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Inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates

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Authors

Sachin S Shah1, Arne Ohlsson2, Henry L Halliday3, Vibhuti S Shah4

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


1Neonatal and Pediatric Intensive Care Services, Aditya Birla Memorial Hospital, Pune, India [top]
2Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada [top]
3Honorary Professor of Child Health, Queen's University, Belfast, UK [top]
4Associate Professor, Department of Paediatrics and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada [top]

Citation example: 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 2012, Issue 5. Art. No.: CD002058. DOI: 10.1002/14651858.CD002058.pub2.

Contact person

Sachin S Shah

Neonatal and Pediatric Intensive Care Services
Aditya Birla Memorial Hospital
Office no. 2, Arihant Building
39/32 Karve Road
411004 Pune
India

E-mail: sshahdoc@gmail.com

Dates

Assessed as Up-to-date: 23 June 2011
Date of Search: 23 June 2011
Next Stage Expected: 26 July 2013
Protocol First Published: Issue 2, 2000
Review First Published: Issue 1, 2003
Last Citation Issue: Issue 5, 2012

What's new

Date / Event Description
26 March 2012
New citation: conclusions not changed

Updated search in June 2011 found no new trials.
No changes to conclusions.

26 March 2012
Updated

This review updates the existing review "Inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates" published in the Cochrane Database of Systematic Reviews Shah 2003.

History

Date / Event Description
26 June 2008
Amended

Converted to new review format.

19 July 2007
Updated

This updates the review "Inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates" published in The Cochrane Library, Issue 1, 2003 (Shah 2003).

For this update two additional trials were identified, but both trials had to be excluded as the infants received systemic steroids prior to the use of inhaled steroids.

02 November 2002
New citation: conclusions changed

Substantive amendment

Abstract

Background

Chronic lung disease (CLD) remains an important cause of mortality and morbidity in preterm infants and inflammation plays an important role in its pathogenesis. The use of inhaled corticosteroids may modulate the inflammatory process without concomitant high systemic steroid concentrations and less risk of adverse effects.

Objectives

To determine the effect of inhaled versus systemic corticosteroids started within the first two weeks of life on preventing CLD in ventilated very low birth weight (VLBW) infants.

Search methods

Randomised and quasi-randomised trials were identified by searching The Cochrane Library, MEDLINE, EMBASE, CINAHL, reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies web site in June 2007.This search was updated in June 2011 and included additional searches of Clinical Trials, Controlled-Trials.com External Web Site Policy, and Web of Science.

Selection criteria

Randomised or quasi-randomised clinical trials comparing inhaled versus systemic corticosteroid therapy (regardless of the dose and duration of therapy) started in the first two weeks of life in VLBW infants receiving assisted ventilation.

Data collection and analysis

Outcomes including CLD at 28 days or 36 weeks postmenstrual age (PMA), mortality, the combined outcome of death or CLD at 28 days or 36 weeks PMA, other pulmonary outcomes and adverse effects were evaluated. All data were analysed using RevMan 5.1. Meta-analyses were performed using relative risk (RR), risk difference (RD), and mean difference (MD) with their 95% confidence intervals (CI). If RD was significant, the numbers needed to benefit (NNTB) or to harm (NNTH) were calculated.

Results

No new trials were identified in this update. Two trials qualified for inclusion in this review. The incidence of CLD at 36 weeks PMA was increased (of borderline statistical significance) in the inhaled steroid group [RR 1.45 (95% CI 0.99 to 2.11); RD 0.11 (95% CI 0.00 to 0.21), p = 0.05, one trial, n = 278]. The incidence of CLD at 36 weeks PMA among all survivors [RR 1.34 (95% CI 0.94 to 1.90); RD 0.11 (95% CI -0.02 to 0.24), one trial, n = 206], oxygen dependency at 28 days (two trials, n = 294), death by 28 days (two trials, n = 294) or 36 weeks PMA (two trials, n = 294) and the combined outcome of death or CLD by 28 days (two trials, n = 294) or 36 weeks PMA (one trial, n = 278) did not differ significantly between the groups. The duration of mechanical ventilation was significantly longer in the inhaled steroid group as compared to the systemic steroid group [typical MD 4 days (95% CI 0.2 to 8); two trials, n = 294] as was the duration of supplemental oxygen [typical MD 11 days (95% CI 2 to 20); two trials, n = 294].

The incidence of hyperglycaemia was significantly lower in the group receiving inhaled steroids [RR 0.52 (95% CI 0.39 to 0.71); RD -0.25 (95% CI -0.37 to -0.14); one trial, n = 278; NNTB 4 (95% CI 3 to 7) to avoid one infant experiencing hyperglycaemia]. The rate of patent ductus arteriosus was increased in the group receiving inhaled steroids [RR 1.64 (95% CI 1.23 to 2.17); RD 0.21 (95% CI 0.10 to 0.33); one trial, n = 278; NNTH 5 (95% CI 3 to 10)]. No information was available on long-term neurodevelopmental outcomes.

Authors' conclusions

This review found no evidence that early inhaled steroids confer important advantages over systemic steroids in the management of ventilator dependent preterm infants. Neither inhaled steroids nor systemic steroids can be recommended as a part of standard practice for ventilated preterm infants. Because they might have fewer adverse effects than systemic steroids, further randomised controlled trials of inhaled steroids are needed that address risk/benefit ratio of different delivery techniques, dosing schedules and long-term effects, with particular attention to neurodevelopmental outcome.

Plain language summary

Inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates

Preterm babies who require breathing support often develop chronic lung disease. It is thought that inflammation in the lungs may be part of the cause. Corticosteroid drugs when given orally or through a vein reduces this inflammation, but the use of corticosteroids is associated with serious side effects. Corticosteroids use has been associated with cerebral palsy (motor problem) and developmental delay. It is possible that inhaling steroids, so that the drug directly reaches the lung, may reduce the adverse effects. The review looked at trials that compared preterm babies who received steroids by inhalation to those who received steroids systemically (through a vein or orally) while they were receiving breathing support. There was no evidence that inhaling steroids prevented chronic lung disease or the number of days the baby needed breathing support and additional oxygen.

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Background

Description of the condition

Despite the availability of antenatal corticosteroids (Crowley 2002), surfactant replacement therapy (Yost 2002; Soll 2002) and other advances in neonatal intensive care, chronic lung disease (CLD) remains a substantial cause of mortality and morbidity (Horbar 1993; Schwartz 1994; Lee 2000) in preterm infants. The incidence of CLD has an inverse relationship with both birth weight and gestational age (Sinkin 1990; Lee 2000) and has increased partly due to improved survival of extremely low birth weight infants (Shaw 1993). Among survivors, CLD results in prolonged hospitalisation, an increased risk for rehospitalization and adverse neurodevelopmental outcome.

There is increasing evidence from cellular and biochemical research that inflammation plays an important role in the pathogenesis of CLD (Watts 1992; Speer 1993; Groneck 1994; Pierce 1995; Kotecha 1996; Watterberg 1994; Watterberg 1996). In many infants, the inflammatory reaction is evident shortly after birth suggesting that the process may have been triggered in utero (Watterberg 1996). Postnatally, a number of factors may also initiate or aggravate this inflammatory process. These include baro or volutrauma induced by mechanical ventilation, oxygen toxicity, infections and presence of patent ductus arteriosus (PDA). Interventions aimed at reducing or modulating the inflammatory process may reduce the incidence or severity of CLD.

Description of the intervention

Systemic corticosteroids due to their strong anti-inflammatory properties are being used clinically to reduce or limit the inflammatory process associated with development of CLD. The rationale for early administration of postnatal corticosteroids is that corticosteroids may prevent or minimise the inflammatory changes associated with mechanical ventilation and decrease the need for steroids later for the treatment of CLD. Several systematic reviews on the use of postnatal systemic corticosteroids [early (< 96 hours) and moderately early (7 to 14 days)] have demonstrated a reduction in CLD at 28 days and 36 weeks postmenstrual age (PMA) (Bhuta 1998; Halliday 1999; Arias-Camison 1999; Shah 2001; Halliday 2009; Halliday 2010). Marked heterogeneity of the doses and duration of dexamethasone therapy among the trials has been noted.

