Hypercapnia causes injury of the cerebral cortex and cognitive deficits in newborn piglets.

In critically ill newborns, exposure to hypercapnia (HC) is common and often accepted in neonatal intensive care units (NICUs) to prevent severe lung injury. However, as a "safe" range of arterial partial pressure of carbon dioxide (PaCO2 ) levels in neonates has not been established, the potential impact of HC on the neurodevelopmental outcomes in these newborns remains a matter of concern. Here, in a newborn Yorkshire piglet model of either sex, we show that acute exposure to HC induced persistent cortical neuronal injury, associated cognitive and learning deficits, and long-term suppression of cortical electroencephalographic (EEG) frequencies. HC induced a transient energy failure in cortical neurons, a persistent dysregulation of calcium-dependent pro-apoptotic signaling in the cerebral cortex, and activation of the apoptotic cascade, leading to nuclear deoxyribonucleic acid (DNA) fragmentation. While neither one hour of HC nor the rapid normalization of HC were associated with changes in cortical bioenergetics, rapid resuscitation resulted in a delayed onset of synaptosomal membrane lipid peroxidation, suggesting a dissociation between energy failure and the occurrence of synaptosomal lipid peroxidation. Even short durations of HC triggered biochemical responses at the subcellular level of the cortical neurons resulting in altered cortical activity and impaired neurobehavior. The deleterious effects of HC on the developing brain should be carefully considered as crucial elements of clinical decisions in the neonatal intensive care unit. Significance Statement Hospitalized critically ill neonates commonly experience hypercapnia as part of common practice in neonatal intensive care, as ventilated newborns are subjected to "permissive hypercapnia" to reduce lung injury associated with positive pressure ventilation. To answer the clinically important question of how "safe" that practice is, the present study provides new insights into the complex effects of hypercapnia on neuronal processes, with significant ramifications for ongoing neurodevelopment.