Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates

Shah V, Ohlsson A, Halliday HL, Dunn MS

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs

Dates

Date edited: 20/08/2007
Date of last substantive update: 03/08/2007
Date of last minor update: / /
Date next stage expected 03/08/2009
Protocol first published: Issue 1, 2000
Review first published: Issue 1, 2000

Contact reviewer

Dr Vibhuti S Shah
Staff Neonatologist
Department of Paediatrics
Mount Sinai Hospital
Room 775A
600 University Avenue
Toronto
Ontario CANADA
M5G 1X5
Telephone 1: 416 586 4816
Telephone 2: 416 664 6708
Facsimile: 416 586 8745
E-mail: vshah@mtsinai.on.ca

Contribution of reviewers

Vibhuti Shah: performance of literature search, abstraction and analysis of data, writing of the original and updated review.
Michael Dunn: performance of literature search, abstraction and analysis of data and editing of the reveiw.
Henry H Halliday: performance of literature search, abstraction and analysis of data and editing of the review.
Arne Ohlsson: performance of literature search, abstraction and analysis of data and editing of the original and updated review.

This update was conducted by Vibhuti Shah and Arne Ohlsson.

Internal sources of support

Mount Sinai Hospital, Toronto, CANADA

External sources of support

None

What's new

This updates the review "Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates" published in The Cochrane Library, Issue 1, 2000 (Shah 2000).

The updated search conducted in August 2007 identified three additional trials. Two of these trials were excluded.

The results of the seven included trials found no evidence that the early use of inhaled steroids prevents the development of chronic lung disease.

Dates

Date review re-formatted: 21/10/1999
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

Preterm babies who require breathing support often develop chronic lung disease. 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. However, 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. This review looked at trials that compared preterm babies who received steroids by inhalation to those who received inhaled placebo (pretend drug) while they were receiving breathing support. There was no evidence that the early administration of inhaled steroids for babies on mechanical ventilation in neonatal intensive care reduces chronic lung disease.

Abstract

Background

Chronic lung disease remains a common complication among preterm infants. There is increasing evidence that inflammation plays an important role in the pathogenesis of CLD. Due to their strong anti-inflammatory properties, corticosteroids are an attractive intervention strategy. However, there are growing concerns regarding short and long-term effects of systemic corticosteroids. Theoretically, administration of inhaled corticosteroids may allow for beneficial effects on the pulmonary system with a lower risk of undesirable systemic side effects.

Objectives

To determine the impact of inhaled corticosteroids administered to ventilated very low birth weight preterm neonates in the first two weeks of life for the prevention of chronic lung disease (CLD).

Search strategy

Randomized and quasi-randomized trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1966 - July 2007), EMBASE (1980 - July 2007), CINAHL (1982 - July 2007), reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies web-site (1990 - April 2007).

Selection criteria

Randomized controlled trials of inhaled corticosteroid therapy initiated within the first 2 weeks of life in ventilated preterm infants with birth weight <1500 grams were included in this review.

Data collection & analysis

Data regarding clinical outcomes including chronic lung disease at 28 days or 36 weeks postmenstrual age (PMA), mortality, combined outcome of death or CLD at 28 days of age and at 36 weeks PMA, the need for systemic corticosteroids, failure to extubate within 14 days and adverse effects of corticosteroids were evaluated. All data were analyzed using RevMan 4.2.10. When possible, meta-analysis was performed using relative risk (RR), risk difference (RD), along with their 95% confidence intervals (CI). If RD was significant, the number needed to treat (NNT) was calculated.

Main results

Three additional trials were identified for inclusion in this update. Eleven trials assessing the impact of inhaled corticosteroid for the prevention of CLD were identified. Four trials were excluded. The present review includes data analyses based on seven qualifying trials. There was no statistically significant effect of inhaled steroids on CLD either at 28 days [typical RR 1.05 (95% CI 0.84, 1.32); typical RD 0.02 (95% CO -0.07, 0.11)] or at 36 weeks PMA [typical RR 0.97 (95% CI 0.62, 1.52); typical RD 0.00 (95% CI -0.07, 0.06)], when analyzed either for all randomized infants or among survivors. No statistically significant differences were noted for mortality or for the combined outcome of mortality and CLD either at 28 days of age or at 36 weeks PMA. There were no statistically significant differences in adverse events between groups.

Reviewers' conclusions

Based on this updated review, there is no evidence from the trials reviewed that early administration (in the first two weeks of life) of inhaled steroids to ventilated preterm neonates was effective in reducing the incidence of CLD. Currently, use of inhaled steroids in this population cannot be recommended. Studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. Studies need to address both the short-term and long-term benefits and adverse effects of inhaled steroids with particular attention to neurodevelopmental outcome.

Background

Chronic lung disease (CLD) remains a common complication among survivors of neonatal intensive care. Despite the use of antenatal corticosteroids and postnatal surfactant treatment, the incidence of CLD has increased. This is partly explained by increased survival of extremely low birth weight infants (Shaw 1993), in that the incidence of CLD has an inverse relationship with birth weight and gestational age (Sinkin 1990).

O'Brodovich and Mellins (O'Brodovich 1985) have used the term "unresolved neonatal acute lung injury" to describe CLD. According to their model, CLD results from disordered repair processes in a susceptible baby following acute lung injury induced by various pulmonary disorders and positive pressure ventilation. Preventive strategies can focus on any point in the cascade, including prevention or amelioration of the primary pulmonary disorders affecting preterm babies, reduction in ventilator-induced lung injury or modification of the response to tissue injury (Sinkin 1987).

There is increasing evidence that inflammation plays an important role in the pathogenesis of CLD (Pierce 1995). In many infants, an inflammatory reaction is evident shortly after birth suggesting that the process may have been triggered in utero (Watterberg 1996). Therefore, interventions aimed at reducing or modulating the inflammatory process may reduce the incidence or severity of CLD. Treatment with corticosteroids is an attractive intervention strategy to achieve this goal due to their strong anti-inflammatory properties. Systematic reviews on the use of postnatal systemic corticosteroids [early (< 96 hours) and moderately early (7 - 14 days)] have demonstrated a reduction in CLD at 28 days and 36 weeks postmenstrual age (PMA) (Bhuta 1998; Halliday 1999a; Halliday 1999b). However, there are concerns regarding the short and long-term adverse effects of systemic corticosteroid therapy in this population (Ng 1993; Yeh 1998; Halliday 1999a). These include hyperglycemia, hypertension, hypertrophic obstructive cardiomyopathy, gastrointestinal hemorrhage and perforation, growth failure and hypothalamic-pituitary-adrenal axis suppression. The potential effects on brain growth and neurodevelopment are most alarming. Studies in animals have shown that steroids can permanently affect brain cell division, differentiation and myelination, as well as the ontogeny of cerebral cortical development (Weichsel 1977; Johnson 1979). The available human literature regarding neurodevelopmental outcome is inconclusive. Follow-up of double blind randomized controlled trials of dexamethasone, commenced within 12 hours of birth, showed a 2-fold increase in neuromotor impairments in surviving dexamethasone treated infants as compared with controls at two years corrected age (Yeh 1998; Doyle 1999). Theoretically, administration of corticosteroids topically may allow for beneficial effects on the pulmonary system with a lower risk of undesirable systemic side effects.

This review aims to examine the impact of inhaled corticosteroid therapy when administered to ventilated very low birth weight preterm infants within the first two weeks of life for the prevention of CLD.

Objectives

Primary objective: To determine the impact of inhaled corticosteroids administered to ventilated preterm infants with birth weight of < 1500 g beginning in the first two weeks of life for the prevention of CLD as reflected by the requirement for supplemental oxygen at 36 weeks PMA.

Secondary objectives: Assessment of the effect of inhaled corticosteroids on:
1. Other indicators of CLD including:

Requirement for supplemental oxygen at 28 days of age
Death by or CLD at 28 days of age
Death by or CLD at 36 weeks PMA
Duration of requirement for supplemental oxygen
Duration of assisted ventilation
Requirement for systemic corticosteroids
Change in pulmonary function tests

2. The incidence of adverse events including:

Mortality
Hyperglycemia
Sepsis (bacterial or fungal)
Hypertension
Hypertrophic obstructive cardiomyopathy
Gastrointestinal hemorrhage or perforation
Growth (weight, length/height and head circumference)
Cataracts
Hypertrophy of tongue
Nephrocalcinosis
Suppression of the hypothalamic-pituitary-adrenal axis

3. Long-term neurodevelopmental outcome: Neurodevelopmental impairment is defined as presence of cerebral palsy and/or mental retardation [Bayley Scales of Infant Development (BSID), Mental Development Index (MDI) < 70] and/or legal blindness (< 20/200 visual acuity) and/or deafness (aided or < 60 dB on audiometric testing) assessed at 18 - 24 months.

