Methods

Multicentre, randomised open study.

1. Blinding of randomisation: 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: Yes

Study period: February 1994 to December 1998. Study location: 47 neonatal intensive care units worldwide (UK, Ireland, Canada, Switzerland, Norway, Greece, Portugal, Sweden, Slovenia, Poland, Israel, Singapore, UAE)

Participants

570 infants from 47 neonatal intensive care units worldwide (UK, Ireland, Canada, Switzerland, Norway, Greece, Portugal, Sweden, Slovenia, Poland, Israel, Singapore, UAE) were enrolled. Inclusion criteria: Gestational age < 30 weeks, postnatal age < 72 hours and need for mechanical ventilation and inspired FiO₂ > 30%. Delayed selective treatment was started if infants needed mechanical ventilation and > 30% FiO₂ for > 15 days. Infants of 30 ‐ 31 weeks GA could also be included if they needed > 50% FiO₂.

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

The trial had factorial design and a similar number of infants was allocated to each group. Group 1 received early (< 72 hours) dexamethasone (N = 135); group 2 received delayed (> 15 days) dexamethasone (N = 150); group 3 received early budesonide (N = 143); Group 4 received delayed selective budesonide
(N = 142).

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

Group 1: Early (< 72 hours) dexamethasone (N = 135) Data not included in this systematic review

Group 2: Delayed (> 15 days) dexamethasone (N = 150)

Gestational age: 27.1 weeks (1.9)
Birth weight: 1007 g (283)
Sex (f/m): 71/79
Antenatal steroids: N = 82 (55%)
Surfactant treatment: N = 138 (92%)
Clinical risk index for babies score: median 7, range 1 to 16

Group 3: Early budesonide (N = 143) Data not included in this systematic review

Group 4: Delayed selective budesonide group N = 142
Gestational age: 27 weeks (2)
Birth weight: 994 g (279)
Sex (f/m): 64/78
Antenatal steroids: N = 89 (63%)
Surfactant treatment: N = 132 (93%)
Clinical risk index for babies score: median = 6, range 1 to 18

Interventions

1. Dexamethasone was administered IV or orally 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 for a total of 12 days of treatment.

2. Budesonide was administered using a metered dose inhaler (200 µg/puff; Pulmicort, Astra Draco, Lund, Sweden) connected to spacing device (Aerochamber MV 15; Trudell Medical, Canada). The aero chamber was a rigid, clear plastic cylinder, 11 by 4.1 cm with an approximate capacity of 145 mL. After endotracheal suctioning, the metered dose inhaler was shaken and inserted into the spacing chamber. The spacer was then filled with 100% oxygen and the infant's FiO₂ was increased by 20%. The aero chamber 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 to 1000 g infant was given 2 puffs twice daily and 1000 to 1500 g infant was given 3 puffs twice daily. The puffs were given one at a time, activating metered dose inhaler 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

Outcomes

1. Primary outcome measure was death or oxygen dependency at 36 weeks' postmenstrual age.

2. Secondary outcome measures included death or major cerebral abnormality on ultrasound nearest to 6 weeks' postnatal age, death or oxygen dependency at 28 days and expected date of delivery, duration > 40% FiO₂, 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, necrotising enterocolitis, acquired pneumonia, patent ductus arteriosus requiring treatment, pulmonary haemorrhage requiring increased ventilation, seizures treated with anticonvulsants, recurrent apnoea needing treatment, retinopathy of prematurity at 36 weeks' postmenstrual age, gastric haemorrhage and GI perforation were noted. All neonates were monitored daily for blood pressure and blood glucose. Also, withdrawals from the intervention because of hypertension, hyperglycaemia, sepsis, gastric bleeding, or intestinal perforation were noted. An intention‐to‐treat analysis was performed

Notes

The study was performed double blind in 11 centres, and in these centres placebo metered dose inhalers and intravenous saline were used to mask treatment allocation. The study design was open rather than double‐blind because some clinicians wanted to prescribe broad spectrum antibiotics or H₂ blockers such as cimetidine or ranitidine to infants receiving dexamethasone. 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

This study was supported by a grant from Action Research, United Kingdom. Trudell Medical, London Ontario, Canada supplied Aerochambers, and Astra, Draco, Lund, Sweden supplied the metered dose inhalers (MDIs) of budesonide and placebo.

