EBNEO Commentary: Early Administration of Hydrocortisone Versus Placebo in Neonatal Shock—A Double Blind Randomised Controlled Trial

Prior studies suggested a possible role for hydrocortisone in improving haemodynamic parameters, leading to hypotheses that early administration could improve survival outcomes in neonatal shock [1]. This trial by Dudeja et al. [2] attempted to address a critical gap in evidence by testing this hypothesis in a double-blinded, randomised controlled trial (RCT) to evaluate whether early administration of hydrocortisone alongside vasoactive therapy reduces mortality in neonates with fluid-refractory shock in comparison with placebo alongside vasoactive therapy. Nevertheless, the trial did not find any statistically significant difference in mortality between the two groups, but there was an 11% reduction in mortality in the early hydrocortisone group, which could be clinically important. This trial included a predominantly preterm population, with nearly 75% of neonates developing catecholamine-resistant shock and receiving open-label hydrocortisone. The high rate of rescue therapy may have diluted any potential benefits of early hydrocortisone administration. In this study, if a neonate developed catecholamine-resistant shock, the trial drug was discontinued, and open-label hydrocortisone was initiated. In this trial, the most common causes of shock were neonatal sepsis and PDA, which may limit the applicability of findings to other aetiologies such as transitional circulation. Additionally, the high mortality rate observed (72%–83%) likely reflects the severity of illness and high burden of sepsis in the study population. This, combined with the limited ability to detect modest treatment effects, may impact the external validity of the results. Although the authors provided justification for their sample size, the assumption of a 30% absolute reduction in mortality was overly ambitious. This likely resulted in an underpowered study, limiting its ability to detect smaller meaningful differences and increasing the Type II error. The sample size calculation did not account for the high rate of open-label hydrocortisone use or potential dropouts. In contrast to this trial, the routine use of fluid boluses and dopamine as first-line inotropes may not align with current practices in many centres [3, 4]. There was no increase in adverse effects seen with early steroid use; however, the lack of long-term neurodevelopmental follow-up is a limitation. Reassuringly, international agencies recommend early use of hydrocortisone in extremely low-gestational-age neonates born through chorioamnionitis [5, 6]. In a recent meta-analysis on the timing of hydrocortisone in neonates with shock, 7 RCTs and 13 non-RCTs [1] did not show any benefit or harm with the timing of hydrocortisone for the outcome of mortality. With low certainty of evidence, both early and late hydrocortisone improved the response to ionotropic therapy. The authors conclude that early hydrocortisone did not significantly reduce mortality in neonates with fluid-refractory shock. However, the observed trend towards lower mortality and the absence of adverse effects support the rationale for larger, well-powered multicentre trials. Future studies should consider stratifying by the underlying aetiology of shock and assess whether combining early hydrocortisone with pathophysiology-guided inotrope selection improves outcomes. Importantly, sample size calculations should be based on realistic effect sizes. Until definitive evidence emerges, clinicians must weigh the unproven benefits of early hydrocortisone against illness severity and shock aetiology. URL LINK: https://ebneo.org/ebneo-commentary-early-hydrocortisone-vs-placebo-in-shock. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.