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

Shah SS, Ohlsson A, Halliday H, Shah VS

 

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

 

Dates

Date edited: 22/08/2007
Date of last substantive update: 02/11/2002
Date of last minor update: 19/07/2007
Date next stage expected / /
Protocol first published: Issue 2, 2000
Review first published: Issue 1, 2003

Contact reviewer

Dr Sachin S Shah, MBBS, MD, DM
Director
Neonatal and Pediatric Intensive Care Services
Aditya Birla Memorial Hospital
Office no. 2, Arihant Building
39/32 Karve Road
Pune
INDIA
411004
Telephone 1: 91 20 30717644
Facsimile: 91 20 27277003
E-mail: sshahdoc@hotmail.com
Secondary address:
39/32 Karve Road
1st Floor, Arihant Building
Pune INDIA
411004
Telephone: 91 20 25442244

Contribution of reviewers

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

This update was conducted by Vibhuti Shah and Arne Ohlsson.

Internal sources of support

Mount Sinai Hospital, Toronto, Ontario, CANADA

External sources of support

None

What's new

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.

Dates

Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: 30/06/2007
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis


Preterm babies who require breathing support often develop chronic lung disease. It is thought that inflammation in the lungs may be part of the cause. Corticosteroid drugs when given orally or through a vein reduces this inflammation, 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.

Abstract



Background


Chronic lung disease (CLD) remains an important cause of mortality and morbidity in preterm infants despite the administration of antenatal corticosteroids, surfactant replacement therapy and other advances in neonatal intensive care. There is increasing evidence from cellular and biochemical research that inflammation plays an important role in the pathogenesis of CLD. Interventions aimed at reducing or modulating the inflammatory process may reduce the incidence or severity of CLD. 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.

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 infants.

Search strategy


Randomized and quasi-randomized trials were identified by searching the Cochrane Controlled Trials Register (The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - June 2007), EMBASE (1980 - June 2007), CINAHL (1982 - June 2007), reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies web-site (1990 - April 2007).

Selection criteria


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

Data collection & analysis


Data regarding clinical outcomes including CLD at 28 days or 36 weeks postmenstrual age (PMA), mortality, combined outcome of death or CLD at 28 days or 36 weeks PMA, other pulmonary outcomes and adverse effects were evaluated. All data were analyzed using RevMan 4.2. When appropriate, meta-analysis was performed using relative risk (RR), risk difference (RD), and weighted mean difference (WMD) along with their 95% confidence intervals (CI). If RD was significant, the number needed to treat (NNT) or the number needed to harm (NNH) was calculated.

Main results


Two additional trials were identified that evaluated systemic and inhaled steroids for this updated review. These trials had to be excluded as in both studies the neonates received systemic corticosteroid or placebo prior to randomization to inhaled steroids. Two trials qualified for inclusion in this review. There was an increase in the incidence of CLD at 36 weeks PMA in the inhaled steroid group among all randomized infants, which was of borderline statistical significance: [RR 1.45 (95% CI 0.99, 2.11); RD 0.11 (95% CI 0.00, 0.21), p = 0.05, 1 trial and n = 278]. There was no statistically significant difference in the incidence of CLD at 36 weeks PMA among all survivors [RR 1.34 (95% CI 0.94, 1.90); RD 0.11(95% CI -0.02, 0.24), one trial and n = 206]. There were no statistically significant differences for oxygen dependency at 28 days (two trials and n = 294), death by 28 days (two trials and n = 294) or 36 weeks PMA (two trials and n = 294) and the combined outcome of death or CLD by 28 days (two trials and n = 294) or 36 weeks PMA (one trial and n = 278). The duration of mechanical ventilation was statistically significantly longer in the inhaled steroid group as compared to the systemic steroid group (typical WMD four days, 95% CI 0.2, 8; two trials and n = 294). The duration of supplemental oxygen was statistically significantly longer in the inhaled as compared to the systemic steroid group (typical WMD 11 days, 95% CI 2, 20; two trials and n = 294).

