Methods

Multi‐national randomised placebo‐controlled clinical trial. Study setting: 40 centres in 9 European countries. Study period: 1 April 1 2010 to 3 August 2013.

Blinding of randomisation: yes
Blinding of intervention: yes
Complete follow‐up: yes
Blinding of outcome measurement: yes

Participants

Infants with PMA 23^0/7 weeks to 27^6/7 weeks and chronological age of 12 hours or less, who required any form of positive pressure support. Exclusion criteria: palliative care; dysmorphic feature or congenital abnormalities likely to affect life expectancy or neurologic development; strongly suspected cyanotic heart disease; were from a multiple‐birth pregnancy (other than the second infant in birth order).

Demographic data: values are presented as mean (SD) or percentage or median (IQR)

Budesonide group: n = 437; followed to first discharge home

Birth weight (g): 798 (193)

Gestational age (weeks): 26.1 (1.3)

Sex (% male): 50.8

Age at randomisation (hours): 6.7 (4.0 to 10.3)

Placebo group: n = 419; followed to first discharge home

Birth weight (g): 803 (189)

Gestational age (weeks): 26.1 (1.2)

Sex (% male): 50.8

Age at randomisation (hours): 6.6 (3.8 to 10.6)

Interventions

The Budesonide group (n = 441 were assigned to budesonide; 437 were followed to first discharge home) received two puffs of budesonide (200µg/puff) administered every 12 hours for the first 14 days of life and one puff administered every 12 hours from day 15 until the last dose of study drug had been administered. Study drugs were administered until infants no longer needed supplemental oxygen and positive pressure support or reached a PMA of 32^0/7 weeks, regardless of ventilator status.

The control group (n = 422; 419 were followed to first discharge home) received placebo containing hydrofluoroalkane propellant

Outcomes

Primary outcome: a composite of death or BPD at 36 weeks' PMA. BPD defined as the requirement for positive pressure support, the requirement for supplemental oxygen at FiO₂ > 0.30, or, if infants receiving low amounts of oxygen, an inability to maintain an oxygen saturation value above 90% during a structured, short period of saturation monitoring coupled with gradual weaning from oxygen to ambient air (oxygen reduction test).

Secondary outcomes: death by any cause at 36 weeks' PMA, BPD at 36 weeks' PMA (defined as per above), duration of positive pressure respiratory support or supplemental oxygen, ventriculomegaly with or without IVH on ultrasound at or before 36 weeks' PMA, PDA requiring medical or surgical treatment, intestinal perforation or NEC (we included this outcome under NEC), ROP (≥ stage 2), culture‐proven infections, increase in body weight and head circumference from birth to day 28, length of hospital stay, need for reintubation after the last dose of drug had been administered, occurrence of oral candidiasis requiring treatment, hyperglycaemia requiring insulin treatment, hypertension requiring treatment.

Neurodevelopmental disability testing to be conducted at 18 to 22 months (results not reported in this publication).

Notes

ClinicalTrials.gov: NCT01035190

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A computer generated randomisation scheme.

Allocation concealment (selection bias)

Low risk

The manufacturer of the study drug received the sequence of study drug assignments from a statistician at the coordinating centre and prepared drug packages, each of which contained 8 sequentially numbered metered dose inhalers that were identical in appearance. Packages of coded inhalers containing the study drugs were delivered to each participating centre to ensure concealment of randomisation.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

See comments above.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

No one involved in patient care or in the assessment and analysis of outcomes was aware of the individual study group assignments before completion of the analysis.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

4 in the budesonide group and 3 in the control group had unknown outcome because of withdrawal of consent or right to use data.

Selective reporting (reporting bias)

Low risk

The study was registered as ClinicalTrials.gov number NCT01035190. There does not seem to be any major deviations from the protocol.

Other bias

Low risk

Appears free of other bias.

Methods

Multicentre randomised, double‐blind, placebo‐controlled trial.