Criteria for considering studies for this review

Types of studies

Randomized or quasi-randomized clinical trials of inhaled corticosteroid therapy in ventilator-dependent very low birth weight preterm infants enrolled in the first two weeks of life (early). Studies which evaluated a combination of systemic and inhaled corticosteroids were excluded.

Types of participants

Ventilator dependent preterm neonates with birth weight < 1500 g and postnatal age of < 2 weeks.

Types of interventions

Inhaled corticosteroids versus placebo or no intervention.

Types of outcome measures

Studies had to report one or more of the following outcomes:
1. Among all randomized:

CLD at 36 weeks PMA
CLD at 28 days of age
Death by 28 days of age
Death by 36 weeks PMA
Death by or CLD at 28 days of age
Death by or CLD at 36 weeks PMA
Requirement for systemic steroids
Failure to extubate within 14 days
Adverse events: Infection, hyperglycemia, hypertension, gastrointestinal bleeding, cataracts, intraventricular hemorrhage (IVH), periventricular leucomalacia (PVL), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), pituitary-adrenal suppression, and patent ductus arteriosus (PDA)

2. Among survivors:

CLD at 36 weeks PMA
CLD at 28 days of age

Search strategy for identification of studies

See: Cochrane Neonatal Review Group search strategy
Randomized controlled trials of inhaled corticosteroid therapy in preterm neonates were identified from MEDLINE (1966 to July 2007) using MeSH headings: infant-newborn, bronchopulmonary dysplasia, lung diseases, anti-inflammatory agents, steroids; administration, inhalation; aerosols, budesonide, beclomethasone dipropionate, flunisolide and fluticasone propionate.

Other databases were searched including: Embase (1980 to July 2007), CINAHL (1982 to July 2007), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies website (1990 - April 2007). No language restrictions were applied. The candidate articles were screened by three review authors (VS, MD, AO) to identify articles eligible for inclusion in the original review. For this update, two review authors (VS, AO) conducted the literature search and reviewed the articles retrieved.

Methods of the review

Criteria and methods used to assess the methodological quality of the trials: standard methods of the Cochrane Neonatal Review Group were used.
For each trial, information was sought regarding the method of randomization, blinding and reporting of all outcomes of all the infants enrolled in the trial. Data from the primary investigator were obtained for unpublished trials or when published data were incomplete. Retrieved articles were assessed and data abstracted independently by three review authors (VS, MD, AO). The update of the review was performed by two review authors (VS, AO). The statistical methods used were relative risk (RR), risk difference (RD) and number needed to treat (NNT). Heterogeneity tests [including the I squared (I² ) test] were performed to assess the appropriateness of pooling the data.

Description of studies

Eleven trials assessing the impact of inhaled corticosteroids were identified, of which four trials were excluded (Beresford 2002; Denjean 1998; Dugas 2005; Kovacs 1998). The study by Beresford 2002 (Beresford 2002) was excluded as infants had to be receiving supplemental oxygen at 36 weeks PMA at the time of randomization. The study by Denjean 1998 (Denjean 1998) was excluded as both ventilated and non-ventilated infants were included and we were unable to obtain data for ventilated infants from the authors. The study by Dugas 2005 (Dugas 2005) was excluded as infants were randomized between 28 and 60 days of age (late). The study by Kovacs 1998 (Kovacs 1998) was excluded as investigators evaluated the impact of a combination of systemic and inhaled corticosteroid for prevention of CLD. Seven trials qualified for inclusion in this review: Cole 1999a; Fok 1999; Jangaard 2002; Jonsson 2000; Merz 1999; Townsend 1998; Yong 1999. Five included studies have been published as complete articles while two studies were presented at scientific meetings and published in abstract form. Complete data from the investigators were available for the trial of Yong 1999 (Yong 1999), while information published in abstract form is presented for the trial of Townsend et co-workers (Townsend 1998). Details of each study are given in the table "Characteristics of Included Studies".

Although all studies attempted to include infants thought to be at risk of developing CLD, the inclusion criteria, the intervention (type of inhaled corticosteroid) and duration of therapy varied between studies. All studies except one (Jonsson 2000) used metered dose inhaler (MDI) and an Aerochamber interposed between the endotracheal tube and the ventilatory circuit or a manual puffer (anesthesia bag). In the study by Cole 1999a, the drug was administered to infants who were extubated using the same procedure through a nasopharyngeal tube. In the study by Jonsson 2000, a dosimetric jet nebulizer was used to deliver the aerosol.

The study by Cole and co-workers (Cole 1999a) enrolled infants < 33 weeks GA and with birth weight < to 1250 g who required assisted ventilation at 3 - 14 days of life. The infants were randomly assigned to receive inhaled beclomethasone dipropionate (n = 123) or placebo (n = 130). The desired dose was calculated to deliver to the lung 40 micrograms/kg/day for the first week, 30 and 15 micrograms/kg/day for the second and third weeks respectively, and then 10 and 5 micrograms/kg/day during the fourth week. The primary outcome was the incidence of bronchopulmonary dysplasia (BPD) in survivors defined as an abnormal chest x-ray and need for supplemental oxygen at 28 days of life. Secondary outcomes included the incidence of BPD in survivors at 36 weeks PMA (defined as an abnormal chest x-ray and need for supplemental oxygen at that age), duration of respiratory support (oxygen, mechanical ventilation and continuous positive airway pressure), the need for systemic glucocorticoids, diuretic or bronchodilator therapy, death, length of hospitalization and the incidence of complications possibly attributable to the use of inhaled steroids. Systemic glucocorticoid therapy was permitted at the discretion of the infant's physician. The baseline characteristics of the two groups were similar except for maternal race or ethnic group. (p = 0.03). Two additional reports from the same trial have been published as separate articles. One of these reports evaluated the effect of inhaled beclomethasone therapy on adrenal response (Cole 1999a) and the other report (Cole 1999a) evaluated its effect on tracheal aspirate inflammatory mediators (IL-8 and IL-1ra)

The study by Fok and co-workers (Fok 1999) enrolled 53 babies born at < 32 weeks GA, birth weight < 1.5 kg, requiring mechanical ventilation with an arterial PO₂/alveolar PO₂ ratio of < 0.25 at 6 to 10 hours after the second dose of surfactant was administered. Infants were excluded if they needed high frequency ventilation at the time of enrolment. Infants were randomized to receive inhaled fluticasone propionate or placebo. Two puffs of fluticasone propionate (250 micrograms/puff) or placebo were administered 12 hourly for two weeks. The first dose was administered within 24 hours of birth. The primary outcome was successful extubation by day 7 or day 14 of life. Secondary outcomes included mortality, oxygen dependency at 28 days of postnatal age and at 36 weeks PMA. The incidence of complications possibly attributable to the use of inhaled steroids was monitored. Twenty seven infants were enrolled in the fluticasone propionate group and 26 in the placebo group. The two groups were similar in their demographic and perinatal characteristics.

The study by Jangaard and co-workers (Jangaard 2002) enrolled 60 preterm infants < 1250 g with respiratory distress syndrome (RDS) and requiring ventilatory support at 72 hours of age. Infants were randomly assigned to receive inhaled beclomethasone dipropionate (250 micrograms/puff) or placebo for four weeks. Medication dosage assumed a 10% deposition of the administered dose with the aim to provide a total dose of 0.2 mg/kg/day. When the infants were extubated, the study drug was administered using an infant-sized Aerochamber (Boehringer Ingelheim, Canada) with an appropriately fitted mask. The primary outcome for this study was BPD defined as oxygen dependency at 28 days of life. The demographic characteristics of the two groups were similar. This trial (Jangaard 2002) has been previously published in abstract form (Jangaard 2002). The results of the published report are presented in this review.