There was a significantly lower incidence of hyperglycemia in the group receiving inhaled steroids (RR 0.52, 95% CI 0.39, 0.71; RD -0.25, 95% CI -0.37, -0.14; one trial and n = 278). The NNT was 4 (95% CI 3, 7) to avoid one infant experiencing hyperglycemia. There was a statistically significant increase in the rate of patent ductus arteriosus (RR 1.64, 95% CI 1.23, 2.17; RD 0.21, 95% CI 0.10, 0.33; one trial and n = 278) in the group receiving inhaled steroids. The NNH was 5, 95% CI 3, 10. There were decreases of borderline statistical significance in the incidences of gastrointestinal hemorrhage and gastrointestinal perforation in the inhaled as compared to systemic steroid group: for gastrointestinal hemorrhage, RR 0.40, 95% CI 0.16, 1.02; RD -0.06, 95% CI -0.12, 0.00, p = 0.05 (one trial and n = 278); for gastrointestinal perforation, RR 0.16, 95% CI 0.02, 1.29; RD -0.04, 95% CI -0.07, 0.00, p = 0.05 (one trial and n = 278). The incidence of other side effects was not statistically significantly different in the two groups. No information was available on long-term neurodevelopmental outcomes.

Reviewers' 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 randomized 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.

Background


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 hospitalization, 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 (Groneck 1994; Kotecha 1996; Pierce 1995; Speer 1993; Watts 1992; 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.

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 - 14 days)] have demonstrated a reduction in CLD at 28 days and 36 weeks postmenstrual age (PMA) (Arias-Camison 1999; Bhuta 1998; Halliday 1999; Halliday 2002a; Halliday 2002b; Shah 2001). 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; Halliday 2002a; Ng 1993; Stark 2001; Soll 1999; Yeh 1997; Yeh 1998). Short-term serious complications with early systemic corticosteroid therapy include gastrointestinal hemorrhage and perforation, hyperglycemia 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 (typical RR 2.32; 95% CI 1.48, 3.65) (Halliday 2002a).

In recent 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 randomized 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.

The aim of this review was to assess the effectiveness of inhaled versus systemic corticosteroid therapy when administered to ventilated preterm infants within the first two weeks of life for prevention of CLD.


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 < 1500 grams or gestational age < 32 weeks.

Secondary objectives were to compare the effectiveness of inhaled versus systemic corticosteroids on:
1. Other indicators of CLD including:

2. The incidence of adverse events including:

3. 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 - 24 months.

Criteria for considering studies for this review



Types of studies


Randomized or quasi randomized 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 < 1500 grams or gestational age < 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


Studies reporting one or more of the following outcomes:

1. Amongst all randomized:


2. Amongst survivors

3. 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 - 24 months.


Search strategy for identification of studies


See: Collaborative Review Group search strategy

Randomized controlled trials comparing inhaled versus systemic corticosteroid therapy in preterm infants were identified from MEDLINE (1966 - 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 - June 2007), reference lists of published trials and abstracts published in Pediatric Research or electronically on the Pediatric Academic Societies web-site (1990 - 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, two review authors (VS, AO) conducted the literature search and reviewed the articles obtained.

Methods of the review


Criteria and methods used to assess the methodological quality of the trials: standard method of the Cochrane Collaboration and its Neonatal Review Group was used.
For each trial, information was sought regarding the method of randomization, 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 two review authors (VS, AO). The treatment effect estimators used were RR, RD, and WMD when appropriate along with their 95% CI. If RD was statistically significant, NNT or NNH was calculated. A fixed effect model was used for meta-analysis. Heterogeneity tests [including the I2 test] were to be performed to assess the appropriateness of pooling the data.


Description of studies


Two additional trials (Kovacs 1998, Parikh 2004) that evaluated systemic and inhaled steroids were identified for this updated review, but had to be excluded for reasons described below. Five trials comparing inhaled versus systemic corticosteroids in prevention of CLD were identified, of which three were excluded. 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 randomized to receive either inhaled beclomethasone or placebo. Two trials qualified for inclusion in this review: Groneck et al (Groneck 1999) and Halliday et al (Halliday 2001). 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 3 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 11-13; thereafter the dose was gradually tapered over 10-28 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 2001):
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 randomized to the early budesonide group while 135 were randomized to the early dexamethasone group. Out of 143 infants randomized to early budesonide, 53 received full course, 87 received partial course, while three did not receive budesonide. Out of 135 infants randomized 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) .