There is growing concern that the beneficial effects on the pulmonary system may be negated by increased risk of short and long-term adverse effects with corticosteroid therapy (Garland 1999; Ng 1993; Stark 2001; Soll 1999; Yeh 1997; Yeh 1998). Short-term serious complications with early systemic corticosteroid therapy include gastrointestinal haemorrhage and perforation, hyperglycaemia requiring insulin therapy and hypertension (Garland 1999; Soll 1999; Stark 2001). The potential effects on brain growth and neurodevelopment are the most alarming. Two follow up studies of early systemic corticosteroid administration have shown a two to four fold increase in neuromotor impairments in surviving dexamethasone treated infants as compared with controls at two years corrected age (Yeh 1998; Shinwell 2000). The meta-analysis shows increased risk of cerebral palsy in infants treated early with dexamethasone (Halliday 2010).

In statements released by the European Association of Perinatal Medicine (Halliday 2001b), American Academy of Pediatrics (CFN/AAP 2002) and Canadian Pediatric Society (FNC/CPS 2002) routine use of systemic dexamethasone for the prevention or treatment of CLD is not recommended. Outside the context of randomised controlled trials, the use of corticosteroids should be limited to exceptional clinical circumstances. This recommendation was based on concerns regarding short and long-term complications, especially cerebral palsy.

Theoretically, the use of inhaled corticosteroids may allow for beneficial effects on the pulmonary system without concomitant high systemic concentrations and less risk of adverse effects.

Why it is important to do this review

A variety of Cochrane reviews address the use of systemic or inhaled corticosteroids in the prevention or treatment of bronchopulmonary dysplasia or chronic lung disease.

These include reviews of the early use (< 8 days) of systemic postnatal corticosteroids to prevent chronic lung disease (Halliday 2010) as well as the late use (> 7 days) of systemic postnatal corticosteroids for chronic lung disease (Halliday 2009).

In addition, a variety of reviews address the use of inhaled corticosteroids in the prevention or treatment of chronic lung disease.

Shah and colleagues reviewed the effects of early administration of inhaled corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates (Shah 2007a). Onland and colleagues have reviewed the late use (greater than/or equal to 7 days) of inhaled corticosteroids to reduce bronchopulmonary dysplasia in preterm infants (Onland 2012).

Cochrane reviews have compared systemic and inhaled corticosteroids. Shah and colleagues have compared the use of inhaled versus systemic corticosteroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates (Shah 2003) and the use of inhaled versus systemic corticosteroids for the treatment of chronic lung disease in ventilated very low birth weight preterm infants (Shah 2007b).

The use of corticosteroids for other indications in neonates including intravenous dexamethasone to facilitate extubation (Davis 2001), corticosteroids for the treatment of hypotension (Ibrahim 2011) and corticosteroids for the treatment of meconium aspiration syndrome (Ward 2003) are reviewed.

The aim of this review is to assess the effectiveness of inhaled as compared to systemic corticosteroid therapy when administered to ventilated preterm infants within the first two weeks of life for prevention of CLD. This is an update of our review in 2003 (Shah 2003).

Objectives

The primary objective was to compare the effectiveness of inhaled versus systemic corticosteroids started within the first two weeks of life in preventing CLD (defined as requirement of supplemental oxygen at 36 weeks PMA) in ventilated infants with birth weight less than/or equal to 1500 grams or gestational age less than/or equal to 32 weeks.

Secondary objectives were to compare the effectiveness of inhaled versus systemic corticosteroids on:

  • Other indicators of CLD including:
    • requirement of supplemental oxygen at 28 days of age;
    • duration of requirement for supplemental oxygen;
    • duration of mechanical ventilation;
    • later requirement for systemic corticosteroid therapy;
    • change in pulmonary function tests (lung compliance and resistance).
  • The incidence of adverse events including:
    • mortality (expressed as early neonatal mortality < 7 days; neonatal mortality < 28 days and mortality prior to hospital discharge);
    • hyperglycemia (defined as blood glucose of > 10 mmol/l) during the period of intervention;
    • hypertension [defined as systolic or diastolic blood pressure > 2 standard deviations (SD) above the mean for infant's gestational and postnatal age] during the period of intervention (Zubrow 1995);
    • gastrointestinal haemorrhage (defined as presence of bloody nasogastric or orogastric aspirate);
    • gastrointestinal perforation (defined by presence of free air in peritoneal cavity on an abdominal x-ray);
    • necrotizing enterocolitis (NEC) (Bell's stage II and III) (Bell 1978);
    • intraventricular haemorrhage (IVH) any grade [defined as per Papile et al (Papile 1978)];
    • periventricular leukomalacia (PVL) (defined as cysts in periventricular area on US or CT scan);
    • retinopathy of prematurity (ROP) any grade based on international classification (ICROP 1984);
    • PDA defined by presence of clinical symptoms or signs and/or demonstration by echocardiography;
    • hypertrophic cardiomyopathy defined as thickening of interventricular septum and/or of the left ventricular wall on echocardiography;
    • sepsis defined by presence of clinical symptoms and signs of infection and a positive culture from normally sterile site (blood, CSF or urine);
    • pneumonia based on clinical and radiologic signs and a positive endotracheal tube aspirate culture;
    • growth (weight, length/height and head circumference) at 36 weeks PMA;
    • cataracts (defined by presence of opacities in the lens);
    • hypertrophy of the tongue;
    • nephrocalcinosis (defined by presence of echodensities in the medulla of the kidney on US) (Saarela 1999);
    • suppression of hypothalamic-pituitary-adrenal axis assessed by metyrapone or ACTH stimulation test.
  • Long-term neurodevelopmental outcome: Neurodevelopmental impairment was defined as presence of cerebral palsy and/or mental retardation [Bayley scales of infant development (BSID), Mental Developmental Index (MDI) < 70] and/or legal blindness (< 20/200 visual acuity) and/or deafness (aided or < 60 dB on audiometric testing) assessed at 18 to 24 months.

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Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi randomised clinical trials comparing inhaled versus systemic corticosteroid therapy (regardless of the dose and duration of therapy) starting in the first two weeks of life in very low birth weight preterm infants receiving assisted ventilation.

Types of participants

Preterm infants with birth weight less than/or equal to 1500 grams or gestational age less than/or equal to 32 weeks receiving assisted ventilation and postnatal age of less than two weeks.

Types of interventions

Inhaled versus systemic corticosteroid therapy.

Types of outcome measures

Primary outcomes
  • CLD at 36 weeks PMA:
    • amongst all randomised;
    • amongst survivors.
Secondary outcomes
  • Amongst all randomised:
    • CLD at 28 days of age;
    • death by 36 weeks PMA;
    • death by 28 days of age;
    • CLD or death by 28 days of age;
    • CLD or death by 36 weeks PMA;
    • failure to extubate within 14 days of starting treatment;
    • additional administration of systemic corticosteroids (during or beyond study period) at the discretion of the attending clinician;
    • duration of requirement for supplemental oxygen;
    • duration of mechanical ventilation;
    • change in pulmonary function tests (lung compliance and resistance);
    • adverse events: sepsis, hyperglycaemia, hypertension, gastrointestinal bleeding or perforation, NEC, IVH, PVL, cataracts, ROP, hypothalamic-pituitary-adrenal suppression and PDA.
  • Amongst survivors:
    • CLD at 28 days of age.
  • Long-term neurodevelopmental outcome: Neurodevelopmental impairment was defined as presence of cerebral palsy and/or mental retardation [Bayley scales of infant development (BSID), Mental Developmental Index (MDI) < 70] and/or legal blindness (< 20/200 visual acuity) and/or deafness (aided or < 60 dB on audiometric testing) assessed at 18 to 24 months.

