Abstract

We conducted this double blind randomized controlled trial to compare the rapid bronchodilator effect of salmeterol and formoterol in 60 children with stable asthma. Participants were randomized to receive either salmeterol (50 mg) (n=31) or formoterol (24 mg) (n=29) by metered dose inhaler and spacer. Spirometry was performed at baseline, at 30 minutes, and at 60 minutes. Bronchodilatation was assessed by changes in FEV1 at 30 and 60 minutes. Baseline parameters were comparable in the two groups. There was no significant difference in the FEV1 at 30 and 60 minutes between two groups. We conclude that salmeterol and formoterol both cause bronchodilator response at end of 60 minutes and are not different with regards to their rapid bronchodilator response.

Key words: Childhood asthma, Formoterol, Long-acting beta-agonists, Salmeterol.

Inhaled corticosteroids (ICS) are the mainstay of long-term treatment of asthma. In moderate and severe persistent asthma, long acting beta-2 agonists (LABA) such as salmeterol and formoterol are added to ICS. Efficacy and safety of LABA has been demonstrated in children in long-term management of asthma(1-2). Studies done in adult asthmatics reveal a comparable bronchodilating and broncho-protective effects of the two drugs(3). However, there are no studies in children comparing rapid bronchodilator action of these two drugs. We conducted this trial to fill this void in literature.

This double blind randomized controlled trial was carried out in Pediatric Chest Clinic (PCC) of a tertiary care hospital in north India. Children of either sex between ages of 5-15 years with moderate persistent asthma(4) were enrolled. Those with acute exacerbation of asthma or who had taken any bronchodilator drugs in last 24 hours were excluded. Informed consent was obtained from the parents.

Randomization was done by computer-generated numbers. For blinding, similar looking metered dose inhalers (MDIs) were labeled A, B, C, D, E, F; 3 of which contained salmeterol and 3 contained formoterol. As per random numbers patients were given drugs from these MDIs. The MDIs were purchased from market (Foratec and Serobid, Protec and Cipla India); a person not involved in the study evaluation removed the labels of drugs and put a sticker with label of A,B,C,D,E,F (3 formoterol and 3 salmeterol). Children received either salmeterol (50 microgram) or formoterol (24 microgram) by spacer. Participants were explained about the study, spirometry and inhalation of medicines with metered dose inhaler and spacer. Details of history and physical examination including duration, severity of asthma and medications were recorded in a structured performa. A base-line spirometry was done using AutoSpiro portable spirometer. FVC, PEFR, FEV₁, FEF25 and FEF75 were recorded. Children were administered two actuations of study drug (salmeterol 25 µg/ actuation or formoterol 12 µg/ actuation) using metered dose inhaler and spacer. Children took at least 5 tidal breathing after each actuation of MDI. All clinical parameters and spirometry were repeated after 30 and 60 minutes of drug administration. Investigator collecting the data also asked for any adverse effect in form of tremors, nausea, vomiting, etc. before performing spirometry each time.

A sample size of 30 in each group was calculated to detect the difference in FEV₁ of more than 15% at 60 minutes with power of 80% and confidence level of 95%. All details were entered in Excel spread sheet and analyzed by STATA software (Stata Inc. College Station, TX) before breaking the code.

The baseline parameters between two groups were compared. Change in spirometric parameters was calculated and percentage increase in two groups was compared. Continuous variables were compared by applying ‘t’ test and for discreet data chi square test was applied. A P value of <0.05 was considered significant.

A total of 60 children were enrolled in the study (Fig. 1). The average age of children in two groups were similar (formoterol 9.7±3.1 years and salmeterol 9.6±3.1 years). The male to female ratio in formoterol group was 22:7 as compared to 16:15 in the salmeterol group (P=0.003). The baseline spirometric parameters were also comparable in the two groups.

Fig. 1. Study flow chart

There was significant increase in all the spirometric parameters within each group (Table I). There was no significant difference between the two groups at baseline, 30 minutes and 60 minutes (Table I). The percent increases in the spirometric parameters were also comparable in the 2 groups. Number of patients who had more than 12% increase in the FEV₁ from baseline to 30 and 60 minutes were 12 (41%) in formoterol and 17 (54%) in salmeterol group (P=0.3).

Values are median (95% confidence interval); FEV1: Forced expiratory volume in first second, 
FVC: Forced vital capacity, PEFR: Peak expiratory flow rate

The present study aimed to compare rapid bronchodilator response of salmeterol and formoterol. We used maximum recommended doses of salmeterol and formoterol(5) to take care of dose response relationship that has been documented with formoterol(6). The rapid bronchodilator response in form of improvement in FEV1 was measured at 0,30 and 60 minutes because the bronchodilator response of rapid acting bronchodilators is optimal at 30 minutes(7). The results suggested that there was no significant difference in the bronchodilator response in children between 5-15 years with stable asthma at 30 and 60 minutes.

There is no study in children that compares the two drugs. Avila-Castañón, et al.(8) in their double-blind, parallel-group study involving 36 adolescents comparing rapid bronchodilator response of salbutamol and formoterol reported that %FEV₁ values at 3, 30 and 60 minutes were similar in both groups suggesting rapid onset of action of formoterol. Ferrari, et al.(9) in their double-blind, two-period cross-over study comparing salmeterol and formoterol on 11 adults with exercise induced bronchoconstriction (EIB) (mean age 21.2 years) demonstrated that formoterol provided significantly better protection against EIB than salmeterol at 30 minutes.

We do not have ready explanations for our findings. Possible reasons for no difference in rapid bronchodilator response in our study may be less severe bronchospasm. It has been reported that rapid bronchodilator response with formoterol was more when there was severe exacerbation with FEV₁ less than 50% predicted(10). We included stable asthmatics only. Beta 2 AR polymorphism has been suggested as one of the reason for difference in the response to both LABA(11).

The major limitation of this study was that we did not measure FEV₁ before 30 minutes. The onset of bronchodilator action of formoterol has been demonstrated to be three minutes (8). Measurement before 30 minutes and longer follow up after 60 minute might have given better idea about the trends in rapid bronchodilator response of LABA.

Contributors: SKK and RL: Designed study, helped in data collection and analysis, and manuscript writing. Will act as guarantor for the paper. NS and RD: designed the study, collected data and helped in data analysis.

Competing interest: None.

Funding: None stated.