Risk of bias

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 researchers

Allocation concealment (selection bias)

Low risk

Once an infant had full filled entry criteria, the supervising clinician telephoned the randomisation centre in Belfast to enrol an infant and determine the treatment group

Blinding (performance bias and detection bias)
All outcomes

High risk

Not in all centres. 11 centres ‐ Yes; 36 centres ‐ No

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not in all centres. 11 centres ‐ Yes; 36 centres ‐ No

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Not in all centres. 11 centres ‐ Yes; 36 centres ‐ No

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcome data reported on all enrolled infants

Selective reporting (reporting bias)

Low risk

There was no selective reporting according to the first author (HH)

Other bias

Unclear risk

Appears free of other bias

Methods

Prospective randomised controlled trial.
1. Blinding of randomisation: Yes
After parental consent, infants were stratified into two birth weight groups (650 to 1000 g and 1001 to 2000 g birth weight) and then into four dosing groups using a random table number
2. Blinding of intervention: Yes
3. Blinding of outcome assessment: Unclear
4. Complete follow up: Yes

Study period: January 1992 to March 1995. Study location: Division of Neonatal‐Perinatal Medicine, Medical College of Virginia at Virginia Commonwealth University, Richmond, Virginia, USA

Participants

61 preterm infants with birth weights between 650 g and 2000 g if at 14 days of age were at significant risk for developing moderate to severe BPD, defined as need for mechanical ventilation and oxygen, along with X‐ray changes beyond 28 days of life were enrolled.
Infants with proven sepsis and receiving FiO₂ of ≥ 0.3 and had a ventilatory index of < 0.8 were eligible while for infants without culture‐proven sepsis, the oxygen requirement was the same but the ventilatory index threshold was < 0.510.

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

Group A: Dexamethasone group N = 15
Birth weight: 773 g (132)
Gestational age: 26 weeks (24 to 27)
Sex (m/f): 7/8
Prenatal steroids: 2/15
Inborn: 12
Prestudy sepsis: 8
Initial ventilation index: 0.252 (0.094)

Group B: High dose beclomethasone group N = 16
Birth weight: 710 g (148)
Gestational age: 26 weeks (23 to 29)
Sex (m/f): 6/10
Prenatal steroids: 1/15
Inborn: 13
Prestudy sepsis: 10
Initial ventilation index: 0.300 (0.184)

Group C: Medium dose beclomethasone group N = 15
Birth weight: 796 g (152)
Gestational age: 26 weeks (24 to 30)
Sex (m/f): 8/7
Prenatal steroids: 3/16
Inborn: 11
Prestudy sepsis: 7
Initial ventilation index: 0.294 (0.106)

Group D: Low dose beclomethasone group N = 15
Birth weight: 760 g (124)
Gestational age: 25 weeks (24 to 31)
Sex (m/f): 9/6
Prenatal steroids: 2/15
Inborn: 13
Prestudy sepsis: 9
Initial ventilation index: 0.293 (0.158)

Interventions

Infants were randomised into 4 groups:
Group A: aerosol placebo‐systemic dexamethasone
Group B: high dose beclomethasone‐systemic placebo
Group C: medium dose beclomethasone‐systemic placebo
Group D: low dose beclomethasone‐systemic placebo

Dexamethasone group: 42 day course of dexamethasone as described by Avery et al followed by a 7 day course of placebo to ensure that all subjects ended the study at the same time.

Subjects in the aerosol steroid groups (B, C, or D) began a similar 42 day systemic dexamethasone course on day 8 if extubation was unsuccessful while on inhaled steroids.

