Inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates

Review question

The primary objective was to compare the effectiveness of inhaled versus systemic corticosteroids started within the first week of life in preventing death or bronchopulmonary dysplasia (defined as requirement of supplemental oxygen at 36 weeks' postmenstrual age) in infants on invasive mechanical ventilation with birth weight ≤ 1500 g or gestational age ≤ 32 weeks.

Background

Preterm babies who require breathing support often develop bronchopulmonary dysplasia. It is thought that inflammation in the lungs may be part of the cause. Corticosteroid drugs when given orally or through a vein reduces this inflammation, but the use of corticosteroids is associated with serious side effects. Corticosteroids use has been associated with cerebral palsy (motor problem) and developmental delay. It is possible that inhaling steroids, so that the drug directly reaches the lung, may reduce the adverse effects.

Study characteristics

The review looked at trials that compared preterm babies who received steroids by inhalation to those who received steroids systemically (through a vein or orally) while they were receiving mechanical ventilation. We included two trials that involved 294 infants. One study included 278 infants and the other study included 16 infants. No new studies were included for the 2017 update.

Both studies received grant support and the industry provided aero chambers and metered dose inhalers of budesonide and placebo for the larger study. No conflict of interest was identified.

Key results

There was no evidence that inhaling steroids compared to systemic steroids prevented the primary outcome of death or bronchopulmonary dysplasia. The number of days the baby needed mechanical ventilation support or additional oxygen were increased in infants who received inhaled steroids versus infants who received systemic steroids. These outcomes were reported in both the trials. The rate of patent ductus arteriosus (failure for the ductus arteriosus, an arterial shunt in fetal life, to close after birth) was increased in the group receiving inhaled steroids. There was a lower incidence of high blood sugars in the inhaled steroid group compared with the systemic steroid group. These secondary outcomes were reported in only one trial (the larger trial). In a sub-sample of 52 children at age 7 years there were no differences in long-term follow-up outcomes between the inhaled and the systemic steroid groups. in an even smaller sample of 48 infants the outcome of 'ever diagnosed as asthmatic by seven years of age' was significantly lower in the inhaled steroid group compared with the systemic steroid group.

Quality of evidence

According to GRADE the quality of the evidence was moderate to low.

Authors' conclusions: 

We found no evidence that early inhaled steroids confer important advantages over systemic steroids in the management of ventilator-dependent preterm infants. Based on this review inhaled steroids cannot be recommended over systemic steroids as a part of standard practice for ventilated preterm infants. Because they might have fewer adverse effects than systemic steroids, further randomised controlled trials of inhaled steroids are needed that address risk/benefit ratio of different delivery techniques, dosing schedules and long-term effects, with particular attention to neurodevelopmental outcome.

Read the full abstract...
Background: 

Bronchopulmonary dysplasia (BPD) remains an important cause of mortality and morbidity in preterm infants and inflammation plays a significant role in its pathogenesis. The use of inhaled corticosteroids may modulate the inflammatory process without concomitant high systemic steroid concentrations and less risk of adverse effects. This is an update of a review published in 2012 (Shah 2012). We recently updated the related review on "Inhaled versus systemic corticosteroids for treating bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates".

Objectives: 

To determine the effect of inhaled versus systemic corticosteroids started within the first 7 days of life on preventing death or BPD in ventilated very low birth weight infants.

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 searched clinical trials registers, conference proceedings and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials.

Selection criteria: 

Randomised or quasi-randomised controlled trials comparing inhaled versus systemic corticosteroid therapy (irrespective of dose and duration) starting in the first seven days of life in very low birth weight preterm infants receiving assisted ventilation.

Data collection and analysis: 

Clinical outcomes data were extracted and analysed using Review Manager. When appropriate, meta-analysis was performed using typical relative risk (RR), typical risk difference (RD) and weighted mean difference (WMD). Meta-analyses were performed using typical relative risk, typical risk difference (RD), and weighted mean difference with their 95% confidence intervals (CI). If RD was statistically significant, the number needed to benefit or the number needed to harm was calculated. We assessed the quality of evidence was evaluated using GRADE principles.

Main results: 

We included two trials that involved 294 infants. No new studies were included for the 2017 update. The incidence of death or BPD at 36 weeks' postmenstrual age was not statistically significantly different between infants who received inhaled or systemic steroids (RR 1.09, 95% CI 0.88 to 1.35; RD 0.05, 95% CI -0.07 to 0.16; 1 trial, N = 278). The incidence of BPD at 36 weeks' postmenstrual age among survivors was not statistically significant between groups (RR 1.34, 95% CI 0.94 to 1.90; RD 0.11, 95% CI -0.02 to 0.24; 1 trial, N = 206). There was no statistically significant difference in the outcomes of BPD at 28 days, death at 28 days or 36 weeks' postmenstrual age and the combined outcome of death or BPD by 28 days between groups (2 trials, N = 294). The duration of mechanical ventilation was significantly longer in the inhaled steroid group compared with the systemic steroid group (typical MD 4 days, 95% CI 0.2 to 8; 2 trials, N = 294; I² = 0%) as was the duration of supplemental oxygen (typical MD 11 days, 95% CI 2 to 20; 2 trials, N = 294; I² = 33%).

The incidence of hyperglycaemia was significantly lower with inhaled steroids (RR 0.52, 95% CI 0.39 to 0.71; RD -0.25, 95% CI -0.37 to -0.14; 1 trial, N = 278; NNTB 4, 95% CI 3 to 7 to avoid 1 infant experiencing hyperglycaemia). The rate of patent ductus arteriosus increased in the group receiving inhaled steroids (RR 1.64, 95% CI 1.23 to 2.17; RD 0.21, 95% CI 0.10 to 0.33; 1 trial, N = 278; NNTH 5, 95% CI 3 to 10). In a subset of surviving infants in the United Kingdom and Ireland there were no significant differences in developmental outcomes at 7 years of age. However, there was a reduced risk of having ever been diagnosed as asthmatic by 7 years of age in the inhaled steroid group compared with the systemic steroid group (N = 48) (RR 0.42, 95% CI 0.19 to 0.94; RD -0.31, 95% CI -0.58 to -0.05; NNTB 3, 95% CI 2 to 20).

According to GRADE the quality of the evidence was moderate to low. Evidence was downgraded on the basis of design (risk of bias), consistency (heterogeneity) and precision of the estimates.

Both studies received grant support and the industry provided aero chambers and metered dose inhalers of budesonide and placebo for the larger study. No conflict of interest was identified.

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