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. (E-mail: [email protected]) (C) 2011 World Federation for Ultrasound in Medicine & Biology

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

Summary of hemodynamic data in all animals prior to, during and for 30 minutes following treatment.

*<p>ultrasound,</p>†<p>microbubble.</p>‡<p>heart rate,</p>§<p>systolic blood pressure,</p><p>||diastolic blood pressure,</p><p>#systemic oxygen saturation,</p>**<p>activated clotting time.</p

Intracardiac and transcutaneous echocardiographic images during treatment.

<p>Panel A demonstrates clean tip of the CVC (arrow) at baseline without any adherent thrombus. Panel B shows a stable thrombus formed at the CVC tip (arrow) 24 hrs after withdrawing 0.5–0.7 milliliters of blood into the CVC. Panels C and E show intracardiac (ICE) images demonstrating high concentration of microbubbles within the distal end and around the CVC in the superior vena cava on low MI imaging. Panels D and F show rapid and complete clearing of microbubbles with the application of high mechanical index pulse sequences to insonify the CVC tip (white arrows).</p

Intracardiac echocardiography before and after treatment.

<p>Examples of intracardiac echocardiographic images of the CVC tip before (panels A, C) and after (panels B, D) long pulse ultrasound and microbubble treatments demonstrating varying grades of thrombus reduction after treatment. Thrombus dissolution was complete (Panel B), near complete (Panel D).</p

Histologic examination of residual post-treatment thrombus.

<p>Panel A shows organized thrombus at the tip of a catheter explanted from the superior vena cava. Panel B shows cross section of the superior vena cava with its proliferated and inflamed intima and organized thrombus within. Panel C demonstrates a combination of newer and older organized thrombi and evidence of chronic inflammatory cells including eosinophils on light microscopy.</p