Superthreshold behavior and threshold estimation of ultrasound-induced lung hemorrhage in pigs: Role of age dependency

Abstract

Age-dependent threshold and superthreshold behavior of ultrasound-induced lung hemorrhage were investigated with 116 2.1 0.3-kg neonate crossbred pigs (4.9 1.6 days old), 103 10 1.1-kg crossbred pigs (39 5 days old), and 104 20 1.2-kg crossbred pigs (58 5 days old). Exposure conditions were: 3.1 MHz, 10-s exposure duration, 1-kHz pulse repetition frequency (PRF), and 1.2-s pulse duration. The in situ (at the pleural surface) peak rarefactional pressure ranged between 2.2 and 10.4 MPa with either eight or nine acoustic pressure groups for each of the three pig ages (12 pigs/exposure group) plus sham exposed pigs. There were no lesions in the shams. Pigs were exposed bilaterally with the order of exposure (left then right lung, or right then left lung) and acoustic pressure both randomized. Pig age was not randomized. Individuals involved in animal handling, exposure, and lesion scoring were blinded to the exposure condition. Logistic regression analysis was used to examine the dependence of the lesion incidence rates on in situ peak rarefactional pressure, left versus right lung exposure, order of exposure (first versus second), and age in three age groups. Likewise, lesion depth and lesion root surface area were analyzed using Gaussian tobit regression analysis. A significant threshold effect on lesion occurrence was observed as a function of age; younger pigs were less susceptible to lung damage given equivalent in situ exposure. Overall, the oldest pigs had a significantly lower threshold (2.87 0.29 MPa) than middle-aged pigs (5.83 0.52 MPa). The oldest pigs also had a lower threshold than neonate pigs (3.60 0.44 MPa). Also, an unexpected result was observed. The ultrasound exposures were bilateral, and the threshold results reported above were based on the lung that was first exposed. After the first lung was exposed, the pig was turned over and the other lung was exposed to the same acoustic pressure. There was a significant decrease (greater than the confidence limits) in occurrence thresholds: 3.60 to 2.68, 5.83 to 2.97, and 2.87 to 1.16 MPa for neonates, middle-aged, and oldest pigs, respectively, in the second lung exposed. Thus, a subtle effect in lung physiology resulted in a major effect on lesion thresholds.

Ultrasound–biophysics mechanisms

“…Fig. 21 shows all of occurrence threshold findings across four species using the same methodology [mouse (Zachary et al, 2001a), rat (Zachary et al, 2001a;O'Brien et al, 2001O'Brien et al, , 2003b, rabbit , and pig (O'Brien et al, 2003a)]. Pre-2000 occurrence threshold findings (Fig.…”

“…Error bars are SEMs. These data, by groupings from left to right, are derived, respectively, from Zachary et al (2001a) and O'Brien et al (2001O'Brien et al ( ,2003aO'Brien et al ( ,b,2006. Summary of lesion occurrence thresholds in terms of p r(in situ) (MPa) (bars; left axis) and MI (lines, right axis) from studies not using our experimental techniques and statistical approach.…”

Threshold estimation of ultrasound-induced lung hemorrhage in adult rabbits and comparison of thresholds in mice, rats, rabbits and pigs

“…The exposimetry and calibration procedures have been described previously in detail (Frizzell et al 2003;O'Brien et al 2001bO'Brien et al ,2003aO'Brien et al ,2003bO'Brien et al ,2005Zachary et al 2001aZachary et al ,2001b. Ultrasonic exposures were conducted using a focused f/2, 19-mm-diameter, lithium niobate ultrasonic transducer (Valpey Fisher, Hopkinton, MA, USA).…”

“…However, concerns for its safety continue to be raised and addressed by members of the bioeffects research community (WFUMB 1998;AIUM 2000). These concerns are the result of numerous US-induced lung hemorrhage studies in mice, rats, rabbits, monkeys and pigs at exposure conditions similar to those used for scanning in humans Hartman et al 1990;Penney et al 1993;Raeman et al ,1996Frizzell et al 1994Frizzell et al ,2003Tarental and Canfield 1994;Zachary and O'Brien 1995;Harrison et al 1995;Baggs et al 1996;Holland et al 1996;O'Brien and Zachary 1997;Dalecki et al 1997aDalecki et al ,1997bWFUMB 1998;AIUM 2000;O'Brien et al 2000O'Brien et al ,2001aO'Brien et al , 2001bO'Brien et al ,2003aO'Brien et al ,2003bO'Brien et al ,2005Kramer et al 2001;Zachary et al 2001aZachary et al ,2001b.…”

“…Further, because there have been other threshold studies conducted using the same experimental and analysis protocols, but with different species, the rabbit threshold findings are compared against adult mouse ) and adult rat O'Brien et al 2001b), as well as pig threshold findings (O'Brien et al 2003a). These threshold findings represent a unique species-dependent dataset that is not available for any other in vivo US-induced biologic effect.…”