AUGMENTATION OF TISSUE PERFUSION WITH CONTRAST ULTRASOUND: INFLUENCE OF 3-D BEAM GEOMETRY AND CONDUCTED VASODILATION.

BACKGROUND Cavitation of microbubble contrast agents with ultrasound produces shear-mediated vasodilation and an increase in tissue perfusion. We investigated the influence of the size of the cavitation volume by comparing flow augmentation produced by 2-D versus 3-D therapeutic ultrasound. We also hypothesized that cavitation could augment flow beyond the ultrasound field through release of vasodilators that are carried downstream. METHODS In 11 rhesus macaques, cavitation of intravenously-administered lipid-shelled microbubbles was performed in the proximal forearm flexor muscles unilaterally for 10 minutes. Ultrasound cavitation (1.3 MHz, 1.5 MPa peak negative pressure) was performed with 2-D or 3-D transmission with beam elevations of 5 and 25 mm, respectively; and pulsing intervals (PI) sufficient to allow complete post-destruction refill (5 and 12 seconds for 2-D and 3-D, respectively). Contrast ultrasound perfusion imaging was performed before and after cavitation, using multiplane assessment within and beyond the cavitation field at 1.5 cm increments. Cavitation in the hindlimb of mice using 2-D ultrasound at PI of 1 or 5 seconds was performed to examine microvascular flow changes from cavitation in only arteries versus the microcirculation. RESULTS In primates, the degree of muscle flow augmentation in the center of the cavitation field was similar for 2-D and 3-D conditions (5-6-fold increase for both, p<0.01 vs baseline). The spatial extent of flow augmentation was only modestly greater for 3-D cavitation owing to an increase in perfusion with 2-D transmission well beyond the cavitation field. In mice, cavitation in the microvascular compartment (PI 5 second) produced the greatest degree of flow augmentation, yet cavitation in the arterial compartment (PI 1 second) still produced a 3-4-fold increase in flow (p<0.001 vs control). Mechanism for flow augmentation beyond the cavitation zone was investigated by in vitro studies that demonstrated cavitation-related release of vasodilators, including ATP and nitric oxide, from erythrocytes and endothelial cells. CONCLUSION Compared with 2-D transmission, 3-D cavitation of microbubbles generates a similar degree of muscle flow augmentation, possibly because of a tradeoff between volume of cavitation and PI; and only modestly increases the spatial extent of flow augmentation because of the ability of cavitation to produce conducted effects beyond the ultrasound field.