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Low-dose hydrocortisone in extremely preterm infants – Authors' reply

2016; Elsevier BV; Volume: 388; Issue: 10050 Linguagem: Inglês

10.1016/s0140-6736(16)31611-7

1474-547X

Olivier Baud, Corinne Alberti, Damir Mohamed, Kristi L. Watterberg,

Respiratory Support and Mechanisms

We thank the correspondents for their comments on the PREMILOC trial,1Baud O Maury L Lebail F et al.Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial.Lancet. 2016; 387: 1827-1836Summary Full Text Full Text PDF PubMed Scopus (186) Google Scholar which reported the beneficial effect of prophylactic hydrocortisone in extremely preterm infants. Regarding Francesco Bonsante and Silvia Iacobelli's concern, we found a similar and very low incidence of hypertrophic cardiomyopathy and invasive candidiasis in the PREMILOC trial. One infant (<1%) had hypertrophic cardiomyopathy and three infants (1%) had invasive candidiasis in the hydrocortisone-treated group (n=255), and one infant (<1%) had cardiomyopathy and eight infants (3%) had invasive candidiasis in the placebo group (n=266). These incidences were lower than those reported after dexamethasone treatment.2Paech C Wolf N Thome UH Knupfer M Hypertrophic intraventricular flow obstruction after very-low-dose dexamethasone (Minidex) in preterm infants: case presentation and review of the literature.J Perinatol. 2014; 34: 244-246Crossref PubMed Scopus (8) Google Scholar, 3Pera A Byun A Gribar S Schwartz R Kumar D Parimi P Dexamethasone therapy and Candida sepsis in neonates less than 1250 grams.J Perinatol. 2002; 22: 204-208Crossref PubMed Scopus (44) Google Scholar We fully agree with Clever Banda that ethical considerations must be taken into account when designing any clinical trial. This was carefully done for the PREMILOC study through several mechanisms. First, the study was based on a sequential design using a stratified triangular test, which avoided unnecessary recruitment of patients. Second, a data and safety monitoring board evaluated the incidence of all severe adverse events for every 100 patients enrolled to ensure safety. Finally, we used the lowest hydrocortisone dose ever tested to reduce the risk of potential adverse events previously reported in trials with higher cortisol-equivalent doses. We do not believe that an increase in late-onset sepsis observed in the most premature infants poses substantial ethical challenges for carrying out further research in this gestational age group. Findings from subgroup analyses of secondary outcomes must always be interpreted with caution, and be used to generate hypotheses, but not to draw definitive conclusions.4Sun X Ioannidis JP Agoritsas T Alba AC Guyatt G How to use a subgroup analysis: users' guide to the medical literature.JAMA. 2014; 311: 405-411Crossref PubMed Scopus (299) Google Scholar Additionally, overall benefits and risks have to be weighed together. To have a global assessment of the benefit–risk ratio associated with hydrocortisone, we studied a composite of major adverse outcomes frequently associated with preterm birth, including not only bronchopulmonary dysplasia, death, or persistent ductus arteriosus ligation, but also late-onset sepsis, retinopathy of prematurity, severe brain damage, and necrotising enterocolitis. Of the infants born at 24–25 weeks of gestation, 70 (84%) of 83 infants treated with hydrocortisone had at least one of these complications, compared with 80 (89%) of 90 infants in the placebo group. Of the infants born at 26–27 weeks of gestation, 91 (53%) of 172 infants in the hydrocortisone group had at least one major adverse outcome, compared with 104 (59%) of 176 infants in the placebo group. Banda questions whether more studies of hydrocortisone should be done because of harm, and suggests treatment of infants with dexamethasone, which is a molecule associated with numerous risks presumably outweighing benefit, especially in the first postnatal week.5Doyle LW Ehrenkranz RA Halliday HL Early (<8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants.Cochrane Database Syst Rev. 2014; 5 (CD001146)Google Scholar Replacing placebo with dexamethasone might, therefore, be considered unethical. By contrast, the overall benefit of hydrocortisone appears to outweigh the risk and justifies future studies, pending the follow-up assessments currently in progress. We declare no competing interests. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trialIn extremely preterm infants, the rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was significantly increased by prophylactic low-dose hydrocortisone. This strategy, based on a physiological rationale, could lead to substantial improvements in the management of the most premature neonates. Full-Text PDF Low-dose hydrocortisone in extremely preterm infantsWe read with interest the results of the PREMILOC trial (April 30, p 1827)1 and would like to underline some shortcomings. The authors are to be highly congratulated because this is the largest randomised controlled trial (RCT) concluding that early, low-dose hydrocortisone significantly improves the rate of survival without bronchopulmonary dysplasia in extremely preterm infants. Previous RCTs2,3 did not achieve sufficient statistical power or were discontinued because of spontaneous gastrointestinal perforation. Full-Text PDF Low-dose hydrocortisone in extremely preterm infantsThe study by Olivier Baud and colleagues1 provides additional insight into the use of hydrocortisone in the prevention of bronchopulmonary dysplasia in premature infants. The large, multicentre, double-blind randomised controlled trial showed that, in extremely preterm infants born before 28 weeks, the rate of survival without bronchopulmonary dysplasia (defined as a requirement for respiratory support and oxygen requirement at 36 weeks of postmenstrual age) was significantly increased by prophylactic low-dose hydrocortisone given in the first 10 days of life. Full-Text PDF