Zhang et al.

BMC Pulmonary Medicine (2017) 17:207

DOI 10.1186/s12890-017-0550-z

RESEARCH ARTICLE Open Access

Airway administration of corticosteroids for

prevention of bronchopulmonary dysplasia
in premature infants: a meta-analysis with
trial sequential analysis
Zhi-Qun Zhang1,2, Ying Zhong1, Xian-Mei Huang2 and Li-Zhong Du1*

Abstract
Background: Uncertainly prevails with regard to the use of inhalation or instillation steroids to prevent
bronchopulmonary dysplasia in preterm infants. The meta-analysis with sequential analysis was designed to evaluate the
efficacy and safety of airway administration (inhalation or instillation) of corticosteroids for preventing bronchopulmonary
dysplasia (BPD) in premature infants.
Methods: We searched MEDLINE, EMBASE, CINAHL, and Cochrane CENTRAL from their inceptions to February 2017. All
published randomized controlled trials (RCTs) evaluating the effect of airway administration of corticosteroids (AACs) vs
placebo or systemic corticosteroid in prematurity were included. All meta-analyses were performed using Review
Manager 5.3.
Results: Twenty five RCTs retrieved (n = 3249) were eligible for further analysis. Meta-analysis and trial sequential analysis
corrected the 95% confidence intervals estimated a lower risk of the primary outcome of BPD (relative risk 0.71, adjusted
95% confidence interval 0.57–0.87) and death or BPD (relative risk 0.81, adjusted 95% confidence interval 0.71–0.97) in
AACs group than placebo and it is equivalent for preventing BPD than systemic corticosteroids. Moreover, AACs fail to
increasing risk of death compared with placebo (relative risk 0.90, adjusted 95% confidence interval 0.40–2.03) or systemic
corticosteroids (relative risk 0.81, 95% confidence interval 0.62–1.06).
Conclusions: Our findings suggests that AACs (especially instillation of budesonide using surfactant as a vehicle) are an
effective and safe option for preventing BPD in preterm infants. Furthermore, the appropriate dose and duration,
inhalation or instillation with surfactant as a vehicle and the long-term safety of airway administration of corticosteroids
needs to be assessed in large trials.
Keywords: Inhaled corticosteroids, Bronchopulmonary dysplasia, Preterm infants, Meta-analysis, Neurodevelopmental
outcomes

Background 23 weeks [1].The survival infants of BPD are at high risk

Bronchopulmonary dysplasia (BPD), defined as oxygen for long-term injury to both lung and brain [2–4].
dependence at 36 weeks of postmenstrual age (PMA), is a Pulmonary inflammation plays a central, modulating role
severe complications of extremely premature infants. The in the pathogenesis of BPD [5–7]. It has been confirmed
reported morbidity of BPD ranges from 24% in preterm that corticosteroids have strong anti-inflammatory effects.
infants born at 28 weeks to 79% in preterm infants born at Randomized controlled trials (RCTs) have shown that
systemic administration of corticosteroids reduces the
incidence of BPD but aggravate short-term and long-term
* Correspondence: dulizhong@zju.edu.cn
1
Department of Neonatology, the Children’s Hospital, Zhejiang University
adverse effects [8–11]. Theoretically, airway administra-
School of Medicine, No. 3333 Bingsheng Road, Hangzhou City, Zhejiang tion (inhalation or instillation) of corticosteroids, on the
310002, China other hand, demonstrate high pulmonary deposition, low
Full list of author information is available at the end of the article

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Zhang et al. BMC Pulmonary Medicine (2017) 17:207 Page 2 of 16