The study by Jónsson and co-workers (Jonsson 2000) randomized 30 very low birth weight infants with median (range) gestational age of 26 weeks (23 - 29 weeks) and birth weight of 805 g (525 - 1227 g). Inclusion criteria were 1) mechanical ventilation on day six of life, or 2) if extubated, nasal continuous positive airway pressure with FiO₂ > 0.3. Infants with the following conditions were excluded: congenital malformations, congential heart disease and grades III-IV IVH. Infants on high frequency oscillatory ventilation (HFOV) were excluded as the inhalations could not be given through the electronic dosimeteric jet nebulizer. Infants were randomized to receive 500 μg bid or placebo delivered using a dosimetric jet nebulizer with variable inspiratory time and breath sensitivity. Inhalations were started on day seven of life. The primary objective was to attain a 30% reduction in FiO₂ levels in the budesonide treatment group after 14 days of therapy. Secondary outcomes included: duration of supplemental oxygen, duration of mechanical ventilation, duration of NCPAP, oxygen requirements at 28 days of age and at 36 weeks postmenstrual age. Adrenal cortisol response to stimulation was measured at baseline (prior to commencement of inhalation) and at the end of the study period. Information on adverse events: hyperglycemia, hypertension, sepsis, PDA, IVH and gastrointestinal problems were collected. Of the 30 infants enrolled, one parent declined to participate and two eligible patients could not be included due to ongoing HFOV on day seven of life. Thirteen infants were enrolled in the budesonide group, of which eight were ventilated, while 14 infants were enrolled in the placebo group, of which 9 were ventilated at the commencement of therapy. Only one outcome for ventilated infants was reported (successful extubation during the study period - 14 days).

The study by Merz and co-workers (Merz 1999) enrolled 24 infants with a birth weight of 750 - 1500 g, GA of 25 - 32 weeks, ventilator dependency on day three of life with a rate of more than or equal to 15 breaths/minute and FiO₂of more than or equal to 0.25 to maintain oxygen saturation of more than or equal to 90%. Infants were randomly assigned to inhaled budesonide (200 micrograms/puff) or placebo. Two puffs were administered four times a day for a total of 10 days. The primary outcome was duration of artificial ventilation. Secondary outcomes included the duration of supplemental oxygen and the release of albumin and different inflammatory mediators in the tracheobronchial aspirate fluid. Adverse events such as frequency of acute infections, hypertension, hyperglycemia, and adrenal suppression were evaluated. The demographic and perinatal data were similar in both groups on the day of randomization.

The study by Townsend and co-workers (Townsend 1998) enrolled 32 infants with GA < 28 weeks and birth weight < 1100 g at birth who were ventilator dependent with RDS. Infants were randomized to receive flunisolide or placebo in the dose of 500 μg tid delivered via spacer chamber. Treatment was begun at 48 - 96 hours of age and continued for 28 days or until extubation. Outcomes included were: need for systemic dexamethasone, duration of ventilation, duration of hospitalization, duration of supplemental oxygen and the incidence of adverse events (hyperglycemia, hypertension, weight gain).

The study by Yong and co-workers (Yong 1999) enrolled 40 infants born at < 32 weeks GA and requiring mechanical ventilation at birth within 18 hours after birth. Infants were randomly assigned to receive fluticasone propionate or placebo. One puff (250 microgram/puff) was administered twice a day for 2 weeks. There was no difference in the baseline characteristics between groups. Study outcomes included frequency of BPD at 28 days of life and at 36 weeks PMA, duration of respiratory support, need for systemic corticosteroids, mortality, duration of hospitalization, successful extubation by seven and 14 days of age, pulmonary function tests (compliance and resistance), inflammatory markers in the tracheal aspirates and incidence of adverse events.

Methodological quality of included studies

See: Table of included studies

Overall, the studies included for this review were of high methodological quality. Specific methodological issues are discussed below.

Cole 1999a: A randomization schedule was provided by the data coordinating center to the pharmacy at each study center. Infants were stratified for randomization according to the study site, sex, birth weight (less than or equal to 900 g or more than 900 g), and severity of pulmonary disease (oxygenation index more than or equal to five or less than five). Blinding of the intervention and outcome assessments was ensured. Outcomes were not reported on all infants enrolled in the trial.

Fok 1999: Infants were randomized using computer generated random numbers to treatment and control groups and allocation to the groups was performed using opaque, sealed envelopes. Blinding of the intervention was ensured; however, blinding of outcome assessments could not be determined. Outcomes were given for all infants enrolled in the study.

Merz 1999: A randomization list was provided to the pharmacy and MDIs were numbered from 1 to 24. The MDIs were identical in appearance and the members of the staff were blinded to the intervention. Blinding of the outcome measurement was not ensured. Outcomes were presented for all but one infant enrolled in the study.

Jangaard 2002: Randomization was performed for three weight strata in blocks of four using sealed envelopes. Blinding of intervention was ensured but we were unable to determine blinding of outcome assessments. All infants enrolled in the study were accounted for. Discrepancies were noted in the information in the abstract and the full publication.

Jonsson 2000: Randomization was computer generated and consecutively numbered envelopes were used (from 1 to 30). Clinical staff were blinded to group assignment and the code was broken after the last patient completed the treatment. Blinding of the intervention was ensured but blinding of outcome assessments could not be determined. Outcomes for all enrolled infants were provided.

Townsend 1998: The authors in the abstract state that this was a double-blind randomized trial but no information was available regarding the method of randomization. Blinding of intervention was ensured but blinding of outcome assessments could not be determined. Outcomes for all enrolled infants were provided.

Yong 1999: No information was available regarding the method of randomization. Blinding of the intervention was ensured but blinding of outcome assessments could not be determined. Outcomes for all enrolled infants were provided.

Exclusions after randomization:

In the study by Cole 1999a, three infants were withdrawn before the study drug was administered (two due to sepsis and one due to prior receipt of systemic glucocorticoid therapy). In the treatment group, one infant had been withdrawn prior to 28 days of life and eight more were withdrawn by 36 weeks PMA. Similarly, in the placebo group, two infants had been withdrawn by 28 days of age and four more were withdrawn by 36 weeks PMA. Reasons for these later withdrawals were not described. The outcome data for withdrawn infants were not provided. Thus, outcomes were reported at 28 days for 122 treated and 128 control infants, and at 36 weeks PMA for 114 treated and 124 control infants.

One infant in the placebo group was withdrawn from the study by Merz 1999 due to severe sepsis.

Results

EARLY INHALED STEROIDS (< 2 WEEKS) VS. PLACEBO AMONG ALL RANDOMIZED (Comparison 01):

PRIMARY OUTCOME:

CLD at 36 weeks PMA (Outcome 01.01):

Five trials enrolling 429 neonates reported on the incidence of CLD at 36 weeks PMA among all randomized. There was no statistically significant difference in the incidence of CLD at 36 weeks PMA in the inhaled steroid group vs. the placebo group [typical RR 0.97 (95% CI 0.62, 1.52); typical RD 0.00 (95% CI -0.07, 0.06)]. There was no statistically significant heterogeneity for this outcome for RR (p = 0.34, I² = 11%) nor for RD (p = 0.41, I² = 0%).

SECONDARY OUTCOMES:

CLD at 28 days of age (Outcome 01.02):

Five trials enrolling 429 neonates reported on the incidence of CLD at 28 days of age among all randomized. There was no statistically significant difference in the incidence of CLD at 28 days [typical RR 1.05 (95% CI 0.84, 1.32), typical RD 0.02 (95% CI -0.07, 0.11)]. There was no heterogeneity for this outcome for RR (p = 0.39, I² = 4%) and low heterogeneity for RD (p = 0.27, I² = 23%).

Death by 28 days of age (Outcome 01.03):

Five trials enrolling 429 neonates reported on the incidence of death by 28 days of age among all randomized. There was no statistically significant effect on death by 28 days of age and the typical estimates from the meta-analysis were RR 0.66 (95% CI 0.39, 1.14), RD -0.04 (95% CI -0.09, 0.01)]. There was no heterogeneity for this outcome for RR (p = 0.41, I² = 0%); however, there was moderate heterogeneity for RD (p = 0.05, I² = 59%).

Death by 36 weeks PMA (Outcome 01.04):

Five trials enrolling 429 neonates reported on the incidence of death by 36 weeks PMA among all randomized. No statistically significant effect on mortality by 36 weeks PMA was noted [typical RR 0.73 (95% CI 0.44, 1.21), typical RD -0.04 (95% CI -0.09, 0.02)]. There was low heterogeneity for this outcome for RR (p = 0.18, I² = 38%); however, there was moderate heterogeneity for RD (p = 0.03, I² = 62%).

