Manuscript Citation:

Dudeja S, Saini SS, Sundaram V, Dutta S, Sachdeva N, Kumar P. Early hydrocortisone versus placebo in neonatal shock: a double-blind randomized controlled trial. J Perinatol. 2025. https://doi.org/10.1038/s41372-025-02222-3. PMID: 39948354

Reviewed by:

Dr Prakash Kannan Loganathan, Neonatologist Consultant
Dr Su Wei Ng, Paediatric Speciality Trainee
Neonatal unit, James Cook University Hospital
South Tees Hospitals NHS Foundation Trust
Middlesbrough, UK.
Email: pkannanloganathan@nhs.net, suwei.ng@nhs.net

Corresponding Author:

Prakash Kannan Loganathan (ORCID: 0000-0003-3717-8569)
James Cook University Hospital,
Marton Road, Middlesbrough TS4 3BW.
Email : pkannanloganathan@nhs.net
Phone : 01642 854874
Fax : 01642854488

Type of Investigation:

randomised controlled trial

Question:

P: Neonates with fluid-refractory shock
I: Early administration of hydrocortisone alongside vasoactive drugs
C: Saline placebo administration alongside vasoactive drugs
O: Any reduction in 14-day all-cause mortality

Methods:

• Design: Double-blind randomised controlled trial

• Randomisation: random sequence through website. Block and stratified (≤30 weeks and >30 weeks).

• Allocation: concealment.

• Blinding: Double-blind (Investigator, outcome assessor), bedside nurses unblinded

• Follow-up period: 14 days

• Setting: Level 3 Neonatal Intensive Care Unit, single center in India.

• Consent: written informed consent before enrolment.

• Time period: 2016 to 2018.

• Patients:
o Inclusion criteria:
 Fluid-refractory shock diagnosed if shock needing 10-20ml/kg normal saline infusion given over 40-60 minutes (as per unit protocol , physician) with either of both of the following
• Systolic or diastolic blood pressure less than 5th centile.
• Or any two of the following five criteria
o Capillary refill time > 4 seconds
o Core-periphery temperature difference > 3 degree Celsius.
o Urine output <0.5ml/kg/hr. in previous 6 hours o Base excess worse than -5 mmol/L o Lactate >5 mmol/L
o Exclusion criteria:
 Neonates with clinical settings of obvious blood loss or dehydration, hypoxic-ischaemic encephalopathy (moderate or severe), congenital heart diseases, congenital adrenal hyperplasia, or who had received postnatal steroids in the last 7 days

• Intervention:
o Intervention group: IV Hydrocortisone1 mg/kg every 6 hourly for 2 days, then 1mg/kg every 12 hourly for 3 days.
o Placebo group: Normal saline injection in identical dosing schedule. Open label hydrocortisone allowed for catecholamine resistant shock.

• Outcomes:
o Primary outcome: all-cause mortality within 14 days of shock onset.o Secondary outcome: incidence of catecholamine-resistant shock, duration of vasoactive drug administration, vasoactive-inotrope scores, LV systolic and diastolic functions, incidence of adverse effects of hydrocortisone and medium-term complication of prematurity
• Sample Size: Powered to detect a 30% absolute mortality reduction; 84 neonates needed.
• Patient follow-up: 100% included in intention-to-treat analysis

Main results:

– Median birth gestational age (Inter-quartile range): 30.3 (IQR: 27.7- 32.5) weeks. Thirty-six (43%) neonates were ≤30weeks.
– Median birth weight was 1148 (IQR: 860-14190 grams).
– Twenty-seven (32%) culture positive sepsis and 55 (65.4%) has screen-positive probable sepsis.
– Thirty-nine (46%) neonates received treatment for patent ductus arteriosus (PDA).
– No statistically significant differences in adverse effects between the two groups: gastro-intestinal hemorrhage, hyperglycemia and others.

Conclusion:

Early hydrocortisone administration in neonates with fluid-refractory shock did not significantly reduce 14-day mortality as compared to the placebo group.

Commentary:

Prior studies suggested 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. attempted to addresses 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 to placebo alongside vasoactive therapy(2). Nevertheless, the trial did not find any statistically significant difference in mortality between the two groups, but there was 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 centers(3, 4).

 

There was no increase in adverse effects was 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 timing of hydrocortisone in neonates with shock included 7 RCTs and 13 non-RCTs(1) did not show any benefit or harm with 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 toward lower mortality and the absence of adverse effects supports the rationale for larger, well-powered multicenter trials. Future studies should consider stratifying by the underlying etiology 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 etiology.

References:

1. Ramaswamy VV, Kumar G, Pullattayil SA, Aradhya AS, Suryawanshi P, Sahni M, et al. Timing of hydrocortisone therapy in neonates with shock: a systematic review, meta-analysis, and clinical practice guideline. Front Pediatr 2025; 13:1491976.
2. Dudeja S, Saini SS, Sundaram V, Dutta S, Sachdeva N, Kumar P. Early hydrocortisone verses placebo in neonatal shock- a double blind Randomized controlled trial. J Perinatol 2025; 45 3:342-9.
3. Van de Voorde P, Turner NM, Djakow J, de Lucas N, Martinez-Mejias A, Biarent D, et al. European Resuscitation Council Guidelines 2021: Paediatric Life Support. Resuscitation 2021; 161:327-87.
4. Ishiguro A, Suzuki K, Sekine T, Kawasaki H, Itoh K, Kanai M, et al. Effect of dopamine on peripheral perfusion in very-low-birth-weight infants during the transitional period. Pediatr Res 2012; 72 1:86-9.
5. Lemyre B, Dunn M, Thebaud B. Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia in preterm infants. Paediatr Child Health 2020; 25 5:322-31.
6. Cummings JJ, Pramanik AK. Postnatal Corticosteroids to Prevent or Treat Chronic Lung Disease Following Preterm Birth. Pediatrics 2022; 149 6.