Search methods for identification of studies

See: Collaborative Review Group search strategy

Randomised controlled trials comparing inhaled versus systemic corticosteroid therapy in preterm infants were identified from MEDLINE (1966 to June 2007) using MeSH headings: infant-newborn, chronic lung disease, bronchopulmonary dysplasia, anti-inflammatory agents, steroids; dexamethasone, administration, inhalation; aerosols, budesonide, beclomethasone dipropionate, flunisolide and fluticasone propionate.

Other databases were searched including: Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2007), EMBASE (1980 to June 2007), CINAHL (1982 to June 2007), reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies web site (1990 to April 2007). No language restrictions were applied. For the original review, the articles were screened by the four review authors (SS, AO, HH, VS) to identify studies eligible for inclusion in the review. For this update additional electronic searches of ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy and Web of Science were conducted. For this update, three review authors (VS, AO, SS) conducted the literature search and reviewed the articles obtained.

This search was update in June 2011. See: Appendix 1

Data collection and analysis

We used the methods of the Cochrane Neonatal Review Group for data collection and analysis.

Selection of studies

We included all randomised and quasi-randomised controlled trials that fulfilled the selection criteria described in the previous section. The review authors independently reviewed the results of the updated search and selected studies for inclusion. We resolved any disagreement by discussion.

Data extraction and management

For each trial, information was sought regarding the method of randomisation, blinding and reporting of all outcomes for all the infants enrolled in the trial. Data from primary investigator were obtained for unpublished trials or when published data were incomplete. Retrieved articles were assessed and data abstracted independently by four review authors (SS, AO, HH, VS). The update of the review was performed by three review authors (VS, AO, SS).

For each study, final data was entered into RevMan by one review author and then checked for accuracy by a second reviewer author. We resolved discrepancies through discussion.

We attempted to contact authors of the original reports to provide further details when information regarding any of the above was unclear.

Assessment of risk of bias in included studies

The review authors independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion.

The methodological quality of the studies was assessed using the following criteria:

  • Sequence generation (checking for possible selection bias): For each included study, we categorized the method used to generate the allocation sequence as:
    • low risk (any truly random process e.g. random number table; computer random number generator);
    • high risk (any non random process e.g. odd or even date of birth; hospital or clinic record number);
    • unclear risk.
  • Allocation concealment (checking for possible selection bias): For each included study, we categorized the method used to conceal the allocation sequence as:
    • low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
    • high risk (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
    • unclear risk.
  • Blinding (checking for possible performance bias): For each included study, we categorized the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or classes of outcomes. We characterised the methods used for blinding as:
    • low risk, high risk or unclear risk for participants;
    • low risk, high risk or unclear risk for personnel;
    • low risk, high risk or unclear risk for outcome assessors.
  • Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations): For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorized the methods as:
    • low risk (< 20% missing data);
    • high risk (greater than/or equal to 20% missing data);
    • unclear risk
  • Selective reporting bias: For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:
    • low risk (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
    • high risk (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
    • unclear risk.
  • Other sources of bias: For each included study, we described any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:
    • low risk ;high risk ;unclear risk.
  • Overall risk of bias.
    • We made explicit judgements regarding whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it is likely to impact on the findings.If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses (see 'Sensitivity analysis' below).

Measures of treatment effect

We performed statistical analyses using Review Manager software (RevMan 2011). Dicotomous data were analysed using relative risk (RR), risk difference (RD) and the number needed to benefit (NNTB) or number needed to harm (NNTH). The 95% Confidence interval (CI) were reported on all estimates.

We analysed continuous data using weighted mean difference (WMD) or the standardized mean difference to combine trials that measure the same outcome but use different methods.

Unit of analysis issues

For clinical outcomes such as episodes of sepsis, we analysed the data as proportion of neonates having one or more episodes.

Dealing with missing data

For included studies, levels of attrition were noted. The impact of including studies with high levels of missing data in the overall assessment of treatment effect was explored by using sensitivity analysis.

All outcomes analyses were on an intention to treat basis i.e. we included all participants randomised to each group in the analyses. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity

We examined heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I-squared statistic. If noted, we planned to explore the possible causes of statistical heterogeneity using pre-specified subgroup analysis (for example, differences in study quality, participants, intervention regimens, or outcome assessments).

Assessment of reporting biases

We planned to assess possible publication bias and other biases using symmetry/asymmetry of funnel plots.

For included trials that were recently performed (and therefore prospectively registered), we planned to explore possible selective reporting of study outcomes by comparing the primary and secondary outcomes in the reports with the primary and secondary outcomes proposed at trial registration, using the web sites ClinicalTrials.gov and Controlled-Trials.com External Web Site Policy. If such discrepancies were found, we planned to contact the primary investigators to obtain missing outcome data on outcomes pre-specified at trial registration.

Data synthesis

Where meta-analysis was judged to be appropriate, the analysis was done using Review Manager software (RevMan 2011), supplied by the Cochrane Collaboration. We used the Mantel-Haenszel method for estimates of typical relative risk and risk difference. No continuous outcomes were included in this review. We planned to analyse continuous measures using the inverse variance method, if included.

We used the fixed effect model for all meta-analyses.

Subgroup analysis and investigation of heterogeneity

Groups were analysed based on "all randomised" and "survivors only".

Sensitivity analysis

We planned sensitivity analyses for situations where this might affect the interpretation of significant results (for example, where there is risk of bias associated with the quality of some of the included trials or missing outcome data). None were thought necessary in this review.

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Results

Description of studies

Results of the search

Five trials comparing inhaled versus systemic corticosteroids in prevention of CLD were identified, of which three were excluded. No new trials were identified in the 2011 update.

Included studies

Two trials qualified for inclusion in this review: Groneck et al (Groneck 1999) and Halliday et al (Halliday 2001a). Both studies have been published as full text articles. Details of each study are given in the table 'Characteristics of Included Studies'. Although both studies attempted to include infants thought to be at risk of developing CLD, the inclusion criteria, the intervention type (dose and type of inhaled steroid) and duration of therapy varied between the two studies.

Groneck et al (Groneck 1999): This was a open comparative trial which enrolled preterm infants < 1200 grams while they were mechanically ventilated and had fractional inspired oxygen (FiO2) requirement > 0.3 on the third day of life. Sixteen patients were enrolled into the study and were alternatively allocated to treatment with inhaled beclomethasone or systemic dexamethasone. Due to poor clinical results (CLD in six of seven patients), alternate allocation to inhaled steroids was stopped for ethical reasons after inhaled steroid treatment of seven patients. Thus, seven patients were treated with inhaled steroids and nine received systemic steroids. Inhaled beclomethasone was given from day three to day 28 of life. It was administered by an aerochamber into the ventilatory circuit at a dose of 3x2 puffs of 250 µg (=1.5 mg/day). After extubation, inhalation therapy was continued by face mask, and the aerochamber was connected to a ventilation bag. No systemic steroids were given to infants treated with inhaled steroids during the first month of life. Systemic dexamethasone was given at a starting dose of 0.5 mg/kg/day for three days, starting between days 11 to 13; thereafter the dose was gradually tapered over 10 to 28 days, according to clinical status of the infant. Duration of systemic steroids was at the discretion of attending physician. Primary outcome was assessment of lung inflammation and lung permeability. Other outcome measures were days on mechanical ventilation, days on supplemental oxygen and CLD (oxygen dependency and radiological abnormalities on day 28). Pulmonary inflammation and lung permeability were assessed by analysing inflammatory mediators (interleukin -8, elastase alpha -1 proteinase inhibitor, free elastase, secretory component for IgA and albumin) in tracheal aspirates on day 10 (before starting dexamethasone) and day 14 (three days after starting dexamethasone). The baseline characteristics were similar between the two groups.