Methodological quality of 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 2001) - This was a multicentre randomized controlled trial involving 47 centres. The intervention was not blinded in the majority of centers. 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. Randomization was performed by telephoning the central randomization centre. After identifying an eligible infant, the clinician telephoned the randomization centre to enroll 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.

Results


INHALED VERSUS SYSTEMIC STEROIDS AMONG ALL RANDOMIZED (Comparison 01):

PRIMARY OUTCOMES:

CLD at 36 weeks PMA (Outcome 01.01):

One trial enrolling 278 neonates reported on the incidence of CLD at 36 weeks PMA among all randomized (Halliday 2001). 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, 2.11); RD 0.11 (95% CI 0.00, 0.21), p = 0.05].

SECONDARY OUTCOMES:

CLD at 28 days of age (Outcome 01.02):

Two trials enrolling 294 neonates reported on the incidence of CLD at 28 days of age among all randomized. There was no statistically significant difference in the incidence of CLD at 28 days [typical RR 1.21 (95% CI 0.98, 1.48), RD 0.11 (95% CI -0.01, 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 01.03):

Two trials enrolling 294 neonates reported on the incidence of death by 28 days among all randomized. 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, 1.25), RD -0.05 (95% CI -0.14, 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 01.04):

Two trials enrolling 294 neonates reported on the incidence of death by 36 weeks PMA among all randomized. No statistically significant effect on mortality by 36 weeks PMA was noted [typical RR 0.83 (95% CI 0.56, 1.23), typical RD -0.05 (95% CI -0.15, 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 01.05):

Two trials enrolling 294 neonates reported on the incidence of death or CLD by 28 days among all randomized. 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, 1.20), RD 0.04 (95% CI -0.06, 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 01.06):

One trial enrolling 278 neonates reported on this outcome (Halliday 2001). 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, 1.35), RD 0.05 (95% CI -0.07, 0.16)].

Duration mechanical ventilation (days) (Outcome 01.07):

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, 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 01.08):

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, 20). There was no statistically significant heterogeneity for this outcome (p=0.22, I2 = 33.5 %).

Pneumothorax (Outcome 01.09):

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

Other air leaks (Outcome 01.10):

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

Pulmonary hemorrhage (Outcome 01.11):

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

Hyperglycemia (Outcome 01.12):

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

Hypertension (Outcome 01.13):

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

Necrotizing enterocolitis (Outcome 01.14):

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

Gastrointestinal hemorrhage (Outcome 01.15):

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

Gastrointestinal perforation (Outcome 01.16):

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

Patent ductus arteriosus (Outcome 01.17):

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

Retinopathy of prematurity - any stage (Outcome 01.18):

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

Retinopathy of prematurity > stage 3 (Outcome 01.19):

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

Sepsis (Outcome 01.20):

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

Infants with free elastase (inflammatory mediator) in tracheal aspirate on day 14 (Outcome 01.21):

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, 145.86; RD 0.43, 95% CI 0.06, 0.80).

INHALED VERSUS SYSTEMIC STEROIDS AMONG SURVIVORS (Comparison 02):

PRIMARY OUTCOME:

CLD at 36 weeks PMA (Outcome 02.01):

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, 1.90); RD 0.11 (95% CI -0.02, 0.24)].

SECONDARY OUTCOMES:

CLD at 28 days of age (Outcome 02.02):

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, 1.34), typical RD 0.09 (95% CI -0.02, 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 (Halliday 2002a; Shah 2001) of early postnatal systemic corticosteroids (< 96 hours 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 between 7 -14 days (Halliday 2002b; Shah 2001) a decrease in the combined outcome of CLD at 36 weeks and mortality was shown. There was no evidence that the duration of hospitalization or need for supplemental oxygen was decreased (Shah 2001). Early administration of inhaled steroids in the first 2 weeks of life to ventilated very low birth weight infants showed no evidence of decrease in the incidence of CLD (Shah 2002).