systemic bioavailability, and rapid systemic clearance, Search terms included: preterm infant, premature infant,
thereby reducing the adverse effects [12, 13]. infant-newborn, bronchopulmonary dysplasia, chronic
A range of reviews address the use of inhaled corticoste- lung diseases, anti-inflammatory agents, neurodevelop-
roids for preventing BPD [14, 15]. Onland et al. [14] have mental outcomes, steroids, glucocorticoids, corticoste-
attempted the late use (≥7 days)) of inhaled corticosteroids roids; administration, inhalation; aerosols, budesonide,
to reduce BPD incidence in preterm infants and con- beclomethasone, dipropionate, flunisolide, and fluticasone
cluded that such treatment do not reduce the outcomes of propionate. No language restriction was applied. The
BPD and death or BPD. Similarly, Shah et al. [15] also protocol of this systematic review was registered before
concluded that early (<2 weeks) administration of inhaled the literature search in PROSPERO (Prospero2016
corticosteroids was ineffective for reducing the incidence CRD42016054098) [27].
of BPD in ventilated very low birth weight premature in-
fants. However, some overlap in ages at administration of Eligibility criteria
the inhaled corticosteroid existed in the included studies Studies had to meet the following criteria: 1) randomized
in their meta-analysis. In recent, a large RCT confirmed controlled trials; 2) infants were randomized to receive
that inhalation of budesonide reduces both BPD and per- treatment with an airway administration (inhalation or in-
sistent ductus arteriosus (PDA) [16]. However, there was a stillation) of corticosteroid vs placebo or systemic cortico-
trend toward increased mortality. Subsequently, a meta- steroids; 3) reported more than one of the following
analysis including the RCT by Bassler D et al. [17] showed outcome parameters: primary outcome of BPD (defined
that inhaled corticosteroids reduced risk for BPD and had by the need for supplemental oxygen or positive pressure
no effect on death. Their meta-analysis included several support at 36 weeks PMA) or/and death; secondary out-
therapeutic studies and failed to evaluate the intratracheal comes of the use of systemic corticosteroids, effect on
instillation of steroids [18, 19]. In addition, when valuating extubation and not extubate (including extubated within
for the outcome of death, the meta-analysis included a 14 days and duration of mechanical ventilation), adverse
study published as an abstract, which had a large impact outcomes of sepsis, hyperglycemia requiring treatment, in-
on the results [17, 20]. The authors did not carry out sen- traventricular hemorrhage (IVH), periventricular leuko-
sitive analysis to determine the stability of the results [17]. malacia (PVL), necrotizing enterocolitis (NEC) Bell’s stage
In addition, Cochrane reviews also have compared inhaled > or = II, retinopathy of prematurity (ROP), PDA requiring
and systemic corticosteroids [19, 21, 22]. Most of the main drug treatment or surgery, and neurodevelopmental out-
outcome were concluded from a small number of the comes of neurodevelopmental impairment and cerebral
studies with few infants providing data [21, 22]. palsy. Exclusion criteria were: a) non-clinical studies (ex-
Uncertainty prevails with regard to the use of inhalation perimental and basic studies); b) observational or retro-
or instillation steroids to prevent BPD in preterm infants spective studies; c) duplicate reports or secondary or post
[23]. Recently, 2 RCTS about airway administration of hoc analyses of the same study population; d) lack of suffi-
corticosteroids (AACs) for preventing BPD and neurode- cient information on baseline or primary or secondary
velopmental outcomes have been published [24, 25]. outcome data; and e) therapeutic study.
Therefore, to better understand the potential efficacy and
safety of AACs for reducing the risk of BPD or/and death Assessment of the risk of bias
in preterm infants, as compared with placebo or systemic Two reviewers (Zhang and Zhong) independently
corticosteroids, we performed an up-to-date systematic assessed the risk of bias of individual studies and the
review of published RCTs. We verified the robustness and bias domains across studies using the Cochrane collab-
reliability of our findings by implementing trial sequential oration tool [28]. All discrepancies were resolved by dis-
analysis and sensitivity analyses. cussion and consensus. The studies were rated to be at
high risk of bias, low risk of bias, or unclear risk of bias
Methods based on sequence generation, concealment of alloca-
Study identification tion, blinding of participants/parents and personnel,
This systematic review was conducted and is reported ac- blinding of outcome assessment, incomplete outcome
cording to the recommendations of the Preferred Report- data, and selective outcome reporting.
ing Items for Systematic Reviews and Meta-Analyses
(PRISMA) statement [26]. Electronic searches were carried Data collection
out in multiple databases, including PubMed, Web of For each study, data were extracted independently by two
Science, Embase, Cochrane Library, Clinicaltrials.gov, reviewers (Zhang and Zhong) using a predesigned form.
Controlled-trials.com, Google scholar, VIP, WangFang and Any differences and disagreements in the abstracted data
proceedings of the Pediatric Academic Society meetings were discussed and resolved by consensus. Details of
(from 1980) on December 31, 2016 for relevant studies. methodological quality, study design, analysis, and results
Zhang et al. BMC Pulmonary Medicine (2017) 17:207 Page 3 of 16

were abstracted. For each outcome, the numeric results, because of therapeutic study of inhaled steroids for BPD
the statistic used, and the P value were abstracted. We [18, 19, 58–61] and when the raw data in Ref. [62, 63] is
contacted authors of the original reports to obtain further lacking due to unable to reach the original investigators.
details when information regarding any of the above infor- Overall, the 20 trials of airway administration of cortico-
mation was unclear. steroid (16 trials of inhaled corticosteroid and 4 trials of
instillation of steroids) vs placebo included 2484 infants,
Statistical analysis and 5 trials of inhaled corticosteroid vs systemic cortico-
The statistical analyses were performed by the steroids included 765 infants. Two studies were published
DerSimonian and Laird method (random-effect model) in abstract form [20, 47]. Two articles [50, 55] were
using the Review Manager meta-analysis software (version follow-up studies of two included trials [49, 54]. Fig. 1
5.3, 2012; The Cochrane Collaboration, Copenhagen, shows the details of the selection process.
Denmark). TSA viewer version 0.9 β was used for trial se-
quential analysis. Treatment effect estimates for all trials Characteristics of the included studies
were calculated, expressed as typical relative risk (RR) for The 25 RCTs (27 articles) selected for analysis included a
dichotomous outcomes and weighted mean difference total of 3249 participants (Tables 1 and 2, Table S1-S2 in
(WMD) for continuous outcomes, all with a 95% confi- Additional file 1: Table S1 and Additional file 2: Table S2)
dence interval. If the continuous measures were reported [16, 20, 24, 25, 35–57]. The publication dates of the RCTs
in median and inter-quartile range, mean and standard SD ranged from 1993 to 2016. The AACs group vs the placebo
values were estimated using the method described by Wan group or systemic corticosteroids group were well matched;
et al. [29]. P values of ≤0.05 and RR point estimate 95% CIs birth weight and gestational age did not differ significantly
that excluded the null (<1.00 or >1.00) were considered sta- significance. Other aspects of respiratory treatment, includ-
tistically significant. Where the pooled estimates of relative ing the resuscitation devices used and the criteria for using
risk were statistically significant. We calculated the num- antenatal glucocorticoids as well as surfactant, were ad-
bers needed to treat (NNT) for all outcomes. The hetero- equately described in the studies and conformed to current
geneity between-trial regarding treatment effects was international guidelines [64–66]. The incidence of neonatal
analyzed by the χ2 test for heterogeneity and I2 statistics. respiratory distress syndrome (was diagnosed based on re-
Heterogeneity was deemed significant when the corre- spiratory symptoms and corresponding X-ray changes) was
sponding p-value was <0.1 or when the I2 percentage was comparable among the airway administration of cortico-
>50 [30]. Subgroup analyses were carried out to assess the steroid group and comparative groups.
source of heterogeneity. When more than 10 articles were Although all studies attempted to include infants at risk
included, the presence of publication bias was assessed and of developing BPD, the inclusion criteria, the intervention
displayed through a funnel plot. Analysis by excluding stud- (type of AACs), and duration of therapy varied between
ies at high risk of bias or abstract forms was part of a pre- studies. The intervention regimens,including the prescribed
defined subgroup analysis [28]. Sensitivity analysis with trial dosages and administration schedules, varied considerably
sequential analysis was performed to correct for random between the RCTs. Overall, the duration of AACs treat-
error and repetitive testing of accumulating and sparse ment ranged from 3 to 28 days, and the types of AACs in-
data; meta-analysis monitoring boundaries and required in- cluded beclomethasone, budesonide, fluticasone, and
formation size (meta-analysis sample size) were quantified, dexamethasone. Delivery systems included metered dose
along with D2 (diversity adjusted information size) and inhaler (MDI) with a spacer device, nebulization, and air-
adjusted 95% CIs [31–34]. Risk of type 1 error was consid- way instillation. Four studies used airway instillation of
ered 5% with a power of 80%. A clinically meaningful budesonide using surfactant as a vehicle [25, 36, 48, 49].
anticipated relative risk reduction was used based on the
low bias trial [16]. Trial sequential analysis 95% CI Risk of bias within individual studies
boundaries that excluded the null (<1.00 or >1.00) were Three studies were deemed to have a low risk of bias [16,
considered statistically significant. 24, 25], seven studies were deemed to have a high risk of
bias [36, 38, 53–57] due to selection bias, detection bias,
Results attrition bias or performance bias, and 17 studies were
Study selection classified as having an unclear risk of bias [20, 35, 37, 39–
Our search identified 121 potentially relevant articles dur- 52]. Although all studies were presented as randomized tri-
ing the initial electronic database search, of which 35 als, the method of randomization was determined to be in-
RCTs were involving the use of AACs in premature in- adequate in 17 studies [20, 35, 37, 39–48, 51, 53, 56, 57].
fants. However, only 25 (27 articles) of 35 trials presented Sixteen studies were found to have adequate concealment
appropriate and sufficient data for further analysis [16, 20, of allocation and clearly described blinding for the inter-
24, 25, 35–57], and the remaining eight were excluded vention method [16, 20, 24, 25, 38, 39, 41, 42, 44, 45, 47,
Zhang et al. BMC Pulmonary Medicine (2017) 17:207 Page 4 of 16