Halliday et al (Halliday 2001a): This trial enrolled infants born at < 30 week gestation, postnatal age < 72 hours and needing mechanical ventilation and FiO2 >30%. Infants of 30 and 31 weeks could also be included if they needed FiO2 > 50%. Infants with lethal congenital anomalies, severe IVH (grade 3 or 4) and proven systemic infection before entry were excluded from the trial. The trial was designed to evaluate the effectiveness of early (< 72 hours) and delayed (> 15 days) administration of systemic dexamethasone and inhaled budesonide. Infants were randomly allocated to one of four treatment policies in a factorial design: early (< 72 hours) dexamethasone, early budesonide, delayed selective (> 15 days) dexamethasone and delayed selective budesonide. Only the groups allocated to early budesonide or early dexamethasone are included in this review. Budesonide was administered by metered dose inhaler and a spacing chamber in a dose of 400 µg/kg twice daily for 12 days. Dexamethasone was given intravenously (IV) or orally (PO) in a tapering course beginning with 0.5 mg/kg/day in two divided doses for three days reducing by half every three days for a total of 12 days of therapy. One hundred and forty-three infants were randomised to the early budesonide group while 135 were randomised to the early dexamethasone group. Out of 143 infants randomised to early budesonide, 53 received full course, 87 received partial course, while three did not receive budesonide. Out of 135 infants randomised to early dexamethasone, 53 received a full course, 76 received a partial course while six infants did not receive dexamethasone. The primary outcome was death or oxygen dependency at 36 weeks. Secondary outcome measures included death or major cerebral abnormality, duration of oxygen treatment, duration of assisted ventilation, duration of hospitalisation, death or oxygen dependency at 28 days and complications of preterm birth. An intention to treat analysis was performed. Additional data were obtained from the authors for the outcomes of duration of ventilation and duration of supplemental oxygen (expressed as mean and SD) .

Excluded studies

Three trials were excluded from this systematic review: The study by Dimitriou et al (Dimitriou 1997) was excluded as the investigators included non-ventilator dependent patients in their study and the age of commencement of treatment varied from five to 118 days of life. The study by Kovács et al (Kovacs 1998) was excluded as the participants received systemic dexamethasone initially followed by inhaled steroids while the control group received normal saline systemically and then by nebulization. The trial of Parikh et al (Parikh 2004) was excluded as all study participants received systemic dexamethasone for seven days and then randomised to receive either inhaled beclomethasone or placebo. See 'Characteristics of excluded studies' table.

Risk of bias in included studies

Groneck et al (Groneck 1999) - Infants were alternately allocated to treatment with inhaled beclomethasone or systemic dexamethasone. Alternate allocation to inhaled steroids was stopped after treatment of seven neonates due to poor clinical results. The intervention was not blinded. Outcome data were presented for all 16 babies enrolled in the study. Outcome measures were not blinded.

Halliday et al (Halliday 2001a) - This was a multicentre randomised controlled trial involving 47 centres. The intervention was not blinded in the majority of centres. However, in 11 centres the trial was conducted double blind, and in these centres placebo metered dose inhalers and intravenous saline were used to mask treatment allocation. Randomisation was performed by telephoning the central randomisation centre. After identifying an eligible infant, the clinician telephoned the randomisation centre to enrol the infant and determine the treatment group. Outcomes have been reported for all infants enrolled in the study. Outcome assessments were not blinded. An intention to treat analysis was performed. Comparisons were also made for primary outcome variables between the centres observing double blind strategy and other centres.

Effects of interventions

INHALED VERSUS SYSTEMIC STEROIDS AMONG ALL RANDOMISED (Comparison 1):

PRIMARY OUTCOMES:
CLD at 36 weeks PMA (Outcome 1.1):

One trial enrolling 278 neonates reported on the incidence of CLD at 36 weeks PMA among all randomised (Halliday 2001a). There was an increase (of borderline statistical significance) in the incidence of CLD by 36 weeks PMA in the inhaled steroid group [RR 1.45 (95% CI 0.99 to 2.11); RD 0.11 (95% CI 0.00 to 0.21), p = 0.05].

SECONDARY OUTCOMES:
CLD at 28 days of age (Outcome 1.2):

Two trials enrolling 294 neonates reported on the incidence of CLD at 28 days of age among all randomised. There was no statistically significant difference in the incidence of CLD at 28 days [typical RR 1.21 (95% CI 0.98 to 1.48), RD 0.11 (95% CI -0.01 to 0.22)]. There was moderate heterogeneity for this outcome for RR (p = 0.06, I2 = 71.7 %) and for RD (p = 0.005, I2 = 87.3).

Death by 28 days (Outcome 1.3):

Two trials enrolling 294 neonates reported on the incidence of death by 28 days among all randomised. There was no statistically significant effect on death by 28 days and the typical estimates from the meta-analysis were RR 0.80 (95% CI 0.51 to 1.25), RD -0.05 (95% CI -0.14 to 0.05)]. Test for heterogeneity not applicable for RR; there was no heterogeneity for RD (p = 0.67, I2 = 0%).

Death by 36 weeks PMA (Outcome 1.4):

Two trials enrolling 294 neonates reported on the incidence of death by 36 weeks PMA among all randomised. No statistically significant effect on mortality by 36 weeks PMA was noted [typical RR 0.83 (95% CI 0.56 to 1.23), typical RD -0.05 (95% CI -0.15 to 0.05)]. There was no statistically significant heterogeneity for this outcome for RR (p = 0.33, I2 = 0%) nor for RD (p = 0.21, I2 = 36%).

Death or CLD by 28 days (Outcome 1.5):

Two trials enrolling 294 neonates reported on the incidence of death or CLD by 28 days among all randomised. There was no statistically significant difference between the groups for the combined outcome of CLD or death by 28 days. The typical estimate was RR 1.05 (95% CI 0.93 to 1.20), RD 0.04 (95% CI -0.06 to 0.13)]. There was statistically significant heterogeneity for this outcome for RR (p = 0.03, I2 = 78%) for RD (p = 0.001, I2 = 90.1%).

Death or CLD by 36 weeks PMA (Outcome 1.6):

One trial enrolling 278 neonates reported on this outcome (Halliday 2001a). There was no statistically significant difference noted for the combined outcome of CLD or death by 36 weeks PMA [RR 1.09 (95% CI 0.88 to 1.35), RD 0.05 (95% CI -0.07 to 0.16)].

Duration mechanical ventilation (days) (Outcome 1.7):

Two trials enrolling 294 neonates reported on the duration of mechanical ventilation. The duration of mechanical ventilation was statistically significantly longer in the inhaled steroid group as compared to the systemic steroid group (typical WMD 3.89 days, 95% CI 0.24 to 7.55); n = 294). There was no statistically significant heterogeneity for this outcome (p=0.32, I2 = 0.0%).

Duration of supplemental oxygen (days) (Outcome 1.8):

Two trials enrolling 294 neonates reported on this outcome. The duration of supplemental oxygen was statistically significantly higher in the inhaled steroid group as compared to the systemic steroid group (typical WMD 11 days, 95% CI 2 to 20). There was no statistically significant heterogeneity for this outcome (p=0.22, I2 = 33.5 %).

Pneumothorax (Outcome 1.9):

One trial enrolling 278 neonates reported on the incidence of pneumothorax (Halliday 2001a). There was no statistically significant difference in the incidence of pneumothorax (RR 0.88, 95% CI 0.56 to 1.39; RD -0.03, 95% CI -0.12 to 0.07).

Other air leaks (Outcome 1.10):

One trial enrolling 278 neonates reported on the incidence of other air leaks (Halliday 2001a). There was no statistically significant difference in the incidence of other air leaks (RR 1.05, 95% CI 0.58 to 1.90; RD 0.01 95% CI -0.07 to 0.09).

