Feasibility of Microbubble-Accelerated Low-Dose Thrombolysis of Peripheral Arterial Occlusions Using an Ultrasound Catheter

Abstract

Purpose: Intra-arterial administration of microbubbles (MBs) through an ultrasound (US) catheter increases the local concentration of MBs into the thrombus and may further enhance outcomes of contrast-enhanced sonothrombolysis (CEST). The objective of this study was to evaluate the feasibility and lytic efficacy of intra-arterial infusion of MBs during US-enhanced thrombolysis in both in vitro and in vivo peripheral arterial occluded models.

Materials and methods: SonoVue and Luminity MBs were infused at a flow rate of 20 mL/h through either the drug delivery lumen of the US catheter (DDC, n=20) or through the tube lumen of the vascular phantom (systematic infusion, n=20) during thrombolysis with a low-dose urokinase (UK) protocol (50 000 IU/h) with(out) US application to assess MB survivability and size by pre-treatment and post-treatment measurements. A human thrombus was placed into a vascular phantom of the flow system to examine the lytic effects of CEST by post-treatment D-dimer concentrations measurements of 5 treatment conditions (saline, UK, UK+US, UK+US+SonoVue, and UK+US+Luminity). Thrombolytic efficacy of localized MBs and US delivery was then investigated in vivo in 5 porcine models by arterial blood flow, microcirculation, and postmortem determined thrombus weight and remaining length.

Results: US exposure significantly decreased SonoVue (p=0.000) and Luminity (p=0.000) survivability by 37% and 62%, respectively. In vitro CEST treatment resulted in higher median D-dimer concentrations for the SonoVue (0.94 [0.07-7.59] mg/mL, p=0.025) and Luminity (0.83 [0.09-2.53] mg/mL, p=0.048) subgroups when compared with thrombolysis alone (0.36 [0.02-1.00] mg/mL). The lytic efficacy of CEST examined in the porcine model showed an improved median arterial blood flow of 21% (7%-79%), and a median thrombus weight and length of 1.02 (0.96-1.43) g and 2.25 (1.5-4.0) cm, respectively. One allergic reaction and 2 arrhythmias were observed due to the known allergic reaction on lipids in the porcine model.

Conclusion: SonoVue and Luminity can be combined with an US catheter and could potentially accelerate thrombolytic treatment of peripheral arterial occlusions.

Clinical impact: Catheter-directed thrombolysis showed to be an effective alternative to surgery for acute peripheral arterial occlusions, but this technique is still associated with several limb and life-threatening complications. The effects of thrombolysis on clot dissolution may be further enhanced by intra-arterial administration of microbubbles through an ultrasound catheter. This study demonstrates the feasibility and lytic efficacy of intra-arterial infusion of microbubbles during US-enhanced thrombolysis in both in vitro and in vivo peripheral arterial occluded models.

Keywords: contrast-enhanced sonothrombolysis; drug delivery; endovascular treatment/therapy; in vitro; in vivo; microbubbles; peripheral artery disease; thrombolysis; ultrasound.

Figure 1.

In vitro setup with ultrasound catheter in vascular phantom. Overall in vitro experimental setup. Solid red arrows indicate the direction of flow.

Figure 2.

Microbubble survivability after infusion in a vascular phantom. Microbubble survivability is measured by the microbubble concentration ratio post-infusion/pre-infusion. The post-infusion concentration was corrected for dilution by the tube flow following from the infusion rates and collected volumes. Left boxplot shows survivability of SonoVue and Luminity microbubbles per ultrasound mode (n=20 per group), and middle and right boxplots show survivability of SonoVue (n=10 per group) or Luminity microbubbles (n=10 per group) per ultrasound mode infused through the drug delivery lumen of the catheter (DDC, simulating intra-arterial infusion) or directly into the vascular phantom (simulating intravenous infusion). DDC, drug delivery lumen catheter.

Figure 3.

Change in microbubble size after infusion in a vascular phantom. Change in microbubble size is measured by the microbubble concentration ratio post-infusion/pre-infusion. The change in size was corrected for dilution by the tube flow following from the infusion rates and collected volumes. Left boxplots show change in size of SonoVue and Luminity microbubbles per ultrasound mode (n=20 per group), and middle and right boxplots show change in size of SonoVue (n=10 per group) and Luminity microbubbles (n=10 per group) per ultrasound mode infused through the drug delivery lumen of the catheter (DDC, simulating intra-arterial infusion) or directly into the vascular phantom (simulating intravenous infusion). DDC, drug delivery lumen catheter.

Figure 4.

D-dimer concentrations after various treatment regimens in a vascular phantom. Clot lysis is measured by the post-D-dimer concentration for all treatment groups, including saline (n=13), urokinase (n=15), urokinase+US (n=12), urokinase+US+SonoVue (n=12) and urokinase+US+Luminity (n=12) infused through the drug delivery lumen of the catheter (DDC, simulating intra-arterial infusion). US, ultrasound; DDC, drug delivery lumen catheter.