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Late (greater than/or equal to 7 days) inhalation corticosteroids to reduce bronchopulmonary dysplasia in preterm infants

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Authors

Wes Onland1, Martin Offringa2, Anton van Kaam3

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


1Department of Neonatology, Emma Childrens' Hospital AMC, University of Amsterdam, Meibergdreef 9, Netherlands [top]
2Child Health Evaluative Sciences, Hospital for Sick Children, Toronto, Canada [top]
3Department of Neonatology, Emma Children's Hospital AMC, University of Amsterdam, Meibergdreef 9, Netherlands [top]

Citation example: Onland W, Offringa M, van Kaam A. Late (greater than/or equal to 7 days) inhalation corticosteroids to reduce bronchopulmonary dysplasia in preterm infants. Cochrane Database of Systematic Reviews 2012, Issue 4. Art. No.: CD002311. DOI: 10.1002/14651858.CD002311.pub3.

Contact person

Wes Onland

Department of Neonatology
Emma Childrens' Hospital AMC, University of Amsterdam
h4-144, Emma Children's Hospital
Meibergdreef 9
1105 AZ Amsterdam
Netherlands

E-mail: W.Onland@amc.uva.nl

Dates

Assessed as Up-to-date: 12 March 2012
Date of Search: 02 February 2012
Next Stage Expected: 12 March 2014
Protocol First Published: Issue 4, 1999
Review First Published: Issue 2, 2001
Last Citation Issue: Issue 4, 2012

What's new

Date / Event Description
04 February 2011
Updated

This updates the review "Inhaled steroids for neonatal chronic lung disease" published in the Cochrane Database of Systematic Reviews (Lister 2000).

In October 2009, editorial responsibility for this review was transferred to the Neonatal Group from Airways Group. New authorship assigned.

The revised title is "Late (greater than/or equal to 7 days) inhalation corticosteroids to reduce bronchopulmonary dysplasia in preterm infants".

The inclusion criteria for this review have been changed from the previous version (inclusion of studies initiating therapy greater than/or equal to 7 days postnatal age and exclusion of studies initiating therapy greater than/or equal to 36 weeks postmenstrual age).

24 January 2011
New citation: conclusions changed

Conclusions have changed. New authorship.

History

Date / Event Description
23 October 2009
Amended

October 2009, editorial responsibility for review transferred to Neonatal Group from Airways Group. New authorship assigned.

05 August 2008
Amended

Converted to new review format.

06 August 1999
New citation: conclusions changed

Substantive amendment

Abstract

Background

Bronchopulmonary dysplasia (BPD), defined as oxygen dependence at 36 weeks postmenstrual age (PMA), remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD. Attenuating pulmonary inflammation with postnatal systemic corticosteroids reduces the incidence of BPD in preterm infants but may be associated with an increased risk of adverse neurodevelopmental outcomes. Local administration of corticosteroids via inhalation might be an effective and safe alternative.

Objectives

To determine if administration of inhalation corticosteroids after the first week of life to preterm infants at high risk of developing BPD is effective and safe in reducing the incidence of death and BPD as separate or combined outcomes.

Search methods

We identified randomised, controlled trials by searching the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), PubMed (from 1966), EMBASE (from 1974), CINAHL (from 1982), references from retrieved trials and handsearches of journals, all assessed to February 2012.

Selection criteria

Randomised controlled trials comparing inhalation corticosteroids, started greater than/or equal to 7 days postnatal age (PNA) but before 36 weeks PMA, to placebo in ventilated and non-ventilated infants at risk of BPD were included. Trials investigating systemic corticosteroids versus inhalation corticosteroids were excluded.

Data collection and analysis

Data on patient characteristics, trial methodology, and inhalation regimens were collected. The primary outcomes were death or BPD, or both, at 28 days PNA or 36 weeks PMA. Secondary outcomes were short-term respiratory outcomes, such as failure to extubate, total days of mechanical ventilation and oxygen use, and the need for systemic corticosteroids. The original trialists were contacted to verify the validity of extracted data and to provide missing data. All data were analysed using RevMan 5.0.24. When possible, meta-analysis was performed using typical risk ratio (TRR) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes along with their 95% confidence intervals (CI). Ventilated and non-ventilated participants were analysed separately.

Results

Eight trials randomising 232 preterm infants were included in this review. Inhalation corticosteroids did not reduce the separate or combined outcomes of death or BPD. Furthermore, inhalation steroids did not impact short-term respiratory outcomes such as failure to extubate and total duration of mechanical ventilation or oxygen dependency. There was a trend to a reduced use of systemic corticosteroids in favour of inhalation corticosteroids (TRR 0.51; 95% CI 0.26 to 1.00). There was a paucity of data on short-term and long-term adverse effects. These results should be interpreted with caution because the total number of randomised patients is relatively small and most trials differed considerably in patient characteristics, inhalation therapy and outcome definitions.

Authors' conclusions

Based on the results of the currently available evidence, inhalation corticosteroids initiated at greater than/or equal to 7 days of life for preterm infants at high risk of developing BPD cannot be recommended at this point in time. More and larger randomised, placebo-controlled trials are needed to establish the efficacy and safety of inhalation corticosteroids.

Plain language summary

Inhalation corticosteroids for bronchopulmonary dysplasia

Preterm infants have an increased risk of developing chronic lung disease or bronchopulmonary dysplasia (BPD). Inflammation in the lung seems to play a central role in the development of BPD. Administration of the anti-inflammatory drugs called corticosteroids into the bloodstream (systemically) reduces the risk of BPD but may also have serious side effects. Administering corticosteroids via inhalation directly into the lungs may reduce these adverse effects. This review looked at trials that compared inhalation corticosteroids to inhalation placebo in preterm infants at risk of developing BPD after the first week of life. These trials did not show a beneficial effect of inhalation corticosteroids on death or BPD. In addition, the safety of inhalation corticosteroids was assessed in only a small number of trials. Based on these results, inhalation corticosteroids cannot be recommended for preterm infants at risk of BPD. More studies are needed.

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Background

Description of the condition

Bronchopulmonary dysplasia (BPD), defined as oxygen dependency at 36 weeks postmenstrual age (PMA), is the most important complication of prematurity with a reported incidence of 23% in infants born at 28 weeks and increasing to 73% in infants born at 23 weeks (Stoll 2010). BPD is characterized by prolonged respiratory support, compromised lung function and recurrent respiratory infections during the first years of life. Furthermore, BPD is considered an independent risk factor for neurodevelopmental impairment (Walsh 2005; Doyle 2006; Short 2007). BPD is a multifactorial disease with mechanical ventilation, oxygen toxicity and pre- and postnatal infection as the most important risk factors, and pulmonary inflammation playing a central, mediating role.

Description of the intervention

The intervention of interest is inhaled corticosteroids administered to either ventilated or non-ventilated newborn infants at risk of developing BPD. Budesonide, beclomethasone and fluticasone are the most frequently used inhaled corticosteroids in newborn infants and these drugs are almost exclusively delivered using a pressurized metered dose inhaler or a nebulizer. Studies in preterm infants revealed that metered-dose inhalation results in a far better deposition than nebulization. In addition, inhalation via an endotracheal tube provides better deposition than inhalation via a face mask (Fok 1996).

How the intervention might work

Pulmonary inflammation plays a central, modulating role in the pathogenesis of BPD (Pierce 1995; Jobe 2001). Corticosteroids have a strong anti-inflammatory effect, making them an ideal candidate to attenuate the inflammatory response associated with BPD. Randomised controlled trials (RCTs) have shown that systemic administration of corticosteroids reduces the incidence of BPD and the combined outcome of death or BPD in ventilated preterm infants. However, systemic corticosteroids are also associated with short-term (for example hyperglycaemia, hypertension, infection) and long-term (neurodevelopmental impairment) adverse effects. This balance between beneficial and adverse effects of corticosteroids may be more favourable when using the inhalation route because, ideally, inhaled corticosteroids should demonstrate high pulmonary deposition in addition to a low systemic bioavailability and rapid systemic clearance.

Why it is important to do this review

The association between early (< 7 days of life) systemic corticosteroids use and adverse neurodevelopmental outcomes has resulted in a reduction in the overall use of corticosteroids in ventilated preterm infants (Yoder 2009). Administering corticosteroids by inhalation might be a safe and effective alternative. A systematic review of the randomised evidence on inhaled corticosteroids in preterm infants was first published in The Cochrane Library in 1999, followed by an update in 2002. The conclusions of that review were that in ventilated infants administration of inhalation corticosteroids resulted in an improved rate of extubation without any apparent adverse effects. No firm conclusions could be drawn for non-ventilated infants. The present systematic review provides a second update, including a discussion of RCTs published after 2002. In addition, we extended the inclusion criteria by including all RCTs initiating inhalation corticosteroids after the first week of life, in line with the Cochrane reviews on systemic corticosteroids (Halliday 2010; Halliday 2009).

OTHER COCHRANE NEONATAL SYSTEMATIC REVIEWS OF CORTICOSTEROIDS IN THE COCHRANE LIBRARY

Additional neonatal systematic reviews in The Cochrane Library that address the use of corticosteroids in the prevention or treatment of chronic lung disease include the following:

Use of systemic steroids: (1) Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants (Halliday 2010); (2) Late (>7 days) postnatal corticosteroids for chronic lung disease in preterm infants. (Halliday 2009).

Inhaled steroids: (1) Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates (Shah 2007a).

Comparison trials (inhaled versus systemic corticosteroids): (1) Inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates (Shah 2003);(2) Inhaled versus systemic corticosteroids for the treatment of chronic lung disease in ventilated very low birth weight preterm infants (Shah 2007b).

Other studies of corticosteroids in neonates: (1) Intravenous dexamethasone for extubation of newborn infants (Davis 2001); (2) Corticosteroids for treating hypotension in preterm infants (Ibrahim 2011); (3) Steroid therapy for meconium aspiration syndrome in newborn infants (Ward 2003).

Objectives

The primary objective was to compare the effectiveness of inhaled corticosteroids versus placebo, administered after the first week of life until 36 weeks PMA, in preterm infants at high risk of developing BPD on the incidence of death or BPD at 36 weeks PMA. The secondary objective was to compare the effectiveness of inhaled corticosteroids versus placebo on respiratory support, the need for systemic corticosteroids, and adverse effects during hospitalisation and long-term follow-up. Furthermore, we perform subgroup analyses on the timing of therapy onset and the difference in effect estimates for ventilated and non-ventilated infants.

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Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi-randomised placebo controlled trials (RCTs).

Types of participants

Preterm infants greater than/or equal to 7 days postnatal age (PNA) but before 36 weeks PMA (postmenstrual age) needing mechanical ventilation or supplemental oxygen, or both.

