The neural and vascular effects of killed Su-Streptococcus pyogenes (OK-432) in preterm fetal sheep

Abstract

Fetal exposure to inflammatory mediators is associated with a greater risk of brain injury and may cause endothelial dysfunction; however, nearly all the evidence is derived from gram-negative bacteria. Intrapleural injections of OK-432, a killed Su-strain of Streptococcus pyogenes, has been used to treat fetal chylothorax. In this study, we evaluated the neural and cardiovascular effects of OK-432 in preterm fetal sheep (104 +/- 1 days, term 147 days). OK-432 (0.1 mg, n = 6) or saline vehicle (n = 7) was infused in the fetal pleura, and fetuses were monitored for 7 days. Blood samples were taken routinely for plasma nitrite measurement. Fetal brains were taken for histological assessment at the end of the experiment. Between 3 and 7 h postinjection, OK-432 administration was associated with transient suppression of fetal body and breathing movements and electtroencephalogram activity (P < 0.05), increased carotid and femoral vascular resistance (P < 0.05), but no change in blood pressure. Brain activity and behavior then returned to normal except in one fetus that developed seizures. OK-432 fetuses showed progressive, sustained vasodilatation (P < 0.05), with lower blood pressure after 4 days (P < 0.05), but normal heart rate. There were no changes in plasma nitrite levels. Histological studies showed bilateral infarction in the dorsal limb of the hippocampus of the fetus that developed seizures, but no injury in other fetuses. We conclude that a single low-dose injection of OK-432 can be associated with risk of focal cerebral injury in the preterm fetus and chronic central and peripheral vasodilatation that does not appear to be mediated by nitric oxide.

Limited predictive value of early changes in EEG spectral power for neural injury after asphyxia in preterm fetal sheep

“…Thus, it is critical to find ways of identifying injured infants as soon as possible in the early recovery phase (18). Disappointingly, this study shows that in preterm fetal sheep, total EEG power and power Articles Keogh et al…”

“…Total EEG power (µV 2 ) was calculated from the intensity spectra. Quantitative EEG measurements for each waveform were performed to quantify power in the Δ (0-3.9 Hz), θ (4-7.9 Hz), α (8-12.9 Hz), and β (13)(14)(15)(16)(17)(18)(19)(20)(21)(22) bands. This involved calculating power spectra (by fast Fourier transform) of the EEG on sequential epochs, using a 10 s Hanning window to minimize spectral leakage.…”

Towards improved animal models of neonatal white matter injury associated with cerebral palsy

“…Advantages of this model include: (1) neurodevelopment of the preterm sheep fetus (65% gestation) is comparable to that of the preterm human between approximately 24 and 28 weeks of gestation, and (2) the size of the fetal sheep permits longerterm procedures that cause damage, as well as invasive monitoring of fetal physiological status (e.g. brain oxygenation and electroencephalography) (Bennet et al, 2010;Rees et al, 2010). It is feasible to generate selective focal or more diffuse white matter lesions without necrotic PVL-like lesions; this leads to lesions that resemble the types of injury that are now common in surviving preterm infants (Riddle et al, 2006).…”

Successful Treatment of Severe Fetal Chylothorax Resistant to Repeated Pleuroamniotic Shunting by OK-432 Pleurodesis

“…Further evidence is needed to determine not only the efficacy of OK-432 in various patient groups, but also its safety. Hippocampal infarction after intrapleural OK-432 was reported in preterm fetal sheep [12]. There was no mention of such happening in the largest human series of 45 cases in Yang et al [10].…”

“…Conventionally, thoracoamniotic shunting is the gold standard of treatment in fetal chylothorax [10,12]. In selected cases, however, OK-432 could be considered in preference to shunting.…”