Hydrocortisone in very preterm infants does not improve rates of bronchopulmonary dysplasia and mortality

1. There were no significant differences in rates of bronchopulmonary dysplasia (BPD) and mortality at 36 weeks’ postmenstrual age (PMA) as a composite outcome in ventilator-dependent very preterm infants who received systemic hydrocortisone versus placebo. However, mortality at 36 weeks’ PMA as an individual outcome, was significantly lower in infants receiving hydrocortisone.

Evidence Rating: Level 1 (Excellent)

Study Rundown: BPD is a common complication of preterm birth and is associated with increased mortality and significant pulmonary and neurodevelopmental morbidities. While dexamethasone is less frequently used as a preventative therapy for BPD due to its association with increased risk of neurodevelopmental impairment, hydrocortisone has been studied as an alternative therapy with mixed results. The objective of this randomized controlled trial was to evaluate the incidence of BPD and mortality after the administration of systemic hydrocortisone or placebo in ventilatory-dependent preterm infants. The authors found that there was no significant difference in the composite outcome of death or BPD at 36 weeks’ PMA between the hydrocortisone and control group. Interestingly, death at 36 weeks’ PMA as an individual outcome, was significantly lower in the hydrocortisone group. However, this difference did not remain statistically significant up to time of hospital discharge. BPD as an individual outcome did not differ significantly between groups. Other significant secondary outcomes included lower rates of pneumonia and extubation failure (at days 3, 7, and 14) and higher rates of hyperglycemia requiring insulin therapy in the hydrocortisone compared to the placebo group. Limitations of this study included limited power in detecting smaller differences in the primary outcome, higher use of open-label corticosteroids in the placebo group and using a lower respiratory index  (mean airway pressure x fraction of inspired oxygen) which may have included more patients who were less likely to develop BPD to begin with. For neonatologists, these findings do not support the use of hydrocortisone for reducing rates of BPD in ventilator-dependent preterm infants.

Click to read the study, published today in JAMA

Relevant Reading: Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infant (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial

Study Author, Dr. Anton H. van Kaam, PhD, talks to 2 Minute Medicine: Department of Neonatology, Emma Children’s Hospital, Amsterdam, the Netherlands:

“BPD is still one of the most important complications of preterm birth with serious long term adverse effects. So we need new interventions to reduce its incidence. Dexamethasone is effective but there are concerns on long term adverse effects. Our study explored hydrocortisone as a potential effective and safe alternative for dexa. This is really important because some clinicians have already implemented hydrocortisone in daily clinical practice. The results show that hydrocortisone does not reduce BPD in ventilated preterm infants. So for this indication, HC is probably not a good alternative for dexa. It does facilitate extubation. Somewhat surprisingly we found a clinically relevant reduction in mortality (8% total group and even 12% in preterm < 28 wks). This improved survival is not outweighed by an increase in short term morbidity. We will have to wait for the two year outcome assessment to see if there is still no adverse effect of HC. If this is the case, HC might be a potential intervention for the outcome death. This should probably be confirmed by another future trial.”

In-Depth [randomized controlled trial]: From November 2011 through December 2016, 372 infants across 19 neonatal intensive care units in the Netherlands and Belgium were randomized to a hydrocortisone group (n = 182, one subject had parental consent withdrawn) or a placebo group (n = 190). Infants were included if they were born <30 weeks’ gestational age (GA) and/or weighed <1250g and were ventilator dependent between 7-14 days of age with a respiratory index of ≥2.5 for more than 12 hours per day for at least 2 days. Infants with chromosomal defects, major congenital anomalies or receipt of corticosteroids at <7 days of age were excluded. Infants in the treatment group received a cumulative dose of 72.5mg/kg of hydrocortisone that was tapered over 22 days and the control group received mannitol. BPD was diagnosed if infants required positive pressure support, required supplemental oxygen with a fraction of inspired oxygen >0.30 (severe BPD), or had a fraction of inspired oxygen of 0.22-0.29 and a failed to wean off supplemental oxygen (moderate BPD). The rate of primary composite outcome of death or BPD at 36 weeks’ PMA was 70.7% (128/181 infants) in the treatment group and 73.7% (140/190 infants) in the control group. There was no significant difference between the 2 groups (aOR = 0.87, 95%CI = 0.54-1.38, p = 0.54). Logistic regression model adjusted for gestational age and study center for the primary outcome.

Secondary outcomes included individual components of the primary outcome and other common preterm neonatal morbidities. The rate of death at 36 weeks’ PMA was significantly lower in the hydrocortisone compared to the control group (15.5% versus 23.7%, OR = 0.59, 95%CI = 0.35-0.995, p = 0.048). Rates of pneumonia were significantly lower in the hydrocortisone compared to the placebo group (24.9% versus 33.7%, sub-hazard ratio = 0.68, 95%CI = 0.47-0.997, p = 0.048). Rates of hyperglycemia requiring insulin therapy were significantly higher in the hydrocortisone (18.2%) compared to the placebo group (18.2% versus 7.9%, sub-hazard ratio = 2.44, 95%CI = 1.34-4.47, p = 0.004). Rates of extubation failure were significantly lower in the hydrocortisone group at days 3, 7 and 14, but not 21. There were no significant differences between groups for rates of BPD at 36 weeks’ PMA, death before hospital discharge, duration of mechanical ventilation, duration of supplemental oxygen, intraventricular hemorrhage grade >2, periventricular leukomalacia, patent ductus arteriosus, necrotizing enterocolitis grade ≥2, gastrointestinal bleeding, spontaneous intestinal perforation, hypertension, clinical or culture proven sepsis, meningitis, and retinopathy of prematurity grade >2.

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