Types of interventions

Trials were included if infants were randomised to treatment with inhalation corticosteroid or placebo. The intervention had to be a standardized (non-individualized) dosage regimen of inhalation corticosteroids, initiated between seven days of life and 36 weeks PMA. Studies investigating inhalation corticosteroids compared to, or in addition to, systemic corticosteroids (dexamethasone, hydrocortisone or methylprednisolone) were excluded.

Types of outcome measures

To be included in the review, the trials had to report on one or more of the following outcome parameters:

  • death at 28 days PNA, 36 weeks PMA and hospital discharge;
  • BPD (defined by the need for supplemental oxygen) at 28 days PNA and 36 weeks PMA;
  • the combined outcome death or BPD at 28 days PNA and 36 weeks PMA;
  • failure to extubate at day seven and 14 after initiating therapy and at the latest reported time point;
  • days of mechanical ventilation;
  • days of supplemental oxygen;
  • days of hospitalisation;
  • the use of systemic corticosteroids;
  • sepsis, defined as clinical suspected or culture proven;
  • hypertension;
  • hyperglycaemia;
  • gastrointestinal bleeding or perforation (SIP);
  • necrotizing enterocolitis;
  • patent ductus arteriosus (PDA);
  • intraventricular haemorrhage (IVH), any grade;
  • periventricular leukomalacia (PVL);
  • retinopathy of prematurity (ROP), any grade;
  • long term neurodevelopmental sequelae, assessed after at least one year corrected gestational age (CGA) and before a CGA of four years including cerebral palsy and Bayley’s Scales of Infant Development (Mental Development Index, MDI);
  • blindness;
  • deafness.
Primary outcomes

Mortality at 36 weeks PMA and BPD, defined as oxygen dependency at 36 weeks PMA.

Secondary outcomes

Secondary outcomes in the ventilated infants were total duration of mechanical ventilation, failure to extubate at day seven and day 14 after initiating therapy and, in the non-ventilated infants, the supplemental fractional concentration of inspired oxygen (FiO2). In both groups further secondary outcomes were mortality at hospital discharge, the airway resistance, dynamic lung compliance, the use of systemic corticosteroids; incidence of persistent ductus arteriosus, necrotising enterocolitis, hypertension, sepsis or hyperglycaemia during hospitalisation; long-term neurodevelopmental sequelae, assessed after at least one year corrected gestational age (CGA) and before a CGA of four years including cerebral palsy and Bayley’s Scales of Infant Development (Mental Development Index, MDI).

Search methods for identification of studies

We used the following Medical Subject Heading terms (MeSH) and text words:

(steroids or glucocorticoids or flixotide or fluticasone or becotide or beclomethasone or pulmicort or budesonide or anti inflammatory agents) and (inhal* or nebulis* or nebuliz* or aerolis* or aeroliz*) and (neonatal chronic lung disease or bronchopulmonary dysplasia or neonatal respiratory distress syndrome or chronic lung disease of prematurity or chronic lung disease of infancy).

No search limits were used.

Electronic searches

Clinical trials were identified by electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (from 1966 onwards), EMBASE (from 1974 onwards) and CINAHL (from 1982 onwards). These searches were performed until the end date Febuary 2012.

Searching other resources

Reference lists of published trials and review articles, and the abstracts of the Pediatric Academic Societies and the European Society for Pediatric Research (from 1990 onwards) were handsearched.

Data collection and analysis

Selection of studies

The relevant citations found following the database searches were further classified into three groups by two review authors (WO and AvK), namely 'clearly a RCT', 'clearly not a RCT' and 'possibly a RCT'. Full-text review was done on all except those 'clearly not a RCT'. We resolved any disagreements by consensus.

Data extraction and management

In addition to the predefined outcome parameters, two review authors (WO and AvK) independently extracted the following clinical data using a preset data extraction form: patient characteristics (birth weight, gestational age, gender), number of patients randomised, treatment with antenatal glucocorticoids, postnatal surfactant. We resolved any disagreement by consensus.

We asked original investigators of the included RCTs to confirm whether the data extraction was accurate and, where necessary, to provide additional (unpublished) data.

Assessment of risk of bias in included studies

We assessed the methodological qualities of the included trials using the standard methods of the Cochrane Neonatal Review Group. Trial quality assessment of the included trials was performed independently by two review authors (WO and AvK) rating the following: risk for bias by insufficient allocation sequence and concealment, blinding of intervention, completeness of follow-up and blinding of outcome measurements. We resolved any disagreement by consensus. If necessary, we asked the original investigators to provide additional information. We included information regarding the risk of bias of individual trials in the 'Risk of Bias' table.

Measures of treatment effect

We performed meta-analysis of the extracted data using the standard methods of the Cochrane Neonatal Review Group. We processed the extracted data using the Cochrane statistical package, RevMan 5.0.24. Treatment effect estimates for all trials were calculated, expressed as typical relative risk (TRR) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes, all with a 95% confidence interval (CI).

Unit of analysis issues

This review did not include trials with non-standard designs and no effect measures for counts and rates were necessary.

Dealing with missing data

All trials were performed with an intention-to-treat analysis. We asked original investigators of the included RCTs to provide additional (unpublished) data.

Assessment of heterogeneity

Due to clinical and methodological heterogeneity, subgroup analyses were performed as described below. In the absence of statistical heterogeneity (P > 0.05), fixed-effect models were used for the meta-analyses, otherwise random-effects models were used.

Assessment of reporting biases

Funnel plots were planned to assess possible reporting biases. No language restriction was used in the search strategy.

Data synthesis

Fixed-effect models were used, when appropriate.

Subgroup analysis and investigation of heterogeneity

Data on outcomes of ventilated and non-ventilated patients at trial entry were handled as two separate subgroups.

Sensitivity analysis

We planned sensitivity analyses to examine the potential influence of treatment variation (type and dose of inhalation corticosteroid, duration of treatment and delivery system).

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Results

Description of studies

See Characteristics of Included Studies

Results of the search

The search strategy identified 46 relevant manuscripts (27 published in MEDLINE and 19 by handsearching) (Figure 1). Electronic searches of EMBASE, CINAHL and CENTRAL revealed no new relevant manuscripts. The abstracts of these studies were reviewed independently by the two review authors for inclusion in this meta-analysis. There was consensus between the review authors.

Included studies

Eight randomised controlled trials, reported in a total of 12 manuscripts, met the inclusion criteria for this review. Seven trials were available as full-text publications (LaForce 1993; Arnon 1996; Giep 1996; Denjean 1998; Pappagallo 1998; Jonsson 2000; Dugas 2005) and one as an abstract (Pokriefka 1993).

Description of separate trials

Arnon 1996: this double-blind trial included 20 preterm infants with a birthweight < 2000 grams and a gestational age < 33 weeks that were still in need of mechanical ventilation at 14 days PNA with a fraction of inspired oxygen (FiO2) greater than/or equal to 0.30. Patients with PDA, sepsis, air leak or congenital malformation were not included. Eligible patients were randomly assigned to budesonide 600 μg twice daily or placebo given by metered-dose inhalation (MDI), inserted into small volume spacer, for seven days or until extubation, whichever came first. From the reported outcome parameters, only the rate of PDA and sepsis rate during the study period could be used for this review. The authors provided additional data on extubation rate.

Denjean 1998: this was a double-blinded placebo-controlled multicentre trial conducted in six centres in France over a two-year period. A total of 86 preterm infants with gestational age < 31 weeks, respiratory distress syndrome (RDS) and in need of mechanical ventilation, nasal ventilation or continuous positive airway pressure (CPAP) at 10 days PNA were included in this study. Patients with PDA, sepsis, pulmonary infections, major malformation or prior treatment with corticosteroids or bronchodilators were excluded. Although this study consisted of four treatment arms, only those patients treated with beclomethasone 250 μg/puff delivered by a MDI (inserted into a small volume spacer) four times a day or placebo were included in this review. Therapy was started on the tenth or eleventh day and given for 28 days with a tapering dose for the last eight days. The primary outcome was BPD, defined as oxygen dependency at 28 days PNA in combination with radiographic abnormalities consistent with BPD. However, except for the total duration of supplemental oxygen, all outcomes of interest for this review were presented for the combined group of ventilated and non-ventilated infants and were therefore excluded from the final analysis. The use of intravenous corticosteroids was only reported for the ventilated infants. The author provided additional data on the randomisation process.

Dugas 2005: this was a double-blinded randomised trial of 32 infants with a gestational age less than/or equal to 32 weeks, postnatal age between 28 and 60 days and a diagnosis of BPD, which was defined as FiO2 greater than/or equal to 0.25 to maintain oxygen saturation between 88% and 92%, pCO2 greater than/or equal to 45 mmHg and chest radiography consistent with BPD. Reasons for exclusion were hypertension, hyperglycaemia, sepsis, pneumonia, renal failure, treatment with corticosteroids five days prior to inclusion, a FiO2 greater than/or equal to 0.30 in ventilated or FiO2 greater than/or equal to 0.40 in non-ventilated infants, and congenital heart disease. The participants were treated with placebo or fluticasone propionate 125 μg/puff given by MDI inserted into a small volume spacer and interposed between an anaesthesia bag and the tube or a face mask. Infants with a birth weight between 500 and 1200 grams received one puff twice daily for three weeks and once daily in the fourth week. The number of puffs was double if the infant's weight was greater than/or equal to 1200 grams. The primary outcome was the total duration of supplemental oxygen. Other outcomes, such as total duration of hospitalisation or duration of mechanical ventilation, were only reported for the combined group of ventilated and non-ventilated infants and could not, therefore, be used for this review. From the reported outcome parameters, only mortality at 36 weeks PMA, mortality at hospital discharge, open label intravenous glucocorticoids and hyperglycaemia during the study period in the ventilated subgroup could be used for this review. The original authors did not provide additional data.

Giep 1996: a total of 19 patients were included in this feasibility and safety study with a randomised design. Patients were eligible if their birth weight was between 500 and 1500 grams, the X-ray showed signs of RDS or BPD, the postnatal age was at least 14 days and they were still mechanically ventilated with a FiO2 > 0.40 and a peak inspiratory pressure (PIP) > 14 cm H2O after failing an extubation attempt. Patients with PDA, sepsis, congenital heart disease, congenital malformations or previous postnatal or concurrent administration of corticosteroids were not included. The participating infants were randomised to be treated with beclomethasone (1 mg/kg/day) or placebo delivered by MDI and an Aerochamber. Infants weighing 500 to 799 grams, 800 to 1000 grams, 1001 to 1300 grams and above 1300 grams were treated with three, four, five and six puffs every eight hours, respectively, for a total duration of seven days. The reported outcomes failure to extubate, use of systemic corticosteroids, sepsis rate and IVH were included in this review. Although data on blood pressure and blood glucose were reported on a daily basis, the number of infants with hypertension and hyperglycaemia were not reported. Attempts to contact the original authors failed.