Infants were stratified for randomisation according to: study site, sex, birth weight (≤ 900 g or > 900 g), and severity of pulmonary disease (oxygenation index ≤ 5).

Blinding of randomisation: yes
Blinding of intervention: yes
Complete follow‐up: no
Blinding of outcome measurement: yes

Participants

Preterm infants < 33 weeks gestational age and birth weight ≤ 1250 g who required assisted ventilation between 3 and 14 days of life were eligible.

256 infants were enrolled in the study, 3 excluded due to sepsis (n = 2) and one infant had received systemic glucocorticoid therapy prior to enrolment.

Demographic data: values presented as mean (SD)

Beclomethasone dipropionate group: n = 123
7 died and 1 withdrawn prior to 28 days of age
4 died and 8 withdrawn between 28 days and 36 weeks' PMA

Birth weight (g): 800 (193)
Gestational age (weeks): 26 (2)
Sex (%) male: 51
Age at enrolment (days): 5.7 (3.4)
Oxygenation index at entry: 3.7 (3.1)

Placebo group: n = 130
7 died and 2 withdrawn prior to 28 days
1 died and 4 withdrawn between 28 days and 36 weeks' PMA
Birth weight (g): 802 (189)
Gestational age (weeks): 26 (2)
Sex (%) male: 53
Age at enrolment (days): 5.4 (2.9)
Oxygenation index at entry: 4.1 (3.8)

Exclusion criteria:
Preterm infants with evidence of sepsis (clinical diagnosis or positive blood, cerebrospinal fluid, or urine culture), glucose intolerance (blood glucose > 6.7 mmol/L), hypertension (systolic blood pressure > 100 mmHg), NEC (according to physical and radiographic findings), abnormal renal function (serum creatinine > 186 mmol/L and a urine output of < 0.3 ml/kg/day), abnormal liver function (serum alanine aminotransferase concentration of > 108 U/L and serum aspartate aminotransferase concentration of > 150 U/L), major congenital anomalies, or prior systemic glucocorticoid therapy.
Study centres: 3 in the US
Study period: October 1993 to April 1997

Interventions

Beclomethasone dipropionate (n = 123)
Placebo (n = 130)
Beclomethasone dipropionate (Beclovent, Allen and Hansbury, Glaxo Wellcome) and placebo metered‐dose inhalers (MDI) providing 42 µg/actuation were obtained from the drug manufacturer.
Mode of delivery: from the MDI with a valve‐holding chamber (Aerochamber, Monaghan Medical) interposed between the neonatal anaesthesia bag and infant's endotracheal tube.
The delivery procedure was standardized with respect to ventilation technique and actuation procedure for the MDI.
For infants not requiring mechanical ventilation the study drug was administered by the same procedure through endotracheal tube in the pharynx.
Dose: based on the desired dose of study drug to be delivered (µg/kg/day) times the infant's weight (in kg) divided by the dose exiting the endotracheal tube (in µg/actuation) equalled the total number of actuations per day.
The mean dose of beclomethasone exiting the endotracheal tube was 1.7 µg/actuation (4%/actuation dose), as measured in prior studies in vitro.
The desired dose was calculated to deliver 40 µg/kg/day for the first week, 30 and 15 µg/kg/day for second and third week respectively, and 10 and then 5 µg/kg/day in the fourth week.
Duration of treatment: 4 weeks.
Systemic glucocorticoid therapy permitted at the discretion of infant's physician (if the infant had an increasing oxygen requirement that was greater than the baseline for at least 5 days and had received the study drug for a minimum of 7 days). Treatment with the study drug was discontinued but intention‐to‐treat analysis was performed.

