Background We tested the hypotheses that caffeine therapy would increase the ventilatory response to hypercarbia in infants above the effect of maturation and those with a weaker ventilatory response to hypercarbia would be more likely to subsequently develop apnea that required treatment.MethodsInfants born at less than 34 weeks of gestation underwent a steady-state hypercarbic challenge using 0, 2, and 4% carbon dioxide soon after birth that was repeated at weekly intervals. The results of the initial study were compared between infants who did or did not subsequently develop apnea requiring treatment with caffeine.ResultsTwenty-six infants born at a median gestation of 32 (range 31-33) weeks were assessed. Caffeine administration was associated with an increase in CO2 sensitivity, and the mean increase was 15.3 (95% CI: 1-30) ml/kg/min/% CO2. Fourteen infants subsequently developed apnea treated with caffeine. After controlling for gestational age and birth weight, they had significantly lower carbon dioxide sensitivity at their initial study compared with those who did not require treatment.ConclusionCaffeine administration was associated with an increase in the ventilatory response to hypercarbia. An initial weaker ventilatory response to hypercarbia was associated with the subsequent development of apnea requiring treatment with caffeine.Pediatric Research advance online publication, 23 May 2018; doi:10.1038/pr.2018.48.