Biological Effects Of Lithotripter Fields

Both cavitation and purely mechanical processes are involved in reduction of stones by lithotripter fields. However, cavitation appears to play a dominant role in most of our experimental studies of this subject. Current research indicates that cavitation also plays a major role in many biological effects in soft tissues. Examples: (1) A single positive shock of 5 MFa kills approximately 50% of population of Drosophila larvae. (2) Shock fields (3 MPa with 10 shocks) cause extravasation in mouse kidneys. (3) Abnormal development in chick embryos occurs after exposure to shock fields above a threshold of approximately 5 MPa (with three shocks). (4) Single shocks at 10 MPa have been shown to interrupt the activity of frog hearts. (5) The threshold for lung damage in mice appears to be -1 MPa. These studies have opened our eyes to a new class of in vivo biological effects of pulsed ultrasound. Recent experiments have yielded a rich inventory of thresholds for effects in mammalian kidney, lung and heart, in the development of chick embryos and fruit fly larvae. In comparison with the pressures used to fragment stones, the thresholds for most of these effects are remarkably low. Successful treatment of kidney stones and gallstones require peak pressures between 20 and 100 MPa and, with those pressure levels, treatments consist of many hundreds or thousands of individual shocks. We are finding thresholds for tissue damage in the range from 3 to 10 MPa with pulse numbers between 3 and 20. The guiding postulate for these studies is that intense pressure waves cause violent collapse and expansion of minute bubbles within the tissues. It has been assumed that one site for this bubble activity is in the blood and that, as a result, small holes are created in the vessel walls which would permit leakage of the blood cells into the surrounding tissues (extravasation). This is a extremely sensitive test because extravasation is almost never observed in normal (sham exposed) tissues. In the mouse, the kidney is more sensitive than the overlying tissues and the interior of the kidney (medulla) is consistently more sensitive than the outer layer (cortex). Some extravasation has been observed in kidneys exposed to 10 shocks at pressures as low as 3 MPa. One can speculate that lung with its rich collection of gas bodies should be particularly susceptible to injury by lithotripter fields. The low frequencies included in the spectrum of the lithotripter are ideally suited to penetrate and to excite cavitation-like activity. Tests with mice show negligible attenuation of the shock wave through the rib cage. Specifically, the experimental tests showed thresholds decreasing monotonically with pulse number leading to 1.5 MPa peak positive pressure with 20 pulses. The experimental protocol did not permit an extension of the studies below that level. Severe damage occurs at levels between 5 and 6 ma. Fetal lung, in contrast, did not show signs of damage at 20 ma. The lower sensitivity of fetal lung is consistent with a cavitation-related mechanism for lung damage by shock waves. Similar thresholds have been found for killing larvae of the fruit fly, Drosophila. Greater mechanistic detail has been obtained through studies of this comparatively simple biological model. Larvae contain small gas bodies stabilized within their respiratory system. Because these bubbles are inhibited in their capacity to expand by the surrounding tissues, it is probable that they do not respond to acoustic fields in the manner described by classical cavitation theory that assumes a spherical bubble in an infinite fluid. However, just because of this inhibited expansion, they may serve as reasonable models for the gas bodies in mammalian tissues. Approximately one half of a population of Drosophila larvae is killed by exposure to 3 to 10 double lithotripter shocks with a positive pressure of 2-3 MPa. In contrast with the predictions of classical cavitation theory, adding a negative pressure to the exposure has little influence on the killing rate or its threshold pressure. The available evidence suggests that interaction of gas bodies in tissues with pressure fields and the resultant biological effects may be qualitatively different than predicted by classical cavitation theory, and that positive rather than negative pressure may be a predictor of these effects. Vertebrate development was studied directly using chick embryos. At 72 hr incubation, embryos in ovo were subjected to three double shockwaves from a Wolf Model 2137.50 Electrohydraulic Lithotripter. Then, after a total of 120 hr of incubation, they were assessed for developmental abnormalities. Early deaths, delayed deaths and malformations were all significantly increased at pressures of 10 MPa with suggestions for possible effects at lower pressure levels. Piezoelectrically or electrohyudraulically-generated shock waves have been shown to interfere with the normal rhythm of frog hearts. The most common and reproducible effect has been the generation of a premature ventricular contraction (PVC). The most sensitive part of the heart cycle is at the time that the muscle cells are repolarized and ready to contract. At that moment, the threshold for PVC generation is of the order of 10 MPa peak positive pressure. The important spin-off of these studies is the guidance which they provide in the search for nonthermal effects of pulsed ultrasound as used in medical diagnosis. The most important result thus far has been the finding that thresholds for lung damage hemorrhage in mice with pulsed ultrasound is of the order of 1-2 MPa. The threshold depends upon temporal peak properties of the wave and is almost independent pulse repetition frequency and temporal average intensitY. Address: Given above.