Fig. 1 Flowchart of the study selection process. * Two article [48, 53] were follow-up study of two included trials [47, 52]

49–51, 56]. Thirteen studies were found to have adequate cumulative z score crossed the sequential monitoring
blinding of outcome assessment [16, 24, 25, 35, 37, 38, 40, boundary of benefit and the required information size
44, 46, 49, 50, 52, 56]. Follow-up data were reported in five (Fig. 5), suggesting that further studies have little chance to
studies [24, 25, 41, 50, 56]. Fig. 2 and 3 summarise the risks perturbation the finding of benefit from AACs.
of bias.
Death
Systematic review of the findings from synthesis of the Eleven trials enrolling 2041 neonates reported on the inci-
results dence of death. Meta-analysis indicated that the incidence
of death was not significantly different between the AACs
ACCs vs placebo group and the placebo group (RR = 0.90, 95% CI 0.65 to
Primary clinical outcome 1.25, I2 = 37%, P = 0.55) (Fig. 4). Trial sequential analysis
BPD correction of the 95% confidence interval (0.40 to 2.03;
Fourteen trials enrolling 2388 neonates reported on the in- D2 = 55%) did demonstrate no increasing risk of death
cidence of BPD. Meta-analysis indicated that AACs was as- with airway administration of corticosteroid (Fig.5). The
sociated with a lower likelihood of BPD than was placebo finding was robust to sensitivity analysis (Table 3), and
(RR = 0.71, 95% CI 0.58 to 0.86, NNT = 10, I2 = 34%, P = clear evidence of publication bias was not present
0.0005) (Fig. 4). Trial sequential analysis correction of the (Figure S1 in Additional file 3). Sensitivity analysis showed
95% confidence interval (0.57 to 0.87; D2 = 53%) did not that instillation of steroids using surfactant as a vehicle
alter the finding of BPD morbidity benefit with AACs had a nonsignificant reduction mortality (12.1% vs. 17.8%,
(Fig.5). The finding was robust to sensitivity analysis (high- RR = 0.67; 95% CI 0.43 to 1.04, I2 = 0%, P = 0.07) (Table 3).
est P value 0.007) and the subgroup of instillation of steroids
had the lowest NNT (Table 3), and clear evidence of publi- Death or BPD
cation bias was not present (Figure S1 in Additional file 3). Eight trials enrolling 1761 neonates reported on the inci-
Subgroup analysis based on type of corticosteroid showed dence of death or BPD. Meta-analysis indicated that air-
that the incidence of BPD was significantly lower only in way administration of corticosteroid was associated with
the group treated with budesonide compared to placebo a lower likelihood of death or BPD than was placebo
(RR = 0.59, 95% CI 0.44 to 0.79, NNT = 8, I2 = 40%, P = (RR = 0.81, 95% CI 0.71 to 0.93, NNT = 12, I2 = 27%, P =
0.0004) (Fig. 4). In the trial sequential analysis, the 0.003) (Fig. 4). Trial sequential analysis correction of the
Zhang et al. BMC Pulmonary Medicine (2017) 17:207 Page 5 of 16

Table 1 Characteristics of 25 RCTs reported in 27 articles and baseline characteristics of patients

