No abstract

Ultrasound cavitation of microbubble contrast agents has a potential for therapeutic applications such as sonothrombolysis (STL) in acute ischemic stroke. For safety, efficacy, and reproducibility of treatment, it is critical to evaluate the cavitation state (moderate oscillations, stable cavitation, and inertial cavitation) and activity level in and around a treatment area. Acoustic passive cavitation detectors (PCDs) have been used to this end but do not provide spatial information. This paper presents a prototype of a 2-D cavitation imager capable of producing images of the dominant cavitation state and activity level in a region of interest. Similar to PCDs, the cavitation imaging described here is based on the spectral analysis of the acoustic signal radiated by the cavitating microbubbles: ultraharmonics of the excitation frequency indicate stable cavitation, whereas elevated noise bands indicate inertial cavitation; the absence of both indicates moderate oscillations. The prototype system is a modified commercially available ultrasound scanner with a sector imaging probe. The lateral resolution of the system is 1.5 mm at a focal depth of 3 cm, and the axial resolution is 3 cm for a therapy pulse length of 20 µs. The maximum frame rate of the prototype is 2 Hz. The system has been used for assessing and mapping the relative importance of the different cavitation states of a microbubble contrast agent. In vitro (tissue-mimicking flow phantom) and in vivo (heart, liver, and brain of two swine) results for cavitation states and their changes as a function of acoustic amplitude are presented.

During a microbubble infusion, guided high mechanical index impulses from a diagnostic two dimensional transducer improve microvascular recanalization in acute ST segment elevation myocardial infarction (STEMI). The purpose of this study was to further elucidate the mechanism of improved microvascular flow in normal and hyperlipidemic, atherosclerotic pigs. In 14 otherwise normal pigs, an acute left anterior descending thrombotic coronary occlusion was created. Pigs subsequently received aspirin, heparin and ½ dose fibrinolytic agent (Tenecteplase or tissue plasminogen activator), followed by randomization to either no additional treatment (Group I), or a continuous infusion of non-targeted microbubbles and guided high mechanical index impulses from a three dimensional transducer (3D/mechanical index; Group II). Epicardial recanalization rates, ST segment resolution, microsphere-derived myocardial blood flow (MBF), and ultimate infarct size using myocardial contrast echocardiography were compared. The same coronary thrombosis was created in a set of 12 hypercholesterolemic pigs who were then treated with the same pharmacologic and ultrasound regimen (Group III; n=6) or the pharmacologic regimen alone (Group IV; n=6). Epicardial recanalization rates in Group I and II pigs were the same (29%), however, peri-infarct MBF and ultimate infarct size improved following treatment in Group II pigs (p <0.01 versus Group I). In Group III pigs, epicardial recanalization was 100% (compared to 50% in Group IV), and there were significant reductions in ultimate infarct size (p=0.02 compared to Group IV). We conclude that guided high mechanical index impulses from a diagnostic transducer and non-targeted microbubbles improve peri-infarct microvascular flow in acute STEMI, even when epicardial recanalization does not occur.

Ultrasound induced cavitation has been explored as a method of dissolving intravascular and microvascular thrombi in acute myocardial infarction. The purpose of this study was to determine the type of cavitation required for success, and whether longer pulse duration therapeutic impulses (sustaining the duration of cavitation) could restore both microvascular and epicardial flow with this technique. Accordingly, in 36 hyperlipidemic atherosclerotic pigs, thrombotic occlusions were induced in the mid-left anterior descending artery. Pigs were then randomized to either a) ½ dose tissue plasminogen activator (0.5 mg/kg) alone; or same dose plasminogen activator and an intravenous microbubble infusion with either b) guided high mechanical index short pulse (2.0 MI; 5 usec) therapeutic ultrasound impulses; or c) guided 1.0 mechanical index long pulse (20 usec) impulses. Passive cavitation detectors indicated the high mechanical index impulses (both long and short pulse duration) induced inertial cavitation within the microvasculature. Epicardial recanalization rates following randomized treatments were highest in pigs treated with the long pulse duration therapeutic impulses (83% versus 59% for short pulse, and 49% for tissue plasminogen activator alone; p<0.05). Even without epicardial recanalization, however, early microvascular recovery occurred with both short and long pulse therapeutic impulses (p<0.005 compared to tissue plasminogen activator alone), and wall thickening improved within the risk area only in pigs treated with ultrasound and microbubbles. We conclude that although short pulse duration guided therapeutic impulses from a diagnostic transducer transiently improve microvascular flow, long pulse duration therapeutic impulses produce sustained epicardial and microvascular re-flow in acute myocardial infarction.