Outcomes

Primary outcome:
Frequency of BPD at 28 days of life

Secondary outcomes:
Frequency of BPD at 36 weeks' PMA
Duration of respiratory support
Need for systemic glucocorticoid, diuretic, or bronchodilator therapy
Frequency of air leak
Death
Length of hospitalisation

The incidence of adverse events:
Hypertension, hyperglycaemia, NEC, gastrointestinal haemorrhage, intracranial haemorrhage, periventricular leukomalacia, ROP, cataracts, suppression of pituitary‐adrenal axis, and growth. Chest x‐rays obtained at 28 days of age and 36 weeks' PMA were reviewed by a single radiologist unaware of the infants' study‐group assignment.

Notes

Randomisation schedule was provided by the data coordinating centre to the pharmacy at each study centre.
An interim analysis was performed after 125 infants had reached 28 days of age. According to the Lan‐DeMets data monitoring rule, no significant difference was noted (P = 0.20) and therefore the study was continued.
Reason for withdrawal of infants not described.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Multicentre randomised, double‐blind, placebo‐controlled trial.

Infants were stratified for randomisation according to: study site, sex, birth weight (≤ 900 grams or > 900 grams), and severity of pulmonary disease (oxygenation index ≥ 5 or < 5).

Method of sequence allocation unknown.

Allocation concealment (selection bias)

Low risk

Blinding of randomisation: yes

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Complete follow‐up: no

Selective reporting (reporting bias)

Unclear risk

The trial was not registered so we cannot tell if there was selective reporting or not.

Other bias

Low risk

Appears free of other bias.

Methods

Multi‐centre randomised placebo‐controlled clinical trial. Study setting: 6 neonatal intensive care units in France. Study period: April 1993 to April 1995

Blinding of randomisation: no information provided
Blinding of intervention: no information provided
Complete follow‐up: yes
Blinding of outcome measurement: no information provided

Participants

Infants with respiratory distress syndrome and PMA < 31 weeks were eligible for the study if they required ventilator support on the 10^th postnatal day. 178 infants were randomised, 5 were withdrawn leaving 173 infants in the trial who were assigned to 4 groups of which 2 are included in our review.

Beclomethasone: n = 43

Birth weight (g): 1082 (260)
Gestational age (weeks): 27.8 (1.6)

Placebo group: n = 43
Birth weight (g): 1060 (248)
Gestational age (weeks): 27.6 (1.5)
Exclusion criteria: infants with major malformations, sepsis, current bronchopulmonary infection, or treatment with corticosteroids or bronchodilators were not included.

Interventions

Beclomethasone (n = 43): 250 µg was given 4 times a day (1000 µg daily) starting on the 10^th or 11^th postnatal day and given for 28 days, with dose tapering over a period of 8 days.

Placebo (n = 43): 250 µg was given 4 times a day (1000 µg daily) starting on the 10^th or 11^th postnatal day and given for 28 days, with dose tapering over a period of 8 days.

Outcomes

The main outcome criterion was CLD. The diagnosis of CLD was made at 28 days of age on the basis of clinical (oxygen dependence) and radiographic criteria.

CLD was categorized in 3 grades of severity:

severe: ventilation with ET > 3 months or oxygen supplementation > 4 months; moderate: ventilation with ET > 1 month or oxygen supplementation > 2 months; and mild: ventilation with ET < month and oxygen supplementation < 2 months

Survival without CLD

Death (during hospital stay)

Ventilatory support (nasal IMV, CPAP or IMV) (days)

Need for supplementary oxygen (days)

Need for systemic dexamethasone (IV)

Sepsis (positive blood culture) (no mention of meningitis)

Notes

The definition of CLD is unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information provided

Allocation concealment (selection bias)

Unclear risk

No information provided

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

The trial is described as a prospective, randomised, double‐blind trial, but no supporting evidence is provided by the authors

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

The trial is described as a prospective, randomised, double‐blind trial, but no supporting evidence is provided by the authors

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Initially 178 infants were randomised, but informed consent was either not obtained or withdrawn for five infants leaving 173 infants in the trial. Data reported for those 173 infants who were randomised into 4 groups. Data reported for 43 infants in each of the beclomethasone and placebo groups, which are included in this review.

