Van Dijk 2002.

Study characteristics
Methods	Study design: Double‐blind, randomized clinical trial Study grouping: Intermittent morphine versus continuous morphine
Participants	Baseline Characteristics Inclusion criteria: Children aged 0–3 years, admitted for major abdominal or thoracic surgery. In addition, included patients were neonates (greater than or equal to 35 weeks gestation and body weight greater than or equal to 1500 g) and infants aged up to 3 years. Exclusion criteria: Exclusion criteria were use of analgesic or sedative co‐medication (e.g. acetaminophen or midazolam) influencing the measured amount or potency of morphine, use of neuromuscular blockers, hepatic or renal dysfunction, seriously compromised neurological status, or altered muscle tone. Pretreatment: Anesthetic management was standardized. Perioperative fluids were standardized to maintain a glucose infusion rate between 4 and 6 mg/kg/min; body temperature was kept within normal ranges. After the first arterial blood sample (baseline), patients received a second dose of 5 mcg/kg of fentanyl before surgical incision. At the end of surgery, all patients were given an intravenous loading dose of 100 mg/kg morphine.
Interventions	Intervention Characteristics Continuous infusion versus bolus administration Dose regimen: Morphine continuous intravenous infusion 10 mcg/kg/h versus morphine every 3 hours after surgery 30 mcg/kg Description of procedure: The continuous morphine group started with a morphine infusion of 10 mcg/kg/h, combined with an intravenous placebo bolus (saline) every 3 h. The intermittent group received a continuous placebo infusion (saline), combined with an i.v. morphine bolus of 30 mcg/kg every 3 h. The first intermittent bolus (morphine or placebo) was given 3 h after surgery.
Outcomes	Pain assessed with validated methods during the administration of selected drugs Outcome type: Continuous outcome Pain was assessed with the behavioral part of the COMFORT scale. In addition, the nurses completed an observational VAS for a clinical rating of pain in each child.
Identification	Sponsorship source: Supported by the Dutch Organization for Scientific Research Country: The Netherlands Setting: Neonatal Intensive Care Unit Comments: None Authors names: Monique van Dijk, Nancy J. Bouwmeester, Hugo J. Duivenvoorden, Hans M. Koot, Dick Tibboel, Jan Passchier, Josien B. de Boer Institution: Department of Pediatric Surgery, Erasmus MC‐Sophia Email: vandijk@psys.azr.nl Address: Department of Pediatric Surgery, Erasmus MC‐Sophia, Rotterdam, The Netherlands
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Infants within these age categories were randomly assigned to CM or IM administration." "The hospital pharmacist prepared the study drugs; the randomization schedule was known to the pharmacist only and retained until the end of the trial." Not specified how the randomization schedule was generated
Allocation concealment (selection bias)	Low risk	"The hospital pharmacist prepared the study drugs; the randomization schedule was known to the pharmacist only and retained until the end of the trial".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"The hospital pharmacist prepared the study drugs; the randomization schedule was known to the pharmacist only and retained until the end of the trial." Blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Pharmacist prepared the study drugs; the randomization schedule was known to the pharmacist only and retained until the end of the trial. Pain was assessed prior to surgery." Blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	"Excluded infants did not significantly differ with regard to background characteristics, except age. This is primarily due to the low number of excluded neonates." "204 infants were allocated to this trial. However, five were lost to follow‐up; one infant died within the first hours after surgery due to irreversible pulmonary hypertension, three patients had a failing arterial line, and one patient experienced clinical signs of ventilatory depression. In addition, 18 patients were excluded because they did not comply with the inclusion criteria:"
Selective reporting (reporting bias)	Unclear risk	No registry reported so unable to compare to protocol
Other bias	Low risk	None