Jonsson 2000: in this double-blind placebo controlled study 30 very low birth weight infants, either mechanically ventilated or supported by continuous positive airway pressure with FiO2 greater than/or equal to 0.3, were randomised to budesonide or placebo, delivered by an electronic dosimetric jet nebulizer. Infants with malformations, congenital heart disease, intraventricular haemorrhage (IVH) grades III-IV, deteriorating ventilator settings or on high frequency ventilation were excluded. Starting on day seven of life, infants were treated with a dose of 500 μg twice a day for a total duration of 14 days. Reported outcomes of interest for this review were use of open label corticosteroids, failure to extubate on day 14 in the ventilated subgroup and mortality at hospital discharge and at 36 weeks PMA. The authors provided data on the outcomes, oxygen requirements at 28 days of age and at 36 weeks PMA, duration of supplemental oxygen, duration of mechanical ventilation, failure to extubate and the adverse outcomes hyperglycaemia, hypertension and sepsis for the ventilated and non-ventilated subgroups, separately.

LaForce 1993: this prospective, randomised, paired analysis study included infants with a birth weight < 1500 grams and RDS who were ventilator dependent at 14 days with X-ray abnormalities indicative of BPD. Patients with a PDA, pneumonia, sepsis, congenital heart disease or an air leak were not included. Those allocated to the intervention group were treated with nebulized beclomethasone dipropionate 50 μg three times a day for 28 days. Medication was delivered via a Whisper Jet nebulizer system in the ventilator circuit or a blow by with 8 litre of humidified gas per minute in ventilated and non-ventilated infants, respectively. The reported outcome of interest for this review was mortality at hospital discharge.The original authors provided data on randomisation and sepsis rates.

Pappagallo 1998: this single centre study included preterm infants with a birthweight < 1500 gram of more than seven days PNA with a high probability of developing BPD based on a prediction model or ventilator dependency. This study had two phases, with only the second phase having a randomised placebo-controlled design. Data on the 18 infants included in this second phase were used for this review. Infants with sepsis, pulmonary hypoplasia, congenital anomalies or heart disease were excluded. Patients were randomly assigned to dexamethasone inhalation 1 mg/kg 8-hourly for seven days followed by 0.5 mg/kg for three days or placebo using a jet nebulizer. The reported outcomes of interest for this review were the use of intravenous corticosteroids, duration of mechanical ventilation, days on supplemental oxygen and total duration of hospitalisation. The rate of failure to extubate was found in an abstract identified by handsearching, which reported on the preliminary outcomes of 10 patients. The original authors could not provide additional data.

Pokriefka 1993: in this study, only published in as an abstract, 14 ventilator-dependent preterm infants with moderate to severe BPD were enrolled and treated with flunisolide or placebo for 28 days, followed by a weaning schedule. No inclusion or exclusion criteria were described. This RCT was only available as an abstract, reporting clinical and respiratory outcomes without dichotomous or continuous data. Continuous data on the mean number of intubation days were reported with neither standard deviations nor standard errors. Therefore, these data could not be used. The rates of extubation were stated although not on which day after initiating therapy. These data were used in the outcome failure to extubate at the latest reported time point. All attempts to contact the original authors failed.

Description of aggregated patient characteristics and intervention

Five trials (Pokriefka 1993; LaForce 1993; Arnon 1996; Giep 1996; Pappagallo 1998) included only ventilated infants at trial entry, whereas three trials (Denjean 1998; Jonsson 2000; Dugas 2005) included both ventilated and non-ventilated preterm infants. Criteria for including participants were comparable between trials, that is ventilator or oxygen dependency, or both, at greater than/or equal to 7 days PNA. The exclusion criteria were the presence of a persistent ductus arteriosus, signs of sepsis, congenital malformations and treatment with postnatal corticosteroids prior to inclusion. Most trials started therapy moderately early (seven to 21 days PNA), whereas one study (Dugas 2005) started therapy > 21 days PNA (delayed onset). The gestational age and birth weight of the included infants were comparable between trials.

Three trials (LaForce 1993; Pokriefka 1993; Pappagallo 1998) did not report on the use of antenatal corticosteroids or postnatal surfactant. In the remaining trials the use of antenatal corticosteroids and postnatal surfactant varied from 25% to 80% and 69% to 100%, respectively.Within the trials, participants in the treatment and placebo groups were similar with regards to clinical characteristics such as birth weight, gestational age, gender, use of antenatal corticosteroids and surfactant, Apgar scores, FiO2 and ventilator settings or respiratory support at trial entry.

Interventions differed in every trial with regard to the type of corticosteroid, dosage, delivery system and duration of treatment. The corticosteroids used included beclomethasone, flunisolide, budesonide and dexamethasone. Delivery systems included MDI with a spacer device and nebulization. Total duration of study medication ranged from seven to 28 days.

Description of aggregated outcome parameters

Three trials (LaForce 1993; Jonsson 2000; Dugas 2005) reported or provided data on mortality in the ventilated infants at the different points in hospitalisation (mortality at 28 days PNA, 36 weeks PMA and at hospital discharge), whereas Jonsson 2000 provided us with additional data on non-ventilated infants.

None of the manuscripts reported the incidence of BPD at 28 days PNA or 36 weeks PMA for the ventilated and non-ventilated infants separately; however, these data were obtained for the study of Jonsson 2000 by personal communication.

Failure to extubate seven days after initiating therapy was reported by five trials (Arnon 1996; Giep 1996; Pappagallo 1998; Dugas 2005; Jonsson 2000), whereas Pokriefka 1993 reported failure to extubate at an unknown date. Three trials reported on the duration of mechanical ventilation for the subgroup of ventilated infants at trial entry (Pappagallo 1998; Jonsson 2000; Dugas 2005). Four trials reported data on the total days of supplemental oxygen in the subgroup of ventilated infants (Denjean 1998; Pappagallo 1998; Jonsson 2000; Dugas 2005) and two in the subgroup of non-ventilated infants (Denjean 1998; Jonsson 2000). Total days of hospitalisation in the intervention and placebo arms were reported by Pappagallo 1998.

Five trials reported the incidence of open label corticosteroid use outside the study protocol in both arms (Giep 1996; Denjean 1998; Pappagallo 1998; Jonsson 2000; Dugas 2005). Four studies (LaForce 1993; Arnon 1996; Giep 1996; Jonsson 2000) reported or provided additional data on the outcome of sepsis. The studies of Arnon 1996, Giep 1996, Jonsson 2000 and LaForce 1993 also reported or provided additional data on one of the following outcomes in both arms: persistent ductus arteriosus (PDA), hypertension, necrotising enterocolitis and intraventricular haemorrhage (IVH).

In three studies (Pokriefka 1993; Arnon 1996; Giep 1996) no increase in adverse side effects, such as impaired glucose homeostasis and hypertension, was reported but the actual data were not provided in the manuscripts.

None of the included trials reported on gastrointestinal bleeding or perforation, periventricular leukomalacia, retinopathy of prematurity and long-term neurodevelopmental sequelae. None of the original authors were able to provide data on these outcomes.

Excluded studies

See table Characteristics of excluded studies.

Twenty-eight trials (16 full-text publications and 12 abstracts) were excluded for the following reasons (Figure 1): non-randomised design or without placebo (N = 9) (Eisenberg 1990; Pappagallo 1990; Konig 1992; Thorson 1992; Cloutier 1993; Giffin 1994; Liu 1996; Pelkonen 2001; Shah 2007), initiation of therapy before seven days PNA or after 36 weeks PMA (N = 7) (Dunn 1989; Dunn 1992; Yuksel 1992; Ng 1998; Inwald 1999; Yeh 2008; Beresford 2002), administration of systemic steroids as co-intervention or as control intervention (N = 6) (Abbasi 1993; Suchomski 1996; Suchomski 1996; Suchomski 1996; Kovacs 1998; Parikh 2002; Rozycki 2003) and double publications of excluded trials (N = 6) (Thorson 1992; Liu 1996; Suchomski 1996; Kovacs 1998; Shah 2007; Parikh 2002).

Two trials (Rajamani 1998; Cole 1999a) might have included participants within the inclusion criteria of this review. However, all attempts at contacting the original trialist to request subgroup data failed, therefore these trials were excluded.

Risk of bias in included studies

All of the included trials were randomised, double-blinded with placebo controls. LaForce 1993, Arnon 1996, Giep 1996 and Jonsson 2000 provided additional information to assist us. The quality of the trials ranged from moderate to high, with some trials failing to provide sufficient details on the randomisation process, method of blinding and the management of withdrawals.

Risk of bias in individual studies

Arnon 1996: the method of randomisation was not mentioned in the manuscript. Personal communication revealed that randomisation was performed by the pharmacy. The code and drugs were kept until the end of the trial and released from the hospital pharmacy in sealed envelopes. Blinding was established by using identical MDIs for corticosteroids and placebo administration. Ten patients were withdrawn and did not complete the study: five because of sepsis (three placebo, two treatment group), four because of PDA (two in each group) and one because of an air leak (treatment group). These infants were excluded from the analysis in the original manuscript but were included in this review. It was unclear whether the study was free of selective reporting.

Denjean 1998: the methods of allocation concealment or randomisation process were not mentioned in the manuscript, however accuracy was confirmed by personal communication. Randomisation by pre-established tables was stratified by centre, gestational age and type of ventilator support. The method of blinding was not clearly stated in the manuscript but again we ensured it to be genuine by personal communication. Due to severe clinical deterioration, for three patients the code was broken. Furthermore, it was stated that of the 178 infants randomised, informed consent was either not obtained or withdrawn for five patients for unclear reasons. It was unclear whether the study was free of selective reporting.

Dugas 2005: the method of concealment was not mentioned in the manuscripts. Infants were assigned to the treatment or placebo arm by block randomisation with stratification of intubated and extubated infants. Blinding was ensured by identical MDIs supplied by the drug manufacturer. The pharmacist in charge of the medication, the treating physician and the investigators were unaware of treatment allocation. Three infants in the placebo group did not complete the study protocol (two because of clinical pulmonary deterioration and one because of central line sepsis). All participants were analysed on an intention-to-treat basis. Mean supplemental oxygen at study enrolment differed between the treatment and placebo arms, being significantly lower in the treatment group. The pre-defined outcomes were reported accurately.

Giep 1996: methods of allocation concealment or randomisation of the participants were not described in the manuscript. Observers were blinded to treatment allocation, however the method ensuring this was not reported. Three infants in the placebo group and two in the treatment group received systemic corticosteroids after study entry and continuous data which were not of interest for this review were excluded from the analysis thereafter.