Study Study Group N Male GA (wk) BW (g) Antenatal RDS (n) Surfactant
characteristics (n) glucocorticoid (n)
AACs vs placebo
Arnon [35] 1996 1 centre T 15 NA 27.5 (0.7)a 1024 (92.3)a 7 (46.7%) NA NA
UK C 15 NA 27.1 (0.89)a 1041 (113)a 8 (53.3%) NA NA
Bassler [16] 2015 10 centres T 437 NA 26.1 (1.3)a 798 (193)a 388 (88.8%) NA NA
Switzerland C 419 NA 26.1 (1.2)a 803 (189)a 383 (91.4%) NA NA
Cao [36] 2016 1 centre T 40 NA 30.1 (2.2)a 1333 (110)a NA 40 40
China C 40 NA 30.7 (1.8)a 1339 (105)a NA 40 40
Cole [37] 1999 4 centres T 123 51 26 (2)a 800 (193)a 77 (62.6%) 123 95
USA C 130 53 26 (2)a 802 (189)a 68 (52.3%) 129 97
Denjean [38] 1998 6 centres T 43 26 27.6 (1.5)a 1060 (218)a 11 (25.6%) 43 31
France C 43 26 27.8 (1.6)a 1082 (260)a 11 (25.6%) 43 34
Fok [39] 1999 1 centre T 27 NA 27.9 (0.5)a 993 (71)a 15 (55.6%) NA NA
Hong Kong C 26 NA 27.1 (0.5)a 981 (71)a 13 (50.0%) NA NA
Giep [40] 1996 1 centre T 10 6 26 (2.0)a 752 (110)a 4 (40.0%) 8 8
USA C 9 3 25 (1.6)a 784 (141)a 2 (22.2%) 9 9
Jangaard [41] 2002 1 centre T 30 13 27.2 (2)a 882 (204)a 15 (50.0%) 19 19
Germany C 30 13 27.9 (2)a 917 (178)b 16 (53.3%) 25 25
Jonsson [42] 2000 1 centre T 15 8 25 (23,27)b 766 (525,1122)b 12 (80.0%) 14 14
Sweden C 15 11 26 (24,29)b 813 (630,1227)b 10 (66.7%) 15 15
Ke [43] 1 centre T 46 20 <32 <1500 NA 46 46
2016 China C 46 27 <32 <1500 NA 46 46
LaForce [44] 1993 1 centre T 10 NA NA <1500 NA NA NA
USA C 11 NA NA <1500 NA NA NA
Merz [45] 1999 1 centre T 12 5 28 (27,32)b 1108 (820,1420)b 7 (58.3%) 12 10
Germany C 11 7 29 (27,31)b 1120 (880,1480)b 7 (63.6%) 11 9
Nakamura [24] 2016 1 centre T 107 63 26 (25,27)b 783.87 (134.8)b 45 (42.1%) 90 NA
Japan C 104 50 26 (25,27)b 784.06 (127.2)b 42 (40.4%) 88 NA
Pappagallo [46] 1998 1 centre T 9 5 26.8 (1.1)a 828 (64)a NA NA NA
USA C 9 5 26.6 (0.8)a 849 (89)a NA NA NA
Townsend [47] 1998 1 centre T 15 8 25.8 728 NA 15 NA
Denver C 17 8 25.5 695 NA 17 NA
Wen [48] 2016 1 centre T 80 54 30.5 (2.6)a 1220 (183)a NA NA NA
China C 80 51 31.2 (2.3)a 1250 (167)a NA NA NA
Yeh [49] 2008 1 centre T 60 31 26.4 (2.2)a 881 (245)a 46 (76.7%) 60 60
Kuo [50] 2010 Taiwan C 56 29 26.7 (2.3)a 919 (272)a 42 (75.0%) 56 56
Yeh [25] 2016 1 centre T 131 NA 26.5 (2.2)a 882 (249)a NA 131 131
Taiwan C 134 NA 26.8 (2.2)a 935 (283)a NA 134 134
Yong [20] 1999 1 centre T 20 13 27.4 (1.7)a 1011 (223)a NA NA NA
UK C 20 12 27.7 (1.7)a 932 (401)a NA NA NA
Zimmerman [51] 2000 1 centre T 20 12 26 (2.0)a 910 (198)a 14 (70.0%) 15 15
USA C 19 8 26 (2.0)a 802 (225)a 15 (78.9%) 18 18
Inhaled corticosteroids vs systemic corticosteroids
Dimitriou [52] 1997 1 centre T 20 NA 27 (24,30)b 849 (584,1270)b 12 (60.0%) NA 14
UK C 20 NA 27 (24,31) 818 (425,1460)b 11 (55.0%) NA 12
Groneck [53] 1999 1 centre T 7 3 26 (25,28)b 800 (500,1020)b NA NA NA
Germany C 9 3 26 (25,28)b 847 (660,1030)b NA NA NA
Halliday [54] 2001 47 centre T 285 142 27.2 (1.9)a 1002 (281)a 177 (62.1%) NA 265
Wilson [55] 2006 Europe C 285 164 27.2 (1.9)a 1011 (285)a 164 (57.5%) NA 260
Rozycki [56] 2003 1 centre T 46 23 <31 <1500 6 (13.0%) 46 46
USA C 15 7 <31 <1500 2 (13.3%) 15 15
Suchomski [57] 2002 1 centre T 51 25 26 (1.6)a 844 (157)a 34 (66.7%) NA NA
USA C 27 19 26 (2.0)a 843 (227)a 16 (59.3%) NA NA
RCTs Randomized controlled trials, AACs Airway administration of corticosteroids, RDS Respiratory distress syndrome, PS Pulmonary surfactant, AG
Antenatal glucocorticoid, GA Gestational age, BW Brith weight, ameans ± SD, bmedian (25th, 75th percentiles), NA: Not Applicated
Zhang et al. BMC Pulmonary Medicine (2017) 17:207 Page 6 of 16

