Pulsed High–Intensity-focused US and Tissue Plasminogen Activator (TPA) Versus TPA Alone for Thrombolysis of Occluded Bypass Graft in Swine

Prosthetic grafts have several clinical applications but are used mainly as arteriovenous shunts for hemodialysis and as bypass grafts to treat peripheral vascular disease. Graft occlusion can occur in as many as 50% of lower-extremity bypass grafts (1). Several factors contribute to bypass graft failure: the inherent thrombogenicity of the graft caused by the lack of endothelial cell lining, mismatch between graft size and native vessel, and low flow associated with smaller grafts (ie, diameter < 6 mm) (2). Catheter-directed thrombolysis is the recommended initial treatment according to the Trans-Atlantic Inter-Society Consensus (3) and is generally well accepted. However, the potential to improve lytic efficacy and reduce time and dose associated with pharmacologic thrombolysis have fueled interest in adjunctive therapies (3,4). Ultrasound (US)-enhanced thrombolysis is one example; both catheter-delivered (ie, endovascular) and externally applied (ie, transcutaneous) US systems exist (5,6). US is defined in part by its frequency and acoustic intensity parameters. Low frequency ranges are assigned between 20 and 400 kHz and high frequency ranges between 0.5 and 3 MHz. US intensity is defined as low when tissue exposure is less than 2 W/cm2 and high if greater than 2 W/cm2 (7). US parameters are mutually linked (7). Low-frequency US waves penetrate deeper in tissue without loss of energy whereas high-frequency US waves require higher intensities to achieve a similar effect at a given depth. These higher intensities delivered in continuous manner result in tissue heating (7,8); however, intermittent or pulsed high–intensity-focused US (HIFU; pHIFU) sonication lowers the rate of energy deposition and diminishes tissue heating (7,9). Commercially available tools currently consist of catheter-delivered intravascular low-intensity US (10,11); therefore, the beam is not focused and tissue exposure is low. This tool has shown some clinical benefit in the setting of peripheral arterial and venous thrombosis (5,8,12,13), and randomized studies are currently under way (13). Low-intensity focused US in conjunction with microbubbles has been shown to rapidly dissolve thrombi without lytic agents in swine and dog models (14–16). The theoretical mechanism of action is cavitation (17). However, the use of microbubbles may have regulatory implications impeding translation to clinic and can have undesirable side effects, mainly soft-tissue injury (17). One advantage of HIFU is the ability to generate a small focus area (6). Preliminary data with the use of pHIFU to enhance pharmacologic thrombolysis in vitro and in small animal models are encouraging (18,19). pHIFU is a noninvasive external focused high-intensity beam, which is applied to the treatment area in a defined time frame (1 minute per sonication point), unlike current commercial technologies that require catheterization of the vessel and continuous delivery of a low-intensity beam over a period of several hours (10,11). The goals of the present study were to develop a large animal model of bypass graft thrombosis, determine the dose response of tissue plasminogen activator (TPA) in 7-day-old thrombus, and evaluate the safety and effectiveness of thrombolysis in conjunction with pHIFU. This study examined the hypothesis that pretreating a thrombosed arterial bypass graft with pHIFU, followed by the administration of a commonly used thrombolytic agent such as TPA, would enhance thrombolysis compared with the thrombolytic agent alone, thereby reducing the thrombolytic agent dose needed.