Hypercapnia Causes Injury of the Cerebral Cortex and Cognitive Deficits in Newborn Piglets

Karen Fritz, Drexel University College of Medicine, Philadelphia, Pennsylvania 19104.
Georgios Sanidas, Center for Neuroscience Research, Children's National Research Institute, Washington, DC 20010.
Rodolfo Cardenas, Center for Neuroscience Research, Children's National Research Institute, Washington, DC 20010.
Javid Ghaemmaghami, Center for Neuroscience Research, Children's National Research Institute, Washington, DC 20010.
Chad Byrd, Center for Neuroscience Research, Children's National Research Institute, Washington, DC 20010.
Gabriele Simonti, Center for Neuroscience Research, Children's National Research Institute, Washington, DC 20010.
Adriana Valenzuela, Center for Neuroscience Research, Children's National Research Institute, Washington, DC 20010.
Ignacio Valencia, Drexel University College of Medicine, Philadelphia, Pennsylvania 19104.
Maria Delivoria-Papadopoulos, Drexel University College of Medicine, Philadelphia, Pennsylvania 19104.
Vittorio Gallo, Seattle Children's Research Institute, Seattle, Washington 98101 pankratimenos@gwu.edu vittorio.gallo@seattlechildrens.org.
Ioannis Koutroulis, Center for Neuroscience Research, Children's National Research Institute, Washington, DC 20010.
Terry Dean, Center for Neuroscience Research, Children's National Research Institute, Washington, DC 20010.
Panagiotis Kratimenos, Center for Neuroscience Research, Children's National Research Institute, Washington, DC 20010 pankratimenos@gwu.edu vittorio.gallo@seattlechildrens.org.

Document Type

Journal Article

Publication Date

3-1-2024

Journal

eNeuro

Volume

11

Issue

3

DOI

10.1523/ENEURO.0268-23.2023

Keywords

cortex; hypercapnia; hypercarbia; neonatal; permissive; piglet

Abstract

In critically ill newborns, exposure to hypercapnia (HC) is common and often accepted in neonatal intensive care units to prevent severe lung injury. However, as a "safe" range of arterial partial pressure of carbon dioxide 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 electroencephalogram frequencies. HC induced a transient energy failure in cortical neurons, a persistent dysregulation of calcium-dependent proapoptotic signaling in the cerebral cortex, and activation of the apoptotic cascade, leading to nuclear deoxyribonucleic acid fragmentation. While neither 1 h of HC nor the rapid normalization of HC was 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.

Department

Pediatrics

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