1014 Archives ofDisease in Childhood 1992; 67: 1014-1017 Prevention of exercise induced asthma by inhaled Arch Dis Child: first published as 10.1136/adc.67.8.1014 on 1 August 1992. Downloaded from salmeterol xinafoate C P Green, J F Price Abstract It has been shown to inhibit in vitro constriction The effect of inhaled salmeterol xinafoate, a of airway smooth muscle'5 and the release of long acting P2 agonist, on exercise induced mediators from mast cells.'3 It produces pro- asthma was studied in a double blind, cross- longed bronchodilatation in adult asthmatic over, and placebo controlled trial. Thirteen patients. "' The long duration of effect is attri- asthmatic children with a fall of at least 15% in buted to an action of the long non-polar side their forced expiratory volume in one second chain. Salmeterol also ablates both the early and (FEVI) after a standard exercise test on a late bronchial reaction and the increase in motorised treadmill, on separate days per- bronchial responsiveness that follows allergen formed the same test 1, 5, and 9 hours after a challenge. 16 single dose of 50 [tg salmeterol or placebo. There are no published data on the effect of FEV1 was measured before treatment, and salmeterol in exercise induced asthma or of its before and for 30 minutes after each exercise use in children. Our aim was to study the effect test. After placebo the number of children of a single dose of inhaled salmeterol on exercise with exercise induced asthma was: 10 at induced asthma in children. It has been shown 1 hour, 11 at 5 hours, and 12 at 9 hours. in previous studies that the degree of broncho- Salmeterol prevented exercise induced constriction after exercise is reproducible' and asthma in all 13 children studied, at 1, 5, and does not alter significantly with repetition, at 9 hours. Mean maximum falls in FEV1 after intervals of greater than two hours, during the exercise were at 1 hour: salmeterol 2-7% and day.3 We therefore investigated the response to placebo 24-6%, 5 hours: salmeterol 5-3% and exercise in a group of asthmatic children 1, 5, placebo 22-7%; and 9 hours: salmeterol 3-4% and 9 hours after a single morning dose of and placebo 26-6%. After salmeterol the mean salmeterol. The study was placebo controlled increase in FEV1 was 17-8% at 1 hour, 19-6% because placebo has been shown to reduce signi- at 5 hours, and 19-2% at 9 hours. Inhaled ficantly exercise induced asthma in up to 40% of salmeterol prevents exercise induced asthma children.'7 and produces significant bronchodilatation http://adc.bmj.com/ for at least 9 hours. Methods (Arch Dis Child 1992;67:1014-1017) TRIAL DESIGN The study was double blind, randomised, Exercise is a common problem for children with crossover, and placebo controlled. Children asthma, who tend to be more physically active attending the paediatric asthma clinic at King's than adults. Over 70% of asthmatic children College Hospital who gave a clear history of on September 28, 2021 by guest. Protected copyright. studied with treadmill exercise tests have exer- exercise induced cough or wheeze and who were cise induced asthma,' 2 and 98% of children proficient in spirometry, were recruited. The attending an asthma clinic complained of symp- parents gave informed consent for their children toms on exercise.3 to participate and the study was approved by The airway response to exercise is a measure the hospital ethical committee. We calculated of indirect bronchial responsiveness; the from a previous study of exercise induced mechanism is not fully understood but probably asthma in children' that to detect a 20% involves bronchial smooth muscle cells, mast difference in the mean maximum fall in forced cells, and neurons4'5 with the release of media- expiratory volume in one second (FEV1) after tors.5-7 This response to exercise has been used exercise between salmeterol and placebo with to assess the efficacy and duration of action of 90% power at the 5% level we would require a asthma treatments.3 Inhaled 132 adrenoceptor sample size of 13 patients. agonists are the most effective drugs for the Each child attended the paediatric respiratory prevention of exercise induced asthma when laboratory for an initial exercise test. All medi- taken five to 15 minutes before exercise. cation except inhaled steroids was stopped for at This protective effect, however, lasts for only least 12 hours beforehand. was measured Department of FEV, Thoracic Medicine, two hours in the majority of asthmatics7 8 " and in a Jaeger Bodytest reverse plethysmograph, King's College Hospital, the duration varies widely.8 12 with a capacity of 800 litres, checked against a Bessemer Road, Salmeterol xinafoate is a long acting 1-,2 IL calibration syringe on each occasion. This London SE5 9PJ C P Green adrenoceptor agonist. It has a polar phenyl- system was used because many of the children J F Price ethanolamine head which binds reversibly to were already familiar with it, the scale could be C(orrespondence to: the 132 receptor. '3 In addition to this it has a long easily adjusted for different sized children, and Dr Price or Dr Green. non-polar side chain which is thought to bind to for its convenience in making multiple record- Accepted 9 April 1992 the cell membrane adjacent to the 1)2 receptor. 