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

Low risk

Appears free of other bias.

Methods

Randomised controlled trial.

Blinding of randomisation: yes
Blinding of intervention: yes
Complete follow‐up: yes
Blinding of outcome measurement: can't tell

Participants

Preterm infants < 32 weeks gestational age, birth weight < 1.5 kg and requiring mechanical ventilation were eligible if 6 to 10 hours after the second dose of surfactant the arterial PO₂:alveolar PO₂ was < 0.25.

Demographic data: values are presented as mean (SD)
Fluticasone propionate group: n = 27
Birth weight (g): 993 (369)
Gestational age (weeks): 27.9 (2.6)
arterial PO₂: alveolar PO₂ ratio at enrolment: 0.19 (0.05)

Placebo group: n = 26
Birth weight (g): 981 (362)
Gestational age (weeks): 27.1 (2.6)
arterial PO₂: alveolar PO₂ ratio at enrolment: 0.19 (0.05)

Exclusion criteria:
Infants who were dying and those with significant congenital anomalies were excluded.
Study centre: Hong Kong, China
Study period: not stated

Interventions

Fluticasone propionate group (n = 27)
Placebo group (n = 26)
Mode of delivery: aerosol delivery was carried out using an MV15s Aerochamber inserted between the Y‐connector of the ventilator circuit and endotracheal tube.
Infants extubated before day 14 received aerosol through a neonatal Aerochamber (Trudell, Canada), which was modified by removing its one way non‐rebreathing valve. This modification has been shown to increase the amount of aerosol delivery. The face mask of Aerochamber was replaced with a Laerdal Resuscitation mask (Laerdal, Stavanger, Norway) as it has a smaller dead space and a tighter fit to the face.
Dose: two puffs of Fluticasone propionate (Flixotide; Glaxo, UK; 250 µg/ puff) or placebo by metered dose inhaler 12 hourly.
Duration of treatment: 2 weeks.
The first dose was given within 24 hours of birth.

Outcomes

Primary outcomes:
Successful extubation by days 7 and 14 of age

Secondary outcomes:
Mortality
Oxygen dependency at 28 days of postnatal age and 36 weeks' PMA
Adverse events:
hyperglycaemia, hypertension, sepsis confirmed by blood culture, pulmonary air leak (interstitial emphysema, pneumothorax, or pneumomediastinum), periventricular haemorrhage and leukomalacia, ROP, PDA, NEC and bacterial colonization of the airway

Hyperglycemia was defined as a blood glucose reading > 7 mmol/L.
Hypertension was defined as 2 consecutive readings of systolic or diastolic blood pressure ˃ 80 mmHg and 45 mmHg respectively.
Symptomatic PDA was treated with intravenous indomethacin after confirmation by echocardiogram and refractory duct was closed by surgical ligation.
Cranial ultrasound scans were performed at 6, 14 and 28 days of age, and when periventricular haemorrhage was suspected clinically.
Ophthalmology screening for ROP was started at 4 weeks of age.
NEC was diagnosed by the presence of pneumatosis intestinalis or intestinal perforation on abdominal radiograph, of for those requiring surgical intervention, on laparotomy.
Tracheal aspirates for bacterial and fungal cultures were obtained immediately before the first dose of aerosol, and at 3, 5, 7 and 14 days of age.

Static respiratory system compliance (Crs) and resistance (Rrs) were measured immediately before the start of aerosol treatment, and repeated on days 3, 7, and 14 in infants who remained intubated and ventilated. Both Crs and Rrs were measured using a SensorMedics Pulmonary Cart (SensorMedics Inc., Yorba Linda, CA, USA) using the passive flow‐volume technique. The measurement were carried out using a pneumotachograph (Hans Rudolph Inc., USA) with a small dead space (1.8 ml) connected to the endotracheal tube.