Pulmonary haemorrhage (Outcome 1.11):

One trial enrolling 278 neonates reported on the incidence of pulmonary haemorrhage (Halliday 2001a). There was no statistically significant difference in the incidence of other air leaks between groups (RR 1.02, 95% CI 0.48 to 2.16; RD 0.00 95% CI -0.07 to 0.07).

Hyperglycemia (Outcome 1.12):

One trial enrolling 278 neonates reported on the incidence of hyperglycaemia (Halliday 2001a). A statistically significant decrease in the incidence of hyperglycaemia was noted in the inhaled steroid group (RR 0.52, 95% CI 0.39 to 0.71; RD -0.25, 95% CI -0.37 to -0.14). The NNTB was 4.0 (95% CI 3 to 7).

Hypertension (Outcome 1.13):

One trial enrolling 278 neonates reported on the incidence of hypertension (Halliday 2001a). There was no statistically significant difference in the incidence of hypertension between groups (RR 0.76, 95% CI 0.44 to 1.29; RD -0.05, 95% CI -0.13 to 0.04).

Necrotizing enterocolitis (Outcome 1.14):

One trial enrolling 278 neonates reported on the incidence of NEC (Halliday 2001a). There was no statistically significant difference in the incidence of NEC between groups (RR 1.42, 95% CI 0.60 to 3.36; RD 0.02, 95% CI -0.04 to 0.09).

Gastrointestinal haemorrhage (Outcome 1.15):

One trial enrolling 278 neonates reported on the incidence of gastrointestinal haemorrhage (Halliday 2001a). There was no statistically significant difference in the incidence of gastrointestinal haemorrhage between groups (RR 0.40, 95% CI 0.16 to 1.02; RD -0.06, 95%CI -0.12 to 0.00 ).

Gastrointestinal perforation (Outcome 1.16):

One trial enrolling 278 neonates reported on the incidence of gastrointestinal perforation (Halliday 2001a). There was no statistically significant difference in the incidence of gastrointestinal perforation between groups (RR 0.16, 95% CI 0.02 to 1.29; RD -0.04, 95% CI -0.07 to 0.00).

Patent ductus arteriosus (Outcome 1.17):

One trial enrolling 278 neonates reported on the incidence of PDA (Halliday 2001a). There was a statistically significant increase in the rate of PDA (RR 1.64, 95% CI 1.23 to 2.17; RD 0.21, 95% CI 0.10 to 0.33) in the group receiving inhaled steroids. The NNTH was 5 (95% CI 3 to 10).

Retinopathy of prematurity - any stage (Outcome 1.18):

One trial enrolling 278 neonates reported on the incidence of ROP (any stage) (Halliday 2001a). There was no statistically significant difference in the incidence of ROP (any stage) between the two groups (RR 1.11, 95% CI 0.72 to 1.71; RD 0.02 95% CI -0.08 to 0.12).

Retinopathy of prematurity greater than/or equal to stage 3 (Outcome 1.19):

One trial enrolling 278 neonates reported on the incidence of ROP (greater than/or equal to stage 3) (Halliday 2001a). There was no statistically significant difference in the incidence of ROP greater than/or equal to stage 3 (RR 1.32, 95% CI 0.43 to 4.06; RD 0.01, 95% CI -0.04 to 0.06).

Sepsis (Outcome 1.20):

One trial enrolling 278 neonates reported on the outcome (Halliday 2001a). There was no statistically significant difference in the incidence of culture proven sepsis between groups (RR 1.04, 95% CI 0.73 to 1.49; RD 0.01, 95% CI -0.10 to 0.12).

Infants with free elastase (inflammatory mediator) in tracheal aspirate on day 14 (Outcome 1.21):

One trial enrolling 16 neonates reported on this outcome (Groneck 1999). There was no statistically significant difference in the number of infants with detectable free elastase in tracheobronchial aspirate fluid between groups (RR 8.75, 95% CI 0.52 to 145.86; RD 0.43, 95% CI 0.06 to 0.80).

INHALED VERSUS SYSTEMIC STEROIDS AMONG SURVIVORS (Comparison 2):

PRIMARY OUTCOME:
CLD at 36 weeks PMA (Outcome 2.1):

One trial enrolling 206 neonates reported on this outcome among survivors. There was no statistically significant difference in the incidence of CLD at 36 weeks among survivors [RR 1.34 (95% CI 0.94 to 1.90); RD 0.11 (95% CI -0.02 to 0.24)].

SECONDARY OUTCOMES:
CLD at 28 days of age (Outcome 2.2):

Two trials enrolling 233 neonates reported on this outcome. There was no statistically significant difference in the incidence of CLD at 28 days among survivors [typical RR 1.14 (95% CI 0.96 to 1.34), typical RD 0.09 (95% CI -0.02 to 0.21)]. There was statistically significant heterogeneity for this outcome for RR (p=0.04, I2 = 75.4 %) and for RD (p = 0.004, I2 = 88.2%).

No relevant data for the following outcomes were available for analyses: long-term neurodevelopmental outcome, PVL, measurement of pulmonary functions, pneumonia, growth, nephrocalcinosis, cataracts, hypertrophy of tongue, hypertrophic cardiomyopathy and suppression of hypothalamic-pituitary-adrenal axis.

Discussion

This review demonstrated that early use of inhaled steroids is associated with a borderline increase in the incidence of CLD at 36 weeks PMA as compared to the early use of systemic steroids. This review found no evidence that inhaled steroids decrease the incidence of CLD at 28 days or 36 weeks PMA or the combined outcome of CLD or mortality at 28 days or 36 weeks, as compared to systemic steroids. Inhaled steroid use was associated with increase in the incidence of PDA, longer duration of mechanical ventilation and longer duration of supplemental oxygen.

Systematic reviews (Shah 2001; Halliday 2010) of early postnatal systemic corticosteroids (less than 7 days of age) versus placebo or no treatment have shown a significant decrease in the incidence of CLD and the combined outcome of CLD and death at 28 days and 36 weeks PMA. A borderline increased risk of PVL was noted in the infants who received dexamethasone. In the reviews of systemic postnatal corticosteroid therapy administered after seven days of age (Shah 2001; Halliday 2009) a decrease in the combined outcome of CLD at 36 weeks and mortality was shown. There was no evidence that the duration of hospitalisation or need for supplemental oxygen was decreased (Shah 2001). Early administration of inhaled steroids in the first two weeks of life to ventilated very low birth weight infants showed no evidence of decrease in the incidence of CLD (Shah 2007a).

One of the intriguing observations in the study of Halliday 2001a was the statistically significant decrease in the incidence of PDA in infants treated with systemic as compared with inhaled steroids. Use of antenatal corticosteroids has shown to decrease the PDA incidence (Aghajafari 2001). Also, early postnatal dexamethasone therapy in preterm infants with RDS has been shown to decrease the incidence of PDA (Yeh 1997; Halliday 2010). Heyman et al proposed that closure of PDA could be achieved by dexamethasone (Heyman 1990). Glucocorticoids may have an effect on PDA through an interference in prostaglandin synthesis or through a reduction in sensitivity of ductal muscle to prostaglandin E2 (Clyman 1981; Clyman 1987).

In the current review, hyperglycaemia was less common in the inhaled steroid group. There was a decrease in the incidence of gastrointestinal haemorrhage and gastrointestinal perforation in the inhaled steroid group which was of borderline statistical significance. There were no significant differences in incidences of other adverse effects between the groups. Overall, it would appear that inhaled steroids are less likely to have short-term adverse effects than systemic steroids. However, data from long-term follow-up studies are needed before use of inhaled steroids can be said to be preferable to systemic steroids. Early use of either inhaled or systemic steroids cannot presently be recommended for the prevention of CLD in the preterm infant.

