Does hydrocortisone reduce death and BPD in preterm infants who remain intubated beyond a week of life?

Abstract

Bronchopulmonary dysplasia affects a majority of extremely low birthweight infants, leading to poor pulmonary and neurologic outcomes. Dexamethasone, a potent anti-inflammatory steroid, facilitates extubation and reduces the risk of bronchopulmonary dysplasia (BPD) or death.1 However, it can cause hyperglycaemia and hypertension, and may lead to abnormal neurologic development.1 Low dose prophylactic hydrocortisone also improves these outcomes,2 but this approach exposes some babies at low risk of death or BPD to potential side effects. Seeking a safer alternative, this is the first controlled trial to evaluate hydrocortisone in preterm babies that remain intubated beyond a week of life. While this study failed to demonstrate a significant decrease in the composite primary outcome of death or BPD, there was a trend towards reduced death (16% vs 24%, P value .048, at 36 weeks; 20% vs 28%, P value .06, at hospital discharge) in infants treated with hydrocortisone. When using a composite outcome, an outcome that exhibits no effect can negate the effect of treatment on another outcome.3 Here, BPD occurred in 65% of all survivors regardless of treatment (100/(181-28) hydrocortisone; 95/(190-45) placebo). Importantly, the rate of severe BPD was not different between groups, suggesting that hydrocortisone did not lead to more survivors with severe morbidity. In contrast, treated patients were more likely to be extubated after starting treatment, less likely to be diagnosed with pneumonia, and gained more weight. Currently, the use of steroids in preterm babies requiring mechanical ventilation beyond the first week of life varies. In an American survey, only 13% of responding neonatologists would start steroids in a 21 day old requiring moderate ventilatory support.4 In contrast, 90% of responding UK providers would treat intubated babies with steroids after the first week.5 Similarly, participants in this study started hydrocortisone around 10 days of life and required a median 0.35 FiO2. While the inclusion of infants requiring moderate FiO2 relatively early in their course could attenuate hydrocortisone's effect, the high rate of the primary outcome in all study participants argues against this possibility. Additionally, high rates of off label steroid use in the placebo could decrease hydrocortisone's effect in the treatment group, but preplanned per-protocol and as-treated analyses also revealed no difference in the primary outcome. Many neonatologists treat preterm babies who remain intubated after the first week of life with steroids.4, 5 Although this study did not show a reduction in the combined outcome of death or BPD, it suggests that hydrocortisone may aid in successful extubation and reduce the risk of death. Given the morbidity associated with prolonged mechanical ventilation including air leak, ventilator-associated pneumonia and worse neurodevelopment,6 early extubation may improve longer term outcomes not yet reported for this study. Furthermore, those with severe BPD represent a diverse group with heterogenous outcomes7; whether hydrocortisone has a meaningful treatment effect in any of these subgroups is unknown. Finally, we await the results of the NICHD Neonatal Research Network study: hydrocortisone for BPD, which will also assess survival without BPD and neurodevelopmental outcomes at 18-22 months. https://ebneo.org/2020/02/hydrocortisone-bpd/ None.