Contrast-enhanced sonothrombolysis for the acute ischemic limb

Acute limb ischemia is a serious condition where the blood flow to the affected limb is insufficient for its need. The condition is both limb and life threatening and requires urgent intervention. Currently the most commonly used treatment for acute limb ischemia is catheter directed intra-arterial thrombolysis. It is a minimally invasive therapy, but it has the drawback of being time consuming and it carries a risk of (major) bleeding. This thesis focuses on contrast-enhanced sonothrombolysis (CEST) for acute peripheral arterial thrombosis. CEST is a form of thrombolysis where ultrasound contrast agents (a.k.a. microbubbles) and ultrasound are used to enhance thrombolysis. After intravascular administration, microbubbles follow the flow of blood to the site of the thrombus. Under influence of ultrasound, microbubbles start to oscillate. When the ultrasound pressure gets high enough, the microbubbles will destabilize and eventually burst, causing microstreams in the surrounding fluid and with it shear stress to the surface of the thrombus. Part I of this thesis is focused on results of current clinical practice for thrombolysis in peripheral arterial occlusion and on what we know about CEST for this pathology. Although CEST has been used in an experimental setting in patients with ischemic stroke and myocardial infarction, no investigations have been done in patients with peripheral arterial thrombosis. In part II of this thesis we present the results of various preclinical trials on the use of CEST for peripheral arterial thrombosis. We developed a porcine model for investigating CEST in acute peripheral arterial occlusion and used this model to investigate different aspects of microbubbles and with it different protocols for CEST. In part III of this thesis we present the results of the first clinical trial testing the safety and feasibility of CEST in acute peripheral arterial occlusion. We found CEST to be feasible in a clinical setting and there were no serious adverse events related to the experimental treatment in this small trial of 20 patients