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Are inhaled steroids safe and effective for prevention or treatment of

bronchopulmonary dysplasia?

Article  in  Acta Paediatrica · December 2017

DOI: 10.1111/apa.14180

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 Acta Pædiatrica ISSN 0803-5253

A DIFFERENT VIEW

Are inhaled steroids safe and effective for prevention or treatment

of bronchopulmonary dysplasia?
Eric S. Shinwell (eric.s@ziv.health.gov.il)
Department of Neonatology, Ziv Medical Center, Faculty of Medicine in the Galil, Bar-Ilan University, Tsfat, Israel

Correspondence
E S Shinwell, MD, Department of Neonatology,
Faculty of Medicine in the Galil, Ziv Medical Center,
Tsfat 13100, Israel.
Tel: +972508434418 |
Fax: +97246828688 |
Email: eric.s@ziv.health.gov.il

Received
2 October 2017; revised 13 November 2017;
accepted 1 December 2017

DOI:10.1111/apa.14180

INTRODUCTION organ, the lungs, without leading to adverse effects on other

Bronchopulmonary dysplasia (BPD) represents a major organs, in particular, the brain. A limitation of this approach
threat to the short-term and long-term health and develop- is the absence of studies that evaluated the pharmacokinetics
ment of very preterm infants. Unfortunately, despite much of inhaled steroids in the lungs and other organs. Many
study and progress in neonatology in recent years and some studies have been reported although many were small and
modest improvements in survival, both the incidence and inconclusive and included a variety of medications, dosage
severity of BPD remain frustratingly stable (1). Numerous schedules and timing of intervention. Also, these studies
approaches have been proposed for both prevention and purported to offer two alternative approaches. Treatment
treatment of developing BPD, but only a few have achieved begun shortly after birth aimed to supposedly prevent BPD,
the status of standard therapy. A variety of kinder, gentler while treatment begun after one week of age was considered
forms of ventilation and surfactant administration are in to represent treatment of established disease (3,4). However,
various phases of study and adoption into clinical practice. this differentiation into two seemingly distinct groups is
All offer modest but measurable benefits. Numerous phar- problematic as there is marked overlap between the studies as
macologic approaches have been studied, including ster- some of the early studies continued the intervention for long
oids, either systemic or inhaled, caffeine, vitamins E and C, periods of time, even as long as two months. Whether defined
N-acetyl cysteine, antioxidants and nitric oxide. Of these, as prevention or treatment, inhaled steroids are widely used
only caffeine has been shown to significantly reduce the in many countries and at varying stages of the disease (5). A
incidence and severity of BPD and, thus, is considered significant body of new information from randomized con-
accepted practice. trolled trials (RCTs) has now been added, necessitating
Corticosteroids, presumably via anti-inflammatory effects, updated systematic reviews and meta-analyses (3,6). The
play a central role in the management of BPD. Systemic findings have generated much interest, and therefore, this
steroids, mainly dexamethasone and hydrocortisone, have review will focus on the most pertinent findings and the
been extensively studied and appear to be effective in controversies arising from them.
reducing BPD. However, the adverse effects of systemic
steroids, particularly on the developing brain leading to
cerebral palsy and neurodevelopmental impairment, force REVIEW OF RANDOMISED CONTROLLED TRIALS (RCTS)
neonatologists to limit use of this therapy to a small Overall, 17 RCTs that compared inhaled steroids to placebo
proportion of infants in whom the risks associated with the have been reported between 1993 and 2016. These studies
disease are considered to outweigh the risks of the therapy included 1807 preterm infants, although no less than 1327
(2). Accordingly, there has been a long-running interest in were from just three large trials. As these studies heavily
inhaled steroids based on the hope that this approach would influence each of the meta-analyses that have been
produce positive anti-inflammatory effects on the target performed, they will be described here in some detail.

ª2017 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 1
Inhaled steroids for BPD Shinwell