Notes

Infants were randomised using computer‐generated random numbers into treatment and control groups and allocation to the groups was performed using opaque, sealed envelopes.
All infants were given two doses (5 ml/kg/dose) of intratracheal synthetic surfactant (Exosurf) 12 hours apart. The first dose was given within 1 hour of birth.

Extubation was considered when the FiO₂ and ventilator rate decreased to < 0.4 and < 10 breaths/minute, respectively. The decision to extubate was made by the attending neonatologists who were blinded to the study protocol and the nature of the aerosol given to the infants.
All infants were given a loading dose of intravenous aminophylline (6 mg/kg) prior to extubation followed by a maintenance dose of 2.5 mg/kg every 12 hourly.
Extubation was considered successful if the infant was able to breathe spontaneously without the endotracheal tube or assisted ventilation for at least 48 hours without a significant increase in respiratory effort and deterioration in blood gas values.
In both groups infants with significant respiratory problems after 14 days of age were given open label systemic dexamethasone as decided by the attending neonatologists.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised controlled trial

Method of sequence generation unknown

Allocation concealment (selection bias)

Low risk

Blinding of randomisation: yes

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome measurement: can't tell

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up: yes

Selective reporting (reporting bias)

Unclear risk

The trial was not registered so we cannot tell if there was selective reporting or not.

Other bias

Low risk

Appears free of other bias.

Methods

Randomised controlled trial

Blinding of randomisation: yes
Blinding of intervention: yes
Complete follow‐up: yes
Blinding of outcome measurement: can't tell

Participants

Preterm infants < 1250 grams diagnosed with RDS and requiring ventilatory support at 72 hours

Demographic data: values presented as mean (SD)
Beclomethasone group: n = 30
Birth weight (g): 882 (204)
Gestational age (weeks): 27.2 (2)
Sex (%) male: 43
Age at enrolment (hours): 72

Placebo group: n = 30
Birth weight (g): 917 (178)
Gestational age (weeks): 27.9 (2)
Gender (%) male: 43
Age at enrolment (hours): 72

Exclusion criteria:
Infants with congenital anomalies
Non‐survival to 72 hours

Study centre: Halifax, Canada
Study period: October 1996 to October 1998

Interventions

Beclomethasone dipropionate (n = 30)
Placebo (n = 30)
Beclomethasone dipropionate (250 µg/puff)
Mode of delivery: in‐line in respiratory limb of ventilator circuit with Medilife spacer via Aerochamber with mask.
Dose: medication dosage assumed a deposition of 10% of the dose given and aimed for a total dose of 0.2 mg/kg/day.
Based on birth weight:
500 to 749 g 1 puff q6h
750 to 999 g 2 puffs q8h
1000 to 1249 g 2 puffs q6h
Duration of treatment: 28 days

Outcomes

Primary outcome:
BPD ‒ defined by 28 day oxygen dependency

Secondary outcomes:
Need for systemic corticosteroid therapy, incidence of sepsis, PVL, ROP, hypertension.

Notes

Randomisation was performed for 3 weight strata in blocks of 4 using sealed envelopes.
Data obtained from the author regarding the mode of delivery, demographic characteristics of the study groups, and adverse events.
Data published in the abstract differ from those obtained from the investigator.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised controlled trial

Method of sequence generation unknown

Allocation concealment (selection bias)

Low risk

Blinding of randomisation: yes

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome measurement: can't tell

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up: yes

Selective reporting (reporting bias)

Unclear risk

The trial was not registered so we cannot tell if there was selective reporting or not.

Other bias

Low risk

Appears free of other bias.

Methods

Randomised double‐blind placebo‐controlled trial

Blinding of randomisation: yes
Blinding of intervention: yes
Complete follow‐up: yes
Blinding of outcome measurement: can't tell

Participants

Very low birth weight infants who were mechanically ventilated on day 6 of life or if extubated, nasal continuous positive airway pressure with FiO₂ of ≥ to 0.3 were included.

