Early Hyperoxaemia and 2-year Outcomes in Infants with Hypoxic-ischemic Encephalopathy- a Secondary Analysis of the Infant Cooling Evaluation (ICE) trial

Objective(s)To determine the causal relationship between exposure to early hyperoxaemia and death/disability in infants with hypoxic-ischemic encephalopathy (HIE). Study designWe analyzed data from the Infant Cooling Evaluation (ICE) trial that enrolled newborns [≥]35 weeks gestation with moderate-severe HIE, randomly allocated to hypothermia or normothermia. The primary outcome was death or major sensorineural disability at 2 years. We included infants with arterial pO2 measured within 2 h of birth. Using a directed acyclic graph, we established that markers of severity of perinatal hypoxia-ischemia and pCO2 were a minimally sufficient set of variables for adjustment in a regression model to estimate the causal relationship between arterial pO2 and death/disability. ResultsAmong 221 infants, 116 (56%) had arterial pO2 and primary outcome data. The unadjusted analysis revealed a U-shaped relationship between arterial pO2 and death/disability. Among hyperoxaemic infants (pO2 100-500 mmHg) the risk of death/disability was 40/58 (0.69), while the risk in normoxaemic infants (pO2 40 - 99mmHg) was 20/48 (0.42). In the adjusted model, hyperoxaemia increased the risk of death/disability (adjusted risk ratio 1.61, 95% CI 1.07 - 2.00, p= 0.03) in relation to normoxaemia. ConclusionsEarly hyperoxaemia increased the risk of death/disability among infants who had an early arterial pO2 in the ICE trial. Limitations include the possibility of residual confounding and other causal biases. Further work is warranted to confirm this relationship in the era of routine therapeutic hypothermia.