Inhaled versus systemic corticosteroids for the treatment of bronchopulmonary dysplasia in ventilated very low birth weight preterm infants

Review question

To compare the effectiveness of inhaled versus systemic corticosteroids administered to ventilator-dependent preterm neonates with birth weight ≤ 1500 g or gestational age ≤ 32 weeks after 7 days of life on the incidence of chronic lung disease at 36 weeks' corrected postmenstrual age.

Background

Preterm babies (babies born before term, 40 weeks pregnancy) often need breathing (ventilator) support. Babies who need invasive (placing a breathing tube in the wind pipe) mechanical breathing support for a prolonged period often develop bronchopulmonary dysplasia (defined as requirement for supplemental oxygen at 36 weeks' postmenstrual age). It is thought that inflammation in the lungs may be part of the cause. Corticosteroid drugs reduce inflammation and swelling in the lungs, but can have serious side effects. Corticosteroid use has been associated with cerebral palsy (motor problem) and developmental delay. Inhaling steroids, so that the drug reaches the lungs directly, has been tried as a way to limit adverse effects.

Search date

23 February 2017.

Study characteristics

All three included trials were randomised, but the blinding of intervention and outcome measurement varied. Data from two trials (enrolling 139 infants) were combined as they enrolled infants between 12 and 21 days of age, but data from one trial (enrolling 292 infants) were reported separately because researchers randomised infants aged less than 72 hours. The timing when the outcomes were measured varied among studies so it was not appropriate to combine some results. In one study all deaths that occurred were reported from the time babies were randomised not from when treatment started, hence there was a greater number of babies who died in that study.

One study received grant support and the industry provided Aerochambers and metered dose inhalers of budesonide and placebo for the same study. No conflict of interest was identified.

Key results

Evidence from two studies in 370 infants, who were randomised between 12 and 21 days of age and who contributed data to the primary outcome of this review, showed that inhaled steroids administered after 7 days of age compared with systemic steroids did not decrease the incidence of death or bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age. Evidence from the single study in which infants were randomised at less than 72 hours of age did not show difference the incidence of death or BPD.

Evidence from three studies in 431 infants contributing to secondary outcomes showed that inhaled steroids administered after seven days of age compared with systemic steroids did not significantly alter the incidence of BPD at 36 weeks' postmenstrual age, hyperglycaemia, hypertension, duration of ventilation, duration of oxygen supplementation, length of hospital stay, intraventricular haemorrhage grade III-IV, periventricular leukomalacia, necrotising enterocolitis, gastrointestinal bleed, retinopathy of prematurity stage > 3, culture-proven sepsis or the incidence of adverse effects.

Adverse event profiles did not differ for inhaled versus systemic steroids but some potential complications of steroid treatment have not been reported. More research is needed to show whether any form of routine use of steroids results in overall health improvements for babies at risk of bronchopulmonary dysplasia.

Quality of the evidence

Evidence quality (according to GRADE criteria) was moderate to low.

Authors' conclusions: 

We found no evidence that inhaled corticosteroids confer net advantages over systemic corticosteroids in the management of ventilator-dependent preterm infants. There was no evidence of difference in effectiveness or adverse event profiles for inhaled versus systemic steroids.

A better delivery system guaranteeing selective delivery of inhaled steroids to the alveoli might result in beneficial clinical effects without increasing adverse events.

To resolve this issue, studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for administration of these medications. The long-term effects of inhaled steroids, with particular attention to neurodevelopmental outcomes, should be addressed in future studies.

Read the full abstract...
Background: 

This is an update of a review published in 2012. A related review "Inhaled versus systemic corticosteroids for preventing bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates" has been updated as well. Bronchopulmonary dysplasia (BPD) is a serious and common problem among very low birth weight infants, despite the use of antenatal steroids and postnatal surfactant therapy to decrease the incidence and severity of respiratory distress syndrome. Due to their anti-inflammatory properties, corticosteroids have been widely used to treat or prevent BPD. However, the use of systemic steroids has been associated with serious short- and long-term adverse effects. Administration of corticosteroids topically through the respiratory tract may result in beneficial effects on the pulmonary system with fewer undesirable systemic side effects.

Objectives: 

To compare the effectiveness of inhaled versus systemic corticosteroids administered to ventilator-dependent preterm neonates with birth weight ≤ 1500 g or gestational age ≤ 32 weeks after 7 days of life on the incidence of death or BPD at 36 weeks' postmenstrual age.

Search strategy: 

We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 1), MEDLINE via PubMed (1966 to 23 February 2017), Embase (1980 to 23 February 2017), and CINAHL (1982 to 23 February 2017). We also searched clinical trials registers, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection criteria: 

Randomised or quasi-randomised controlled trials comparing inhaled versus systemic corticosteroid therapy (irrespective of dose and duration) starting after the first week of life in ventilator-dependent very low birth weight infants.

Data collection and analysis: 

We used standard methodological procedures expected by the Cochrane Collaboration.

Main results: 

We included three trials that involved a total of 431 participants which compared inhaled versus systemic corticosteroids to treat BPD. No new trials were included for the 2017 update.

Although one study randomised infants at < 72 hours (N = 292), treatment started when infants were aged > 15 days. In this larger study, deaths were included from the point of randomisation and before treatment started. Two studies (N = 139) randomised and started treatment at 12 to 21 days.

Two trials reported non-significant differences between groups for the primary outcome: incidence of death or BPD at 36 weeks' postmenstrual age among all randomised infants. Estimates for the largest trial were Relative risk (RR) 1.04 (95% Confidence interval (CI) 0.86 to 1.26), Risk difference (RD) 0.03 (95% CI -0.09 to 0.15); (moderate-quality evidence). Estimates for the other trial reporting the primary outcome were RR 0.94 (95% CI 0.83 to 1.05), RD -0.06 (95% CI -0.17 to 0.05); (low-quality evidence).

Secondary outcomes that included data from all three trials showed no significant differences in the duration of mechanical ventilation or supplemental oxygen, length of hospital stay, or the incidence of hyperglycaemia, hypertension, necrotising enterocolitis, gastrointestinal bleed, retinopathy of prematurity or culture-proven sepsis moderate- to low-quality evidence).

In a subset of 75 surviving infants who were enrolled from the United Kingdom and Ireland, there were no significant differences in developmental outcomes at seven years of age between groups (moderate-quality evidence). One study received grant support and the industry provided aerochambers and metered dose inhalers of budesonide and placebo for the same study. No conflict of interest was identified.

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