sonothrombolysis

ECMUS – The Safety Committee of EFSUMB :

Clinical Application of Sonothrombolysis (update 2011) 1 Introduction Some of the most common human cardiovas‐ cular diseases, such as myocardial infarction and stroke, share a common origin and are caused by thromboembolic events. In myo‐ cardial infarction, a coronary artery is occlu‐ ded by a blood clot triggered by atherosclero‐ tic plaque rupture. In stroke, ischaemia is caused by a thrombus that develops within the cerebral vasculature, or by an embolus from an atherothrombotic carotid artery or the fibrillating atrium. Recent reports of stroke patient treatments using ultrasound signal a new therapeutic application of ultrasound. This tutorial intro‐ duces the principle of clot sonolysis, and dis‐ cusses the physical ultrasound parameters involved. Ultrasound contrast agents enhance lysis. Clinical trials of the ultrasonic treatment of stroke are discussed. 2 Drug‐induced Clot Dissolution without US Strategies for dissolution of clots impeding or obstructing flow in a blood vessel, with the aim of reopening and re‐establishing perfu‐ sion, have been pursued for several decades. A number of drugs have been shown to destroy the fibrin mesh in a thrombus (these are known as thrombolytic agents); the main thrombolytic agents currently in use are streptokinase, anistreplase, urokinase and the recombinant tissue plasminogen activators alteplase and reteplase (van Domburg RT et al. 2000). Thrombus dissolution using lytic agents has been successful in the clinical treatment of myocardial infarction and has become the standard clinical therapy world‐wide. Major clinical trials have demonstrated the efficacy of the approach and a reduction in mortality. Direct intracoronary administration of strepto‐ kinase or urokinase has been shown to be su‐ perior to intravenous infusion (Simoons ML 1989). It should be noted, however, that per‐ cutaneous transluminal coronary angioplasty is preferred in many centres over intravenous thrombolytic therapy. A review of all major

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publications of the two treatment modalities revealed a better outcome for angioplasty (Keeley et al. 2003). It took a while for the knowledge gained from clot dissolution in the heart to be applied in the brain, but the results obtained in this organ parallel the advances made in myocar‐ dial infarction. Clinical dissolution of thrombus was successfully achieved in large scale trials of the National Institute of Neurological Dis‐ orders and Stroke rt‐PA Stroke Study Group (USA) (1995) and in Europe (Hacke et al. 1995), and intravenous recombinant tissue plasminogen activator is now the major vali‐ dated therapy for acute ischaemic stroke. 3 Thrombolysis with Ultrasound ‐ in vitro 3.1 Initial experiments In 1992 two groups of researchers reported ultrasound facilitated thrombolysis (Francis et al. 1992, Lauer et al. 1992). Freshly prepared human blood clots labelled with fibrinogen were exposed to 1 MHz ultrasound in the pre‐ sence of tissue plasminogen activator. Clot lysis with drug and ultrasound was greater than that obtained with drug alone. A better result was obtained when the sound intensity was increased, the time of exposure was prolonged, and the concentration of plasmino‐ gen activator was raised. Ultrasound released the fibrin degradation product D‐dimer from the clot (Kimura et al. 1994). In order to mimic the clinical situation better, perfusion systems have been built in which fibrin clots block narrow tubes, creating flow resistance. Exposing the clot under hydrostatic pressure to 170 kHz ultrasound and strepto‐ kinase shortened the time to reperfusion more than did 1 MHz (Olsson et al. 1994). A similar result was obtained with urokinase in another system in which flow was measured directly (Harpaz et a. 1994). In all experiments, controls were exposed to thrombolytic agent without ultrasound, resulting in less lysis . An overview of different approaches and techni‐ ques can be found in Pfaffenberger et al. (2005). Clot dissolution by ultrasound has been very‐ fied many times since this. A number of para‐ meters have been investigated.

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