14 ings. Prevention ofexercise induced asthma by inhaled salmeterol xinaJooate 1015 If the baseline FEV, was greater than 60% of after each treatment (salmeterol or placebo) the mean predicted for the child's height'8 the with patient and time after treatment as factors. exercise test was done. This consisted of contin- The change from baseline in values of FEV, Arch Dis Child: first published as 10.1136/adc.67.8.1014 on 1 August 1992. Downloaded from uous running on a motorised treadmill for two before exercise on each study day and at each minutes at 5 degrees upward inclination and a time point were compared using two way speed of 2 5 kilometres per hour (kph), followed ANOVA. On the day salmeterol was given, by six minutes at 10 degrees and 5 kph. FEV, before treatment and FEV, before each of Heart rate was measured before and immedi- the exercise tests were compared by two way ately after the running period and then FEV, ANOVA. Heart rate before treatment and was measured every three minutes for 15 before each of the exercise tests was analysed for minutes and every five minutes for a further 15 treatment effect using two way ANOVA. For minutes. The maximum percentage fall in FEV, the placebo study day the same analyses were from baseline was calculated. Children who performed. attained a pulse rate of at least 170 beats per minute (bpm) and had a fall in FEV, of at least 15% after exercise were entered into the study. Patients The children who fulfilled the entry criteria Thirteen children, five girls and eight boys, attended the laboratory on two more occasions, aged 8 to 15 (mean 12) years fulfilled the entry which were not less than four and not more than criteria and completed the study. All were 10 days apart. On each occasion medication was taking an inhaled bronchodilator as required, withheld as before. FEV, was measured and two were also taking sodium cromoglycate, provided this was within 15% of the previous seven inhaled steroids, and one theophylline. baseline value the study proceeded. The children remained well and free of respira- Either 50 .tg salmeterol or placebo were tory tract infections or exacerbations of their administered as aerosols via a large volume asthma for the duration of the study. spacer device (Volumatic, Allen and Hanburys'9). Exercise tests using the same settings as in the initial test and with the same Results measurements of heart rate and FEV, were Baseline values for FEV, at the first visit were done 1, 5, and 9 hours later. from 66% to 104% of predicted (mean 87%). There was no difference between the pretreat- ment FEV, values for the two study days ANALYSIS OF DATA (p=0 24) and no difference between the initial Group data was expressed as means and 95% values for FEV, on the three visits (p>025). confidence intervals (CI). Parametric analyses The only significant factors for fall in FEV, were used only when normal distribution of after exercise were treatment (p<0-001) and data had been established. The pretreatment patient (p<0-001). When the children were values of FEV, were compared using the paired treated with salmeterol they had a significantly t test. Baseline FEV, before the initial exercise smaller fall in FEVI after exercise at 1 hour http://adc.bmj.com/ test and pretreatment FEV, on the two study (p<00003), at 5 hours (p<0-0015), and at 9 days were compared using a two way analysis of hours (p<0 0003) than when given placebo. variance (ANOVA) with patient and study day After salmeterol there were no children who had as factors. Factors influencing maximum fall in a fall in FEV, of greater than 15% during exer- FEV, after exercise and change in FEVI after cise tests at 1, at 5 and at 9 hours. After placebo treatment were analysed by multiple regression the number of children with a fall in FEV, of analysis of patient, pretreatment FEVy, treat- greater than 15% was 10 at 1 hour, 11 at 5 hours, on September 28, 2021 by guest. Protected copyright. ment, treatment order, and time point after and 12 at 9 hours (table 1).