Benjamin 1986.

Methods	Allocation: randomized Controlled: placebo Blinding: double‐blind Arm: 4 arms, parallel treatment groups Centre: multicentre (5 centres) Study dates and duration: not reported
Participants	Inclusion criteria: known history of SCD (SS, SB/Thal), in a crisis lasting 4–24 hr. 1 crisis per participant Exclusion criteria: pregnant, women of childbearing potential, incarceration, drug abuse history, transfusion 90 days prior to trial, acute cerebrovascular accident, overt infection, renal failure with a serum creatinine concentration > 2 mg percent (0.18 mmol/L), clinical or roentgenographic evidence of pulmonary oedema, glaucoma, urinary retention, high sensitivity to anticholinergic or atropine‐like drugs Baseline characteristics N: 67 participants; 67 VOC episodes Age: ≥ 19 years (67% aged 20–29) years Gender: F 27, M 36 Setting and location: 5 state and university hospitals, and clinical centres, USA Number randomized: 16 cetiedil 0.2 mg/kg group; 18 cetiedil 0.3 mg/kg group; 13 cetiedil 0.4 mg/kg group; 16 control group Number completed: 16 cetiedil 0.2 mg/kg group; 18 cetiedil 0.3 mg/kg group; 13 cetiedil 0.4 mg/kg group; 16 control group (63 included in efficacy analysis, 4 high haemoglobin A, all 67 included in safety analysis
Interventions	Treatment group A (16 participants; 16 VOC episodes): IV cetiedil 0.2 mg/kg body weight in normal saline, every 8 hr, total of 12 doses Treatment group B (18 participants; 18 VOC episodes): IV cetiedil 0.3 mg/kg body weight in normal saline, every 8 hr, total of 12 doses Treatment group C (13 participants; 13 VOC episodes): IV cetiedil 0.4 mg/kg body weight in normal saline, every 8 hr, total of 12 doses Control group (16 participants; 16 VOC episodes): 0.9 mg/mL normal IV saline, every 8 hr, total of 12 doses Duration of treatment period: 4 days Follow‐up period: not reported Cointerventions/additional analgesia: additional analgesics if required – limited to parenteral meperidine hydrochloride 1.2 mg/kg, or oral paracetamol 300 mg with codeine phosphate 30 mg. Standard fluid replacement therapy
Outcomes	Primary outcomes Pain intensity scale (numerical 0–3) Secondary outcomes Number of painful sites Duration of crisis (when 4 criteria met) Need for analgesic medication Investigator's overall evaluation of the participant' responses to study medication
Notes	Sources of funding: supported by Johnson and Johnson Baby Products, McNeil Pharmaceutical, Inc and by General Clinical Research Center Grants (RR 00102 and RR 00046) from the National Institutes of Health and by the Veterans Administration Medical Service Research Fund.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were randomly assigned at a central data centre." "The randomization plan specified a coded ampule and a volume dosage for each patient."
Allocation concealment (selection bias)	Low risk	Quote: "Drug, active or placebo, was presented in identically appearing ampules. The investigators were aware of the volume of medication but were not aware of the ampule's contents."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The study was double‐blind." "The investigators were aware of the volume of medication by were not aware of the ampule's contents."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "The investigators were aware of the volume of medication but were not aware of the ampule's contents." Comment: not entirely clear whether this was extended to the pain evaluators or research nurses being blind to the treatment groups when assessing pain.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "Sixty‐seven patients were entered in the trial. Sixty‐three patients were included in the analysis of efficacy. Four patients were found retrospectively to have high hemoglobin." Comment: reasonable retroactive application of exclusion criteria. Likely to be fairly small attrition bias effect, but small numbers per treatment group, so this randomization 'error' was unfortunate.
Selective reporting (reporting bias)	Low risk	Comment: no protocol available, but all planned end points were reported in results.
Size	High risk	Comment: total participants 67, < 50 participants per treatment arm.
Other bias	Low risk	Comment: no other possible sources of bias.