Jacqz‐Aigrain 1994.

Methods	Randomised, double‐blind, placebo‐controlled trial Randomisation was stratified by 2 gestational age groups (< 33 weeks and ≥ 33 weeks). 1. Blinding of randomisation ‐ cannot determine 2. Blinding of intervention ‐ yes 3. Complete follow‐up ‐ yes 4. Blinding of outcome measure ‐ yes
Participants	Newborn infants ≤ 48 hours of age who required intubation and ventilation for respiratory distress syndrome were eligible for inclusion. Exclusion criteria: previous exposure to benzodiazepines (maternal/infant), congenital anomalies, major neurological abnormalities, low Apgar score at 5 minutes (score not defined by study authors) 48 preterm infants were enrolled. 1 who received midazolam previously and 1 with 5‐minute Apgar score of 0 were excluded. 46 infants (25 at ≤ 33 weeks', 21 at > 33 weeks' gestational age) were included in the analysis. Demographic data: values presented as means (SDs) Midazolam group (n = 24) Gestational age: 32.1 weeks (2.8 weeks) Birth weight: 1820 grams (647 grams) Male: 58.3% 5‐Minute Apgar score: 9.0 (1.2) MAP at enrolment: 12 mmHg (2 mmHg) FiO2 at enrolment: 49% (13%) Duration of infusion: 78.7 hours (30.9 hours) Placebo group (n = 22) Gestational age: 32.8 weeks (2.6 weeks) Birth weight: 2000 grams (548 grams) Male: 59.1% 5‐Minute Apgar score: 8.1 (2.3) MAP at enrolment: 13 mmHg (2 mmHg) FiO2 at enrolment: 51% (16%)
Interventions	24 infants received midazolam infusion. For infants ≥ 33 weeks: 60 microgram/kg/h for up to 5 days For infants < 33 weeks: 60 microgram/kg/h for 1 day, then 30 microgram/kg/h for up to 5 days Infusion could have been stopped after 48 hours if no longer required. 22 infants received a manufactured placebo. Additional sedation with fentanyl or use of muscle relaxant was permitted; the study protocol was interrupted in such cases, but data from these infants were used in the analysis.
Outcomes	Primary outcome Adequacy of sedation was measured 4 times per day (twice by nurses and twice by physicians) on a 5‐item behavioural scale (facial expression, sucking, spontaneous motor activity, excitability and response to stimulation, excessive flexing); physiological measures of sedation level included mean daily values of hourly heart rate, systolic and diastolic blood pressures. Secondary outcomes Incidence of intracranial haemorrhage and epileptiform movement; haemodynamic instability (need for fluid, albumin, vasoactive drugs); ventilation requirement (PIP, PEEP, MAP); days of ventilation; days of supplemental oxygen; incidence of pneumothorax and pulmonary interstitial emphysema; total days of NICU stay Serum concentrations of midazolam were monitored before and 24 and 48 hours after the start of infusion and at the end of treatment.
Notes	Randomisation was performed by selecting the next envelope in 2 boxes, 1 for each gestational age stratum. Protocol for weaning of study drug was not described. Midazolam and placebo were supplied by Laboratories Roche, Paris, France.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information was provided.
Allocation concealment (selection bias)	Low risk	Randomisation to treatment or placebo was stratified by gestational age at birth (< 33 weeks and ≥ 33 weeks). The intensive care unit had 2 boxes containing individual treatments for 5 days. When an infant met all entry criteria, investigators used the next envelope in the appropriate box.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Medical staff, radiologist and pharmacologist interpreting the study were blinded to treatment assignment.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Medical staff, radiologist and pharmacologist interpreting the study were blinded to treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcomes were reported for all enrolled infants except 1; 1 infant was immediately excluded because he had previously received midazolam, and 1 was excluded because of an Apgar score of 0 at 5 minutes of age. Data for the remaining 46 infants were analysed.
Selective reporting (reporting bias)	Unclear risk	The protocol for the study was not available to us, so we cannot ascertain whether deviations from the protocol occurred.
Other bias	Low risk	Trial appears free of other bias.

AaDO₂: alveolar‐arterial oxygen gradient; CRIB: Clinical Risk Index for Babies; FiO₂: fraction of inspired oxygen concentration; IVH: intraventricular haemorrhage; MAP: mean airway pressure; NAPI: Neurobehavioral Assessment of the Premature Infant; NICU: neonatal intensive care unit; NMI: Neonatal Medical Index; NOPAIN: Neonatal Outcome and Prolonged Analgesia In Neonates; OI: oxygenation index; PEEP: positive end‐expiratory pressures; PIP: peak inspiratory pressure; PIPP: Premature Infant Pain Profile; PVL: periventricular leukomalacia; SD: standard deviation.