Changes in brain interstitial pH induced by hypoxia versus asphyxia in normothermic or hypothermic newborn pigs: implications for the preclinical study of neonatal hypoxic-ischemic encephalopathy.

Brain interstitial pH (pH ) alterations contribute to neuronal injury in neonatal hypoxic-ischemic encephalopathy (HIE), the severe neurodevelopmental consequence of birth asphyxia affecting millions of neonates each year. In various HIE animal models, including the established large-animal piglet model, normocapnic hypoxia or asphyxia are both employed as insults to elicit HIE. However, hypoxia or asphyxia may trigger neuronal injury by distinct pathomechanisms as suggested by a recent study reporting that hypoxia triggered an alkalotic while asphyxia an acidotic shift in pH in hypothermic P6 rat pups (Acta Physiol 229:e13467, 2020). We have recently shown that asphyxia results in a profound cerebral acidosis that was restored in the first hour of reventilation then remained stable throughout the 24h observation period in normothermic piglets, but information on the effect of normocapnic hypoxia on pH and the potential confounding effect of body temperature alteration in piglets was unknown. Anesthetized, mechanically ventilated P1 piglets (n=21) were equipped with an open cranial window to determine pH using pH-selective microelectrodes inserted into the parietal cortex. Asphyxia or hypoxia was induced by swithching the ventilation to a 6%O - 20%CO gas mixture or to 6%O for 20 min, respectively in either normothermic (38.5 °C) or hypothermic (33.5 °C) pigs (n=5-6 in each group) followed by 60 min reoxygenation/reventilation. Both arterial blood pH (pH ) and pH (Figure 1) showed an acidotic shift during the insult in all four experimental conditions. Cerebral acidosis was similar in normothermic animals exposed to either asphyxia or hypoxia, despite the shift in pH was 0.46 (0.36-0.56) pH units larger in the asphyxiated animals (Figure 2). In hypothermic conditions, however, the acidotic pH shift was greatly attenuated only in the hypoxia but not in the asphyxia group. Our findings suggest that using hypoxia or asphyxia insults result in similar cerebral but not systemic (blood) acidosis in normothermic piglets. However, the degree of developing cerebral acidosis to hypoxia is greatly attenuated in hypothermic animals, although an alkalotic shift reported in rats could not be observed.