Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia

Abstract

Background: Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown.

Methods: We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age.

Results: We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups.

Conclusions: In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.).

Figure 1 (facing page).. Recruitment, Randomization, and Follow-up.

Infants were enrolled at 50 hospitals; however, the centers participating in the Neonatal Research Network changed over time, and the timing of approval by institutional review boards varied. Therefore, the number of hospitals enrolling at any given time was lower than 50. Although 1523 infants were excluded for previous receipt of glucocorticoids, only 339 of these infants had received glucocorticoid therapy for bronchopulmonary dysplasia (BPD). Thus, 3.4% of the 9837 ineligible infants were excluded for this reason. The majority (1184) had received early therapy for hypotension. There were 11 infants for whom the severity of neurodevelopmental impairment (NDI) could not be determined. According to the protocol for the follow-up study, from which we obtained the NDI data in our trial, NDI could be determined if a component of a binary indicator in the NDI definition was known as “Yes,” but the severity level could be determined only when other components of level of severity were not missing.

Figure 2.. Infants Extubated According to Day of Treatment.

Shown are Kaplan–Meier estimates of the proportion of infants remaining intubated within the first 14 days of the trial. The probability of being extubated by the end of the treatment period was 44.7% in the hydrocortisone group and 33.6% in the placebo group. The rate ratio for extubation estimated from the proportional-hazards model was 1.54 (95% CI, 1.23 to 1.93).