Aerosol steroid groups (limited to data from infants 650 to 1000 g) randomised to receive:

High dose beclomethasone group (2.4 to 3.69 µg/kg/day)
Medium dose beclomethasone group (1.0 change to 1.20 to 1.85 µg/kg/day)
Low dose beclomethasone group (0.48 to 0.74 µg/kg/day)

Beclomethasone dipropionate (42 µg/actuation, Vanceril, Schering‐Plough, Kenilworth, NJ) was administered using a metered dose inhaler placed between the bag and the spacer. After disconnecting the ventilator circuit, a 250 mL Laerdal resuscitation bag with oxygen reservoir connected to an oxygen source (> 90% FiO₂) was connected through a spacer to the endotracheal tube. After activating the metered dose inhaler, infants were given three manual breaths. Infants < 1001 g at birth received one dose of beclomethasone every 12 hourly while larger infants received a dose every 8 hourly.
Inhaled steroids were administered for a maximum of 7 days. The medication was stopped if the infant was successfully extubated for more than 12 hours even if not all doses had been administered.

Outcomes

1. Primary outcome measure was extubation within the first 7 days of the study

2. Secondary outcome measures included changes in ventilator settings and oxygen delivery
over the first 7 days. The rates of hypertension, hyperglycaemia, infection and growth over the first 7 days were analysed. Death was not included as an outcome

Long‐term outcomes were not included.

Our primary outcome of death or BPD at 36 weeks' postmenstrual age was not reported on. BPD at 36 weeks' postmenstrual age and deaths during hospital stay were reported on. There were 3 deaths in the dexamethasone group (3/15) and 4 deaths in the beclomethasone groups (4/46)

Notes

Infants were ventilated with time‐cycled, pressure limited, non synchronized ventilators during this study. Ventilator management was prescribed during the first 2 weeks of the study. If the pCO₂ was < 50 mm Hg, the peak pressure was lowered until it was < 15 cm H₂O. Then, if the pCO₂ was < 50 mm Hg, the ventilator rate was lowered, FiO₂ was adjusted to maintain oxygen saturation between 88 to 92%. No subjects received bronchodilators during the study period. The use of caffeine or diuretics was left to the discretion of the attending physician

No funding resources were reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A random number table was used.

Allocation concealment (selection bias)

Low risk

After parental consent, infants were stratified into two birth weight groups (650 to 1000 g and 1001 to 2000 g birth weight) and then into four dosing group using a random table number. Only the pharmacy was aware of the individual group assignment.

Blinding (performance bias and detection bias)
All outcomes

Low risk

There was aerosol and systemic placebo in all participants in the control groups

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Yes

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Unclear

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcome data were provided on all enrolled infants

Selective reporting (reporting bias)

Unclear risk

The protocol for the study was not available to us so we cannot judge if there were any deviations from the protocol

Other bias

Unclear risk

Appears free of other bias

Methods

Prospective randomised controlled trial.
1. Blinding of randomisation: Yes
Random allocation using 3 sets of 27 assembled, opaque envelopes.
As infants were enrolled, a card was sequentially pulled and infant assigned to appropriate study group. In case of multiple gestation, all eligible siblings were assigned to same group to minimize parental anxiety.

2. Blinding of intervention: No

3. Blinding of outcome measurement: No

4. Complete follow up: Yes

Study period: July 1994 to July 1996. Study location: Neonatal intensive care unit (NICU) at Children’s Hospital of Buffalo, State of New York.

Participants

78 preterm infants ≤ 30 weeks, birth weight ≤ 1500 g and conventional ventilator dependence at 12 to 21 days of age with a rate > 15/min and FiO₂ > 0.30 with persistence of these ventilator settings for a minimum of 72 hours were enrolled in the study.

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

Inhaled beclomethasone 800 µg/d group N = 25
Gestational age: 26 weeks (1)
Birth weight: 843 g (177)
Sex (female/male) (number of infants): 14/11
Maternal steroids (number and percentage): 12 (48%)
Age of commencement of steroids (days): 17 (3)
Baseline mean airway pressure: 7.1 (1.2)
Baseline FiO₂: 0.44 (0.10)

Inhaled beclomethasone 400 µg/day group N = 26
Gestational age: 26 weeks (2)
Birth weight: 846 g (N = 139)
Sex (female/male) (number of infants): 12/14
Maternal steroids (number and percentage): 22 (84.6%)
Age of commencement of steroids (days): 18 (3)
Baseline mean airway pressure: 7.3 (1.9)
Baseline FiO₂: 0.42 (0.13)