Table 2 Interventions used in the 25 RCTs

Study Age at Type of Intervention dose Mode of delivery Intervention treatment
enrollment AACS
AACs vs placebo
Arnon [35] 15 (0.6)a BUD 600 μg BID MDI 7 days or until the infant
1996 14 (0.5)a had been extubated
Bassler [16] 2015 within 12 h BUD 400 μg Q12H for MDI Until extubation and no
14 days oxygen dependent or 32
200 μg Q12H for weeks PMA
15 days
Cao [36] 2016 within 6 h BUD 250 μg Q8H Airway instillation Until FIO2 < 0.4 or extubation
Cole [37] 1999 5.7 (3.4)a BDP 40 μg/kg for 7 days MDI 28 days
5.4 (2.9)a 30 μg/kg for 7 days
15 μg/kg for 7 days
5-10 μg/kg for 7 days
Denjean [38] 1998 10 days BDP 250 μg Q6H MDI 28 days
Fok [39] 1999 within 24 h of FPP 250 μg MDI 14 days
birth Q12H
Giep [40] 1996 14 days BDP 1 mg/kg/d MDI 7 days
Jangaard [41] 3 years BDP 0.2 mg/kg/d MDI Until 28 days of age
2002
Jonsson [42] 2000 6 days BUD 0.5 mg/times Electronic dosimetric 14 days
BID jet nebulizer
Ke [43] 2016 within 6 h BUD 250 μg Q12H Airway instillation Until stop respiratory support
LaForce [44] 1993 14 days BDP 50 μg Q8H A Whisper Jet nebulizer 28 days
system
Merz [45] 1999 3 days BUD 1.6 mg/d Q6H MDI 10 days or until extubation
Nakamura [24] within 24 h of FPP 50 μg BID MDI Until 6 weeks of age or extubation
2016 birth
Pappagallo [46] 22.6 (3.0)a DXM 1 mg/kg Q8H for A jet nebulizer 10 days
1998 19.1 (1.6)a 7 days
0.5 mg/kg Q8H for
7 days
Townsend [47] at 48-96 h of age FPP 500 μg TID MDI 28 days or until extubation
1998
Wen [48] 2016 within 24 h of BUD 0.4 mg/kg MDI 14 days
birth Q12H
Yeh [49] 2008 2.1 (2.2)a BUD 0.25 mg/kg Airway instillation Until the infant required ≤0.4 of FIO2
Kuo [50] 2010 Q8H or until the infant was extubated
Yeh [25] 2.0 (1.5)a BUD 0.25 mg/kg Airway instillation Until the infant required ≤0.4 of
2016 1.8 (1.6)a Q8H FIO2 or until extubation
Yong [20] within 18 h of FPP 250 μg MDI 14 days
1999 birth Q12H
Zimmerman [51] within 24 h of BDP 2MDI, Q6H for 3 days; MDI 12 days
2000 birth 2MDI, Q8H for 3 days;
2MDI Q12H for 3 days;
2MDI QD for 3 days
Inhaled corticosteroids vs systemic corticosteroids
Dimitriou [52] After 5 days BUD 100 μg QD A jet nebulizer 10 days
1997
Groneck [53] After 72 h BDP 250 μg QD MDI 10~28 days
1999
Halliday [54] 2001 < 72 h or > 15d BUD <1000 g 0.4 mg BID MDI 12 days or until extubation
Wilson [55] 2006 >1000 g 0.6 mg BID
Rozycki [56] at 14 days of age BDP High: 2.4-3.7 mg/kg/d MDI 7 days or until extubation
2003 Mid: 1.0-1.8 mg/kg/d
Zhang et al. BMC Pulmonary Medicine (2017) 17:207 Page 7 of 16

Table 2 Interventions used in the 25 RCTs (Continued)

Study Age at Type of Intervention dose Mode of delivery Intervention treatment
enrollment AACS
Low: 0.5-0.7 mg/kg/d
Suchomski [57] 12-21 days of BDP High: 800 μg/d MDI Until extubation
2002 age Low: 400 μg/d
RCTs Randomized controlled trials, BUD Budesonide, BDP Beclomethasone dipropionate, FPP Fluticasone propionate, MDI metered-dose inhaler, AACs Airway ad-
ministration of corticosteroids, DXM Dexamethasone
None of the trials were sponsored by the manufacturer
a
means ± SD

