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Mark Hudak MD, Contributing Editor
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Early Low-Dose Hydrocortisone
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.
Comment: In an accompanying editorial, Robin S. Roberts expressed disappointment that both this trial of early physiologic hydrocortisone and a prior NIH study of dexamethasone were prematurely terminated due to an increase in spontaneous gastrointestinal perforations in the treatment groups. These two trials have not unambigously settled whether some regimen of early glucocorticoids given to a well-selected group of infants might increase survival without chronic lung disease. The first NIH trial found that dexamethasone therapy reduced the odds ratio of death or chronic lung disease by 10%; this study found that hydrocortisone therapy was associated with an increase in survival without chronic lung disease from 33.7% to 35.2% and an increase in NEC-associated or spontaneous perforation rate from 6% to 12%. The tantalizing suggestion from the current study is that one might expect efficacy among infants with a history of “histologic chorioamnionitis”. In a subanalysis, this efficacy appeared to be limited to that subset of infants who had fetal inflammation (e.g., of the umbilical vessels, Wharton’s jelly, and/or chorionic plate). No subanalysis was reported for infants with “clinical chorioamnionitis”. If the apparent treatment benefit for infants with fetal inflammation could have been more convincingly demonstrated (i.e., with higher power) by having enrolled the targeted 790 infants (rather than the actual 360), it might have resulted in an effort to obtain rapid pathologic examination of the placenta and umbilical cord. So perhaps there is still a place for a third randomized controlled trial of early physiologic hydrocortisone in infants with fetal inflammation – anyone willing to take this on? MLH
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