COLE, 1999 in the budesonide-treated group (budesonide 19.9% vs

This study compared a decreasing dosage regimen of inhaled placebo 14.5%, RR 1.37, 95% CI: 1.01–1.86, p = 0.057). The
beclomethasone with placebo for four weeks from age 3 to authors conducted a detailed review of the causes of death
14 days in 253 ventilated preterm infants born before and clinical course of all study infants who died. No
33 weeks and weighing less than 1250 g (7). The study significant differences were found between the groups, and
protocol determined that if the attending clinician decided to no useful information was gained that may have con-
initiate treatment with systemic steroids for perceived tributed to the development of a biologically plausible
developing BPD, then the inhaled study drug was discontin- hypothesis to explain the seeming excess of deaths in
ued and this occurred in almost 23% of the study participants. treated infants. It is also important to note that the
This may limit the ability of the study to assess the efficacy of difference between the groups is so borderline that if only
the inhaled intervention. No significant difference between two infants who died in the budesonide group had been in
the groups was found for mortality or BPD at either 28 days the placebo group, the finding would not have been
of age or 36 weeks of gestational age. However, the statistically significant.
beclomethasone-treated infants received less systemic ster-
oids and required less mechanical ventilation. These findings
suggest an ameliorating effect of inhaled beclomethasone NAKAMURA, 2016
that may have been more pronounced had systemic steroid This most recent placebo-controlled RCT from 12 NICUs in
administration been more limited per protocol. Japan studied inhaled fluticasone from birth until age six
weeks or extubation in 211 ventilated extremely low birth
weight (ELBW) with birth weight below 1000 g (10). The
BASSLER, 2015 study was halted with less than half of the originally planned
This is the largest reported placebo-controlled RCT of sample because of budgetary restrictions. The primary out-
inhaled steroids for prevention of BPD, enrolling 863 come variable of death or oxygen dependence at discharge, a
infants born at 23–27 weeks in 40 centres (8). Infants surrogate for severe BPD, showed a non-significant reduc-
received either inhaled budesonide or placebo by metered- tion in the fluticasone group (RR 0.77, 95% CI: 0.57–1.05,
dose inhaler from day one of life until age 32 weeks or p = 0.15). No differences were found for neurodevelopmen-
when weaned from oxygen or assisted ventilation. There tal impairment or cerebral palsy or death at age three years.
was a borderline significant reduction in the composite However, in the sub-groups of infants born at 24–26 weeks
primary outcome variable of mortality or BPD at 36 weeks and in infants exposed to histological chorioamnionitis
(relative risk 0.86, 95% confidence interval 0.75–1.0, irrespective of gestational age, fluticasone treatment was
p = 0.05). Separation of the components of the composite associated with a reduction in both mortality and oxygen
outcome variable revealed a significant reduction in BPD dependence at discharge. No effect was seen in the groups
(27.8% budesonide vs 38% placebo, RR 0.74, 95% CI: 0.6– born at 22–23 weeks or above 26 weeks, although the
0.91, p = 0.004). However, this was offset by a non- numbers of infants in these subgroups were small.
significant increase in mortality (budesonide 16.9% vs
placebo 13.6%, RR 1.24, 95% CI: 0.91–1.69, p = 0.17).
Recently, long-term follow-up at age two years has been SMALLER STUDIES
presented at an international meeting (9). The primary The 14 additional studies employed a variety of medica-
outcome variable was a composite of cerebral palsy, tions, dosage schedules, prevention or treatment approach
cognitive delay, hearing loss and blindness, and no differ- and outcome variables. Various of these studies have been
ence was found between the groups (budesonide 44.7% vs included in the recently published meta-analyses.
placebo 48.2%, RR 0.93 95% CI: 0.80–1.10, p = 0.40).
However, in view of the non-significant trend towards
increased mortality in the short-term outcome study, a non- META-ANALYSES
pre-specified analysis of mortality was conducted and this As explained above, with the addition of the newer studies
revealed a now borderline significant increase in mortality of Bassler and Nakamura, new meta-analyses approached

Table 1 Comparison of meta-analyses

Cochrane early (Shah 2017) Early + Late (Shinwell 2016) New analysis (Updated early + Late)
10 studies, n = 1644 16 studies, n = 1596 17 studies, n = 1807

RR 95% CI p RR 95% CI p RR 95% CI p

Death or BPD 36 0.86 0.75–0.99 0.03 0.87 0.77–0.99 0.03 0.87 0.77–0.979 0.03
BPD 36 0.76 0.63–0.93 0.003 0.79 0.68–0.92 0.002 0.79 0.68–0.92 0.002
Death 1.07 0.82–1.4 0.93 1.04 0.59–1.86 0.89 1.04 0.59–1.86 0.89

BPD 36 = Bronchopulmonary dysplasia at 36 weeks of gestational age; RR = Relative risk; 95% CI = 95% confidence interval

2 ª2017 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd
Shinwell Inhaled steroids for BPD

the ongoing controversy of inhaled steroids for BPD. current management of developing BPD in preterm
Shinwell et al. (6) reported a meta-analysis that combined infants.
all 16 prevention and treatment studies (n = 1596). This
analysis was accepted for publication before the study of
Nakamura et al. was available. However, for the purposes CONFLICT OF INTEREST AND FUNDING
of completeness in this review, I have added the study of None.
Nakamura et al. to the previous meta-analysis, employing
the same original methodology, and this appears in the
Table 1 under the heading new analysis. Shortly thereafter, References
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ª2017 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 3

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