Halliday 2001.

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