Jonsson 2000: randomisation was computer generated and sealed envelopes were consecutively numbered. Clinical staff were blinded to group assignment and the code was broken after the last patient finished the treatment. Blinding of the intervention was ensured by supplying the study drug in identical opaque, unmarked plastic vials. Outcome assessments were also blinded. Two patients were withdrawn by attending clinician due to deterioration and received systemic corticosteroids; one died on ninth day of life. Outcomes for all enrolled infants were provided. The pre-defined outcomes were reported accurately.

LaForce 1993: the attending neonatologist was unaware of the treatment regimen. However, the method of allocation concealment or blinding was unclear. Nine patients were withdrawn from the analysis due to technical problems with equipment (two in each group), lost to referring hospital (two in each group) and one because of sudden death before start of the study (in treatment group). These patients were not included in the analyses of the original manuscript but were used for the dichotomous outcomes during the study period in this review. It was unclear whether the study was free of selective reporting.

Pappagallo 1998: the manuscript revealed no information regarding the method of sequence generation, allocation concealment or randomisation. Clinical staff were unaware of the intervention since the vials were prepared by the pharmacist, labelled with a code and both the study and placebo medications were clear solutions and the dosage was calculated on the basis of volume. Outcomes were given for all infants enrolled.

Pokriefka 1993: the authors, in the abstract, stated that this was a double-blind randomised trial but in its brevity no information was available regarding the method of randomisation, blinding of intervention or outcome assessments. Outcomes for all enrolled infants were provided.

Summarized risk of bias

Allocation (selection bias)

Allocation concealment was blinded in five trials (LaForce 1993; Arnon 1996; Denjean 1998; Jonsson 2000; Dugas 2005) and unclear in the remaining trials. Adequate sequence generation, however, was only clear in one trial (Denjean 1998; Jonsson 2000).

Blinding (performance bias and detection bias)

Based on the reported data and personal communications, all studies were judged as having a double-blind design. The double-blind design was not clearly stated in the abstract of Pokriefka 1993.

Incomplete outcome data (attrition bias)

Five trials reported the outcomes of all included participants (Pokriefka 1993; Giep 1996; Pappagallo 1998; Jonsson 2000; Dugas 2005), whereas in two trials (Arnon 1996; Denjean 1998) participants were not included because of not obtaining informed consent or excluded for the outcomes and in one trial it was unclear (LaForce 1993).

Selective reporting (reporting bias)

Five trials reported the pre-defined outcome data completely. In three trials (LaForce 1993; Arnon 1996; Denjean 1998) it was unclear whether all pre-defined outcome data were reported.

Other potential sources of bias

With the exception of three trials (Arnon 1996; Giep 1996; Jonsson 2000) other potential sources of bias could not be excluded based on the available information.

Effects of interventions

Inhaled glucocorticoids versus placebo (Comparison 1)

Mortality, BPD, and combined mortality or BPD

Meta-analysis of separate or combined outcomes mortality and BPD at 28 days PNA or 36 weeks PMA did not show a significant difference between the treatment and placebo arms in either the ventilated or non-ventilated subgroup (typical risk ratio (TRR) 0.93; 95% confidence interval (CI) 0.72 to 1.21 (Outcome 1.4) and 1.00; 95% CI 0.59 to 1.70 (Outcome 1.5) respectively.

Other respiratory outcomes

Due to statistically significant clinical heterogeneity, data on failure to extubate were analysed using a random-effects model. The overall typical risk ratio (TRR) of failure to extubate at seven days (five studies), 14 days (two studies) and latest reported time point (one study) after treatment onset was 0.85 (95% CI 0.62 to 1.18) (Outcome 1.8), 0.36 (95% CI 0.10 to 1.33) (Outcome 1.9) and 0.57 (95% CI 0.27 to 1.20) (Outcome 1.10), respectively.

The meta-analysis of the outcome duration of mechanical ventilation in the ventilated infants showed no significant statistical difference between the treatment arms. In both subgroups (ventilated and non-ventilated participants) meta-analysis showed no significant difference between the treatment and placebo arms regarding duration of supplemental oxygen for the ventilated (WMD 5.53; 95% CI -3.99 to 15.05) (Outcome 1.12) and non-ventilated (-3.74; 95% CI -12.63 to 5.14) (Outcome 1.12.2) infants.

Adverse effects during hospitalisation

Meta-analysis showed that open label intravenous corticosteroids were less often used in ventilated infants treated with inhaled corticosteroids, but this difference only approached statistical significance (TRR 0.51; 95% CI 0.26 to 1.00) (Outcome 1.13). Only one trial reported on the use of open label intravenous corticosteroids in non-ventilated infants (Jonsson 2000), showing that this intervention was not used in any of the included infants.

Five trials reported either suspected (Giep 1996) or documented (LaForce 1993; Arnon 1996; Jonsson 2000; Dugas 2005) sepsis rates and the meta-analysis of these results failed to show a significant difference between the inhaled corticosteroids and placebo groups (TRR 0.88; 95% CI 0.44 to 1.77). Subgroup analysis did not change this finding.

We were unable to perform meta-analysis on the outcomes of persistent ductus arteriosus (PDA), hypertension, necrotising enterocolitis, intraventricular haemorrhage (IVH) and total days of hospitalisation because these outcomes were only reported in single trials. None of these trials reported a significant difference in these outcomes, except for total days of hospitalisation. Pappagallo 1998 showed a significant decrease in the total days of hospitalisation in favour of the inhaled corticosteroids group (WMD -24.70; 95%CI -41.75 to -7.65) (Outcome 1.19).

Discussion

Summary of main results

Based on the pre-defined inclusion criteria, this systematic review identified eight relatively small randomised controlled trials comparing inhalation corticosteroids to placebo in a total of 232 ventilated and non-ventilated preterm infants. These trials differed considerably in the patient characteristics, the intervention (medication, dose, duration and delivery), the reported outcomes and the definitions of these outcomes. This heterogeneity and the small number of randomised patients should be taken into account when interpreting the results of this review.

As the aim was to examine effects to prevent BPD, the end-point of inclusion was chosen to exclude those trials investigating inhaled glucocorticoids in preterms with established BPD after 36 weeks PMA. It is, to our knowledge, unknown how much time before the end-point inhaled glucocorticoids will be effective. One could argue for two weeks before, four weeks before, although it is not really clear. There needs to be an exposure for some time to reduce inflammation. The only trial which could have theoretically included patients around the corrected gestation of 36 weeks PMA (Dugas 2005) could not provide us with data on the primary outcome BPD at 36 weeks PMA. All other trials treated infants for an average of eight weeks (that is 36 weeks gestational age at inclusion, on average).Therefore, we feel that the inclusion criteria fulfil the purpose of this review.

Meta-analysis of reported and provided data showed that inhalation corticosteroids does not improve the separate or combined outcomes mortality or BPD at any time point during hospitalisation. In addition, there were no significant differences in the short-term respiratory outcomes such as failure to extubate at seven, 14 days or at the latest reported time point, the total days of mechanical ventilation or days of supplemental oxygen. This is despite the fact that several studies reported that inhalation corticosteroids improved resistance and compliance of the respiratory system, sometimes resulting in a reduction in FiO2 or respiratory rate. However, the heterogeneity in how lung function was measured and the data were reported prevented a valid meta-analysis of these outcomes (LaForce 1993; Pokriefka 1993; Arnon 1996; Giep 1996; Pappagallo 1998).

Our meta-analysis did show a trend to a reduced use of systemic corticosteroids for the reduction of BPD in the inhaled corticosteroids group. In light of the growing concerns about the adverse effects of systemic corticosteroids, this might prove to be an important and clinically relevant finding. However, the lack of data on short and long-term adverse effects in most trials precludes firm conclusions at this point in time.

Overall completeness and applicability of evidence

The overall completeness and applicability of this review are low for several reasons. First, few trials were of randomised, placebo-controlled design and, therefore, eligible for inclusion. The numbers of participants within each of these included trials were small, which limits their power to detect small but clinically important effects of treatment. Second, most placebo-controlled trials investigating inhalation corticosteroids differed considerably in terms of patient characteristics and study design, including differences in type of inhalation medication, dose, duration of therapy and delivery systems. It is unknown if and how these factors modify the treatment effect of inhalation corticosteroids on the outcome parameters reported in this review since no sensitivity analysis could be done to assess the potential impact of different drugs, dosages, delivery systems and treatment duration on the magnitude of the expected benefit. Third, not all trials reported the primary and secondary outcome parameters. Various definitions were used, and outcomes were assessed at different points in time. Our extended attempts to retrieve unpublished data did not change this shortcoming.

Quality of the evidence

Three out of the eight included studies did not report allocation concealment and the majority did not report adequacy of allocation sequence. However, all but one trial reported adequate blinding of the intervention, therefore, the quality of these RCTs was judged as moderate to high.

Potential biases in the review process

Due to the lack of possible aggregation data reported in the eligible trials, no funnel plots could be performed. Therefore, the potential risk of publication bias cannot be excluded.

Authors' conclusions

Implications for practice

Inhalation corticosteroids administered after the first week of life to preterm infants do not improve the separate or combined outcomes mortality or BPD at any time point during hospitalisation. Although there are indications that inhalation corticosteroids improve lung function, this does not seem to impact on short-term respiratory outcomes such as failure to extubate or the duration of mechanical ventilation. Inhalation corticosteroids may reduce the use of systemic corticosteroids, but the clinical relevance of this treatment effect is unclear as short and long-term adverse effects of inhalation corticosteroids are under-reported. The results of this meta-analysis are compromised by the fact that most trials are underpowered and they are heterogeneous in design. Based on these results the use of inhalation corticosteroids initiated at greater than/or equal to 7 days of life for preterm infants at high risk of developing BPD cannot be recommended.

Implications for research

Studies are needed to determine the optimal inhaled corticosteroid drug, dose, duration and device using short-term markers of lung function and inflammation. The optimal treatment regimen should be tested in a randomised placebo-controlled trial including a large number of preterm infants at high risk of developing BPD. The trial design should avoid bias by using adequate allocation concealment and a double-blinded intervention and outcome assessment. Outcomes should be reported using pre-defined modern definitions and timing and using accepted diagnostic tests for these outcomes. Data on the following primary outcome parameters should be collected for: BPD at 36 weeks PMA, mortality at 36 weeks PMA and at discharge, and a complete assessment made of major neurosensory impairment using pre-defined definitions. Short-term benefits (that is time of extubation, duration of ventilation) and adverse effects (that is hypertension, infection, hyperglycaemia and the use of open label intravenous corticosteroids) can be reported as secondary outcomes.