Exclusion criteria:
Congenital malformations, congenital heart disease and IVH (grades III‐IV)

Demographic data: values are presented as median (range) or number (%)

Budesonide group: n = 15
Gestational age (weeks): 25 (23 to 27)
Birth weight (g): 766 (525 to 1122)
Sex (M/F): 7/8
Prenatal steroids: 12 (80%)
Surfactant treatment: 14 (93%)

Placebo group: n = 15
Gestational age (weeks): 26 (24 to 29)
Birth weight (g): 813 (630 to 1227)
Sex (M/F): 5/10
Prenatal steroids: 10 (67%)
Surfactant treatment: 15 (100%)

Interventions

Budesonide (Pulmicort) (Astra Draco, Lund, Sweden) or placebo aerosol was used. The drug was delivered using an electronic dosimetric jet nebulizer (Spira Electro 4, Respiratory Centre, Hameenlinna, Finland)
Dose: 500 µg twice a day

Outcomes

Primary outcome: reduction in the FiO₂ levels after 14 days of treatment

Secondary outcomes include:
duration of supplemental oxygen, duration of mechanical ventilation, duration of nasal CPAP, oxygen requirements at 28 days of age and at 36 weeks' PMA, adrenal cortisol response to stimulation at baseline (prior to commencement of inhalation) and at the end of the study period. Information on adverse events: hyperglycaemia, hypertension, sepsis, PDA, IVH and gastrointestinal problems were collected.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised controlled trial

Method of sequence generation unknown

Allocation concealment (selection bias)

Low risk

Blinding of randomisation: yes

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome measurement: can't tell

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up: yes

Selective reporting (reporting bias)

Unclear risk

The trial was not registered so we cannot tell if there was selective reporting or not.

Other bias

Low risk

Appears free of other bias

Methods

Randomised double‐blind placebo controlled trial

Blinding of randomisation: yes
Blinding of intervention: yes
Complete follow‐up: yes
Blinding of outcome measurement: can't tell

Participants

Preterm infants with birth weight of 750 to 1500 grams, gestational age of 25 to 32 weeks, ventilator dependency on day 3 of life with a ventilator rate ≥ 15 breaths/min and FiO₂ of > 0.25 to maintain an oxygen saturation of > 90%.

24 infants were enrolled in the study, one infant in the placebo group withdrawn due to severe sepsis 1 day after starting inhalation therapy.

Demographic data: values are presented as median (range)

Budesonide group: n = 12
Birth weight (g): 1108 (820 to 1420)
Gestational age (weeks): 28 (27 to 32)
Sex (% male): 42
Age at enrolment (hours): 72

Placebo group: n = 11
Birth weight (g): 1120 (880 to 1480)
Gestational age (weeks): 29 (27 to 31)
Sex (% male): 45
Age at enrolment (hours): 72

Exclusion criteria:
Infants with multiple or severe congenital anomalies such as complex congenital heart disease, suspected chromosomal abnormalities, evidence or even suspected sepsis or pneumonia, IVH grade III or IV at the time of randomisation and infants intubated with an endotracheal tube size < 2.5 mm.

Study centre: Aachen, Germany
Study period: November 1995 to August 1996

Interventions

Budesonide (Astra Draco, Lund, Sweden) or placebo aerosol were used. Two puffs of budesonide (200 µg/puff) or placebo was administered 4 times a day for a total of 10 days or until the infants were extubated.
The aerosol was delivered using metered dose inhaler and an Aerochamber (Aerochamber MV15, Trudell Medical, Ontario, Canada). The spacer was directly connected to the endotracheal tube and the distal end of the spacer was connected to a manual puffer.

Outcomes

Primary outcome:
duration of artificial ventilation

Secondary outcomes:
duration of supplemental oxygen
Release of albumin and different inflammatory mediators in the tracheobronchial aspirate fluid
Adverse events:
frequency of acute infections, hypertension, hyperglycaemia and adrenal suppression was evaluated.

