available microbubbles and guided high-MI ultrasound from a diagnostic 3D transducer.