Background: Abnormal PCO 2 is common in infants with hypoxic ischemic encephalopathy (HIE). The objective was to determine whether hypocapnia was independently associated with unfavorable outcome (death or severe neurodevelopmental disability at 18 mo) in infants with moderate-to-severe HIE. Methods: This was a post hoc analysis of the CoolCap Study in which infants were randomized to head cooling or standard care. Blood gases were measured at prespecified times after randomization. PCO 2 and follow-up data were available for 196 of 234 infants. Analyses were performed to investigate the relationship between hypocapnia in the first 72 h after randomization and unfavorable outcome. results: After adjusting for pH, amplitude-integrated electroencephalogram background and seizures, birth weight, Apgar score at 5 min, cooling status, and Sarnat stage, PCO 2 was inversely associated with unfavorable outcome (P < 0.001). The probability of unfavorable outcome was 0.20 ± 0.1 (point estimate ± SE), 0.53 ± 0.23 and 0.89 ± 0.16 for a PCO 2 of 40, 30, and 20 mm Hg respectively and was greater in infants with severe HIE than with moderate HIE. conclusions: Hypocapnia in infants with moderate-tosevere HIE was independently associated with unfavorable outcome. Future studies of controlled normocapnia will be important.t he cerebral vasculature is exquisitely sensitive to changes in the partial pressure of carbon dioxide (PCO 2 ). Hypercapnia leads to cerebral vasodilation and hyperperfusion and, reciprocally, hypocapnia is a potent mediator of cerebral vasoconstriction leading to decreased cerebral blood flow (1). Hypocapnia has been associated with brain injury in animals and human infants (2-11). In a large retrospective cohort study of infants with hypoxic ischemic encephalopathy (HIE), severe hypocapnia was associated with increased risk of subsequent death or severe neurodevelopmental impairment, with an odds ratio of 2.3 (12). Consistent with this, in the National Institute of Child Health and Human Development Neonatal Research Network randomized, controlled trial of whole-body hypothermia in term infants with HIE, both minimum and cumulative exposure to hypocapnia in the first 12 h of the trial were associated with death or adverse neurodevelopmental outcome (13). The dose-response relationship between PCO 2 and outcome for infants with moderate-to-severe HIE is unknown.The risk of developing hypocapnia or hypercapnia may be affected by severity of brain injury, intensity and duration of newborn resuscitation, timing after the primary injury, and/or response to metabolic acidosis. Thus, in this secondary analysis of the CoolCap Study (14), we sought to confirm the observation that hypocapnia in infants with moderate-to-severe HIE is associated with unfavorable outcome at 18 mo. Further, we tested the hypothesis that unfavorable outcome would be dose-dependently associated with decreasing PCO 2 and that hypocapnia would be associated with a greater adverse effect in infants with severe than in those with moderate HIE.
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