Published online December 1, 2004
PEDIATRICS Vol. 114 No. 6 December 2004, pp. 1649-1657 (doi:10.1542/peds.2004-1159)
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Prophylaxis of Early Adrenal Insufficiency to Prevent Bronchopulmonary Dysplasia: A Multicenter Trial

Kristi L. Watterberg, MD*, Jeffrey S. Gerdes, MD{ddagger}, Cynthia H. Cole, MD, MPH§, Susan W. Aucott, MD||, Elizabeth H. Thilo, MD, Mark C. Mammel, MD#,**, Robert J. Couser, MD{ddagger}{ddagger}, Jeffery S. Garland, MD, SM§§, Henry J. Rozycki, MD||||, Corinne L. Leach, MD, PhD¶¶, Conra Backstrom, RN## and Michele L. Shaffer, PhD***

* Division of Neonatology
## General Clinical Research Center, University of New Mexico School of Medicine, Albuquerque, New Mexico
{ddagger} Newborn Pediatrics, Pennsylvania Hospital, University of Pennsylvania, Philadelphia, Pennsylvania
§ Department of Pediatrics, Tufts University School of Medicine, Boston, Massachusetts
|| Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado
# Newborn Research, Children’s Hospital of St Paul, St Paul, Minnesota
** Department of Pediatrics, University of Minnesota School of Medicine, St Paul, Minnesota
{ddagger}{ddagger} Division of Neonatology, Children’s Hospital and Clinics of Minneapolis, Minneapolis, Minnesota
§§ Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin
|||| Department of Pediatrics, Virginia Commonwealth University, Richmond, Virginia
¶¶ Department of Pediatrics, State University of New York, Buffalo, New York
*** Department of Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania

Background. Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks’ postmenstrual age, particularly in infants exposed to histologic chorioamnionitis.

Methods. Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks’ postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation ≥90%).

Results. Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, defined clinically or physiologically, as were mortality, head circumference, and weight at 36 weeks. For patients exposed to histologic chorioamnionitis (n = 149), hydrocortisone treatment significantly decreased mortality and increased survival without BPD, defined clinically or physiologically. After treatment, cortisol values and response to adrenocorticotropic hormone were similar between groups. Hydrocortisone-treated infants receiving indomethacin had more gastrointestinal perforations than placebo-treated infants receiving indomethacin, suggesting an interactive effect.

Conclusions. Prophylaxis of early adrenal insufficiency did not improve survival without BPD in the overall study population; however, treatment of chorioamnionitis-exposed infants significantly decreased mortality and improved survival without BPD. Low-dose hydrocortisone therapy did not suppress adrenal function or compromise short-term growth. The combination of indomethacin and hydrocortisone should be avoided.

Key Words: adrenal insufficiency • bronchopulmonary dysplasia • BPD • adrenocorticotropic hormone • hydrocortisone • extremely low birth weight infants

Abbreviations: 3ßHSD, 3ß-hydroxysteroid dehydrogenase • BPD, bronchopulmonary dysplasia • ACTH, adrenocorticotropic hormone • PMA, postmenstrual age • FIO2, fraction of inspired oxygen • NEC, necrotizing enterocolitis • OR, odds ratio • CI, confidence interval

Accepted Sep 1, 2004.


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