Death by or CLD at 28 days of age (Outcome 01.05):

Five trials enrolling 429 neonates reported on the incidence of death by or CLD at 28 days of age among all randomized. There was no statistically significant difference between the groups for the combined outcome of death by or CLD at 28 days of age. The typical estimate for RR was 0.96 (95% CI 0.80, 1.14), RD -0.02 (95% CI -0.11, 0.07)]. There was no statistically significant heterogeneity for this outcome for RR (p = 0.93, I² = 0%) or for RD (p = 0.97, I² = 0%).

Death by or CLD at 36 weeks PMA (Outcome 01.06):

Five trials enrolling 429 neonates reported on this outcome. There was no statistically significant difference noted for the combined outcome of death by or CLD at 36 weeks PMA [typical RR 0.86 (95% CI 0.63, 1.17), typical RD -0.04 (95% CI -0.12, 0.04)]. There was no statistically significant heterogeneity for this outcome for RR (p = 0.43, I² = 0%) or for RD (p = 0.39, I² = 3%).

Requirement for systemic steroids (Outcome 01.07):

Six trials enrolling 429 neonates reported on the requirement for systemic steroids. The need for systemic steroids was not statistically significantly different between groups. The typical estimates for RR were 0.84 (95% CI 0.69, 1.02), RD -0.08 (95% CI -0.16, 0.01)]. There was moderate heterogeneity for this outcome for RR (p = 0.08, I² = 49%) and high heterogeneity for RD (p = 0.002, I² = 73%).

Failure to extubate within 14 days (Outcome 01.08):

Four trials enrolling 176 neonates reported on this outcome. There was no statistically significant difference noted for this outcome. The typical estimates for RR were 0.97 (95% CI 0.76, 1.24); RD -0.02 (95% CI -0.15, 0.12). There was moderate heterogeneity for this outcome for RR (p = 0.04, I² = 61%) and high heterogeneity for RD (p = 0.0005, I² = 80%).

Infection (Outcome 01.09):

Three trials enrolling 116 neonates reported on the incidence of infection. There was no statistically significant difference in the incidence of pneumothorax (typical RR 1.12, 95% CI 0.60, 2.09; typical RD 0.03, 95% CI -0.12, 0.18). There was low heterogeneity for this outcome for RR (p = 0.20, I² = 38%) and moderate heterogeneity for RD (p = 0.11, I² = 55%).

Hyperglycemia (Outcome 01.10):

Three trials enrolling 116 neonates reported on the incidence of hyperglycemia. There was no statistically significant difference in the incidence of hyperglycemia (typical RR 0.84, 95% CI 0.49, 1.44; typical RD -0.05 95% CI -0.19, 0.10). There was no heterogeneity for this outcome for RR (p = 0.67, I² = 0%) or for RD (p = 0.64, I² = 0%).

Hypertension (Outcome 01.11):

Three trials enrolling 116 neonates reported on the incidence of hypertension. There was no statistically significant difference in the incidence of hypertension between groups (typical RR 1.20, 95% CI 0.36, 3.99; typical RD 0.01 95% CI -0.09, 0.12). Test for heterogeneity not applicable for RR and there was not statistically significant heterogeneity for RD (p = 0.93, I² = 0%).

Gastrointestinal bleeding (Outcome 01.12):

One trial enrolling 253 neonates reported on the incidence of gastrointestinal bleeding. There was no statistically significant difference for this outcome between groups (RR 0.35, 95% CI 0.04, 3.34; RD -0.01, 95% CI -0.05, 0.02).

Cataract (Outcome 01.13):

One trial enrolling 253 neonates reported on the incidence of cataracts. There was no statistically significant difference in the incidence of cataracts between groups (RR 0.35, 95% CI 0.01, 8.56; RD -0.01, 95% CI -0.03, 0.01).

Intraventricular hemorrhage (Outcome 01.14):

Two trials enrolling 306 neonates reported on the incidence of IVH. There was no statistically significant difference in the incidence of IVH between groups (typical RR 1.04, 95% CI 0.77, 1.41; typical RD 0.02, 95% CI -0.09, 0.12). There was no heterogeneity for this outcome for RR (p = 0.43, I² = 0%) or for RD (p = 0.44, I² = 0%).

Periventricular leucomalacia (Outcome 01.15):

Two trials enrolling 306 neonates reported on the incidence of PVL. There was no statistically significant difference in the incidence of PVL between groups (typical RR 1.43, 95% CI 0.59, 3.46; typical RD 0.02, 95%CI -0.03, 0.08). There was no heterogeneity for this outcome for RR (p = 0.48, I² = 0%) or for RD (p = 0.43, I² = 0%).

Necrotizing enterocolitis (Outcome 01.16):

Two trials enrolling 306 neonates reported on the incidence of NEC. There was no statistically significant difference in the incidence of NEC between groups (typical RR 0.67, 95% CI 0.41, 1.08; typical RD -0.07, 95% CI -0.16, 0.01). There was no heterogeneity for this outcome for RR (p = 0.54, I² = 0%) or for RD (p = 0.82, I² = 0%).

Retinopathy of prematurity (Outcome 01.17):

Two trials enrolling 306 neonates reported on the incidence of ROP. There was no statistically significant difference in the incidence of ROP (typical RR 1.00, 95% CI 0.87, 1.15; typical RD 0.00, 95% CI -0.09, 0.10). There was no heterogeneity for this outcome for RR (p = 0.50, I² = 0%) or for RD (p = 0.49, I² = 0%).

Patent ductus arteriosus (Outcome 01.18):

One trial enrolling 53 neonates reported on the incidence of PDA. There was no statistically significant difference in the incidence of PDA between the two groups (RR 0.82, 95% CI 0.57, 1.17; RD -0.14, 95% CI -0.38, 0.10).

EARLY INHALED STEROIDS (< 2 WEEKS) VS. PLACEBO AMONG SURVIVORS (Comparison 02):

PRIMARY OUTCOME:

CLD at 36 weeks PMA (Outcome 02.01):

Five trials enrolling 362 neonates reported on this outcome among survivors. There was no statistically significant difference in the incidence of CLD at 36 weeks among survivors [typical RR 0.90 (95% CI 0.57, 1.41); typical RD -0.02 (95% CI -0.10, 0.06)]. There was no heterogeneity for this outcome for RR (p = 0.55, I² = 0%) or for RD (p = 0.71, I² = 0%).

SECONDARY OUTCOMES:

CLD at 28 days of age (Outcome 02.02):

Five trials enrolling 380 neonates reported on this outcome. There was no statistically significant difference in the incidence of CLD at 28 days of age among survivors [typical RR 0.97 (95% CI 0.78, 1.21), typical RD -0.01(95% CI -0.11, 0.08)]. There was no statistically significant heterogeneity for this outcome for RR (p=0.93, I² = 0%) or for RD (p = 0.96, I² = 0%).

Cerebral palsy (Outcome 02.03):

One trial enrolling 56 neonates reported on this outcome. There was no statistically significant difference in the incidence of cerebral palsy among survivors [RR 1.33 (95% CI 0.33, 5.42), RD 0.04 (95% CI -0.14, 0.21)].

Mean developmental index on BSID-II < 2 SD of the mean (Outcome 02.04):

One trial enrolling 56 neonates reported on this outcome. There was no statistically significant difference in the incidence of mean developmental index on BSID-II < 2 SD of the mean among survivors [RR 1.25 (95% CI 0.37, 4.17), RD 0.04 (95% CI -0.16, 0.23)].

Respiratory readmission (Outcome 02.05):

One trial enrolling 56 neonates reported on this outcome. There was no statistically significant difference in the incidence of respiratory readmission [RR 1.00 (95% CI 0.44, 2.29), RD 0.00 (95% CI -0.24, 0.24)].

ADDITIONAL OUTCOMES

The functioning of the hypothalamic-pituitary-adrenal axis in a subset of infants enrolled in the randomized controlled trial by Cole and co-workers (Cole 1999a) is reported in a separate publication (Cole 1999a). Inhaled beclomethasone therapy was associated with a small decrease in the basal cortisol levels. There was no evidence of adrenal suppression as reflected by the response to cosyntropin stimulation. Ng 1998 (Fok 1999) reported on pituitary-adrenal suppression in preterm, very low birth weight infants after inhaled fluticasone proprionate treatment. This study evaluated a subset of infants enrolled in the trial of Fok 1999 using the human CRH stimulation test. Basal and post-stimulation plasma ACTH and serum cortisol concentrations were significantly suppressed in the group receiving inhaled fluticasone when compared to the control group.

