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Are inhaled steroids safe and effective for prevention or treatment of

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Article  in  Acta Paediatrica · December 2017

DOI: 10.1111/apa.14180

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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
Bronchopulmonary dysplasia (BPD) represents a major
threat to the short-term and long-term health and develop-
ment of very preterm infants. Unfortunately, despite much
study and progress in neonatology in recent years and some
modest improvements in survival, both the incidence and
severity of BPD remain frustratingly stable (1). Numerous
approaches have been proposed for both prevention and
treatment of developing BPD, but only a few have achieved
the status of standard therapy. A variety of kinder, gentler
forms of ventilation and surfactant administration are in
various phases of study and adoption into clinical practice.
All offer modest but measurable benefits. Numerous phar-
macologic approaches have been studied, including ster-
oids, either systemic or inhaled, caffeine, vitamins E and C,
N-acetyl cysteine, antioxidants and nitric oxide. Of these,
only caffeine has been shown to significantly reduce the
incidence and severity of BPD and, thus, is considered
accepted practice.
Corticosteroids, presumably via anti-inflammatory effects,
play a central role in the management of BPD. Systemic
steroids, mainly dexamethasone and hydrocortisone, have
been extensively studied and appear to be effective in
reducing BPD. However, the adverse effects of systemic
steroids, particularly on the developing brain leading to
cerebral palsy and neurodevelopmental impairment, force
neonatologists to limit use of this therapy to a small
proportion of infants in whom the risks associated with the
disease are considered to outweigh the risks of the therapy
(2). Accordingly, there has been a long-running interest in
inhaled steroids based on the hope that this approach would
produce positive anti-inflammatory effects on the target
ª2017 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd
Acta Pædiatrica ISSN 0803-5253
organ, the lungs, without leading to adverse effects on other
organs, in particular, the brain. A limitation of this approach
is the absence of studies that evaluated the pharmacokinetics
of inhaled steroids in the lungs and other organs. Many
studies have been reported although many were small and
inconclusive and included a variety of medications, dosage
schedules and timing of intervention. Also, these studies
purported to offer two alternative approaches. Treatment
begun shortly after birth aimed to supposedly prevent BPD,
while treatment begun after one week of age was considered
to represent treatment of established disease (3,4). However,
this differentiation into two seemingly distinct groups is
problematic as there is marked overlap between the studies as
some of the early studies continued the intervention for long
periods of time, even as long as two months. Whether defined
as prevention or treatment, inhaled steroids are widely used
in many countries and at varying stages of the disease (5). A
significant body of new information from randomized con-
trolled trials (RCTs) has now been added, necessitating
updated systematic reviews and meta-analyses (3,6). The
findings have generated much interest, and therefore, this
review will focus on the most pertinent findings and the
controversies arising from them.
REVIEW OF RANDOMISED CONTROLLED TRIALS (RCTS)
Overall, 17 RCTs that compared inhaled steroids to placebo
have been reported between 1993 and 2016. These studies
included 1807 preterm infants, although no less than 1327
were from just three large trials. As these studies heavily
influence each of the meta-analyses that have been
performed, they will be described here in some detail.
1
Inhaled steroids for BPD
COLE, 1999
This study compared a decreasing dosage regimen of inhaled
beclomethasone with placebo for four weeks from age 3 to
14 days in 253 ventilated preterm infants born before
33 weeks and weighing less than 1250 g (7). The study
protocol determined that if the attending clinician decided to
initiate treatment with systemic steroids for perceived
developing BPD, then the inhaled study drug was discontin-
ued and this occurred in almost 23% of the study participants.
This may limit the ability of the study to assess the efficacy of
the inhaled intervention. No significant difference between
the groups was found for mortality or BPD at either 28 days
of age or 36 weeks of gestational age. However, the
beclomethasone-treated infants received less systemic ster-
oids and required less mechanical ventilation. These findings
suggest an ameliorating effect of inhaled beclomethasone
that may have been more pronounced had systemic steroid
administration been more limited per protocol.