Another major concern with studies of inhaled steroid therapy is the uncertainty regarding drug delivery and deposition in the oropharynx and in the peripheral airways. Numerous factors affect drug delivery and deposition including the number of particles in the respirable range, the delivery technique (use of MDI with or without a spacer, nebulizers (jet or ultrasonic) and the presence or absence of an endotracheal tube. Previous workers have shown that the amount of aerosol delivery varies from 0.4% to 14% based on the technique used (Arnon 1992; Grigg 1992; O'Callaghan 1992). Some studies have suggested that the delayed onset of activity (LaForce 1993; Dimitriou 1997) and similar risk profile of inhaled steroids (Shah 2003b) are consistent with their effects being secondary to systemic absorption.

Identification of an effective dose of inhaled steroids and improvements in drug delivery systems guaranteeing selective delivery in the alveoli and smaller airways may improve the clinical efficacy and decrease the side-effect profile of inhalational steroids.

This review found no evidence that early inhaled steroids confer important advantages over systemic steroids in the management of ventilated preterm infants. Since systemic steroids, especially dexamethasone given early (< 4 days), are associated with an increase in cerebral palsy (Halliday 2010), they cannot be recommended for routine use in preterm infants. Further studies need to be performed before early steroids, either inhaled or systemic, can be recommended as safe for prevention of CLD in preterm infants. Follow-up studies are extremely important, and all surviving infants in the OSECT study (Halliday 2001a) are currently being traced and examined by paediatricians and psychologists.

Authors' conclusions

Implications for practice

No new trials meeting inclusion criteria were identified for this update. The use of inhaled steroids, as well as the use of systemic steroids (Halliday 2010), cannot be recommended as a part of standard practice for ventilated preterm infants to prevent CLD.

Implications for research

Further randomised controlled trials are needed that address the risk/benefit ratio of different delivery techniques, dosing schedules and long-term effects of inhaled steroids, with particular attention to neurodevelopmental outcome.

Acknowledgements

We thank Prof. H.L. Halliday and Dr. Chris Patterson for providing additional data for the infants included in the 'OSECT' trial.

Contributions of authors

Sachin Shah (SS): performed literature search, abstraction and analysis of data, writing of the original review.
Arne Ohlsson (AO): writing of the protocol, literature search, abstraction and analysis of data and editing of the original and updated review.
Henry Halliday (HH): writing of protocol, literature search, abstraction and analysis of data and editing of the review.
Vibhuti Shah (VS): writing of protocol, literature search, abstraction and analysis of data and editing of the original and updated review.

The searches for the 2011 update were completed by VS, AO and SS. The administrative update was conducted centrally by the Cochrane Neonatal Review Group staff (Yolanda Montagne, Diane Haughton, and Roger Soll). This update was reviewed and approved by VS, AO, SS and HH.

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Groneck 1999

Methods

Open comparative study.

Blinding of randomisation: No.
(alternate allocation)

Blinding of intervention : No

Blinding of outcome measurement : No

Complete follow up: Yes

Participants

Preterm neonates < 1200 grams, mechanically ventilated and requiring FiO2 > 30% on third day of life.

30 infants were eligible for the study; 3 died within first 3 days of life, 5 did not receive mechanical ventilation, 3 extubated within first 3 days and 3 ventilated babies had FiO2 requirement < 30%.
16 patients entered into the study.

Demographic data:
Values presented as mean (range) or as numbers (percentage)

Inhaled steroid group
n = 7
Birth weight (grams): 800 (500 - 1020)
Gestational age (weeks): 26.1
(25 - 28)
Male/female ratio: 3/4
Maternal steroids: 5
Maximum oxygenation index on day 1: 9.5 (5.6 - 19.6)

Systemic steroid group
n = 9
Birth weight (grams): 847 (660 - 1030)
Gestational age (weeks): 26.2 (25 - 28)
Male/female ratio: 3/6
Maternal steroids: 7
Maximum oxygenation index on day 1: 10.5 (5.3 - 16.0)

Interventions

Inhaled beclomethasone (Sanasthmax, Glaxo, Bad Oldesloe, Germany) was given from day 3 to day 28. It was administered by an Aerochamber (Trudell Medical, London, Ontario, Canada) into the ventilatory circuit at a dose of 3x2 puffs of 250 µg. After extubation, inhalation therapy was continued by face mask, and the aerochamber was connected to a ventilation bag.

7 infants received inhaled beclomethasone while 9 received systemic dexamethasone.

No systemic steroids were given to infants treated with inhaled steroids during the first month. Systemic dexamethasone was given thereafter if the infant was still on mechanical ventilation.

Systemic dexamethasone was given at starting dose of 0.5mg/kg/day for 3 days; thereafter the dose was gradually tapered over 10 or 28 days depending on the clinical status of the baby. Duration of treatment was at the discretion of attending physician.

Outcomes

Pulmonary inflammation (assessed by analysing levels of inflammatory mediators like free elastase, secretory component of IgA albumin, interleukin-8 and elastase alpha-1 proteinase inhibitor) in tracheal aspirates. Other outcome variables were days on mechanical ventilation, days on supplemental oxygen and CLD (oxygen dependency and radiological abnormalities on day 28).

Notes

Due to poor clinical results (CLD in 6 of 7 patients), allocation to inhaled steroids was stopped for ethical reasons after treatment of 7 neonates.

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

Open comparative study

Allocation concealment (selection bias) High risk

Open comparative study

Blinding of randomisation: No.
(alternate allocation)

Blinding (performance bias and detection bias) High risk

Blinding of intervention : No

Blinding of participants and personnel (performance bias) High risk

Blinding of intervention : No

Blinding of outcome assessment (detection bias) High risk

Blinding of outcome measurement : No

Incomplete outcome data (attrition bias) Low risk

Complete follow up: Yes

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

Halliday 2001a

Methods

Multicentre, randomised open study.

Blinding of randomisation: Yes.

Blinding of intervention : Not in all centres. 11 centres : Yes, 36 centres : No

Blinding of outcome measurement : No

Complete follow up : Yes

Participants

570 infants from 47 neonatal intensive care units (United Kingdom, Ireland, Canada, Sweden, Norway, Poland, Switzerland, Greece and UAE and Singapore) were enrolled. Inclusion criteria: Gestational age < 30 weeks, postnatal age < 72 hours, need for mechanical ventilation, inspired FiO2 > 30%. Infants of 30-31 weeks could also be included if they needed > 50% FiO2.

Demographic data: values presented as mean (SD) or as appropriate

Budesonide group
n = 143
Gestational age (weeks): 27.3 (SD 1.8)
Birth weight (grams): 1010 (284)
Gender (female/male) (number of infants): 79/64
Antenatal steroids (number and percentage): 88 (62%)
Surfactant treatment: 133 (93%)
Clinical Risk Index for Babies score: Median 6, Range 1-18

Dexamethasone group
n = 135
Gestational age (weeks): 27.4 (SD 1.9)
Birth weight (grams): 1017 (290)
Gender (female/male) (number): 50/85
Antenatal steroids (number and percentage): 128 (95%)
Clinical Risk Index for Babies score: median 7, range 0-19

Exclusion criteria: congenital lethal anomalies, severe IVH
(grade 3 or 4) and proven systemic infection before entry. A strong suspicion of infection, uncontrolled hypertension and hyperglycaemia was considered to be indication to postpone trial entry until they resolved, provided that this occurred within 72 hours of birth.

Study period: February 1994 to December 1998.
The trial had a factorial design and similar numbers of infants were allocated to each group.
Group 1 was allocated to early (< 72 hours) dexamethasone (n = 135);
Group 2, delayed (> 15 days) dexamethasone (n = 150);
Group 3, early budesonide (n = 143);
Group 4, delayed selective budesonide
(n = 142).

