Sonothrombolysis in the ambulance for ST-elevation myocardial infarction: rationale and protocol

ST-segment elevation on the electrocardiogram (ECG) indicates the occlusion of an epicardial coronary artery, most commonly due to thrombus formation at the site of a ruptured atherosclerotic plaque. The optimal treatment strategy for ST-elevation myocardial infarction (STEMI) is immediate restoration of epicardial coronary blood flow. Currently, primary percutaneous coronary intervention (PCI) with concomitant dual antiplatelet therapy and periprocedural anticoagulation constitutes the treatment of choice in STEMI patients [1]. While successful reperfusion has led to a marked decrease in annual deaths over the past decades, long-term mortality and morbidity remain substantial [2, 3]. In addition to prolonged ischaemia and subsequent infarct size, microvascular injury due to ischaemic and reperfusion processes is a major determinant of adverse left ventricular remodelling and poor prognosis [4] and occurs in up to 50% of the patients [5]. By minimising infarct size and microvascular injury, left ventricular function may be preserved with improved long-term prognosis. Several studies have focused on early therapeutic interventions for reduction of infarct size and microvascular injury. Early drug therapy strategies include the use of low-dose fibrinolysis [6, 7], beta-blockers [8], adenosine [9], cyclosporine [10] and complement inhibition [11]. No or only small beneficial effects in a selected patient population have been demonstrated. Other interventions such as thrombus aspiration to reduce distal embolisation [12] and remote ischaemic conditioning [13] to reduce the possible detrimental effects of spontaneous reperfusion likewise did not improve outcome. A growing number of studies on adjunctive therapies for STEMI are performed in the pre-hospital setting. The time from STEMI diagnosis to PCI provides a window of opportunity for early therapy. A summary of recent studies on pre-hospital therapeutic strategies before PCI to reduce infarct size in STEMI patients and improve clinical outcomes is listed in Tab. 1. Recently, sonothrombolysis has been proposed as an adjunctive therapy for acute myocardial infarction [14]. In-vitro studies and in-vivo STEMI models have shown the potential of sonothrombolysis for restoration of epicardial and microvascular flow [15]. A recent randomised controlled trial on the effects of pre- and post-PCI sonothrombolysis in STEMI patients demonstrated a higher angiographic recanalisation rate prior to PCI and reduced infarct size in the intervention group [16]. Pre-PCI sonothrombolysis was performed at the emergency department in the hospital and resulted in thrombolysis in myocardial infarction (TIMI) flow grade ≥2 in almost half of the patients. By performing sonothrombolysis even before hospital arrival, its efficacy may be further improved. In this study, safety and technical feasibility of sonothrombolysis in STEMI patients in the pre-hospital ambulance setting will be assessed. To our knowledge, this is the first time that therapeutic echocardiography will be used in the ambulance.

Thrombolysis and PCI have significantly improved the prognosis of STEMI patients. However, two major clinical problems remain. Firstly, early reperfusion is restricted by patient factors, delays in transfer to PCI capable centres and delays in PCI initiation [1]. The longer the ischaemic time, the greater the size and transmurality of the infarct zone [21, 22]. Actions have been taken to reduce ischaemic time by facilitating early STEMI diagnosis and prehospital activation of the cardiac catheterisation lab. However, total ischaemic time in STEMI patients remains substantial [23]. Secondly, although successful epicardial revascularisation may be achieved, up to 50% of the patients exhibit microvascular injury, resulting in higher infarct sizes, adverse left ventricle remodelling and worse prognosis [4]. Novel therapeutic interventions for STEMI should preferably be applied within minutes of STEMI diagnosis and should also treat or prevent microvascular injury.

In recent years, sonothrombolysis has emerged as a potential adjunctive therapy in cardiovascular ischaemic disease. The technique is based on the lytic and flow-inducing properties of the ultrasound-induced cavitation of contrast microspheres. Once high MI ultrasound impulses are administered during simultaneous infusion of ultrasound contrast agents, the contrast microspheres compress and expand and eventually collapse, inducing local microstreaming capable of thrombus dissolution (Fig. 3; [24, 25]). Various animal models have been used to examine therapeutic contrast echocardiography with and without fibrinolytic drugs [26‐28]. Xie et al. found unexpectedly that high MI impulses using a diagnostic transducer in combination with microbubbles in pigs with acute left anterior descending occlusions not only resulted in higher epicardial recanalisation rates but also resulted in ST-segment resolution and corresponding recovery of wall thickening in six pigs (40%) that did not have epicardial recanalisation [29]. Improvement of microvascular flow could be related to sonolysis of microvascular thrombi or the increased release of the vasodilator and anti-inflammatory nitric oxide from the microvascular endothelium (Fig. 3). The latter explanation is supported by a study in mice where augmentation of limb perfusion was observed upon ultrasound and microbubbles application, whereas inhibition of endothelial nitric oxide synthase attenuated the flow augmentation by 70% [30]. The first pilot study on clinical application of ultrasound and microbubbles in STEMI patients showed safety and feasibility of pre-PCI sonothrombolysis [31]. As preclinical studies suggested efficacy of thrombus dissolution could be improved by increasing high MI pulse duration [32], a small trial was performed using 20 µs high MI impulses [33]. While feasible for restoring microvascular perfusion, transient focal vasoconstriction was seen in three of six patients. In the subsequent MRUSMI trial, 100 patients were randomised to either diagnostic ultrasound-guided treatment with intermittent high MI impulses (5 µs) during microbubble infusion or to a control group [16]. Treatment was given pre- and post-PCI and lasted approximately 15 min per treatment. Angiographic recanalisation prior to PCI was achieved in 48% in the treatment group versus 20% in the control group. Positive results were observed regarding infarct size, left ventricular ejection fraction and need for defibrillator implantation, while vasoconstriction was not observed. Currently, several trials are ongoing that aim to investigate the effects of post-PCI sonothrombolysis on microvascular injury and infarct size (MRUSMI, EU Clinical Trials Register 2018-001277-24).

Since contrast ultrasound is portable, readily available and non-invasive, this technique can be provided at the point-of-care to the STEMI patient. To prevent system delay, sonothrombolysis in the ambulance may offer a convenient solution to achieve early myocardial reperfusion and concomitantly treat microvascular injury in the setting of a STEMI. This study will be the first study in the ambulance setting to examine feasibility of pre-hospital therapeutic contrast ultrasound in STEMI patients.

Recruitment is expected to start in September 2020, completion of recruitment is expected in December 2020. The date and version of the study protocol approved by the ethical review board are: version 3, January 2020.