Hypocarbia and Adverse Outcome in Neonatal Hypoxic-Ischemic Encephalopathy

Both pH and PCO2 affect vascular tone, cerebral blood flow, cerebral oxygenation1 and may thereby modulate neuronal injury in neonates with hypoxic-ischemic encephalopathy (HIE). Experimental evidence suggests that low PCO2 concentrations mediated by hyperventilation in brain injured patients may restore cerebral autoregulation2 and compensate for metabolic acidosis thus preventing further damage. Yet hypocarbia also reportedly contributes to detrimental effects: cerebral vasoconstriction, decreased partial pressure of arterial oxygen, decreased oxygen release from hemoglobin1,3 and excessive neuronal excitability due to increased oxygen demands4. Moreover, animal models of hypocarbia demonstrate nuclear DNA fragmentation5,6, decreased levels of high energy phosphates as well as neuronal7 and mitochondrial8 alterations that lead to apoptotic cell death. In the preterm infant, hypocarbia has been associated with periventricular leukomalacia9,10, cerebral palsy and neurodevelopmental deficits11. Klinger et al reported that episodic hyperoxia and hypocarbia within the first two hours of life are associated with an increased risk of brain injury after HIE12. They postulated that aggressive early management and resuscitation may be contributory. Hypocarbia, in the context of HIE, also may reflect the severity of neural injury (decreased CO2 production) or the infant’s own respiratory drive and ability to correct metabolic acidosis. Moreover, hypocarbia may be impacted by cooling13; hypothermia decreases the rate of brain energy utilization by 5.3% for every 1°C reduction in brain temperature below 38.2°C14 and decreases the basal metabolic rate by 25-30% at 33°C15. So the initial ventilator minute volume required to maintain normocarbia may be significantly lower for infants undergoing whole body cooling. We hypothesized that infants exposed to early hypocarbia following HIE may be at increased risk for death or disability. The present study examines the association between isolated severe hypocarbia (minimum PCO2) and cumulative exposure to PCO2 <35mmHg in the first 16 hours of life and adverse 18-22 month outcome (death or moderate to severe disability) among the participants of the NICHD Neonatal Research Network trial of whole body cooling for neonatal HIE16.