by Lei Lei Wu, Staff Writer, MedPage Today March 23, 2022

Hydrocortisone given 2 to 4 weeks after birth did not significantly reduce incidence of bronchopulmonary dysplasia (BPD) in preterm infants, a multicenter randomized controlled trial showed.

Among 800 extremely preterm infants, 16.6% receiving hydrocortisone were alive and without moderate-to-severe BPD at 36 weeks postmenstrual age compared with 13.2% of infants in a placebo group (adjusted rate ratio [aRR] 1.27, 95% CI 0.93-1.74), reported Kristi Watterberg, MD, of the University of New Mexico Health Sciences Center in Albuquerque, and colleagues.

During treatment, more infants in the hydrocortisone group were successfully extubated versus the placebo group (44.7% vs 33.6%; RR 1.54, 95% CI 1.23-1.93), and they spent fewer days on mechanical ventilation before 36 weeks of postmenstrual age (median 37 vs 40 days), they noted in the New England Journal of Medicine.

However, by 36 weeks, there were no substantial differences between groups in the number of infants who had been extubated, the duration of supplemental oxygen therapy, or the length of hospital stay.

"Our hypothesis that earlier extubation would result in a decreased incidence of moderate or severe bronchopulmonary dysplasia or death was not supported by these results," Watterberg and team wrote.

BPD is a common condition in extremely premature infants, which may result in continued breathing problems over the long term. Dexamethasone -- a more potent glucocorticoid than hydrocortisone -- has been used in extremely preterm infants for BPD but comes with the risk of harming the infant's neurodevelopment, resulting in cognitive impairment or cerebral palsy, the authors said.

In terms of safety with hydrocortisone, there were no differences in survival rates without moderate-to-severe neurodevelopmental impairment between the intervention and placebo groups (36.9% vs 37.3%; aRR 0.98, 95% CI 0.81-1.18). Of note, dexamethasone was administered to a sizeable proportion of infants in each group -- 39.7% in the hydrocortisone group and 42.1% in the placebo group.

"The cause of BPD is multifactorial," wrote Anne Greenough, MD, MBBS, of King's College London, in a corresponding editorial. "It is highly unlikely that a single therapeutic intervention will have a significant effect on outcome. Given the aforementioned results, we should stop looking for the silver bullet and move toward assessing a combination of interventions."

Rather than focusing on finding the right way to give glucocorticoids to extremely preterm infants, future research should concentrate "on their potential role in the amelioration of severe respiratory disease," she added.

The study results mirror those from a study published in 2019 that also found no difference in BPD incidence with hydrocortisone use, Watterberg and colleagues noted. They suggested that the intervention may be ineffective because it began too late -- injury due to lung inflammation had already been established.

They pointed to a meta-analysis that suggested that earlier therapy with hydrocortisone could reduce risk of BPD. "Because early lung inflammation has been linked to bronchopulmonary dysplasia, earlier therapy could be more effective by ameliorating early adrenal insufficiency and thereby decreasing early lung inflammation," they wrote.

However, Greenough warned that there is a consequence to starting therapy earlier: "Although targeting early lung inflammation might be more effective, hydrocortisone given in the first week after birth has increased the incidence of gastrointestinal perforation," she wrote.

This double-masked, placebo-controlled trial was conducted at 19 academic centers across the U.S. Infants were included if they had an estimated gestational age of <30 weeks, were 14 to 28 postnatal days old, and were receiving mechanical ventilation through an endotracheal tube. Those who had major congenital conditions, indomethacin or ibuprofen treatment 48 hours prior to trial entry, and previous glucocorticoid treatment were excluded.

In total, 800 infants were randomized 1:1 to the hydrocortisone and placebo groups. Hydrocortisone was administered over 10 days, beginning at 4 mg/kg for the first 2 days and gradually decreasing to 0.5 mg/kg by the last 2 days. Infants in the placebo group received a saline solution.

Of the included infants, mean birth weight was 715 g, and mean gestational age was approximately 25 weeks. About 47% of those in the treatment group were boys compared with 58.5% in the placebo group. For both groups, mean maternal age was about 28 years.

Hypertension was more common in the hydrocortisone group, with 4.3% treated with an antihypertensive compared with 1% in the placebo group, although all other adverse events were relatively similar across the two groups, Watterberg and team noted.

They acknowledged that only two-thirds of eligible patients were enrolled in their trial, and many were treated with dexamethasone, which were limitations to the study.

Lei Lei Wu is a staff writer for Medpage Today. She is based in New Jersey. Follow

The study was funded by grants from the National Institutes of Health. Watterberg reported a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Greenough reported grants from SLE and Chiesi.

New England Journal of Medicine

Source Reference: Watterberg KL, et al "Hydrocortisone to improve survival without bronchopulmonary dysplasia" N Engl J Med 2022; DOI: 10.1056/NEJMoa2114897

New England Journal of Medicine

Source Reference: Greenough A "Hydrocortisone to prevent bronchopulmonary dysplasia -- not a silver bullet" N Engl J Med 2022; DOI: 10.1056/NEJMe2200247

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