One of the intriguing observations in the study of Halliday 2001 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 2002a). 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, hyperglycemia was less common in the inhaled steroid group. There was a decrease in the incidence of gastrointestinal hemorrhage 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 (Dimitriou 1997; LaForce 1993) and similar risk profile of inhaled steroids (Shah 2002) 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 2002a), 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 2001) are currently being traced and examined by pediatricians and psychologists.

Reviewers' 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 2002a), cannot be recommended as a part of standard practice for ventilated preterm infants to prevent CLD.

Implications for research


Further randomized 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.

Potential conflict of interest


None

Characteristics of included studies

StudyMethodsParticipantsInterventionsOutcomesNotesAllocation concealment
Groneck 1999Open comparative study.

Blinding of randomization: No.
(alternate allocation)

Blinding of intervention : No

Blinding of outcome measurement : No

Complete follow up: Yes

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)

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.

Pulmonary inflammation
(assessed by analyzing 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).		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.C
Halliday 2001Multicentre, randomized open study. 1. Blinding of randomization: Yes. 2. Blinding of intervention : Not in all centres. 11 centres : Yes, 36 centres : No 3. Blinding of outcome measurement : No 4. Complete follow up : Yes570 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 hyperglycemia 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).

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.

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 hemorrhage requiring increased ventilation, seizures treated with an anticonvulsant

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

Characteristics of excluded studies

StudyReason for exclusion
Dimitriou 1997The 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 1998The study was excluded as infants assigned to the steroid group received intravenous dexamethasone for 3 days followed by nebulized budesonide for 18 days while infants in the control group received saline solution first systemically and then by nebulization.
Parikh 2004The study was excluded as all participants initially received a 7 day course of dexamethasone and then were randomized to receive inhaled beclomethasone or placebo for 28 days.

References to studies

References to included studies

Groneck 1999 {published data only}

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 2001 {published data only}

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.

References to excluded studies

Dimitriou 1997 {published data only}

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 {published data only}

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

Parikh 2004 {published data only}

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.

* indicates the primary reference for the study

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.

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 dvelopment 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 2002a

Halliday HL, Ehrenkranz RA. Early postnatal (< 96 hours ) corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database of Systematic Reviews 2002, Issue 3.

Halliday 2002b

Halliday HL, Ehrenkranz RA. Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database of Systematic Reviews 2002, Issue 3.

Heyman 1990

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

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.

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.

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.

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 2002

Shah V, Ohlsson A, Halliday HL, Dunn MS. Early administration of inhaled steroids for preventing chronic lung disease in ventilated very low birth weight preterm neonates. Cochrane Database of Systematic Reviews 2002, Issue 3.

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.

Sinkin 1990

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

Soll 1999

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.

Speer 1993

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.

Stark 2001

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.

Watterberg 1994

Watterberg KL, Carmichael DF, Gerdes JS, Werner S, Backstorm C, Murphy S. Secretory leukocyte protease inhibitor and lung inflammation in developing bronchopulmonary dysplasia. Journal of Pediatrics 1994;125:264-9.

Watterberg 1996

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

Watts 1992

Watts CL, Fanaroff AA, Bruce MC. Elevation of fibronectin levels in lung secretions of infants with respiratory distress syndrome and development of bronchopulmonary dysplasia. Journal of Pediatrics 1992;120:614-20.

Yeh 1997

Yeh TF, Lin YJ, Hsieh WS, Lin HC, Lin CH, Chen JY, et al. Early postnatal dexamethasone therapy for prevention of chronic lung disease in preterm infants with respiratory distress syndrome: a multicentre clinical trial. Pediatrics 1997;100:E3.

Yeh 1998

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

Yost 2002

Yost CC, Soll RF. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews 1999, Issue 4.

Zubrow 1995

Zubrow AB, Hulman S, Kushner H, Falkner B. Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. Journal of Perinatology 1995;15:470-9.

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.