Interventions
  1. Budesonide was administered using a metered dose inhaler (MDI; 200µg/puff; Pulmicort, Astra Draco, Lund, Sweden) connected to spacing device ( Aerochamber MV 15; Trudell Medical, Canada). The aerochamber was a rigid, clear plastic cylinder, 11 by 4.1 cm with an approximate capacity of 145 ml. After endotracheal suctioning, the MDI was shaken and inserted into the spacing chamber. The spacer was then filled with 100% oxygen and infant's FiO2 was increased by 20%. The aerochamber was connected into the ventilatory circuit and manual inflations were given through the chamber using an inflatable bag. Budesonide was administered as soon as chest wall movements were established. A 500 -1000 g infant was given 2 puffs twice daily and a 1000-1500 g infant was given 3 puffs twice daily. The puffs were given one at a time, activating MDI at end expiration and allowing 10 breaths after each activation. After each administration, the chamber was removed from the ventilator circuit and the infant was reconnected to the ventilator at the previous settings. The duration of budesonide treatment was up to 12 days provided the infant remained intubated. If the infant was extubated before 12 days budesonide was discontinued.
  2. Dexamethasone was administered IV or PO in initial dose of 0.5 mg/kg/day in 2 divided doses for 3 days, followed by 0.25 mg/kg/day in 2 divided doses for 3 days, then 0.10 mg/kg/day for 3 days, and finally 0.05 mg/kg/day in 2 divided doses for 3 days. The total duration of treatment was 12 days.
Outcomes
  1. Primary outcome measure was death or oxygen dependency at 36 weeks CGA.
  2. Secondary outcome measures included death or major cerebral abnormality on ultrasound nearest to 6 weeks, death or oxygen dependency at 28 days and expected date of delivery, duration of FiO2 > 40%, duration of any supplemental oxygen, duration of assisted ventilation by endotracheal tube and duration of hospital stay.
  3. Complications such as pneumothorax, other pulmonary air leaks, NEC, acquired pneumonia, PDA requiring treatment, pulmonary haemorrhage requiring increased ventilation, seizures treated with an anticonvulsant
Notes

The study was conducted double blind in 11 centres, and in these centres placebo MDIs and intravenous saline were used to mask treatment allocation.

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

Multicentre, randomised open study

Random number sequence generation performed by the trial statistician, independent of trialists

Allocation concealment (selection bias) Low risk

Blinding of randomisation: Yes

Blinding (performance bias and detection bias) High risk

Blinding of intervention : Not in all centres. 11 centres : Yes, 36 centres : No

Blinding of participants and personnel (performance bias) High risk

Blinding of intervention : Not in all centres. 11 centres : Yes, 36 centres : No

Blinding of outcome assessment (detection bias) High risk

Blinding of outcome measurement : No

Incomplete outcome data (attrition bias) Low risk

Complete follow up : Yes

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

Characteristics of excluded studies

Dimitriou 1997

Reason for exclusion

The study was excluded because infants who were not ventilator dependent were also included in the study. Also, the age of starting treatment with corticosteroids varied from five to 118 days

Kovacs 1998

Reason for exclusion

The study was excluded as infants assigned to the steroid group received intravenous dexamethasone for three days followed by nebulized budesonide for 18 days while infants in the control group received saline solution first systemically and then by nebulization

Parikh 2004

Reason for exclusion

The study was excluded as all participants initially received a seven day course of dexamethasone and then were randomised to receive inhaled beclomethasone or placebo for 28 days

Characteristics of studies awaiting classification

  • None noted.

Characteristics of ongoing studies

  • None noted.

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References to studies

Included studies

Groneck 1999

Groneck P, Goetze-Speer B, Speer CP. Effects of inhaled beclomethasone compared to systemic dexamethasone on lung inflammation in preterm infants at risk of chronic lung disease. Pediatric Pulmonology 1999;27:383-7.

Halliday 2001a

Halliday HL, Patterson CC, Halahakoon CWNL, on behalf of the European Multicenter Steroid Study Group. A multicentre, randomized open study of early corticosteroid treatment (OSECT) in preterm infants with respiratory illness: Comparison of early and late treatment and of dexamethasone and inhaled budesonide. Pediatrics 2001;107:232-40.

Excluded studies

Dimitriou 1997

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

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;87:792-8.

Parikh 2004

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

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Aghajafari 2001

Aghajafari F, Murphy K, Willan A, Ohlsson A, Amankwah K, Mathews S, et al. Multiple courses of antenatal corticosteroids: a systematic review and meta-analysis. American Journal of Obstetetrics and Gynecology 2001;185:1073-80.

Arias-Camison 1999

Arias-Camison JM, Lau J, Cole CH, Frantz III ID. Meta-analysis of dexamethasone therapy started in the first 15 days of life for prevention of chronic lung disease in premature infants. Pediatric Pulmonology 1999;28:167-74.

Arnon 1992

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

Bell 1978

Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Necrotising enterocolitis. Therapeutic decisions based upon clinical staging. Annals of Surgery 1978;187:1-7.

Bhuta 1998

Bhuta T, Ohlsson A. Systematic review and meta-analysis of early postnatal dexamethasone for prevention of chronic lung disease. Archives of Disease in Childhood 1998;79:26-33.

CFN/AAP 2002

Committee of Fetus and Newborn: American Academy of Pediatrics. Postnatal steroids to treat or prevent chronic lung disease in preterm infants. Pediatrics 2002;109:330-8.

Clyman 1981

Clyman RI, Mauray F, Roman C, Rudolf AM, Heymann MA. Glucocorticoids alter the sensitivity of the lamb ductus arteriosus to prostaglandin E2. Journal of Pediatrics 1981;98:126-8.

Clyman 1987

Clyman RI. Ductus arteriosus: current theories of prenatal and postnatal regulation. Seminars in Perinatology 1987;11:67-71.

Crowley 2002

Crowley P. Prophylactic corticosteroids for preterm delivery. Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD000065. DOI: 10.1002/14651858.CD000065.pub2.

Davis 2001

Davis PG, Henderson-Smart DJ. Intravenous dexamethasone for extubation of newborn infants. Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD000308. DOI: 10.1002/14651858.CD000308.

FNC/CPS 2002

Fetus and Newborn Committee: Canadian Paediatric Society. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Paediatric Child Health 2002;7:20-8.

Garland 1999

Garland JS, Alex CP, Pauly TH, Whitehead VL, Brand J, Winston JF, et al. A three day course of dexamethasone therapy to prevent chronic lung disease in ventilated neonates: a randomised trial. Pediatrics 1999;104:91-9.

Grigg 1992

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

Groneck 1994

Groneck P, Goetze-Speer B, Opperman M, Eiffert H, Speer CP. Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: a sequential analysis of inflammatory mediators in respiratory fluids of high risk preterm neonates. Pediatrics 1994;93:712-8.

Halliday 1999

Halliday HL. Clinical trials of postnatal corticosteroids: inhaled and systemic. Biology of the Neonate 1999;76:29-40.

Halliday 2001b

Halliday HL. Guidelines on neonatal steroids. Prenatal and Neonatal Medicine 2001;6:371-3.

Halliday 2009

Halliday HL, Ehrenranz 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.

Heyman 1990

Heyman E, Ohlsson A, Shennan AT, Heilbut M, Coceani F. Closure of patent ductus arteriosus after treatment with dexamethasone. Acta Paediatrica Scandinavica 1990;79:698-700.

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

Horbar 1993

Horbar JD, Wright EC, Onstad L. The members of the National Institute of Child Health and Human Development Neonatal Research Network. Decreasing mortality associated with introduction of surfactant therapy: an observational study of neonates weighing 601 to 1300 grams at birth. Pediatrics 1993;92:191-6.

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.pub4.

ICROP 1984

The Committee for the classification of retinopathy of prematurity. An international classification of retinopathy of prematurity. Archives of Ophthalmology 1984;102:1130-4.

Kotecha 1996

Kotecha S, Wangoo A, Silverman M, Shaw RJ. Increase in the concentrations of transforming growth factor beta-1 in bronchoalveolar lavage fluid before development of chronic lung disease of prematurity. Journal of Pediatrics 1996;128:464-9.

