Ceelie 2013.

Study characteristics
Methods	RCT, parallel groups
Participants	71 infants admitted to a level 3 pediatric intensive care unit in Netherlands Inclusion criteria: Children with post‐conceptual age of 36 1/7 week or older to 1 year of age; bodyweight greater than 1500g; and undergoing major thoracic (noncardiac) or abdominal surgery Exclusion criteria: Exclusion criteria were extracorporeal membrane oxygenation treatment; neurologic dysfunction, hepatic dysfunction, or renal insufficiency; prenatal or postnatal administration of opioids or psychotropic drugs (anti‐epileptics, benzodiazepines, antidepressants) for more than 24 hours; known allergy to or intolerance for paracetamol or morphine; and administration of opioids in the 24 hours prior to surgery.
Interventions	Continuous morphine, Patients aged 10 days, 2.5 g/kg/hour; patients aged 11 days to 1 year, 5 g/kg/hour Intermittent paracetamol, 30 mg/kg per day in 4 doses
Outcomes	Primary: cumulative morphine dose (i.e. the sum of the intraoperative loading dose, the morphine study dose, and the rescue morphine doses) Secondary: morphine rescue dose (microgram/kg) in the first 48 postoperative hours; number of extra rescue morphine doses and infusions; number of patients receiving rescue doses; pain scores (NRS‐11, COMFORT‐B); morphine‐related adverse effects (need for mechanical ventilation or/and reintubation, apnea, naloxone administration, bradycardia, hypotension, seizures, gastrointestinal adverse effects, urinary retention)
Notes	Authors had nothing to declare.  Funding source:  ZonMw Priority Medicines for Children grant
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients had an equal probability of assignment to study groups. Stratified randomization was used in combination with random permuted blocks."
Allocation concealment (selection bias)	Unclear risk	Quote: "A hospital pharmacist carried out computer randomization in advance, and codes were safely stored. (...) A new randomization schedule was computer generated by the same pharmacist. Only the pharmacist had access to group allocation during the study period, for preparation of study medication."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "When patients were randomized to receive paracetamol (30 mg/kg per day in 4 doses), a placebo infusion of normal saline was administered continuously at the same rate as an equivalent morphine infusion. When randomized to receive morphine (...), normal saline was administered 4 times daily as placebo in a volume similar to the intravenous paracetamol dose. Placebos could not be distinguished from the active study drug in color, odor, or viscosity."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The clinical personnel (blinded as per the previous point) were outcome assessors. Also, "The pharmacist and the statistician performed this interim evaluation after inclusion of 20 patients; the pharmacist, statistician, and investigators remained blinded."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data reported for all assessed infants
Selective reporting (reporting bias)	Unclear risk	Some of the secondary outcomes planned in the trial registry (www.trialregister.nl/trial/1378) were not reported, for example, saliva cortisol levels
Other bias	Low risk	None