Comparisons and data

Comparison or outcome
Studies
Participants
Statistical method
Effect size
01 Inhaled versus systemic steroids amongst all randomized
01 CLD at 36 weeks PMA
1
278
RR (fixed), 95% CI
1.45 [0.99, 2.11]
02 CLD at 28 days
2
294
RR (fixed), 95% CI
1.21 [0.98, 1.48]
03 Death by 28 days
2
294
RR (fixed), 95% CI
0.80 [0.51, 1.25]
04 Death by 36 weeks PMA
2
294
RR (fixed), 95% CI
0.83 [0.56, 1.23]
05 Death or CLD by 28 days
2
294
RR (fixed), 95% CI
1.05 [0.93, 1.20]
06 Death or CLD by 36 weeks PMA
1
278
RR (fixed), 95% CI
1.09 [0.88, 1.35]
07 Duration of mechanical ventilation (days)
2
294
WMD (fixed), 95% CI
3.89 [0.24, 7.55]
08 Duration of supplemental oxygen (days)
2
294
WMD (fixed), 95% CI
11.10 [1.97, 20.22]
09 Pneumothorax
1
278
RR (fixed), 95% CI
0.88 [0.56, 1.39]
10 Other air leaks
1
278
RR (fixed), 95% CI
1.05 [0.58, 1.90]
11 Pulmonary hemorrhage
1
278
RR (fixed), 95% CI
1.02 [0.48, 2.16]
12 Hyperglycemia
1
278
RR (fixed), 95% CI
0.52 [0.39, 0.71]
13 Hypertension
1
278
RR (fixed), 95% CI
0.76 [0.44, 1.29]
14 Necrotizing enterocolitis
1
278
RR (fixed), 95% CI
1.42 [0.60, 3.36]
15 Gastrointestinal hemorrhage
1
278
RR (fixed), 95% CI
0.40 [0.16, 1.02]
16 Gastrointestinal perforation
1
278
RR (fixed), 95% CI
0.16 [0.02, 1.29]
17 Patent ductus arteriosus
1
278
RR (fixed), 95% CI
1.64 [1.23, 2.17]
18 Retinopathy of prematurity - any stage
1
278
RR (fixed), 95% CI
1.11 [0.72, 1.71]
19 Retinopathy of prematurity >/= stage 3
1
278
RR (fixed), 95% CI
1.32 [0.43, 4.06]
20 Sepsis
1
278
RR (fixed), 95% CI
1.04 [0.73, 1.49]
21 Infants with detectable free elastase (inflammatory mediator) in tracheal aspirate fluid on day 14
1
16
RR (fixed), 95% CI
8.75 [0.52, 145.86]
02 Inhaled versus systemic steroids amongst survivors
01 CLD at 36 weeks PMA
1
206
RR (fixed), 95% CI
1.34 [0.94, 1.90]
02 CLD at 28 days
2
233
RR (fixed), 95% CI
1.14 [0.96, 1.34]

 

01 Inhaled versus systemic steroids amongst all randomized

01.01 CLD at 36 weeks PMA

01.02 CLD at 28 days

01.03 Death by 28 days

01.04 Death by 36 weeks PMA

01.05 Death or CLD by 28 days

01.06 Death or CLD by 36 weeks PMA

01.07 Duration of mechanical ventilation (days)

01.08 Duration of supplemental oxygen (days)

01.09 Pneumothorax

01.10 Other air leaks

01.11 Pulmonary hemorrhage

01.12 Hyperglycemia

01.13 Hypertension

01.14 Necrotizing enterocolitis

01.15 Gastrointestinal hemorrhage

01.16 Gastrointestinal perforation

01.17 Patent ductus arteriosus

01.18 Retinopathy of prematurity - any stage

01.19 Retinopathy of prematurity >/= stage 3

01.20 Sepsis

01.21 Infants with detectable free elastase (inflammatory mediator) in tracheal aspirate fluid on day 14

02 Inhaled versus systemic steroids amongst survivors

02.01 CLD at 36 weeks PMA

02.02 CLD at 28 days


Contact details for co-reviewers

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

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

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

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