LaForce 1993

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

Lee 2000

Lee SK, McMillan DD, Ohlsson A, Pendray M, Synnes A, Whyte R, et al. Variations in practice and outcomes in the Canadian NICU Network: 1996-1997. Pediatrics 2000;106:1070-9.

Ng 1993

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

O'Callaghan 1992

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

Onland 2012

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.pub2.

Papile 1978

Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weight less than 1500 gm. Journal of Pediatrics 1978;92:529-34.

Pierce 1995

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

RevMan 2011

Review Manager (RevMan) [Computer program]. Version 5.1. Copenhagen: The Nordic Cochrane Centre. The Cochrane Collaboration, 2011.

Saarela 1999

Saarela T, Vaarala A, Lanning P, Koivisto M. Incidence, ultrasonic patterns and resolution of nephrocalcinosis in very low birth weight infants. Acta Paediatrica 1999;88:655-60.

Schwartz 1994

Schwartz RM, Luby AM, Scanlon JW, Kellog RJ. Effects of surfactant on morbidity, mortality and resource use in newborn infants weighing 500 to 1500 g. New England Journal of Medicine 1994;330:1476-80.

Shah 2001

Shah V, Ohlsson A. Postnatal dexamethasone in the prevention of chronic lung disease. In: David TJ, ed. Recent advances in Paediatrics 19. London, England: Churchill Livingstone, 2001:77-96.

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.: CD002057. DOI: 10.1002/14651858.CD002057.pub2.

Shaw 1993

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

Shinwell 2000

Shinwell ES, Karplus M, Reich D, Weintraub Z, Blaazer S, Bader D, et al. Early postnatal dexamethasone therapy and increased incidence of cerebral palsy. Archives of Disease in Childhood Fetal and Neonatal Edition 2000;83:F177-81.

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Soll RF for the Vermont Oxford Network Steroid Study Group. Early dexamethasone therapy for the prevention of chronic lung disease. Pediatric Reseasrch 1999;45:226A.

Soll 2002

Soll RF. Synthetic surfactant for respiratory distress syndrome in preterm infants. Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD001149. DOI: 10.1002/14651858.CD001149.

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Speer CP, Ruess D, Harms K, Herting E, Gefeller O. Neutrophil elastase and acute pulmonary damage in neonates with severe respiratory distress syndrome. Pediatrics 1993;91:794-9.

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Stark AR, Carlo WA, Tyson JE, Papile LA, Wright LL, Shankaran EF, et al. Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. New England Journal of Medicine 2001;344:95-101.

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Other published versions of this review

Shah 2003

Shah SS, Ohlsson A, Halliday H, 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.: CD002058. DOI: 10.1002/14651858.CD002058.

Classification pending references

  • None noted.

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Data and analyses

1 Inhaled versus systemic steroids amongst all randomised

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 CLD at 36 weeks PMA 1 278 Risk Ratio (M-H, Fixed, 95% CI) 1.45 [0.99, 2.11]
1.2 CLD at 28 days 2 294 Risk Ratio (M-H, Fixed, 95% CI) 1.21 [0.98, 1.48]
1.3 Death by 28 days 2 294 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.51, 1.25]
1.4 Death by 36 weeks PMA 2 294 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.56, 1.23]
1.5 Death or CLD by 28 days 2 294 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.93, 1.20]
1.6 Death or CLD by 36 weeks PMA 1 278 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.88, 1.35]
1.7 Duration of mechanical ventilation (days) 2 294 Mean Difference (IV, Fixed, 95% CI) 3.89 [0.24, 7.55]
1.8 Duration of supplemental oxygen (days) 2 294 Mean Difference (IV, Fixed, 95% CI) 11.10 [1.97, 20.22]
1.9 Pneumothorax 1 278 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.56, 1.39]
1.10 Other air leaks 1 278 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.58, 1.90]
1.11 Pulmonary haemorrhage 1 278 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.48, 2.16]
1.12 Hyperglycaemia 1 278 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.39, 0.71]
1.13 Hypertension 1 278 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.44, 1.29]
1.14 Necrotizing enterocolitis 1 278 Risk Ratio (M-H, Fixed, 95% CI) 1.42 [0.60, 3.36]
1.15 Gastrointestinal haemorrhage 1 278 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.16, 1.02]
1.16 Gastrointestinal perforation 1 278 Risk Ratio (M-H, Fixed, 95% CI) 0.16 [0.02, 1.29]
1.17 Patent ductus arteriosus 1 278 Risk Ratio (M-H, Fixed, 95% CI) 1.64 [1.23, 2.17]
1.18 Retinopathy of prematurity - any stage 1 278 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.72, 1.71]
1.19 Retinopathy of prematurity greater than/or equal to stage 3 1 278 Risk Ratio (M-H, Fixed, 95% CI) 1.32 [0.43, 4.06]
1.20 Sepsis 1 278 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.73, 1.49]
1.21 Infants with detectable free elastase (inflammatory mediator) in tracheal aspirate fluid on day 14 1 16 Risk Ratio (M-H, Fixed, 95% CI) 8.75 [0.52, 145.86]

2 Inhaled versus systemic steroids amongst survivors

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
2.1 CLD at 36 weeks PMA 1 206 Risk Ratio (M-H, Fixed, 95% CI) 1.34 [0.94, 1.90]
2.2 CLD at 28 days 2 233 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.96, 1.34]

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Sources of support

Internal sources

  • Mount Sinai Hospital, Toronto, Ontario, Canada

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

1 2011 Search Strategy

PubMed

((bronchopulmonary dysplasia OR lung diseases OR chronic lung disease) AND (anti-inflammatory agents OR steroids OR dexamethasone OR inhalation OR aerosols OR budesonide OR beclomethasone dipropionate OR flunisolide OR fluticasone propionate)) AND ((infant, newborn[MeSH] OR newborn OR neon* OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh] NOT humans [mh])) AND (("2007"[PDat] : "3000"[PDat]))

Cinahl

( (bronchopulmonary dysplasia OR lung diseases OR chronic lung disease) AND (anti-inflammatory agents OR steroids OR dexamethasone OR inhalation OR aerosols OR budesonide OR beclomethasone dipropionate OR flunisolide OR fluticasone propionate) ) and ( ( infant, newborn OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW) AND ( randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial) ) 2007 - Present

Cochrane Central Register of Controlled Trials

(bronchopulmonary dysplasia OR lung diseases OR chronic lung disease) AND (anti-inflammatory agents OR steroids OR dexamethasone OR inhalation OR aerosols OR budesonide OR beclomethasone dipropionate OR flunisolide OR fluticasone propionate) and (infant or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW), from 2007 to 2011

Embase:

  1. ((bronchopulmonary dysplasia or lung diseases or chronic lung disease) and (anti-inflammatory agents or steroids or dexamethasone or inhalation or aerosols or budesonide or beclomethasone dipropionate or flunisolide or fluticasone propionate)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] (1849)
  2. (infant, newborn or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] (603948)
  3. (human not animal).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] (11849457)
  4. (randomized controlled trial or controlled clinical trial or randomized or placebo or clinical trials as topic or randomly or trial or clinical trial).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] (1256505)
  5. 1 and 2 and 3 and 4 (336)
  6. limit 5 to yr="2007 -Current" (76)

ClinicalTrials.gov

(infant OR newborn) AND (bronchopulmonary dysplasia OR lung disease) AND (anti-inflammatory agents OR steroids OR dexamethasone OR inhalation OR aerosols OR budesonide OR beclomethasone dipropionate OR flunisolide OR fluticasone propionate)

Controlled-Trials.com External Web Site Policy

(infant OR newborn) AND (bronchopulmonary dysplasia OR lung disease) AND (anti-inflammatory agents OR steroids OR dexamethasone OR inhalation OR aerosols OR budesonide OR beclomethasone dipropionate OR flunisolide OR fluticasone propionate)


This review is published as a Cochrane review in The Cochrane Library, Issue 5, 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.