Acknowledgements

Dr P Lister, Dr R Iles, Dr B Shaw, Dr F Ducharme for writing the previous version of this review, named " Inhaled steroids for neonatal chronic lung disease".
Dr David Schwartz, Dr T Giep, Prof M Silverman and Dr Spencer Brudno provided additional information for the previous version of this review.
Prof Silverman and Dr Jonsson provided precious additional data for this updated version of the review.
Ms Diane Haughton, Ms Yolanda Montagne and Prof Roger Soll of the Cochrane Neonatal Review Group.

Contributions of authors

Drs Onland and D. van Kaamhave full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Onland, van Kaam.
Acquisition of data: Onland, van Kaam.
Analysis and interpretation of data: Onland, Offringa, van Kaam.
Drafting of the manuscript: Onland, van Kaam.
Critical revision of the manuscript for important intellectual content: Onland, Offringa, van Kaam.
Stastical analysis: Onland.
Study supervision: Offringa, van Kaam

Declarations of interest

No financial disclosure to be declared.

No potential conflicts of interest known.

Differences between protocol and review

  • None noted.

Additional tables

Editorial responsibility for the review "Inhaled steroids for neonatal chronic lung disease" has been transferred to the Cochrane Neonatal Review Group from the Cochrane Airways Group.
A new team of review authors has been assigned - Dr Wes Onland, Dr Anton Van Kaam, Dr Martin Offringa.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Arnon 1996

Methods

Single centre double-blind placebo-controlled trial
Blinding of randomisation: yes (sealed envelopes)
Blinding of intervention: yes (identical metered dose inhalers (MDIs) for placebo and corticosteroid administration
Complete follow-up: no, withdrawals n = 10
Blinding of outcome measurements: yes

Participants

Ventilated patients
Eligible: preterm infants with birthweight < 2000 gram and gestational age < 33 weeks, still in need for mechanical ventilation at 14 days PNA with FiO2 greater than/or equal to .30 and no significant changes in respiratory support 3 days prior to study
Excluded if: PDA, sepsis, air leak or congenital malformation
Budesonide group n=9 versus placebo group n=11
Trial entry budesonide group 15 (± 0.6) versus placebo group 14 (± 0.5) days
No significant statistical differences found between groups with regard to birth weight, gestational age, post-natal age, sex, Apgar scores, rates of maternal infection or the use of antenatal steroids

Interventions

Budesonide (Astro Draco, UK 200 μg/puff) 600 μg twice daily or placebo given by MDI for 7 days or until extubation, whichever came earlier. MDI was inserted into small volume spacer (Aerochamber MV15, Trudell Medical, Ontario, Canada), and filled with oxygen without a rubber flap valve. Distal end of spacer was directly connected onto the endotracheal tube

Outcomes

Primary outcome: extubation for 24 hours within the 7 day period. Secondary outcomes: ventilatory efficiency index, FiO2. Alveolar-arterial oxygen difference calculated on 1st daily arterial blood gas measurement, serum cortisol, sepsis rates, bronchoalveolar lavage (BAL)
Ventilator efficiency index (VEI)=k/f x (PIP-PEEP) x PaCO2 (where k is a constant, f is the respiratory rate, PIP is the peak inspiratory pressure and PEEP is the positive end-expiratory pressure

PaCO2 denotes the arterial partial pressure of carbon dioxide)

Notes

Authors provided data on extubation rate.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk
Allocation concealment (selection bias) Low risk

Randomisation by pharmacy. Code and drugs released from hospital pharmacy in sealed envelopes and code was concealed until end of trial. Investigators unaware of treatment group assignment

Blinding (performance bias and detection bias) Low risk

Identical metered dose inhaler (MDI) of placebo and steroid, pharmacy randomised and issued drugs ensuring double-blinding

Incomplete outcome data (attrition bias) Low risk

Ten patients were withdrawn and did not complete the study, 5 due to sepsis (3 placebo, 2 treatment group), 4 had a patent ductus arteriosus (PDA) (2 in each group), 1 air leak (treatment group). No intention to treat analysis

Selective reporting (reporting bias) Low risk
Other bias Low risk

Denjean 1998

Methods

Multicentre (n=6) double-blind placebo-controlled trial
Blinding of randomisation: yes, method not known
Blinding of intervention: yes
Complete follow-up: no, withdrawals n = 5
Blinding of outcome measurements: yes
Infants were randomised into one of 4 groups: placebo + placebo, placebo + beclomethasone, placebo + salbutamol and beclomethasone + salbutamol. For this review only patients treated with placebo + placebo (as the control group) and placebo + beclomethasone (as the treatment group) were included
Stratification by centre, gestational age less than/or equal to 28 weeks versus 29-30 weeks and type of ventilator support

Participants

Ventilated and non-ventilated patients
Eligible: preterm infants with gestational age < 31 weeks, respiratory distress syndrome and in need for mechanical ventilation or nasal ventilation or CPAP at 10 days PNA and no significant changes in respiratory support 3 days prior to study
Excluded if: PDA, sepsis, pulmonary infections, major malformation or prior treatment with corticosteroids or bronchodilators
Beclomethasone group n=43 versus placebo group n = 43
Trial entry beclomethasone group 10 (± 1.5) versus placebo group 10.1 (± 1.6) days
No significant statistical differences found between groups with regard to birth weight, gestational age, mode of delivery, multiple pregnancy or the use of antenatal steroids. No significant differences in outcome criteria at start of study

Interventions

Beclomethasone or corresponding placebo (Glaxo France) 250 μg/puff four times a day given by MDI inserted into small volume spacer (Aerochamber MV15, Trudell Medical, Ontario, Canada). Therapy started on the 10-11th day for 1 month with a tapering course for the last 8 days.

Outcomes

Primary outcome: BPD, based on oxygen dependency at 28 days PNA and radiographic criteria and BPD severity, defined as severe when ventilation > 3 months or oxygen supplementation > 4 months; moderate as ventilation > 1 month or oxygen > 2 months; mild as ventilation < 1 month and oxygen < 2 months
Secondary outcomes: ventilatory index (FiO2 x main airway pressure), pneumothorax, interstitial emphysema, need for IV corticosteroid treatment, infections, hypertension, blood glucoses and plasma electrolytes

Notes

Author gave additional information on randomisation process

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

By personal communication

Allocation concealment (selection bias) Low risk

Method of allocation concealment unknown. Stratification by centre, gestational age less than/or equal to 28 weeks versus 29-30 weeks and type of ventilator support

Blinding (performance bias and detection bias) Low risk

However in 3 patients the code was broken because of severe clinical deterioration

Incomplete outcome data (attrition bias) High risk

It was stated that of 178 infants randomised, 5 were withdrawn or informed consent not obtained without explanation

Selective reporting (reporting bias) Unclear risk
Other bias Unclear risk

Dugas 2005

Methods

Multicentre (n=2) double-blind placebo-controlled trial
Blinding of randomisation: yes, by block randomisation, method not known
Blinding of intervention: yes. Pharmacist in charge of the medication, the treating physician and the investigators were unaware of treatment allocation
Complete follow-up: yes
Blinding of outcome measurements: yes
Intubated and extubated infants were stratified separately at randomisation

Participants

Ventilated and non-ventilated patients
Eligible: preterm infants with gestational age less than/or equal to 32 weeks, postnatal age between 28 and 60 days, and diagnosis of BPD (FiO2 greater than/or equal to 0.25 to maintain oxygen saturation between 88 and 92%, pCO2 greater than/or equal to 45 mmHg and chest radiography consistent with BPD)
Excluded if: hypertension, hyperglycaemia, sepsis, pneumonia, renal failure or treatment with corticosteroids 5 days prior to inclusion, mechanical ventilation with FiO2 greater than/or equal to 0.30 or oxygen dependency FiO2 greater than/or equal to 0.40 if non intubated or congenital heart disease
Fluticasone propionate group n=16 versus placebo group n = 16
Trial entry fluticasone propionate group 44.8 (± 11) versus placebo group 45.4 (± 10) days
No significant statistical differences found between groups with regard to birth weight, gestational age, multiple pregnancy or the use of antenatal steroids and clinical diagnosis as persistent ductus arteriosus, necrotising enterocolitis, intraventricular haemorrhage, hypotension and sepsis
No significant differences in outcome criteria at start of study, with the exception of mean FiO2 which was significantly lower in the treatment group

Interventions

Fluticasone propionate or corresponding placebo (Flovent; Glaxo-SmithKline, St-Laurent, Quebec, Canada; 125 μg/puff) were given by MDI. MDI was inserted into small volume spacer (Aerochamber MV15, Trudell Medical, Ontario, Canada) and interposed between an anaesthesia bag and the tube or a face mask. Infants with weight 500 - 1200 grams, the medication was given one puff twice daily for 3 weeks, then once daily in the 4th week. The number of puffs was double if the infant's weight was greater than/or equal to 1200 grams
Systemic corticosteroids were allowed at the discretion of the attending physician, after which the inhalation medication was stopped

Outcomes

Primary outcome: mean difference in duration of oxygen supplementation
Secondary outcomes: survival without supplemental oxygen at the end of the study protocol, duration of ventilatory support, blood glucose, hypertension, diuresis, growth, cortisol axis, chest radiography score and duration of hospital stay

Notes

Authors did not respond to queries

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk
Allocation concealment (selection bias) Low risk

Block randomisation, stratified intubated and extubated infants separately

Blinding (performance bias and detection bias) Low risk

Identical format of MDIs supplied by the drug manufacturer. Pharmacist in charge of the medication, the treating physician and the investigators were unaware of treatment allocation

Incomplete outcome data (attrition bias) Low risk

Three infants in the placebo group did not complete the study protocol (two because of clinical pulmonary deterioration and one because central line sepsis). All analysed on a intention-to-treat basis

Selective reporting (reporting bias) Low risk
Other bias Unclear risk

Mean FiO2 which was significantly lower in the treatment group

Giep 1996

Methods

Single centre double-blind placebo-controlled trial
Blinding of randomisation: yes, method not known
Blinding of intervention: yes. Respiratory therapists, nurses, medical staff, investigators and parents all blinded
Complete follow-up: yes. Withdrawals (n=5) due to their need for systemic corticosteroids
Blinding of outcome measurements: yes

Participants

Ventilated patients
Eligible: preterm infants with birthweight 500 to 1500 grams, clinical and x-ray changes consistent with respiratory distress syndrome (RDS) and BPD, at least 14 days old, still on mechanical ventilator with FiO2 > 0.40 and PIP > 14 cm H2O and failing previous extubate attempt
Excluded if: PDA, sepsis, congenital heart disease, congenital malformations or previous postnatal or concurrent administration of corticosteroids
Beclomethasone n=10 and placebo group n=9
Trial entry beclomethasone group 18 versus placebo group 20 days
No statistical differences found between groups with respect to birth weight, gestational age, antenatal steroid usage, sex, race, mode of delivery or use of surfactant
At the start of the study there were no significant differences in the outcome variables between groups