No relevant data for the following outcomes were available for analysis: Duration of requirement for supplemental oxygen, duration of assisted ventilation, measurements of pulmonary function, growth, hypertrophy of the tongue, hypertrophic obstructive cardiomyopathy and nephrocalcinosis.

Discussion

This updated review included information from two additional trials. There is no evidence that inhaled steroids are effective in reducing the incidence of CLD at 28 days or at 36 weeks PMA and the need for systemic steroids. Significant suppression of the pituitary-adrenal axis has been shown to occur in some infants treated with inhaled corticosteroids for the prevention of CLD. Thus, the use of inhaled steroids in this population is not routinely justified.

A major concern with studies of inhalation therapy in neonates is the uncertainty regarding drug delivery and deposition in the peripheral airways. Numerous factors affect drug delivery and deposition including the number of particles in the respirable range, the delivery technique [use of MDI in combination with a spacer or face mask and nebulisers (ultrasonic or jet)] and the presence or absence of an endotracheal tube. Previous workers have shown that the amount of aerosol delivery varies from 0.4% to 14% based on the technique used (Grigg 1992; O'Callaghan 1992; Arnon 1992). Delivery technique, type of inhaled steroid and dosage used varied among the studies included in this review, making the interpretation of aggregate data difficult.

In conclusion, there is no evidence from this systematic review that inhaled steroids reduce the incidence of CLD or the need for systemic corticosteroids. There are two possible explanations for the lack of demonstrated effectiveness of inhaled steroids for the prevention of CLD. Firstly, inhaled steroids may simply not be effective for the prevention of this condition and, secondly, the method of delivery, the type of inhaled steroid or the dosage used might not have been optimal.

Studies are needed to examine the effect of different delivery techniques and dosing schedules for the administration of these medications. It is possible that, with improved and/or more consistent delivery of inhaled steroids to the target organ, an important therapeutic effect will be demonstrated.

Reviewers' conclusions

Implications for practice

Based on the evidence from this updated review, early administration of inhaled steroids cannot be recommended as part of the standard of practice for ventilated preterm neonates to prevent CLD.

Implications for research

Studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for the administration of these medications. Studies need to address both short-term and long-term benefits and adverse effects of inhaled steroids, with particular attention to neurodevelopmental outcome.

Acknowledgements

Dr C Cole, Department of Pediatrics, Floating Hospital for Children, New England Medical Center, Boston, USA, Dr T F Fok, Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, People's Republic of China, Dr U Merz, Children's Hospital, Neonatal Intensive Care Unit, Aachen University of Technology, Aachen, Germany, Dr WSC Yong, Jessop Hospital for Women, Sheffield, UK for providing information regarding their studies.

Potential conflict of interest

None.