95% confidence interval (0.71 to 0.97; D2 = 55%) did sup- duration of mechanical ventilation. AACs significantly
port the finding of death or BPD morbidity benefit with reduce the duration of mechanical ventilation compared
airway administration of corticosteroid (Fig.5). The find- with placebo (WMD = −2.99, 95% CI -5.10 to −0.87, I2 =
ing was robust to sensitivity analysis (highest P value 38%, P = 0.006) (Figure S4 in Additional file 6).
0.03) (Table 3). Subgroup analysis based on type of cor-
ticosteroid showed that the incidence of death or BPD Adverse outcomes
was significantly lower only in the group treated with AACs administration had a nonsignificant reduction in
budesonide versus placebo (RR = 0.77, 95% CI 0.61 to incidence of PDA (40.2% vs. 45.2%, RR = 0.89, 95% CI
0.97, NNT = 9, I2 = 75%, P = 0.03) (Fig. 4). 0.79 to 1.0, I2 = 0%, P = 0.05) and NEC (7.3% vs. 9.9%,
RR = 0.75, 95% CI 0.54 to 1.04, I2 = 0%, P = 0.09) com-
Secondary outcomes pared with placebo (Table S3 in Additional file 7). There
Requirement for systemic steroids were no significant differences between interventions in
Fourteen trials enrolling 1886 neonates reported on the re- the likelihood of other adverse outcomes (including in-
quirement for systemic steroids. A significant reduction in fection, hyperglycaemia, IVH, PVL, and ROP) (Table S3
the administration of systemic corticosteroids was found in Additional file 7).
in the group with airway administration of corticosteroids
(RR = 0.86, 95% CI 0.76 to 0.97, NNT = 20 I2 = 1%, P = Neurodevelopmental outcomes
0.02). However, publication bias was present (Figure S1 in Four trials enrolling 474 neonates reported on the neu-
Additional file 3). Subgroup analysis based on type of cor- rodevelopmental outcomes (neurodevelopmental impair-
ticosteroid showed that the requirement for systemic ste- ment and cerebral palsy). Meta-analysis indicated that
roids was significantly different only with beclomethasone the incidence of neurodevelopmental impairment and
versus placebo (Figure S2 in Additional file 4). cerebral palsy ware not significantly different between
the airway administration of corticosteroid group and
Benefit to extubation the placebo group (Table S3 in Additional file 7).
Seven trials enrolling 552 neonates reported on rates of
successful extubation within 14 days. AACs have a non- Inhaled corticosteroids vs systemic corticosteroid
significant increasing rates of successful extubation Primary clinical outcome
within 14 days (55.1% vs. 44.6%, RR = 1.53, 95% CI 1.0 to Bpd
2.33, I2 = 66%, P = 0.05) (Figure S3 in Additional file 5). Four trials enrolling 747 neonates reported on the inci-
Seven trials enrolling 623 neonates reported on the the dence of BPD. Meta-analysis indicated that the morbidity

Fig. 2 Risk of bias graph

Zhang et al. BMC Pulmonary Medicine (2017) 17:207 Page 8 of 16

Fig. 3 Risk of bias summary for all included records

of BPD has no decisive difference between inhaled cortico- Neurodevelopmental outcomes

steroid group and systemic corticosteroid group (RR = One trial enrolling 126 neonates reported on the neuro-
1.02, 95% CI 0.85 to 1.22, I2 = 15%, P = 0.81) (Fig. 6). The developmental outcomes (impairment, disability, and
finding was robust to trial sequential analysis (RR = 1.02, cerebral palsy). There were no significant differences be-
adjusted 95% CI 0.55 to 1.88, D2 = 0%, P = 0.83) (Fig. 7). tween interventions (Table S4 in Additional file 9).

Death Discussion
Five trials enrolling 762 neonates reported on the inci- This meta-analysis including 25 trials with 3249 preterm
dence of death. Meta-analysis indicated that the mortal- infants at high risk of BPD estimated relative effects of
ity was not significantly different between the inhaled AACs. The use of AACs was associated with a lower likeli-
corticosteroid group and the systemic corticosteroid hood of the primary outcomes of BPD and death or BPD,
group (RR = 0.81, 95% CI 0.62 to 1.06, I2 = 0%, P = 0.12) and secondary outcomes of requirement for systemic ste-
(Fig. 6), and this finding was confirmed in trial sequen- roids and the duration of mechanical ventilation than pla-
tial analysis (adjusted 95% confidence interval 0.43 to cebo, and was equivalent for preventing BPD than systemic
1.53). The cumulative Z curve did not cross any bound- corticosteroids. Moreover, AACs were not associated with
aries for benefit or harm (Fig. 7). an increased risk of death compared with placebo or sys-
temic corticosteroids. AACs had less occurrence of hyper-
Secondary outcomes glycemia compared to systemic steroids.
Benefit to extubation
Four trials enrolling 693 neonates reported on the the Interpretation of the findings
duration of mechanical ventilation. Systemic corticoste- Our primary outcomes, were robust to sensitivity and
roids were associated with shorter duration of mechan- trial sequential analyses. When evaluating the incidence
ical ventilation (WMD = 3.21, 95% CI 0.36 to 6.06, I2 = of BPD, death, and death or BPD between AACs and
10%, P = 0.03) (Figure S5 in Additional file 8). placebo, consistent results was observed in trial sequen-
tial analyses and after exclusion of studies at high risk of
Adverse outcomes bias, small sample, non-English literature, abstract, or
Inhaled corticosteroids were associated with less studies of instillation of steroids using surfactants as car-
hyperglycemia (RR = 0.44, 95% CI 0.29 to 0.69, NNT riers. In addition, sensitivity analysis showed that NNT
= 9, I2 = 0%, P = 0.0003) (Table S4 in Additional file 1). of 5 and 4 in subgroup of instillation of steroids using
There were no significant differences between inter- surfactant as a vehicle was lower than the NNT in the
ventions in the likelihood of other adverse outcomes inhaled corticosteroids group (NNT = 14 and 20) for
(including infection, NEC, PDA, PVL, and ROP) preventing one case of BPD and BPD or death (Table 3).
(Table S4 in Additional file 9). Using as a vehicle surfactant may also enhance the
Zhang et al. BMC Pulmonary Medicine (2017) 17:207 Page 9 of 16

Fig. 4 Meta-analysis of primary outcome with the use of AACs or placebo, AACs: Airway administration of corticosteroids
Zhang et al. BMC Pulmonary Medicine (2017) 17:207 Page 10 of 16

Fig. 5 (See legend on next page.)

Zhang et al. BMC Pulmonary Medicine (2017) 17:207 Page 11 of 16

(See figure on previous page.)