Interventions

Beclomethasone or placebo by MDI (Allen and Hansburys, Division of Glaxo, Research Triangle Park, NC) and Aerochamber (Mongahan Medical Corp, Plattsburgh, NE)
The infants were treated with an approximate dose of 1 mg/kg/day in three doses. Infants weighing 500 to 799 grams were treated with three puffs, those weighing 800 to 1000 grams four puffs, those weighing 1001 to 1300 grams five puffs and above 1301 grams six puffs every 8 hours. Total duration of therapy was 7 days

Outcomes

No primary outcomes prespecified since this was a feasibility and safety of administration trial. Outcomes reported were respiratory rate, FiO2, PIP, PEEP, mean airway pressure, inspiration time and
time to extubation, heart rate, blood pressure, infection rate, intraventricular haemorrhage (IVH) rate, retinopathy of prematurity (ROP), weight and caloric intake, cortisol and ACTH levels

Notes

Authors did not respond to queries

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk
Allocation concealment (selection bias) Unclear risk

Information not available

Blinding (performance bias and detection bias) Low risk

Respiratory therapists, nurses, medical staff, investigators and parents all blinded

Incomplete outcome data (attrition bias) Low risk

Three infants in the placebo group and two in the treatment group received systemic corticosteroids after study entry and continuous data were excluded from analysis thereafter

Selective reporting (reporting bias) Low risk
Other bias Low risk

Jonsson 2000

Methods

Single centre randomised double-blind placebo-controlled trial
Blinding of randomisation: yes. Computer generated randomisation, sealed envelopes were numbered consecutively
Blinding of intervention: yes. Clinical staff was blinded to group assignment. Code broken after last patient finished inhalations. Vials were kept in the hospital pharmacy in consecutively numbered cartons
Complete follow-up: yes. Withdrawal (n=3) of two infants by attending clinician due to deterioration and received systemic corticosteroids; one died on 9th day of life due to sepsis, disseminated intravascular coagulation and IVH grade IV
Blinding of outcome measurements: yes

Participants

Ventilated and non-ventilated infants
Eligible: very low birth weight infants on mechanical ventilator postnatal day 6 or if extubated, nasal
continuous positive airway pressure with FiO2 greater than/or equal to 0.3
Excluded if: congenital malformations, congenital heart disease and IVH (grades III-IV), or on ventilator with increasing FiO2 > 60% and/or PCO2 > 8.5 kPa, or on high frequency oscillatory ventilation on day 7
Budesonide group n=13 and placebo group n=14
Trial entry budesonide group 7 (± 0) versus placebo group 7 (± 0) days
Demographic data: values are presented as median (range) or number (%)
No significant statistical differences found between groups with regard to birth weight, gestational age, post-natal age, sex, Apgar scores, rates of maternal infection or the use of antenatal steroids
All participants, except one received surfactant treatment
No significant differences in outcome criteria at start of study

Interventions

Budesonide (Pulmicort®) (Astra-Draco Pharmaceuticals, AB, Lund, Sweden) or placebo aerosol was used. The drug was delivered using an electronic dosimetric jet nebulizer (Spira Electro 4, Respiratory Center, Hameenlinna, Finland), delivering the aerosol during the inspiration but not the expiration phase of mechanical breaths. In spontaneously breathing infants a Laerdal mask modified to fit to the inhalator nozzle was used
The infants were treated with a dose of 500 μg twice a day, starting on day 7 of life, for the total duration of therapy of 14 days

Outcomes

Primary outcome: change in FiO2
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 baselineand at the end of the study period. Information on adverse events, such as hyperglycaemia, hypertension, sepsis, PDA, IVH and gastrointestinal problems were collected

Notes

Author provided additional outcome data and checked data extraction

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer generated randomisation

Allocation concealment (selection bias) Low risk

Sealed envelopes were numbered consecutively

Blinding (performance bias and detection bias) Low risk

Clinical staff was blinded to group assignment. Code broken after last patient finished inhalations. Vials were kept in the hospital pharmacy in consecutively numbered cartons

Incomplete outcome data (attrition bias) Low risk

Withdrawal (n=3) of two infants by attending clinician due to deterioration and received systemic corticosteroids; one died on 9th day of life due to sepsis, disseminated intravascular coagulation and IVH grade IV

Selective reporting (reporting bias) Low risk
Other bias Low risk

LaForce 1993

Methods

Single centre randomised double-blind placebo-controlled trial
Blinding of randomisation: yes. Random number generated, sequential card draws. Odd numbers were allocated to treatment group and even numbers fell into the placebo group. The next patient enrolled was matched with the randomised subject
Blinding of intervention: yes. Pharmacy prepared identical, single use vials labelled with only the patient name, hospital number and the identity code of the study protocol
Complete follow-up: yes. Withdrawals/lost to follow-up n = 9 (4 due to technical problems with equipment (2 in each group), 4 lost after transfer to referring hospital (2 in each group) and one sudden death before start of study (in treatment group)
Blinding of outcome measurements: yes
Stratification by birth weight greater than or less than 1000 grams, and paired by birth weight

Participants

Ventilated infants
Eligible: birth weight < 1500 gram with clinical and X-ray signs of RDS, ventilated at 14 days, X-ray changes consistent with BPD
Excluded if: PDA, pneumonia, sepsis, congenital heart disease or air leak
All participants were treated with Exosurf Neonatal
Six matched pairs and one unmatched in the placebo group
No significant statistical differences found between groups with regard to initial inspired oxygen concentration, ventilator settings or respiratory rate

Interventions

Nebulization with beclomethasone dipropionate (Vancenase AQ Nasal; Schering) 50 μg or placebo, 8 hourly for 28 days. Treatments were delivered through ventilator circuit with a Whisper Jet nebulizer system (model No. 123025; Marquest Medical Products, Inc., Englewood, Colo.) in ventilated patients and through blow by with 8 litre of humidified gas per minute

Outcomes

No primary or secondary outcomes defined. Reported outcomes were weekly measurements of lung compliance and airway resistance, sepsis rate, and weekly tracheal cultures

Notes

Author provided data on randomisation process and sepsis rates

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk
Allocation concealment (selection bias) Low risk

Investigators unaware as to order of treatment group assignment

Blinding (performance bias and detection bias) Low risk

Attending neonatologist was unaware of treatment regimen

Incomplete outcome data (attrition bias) Low risk

Withdrawals/lost to follow-up = 9 (4 due to technical problems with equipment (2 in each group), 4 lost to referring hospital (2 in each group) and one sudden death before start of study (in treatment group)

Selective reporting (reporting bias) Unclear risk
Other bias Unclear risk

Pappagallo 1998

Methods

Single centre randomised double-blind placebo-controlled trial
Blinding of randomisation: unclear
Blinding of intervention: yes. Vials were prepared by the pharmacist labelled with a code. Since both study and placebo medications were clear solutions and dosage was calculated on basis of volume, the clinical staff was unaware of intervention
Complete follow-up: no mention of withdrawals
Blinding of outcome measurements: unclear

Participants

Ventilated patients.
Eligible: preterm infants with birthweight < 1500 gram, older than 7 days of age and with a high probability of BPD based on a prediction model or being ventilator dependent
Excluded if: sepsis, pulmonary hypoplasia, congenital anomalies or heart diseases
Dexamethasone group n=9 and placebo group n=9
Trial entry dexamethasone group 22.6 (± 3.0) versus placebo group 19.13 (± 1.6) days
No differences between groups in gestational age, birth weight, study age nor study weight

Interventions

Dexamethasone 1 mg/kg for 7 days every 8 hours followed by 0.5 mg/kg from day 8 to 10 or placebo by jet nebulizer

Outcomes

Changes in tidal volume, minute ventilation, dynamic compliance, airway resistance, work of breathing, peak oesophageal pressure, extubation rates, cortisol levels and mucosal changes on bronchoscopy

Notes

Manuscript reports on two study phases, the first being a non-randomised pilot study, followed by a RCT. Only the second phase is included in this review. Authors could not provided additional data

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk
Allocation concealment (selection bias) Unclear risk

Information not available

Blinding (performance bias and detection bias) Low risk

Vials were prepared by the pharmacist labelled with a code. Since both study and placebo medications were clear solutions and dosage was calculated on basis of volume, the clinical staff was unaware of intervention

Incomplete outcome data (attrition bias) Low risk
Selective reporting (reporting bias) Low risk
Other bias Unclear risk

Pokriefka 1993

Methods

Single centre randomised, double-blind placebo-controlled study
Blinding of randomisation: unclear
Blinding of intervention: unclear
Complete follow-up: unclear. Withdrawals not mentioned
Blinding of outcome measurements: unclear

Participants

Ventilated infants
Inclusion or exclusion criteria not mentioned
Participants: ventilator-dependent premature infants with moderate to severe BPD
Flunisolide group n=8 and placebo group n=6

Interventions

Treatment with placebo or nebulised flunisolide 0.037 mg, 6 hourly for 28 days.Thereafter weaned over 11 days

Outcomes

No primary or secondary outcomes were mentioned, except for failure to extubate at latest reported time point Manuscripts states that there were changes in FiO2, dynamic compliance, airway resistance, PIP, peak expiratory flow rate, power of breathing without providing the data. Other outcomes were stated not to differ between both arms, but also without reporting data, such as hypertension, hyperglycaemia, glycosuria, adrenal suppression, leucocytosis, sepsis, retinopathy of prematurity, weight gain and mortality
Continuous data reported without standard deviations or standard errors

Notes

Only published abstract form. Authors did not respond to queries

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk
Allocation concealment (selection bias) Unclear risk

Information not available.

