Kuyucu 2004.

Methods	Double‐randomisation/factorial design, 4 arms Single‐centre, conducted in Turkey (Faculty of Medicine, Mersin University)
Participants	Outpatients (paediatric outpatient clinics and emergency department) Inclusion/exclusion criteria Inclusion criteria: age 2 to 21 mo.; admitted with 1st episode of wheezing; clinical findings compatible with acute bronchiolitis; RDAI ≥ 4 Exclusion criteria: history of wheezing; previous therapy with bronchodilators; previous diagnosis of asthma or allergic bronchitis; personal history of atopic dermatitis or allergic rhinitis; chronic cardiac or pulmonary disease; any glucocorticoid therapy in the previous 2 week; signs of severe respiratory disease; bacterial infection; parental history of asthma or atopic disease Participant characteristics All groups Sample size: randomised (N): 90, analysed ‐ trial/review primary outcome (N): 69 (ITT with available case analysis was used) GROUP 1 Sample size: randomised (N): 26, analysed ‐ trial/review primary outcomes (N): 23 Age, mean ± SD: 7.2 ± 0.8 months GROUP 2 Sample size: randomised (N): 24, analysed ‐ trial/review primary trial outcome (N): 23 Age, mean ± SD: 7.9 ± 1.0 months GROUP 3 Sample size: randomised (N): 19, analysed ‐ trial/review primary trial outcome (N): 11 Age, mean ± SD: 9.6 ± 1.3 months GROUP 4 Sample size: randomised (N): 21, analysed ‐ trial/review primary trial outcome (N): 12 Age, mean ± SD: 9.9 ± 1.7 months Males, N (%): NR RSV status NR Atopic status: NR
Interventions	GROUP 1 (with glucocorticoid) Drug name: epinephrine + dexamethasone Dose: 3 mL (3 mg) of 1:1000 L‐epinephrine + 0.6 mg/kg (dex) Mode of administration: nebulised with O2, flow 5 to 6 L/minute for 10 minutes (epi) + IM (dex) Timing/duration: epinephrine ‐ initial dose, if no improvement at 120 minutes, then 2nd dose given; dexamethasone single dose GROUP 2 (with glucocorticoid) Drug name: salbutamol + dexamethasone Dose: 0.15 mg/kg of 1 mg/mL solution of salbutamol added to 0.9% saline to total 3 mL+ 0.6 mg/kg (dex) Mode of administration: nebulised with O2, flow 5 to 6 L/minute for 10 minutes (epi) + IM (dex) Timing/duration: salbutamol ‐ initial dose, if no improvement at 120 minutes, then 2nd dose given; dexamethasone single dose GROUP 3 Drug name: epinephrine + placebo (NR) Dose: 3 mL (3 mg) of 1:1000 L‐epinephrine Mode of administration: nebulised with O2, flow 5 to 6 L/minute for 10 minutes (epi) + IM (pla) Timing/duration: epinephrine ‐ initial dose, if no improvement at 120 minutes, then 2nd dose given; placebo single dose GROUP 4 Drug name: salbutamol + placebo (NR) Dose: 0.15 mg/kg of 1 mg/mL solution of salbutamol added to 0.9% saline solution to make a total of 3 mL Mode of administration: nebulised with O2, flow 5 to 6 L/minute for 10 minutes (epi) + IM (pla) Timing/duration: salbutamol ‐ initial dose, if no improvement at 120 minutes, then 2nd dose given; placebo single dose Additional co‐interventions for all groups: NR Protocolised use of bronchodilators with glucocorticoids: yes (epinephrine Group 1, salbutamol Group 2)
Outcomes	Primary outcome Respiratory rate*; heart rate*; clinical scale*: RDAI, 17‐point score based on wheezing and retractions Outcome used to calculate sample size NR Secondary outcomes Admissions; additional medication; adverse events; respiratory complaints (2 months) *time points: 30, 60, 90, 120 minutes, 24 hours, 5 days
Funding	NR
Notes	Study did not report any study‐level subgroup analyses This study contributed to the following comparisons in this review: steroid versus. Placebo, steroids + epinephrine versus salbutamol, steroids + salbutamol versus epinephrine Factorial design not reported explicitly; analysis was "inside the table", and did not aggregate group results
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomised fashion"; randomised to the first treatment, "randomised fashion independent of the first randomization" for the second treatment; no further information provided
Allocation concealment (selection bias)	Unclear risk	"Preparation and administration of nebulized solutions were performed by a trained emergency department nurse."
Blinding (performance bias and detection bias) Health care use ((re)admissions, LOS, return visits)	Unclear risk	Double‐blind; "parents and investigators remained blinded to administered medications throughout study period"
Blinding (performance bias and detection bias) Clinical parameters (severity scales, SpO2, respiratory and heart rate)	Unclear risk	Double‐blind; "parents and investigators remained blinded to administered medications throughout study period"
Blinding (performance bias and detection bias) Other outcomes (adverse events, others)	Unclear risk	Double‐blind; "parents and investigators remained blinded to administered medications throughout study period"
Incomplete outcome data (attrition bias) Health care use ((re)admissions, LOS, return visits)	High risk	21 patients with missing outcome data, imbalanced between groups; no motives reported
Incomplete outcome data (attrition bias) Clinical parameters (severity scales, SpO2, respiratory and heart rate)	High risk	21 patients with missing outcome data, imbalanced between groups; no motives reported
Incomplete outcome data (attrition bias) Other outcomes (adverse events, others)	High risk	21 patients with missing outcome data, imbalanced between groups; no motives reported
Selective reporting (reporting bias)	Low risk	Published report includes all pre‐specified and expected outcomes; study protocol was not available
Other bias	Unclear risk	Duration of illness was significantly different in G + S group
Overall risk of bias	High risk	> 1 domain as high risk of bias