BASSLER, 2015
This is the largest reported placebo-controlled RCT of
inhaled steroids for prevention of BPD, enrolling 863
infants born at 23–27 weeks in 40 centres (8). Infants
received either inhaled budesonide or placebo by metered-
dose inhaler from day one of life until age 32 weeks or
when weaned from oxygen or assisted ventilation. There
was a borderline significant reduction in the composite
primary outcome variable of mortality or BPD at 36 weeks
(relative risk 0.86, 95% confidence interval 0.75–1.0,
p = 0.05). Separation of the components of the composite
outcome variable revealed a significant reduction in BPD
(27.8% budesonide vs 38% placebo, RR 0.74, 95% CI: 0.6–
0.91, p = 0.004). However, this was offset by a non-
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
presented at an international meeting (9). The primary
outcome variable was a composite of cerebral palsy,
cognitive delay, hearing loss and blindness, and no differ-
ence was found between the groups (budesonide 44.7% vs
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-
pre-specified analysis of mortality was conducted and this
revealed a now borderline significant increase in mortality
Table 1 Comparison of meta-analyses
Cochrane early (Shah 2017)
10 studies, n = 1644
RR 95% CI p RR
Death or BPD 36 0.86 0.75–0.99 0.03
BPD 36 0.76 0.63–0.93 0.003
Death 1.07 0.82–1.4 0.93
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
in the budesonide-treated group (budesonide 19.9% vs
placebo 14.5%, RR 1.37, 95% CI: 1.01–1.86, p = 0.057). The
authors conducted a detailed review of the causes of death
and clinical course of all study infants who died. No
significant differences were found between the groups, and
no useful information was gained that may have con-
tributed to the development of a biologically plausible
hypothesis to explain the seeming excess of deaths in
treated infants. It is also important to note that the
difference between the groups is so borderline that if only
two infants who died in the budesonide group had been in
the placebo group, the finding would not have been
statistically significant.
NAKAMURA, 2016
This most recent placebo-controlled RCT from 12 NICUs in
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
study was halted with less than half of the originally planned
sample because of budgetary restrictions. The primary out-
come variable of death or oxygen dependence at discharge, a
surrogate for severe BPD, showed a non-significant reduc-
tion in the fluticasone group (RR 0.77, 95% CI: 0.57–1.05,
p = 0.15). No differences were found for neurodevelopmen-
tal impairment or cerebral palsy or death at age three years.
However, in the sub-groups of infants born at 24–26 weeks
and in infants exposed to histological chorioamnionitis
irrespective of gestational age, fluticasone treatment was
associated with a reduction in both mortality and oxygen
dependence at discharge. No effect was seen in the groups
born at 22–23 weeks or above 26 weeks, although the
numbers of infants in these subgroups were small.
SMALLER STUDIES
The 14 additional studies employed a variety of medica-
tions, dosage schedules, prevention or treatment approach
and outcome variables. Various of these studies have been
included in the recently published meta-analyses.
META-ANALYSES
As explained above, with the addition of the newer studies
of Bassler and Nakamura, new meta-analyses approached
Early + Late (Shinwell 2016) New analysis (Updated early + Late)
16 studies, n = 1596 17 studies, n = 1807
95% CI p RR 95% CI p
0.87 0.77–0.99 0.03 0.87 0.77–0.979 0.03
0.79 0.68–0.92 0.002 0.79 0.68–0.92 0.002
1.04 0.59–1.86 0.89 1.04 0.59–1.86 0.89
Shinwell
the ongoing controversy of inhaled steroids for BPD.
Shinwell et al. (6) reported a meta-analysis that combined
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
of completeness in this review, I have added the study of
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,
Shah et al. updated the Cochrane early analysis to include
the new studies (10 studies, n = 1644). Strikingly, despite
the differences in overall studies included, the findings of
the three meta-analyses were almost identical. All analyses
showed a modest, but significant reduction in the composite
outcome of death or BPD at 36 weeks (RR 0.86–0.87).
When separated into the constituent parts of this variable, it
can be seen that inhaled steroid therapy is associated with a
marked significant reduction in BPD (RR 0.76–0.79) with
no effect whatsoever on death.