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Cole 1999a	Multicenter randomized, double-blind, placebo-controlled trial. Infants were stratified for randomization according to: study site, sex, birth weight (less than or equal to 900 g or > 900 g), and severity of pulmonary disease (oxygenation index more than or equal to 5 or < 5). Blinding of randomization Yes Blinding of intervention Yes Complete follow up No Blinding of outcome measurement Yes	Preterm infants < 33 weeks gestational age (GA) and birth weight less than or equal to 1250 g who required assisted ventilation between 3-14 days of life were eligible. 256 infants were enrolled in the study, 3 excluded due to sepsis (n=2) and one infant had received systemic glucocorticoid therapy prior to enrollment. Demographic data: Values presented as mean (SD) Beclomethasone dipropionate group: n=123 7 died and 1 withdrawn prior to 28 days of age 4 died and 8 withdrawn between 28 days and 36 weeks PMA Birth weight (g): 800 (193) Gestational age (weeks): 26 (2) Gender (%) male: 51 Age at enrollment (days): 5.7 (3.4) Oxygenation index at entry: 3.7 (3.1) Placebo group: n=130 7 died and 2 withdrawn prior to 28 days 1 died and 4 withdrawn between 28 days and 36 weeks PMA Birth weight (g): 802 (189) Gestational age (weeks): 26 (2) Gender (%) male: 53 Age at enrollment (days): 5.4 (2.9) Oxygenation index at entry: 4.1 (3.8) Exclusion criteria: Preterm infants with evidence of sepsis (clinical diagnosis or positive blood, cerebrospinal fluid, or urine culture), glucose intolerance (blood glucose > 6.7 mmol/l), hypertension (systolic blood pressure > 100 mm Hg), NEC (according to physical and radiographic findings), abnormal renal function (serum creatinine > 186 mmol/l and a urine output of < 0.3 ml/kg/day), abnormal liver function (serum alanine aminotransferase concentration of > 108 U/l and serum aspartate aminotransferase concentration of > 150 U/l), major congenital anomalies, or prior systemic glucocorticoid therapy. Study Centers: Three in the US Study Period: October 1993 to April 1997	Beclomethasone dipropionate (n=123) Placebo (n=130) Beclomethasone dipropionate (Beclovent, Allen and Hansbury, Glaxo Wellcome) and placebo metered-dose inhalers (MDI) providing 42 microgram/actuation were obtained from the drug manufacturer. Mode of delivery: Fom the MDI with a valved holding chamber (Aerochamber, Monaghan Medical) interposed between the neonatal anesthesia bag and infant's endotracheal tube. The delivery procedure was standardized with respect to ventilation technique and actuation procedure for the MDI. For infants not requiring mechanical ventilation the study drug was administered by the same procedure through endotracheal tube in the pharynx. Dose: Based on the desired dose of study drug to be delivered (microgram/kg/day) times the infant's weight (in kg) divided by the dose exiting the endotracheal tube (in micrograms/actuation) equaled the total number of actuations per day. The mean dose of beclomethasone exiting the endotracheal tube was 1.7 microgram/actuation (4%/actuation dose), as measured in prior studies in vitro. The desired dose was calculated to deliver 40 microgramg/kg/day for the first week, 30 and 15 microgram/kg/day for second and third week respectively, and 10 and then 5 microgram/kg/day in the fourth week. Duration of treatment: 4 weeks. Systemic glucocorticoid therapy permitted at the discretion of infant's physician (if the infant had an increasing oxygen requirement that was greater than the baseline for at least five days and had received the study drug for a minimum of seven days). Treatment with the study drug was discontinued but intention to treat analysis was performed.	Primary outcome: Frequency of BPD at 28 days of life Secondary outcomes: Frequency of BPD at 36 weeks PMA Duration of respiratory support Need for systemic glucocorticoid, diuretic, or bronchodilator therapy Frequency of air leak Death Length of hospitalization The incidence of adverse events: Hypertension, hyperglycemia, NEC, gastrointestinal hemorrhage, intracranial hemorrhage, periventricular leukomalacia, ROP, cataracts, suppression of pituitary-adrenal axis, growth and systemic infections Chest X-ray obtained at 28 days of age and 36 weeks PMA were reviewed by a single radiologist unaware of the infants' study-group assignment.	Randomization schedule was provided by the data coordinating center to the pharmacy at each study center. An interim analysis was performed after 125 infants had reached 28 days of age. According to the Lan-DeMets data monitoring rule, no significant difference was noted (p = 0.20) and therefore the study was continued. Reason for withdrawal of infants not described.	A
Fok 1999	Randomized controlled trial. Blinding of randomization Yes Blinding of intervention Yes Complete follow up Yes Blinding of outcome measurement Can't tell	Preterm infants < 32 weeks GA, birth weight < 1.5 kg and requiring mechanical ventilation were eligible if 6-10 hours after the second dose of surfactant the arterial PO2: alveolar PO2 was < 0.25. Demographic data: Values are presented as mean (SD) Fluticasone propionate group: n=27 Birth weight (g): 993 (369) Gestational age (weeks): 27.9 (2.6) PaO2: alveolar PO2 ratio at enrollment: 0.19 (0.05) Placebo group: n=26 Birth weight (g): 981 (362) Gestational age (weeks): 27.1 (2.6) PaO2: alveolar PO2 ratio at enrollment: 0.19 (0.05) Exclusion criteria: Infants who were dying and those with significant congenital anomalies were excluded. Study Center: Hong Kong, China Study Period: Not stated	Fluticasone propionate group (n=27) Placebo group (n=26) Mode of delivery: Aerosol delivery was carried out using an MV15s Aerochamber inserted between the Y-connector of the ventilator circuit and endotracheal tube. Infants extubated before day 14 received aerosol through a neonatal Aerochamber (Trudell, Canada), which was modified by removing its one way non-rebreathing valve. This modification has been shown to increase the amount of aerosol delivery. The face mask of Aerochamber was replaced with a Laerdal Resuscitation mask (Laerdal, Stavanger, Norway) as it has a smaller dead space and a tighter fit to the face. Dose: Two puffs of Fluticasone propionate (Flixotide; Glaxo, UK; 250 microgram/ puff) or placebo by metered dose inhaler 12 hourly. Duration of treatment: 2 weeks. The first dose was given within 24 hours of birth.	Primary outcomes: Successful extubation by days 7 and 14 of age Secondary outcomes: Mortality Oxygen dependency at 28 days of postnatal age and 36 weeks PMA Adverse events: Hyperglycemia, hypertension, sepsis confirmed by blood culture, pulmonary air leak (interstitial emphysema, pneumothorax, or pneumomediastinum), periventricular haemorrhage and leucomalacia, ROP, patent ductus arteriosus (PDA), NEC and bacterial colonization of the airway Hyperglycemia was defined as a blood glucose reading > 7 mmol/l. Hypertension was defined as two consecutive readings of systolic or diastolic blood pressure greater than 80 mm Hg and 45 mm Hg respectively. Symptomatic PDA was treated with intravenous indomethacin after confirmation by echocardiogram and refractory duct was closed by surgical ligation. Cranial ultrasound scans were performed at 6, 14, and 28 days of age, and when periventricular hemorrhage was suspected clinically. Ophthalmology screening for ROP was started at 4 weeks of age. NEC was diagnosed by the presence of pneumatosis intestinalis or intestinal perforation on abdominal radiograph, of for those requiring surgical intervention, on laparotomy. Tracheal aspirates for bacterial and fungal cultures were obtained immediately before the first dose of aerosol, and at 3, 5, 7 and 14 days of age. Static respiratory system compliance (Crs) and resistance (Rrs) were measured immediately before the start of aerosol treatment, and repeated on days 3, 7, and 14 in infants who remained intubated and ventilated. Both Crs and Rrs were measured using a SensorMedics Pulmonary Cart (SensorMedics Inc., Yorba Linda, CA, USA) using the passive flow-volume technique. The measurement were carried out using a pneumotachograph (Hans Rudolph Inc., USA) with a small dead space (1.8 ml) connected to the endotracheal tube.	Infants were randomised using computer generated random numbers into treatment and control groups and allocation to the groups were performed using opaque, sealed envelopes. All infants were given two doses (5 ml/kg/dose) of intratracheal synthetic surfactant (Exosurf) 12 hours apart. The first dose was given within 1 hour of birth. Extubation was considered when the FiO2 and ventilator rate decreased to < 0.4 and < 10 breaths/minute, respectively. The decision to extubate was made by the attending neonatologists who were blinded to the study protocol and the nature of the aerosol given to the infants. All infants were given a loading dose of intravenous aminophylline (6 mg/kg) prior to extubation followed by a maintenance dose of 2.5 mg/kg every 12 hrly. Extubation was considered successful if the infant was able to breathe spontaneously without the endotracheal tube or assisted ventilation for at least 48 hrs without a significant increase in respiratory effort and deterioration in blood gas values. In both groups infants with significant respiratory problems after 14 days of age were given open label systemic dexamethasone as decided by the attending neonatologists.	A
Jangaard 2002	Randomized controlled trial. Blinding of randomization Yes Blinding of intervention Yes Complete follow-up Yes Blinding of outcome measurement Can't tell	Preterm infants < 1250 g diagnosed with RDS and requiring ventilatory support at 72 hours. Demographic data: Values presented as mean (SD) Beclomethasone group: n=30 Birth weight (g): 882 (204) Gestational age (weeks): 27.2 (2) Gender (%) male: 43 Age at enrollment (hours): 72 Placebo group: n=30 Birth weight (g): 917 (178) Gestational age (weeks): 27.9 (2) Gender (%) male: 43 Age at enrollment (hours): 72 Exclusion criteria: Infants with congenital anomalies Non-survival to 72 hours Study Center: Halifax, Canada Study Period: October 1996 - October 1998	Beclomethasone dipropionate (n=30) Placebo (n=30) Beclomethasone dipropionate (250 microgram/ puff) Mode of delivery: In-line in respiratory limb of ventilator circuit with medilife spacer via aerochamber with mask. Dose: Medication dosage assumed a deposition of 10% of the dose given and aimed for a total dose of 0.2 mg/kg/day. Based on birth weight: 500 - 749 g 1 puff q6h 750 - 999 g 2 puffs q8h 1000 - 1249 g 2 puffs q6h Duration of treatment: 28 days.	Primary outcome: BPD- defined by 28 day oxygen dependency Secondary outcomes: Need for systemic corticosteroid therapy, incidence of sepsis, PVL, ROP, hypertension.	Randomization was performed for 3 weight strata in blocks of 4 using sealed envelopes. Data obtained from the author regarding the mode of delivery, demographic characteristics of the study groups, and adverse events. Data published in the abstract differs from those obtained from the investigator.	A
Jonsson 2000	Randomized double-blind placebo controlled trial. Blinding of randomization Yes Blinding of intervention Yes Complete follow-up Yes Blinding of outcome measurement Can't tell	Very low birth weight infants who were mechanically ventilated on day 6 of life or if extubated, nasal continuous positive airway pressure with FiO2 of > than or equal to 0.3 were included. Exclusion criteria: Congenital malformations, congenital heart disease and IVH (grades III-IV) Demographic data: Values are presented as median (range) or number (%) Budesonide group (N = 15) GA (wk): 25 (23-27) Birth weight (g): 766 (525-1122) Sex (M/F): 7/8 Prenatal steroids: 12 (80%) Surfactant treatment: 14 (93%) Placebo group (N = 15): GA (wk): 26 (24-29) Birth weight (g): 813 (630-1227) Sex (M/F): 5/10 Prenatal steroids: 10 (67%) Surfactant treatment: 15 (100%)	Budesonide (Pulmicort) (Astra Draco, Lund, Sweden) or placebo aerosol was used. The drug was delivered using an electronic dosimeteric jet nebulizer (Spira Electro 4, Respiratory Center, Hameenlinna, Finland) Dose: 500 micrograms twice a day	Primary outcome: Reduction in the FiO2 levels after 14 days of treatment Secondary outcomes include: duration of supplemental oxygen, duration of mechanical ventilation, duration of NCPAP, oxygen requirements at 28 days of age and at 36 weeks PMA, adrenal cortisol response to stimulation at baseline (prior to commencement of inhalation) and at the end of the study period. Information on adverse events: hyperglycemia, hypertension, sepsis, PDA, IVH and gastrointestinal problems were collected.		A
Merz 1999	Randomized double-blind placebo controlled trial. Blinding of randomization Yes Blinding of intervention Yes Complete follow-up Yes Blinding of outcome measurement Can't tell	Preterm infants with birth weight of 750-1,500 g, GA of 25-32 weeks, ventilator dependency on day 3 of life with a ventilator rate more than or equal to 15 breaths/min and FiO2 of > 0.25 to maintain an oxygen saturation of > 90%. 24 infants were enrolled in the study, one infant in the placebo group withdrawn due to severe sepsis 1 day after starting inhalation therapy. Demographic data: Values are presented as median (range) Budesonide group: n=12 Birth weight (g): 1108 (820 - 1420) Gestational age (weeks): 28 (27 - 32) Gender (%) male: 42 Age at enrollment (hours): 72 Placebo group: n=11 Birth weight (g): 1120 (880 - 1480) Gestational age (weeks): 29 (27 - 31) Gender (%) male: 45 Age at enrollment (hours): 72 Exclusion Criteria: Infants with multiple or severe congenital anomalies such as complex congenital heart disease, suspected chromosomal abnormalities, evidence or even suspected sepsis or pneumonia, IVH grade III or IV at the time of randomization and infants intubated with an endotracheal tube size < 2.5mm. Study Center: Aachen, Germany Study Period: November 1995 to August 1996	Budesonide (Astra Draco, Lund, Sweden) or placebo aerosol were used. Two puffs of budesonide (200 microgram/puff) or placebo was administered 4 times a day for a total of 10 days or until the infants were extubated. The aerosol was delivered using metered dose inhaler and an Aerochamber (Aerochamber MV15, Trudell Medical, Ontario, Canada). The spacer was directly connected to the endotracheal tube and the distal end of the spacer was connected to a manual puffer.	Primary outcome: Duration of artificial ventilation Secondary outcomes: Duration of supplemental oxygen Release of albumin and different inflammatory mediators in the tracheobronchial aspirate fluid Adverse events: Frequency of acute infections, hypertension, hyperglycemia and adrenal suppression was evaluated. CLD was defined as requirement of supplemental oxygen at 28 days of life and at 36 weeks PMA. Hyperglycemia was defined as blood glucose > 8.3 mmol/l. Hypertension was defined as systolic and diastolic blood pressure > 2 SD from mean values. Acute infection was suspected if clinical deterioration was observed accompanied by a rise in C-reactive protein or by ratio of immature to mature granulocytes above 0.2 in complete blood cell count. A corticotropin-releasing hormone stimulation test (CRH test) was performed on day 14 after completion of the inhalation treatment.	Infants were ventilated with Stephan respirator HF 300 (Fa. Stephan, Gackenbach, Germany) in the IPPV or IMV mode. To facilitate weaning from the ventilator infants were treated with fluid restriction (120 ml/kg/day) No nebulized bronchodilators or diuretics or supplemental vitamin A or E were used. Infants with respiratory distress syndrome were treated with natural surfactant (Alveofact) up to a maximum of three doses. Extubation was performed if the ventilator rate was down to 8 breaths/minute and two periods of tracheal continuous positive airway pressure lasting 20 minutes were tolerated. Theophylline or caffeine citrate were used to treat apnea of prematurity. Infants who could not be weaned from ventilator on day 14 were treated with systemic glucocorticoids after day 14. Dexamethasone was administered intravenously and divided into two doses: starting dose of 0.5 mg/kg/day for the first 3 days followed by 0.3 mg/kg/day of day 4-6. From day 7 the dose was reduced to 0.1 mg/kg/day and this was administered on alternate day from day 10 to day 16.	A
Townsend 1998	Randomized double-blind placebo controlled trial. Blinding of randomization Yes Blinding of intervention Yes Complete follow-up Yes Blinding of outcome measurement Can't tell	Preterm infants < 28 weeks and < than or equal to 1100 g at birth who were ventilator dependent due to RDS were enrolled at 48-96 hours of age. Demographic values: Flunisolide group (N = 15) GA (wks): 25.8 Birth weight (g): 728 g Age at enrollment: 3.1 days Placebo group (N = 17): GA (wks): 25.5 Birth weight (g): 695 g Age at enrollment: 3.4 days	Flunisolide or placebo 500 micrograms tid via spacer chamber connected to the ventilator	Outcome assessed: Need for systemic steroids Days on ventilator, in hospital and oxygen supplementation Information on adverse events were collected: hypertension, hyperglycemia, infection, weight gain and complications of prematurity	The authors do not state whether the demographic data are presented as means or medians	B
Yong 1999	Randomized double-blind placebo controlled trial. Infants were stratified for gestational age: 24-26 weeks and 27-32 weeks. Blinding of randomization Yes Blinding of intervention Yes Complete follow up Yes Blinding of outcome measurement Can't tell	Preterm infants < 32 weeks and requiring mechanical ventilation from birth were recruited within 18 hours of birth. 40 infants enrolled in the study. Demographic data: Values are presented as mean (SD) Fluticasone propionate group: n=20 Birth weight (g): 1011 (223) Gestational age (weeks): 27.4 (1.7) Gender (%) male: 65 Placebo group: n=20 Birth weight (g): 932 (401) Gestational age (weeks): 27.7 (1.7) Gender (%) male: 60 Exclusion Criteria: Preterm infants with major congenital anomalies, congenital pneumonia, pneumothorax and pulmonary hypoplasia Study Center: Jessop Hospital for Women, Sheffield, UK.	Fluticasone propionate or placebo (expient without active ingredient) Mode of delivery: MDI and Aerochamber if ventilated, babyhaler if extubated Dose: One puff of fluticasone propionate (250 microgram/puff) twice daily Duration of therapy: 14 days	Data were collected on survival, duration of mechanical ventilation and oxygen supplementation and other measures of morbidity (BP, glucose and IVH). Weight gain and skeletal growth was assessed by knemometry.		A

