Microbubbles and Ultrasound Accelerated Thrombolysis for Peripheral Arterial Occlusions: The Outcomes of a Single Arm Phase II Trial

Abstract

WHAT THIS PAPER ADDSSince the introduction of thrombolysis in the 1990s, significant changes have been made in thrombolytic agents and administration techniques. Numerous methods, such as ultrasound assisted thrombolysis, have been investigated to improve the results of the technique. The efficacy and associated complication rates have, nevertheless, remained unchanged. The aim of this study was to investigate an experimental ultrasound technique combined with microbubbles as a potential accelerator of conventional intra-arterial thrombolysis.Objective: Acute peripheral arterial occlusions can be treated by catheter directed thrombolysis (CDT). However, CDT is time consuming and accompanied by the risk of bleeding complications. The addition of contrast enhanced ultrasound and microbubbles could improve thrombus susceptibility to thrombolytic agents and potentially shorten treatment time with a lowered risk of bleeding complications. This article reports the outcomes of the safety and feasibility of this novel technique. Methods: In this single arm phase II trial, 20 patients with acute lower limb ischaemia received CDT combined with an intravenous infusion of microbubbles and locally applied ultrasound during the first hour of standard intra-arterial thrombolytic therapy. The primary endpoint was safety, i.e., occurrence of serious adverse events (haemorrhagic complications and/or amputation) and death within one year. Secondary endpoints included angiographic and clinical success, thrombolysis duration, additional interventions, conversion, and quality of life.Results: The study included 20 patients (16 men; median age 68.0 years; range, 50.0 e 83.0; and 40% native artery and 60% bypass graft). In all patients, the use of microbubble contrast enhanced sonothrombolysis could be applied successfully. There were no serious adverse events related to the experimental treatment. Duplex examination showed flow distal from the occlusion after 23.1 hours (range 3.1 e 46.5) with a median thrombolysis time of 47.5 hours (range 6.0 e 81.0). The short term ABI and pain scores significantly improved; however, no changes were observed before or after thrombolysis in the microcirculation. Overall mortality and amputation rates were both 2% within one year. The one year patency rate was 55%. Conclusion: Treatment of patients with acute peripheral arterial occlusions with contrast enhanced sonothrombolysis is feasible and safe to perform in patients. Further research is necessary to investigate the superiority of this new treatment over standard treatment.

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

“…13,14 The potential use of MBs combined with US and thrombolytic therapy simultaneously shows to be promising in previous (pre-)clinical studies. 9,10,15 The efficacy of thrombolysis might, however, be further improved by intraarterial administration of MBs through an endovascular US catheter. Higher concentrations of MBs within the clot may enlarge the cavitation response, which will ultimately accelerate thrombolysis.…”

“… 9 More recently, we have demonstrated the clinical safety and applicability of CEST in the MUST (Microbubbles and UltraSound-accelerated Thrombolysis for peripheral arterial occlusions) trial, including 20 patients with peripheral arterial occlusion. 10 This novel technique at present has some limitations such as the need for external application of US, which exhibits an interoperator variability that may negatively affect the cavitation effect. Another limitation is that intravenous administration of MBs primarily induces cavitation on the surface of the thrombus and not directly into the thrombus until microchannels are formed or partial reperfusion is ensured.…”

The Updated Role of Transcranial Ultrasound Neuromodulation in Ischemic Stroke: From Clinical and Basic Research

“…Indirect thrombolytic effects of TUS mainly enhance the effectiveness of thrombolytic drugs. In addition, ultrasound can directly dissolve the thrombus through its special physical and chemical properties (Cao et al, 2021;Doelare et al, 2021;Mei and Zhang, 2021). The main thrombolytic effects of TUS are summarized as follows.…”

Ultrasound Combined With Continuous Microbubble Injection to Enhance Catheter‐Directed Thrombolysis in Vitro and in Vivo

“…Some studies have shown that ultrasound combined with microbubbles can enhance the thrombolytic effect of CDT. 9,10 The most important aspect of this treatment modality is that it can reduce the dosage of thrombolytic drugs, which is beneficial for patients at high risk of bleeding who are strictly limited to thrombolytic therapy. Several studies have revealed that the mechanism of ultrasound combined with microbubbles to enhance thrombolysis is cavitation-mediated acoustic radiation, microjet, and microstreaming, which facilitates enzymatic degradation and mechanical destruction of thrombus, [11][12][13] and these responses are mainly regulated by ultrasound parameters and microbubble.…”

“…Recently, sonothrombolysis or ultrasound thrombolysis has emerged as a promising method for thrombolytic therapy. Some studies have shown that ultrasound combined with microbubbles can enhance the thrombolytic effect of CDT 9,10 . The most important aspect of this treatment modality is that it can reduce the dosage of thrombolytic drugs, which is beneficial for patients at high risk of bleeding who are strictly limited to thrombolytic therapy.…”