Fig. 5 Trial sequential analysis of trials reporting primary outcome comparing pooled AACs and placebo. A diversity adjusted information size
was calculated using ɑ = 0.05 (two sided), β = 0.20 (power 80%), D2 = 0%, an anticipated relative risk of 29.8%, −24.5%, 13.5%, respectively, and an
event proportion of 28.2%, 11.4%, 46.3%, respectively in the control arm. The cumulative z curve was constructed using a random-effect model,
and a penalized z curve was also constructed. The adjusted relative risk was 0.71, 0.90, 0.81, respectively, and the 95% confidence interval was
corrected to 0.57–0.87, 0.40–2.03, and 0.71–0.97, respectively, AACs: Airway administration of corticosteroids

solubility of budesonide, increase budesonide absorption, preventing BPD compared with systemic corticosteroids.
and strengthen the function of anti-inflammatory effects The information size for the comparison of inhaled cor-
[25, 67]. Trial sequential analysis corrected the 95% CIs ticosteroids with systemic corticosteroids was too low to
of the already statistically significant point estimates for require futility boundaries in trial sequential analysis.
main comparison of an airway administration of cortico- European Consensus Guidelines on the Management of
steroid with the placebo through accounting for random Respiratory Distress Syndrome do not recommend the
error and repetitive testing of accumulating sparse data. use of inhaled corticosteroid for preventing BPD until
In our analysis of incidence of BPD and death or BPD further safety data become available [68]. The benefit of
between AACs and placebo, the cumulative z score en- preventing BPD and death or BPD associated with AACs
tered the futility area, indicating further trials are not re- found in this systematic review could inform future up-
quired. Considering the overall morbidity, no association dates of these and other clinical guidelines.
with benefit or harm can be found between groups, but
the trial sequential analysis suggested it would be un- Comparison with other studies
necessary to carry out more trials on this outcome. In Several systematic reviews have evaluated inhaled cor-
our analysis of neurodevelopmental outcome between ticosteroids in the prevention of BPD [14, 15, 17, 21,
AACs and placebo, AACs did not increase neurodeve- 22]. A recent meta-analysis aimed to assess inhaled
lopmental impairment. Futhermore, inhaled corticoster- corticosteroids for BPD in preterm infants [17]. The
oid also did not increase mortality and is similar in evidence from this meta-analysis supported inhaled

Table 3 Sensitivity analysis of primary outcomes with the use of AACs or placebo
Outcome or Subgroup Studies Participants P value Effect Estimate NNT
BPD 14 2338 0.0005 0.71 [0.58, 0.86] 10
Exclusion of high risk trials 12 2172 0.0001 0.70 [0.58, 0.84] 10
Exclusion of conference abstracts 13 2298 <0.0001 0.69 [0.58, 0.83] 9
Exclusion of non English studies 11 2006 <0.00001 0.72 [0.63, 0.83] 10
Exclusion of small sample trials 6 1861 <0.0001 0.69 [0.57, 0.83] 10
Inhaled corticosteroids 10 1785 0.003 0.77 [0.65, 0.91] 14
Instillation of steroids using 4 553 0.007 0.44 [0.24, 0.79] 5
surfactants as carriers
Death 11 2041 0.55 0.75 [0.54, 1.04]
Exclusion of high risk trials 9 1875 0.40 0.88 [0.56, 1.39]
Exclusion of conference abstracts 10 2003 0.99 1.00 [0.75, 1.33]
Exclusion of non English studies 10 1961 0.55 0.90 [0.64, 1.27]
Exclusion of small sample trials 5 1701 0.98 1.01 [0.70, 1.45]
Inhaled corticosteroids 8 1580 0.88 1.03 [0.69, 1.53]
Instillation of steroids using 3 461 0.07 0.67 [0.43, 1.04]
surfactants as carriers
Death or BPD 8 1761 0.003 0.81 [0.71, 0.93] 12
Exclusion of conference abstracts 7 1721 0.01 0.82 [0.70, 0.96] 12
Exclusion of small sample trials 4 1585 0.03 0.83 [0.70, 0.99] 13
Inhaled corticosteroids 7 1496 0.03 0.87 [0.77, 0.99] 20
Instillation of steroids using 1 265 <0.0001 0.69 [0.58, 0.82] 4
surfactants as carriers
AACs Airway administration of corticosteroids, BPD Bronchopulmonary dysplasia, NNT Numbers needed to treat
Zhang et al. BMC Pulmonary Medicine (2017) 17:207 Page 12 of 16

Fig. 6 Meta-analysis of primary outcome with the use of inhaled corticosteroids or systemic corticosteroids