Characteristics of excluded studies

Study	Reason for exclusion
Beresford 2002	Excluded as infants who required supplemental oxygen at 36 weeks post menstrual age were included.
Denjean 1998	Excluded as both ventilated and non-ventilated infants were included in the trial. We were unable to obtain data on ventilated infants from the authors.
Dugas 2005	Excluded as infants were randomized between 28 and 60 days of age.
Kovacs 1998	Excluded because a combination of systemic (dexamethasone) and inhaled corticosteroid (budesonide) was used.

References to studies

References to included studies

Cole 1999a {published data only}

Cole CH, Colton T, Shah BL et al. Early inhaled glucocorticoid therapy to prevent bronchopulmonary dysplasia. The New England Journal of Medicine 1999;340:1005-10.

Cole CH, Shah B, Abbasi S, Demissie S, MacKinnon B, Colton T et al. Adrenal function in premature infants during inhaled beclomethasone therapy. The Journal of Pediatrics 1999;135:65-70.

Gupta GK, Cole CH, Abbasi S, Demissie S, Njinimbam C, Nielsen HC et al. Effects of early inhaled beclomethasone therapy on tracheal aspirate inflammatory mediators IL-8 and IL-1ra in ventilated preterm infants at risk for bronchopulmonary dysplasia. Pediatric Pulmonology 2000;30:275-81.

Fok 1999 {published data only}

* Fok TF, Lam K, Dolovich M et al. Randomised controlled study of early use of inhaled corticosteroid in preterm infants with respiratory distress syndrome. Archives of Disease in Childhood. Fetal and Neonatal Edition 1999;80:F203-8.

Ng PC, Fok TF, Wong GWK, Lam CWK, Lee CH, Wong MY et al. Pituitary-adrenal suppression in preterm, very low birth weight infants after inhaled fluticasone propionate treatment. The Journal of Clinical Endocrinology and Metabolism 1998;83:2390-3.

Jangaard 2002 {published data only}

Jangaard KA, Frent GA, Vincer MJ. Prophylactic inhaled beclomethasone dipropionate in infants < 1250 gms for the prevention of BPD. Pediatric Research 1998;43:177A.

Jangaard KA, Stinson DA, Allen AC, Vincer MJ. Early prophylactic inhaled beclomethasone in infants < 1250 gms for the prevention of chronic lung disease. Paediatrics & Child Health 2002;7:13-19.

Jonsson 2000 {published data only}

Jonsson B, Eriksson M, Soder O, Broberger U, Lagercrantz H. Budesonide delivered by dosimetric jet nebulization to preterm very low birthweight infants at high risk for development of chronic lung disease. Acta Paediatrica 2000;89:1499-55.

Merz 1999 {published data only}

Merz U, Kusenbach G, Hausler M, Peschgens T, Hornchen H. Inhaled budesonide in ventilator dependent preterm infants: A randomized, double-blind pilot study. Biology of the Neonate 1999;75:46-53.

Townsend 1998 {unpublished data only}

* Townsend SF, Hale KA, Thilo EH. Early treatment with inhaled steroids does not improve outcome in extremely premature infants wiht respiratory distress. Pediatric Research 1998;43:300A.

Yong 1999 {published and unpublished data}

Yong WSC, Carney S, Pearse RG, Gibson AT. The effect of inhaled fluticasone propionate (FP) on premature babies at risk for developing chronic lung disease of prematurity. Archives of Disease in Childhood 1999;80:G64.

References to excluded studies

Beresford 2002 {published data only}

Beresford MW, Primhak R, Subhedar NV, Shaw NJ. Randomised double blind placebo controlled trial of inhaled fluticasone propionate in infants with chronic lung disease. Archives of Diseases in Childhood. Fetal and Neonatal Edition 2002;87:62-3.

Denjean 1998 {published data only}

Denjean A, Paris-Llado J, Zupan V, Debillon T, Kieffer F, Magny JF et al. Inhaled salbutamol and beclomethasone for preventing bronchopulmonary dysplasia: a randomised double-blind study. European Journal of Pediatrics 1998;157:926-31.

Dugas 2005 {published data only}

Dugas MA, Nguyen D, Frenette L, Lachance C, St-Onge O, Fougeres A et al. Fluticasone inhalation in moderate cases of bronchopulmonary dysplasia. Pediatrics 2005;115:e566-72.

Kovacs 1998 {published data only}

Kovacs L, Davis GM, Faucher D, Papageorgiou A. Efficacy of sequential early systemic and inhaled corticosteroid therapy in the prevention of chronic lung disease of prematurity. Acta Paediatrica 1998;87:792-8.