Intravenous dexamethasone group N = 27
Gestational age: 26 weeks (2)
Birth weight: 843 g (227)
Sex (female/male) (number of infants): 8/19
Maternal steroids (number and percentage): 16 (59.2%)
Age of commencement of steroids (days): 17 (2)
Baseline mean airway pressure: 7.9 (1.6)
Baseline FiO₂: 0.49 (0.13)
Infants were ineligible if they were on high frequency oscillatory ventilation. Exclusion criteria: major congenital malformations, culture positive sepsis, hypertension which required medical management, persistent patent ductus arteriosus, or hyperglycaemia requiring insulin. Infants were also excluded if they received any postnatal steroid therapy (either inhaled or intravenous) before 12 days of age or before entry in the study.

Interventions

1. The inhaled beclomethasone was delivered through a metered dose inhaler with a spacer device (Aerovent) connected in line with the ventilator at 50 µg per puff. Between each puff, the infant was ventilated with 4 or 5 manual breaths delivered at a peak pressure identical to that delivered during mechanical ventilation.
The 400 µg/d group (N = 26) received 4 puffs every 12 hours. The 800 µg/puff group (N = 25) received 4 puffs every 6 hours. Beclomethasone was continued until extubation. If the infant was successfully extubated, then the same dose was administered for 48 hours more. Thereafter, the steroid dose was halved every other day for 6 days, after which the steroid was stopped. After extubation, the inhaled beclomethasone was given using a face mask with inhaler and spacer device.

2. The intravenous dexamethasone group (N = 27) received a 42 day tapering course (Avery 1985), starting with 0.5 mg/kg/day, divided every 12 hours. Cross over from either of the inhaled beclomethasone groups to intravenous dexamethasone was allowed if, after 4 to 5 days of inhaled beclomethasone, the infant's ventilator and oxygen support had not decreased and the attending neonatologist felt that the infant might benefit from intravenous dexamethasone.

3. All data were analysed according to original group assignment.

Outcomes

1. Primary outcome measures: hypertension or hyperglycaemia needing treatment or culture positive sepsis.

2. Other outcome variables: ventilatory settings, specifically rate, mean airway pressure (MAP), peak inspiratory pressure, positive end expiratory pressure, and supplemental oxygen requirement every 6 hours daily on all enrolled patients starting from 5 days before initiation of steroid therapy and daily thereafter, until extubation. After extubation, the supplemental oxygen was recorded daily until patient was discharged or supplemental oxygen was discontinued.

3. The occurrence of the following was also recorded: intraventricular haemorrhage, periventricular leukomalacia, necrotising enterocolitis, retinopathy of prematurity, GI bleed and death.

4. For infants who completed at least a 10 day course of either inhaled or intravenous steroids, an ACTH stimulation test was done 2 weeks after completion of steroid course. The test was completed in 24 neonates and the morning cortisol levels were noted before and one hour after intravenous bolus of 36 µg/kg synthetic ACTH (Cortrosyn, Organon, West Orange, NJ).

Notes

Sample size was determined by assuming a rate of adverse effects (as defined by sepsis or hyperglycaemia or hypertension requiring treatment) of 80% in intravenous steroid‐treated infants. The sample size was calculated to detect a 30% difference in adverse effects at 80% power and P < 0.05.
There was a statistically significant difference between the groups regarding some maternal characteristics such as maternal steroid use and need for caesarean section.

No funding resources were reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information provided

Allocation concealment (selection bias)

Low risk

Random allocation using 3 sets of 27 assembled, opaque envelopes
As infants were enrolled, a card was sequentially pulled and infants were assigned to appropriate study group. In case of multiple gestation, all eligible siblings were assigned to same group to minimize parental anxiety

Blinding (performance bias and detection bias)
All outcomes

High risk

No placebo was used

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No placebo was used

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No placebo was used

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcome data were reported on all enrolled infants

Selective reporting (reporting bias)

Unclear risk

The protocol for the study was not available to us, so we cannot judge if there were any deviations from the protocol or not

Other bias

Unclear risk

Appears free of other bias