Absence of biological damage from prolonged exposure to intravascular ultrasound: A swine model

Abstract

Ultrasound (US) has been used in IMS II (intravascular US) and CLOTBUST (transcranial US) clinical trials for thrombolysis. During the treatment, in addition to the targeted thrombus, other biological components, such as blood and vessel walls are subjected to long durations of US exposure. In this study we explored evidence of biological damage due to mechanical forces or thermal effects of US exposure at the frequency, intensity and duration employed for thrombolysis treatment. Biological effects were investigated by exposing swine ilio-femoral arteries bilaterally to an intravascular US generating catheter and a conventional catheter. A total of 12 animals each underwent 8 h of exposure to intravascular pulsed US with a frequency of 2.2 MHz and spatial peak time average intensity (I_SPTA) of 6 W/cm² per transducer (a total of six transducers per catheter) while the ultrasonic device surface temperature was maintained at ⩽43 °C. The animals were euthanized either 24 ± 3 h or 28 ± 3 days post treatment. A range of physiological and hematological parameters were evaluated pre-, post-, and during US exposure. The vascular diameter was determined pre- and post-US exposure using angiograms. Following euthanasia, each animal underwent a gross pathological examination, and the treated vessels and an unexposed vessel were excised for comparative histopathological evaluation. No evidence of biological damage was found at the end of 8 h exposure to intravascular US.

Introduction

Ultrasound (US) has been shown to enhance the thrombolytic process in vitro[1], [2] and in vivo[3]. This effect has been achieved using US alone [4] or as a thrombolytic adjuvant [1], [2], [5], [6], [7]. Subsequently, catheter-directed ultrasonic thrombolysis has been found to augment in vitro[8], [9] and in vivo[10], [11] clot lysis in combination with various thrombolytics. Despite extensive investigations, the mechanism of the prothrombolytic effect of US has not been entirely understood [12], [13], [14], [15]. However it has been demonstrated that thrombolytic efficacy was increased with longer US exposure time [16], [17], [18]. It is therefore relevant to demonstrate that the mechanisms responsible for prothrombolytic activity, when applied over extended therapy time, do not have the potential to cause any biological damage.

Prior testing of intravascular diagnostic ultrasound to determine acute and long term safety, has been undertaken. Intravascular diagnostic ultrasound has generally been proven safe [19], [20], although sometimes has been associated with (but not necessarily the direct cause of) a minor acute clinical risk of negative effects such as vessel spasm [21]. The acoustic operating parameters in these tests were similar to those used in diagnostic ultrasound, having a frequency range of 5–40 MHz, MI of ∼0.1, and I_SPTA ∼ 4 mW/cm². The acoustic parameters for these devices are considerably different from the Lysus^® Infusion System used for this study; it is therefore necessary to investigate the safety of the specific acoustic parameters generated by this device as well.

The goal of this study was to investigate the potentially harmful effects of US by searching for evidence of biological damage after prolonged exposure to US from an intravascular ultrasonic catheter in a swine model.