EFFECT ON DEATH: META-ANALYSES VS BASSLER STUDY
The meta-analyses show that inhaled steroids are associ-
ated with a significant reduction in BPD at 36 weeks, with
no effect on either mortality or neurodevelopmental
outcome. However, both meta-analyses are highly influ-
enced by one large study, namely the Bassler study, in
which there was the worrisome finding of a slight but
significant increase in mortality. No plausible explanation
has been identified for the mortality finding in this study
which was not reproduced in all the other studies. This is
not the first time in recent years that a large well-
conducted RCT in neonatology has found a small increase
in mortality in the intervention group, while no feasible
biological explanation could be offered either by the
investigators or by the numerous commentators in the
field. The Surfactant, Positive Pressure, and Oxygenation
Randomized Trial (SUPPORT) found marginally increased
mortality risk in infants randomised to lower oxygen
saturation targets, despite the lower range being within
the previously standard target (11). The meta-analysis
including the other studies of the NEOPROM collabora-
tion did not confirm this finding (12). Likewise, the
NICHD RCT of ‘aggressive’ phototherapy in ELBW infants
found a slight increase in mortality together with reduced
impairment in the intervention group (13). This too was an
unexpected finding.
In conclusion, each of these examples of unexpected
but worrisome findings challenges the neonatologist
with balancing statistical significance against clinical
understanding. Current evidence would appear to
suggest that inhaled steroids may be safely added to
ª2017 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd
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Inhaled steroids for BPD
current management of developing BPD in preterm
infants.
CONFLICT OF INTEREST AND FUNDING
None.
References
1. Stensvold HJ, Klingenberg C, Stoen R, Moster D, Braekke K,
Guthe HJ. Neonatal morbidity and 1-year survival of extremely
preterm infants. Pediatrics 2017; 139: e20161821.
2. Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair
JC. An update on the impact of postnatal systemic
corticosteroids on mortality and cerebral palsy in preterm
infants: effect modification by risk of bronchopulmonary
dysplasia. J Pediatr 2014; 165: 1258–60.
3. Shah VS, Ohlsson A, Halliday HL, Dunn M. Early
administration of inhaled corticosteroids for preventing
chronic lung disease in very low birth weight preterm neonates.
Cochrane Database Syst Rev 2017; 1: CD001969.
4. Onland W, Offringa M, vanKaam A. Late (≥ 7 days) inhalation
corticosteroids to reduce bronchopulmonary dysplasia in
preterm infants. Cochrane Database of Syst Rev 2017; 8:
CD002311.
5. Slaughter JL, Stenger MR, Reagan PB, Jadcherla SR. Utilization
of inhaled corticosteroids for infants with bronchopulmonary
dysplasia. PLoS ONE 2014; 9: e106838.
6. Shinwell ES, Portnov I, Meerpohl JJ, Karen T, Bassler D.
Inhaled Corticosteroids for Bronchopulmonary Dysplasia: A
Meta-analysis. Pediatrics 2016; 138: pii: e20162511.
7. Cole CH, Colton T, Shah BL, Abbasi S, MacKinnon BL,
Demissie S, et al. Early inhaled glucocorticoid therapy to
prevent bronchopulmonary dysplasia. N Engl J Med 1999; 340:
1005–10.
8. Bassler D, Plavka R, Shinwell ES, Hallman M, Jarreau PH,
Carnielli V, et al. Early Inhaled Budesonide for the Prevention
of Bronchopulmonary Dysplasia. N Engl J Med 2015; 373:
1497–506.
9. Bassler D. Long-term effects of early inhaled Budesonide for
the prevention of Bronchopulmonary Dysplasia. Hot Topics in
Neonatology, Washington: 2016.
10. Nakamura T, Yonemoto N, Nakayama M, Hirano S, Aotani H,
Kusuda S, et al. Early inhaled steroid use in extremely low
birthweight infants: a randomized controlled trial. Arch Dis
Child Fetal Neonatal Ed 2016; 101: F552–6.
11. SUPPORT Study Group of the Eunice Kennedy Shriver
NICHD Neonatal Research Network, Carlo WA, Finer NN,
Walsh MC, Rich W, Gantz MG, Laptook AR, et al.Target
ranges of oxygen saturation in extremely preterm infants. N
Engl J Med 2010; 362: 1959–69.
12. Stenson BJ. Oxygen Saturation Targets for Extremely Preterm
Infants after the NeOProM Trials. Neonatology 2016; 109:
352–8.
13. Tyson JE, Pedroza C, Langer J, Green C, Morris B, Stevenson
D, et al. Does aggressive phototherapy increase mortality while
decreasing profound impairment among the smallest and
sickest newborns? J Perinatol 2012; 32: 677–84.
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