CLD was defined as requirement of supplemental oxygen at 28 days of life and at 36 weeks' PMA.
Hyperglycaemia was defined as blood glucose > 8.3 mmol/L.
Hypertension was defined as systolic and diastolic blood pressure > 2 SD from mean values.
Acute infection was suspected if clinical deterioration was observed accompanied by a rise in C‐reactive protein or by ratio of immature to mature granulocytes above 0.2 in complete blood cell count.
A corticotropin‐releasing hormone stimulation test (CRH test) was performed on day 14 after completion of the inhalation treatment.

Notes

Infants were ventilated with Stephan respirator HF 300 (Fa. Stephan, Gackenbach, Germany) in the IPPV or IMV mode.
To facilitate weaning from the ventilator infants were treated with fluid restriction (120 ml/kg/day).
No nebulized bronchodilators or diuretics or supplemental vitamin A or E were used.
Infants with respiratory distress syndrome were treated with natural surfactant (Alveofact) up to a maximum of 3 doses.
Extubation was performed if the ventilator rate was down to 8 breaths/minute and 2 periods of tracheal continuous positive airway pressure lasting 20 minutes were tolerated.
Theophylline or caffeine citrate was used to treat apnoea of prematurity.
Infants who could not be weaned from ventilator on day 14 were treated with systemic glucocorticoids after day 14. Dexamethasone was administered intravenously and divided into two doses: starting dose of 0.5 mg/kg/day for the first 3 days followed by 0.3 mg/kg/day of day 4‐6. From day 7 the dose was reduced to 0.1 mg/kg/day and this was administered on alternate day from day 10 to day 16.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised controlled trial

Method of sequence generation unknown

Allocation concealment (selection bias)

Low risk

Blinding of randomisation: yes

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome measurement: can't tell

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up: yes

Selective reporting (reporting bias)

Unclear risk

The trial was not registered so we cannot tell if there was selective reporting or not.

Other bias

Low risk

Appears free of other bias.

Methods

Randomised double‐blind placebo controlled trial

Blinding of randomisation: yes
Blinding of intervention: yes
Complete follow‐up: yes
Blinding of outcome measurement: yes for all outcomes except for neuromotor examination

Participants

Infants (n = 211) with birth weight < 1000 grams who needed endotracheal intubation and respiratory support due to respiratory failure.

Demographic data: values are presented as mean (SD) or mean (range) or percentage

Fluticasone propionate group: n = 107

Birthweight (g): 784 (135)

Gestational age (weeks): 26.1 (25.1 to 27.3)

Sex (% male): 58.9

Placebo group: n = 104

Birth weight (g): 784 (127)

Gestational age (weeks): 26.2 (25.1 to 27.3)

Sex (% male): 48.1

Interventions

Prophylactic inhaled steroids starting within 24 h of birth and continuing until 6 weeks of age or extubation. Two doses of 50 µg fluticasone propionate (FP) were administered every 24 h (n = 107). The placebo contained only hydrofluoroalkane propellant (n = 104).

Outcomes

The primary outcome measure used to indicate the morbidity of severe BPD was death or oxygen dependence at discharge. The secondary outcomes were death, severe BPD and neurodevelopmental outcomes at 18 months' PMA and 3 years of age

Notes

Because of financial constraints the study was stopped early.

The authors reported all outcomes as a combination of death and a clinical complication of preterm birth. We wrote to the first author on 20 May 2016, for clarifications regarding outcomes, but as of 20th July 2016 we have not received a response. We chose to report the data as per the authors.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

An independent Internet‐based patient registration and randomisation robot. Central randomisation.

Allocation concealment (selection bias)

Low risk

Fluticasone propionate (FP) and placebo metered‐dose inhalers providing 50 g per actuation were obtained from the drug manufacturer. Fluticasone propionate and placebo were delivered from the metered‐dose inhaler with a valve space chamber interposed between the neonatal anaesthesia bag and the endotracheal tube. Double‐blind placebo‐controlled trial.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Staff was blinded to FP and placebo.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All outcomes were assessed blinded to the groups except for the neuromotor exams.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All infants enrolled are accounted for.