Blinding (performance bias and detection bias) Unclear risk
Incomplete outcome data (attrition bias) Low risk
Selective reporting (reporting bias) Low risk
Other bias Unclear risk

Characteristics of excluded studies

Abbasi 1993

Reason for exclusion

This was not a randomised controlled trial, the study compared inhalation with systemic corticosteroids, without a placebo arm

Beresford 2002

Reason for exclusion

RCT investigating inhalation corticosteroids for one year in preterm infants with established BPD
Excluded, all infants were randomised > 36 weeks PMA

Cloutier 1993

Reason for exclusion

Cross-over trial, not a randomised trial. The participants between 7 to 18 months of age were not initially randomised to the treatment or placebo arm. All the participants acted as their own controls during the first three months and then all began treatment for the second three months. Some participants were also being treated with systemic steroids during the time of study

Cole 1999a

Reason for exclusion

Randomised controlled trial including patients between 3th and 14th day PNA. Attempts to contact the original trialist for separate data in ventilated and non-ventilated patients failed

Dimitriou 1997

Reason for exclusion

This was a randomised controlled trial, comparing inhalation with systemic corticosteroids, without a placebo arm

Dunn 1989

Reason for exclusion

This is not a controlled trial, but a cross-over trial after one week of life, without a placebo arm. Futhermore, infants were included > 36 weeks PMA

Dunn 1992

Reason for exclusion

This is not a controlled trial but a cross-over trial after one week of life, without a placebo arm. Futhermore, infants were included > 36 weeks PMA

Eisenberg 1990

Reason for exclusion

This is not a controlled trial with a placebo arm. Only a few of the participants would have qualified for inclusion, as three treated on the basis of asthma and not BPD, and two had multiple congenital abnormalities. Several of the participants were treated with systemic steroids

Giffin 1994

Reason for exclusion

This is not a placebo-controlled trial

Inwald 1999

Reason for exclusion

This was a longitudinal study without randomisation, investigating early inhalation corticosteroids

Konig 1992

Reason for exclusion

This was not a controlled trial as it did not have a placebo arm. Some of the participants were treated with systemic steroids during trial. Futhermore, patients were included after 36 weeks PMA

Kovacs 1998

Reason for exclusion

Randomised controlled trial investigating systemic corticosteroids, followed by 18 days of nebulized budesonide in the treatment arm of the trial compared to placebo

Liu 1996

Reason for exclusion

This was not a controlled trial with a placebo arm

Ng 1998

Reason for exclusion

This was a randomised controlled trial starting inhalation corticosteroids within the first 24 hours of life

Pappagallo 1990

Reason for exclusion

This was not a controlled trial with a placebo arm

Parikh 2002

Reason for exclusion

Both treatment arm and placebo arm received systemic corticosteroids for 7 days, after which the treatment arm a tapering course of beclomethasone and the control group placebo inhalation

Pelkonen 2001

Reason for exclusion

Not a randomised study design. Older infants (school age) were included

Rajamani 1998

Reason for exclusion

Only in abstract form. Randomised controlled trial including patients from day 6 PNA. Attempts to contact the original trialist for separate data in ventilated and non-ventilated patients failed

Rozycki 2003

Reason for exclusion

This was a randomised controlled trial, which compared inhalation with systemic corticosteroids, without a placebo arm

Shah 2007

Reason for exclusion

This was a dose effect study, without a placebo arm

Suchomski 1996

Reason for exclusion

This was a randomised controlled trial, which compared inhalation with systemic corticosteroids, without a placebo arm

Thorson 1992

Reason for exclusion

This was not a controlled trial with a placebo arm

Yeh 2008

Reason for exclusion

This was a randomised controlled trial investigating early installation of budesonide using surfactant as a vehicle shortly after birth

Yuksel 1992

Reason for exclusion

Randomised controlled trial investigating inhalation corticosteroids to reduce recurrent respiratory symptoms in preterms less than two years of age. Excluded because all infants were randomised at > 36 weeks PMA

Characteristics of studies awaiting classification

  • None noted.

Characteristics of ongoing studies

  • None noted.

Additional tables

  • None noted.

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References to studies

Included studies

Arnon 1996

Published and unpublished data

Arnon S, Grigg J, Silverman M. Effectiveness of budesonide aerosol in ventilator-dependent preterm babies: a preliminary report. Pediatric Pulmonology 1996;21(4):231-5.

Denjean 1998

Published data only (unpublished sought but not used)

Denjean A, Paris-Llado J, Zupan V, Debillon T, Kieffer F, Magny JF, et al. Inhaled salbutamol and beclomethasone for preventing broncho-pulmonary dysplasia: a randomised double-blind study. European Journal of Pediatrics 1998;157(11):926-31.

Dugas 2005

Published and unpublished data

* 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(5):e566-72.

Dugas MA, Nguyen D, Frenette L, et al. Clinical outcome of inhaled fluticasone in moderate bronchopulmonary dysplasia. American Journal of Respiratory Critical Care Medicine 2003;167:A385.

Piedboeuf B, Dugas MA, Nguyen D, Frenette L, Proulx E, Lachance C. Clinical outcome of inhaled fluticasone in moderate bronchopulmonary dysplasia. In: Pediatric Research. Vol. 53. 2003:411A.

Giep 1996

Published data only (unpublished sought but not used)

* Giep T, Raibble P, Zuerlein T, Schwartz ID. Trial of beclomethasone dipropionate by metered-dose inhaler in ventilator-dependent neonates less than 1500 grams. American Journal of Perinatology 1996;13(1):5-9.

Schwartz ID, Giep T. Adrenal function in preterm infants treated with beclomethasone. Journal of Pediatrics 2000;136(6):851-2.

Jonsson 2000

Published and unpublished data

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(12):1449-55.

LaForce 1993

Published and unpublished data

LaForce WR, Brudno DS. Controlled trial of beclomethasone dipropionate by nebulization in oxygen- and ventilator-dependent infants. Journal of Pediatrics 1993;122(2):285-8.

Pappagallo 1998

Published data only (unpublished sought but not used)

* Pappagallo M, Abbasi S, Bhutani VK. Respiratory and systemic effects of inhaled dexamethasone on ventilator dependant preterm infants at risk for bronchopulmonary dysplasia. Indian Journal of Pediatrics 1998;65(2):273-82.

Pappagallo M, Bhutani V, Abbasi S. Nebulised steroid trial in ventilator-dependent preterm infants. Pediatric Research 1991;29:327A.

Pokriefka 1993

Published data only (unpublished sought but not used)

Pokriefka E, Mehdizadeh B, Rabbani A. Inhaled flunisolide in bronchopulmonary dysplasia. Pediatric Research 1993;33:341A.

Excluded studies

Abbasi 1993

Abbasi S, Silva W, Gerdes JS, Bhutani VK. Role of dexamethasone therapy for severe trachebronchial mucosal lesions in mechanically ventilated preterm infants. Pediatric Research 1993;33:198A.

Beresford 2002

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 Disease in Childhood. Fetal and Neonatal Edition 2002;87(1):F62-3.

Cloutier 1993

Cloutier M. Nebulized steroid therapy in bronchopulmonary dysplasia. Pediatric Pulmonology 1993;15(2):111-6.

Cole 1999a

Cole CH, Abbasi S, Dorkin H, Shah B, Demissie S, Mackinnon B, et al. Early inhaled glucocorticoid therapy for prevention of BPD: Assesment of growth, history, and pulmonary function at 6 months corrected age. Pediatric Research 1999;45:190A.

Cole CH, Colton T, Shah BL, Abbasi S, MacKinnon BL, Demissie S, et al. Early inhaled glucocorticoid therapy to prevent bronchopulmonary dysplasia. New England Journal of Medicine 1999;340(13):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. Journal of Pediatrics 1999;135(1):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(4):275-81.

Gupta GK, Cole CH, Abbasi S, Nielsen HC, Demissie S, Colton T, et al. Effect of beclomethasone therapy on tracheal aspirate interleukine-8 and interleukine-1 receptor antagonist in preterm ventilated infants at risk for bronchopulmonary dysplasia (BPD). Pediatric Research 1998;45:303A.

Dimitriou 1997

Dimitriou G, Greenough A, Giffin F, Kavadia V. Inhaled versus systemic steroids in chronic oxygen dependency of preterm infants. European Journal of Pediatrics 1997;156(1):51-5.

Dunn 1989

Dunn MS, Magnani L, Belaiche M. Inhaled corticosteroids in severe bronchopulmonary dysplasia. Pediatric Research 1989;25:213A.

Dunn 1992

Dunn M, Pandit P, Magnani L, Anaka R, Kirpalani H. Inhaled corticosteroids for neonatal chronic lung disease: a randomised, double-blind cross-over study. Pediatric Research 1992;31:201A.

Eisenberg 1990

Eisenberg J. Use of nebulized flunisolide in infants and children with asthma and bronchopulmonary dysplasia. American Review of Respiratory Disease 1990;141:A899.

Giffin 1994

Giffin F, Greenough A. A pilot study assessing inhaled budesonide in chronically oxygen-dependent infants. Acta Paediatrica 1994;83(6):669-71.

Inwald 1999

Inwald DP, Trivedi K, Murch SH, Costeloe K. The effect of early inhaled budesonide on pulmonary inflammation in infants with respiratory distress syndrome. European Journal of Pediatrics 1999;158(10):815-6.

Konig 1992

Konig P, Shatley M, Levine C, Mawhinney T. Clinical observations of nebulised flunisolide in infants and young children with asthma and bronchopulmonary dysplasia. Pediatric Pulmonology 1992;13(4):209-14.

Kovacs 1998

* 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(7):792-8.

Kovacs L, Davis M, Faucher DJ, Papageorgiou AN. Efficacy of early systemic and inhaled corticosteroid therapy in the prevention of chronic lung disease of prematurity. Pediatric Research 1996;39:337A.

Liu 1996

* Liu EA, Heldt GP. A trial of the safety of inhaled beclomethasone in ventilator-treated neonates. Journal of Pediatrics 1996;129(1):154-6.

Liu EA, Heldt GP. Effects of Inhaled Beclomethasone in Intubated Neonates: Phase 1 trial. Pediatric Research 1993;33:334A.

Ng 1998

Ng PC, Fok TF, Wong GW, Lam CW, Lee CH, Wong MY, et al. Pituitary-adrenal suppression in preterm, very low birth weight infants after inhaled fluticasone propionate treatment. Journal of Clinical Endocrinology and Metabolism 1998;83(7):2390-3.

Pappagallo 1990

Pappagallo M, Blondheim O, Bhutani VK, Abbasi S. Effect of inhaled dexamethasone in ventilator dependent preterm infants. Pediatric Research 1990;27:219A.

Parikh 2002

* Parikh NA, Locke RG, Chidekel A, Leef KH, Emberger J, Paul DA, et al. Effect of inhaled corticosteroids on inflammatory cytokines in preterm infants with evolving chronic lung Disease. In: Pediatric Research. Vol. 51. 2002:356A.

Parikh NA, Locke RG, Chidekel A, Leef KH, Emberger J, Paul DA, et al. Effect of inhaled corticosteroids on markers of pulmonary inflammation and lung maturation in preterm infants with evolving chronic lung disease. Journal of the American Osteopathic Association 2004;104(3):114-20.

Pelkonen 2001

Pelkonen AS, Hakulinen AL, Hallman M, Turpeinen M. Effect of inhaled budesonide therapy on lung function in schoolchildren born preterm. Respiratory Medicine 2001;95(7):565-70.

Rajamani 1998

Rajamani S, Dothey C, Super D, Martin J. Early inhaled beclomethasone does not alter the course of lung disease in very low birth weight infants (VLBW) at Risk of Bronchopulmonary Dysplasia (BPD). Pediatric Research 1998;45:219A.