corticosteroids, especially budesonide, as a potentially further reducing the role of contingency. A major
efficacious and safe therapy for the prevention or strength of present systematic review is the use of the
treatment of BPD in preterm infants [17]. However robust Cochrane methodology [26, 28, 30], and the
they fail to implement sensitivity and subgroup ana- meta-analysis is further challenged with trial sequential
lysis for the result of heterogeneity. In addition, they analysis to correct for random error and repetitive test-
did not evaluate the advantage on inhaled corticoste- ing, which often is biased towards an intervention [31–
roids compared with sysetmic corticosteroids. The 33]. Our meta-analysis did focuse on bias and quality of
previous Cochrane reviews examined either inhalation evidence of included studies in accordance with GRADE
or systemic corticosteroids, further divided into early [69]. Predefined sensitivity, subgroup analysis, and trial
and late phases according to the time of administra- sequential analyses that included assessment of bias and
tion. Hence, the analysis used 1 week after birth as a clinically heterogenous groups were presented to aid
boundary [21, 22] However, in our meta-analysis, the healthcare professionals for clinical decisions. However,
duration of inhalation of corticosteroids ranged from subtle underlying bias of the trials included in the review
3 to 29 days, which was different from studies on remains a possible limitation, as in any other systematic
intravenous administration, for which the course was review although we excluded the studies that are at high
about 1 week. For a long course of AACs, the bound- risk of bias.
ary of 1 week after birth is sufficient to reflect the Admittedly, several limitations in our meta-analysis
differences of AACs. Studies set the first delivery time might have affected the interpretation of findings. First,
from 12 h to 14 days after birth and the time span the trials analyzed differed in their study design and
was long (Table 1). Therefore, we hypothesize that clinical characteristics of the study participants. The ef-
the subgroup analysis with 1 week after birth as the fect on mortality and BPD might be quite different be-
boundary is not reliable, and it is difficult to follow. tween very preterm infants (GA: 28~32 weeks) and
The dose and duration of the AACs in each study extremely preterm infants (GA < 28 weeks), and sub-
were not the same, making it difficult to determine group analysis based on GA or BW could not be done
the exact dose and the course of corticosteroids that due to the lack of individual patient data. For extremely
is supposed to be beneficial even via subgroup ana- preterm infants, the BPD definition is based on respira-
lysis. We believe that a unified drug delivery time and tory support and oxygen requirements at 36 weeks,
course of treatment are very important for developing which may be dependent on local practices and satur-
precise treatment and firm recommendations. ation targets. Despite attempts to standardize the defin-
ition of BPD, wide variation among centers has been
Strengths and limitations of this review reported with the diagnosis of BPD ranging from 6 to
The results of our analysis confirm those of the previous 57% depending on the definition chosen [70]. Hence
systematic reviews while improving their precision and the target population in each studies may be very
Zhang et al. BMC Pulmonary Medicine (2017) 17:207 Page 13 of 16

Fig. 7 Trial sequential analysis of trials reporting primary outcome comparing pooled inhaled corticosteroids and systemic corticosteroids. A
diversity adjusted information size was calculated using ɑ = 0.05 (two sided), β = 0.20 (power 80%), D2 = 0%, an anticipated relative risk of −10.5%,
18.4%, respectively, and an event proportion of 36.6%, 20.0%, respectively in the control arm. The cumulative z curve was constructed using a
random-effect model, and a penalized z curve was also constructed. The adjusted relative risk was 1.08, 0.81, respectively, and the 95% confidence
interval was corrected to 0.53–2.20, 0.43–1.53, respectively

different. The duration, dose, type, and inhalation or in- principle, this should not interfere with the meta-
stillation of steroids using surfactants as carriers also analysis results, because publication bias generally re-
were inconsistent across studies. Although we validated sults in an overestimation of the effect estimates.
the stability of the result of our meta-analysis by sub-
group analysis and sensitivity, the direct comparison Conclusions
between inhalation and instillation steroids using sur- In this meta-analysis with sequential analysis, compared
factant as a vehicle was lacking. Furthermore, there with placebo, AACs (especially instillation of budesonide
were few studies on AACs compared with systemic cor- using surfactant as a vehicle) was found to reduce the
ticosteroids, and not all trials presented the primary risk of BPD and death or BPD, with no assocaited in-
and secondary outcomes, be especially neurodevelop- crease in mortality and neurodevelopmental impairment.
mental outcomes. To some extent, the clinical diversity Compared with systemic corticosteroids, inhaled corti-
still potentially compromises the validity of the current costeroids were similar for preventing BPD. The appro-
results, even though we have pooled the data as if they priate dose and duration, inhalation or instillation with
were from clinically homogeneous studies. Third, for- surfactant as a vehicle and the long-term safety of AACs
mal tests for publication bias are still lacking. In needs to be assessed in large trials.
Zhang et al. BMC Pulmonary Medicine (2017) 17:207 Page 14 of 16

Additional files Ethics approval and consent to participate

As the paper did not involve any human or animal, the ethical approval was
not required.
Additional file 1: Table S1. Outcomes measured in the 25 RCTs
(DOCX 27 kb)
Additional file 2: Table S2. Outcomes measured in the 25 RCTs Consent for publication
(DOCX 29 kb) Not applicable.
Additional file 3: Figure S1. Funnel plot of bronchopulmonary
dysplasia, death, and requirement for systemic steroids with the use Competing interests
of AACs or placebo, AACs: Airway administration of corticosteroids. None of the investigators declare any real or perceived conflicts of interest
(JPEG 50 kb) pertaining to the subject of this manuscript.
Additional file 4: Figure S2. Meta-analysis of requirement for systemic
steroids with the use of AACs or placebo, AACs: Airway administration of
corticosteroids. (JPEG 26 kb) Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
Additional file 5: Figure S3. Meta-analysis of success to extubate within published maps and institutional affiliations.
14 days with the use of AACs or placebo, AACs: Airway administration of
corticosteroids. (JPEG 20 kb) Author details
1
Additional file 6: Figure S4. Meta-analysis of duration of mechanical Department of Neonatology, the Children’s Hospital, Zhejiang University
ventilation with the use of AACs or placebo, AACs: Airway administration School of Medicine, No. 3333 Bingsheng Road, Hangzhou City, Zhejiang
of corticosteroids. (JPEG 17 kb) 310002, China. 2Department of Pediatrics, Hangzhou First People’s Hospital,
Additional file 7: Table S3. Subgroup analysis of adverse and Nanjing Medical University, No. 261 Huansha Road, Hangzhou City, Zhejiang
neurodevelopmental outcomes with the use of AACs or placebo 310002, China.
(DOCX 17 kb)
Received: 18 June 2017 Accepted: 30 November 2017
Additional file 8: Figure S5. Meta-analysis of duration of mechanical
ventilation with the use of inhaled corticosteroids or systemic corticosteroids.
(JPEG 11 kb)
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