Hypercapnia-Induced Modifications of Neuronal Function in the Cerebral Cortex of Newborn Piglets

Abstract

There is significant controversy over the effects of hypercapnia on the human newborn brain. Previous studies have shown that 1 h of an arterial CO 2 pressure (PaCO 2 ) of 80 mm Hg alters brain cell membrane Na ϩ K ϩ -ATPase enzyme activity in the cerebral cortex of newborn piglets. The present study tests the hypothesis that hypercapnia (either a PaCO 2 of 65 or 80 mm Hg) results in decreased energy metabolism and alters neuronal nuclear enzyme activity and protein expression, specifically Ca ϩϩ / calmodulin-dependent kinase (CaMK) IV activity, phosphorylation of cAMP response element binding protein (CREB), and expression of apoptotic proteins in cortical neuronal nuclei of newborn piglets. Studies were performed in 20 anesthetized normoxic piglets ventilated at either a PaCO 2 of 65 mm Hg, 80 mm Hg, or 40 mm Hg for 6 h. Energy metabolism was documented by ATP and phosphocreatine (PCr) levels. Results show ATP and PCr levels were significantly lower in the hypercapnic groups than the normocapnic. CaMK IV activity, phosphorylated CREB density, and Bax protein expression were all significantly higher in the hypercapnic groups than the normocapnic group. Bcl-2 protein was similar in all three groups, making the ratio of Bax/Bcl-2 significantly higher in the hypercapnic groups than in the normocapnic group. We conclude that hypercapnia alters neuronal energy metabolism, increases phosphorylation of transcription factors, and increases the expression of apoptotic proteins in the cerebral cortex of newborn piglets and therefore may be deleterious to the newborn brain. The long-term neurologic morbidity for preterm and ill term human newborns remains a serious concern. Among these infants, hypercapnia is a common occurrence. Current clinical practice often allows infants ventilated acutely or chronically to remain hypercapnic (undergoing "permissive hypercapnia") to limit ventilator-induced lung injury. The effects of hypercapnia on the newborn brain are controversial as there is not a known safe range of arterial CO 2 pressure (PaCO 2 ).Some recent clinical studies have not shown an immediate harmful effect of hypercapnia in human infants (1-3). However, in most of these studies, long-term neurologic outcomes were not reported. In addition, subtle alterations in brain structure and function may not be detectable in these clinical studies.Hypercapnia (PaCO 2 Ͼ60 mm Hg) results in increased CBF and decreased cerebral vascular resistance in newborn infants (4 -6) and has been associated with intraventricular hemorrhage in some studies (7-9) but not in others (10,11). There are some clinical data suggesting that hypercapnia may be harmful to the newborn brain even if it does not result in intraventricular hemorrhage (12)(13)(14). Moderate elevations in PaCO 2 (end tidal PCO 2 of 60 mm Hg) in healthy preterm (33-36 wk) infants significantly impeded brain stem auditory evoked responses (15). In other studies, very-low-birth-weight infants and term infants with impaired CBF reactivity during hypercapnia had poor neurologic...

Fetal Hypercapnia and Cerebral Tissue Oxygenation: Studies in Near-Term Sheep

“…Our findings in the present study of hypercapnic-induced increase in cortical tissue PO 2 and ss [HbO 2 ] support these concepts, suggesting a protective role of hypercapnia on the CNS. As a cautionary note, in the newborn piglet one study suggested adverse effects, including altered cerebral cortex nuclear enzyme activity and protein expression, of severe hypercapnia (PaCO 2 ϭ 65-80 torr) (32). In turn, the decrease in fractional O 2 extraction and CMRO 2 seen in the present study may be a basis of these changes.…”

Thoracoscopic repair of congenital diaphragmatic hernia: intraoperative ventilation and recurrence

“…Hypercapnia may alter cerebral metabolism independent of any effect on brain oxygenation. When neonatal piglets were well oxygenated but exposed to increasing levels of CO 2 for 6 hours, there was decreased adenosine triphosphate generation, phosphorylation of transcription factors, and increased apoptosis in the brain [14]. It is therefore worth considering the effects of CO 2 on cerebral metabolism and oxygenation, even though there have been few documented adverse effects of CO 2 insufflation during thoracoscopy in CDH patients.…”

Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat

“…Such adverse effects have included inhibition of surfactant function through increased protein nitration (41,65) or, when hypercapnia was induced by low rate and tidal volume ventilation, an enhancement of inflammatory (lipopolysaccharide induced) lung injury (40). These findings, coupled with evidence that hypercapnia can also have adverse effects on brain and retinal development in newborn animals (16,20), indicates that a great deal of further study is required before hypercapnia can be considered as a potential therapy in the human newborn. Extrapolation of our current findings to human newborns with pulmonary hypertension is also limited by the fact that chronic hypoxia is only an initiating or perpetuating factor in some infants.…”