Steer 2004.

Study characteristics
Methods	Study design: multi‐centre RCT Location: Australia Setting: four neonatal intensive care units (Mater Mothers’ Hospital, Brisbane; Royal Prince Alfred Hospital, Sydney; Mercy Hospital for Women, Melbourne; and Royal Hobart Hospital, Tasmania) Duration: September 1996 to April 1999
Participants	Inclusion criteria: 287 infants < 30 weeks' gestational age requiring methylxanthines for treatment of apnea of prematurity or as a part of peri‐extubation management. Eligible for the peri‐extubation group were infants who received or who were expected to receive at least 48 hours of mechanical ventilation Exclusion criteria: infants with major congenital abnormality, infection (sepsis confirmed by blood culture), major neurological condition, grade 3 or 4 IVH, and previous exposure to methylxanthine therapy. Infants who received short‐term caffeine (≤ seven days)
Interventions	High dose: loading dose 80 mg/kg/day and maintenance dose 20 mg/kg/day Low dose: loading dose 20 mg/kg/day and maintenance dose 5 mg/kg/day
Outcomes	Outcomes reported that are considered for this review: mortality during first admission; chronic lung disease at 36 weeks of corrected age; severe IVH, ≥ grade 3; IVH, any grade; cerebellar hemorrhage; periventricular leukomalacia (PVL); lesions indicative of brain injury (detected by US and MRI): IVH, any grade; major cerebral abnormalities (defined as one or more of porencephalic cysts, cystic periventricular leukomalacia or hydrocephalus); apnea; extubation failure (defined as an inability to extubate from mechanical ventilation within 48 hours of caffeine loading for a planned extubation or the use of reintubation or doxapram within 7 days of caffeine loading); retinopathy of prematurity, ≥ grade 3; any tachycardia; tachycardia, leading to suspension of study intervention; necrotizing enterocolitis (NEC); major cerebral abnormalities at 6 weeks; and major disability (cerebral palsy, bilateral blindness, need for hearing aids at 12 months corrected for prematurity).
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Infants were randomized using a computer generated list of random numbers by a hospital pharmacist who was not associated in any other way with the study or with the clinical management of infants.
Allocation concealment (selection bias)	Unclear risk	Not reported.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The two strengths of caffeine citrate were identical in appearance. Investigators and clinical staff were blind to treatment allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Investigators were blind to treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	41 out 287 infants were excluded after randomization and were not analyzed. This correspond to 14% of the infants, which is still acceptable for our review.
Selective reporting (reporting bias)	Unclear risk	Trial protocol not available.
Other bias	Low risk	None known.