Inhaled salbutamol appears safe for short-term use in children under 2 with acute wheeze; metered-dose inhaler with spacer (MDI-S) is likely safer than nebulisation, which increases minor adverse reactions but not severe events.
Background
Salbutamol is widely used for acute wheeze, but safety data in children under 2 years are limited and regulatory approvals are more restrictive for infants. This meta-analysis evaluated short-term safety of inhaled salbutamol in this age group across randomised controlled trials (RCTs).
Patients
- Infants and toddlers younger than 24 months with acute wheezing disorders, including bronchiolitis.
- Settings: emergency department, inpatient wards, and one ambulatory setting.
- Total included records: 24 RCTs; primary quantitative analysis for adverse drug reactions (ADRs) used 7 RCTs (n=597).
Intervention
- Inhaled salbutamol administered via nebulisation or metered-dose inhaler (MDI) with or without spacer (MDI-S).
- Doses and schedules varied from single ED dosing to repeated dosing; one trial assessed daily MDI-S dosing over 4 weeks.
Control
- Placebo comparators included inhaled normal saline, hypertonic saline 3%, MDI placebo, or no bronchodilator.
- Some trials also compared salbutamol with epinephrine, ipratropium, or magnesium sulfate (not pooled for the primary safety meta-analysis).
Outcome
- Primary: Incidence of total ADRs with inhaled salbutamol versus control.
- Secondary: Types and frequency of specific ADRs; severe ADRs necessitating treatment discontinuation; safety by delivery route (MDI/MDI-S vs nebulisation).
Study Design
- Systematic review and meta-analysis of RCTs conducted per PRISMA guidelines; registered in PROSPERO (CRD42020172441).
- Quality assessed with Cochrane RoB 2; most trials had “some concerns,” six had high risk of bias.
Level of Evidence
Level I (systematic review and meta-analysis of RCTs).
Follow up period
- Short-term during acute treatment (hours to days) in most trials.
- One multi-center trial evaluated daily MDI-S salbutamol for 4 weeks.
Results
Primary outcome: Total ADRs (salbutamol vs control)
- 7 RCTs; n=597 (salbutamol 273; control 324).
- Incidence: 19.0% vs 13.3%; OR 2.12 (95% CI 0.69–6.51); heterogeneity high (I²=57%).
- NNH: ≈18 based on pooled risks (absolute risk increase 5.7%); interpret cautiously given imprecision and heterogeneity.
Secondary outcomes
- Sensitivity (excluding hypertonic saline): 8 cohorts; 237 vs 247 patients. ADRs 21.9% vs 17.4%; OR 1.50 (95% CI 0.80–2.81). NNH ≈22 (ARI 4.5%); not statistically significant.
- Nebulised salbutamol only: 5 RCTs; n=463 (203 vs 260). ADRs 6.4% vs 1.2%; OR 6.76 (95% CI 2.01–22.71); I²=0%. NNH ≈19 (absolute risk increase 5.2%).
- MDI/MDI-S: No increase in total ADRs versus control in pooled analyses; MDI-S considered potentially safer than nebulisation.
- Severe ADRs: No severe cardiac events requiring withdrawal were reported. One study reported severe non-cardiac tremulousness requiring discontinuation.
- Commonly assessed ADRs: Mild tachycardia and small heart rate increases (typically ~5% or 8–9 bpm), tremor, irritability, pallor/facial blanching, vomiting; sporadic monitoring of electrolytes and QT intervals with no consistent clinically significant abnormalities.
Limitations
- Many trials were not primarily designed for ADR detection; variable ADR definitions and ascertainment, and selective reporting.
- Risk of bias concerns (outcome measurement); heterogeneity across dosing, delivery methods, and co-interventions.
- Older trials (1988–2017); limited ECG monitoring and inconsistent tachycardia thresholds.
- Short-term safety only; long-term or repeated-use safety not addressed.
Funding
The authors reported no specific grant funding for this research.
Citation
Pierantoni L, Muratore E, Cerasi S, Zama D, Del Bono C, Gori D, Masetti R, Lanari M. Salbutamol safety in children under 2 years of age with acute wheezing: a meta-analysis of randomised controlled trials. Archives of Disease in Childhood. 2025;110:111–119. doi:10.1136/archdischild-2023-326556.