A few years ago, we published our experience with the use of hydrocortisone in newborn infants in septic shock (Altit G, et al. Corticosteroid Therapy in Neonatal Septic Shock-Do We Prevent Death? Am J Perinatol. 2018;35(2):146-51), like many such studies the numbers were small, but the 39 babies who received hydrocortisone in addition to their inotropic support had rapid haemodynamic improvement, within 6 hours of starting hydrocortisone, mean BP had increased by over 30%, urine output was better, and inotropic support was being weaned. They were, however, somewhat less likely to survive the episode (59% survival vs 78% without hydrocortisone) and to survive until discharge, neither of which comparisons were “statistically significant”, and the babies who got hydrocortisone were sicker, less mature and more likely to have NEC, than the septic babies who did not get hydrocortisone.

Those data suggested that there was a major rapid haemodynamic response to hydrocortisone in newborn infants with septic shock, but they clearly could not answer the important question about whether they improved survival.

A new, single-centre prospectively-registered RCT has examined this issue. (Dudeja S, et al. Early hydrocortisone verses placebo in neonatal shock- a double blind Randomized controlled trial. J Perinatol. 2025). Newborn infants with shock, of any aetiology, were enrolled in 2017 and 2018 (not clear why the delay in publishing) and randomised to receive early hydrocortisone, or placebo. It is also not clear why they bothered with the placebo, as the bedside nurse was not masked to study group assignment. The main problem with the trial is the definition of shock, which was either A or B criteria “(A) either systolic or diastolic blood pressure (BP) less than 5th centile; (B) Any two of the following five criteria- capillary refill time >4sec, core-periphery temperature difference >3 °C, urine output <0.5mL/kg/hr in previous 6 h, base excess worse than −5.0mmol/L and lactate >5mmol/L”.

The use of BP alone to define shock is problematic, at any moment 5% of healthy babies are below the 5th percentile, and therefore over 5% of all babies are in shock at any time according to this definition. In addition, the definition allows cuff, non-invasive, BP to be used, which are very unreliable, and they used standards for BP which are limited (Zubrow AB, et al. Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. Philadelphia Neonatal Blood Pressure Study Group. J Perinatol. 1995;15(6):470-9). Many infants had a large PDA, which will lead to low diastolic pressures satisfying this definition, but without necessarily having other features of shock. Nevertheless, these were babies that the clinicians felt warranted vasopressor/inotrope intervention. To be eligible for the trial the infants had to be “fluid-resistant”, that is not responding to 1 to 2 10 mL/kg fluid boluses, they also excluded infants with NEC, I am unsure why.

Infants were started on vaso-active drugs at the same time as the study drug, and had functional cardiac echography. The primary outcome was survival to 14 days of age, rescue hydrocortisone was allowed if the infant became unresponsive to their vaso-active drugs.

Survival was very poor in both groups, 17% with placebo, and 28% with early hydrocortisone. and 80% of the controls eventually received open label hydrocortisone (compared to 70% of the early HC group).

There are a couple of reasons for this post, the first being that I think this is the first report of an RCT of steroid use in the treatment of circulatory collapse in the newborn, which points out how poor the evidence is to support anything that we do. And also because the survival is reported just as being “not significant”. I mentioned Bayesian analysis in a previous post, and I think that a small trial such as this, which was very unlikely to have a “statistically significant” result, because of low power, is nevertheless informative, and is a good candidate for Bayesian analysis. Using an on-line Bayesian calculator, it seems that likelihood that the early hydrocortisone group is better is about 88% (I am certainly no expert in these calculations, and I may be in error!)

Another way of presenting these results is with the relative risk and its confidence intervals, which is 0.87, 95% CI 0.69 – 1.10. Which means that the results are consistent, with that level of confidence, with no difference in mortality, a small increase in mortality, and a major decrease of 31% in mortality.

The implication of this is that there is certainly enough suggestion of a substantial benefit that further trials are warranted.

I am not against publishing such small trials, I think they can give valuable pointers for the future, but we should be very careful how the results are presented. The abstract of this article just states “we did not observe a significant reduction in 14-day mortality”, which is actually misleading. It would be more accurate to state “we observed a major reduction in mortality with early HC use, but it was not statistically significant, and may have been due to chance effects in a small underpowered trial”. Maybe we should ban the use of the word “significant” from the medical literature. It is often used, as in this abstract, to mean “statistically significant”, but is often interpreted as “real”, “meaningful”, or “important”.

What are we currently doing for this problem? A questionnaire study among Canadian neonatologists was published last year, (Kharrat A, et al. Corticosteroid use in neonatal hypotension: A survey of Canadian neonatologists. Pediatr Neonatol. 2024;65(5):451-6 they were asked if they used HC for hypotension, and if so when. The results showed the variability that you would expect in a situation where there is almost no reliable data.

I can’t remember is I participated in this questionnaire, but, if I had, I would be one of the “other” group! I don’t give fluid boluses for hypotension, unless I have good reason to suppose that the infant is hypovolemic. Early hypotension in the preterm is now much less common, because of delayed cord clamping, and is almost never due to hypovolemia. I will sometimes giving a fluid bolus in shock, if I think that the baby needs more preload, and I tend to start HC very early when I feel that vasopressor/inotrope therapy is needed. In suspected septic shock, for example, I will usually start HC at the same time as the norepinephrine. I have no idea if that is the right thing to do, but 100% of the respondents to the survey reported using HC for hypotensive babies, at least some of the time.

There is clearly a need for further trials; the question of timing of HC use in babies with shock is clearly very important, and could have an important impact on mortality.