Plint 2009.
| Methods | Factorial design, 4 arms Multi‐centre (8), conducted in Canada (hospitals are members of the research group Paediatric Emergency Research Canada) |
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| Participants | Outpatients (paediatric emergency department) Inclusion/exclusion criteria Inclusion criteria: age 6 to 12 mo.; RDAI: 4 to 15; 1st episode wheezing associated with upper respiratory tract infection; presenting bronchiolitis Exclusion criteria: prior bronchodilator treatment in the emergency department; oral or inhaled glucocorticoid during previous 2 weeks; previous episode of wheezing or history of asthma; previous bronchodilator use; chronic cardiopulmonary disease; immunodeficiency; serious distress (defined as a pulse rate > 200 beats per minute, a respiratory rate > 80 breaths per minute, or an RDAI score > 15); lethargy; exposed to varicella < 3 weeks; < 37‐week gestation who had a corrected age of less than 6 weeks at presentation; communication barriers with family Participant characteristics All groups Sample size: randomised (N): 800, analysed ‐ trial/review primary outcome (N): 797 (ITT with available case analysis was performed) GROUP 1 Sample size: randomised (N): 200, analysed ‐ trial/review primary outcomes (N): 199 Age: 5 (median) 3 to 7 (interquartile range) months Males, N (%): 124 (62) RSV status: 128 (64) positive Atopic status: 28 (14) present (infant) GROUP 2 Sample size: randomised (N): 199, analysed ‐ trial/review primary trial outcome (N): 198 Age: 5 (median) 3 to 7 (interquartile range) months Males, N (%): 122 (61) RSV status: 129 (65) positive Atopic status: 20 (10) present (infant) GROUP 3 Sample size: randomised (N): 200, analysed ‐ trial/review primary trial outcome (N): 199 Age: 5 (median) 3 to 7 (interquartile range) months Males, N (%): 127 (64) RSV status: 127 (64) positive Atopic status: 19 (9.5) present (infant) GROUP 4 Sample size: randomised (N): 201, analysed ‐ trial/review primary trial outcome (N): 201 Age: 5 (median) 3 to 7 (interquartile range) months Males, N (%): 120 (60) RSV status: 136 (68) positive Atopic status: 22 (10.9) present (infant) |
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| Interventions |
GROUP 1 (with glucocorticoid)
Drug name: epinephrine + dexamethasone (generic dexamethasone phosphate injection solution mixed with Ora‐Plus and Ora‐Sweet ‐ Paddock Laboratories)
Dose: 3 mL 1:1000 solution (epi)+ 1.0 mg/kg weight (max 10 mg) then 0.6 mg/kg (max 10 mg) after ED (dex)
Mode of administration: nebulised in O2 flow 8L/minute (epi) + oral (dex)
Timing/duration: nebulise 2 doses 30 minutes apart (epi); oral after 1st nebulisation in ED, followed by 5, 1 x daily doses after leaving ED (dex) GROUP 2 Drug name: epinephrine + placebo (Ora‐Plus and Ora‐Sweet) Dose: 3 mL 1:1000 solution (epi) + placebo Mode of administration: nebulised in O2 flow 8 L/minute (epi) + oral (pla) Timing/duration: nebulise 2 doses 30 minutes apart (epi); oral after 1st nebulisation in ED, followed by 5, 1 x daily doses after leaving ED (pla) GROUP 3 (with glucocorticoid) Drug name: dexamethasone + placebo (saline) Dose: 1.0 mg/kg weight (max 10 mg) then 0.6 mg/kg (max 10 mg) after ED (dex) + 3 mL (pla) Mode of administration: oral (dex) + nebulised in O2 flow 8L/minute (pla) Timing/duration: nebulise 2 doses 30 minutes apart (pla); oral after 1st nebulisation in ED, followed by 5, 1 x daily doses after leaving ED (dex) GROUP 4 Drug name: placebo (saline) + placebo (Ora‐Plus and Ora‐Sweet) Dose: 3 mL + oral Mode of administration: nebulised in O2 flow 8 L/minute + oral Timing/duration: nebulise 2 doses 30 minutes apart; oral after 1st nebulisation in ED, followed by 5, 1 x daily doses after leaving ED Additional co‐interventions for all groups: O2 if SaO2 < 92%; acetaminophen (15 mg/kg) if fever; additional interventions allowed after 90' ‐ reported use of other bronchodilators and antibiotics Protocolised use of bronchodilators with glucocorticoids: yes (epinephrine Group 1) |
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| Outcomes |
Primary outcome/outcome used to calculate sample size
Hospital admission by day 7 Secondary outcomes Hospital admission by day 1 and day 22; SaO2*; respiratory rate*; heart rate*, temperature*; RDAI: 17‐point score based on wheezing and retractions*; time to discharge (time between the triage time at the enrolment and the time of discharge from the last emergency department visit or from the last hospitalisation for each patient within the next 7 days); return healthcare visits#; symptoms (length/severity)#; adverse events *time points: 30, 60, 120, 240 minutes #time points: within 22 d |
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| Funding | Grants from the Canadian Institutes of Health Research and Alberta Children’s Hospital Foundation | |
| Notes | Study reported a priori subgroup analyses of presence or absence of atopy, RSV status and duration of illness at presentation; adjusted analysis plan with interaction terms This study contributed to the following comparisons in this review: steroid versus placebo, steroids + epinephrine versus placebo Analysis of factorial design was "inside the table", due to results suggesting unanticipated synergism between epinephrine and dexamethasone |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "computer‐generated randomization sequence, stratified by center, used randomised permuted blocks of 8 and 12." |
| Allocation concealment (selection bias) | Low risk | "Codes were secured at each center’s pharmacy until enrolment and data en‐ try were complete. In order to conceal the allocation sequence, the pharmacy at each site prepared the study drugs in sequentially numbered, visually identical packets." |
| Blinding (performance bias and detection bias) Health care use ((re)admissions, LOS, return visits) | Low risk | Double‐blind; "The active drugs and placebo were identical in appearance, volume, weight, odor, and taste." |
| Blinding (performance bias and detection bias) Clinical parameters (severity scales, SpO2, respiratory and heart rate) | Low risk | Double‐blind; "The active drugs and placebo were identical in appearance, volume, weight, odor, and taste." |
| Blinding (performance bias and detection bias) Patient/parent‐reported outcomes (symptoms, QoL) | Low risk | Double‐blind; "The active drugs and placebo were identical in appearance, volume, weight, odor, and taste." |
| Blinding (performance bias and detection bias) Other outcomes (adverse events, others) | Low risk | Double‐blind; "The active drugs and placebo were identical in appearance, volume, weight, odor, and taste." |
| Incomplete outcome data (attrition bias) Health care use ((re)admissions, LOS, return visits) | Low risk | 3 patients with missing outcome data |
| Incomplete outcome data (attrition bias) Clinical parameters (severity scales, SpO2, respiratory and heart rate) | Low risk | 3 patients with missing outcome data |
| Incomplete outcome data (attrition bias) Patient/parent‐reported outcomes (symptoms, QoL) | Low risk | 3 patients with missing outcome data |
| Incomplete outcome data (attrition bias) Other outcomes (adverse events, others) | Low risk | 3 patients with missing outcome data |
| Selective reporting (reporting bias) | Low risk | Published report includes all pre‐specified and expected outcomes; study protocol was available |
| Other bias | Low risk | No significant baseline imbalances; no other sources of bias |
| Overall risk of bias | Low risk | All applicable domains low risk of bias |