| Study characteristics |
| Methods |
Multi‐centre randomised placebo‐controlled trial |
| Participants |
67 preterm infants (24 to 32 weeks) on a ventilator by < 8 hours were eligible for inclusion
Exclusion criteria: postnatal age > 72 hours, positive‐pressure ventilation ≥ 8 hours, major congenital anomalies, severe intrapartum asphyxia (Apgar score ≤ 3 at 5 min), participation in other studies interfering with NOPAIN trial procedures criteria |
| Interventions |
Morphine group (n = 24): loading dose 100 mcg/kg for all gestational ages
Midazolam group (n = 22): loading dose 200 mcg/kg followed by infusion of 20, 40, or 60 mcg/kg/hour for infants of gestational ages 24 to 26, 27 to 29, and 30 to 32 weeks, respectively
Placebo group (n = 21): dextrose 10%
Treatment continued as long as necessary (written protocol for stopping drugs), max 14 days. Additional analgesia with morphine bolus doses was allowed. Amount and frequency of additional morphine were recorded as an outcome measure |
| Outcomes |
Primary outcome: incidence of adverse neurological events (neonatal death, grade III/IV IVH, PVL)
Secondary outcomes: level of sedation (measured by COMFORT score); pain response to tracheal suctioning (assessed by PIPP) ‐ all scores assessed before start of treatment, after 24 hours of infusion, and at 10 to 12 hours after treatment was discontinued; incidence of pneumothorax; days of ventilatory support; continuous positive airway pressure and oxygen; length of intensive care unit and hospital stay; days needed to reach full enteral feeding; weight gain at hospital discharge; neurodevelopmental outcome (measured by Neurobehavioral Assessment of NAPI cluster scores at 36 weeks' corrected for gestational age) |
| Notes |
|
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
Randomisation was performed by an automated procedure in blocks, stratified by centre |
| Allocation concealment (selection bias) |
Low risk |
Allocation concealment was ensured by an automated telephone response system |
| Blinding of participants and personnel (performance bias) |
Low risk |
Caregivers were blinded to treatment |
| Blinding of outcome assessment (detection bias) |
Low risk |
Outcome assessors were blinded to treatment |
| Incomplete outcome data (attrition bias) |
Low risk |
Outcomes were reported for all patients enrolled |
| Selective reporting (reporting bias) |
Unclear risk |
Trial not registered; protocol not available |
| Other bias |
Low risk |
Study appears to be free of other sources of bias |
