Thirty RCTs were included.
Single-dose effects: exercise challenge (9 RCTs).
In the formoterol (4 RCTs with 59 children) and salmeterol (5 RCTs with 80 children) studies, some of the children received inhaled steroid. On average, the active drugs produced a statistically-significant reduction in the fall in FEV1 on exercise challenge 8 to 12 hours after the drug was given, compared with placebo (P<0.05 to P<0.0001). There was marked heterogeneity in response among children, with a large group of children having clinically important EIB 8 to 12 hours after salmeterol or formoterol. The author states that the reason for this was unclear.
Results of dose finding, onset and duration of action, and methacholine challenge were also reported.
Regular treatment. 1. Monotherapy in steroid-naive children. Salmeterol versus salbutamol (1 RCT with 30 children over 12 weeks): no significant difference in FEV1.
Salmeterol versus inhaled placebo (2 RCTs with 448 children): compared with placebo, salmeterol was associated with a significant increase in FEV1 in one RCT and in morning PEF in both RCTs.
Salmeterol versus BDP (2 RCTs with 308 children): the results were inconsistent with both RCTs reporting no significant difference in morning PEF, and one RCT reporting a decrease in FEV1 in the salmeterol group.
2. Add-on to inhaled steroid therapy (3 RCTs with 273 children): compared with placebo, the results were inconsistent with 2 RCTs reporting a significant benefit in morning PEF for salmeterol, and the third reporting no significant difference in change in FEV1.
3. Mixed groups of children taking and not taking steroids (3 RCTs with 1,346 children).
Salmeterol versus placebo (2 RCTs with 517 children for 6 to 12 months): compared with placebo, the results were inconsistent with one RCT reporting significant benefit in FEV1 for salmeterol, and the other RCT reporting no significant difference in morning PEF.
Salmeterol 50 microg versus salmeterol 25 microg versus salbutamol (one RCT with 847 children over 3 months): both salmeterol doses were significantly better than placebo in improving morning PEF (P<0.05).
Addition of a long-acting beta2-agent versus an increased dose of inhaled steroid (one RCT with 177 children; BDP alone versus BDP plus salmeterol versus a higher dose of BPD alone for 1 year): no significant difference was found in symptom scores, exacerbation rates, PEF, FEV1 or airway hyper-responsiveness.
Tolerance: results from two studies of adults and one RCT in children were reported. Only minimal information was presented on the paediatric study.
Methacholine challenge (5 RCTs).
1. Salmeterol versus placebo (3 RCTs with 372 children): no statistically-significant difference was found in bronchial reactivity.
2. Salmeterol versus BDP (2 RCTs with 308 children): BPD was associated with a statistically-significant greater improvement in bronchial reactivity, compared with salmeterol.
3. Salmeterol 50 microg verus salbutamol (1 RCT with 30 children): salmeterol was associated with a statistically-significant greater improvement in bronchial reactivity, compared with salbutamol.
No studies on formoterol were identified.
Exercise challenge (2 studies involving 32 adults, and one RCT of salmeterol versus placebo for 28 days involving an unknown number of adolescents taking inhaled steroids): inconsistent results were obtained. The adolescent study found salmeterol to be significantly better than placebo at 1 hour, but not 9 hours, after drug administration.
No studies on formoterol were identified.
Disease control: exacerbations.
Salmeterol versus inhaled steroids (1 study with 67 children): salmeterol was associated with more frequent exacerbations and a greater number of withdrawals than inhaled steroids. Significance levels were not stated.
Salmeterol versus placebo (based on 4 RCTs): salmeterol was associated with a borderline statistically-significant increase in exacerbations. No supporting data were reported.
No studies on formoterol were included.
Side-effects (based on 8 studies): it was not stated whether adverse reactions were systematically sought in the included studies.
Formoterol (1 trial compared high-dose formoterol, i.e. 48 to 78 microg, with salbutamol): no difference in systemic side-effects was observed.
Salmeterol (6 studies; design not specified): headache was the most commonly reported adverse effect; 4% in one study over one week. A literature review reported that the development of clinically significant nonpulmonary effects in children was minimal, and increases in heart rate and other cardiac effects were not clinically significant.