Selective reporting (reporting bias)

Unclear risk

The protocol for the study was not available to us so we cannot ascertain if there were any deviations from the protocol. Because of financial constraints the study was stopped early.

Other bias

Low risk

Appears free of other bias.

Methods

Randomised double‐blind placebo‐controlled trial

Blinding of randomisation: yes
Blinding of intervention: yes
Complete follow‐up: yes
Blinding of outcome measurement: can't tell

Participants

Preterm infants < 28 weeks and ≤ 1100 grams at birth who were ventilator dependent due to RDS were enrolled at 48 to 96 hours of age.

Demographic values:
Flunisolide group: n = 15
Gestational age (weeks): 25.8
Birth weight (g): 728 g
Age at enrolment: 3.1 days

Placebo group: n = 17
Gestational age (weeks): 25.5
Birth weight (g): 695 g
Age at enrolment: 3.4 days

Interventions

Flunisolide or placebo 500 µg 3 times a day via spacer chamber connected to the ventilator

Outcomes

Outcome assessed:
Need for systemic steroids
Days on ventilator, in hospital and oxygen supplementation
Information on adverse events were collected:
hypertension, hyperglycaemia, infection, weight gain and complications of prematurity

Notes

The authors do not state whether the demographic data are presented as means or medians

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised controlled trial

Method of sequence generation unknown

Allocation concealment (selection bias)

Low risk

Randomised double‐blind placebo controlled trial

Blinding of randomisation: yes

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome measurement: can't tell

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up: yes

Selective reporting (reporting bias)

Unclear risk

The trial was not registered so we cannot tell if there was selective reporting or not.

Other bias

Unclear risk

Study published in abstract form and not enough information was provided to judge if there were other bias or not.

Methods

Randomised double‐blind placebo controlled trial.
Infants were stratified for gestational age: 24 to 26 weeks and 27 to 32 weeks.

Blinding of randomisation: yes
Blinding of intervention: yes
Complete follow‐up: yes
Blinding of outcome measurement: can't tell

Participants

Preterm infants < 32 weeks and requiring mechanical ventilation from birth were recruited within 18 hours of birth.

40 infants enrolled in the study.

Demographic data: values are presented as mean (SD)

Fluticasone propionate group: n = 20
Birth weight (g): 1011 (223)
Gestational age (weeks): 27.4 (1.7)
Sex (%) male: 65

Placebo group: n = 20
Birth weight (g): 932 (401)
Gestational age (weeks): 27.7 (1.7)
Gender (%) male: 60

Exclusion criteria:
Preterm infants with major congenital anomalies, congenital pneumonia, pneumothorax and pulmonary hypoplasia

Study centre: Jessop Hospital for Women, Sheffield, UK.

Interventions

Fluticasone propionate or placebo (expient without active ingredient)

Mode of delivery: MDI and Aerochamber if ventilated, Babyhaler if extubated
Dose: one puff of fluticasone propionate (250 µg/puff) twice daily
Duration of therapy: 14 days

Outcomes

Data were collected on survival, duration of mechanical ventilation and oxygen supplementation and other measures of morbidity (BP, glucose and IVH). Weight gain and skeletal growth was assessed by knemometry.

Notes

Additional data from the investigators were available for this trial.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised double‐blind placebo controlled trial.
Infants were stratified for gestational age: 24 to 26 weeks and 27 to 32 weeks.

Method of sequence generation unknown.

Allocation concealment (selection bias)

Low risk

Blinding of randomisation: yes

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding of outcome measurement: can't tell

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up: yes

Selective reporting (reporting bias)

Unclear risk

The trial was not registered so we cannot tell if there was selective reporting or not.

Other bias

Low risk

The principal investigator provided additional data.