* indicates the primary reference for the study

Other references

Additional references

Arnon 1992

Arnon S, Grigg J, Nikander K, Silverman M. Delivery of micronised budesonide suspension by metered dose inhaler and jet nebuliser into a neonatal ventilator circuit. Pediatric Pulmonology 1992;13:172-5.

Bhuta 1998

Bhuta T, Ohlssson A. Systematic review and meta-analysis of early postnatal dexamethasone for prevention of chronic lung disease. Archives of Disease in Childhood. Fetal and Neonatal Edition 1998;79:F26-F33.

Doyle 1999

Doyle LW, Davis PG. Postnatal corticosteroids in preterm infants - effects on mortality and cerebral palsy. Pediatric Research 1999;45:194A.

Grigg 1992

Grigg J, Arnon S, Jones T, Clarke A, Silverman M. Delivery of therapeutic aerosols to intubated babies. Archives of Disease in Childhood 1992;67:25-30.

Halliday 1999a

Halliday HL, Ehrenkranz RA. Early postnatal (< 96 hours) corticosteroids for preventing chronic lung disease in preterm infant. Cochrane Database of Systematic Reviews 1999, Issue 2.

Halliday 1999b

Halliday HL, Ehrenkranz RA. Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infant. Cochrane Database of Systematic Reviews 1999, Issue 2.

Johnson 1979

Johnson WCJ, Mitzner W, London WT, Palmer AE, Scott R. Betamethasone and the rhesus fetus: multisystemic effects. American Journal of Obstetrics and Gynecology 1979;133:677-84.

Ng 1993

Ng PC. The effectiveness and side effects of dexamethasone in preterm infants with bronchopulmonary dysplasia. Archives of Disease in Childhood 1993;68:330-6.

O'Brodovich 1985

O'Brodovich HM, Mellins RB. Bronchopulmonary dysplasia. Unresolved neonatal acute lung injury. The American Review of Respiratory Disease 1985;132:694-709.

O'Callaghan 1992

O'Callaghan C, Hardy J, Stammers J, Stephenson T, Hull D. Evaluation of techniques for delivery of steroids to lungs of neonates using a rabbit model. Archives of Disease in Childhood 1992;67:20-4.

Pierce 1995

Pierce MR, Bancalari E. The role of inflammation in the pathogenesis of bronchopulmonary dysplasia. Pediatric Pulmonology 1995;19:371-8.

Shaw 1993

Shaw NJ, Gill AB, Weindling AM, Cooke RW. The changing incidence of chronic lung disease. Health Trends 1993;25:50-3.

Sinkin 1987

Sinkin RA, Phelps DL. New strategies for the prevention of bronchopulmonary dysplasia. Clinics in Perinatology 1987;14:599-620.

Sinkin 1990

Sinkin RA, Cox C, Phelps DL. Predicting risk for bronchopulmonary dysplasia: selection criteria for clinical trials. Pediatrics 1990;86:728-36.

Watterberg 1996

Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996;97:210-5.

Weichsel 1977

Weichsel ME. The therapeutic use of glucocorticoid hormones in the perinatal period: Potential neurologic hazards. Annals of Neurology 1977;2:364-6.

Yeh 1998

Yeh TF, Lin YJ, Huang CC et al. Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics 1998;101:E7.

Other published versions of this review

Shah 2000

Shah V, Ohlsson A, Halliday HL, Dunn MS. Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates. Cochrane Database of Systematic Reviews 2000, Issue 1.

Comparisons and data

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomized)
01 CLD at 36 weeks PMA	5	429	RR (fixed), 95% CI	0.97 [0.62, 1.52]
02 CLD at 28 days of age	5	429	RR (fixed), 95% CI	1.05 [0.84, 1.32]
03 Death by 28 days of age	5	429	RR (fixed), 95% CI	0.66 [0.39, 1.14]
04 Death by 36 weeks PMA	5	429	RR (fixed), 95% CI	0.73 [0.44, 1.21]
05 Death by or CLD at 28 days of age	5	429	RR (fixed), 95% CI	0.96 [0.80, 1.14]
06 Death by or CLD at 36 weeks PMA	5	429	RR (fixed), 95% CI	0.86 [0.63, 1.17]
07 Requirement for systemic steroids	6	461	RR (fixed), 95% CI	0.84 [0.69, 1.02]
08 Failure to extubate within 14 days	5	193	RR (fixed), 95% CI	0.97 [0.76, 1.24]
09 Infection	3	116	RR (fixed), 95% CI	1.12 [0.60, 2.09]
10 Hyperglycemia	3	116	RR (fixed), 95% CI	0.84 [0.49, 1.44]
11 Hypertension	3	116	RR (fixed), 95% CI	1.20 [0.36, 3.99]
12 Gastrointesinal bleeding	1	253	RR (fixed), 95% CI	0.35 [0.04, 3.34]
13 Cataract	1	253	RR (fixed), 95% CI	0.35 [0.01, 8.56]
14 Intraventricular hemorrhage	2	306	RR (fixed), 95% CI	1.04 [0.77, 1.41]
15 Periventricular leucomalacia	2	306	RR (fixed), 95% CI	1.43 [0.59, 3.46]
16 Necrotizing enterocolitis	2	306	RR (fixed), 95% CI	0.67 [0.41, 1.08]
17 Retinopathy of prematurity	2	306	RR (fixed), 95% CI	1.00 [0.87, 1.15]
18 Patent ductus arteriosus	1	53	RR (fixed), 95% CI	0.82 [0.57, 1.17]
02 Early inhaled steroid (< 2 weeks) vs. placebo (among survivors)
01 CLD at 36 weeks PMA	5	362	RR (fixed), 95% CI	0.90 [0.57, 1.41]
02 CLD at 28 days of age	5	380	RR (fixed), 95% CI	0.97 [0.78, 1.21]
03 Cerebral palsy	1	56	RR (fixed), 95% CI	1.33 [0.33, 5.42]
04 Mean developmental index on BSID-II < 2 SD of the mean	1	56	RR (fixed), 95% CI	1.25 [0.37, 4.17]
05 Respiratory readmission	1	56	RR (fixed), 95% CI	1.00 [0.44, 2.29]

01 Early inhaled steroids (< 2 weeks) vs. placebo (among all randomized)

01.01 CLD at 36 weeks PMA

01.02 CLD at 28 days of age

01.03 Death by 28 days of age

01.04 Death by 36 weeks PMA

01.05 Death by or CLD at 28 days of age

01.06 Death by or CLD at 36 weeks PMA

01.07 Requirement for systemic steroids

01.08 Failure to extubate within 14 days

01.09 Infection

01.10 Hyperglycemia

01.11 Hypertension

01.12 Gastrointesinal bleeding

01.13 Cataract

01.14 Intraventricular hemorrhage

01.15 Periventricular leucomalacia

01.16 Necrotizing enterocolitis

01.17 Retinopathy of prematurity

01.18 Patent ductus arteriosus

02 Early inhaled steroid (< 2 weeks) vs. placebo (among survivors)

02.01 CLD at 36 weeks PMA

02.02 CLD at 28 days of age

02.03 Cerebral palsy

02.04 Mean developmental index on BSID-II < 2 SD of the mean

02.05 Respiratory readmission

Contact details for co-reviewers

Dr Michael Dunn
Chief
Department of Newborn and Developmental Paediatrics
Sunnybrook and Women's College Health Sciences Centre
76 Grenville Street
Toronto
Ontario CANADA
M5S 1B2
Telephone 1: 1 416 323 7312
Facsimile: 1 416 323 6274
E-mail: michael.dunn@sunnybrook.ca

Prof Henry L Halliday
Consultant Neonatologist
Regional Neonatal Unit
Royal-Jubilee Maternity Service
Royal Maternity Hospital
Grosvenor Road
Belfast
Northern Ireland UK
BT12 6BA
Telephone 1: + 44 02890 894687
Facsimile: 02890 236203
E-mail: h.halliday@qub.ac.uk

Dr Arne Ohlsson
Director Evidence Based Neonatal Care and Outcomes Research
Department of Paediatrics
Mount Sinai Hospital
600 University Avenue
Toronto
Ontario CANADA
M5G 1X5
Telephone 1: +1 416 586 8379
Telephone 2: +1 416 341 0444
Facsimile: +1 416 586 8745
E-mail: aohlsson@mtsinai.on.ca

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2007 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for hte most recent version of the review.