Rozycki 2003

Rozycki HJ, Byron PR, Elliott GR, Carroll T, Gutcher GR. Randomized controlled trial of three different doses of aerosol beclomethasone versus systemic dexamethasone to promote extubation in ventilated premature infants. Pediatric Pulmonology 2003;35(5):375-83.

Shah 2007

Jangaard K, Vincer MJ, Dunn M, Asztalos E, Shah VS. Neurodevelopmental outcomes in ventilated preterm Infants < 1250 grams enrolled in a dose-ranging study assessing the effect of inhaled corticosteroids. In: E-PAS meeting 2009. 2009:4347.301.

* Shah VS, Jangaard K, Reilly M, Dunn M. Inhaled corticosteroids in ventilated preterm infants: An escalating dose-ranging study. In: E-PAS2007:7935.21. 2007.

Suchomski 1996

Suchomski S, Cummings J. Randomised trial of inhaled vs intravenous steroid in ventilator dependent preterm infants. In: Pediatric Research. Vol. 39. 1996:247A.

* Suchomski SJ, Cummings JJ. A randomized trial of inhaled versus intravenous steroids in ventilator-dependent preterm infants. Journal of Perinatology 2002;22(3):196-203.

Thorson 1992

Gal P, Diaz PR, Ransom JL, Carlos RQ, Thorson DW. Beclomethasone for treating premature infants with bronchopulmonary dysplasia. Journal of Pediatrics 1993;123(3):490-1.

* Thorson DW, Gal P, Diaz PR, Ransom JL, Weaver RL, Carlos RQ. Beclomethasone MDI for treating bronchopulmonary dysplasia in premature infants: a preliminary report. Pharmacotherapy 1992;12:261.

Yeh 2008

Yeh TF, Lin HC, Chang CH, Wu TS, Su BH, Li TC, et al. Early intratracheal instillation of budesonide using surfactant as a vehicle to prevent chronic lung disease in preterm infants: a pilot study. Pediatrics 2008;121(1098-4275 (Electronic), 5):e1310-8.

Yuksel 1992

Yuksel B, Greenough A. Randomised trial of inhaled steroids in preterm infants with respiratory symptoms at follow up. Thorax 1992;47(11):910-3.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Davis 2001

Davis PG, Henderson-Smart DJ. Intravenous dexamethasone for extubation of newborn infants. Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD002057. DOI: 10.1002/14651858.CD002057.

Doyle 2006

Doyle LW, Faber B, Callanan C, Freezer N, Ford GW, Davis NM. Bronchopulmonary dysplasia in very low birth weight subjects and lung function in late adolescence. Pediatrics 2006;118(1):108-13.

Fok 1996

Fok TF, Monkman S, Dolovich M, Gray S, Coates G, Paes B, et al. Efficiency of aerosol medication delivery from a metered dose inhaler versus jet nebulizer in infants with bronchopulmonary dysplasia. Pediatric Pulmonology 1996;21(5):301-9.

Halliday 2009

Halliday HL, Ehrenkranz RA, Doyle LW. Late (>7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD001145. DOI: 10.1002/14651858.CD001145.pub2.

Halliday 2010

Halliday HL, Ehrenkranz RA, Doyle LW. Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD001146. DOI: 10.1002/14651858.CD001146.pub3.

Ibrahim 2011

Ibrahim H, Sinha IP, Subhedar NV. Corticosteroids for treating hypotension in preterm infants. Cochrane Database of Systematic Reviews 2011, Issue 12. Art. No.: CD003662. DOI: 10.1002/14651858.CD003662.

Jobe 2001

Jobe AH, Bancalari E. Bronchopulmonary dysplasia. American Journal of Respiratory and Critical Care Medicine 2001;163(7):1723-9.

Pierce 1995

Pierce MR, Bancalari E. The role of inflammation in the pathogenesis of bronchopulmonary dysplasia. Pediatric Pulmonology 1995;19(6):371-8.

Shah 2003

Shah SS, Ohlsson A, Halliday HL, Shah VS. Inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD001969. DOI: 10.1002/14651858.CD001969.

Shah 2007a

Shah VS, Ohlsson A, Halliday HL, Dunn M. Early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD001969. DOI: 10.1002/14651858.CD001969.pub2.

Shah 2007b

Shah SS, Ohlsson A, Halliday HL, Shah VS. Inhaled versus systemic corticosteroids for the treatment of chronic lung disease in ventilated very low birth weight preterm infants. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD002058. DOI: 10.1002/14651858.CD002058.

Short 2007

Short EJ, Kirchner HL, Asaad GR, Fulton SE, Lewis BA, Klein N, et al. Developmental sequelae in preterm infants having a diagnosis of bronchopulmonary dysplasia: analysis using a severity-based classification system. Archives of Pediatrics and Adolescent Medicine 2007;161(11):1082-7.

Stoll 2010

Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126(3):443-56. [PubMed: 20732945]

Walsh 2005

Walsh MC, Morris BH, Wrage LA, Vohr BR, Poole WK, Tyson JE, et al. Extremely low birthweight neonates with protracted ventilation: mortality and 18-month neurodevelopmental outcomes. Journal of Pediatrics 2005;146(6):798-804.

Ward 2003

Ward MC, Sinn JKH. Steroid therapy for meconium aspiration syndrome in newborn infants. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD003485. DOI: 10.1002/14651858.CD003485.

Yoder 2009

Yoder BA, Harrison M, Clark RH. Time-related changes in steroid use and bronchopulmonary dysplasia in preterm infants. Pediatrics 2009;124(2):673-9.

Other published versions of this review

Lister 2000

Lister P, Iles R, Shaw BNj, Ducharme FM. Inhaled steroids for neonatal chronic lung disease. Cochrane Database of Systematic Reviews 2000, Issue 3. Art. No.: CD002311. DOI: 10.1002/14651858.CD002311.

Classification pending references

  • None noted.

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Data and analyses

1 Inhaled glucocorticoids versus placebo

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup"

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Mortality at 28 days PNA 2 51 Risk Ratio (M-H, Fixed, 95% CI) 3.00 [0.14, 65.90]
1.1.1 Ventilated infants 2 41 Risk Ratio (M-H, Fixed, 95% CI) 3.00 [0.14, 65.90]
1.1.2 Non-ventilated infants 1 10 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.2 Mortality at 36 weeks PMA 3 61 Risk Ratio (M-H, Fixed, 95% CI) 3.00 [0.35, 25.78]
1.2.1 Ventilated infants 3 51 Risk Ratio (M-H, Fixed, 95% CI) 3.00 [0.35, 25.78]
1.2.2 Non-ventilated infants 1 10 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.3 Mortality at hospital discharge 3 53 Risk Ratio (M-H, Fixed, 95% CI) 3.00 [0.35, 25.78]
1.3.1 Ventilated infants 3 43 Risk Ratio (M-H, Fixed, 95% CI) 3.00 [0.35, 25.78]
1.3.2 Non-ventilated infants 1 10 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.4 Bronchopulmonary dysplasia at 28 days PNA 1 30 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.72, 1.21]
1.4.1 Ventilated infants 1 20 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.61, 1.29]
1.4.2 Non-ventilated infants 1 10 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.71, 1.41]
1.5 Bronchopulmonary dysplasia at 36 weeks PMA 1 30 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.59, 1.70]
1.5.1 Ventilated infants 1 20 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.69, 1.90]
1.5.2 Non-ventilated infants 1 10 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.06, 3.91]
1.6 Combined outcome mortality and bronchopulmonary dysplasia at 28 days PNA 1 30 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.85, 1.18]
1.6.1 Ventilated infants 1 20 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.83, 1.20]
1.6.2 Non-ventilated infants 1 10 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.71, 1.41]
1.7 Combined outcome mortality or bronchopulmonary dysplasia at 36 weeks PMA 1 30 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.74, 1.63]
1.7.1 Ventilated infants 1 20 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [0.87, 1.75]
1.7.2 Non-ventilated infants 1 10 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.06, 3.91]
1.8 Failure to extubate day 7 5 79 Risk Ratio (M-H, Random, 95% CI) 0.85 [0.62, 1.18]
1.9 Failure to extubate day 14 2 27 Risk Ratio (M-H, Fixed, 95% CI) 0.36 [0.10, 1.33]
1.10 Failure to extubate at the latest reported moment 6 90 Risk Ratio (M-H, Random, 95% CI) 0.57 [0.27, 1.20]
1.11 Days of mechanical ventilation [days] 3 45 Mean Difference (IV, Random, 95% CI [days]) 2.79 [-3.47, 9.06]
1.12 Days of supplemental oxygen [days] 4 141 Mean Difference (IV, Fixed, 95% CI [days]) 0.57 [-5.92, 7.07]
1.12.1 Ventilated infants 4 100 Mean Difference (IV, Fixed, 95% CI [days]) 5.53 [-3.99, 15.05]
1.12.2 Non-ventilated infants 2 41 Mean Difference (IV, Fixed, 95% CI [days]) -3.74 [-12.63, 5.14]
1.13 Open label intravenous glucocorticoids 4 74 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.26, 1.00]
1.13.1 Ventilated infants 4 64 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.26, 1.00]
1.13.2 Non-ventilated infants 1 10 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.14 Sepsis (clinical suspected or culture proven) 5 107 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.50, 1.64]
1.14.1 Ventilated infants 5 97 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.44, 1.77]
1.14.2 Non-ventilated infants 1 10 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.36, 2.75]
1.15 Persistent ductus arteriosus 1 30 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.16, 6.20]
1.15.1 Ventilated infants 1 30 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.16, 6.20]
1.16 Hypertension (> 2 SD) 1 27 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.16.1 Ventilated infants 1 17 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.16.2 Non-ventilated infants 1 10 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.17 Necrotising enterocolitis 1 27 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.17.1 Ventilated infants 1 17 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.17.2 Non-ventilated infants 1 10 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.18 Intraventricular haemorrhage (any grade) 1 19 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.13, 2.82]
1.18.1 Ventilated infants 1 19 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.13, 2.82]
1.19 Days of hospitalisation [days] 1 18 Mean Difference (IV, Fixed, 95% CI [days]) -24.70 [-41.75, -7.65]
1.19.1 Ventilated infants 1 18 Mean Difference (IV, Fixed, 95% CI [days]) -24.70 [-41.75, -7.65]

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Figures

Figure 1

Refer to figure 1 caption below.

Figure 1. Flow of inclusion randomised controlled trials in different phases of search (Figure 1 description).

Sources of support

Internal sources

  • Department of Neonatology, AMC, Amsterdam, Netherlands
  • Department of Pediatric Clinical Epidemiology, AMC, Netherlands

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA
  • Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

Feedback

  • None noted.

Appendices

  • None noted.

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2012 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.