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* From the Department of Pediatrics (Drs. Hermansen, Nielsen, Buchvald, Jespersen, and Bisgaard), Danish Pediatric Asthma Center, Copenhagen University Hospital, Hellerup, Denmark; and Clinical Science (Mr. Bengtsson), AstraZeneca R&D Lund, Lund, Sweden.
Correspondence to: Hans Bisgaard, MD, Department of Pediatrics, Copenhagen University Hospital, Gentofte, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark; e-mail: Bisgaard{at}copsac.dk
Abstract
Study objective: To compare the acute bronchodilatory effect of the long-acting ß2-agonist formoterol against the short-acting ß2-agonist (SABA) terbutaline during exercise-induced bronchoconstriction (EIB) in children with asthma.
Design: A randomized, double-blind, placebo-controlled, crossover study of the immediate effect of formoterol, 9 µg, vs terbutaline, 0.5 mg, and placebo administered as dry powder at different study days. Exercise challenge test was used as a model of acute bronchoconstriction.
Patients: Twenty-four 7- to 15-year-old children with persistent asthma.
Interventions: The children performed standardized treadmill exercise tests, breathing dry air, with a submaximal workload. Study medication was administered 5 min after exercise if FEV1 dropped 
15% within 5 min after exercise. FEV1 and forced expiratory flows were measured repeatedly until 60 min after dose.
Results: Formoterol and terbutaline offered a significant acute bronchodilatory effect from 3 min after dose compared with placebo (p < 0.001). There was no difference between formoterol and terbutaline in FEV1 5 min after dose (p = 0.15), with a mean increase from each predrug baseline of 62% of the maximum increase for both. Median times to recovery within 5% of baseline FEV1 were 5.0 min and 7.4 min for formoterol and terbutaline, respectively (p = 0.33).
Conclusion: Single-dose formoterol, 9 µg, via dry powder inhaler provided an acute bronchodilatory effect similar to terbutaline during EIB in schoolchildren with persistent asthma. Formoterol is at least as effective as SABA and may be considered an alternative in the treatment of acute bronchoconstriction in school children.
Key Words: asthma, exercise-induced • bronchodilators • children
Relief therapy is pivotal to any asthma management plan. The aims of such a therapy are rapid lung function improvement and preferably prolonged action with the option of repeated dosing without risk of side effects. In addition, bronchoprotection against asthma triggers such as exercise is desired.
Inhaled formoterol is a full ß2-agonist. Onset of bronchodilation has been reported to be similar to that of terbutaline and salbutamol in both stable and acute severe asthma1234567 and with similar systemic activity.891011 Increasing the dose of formoterol provides an increased therapeutic effect during asthma worsening, as the standard therapeutic dose is at the steep part of its dose-response curve.110 This allows repetitive dosing during days of exacerbations without concerns of safety and potentially increases the effect to the maximal level. In addition, single doses provide a sustained, significant bronchodilation and bronchoprotection over 8 to 12 h in contrast to the 2 to 4 h after short-acting ß2-agonist (SABA) as assessed by methacholine challenge,1 exercise challenge,12131415 and cold dry-air hyperventilation.6
This profile seems useful for relief therapy and superior to that of SABA, and therefore we previously suggested a reappraisal of the position of formoterol in pediatric asthma management.16 Indeed, in adult asthmatics the use of formoterol as relief therapy has since been reported to reduce exacerbation risk compared to the use of SABAs.17
Exercise is one of the important triggers of asthma symptoms in children necessitating relief therapy, and adherence to prophylactic pre-exercise ß2-agonist treatment in school children might be poor and rarely applicable for spontaneous activity in childhood. Therefore, to research a reappraised positioning of formoterol as rescue therapy in pediatric asthma, we have compared the potential of formoterol and terbutaline for acute relief of exercise-induced bronchoconstriction (EIB) in children.
Materials and Methods
The study was performed in accordance with the declaration of Helsinki and approved by the local ethics committee (KF 02–082/00) and the Danish Medicines Agency (2612–1507). Before enrollment, informed consent was obtained from both children and parents/legal guardians.
Study Patients
Patients were recruited from two pediatric outpatient clinics in Copenhagen. Children 7 to 15 years old with a diagnosis of persistent asthma and a fall in FEV1 of at least 15% after exercise at enrollment were eligible for participation. Concurrent use of inhaled corticosteroids (ICS) was unchanged during the month prior to enrollment and was kept constant throughout the study. Children who had an asthma exacerbation necessitating a change in dose of ICS or treatment with systemic steroids within 2 months prior to the study were excluded. Before each visit, long-acting ß2-agonists (LABAs) were withheld for 24 h, SABAs were withheld for 6 h, and leukotriene receptor antagonists were withheld for 5 days.
Protocol
The study was of a randomized, double-blind, cross-over design with one screening visit and 3 study days with single-dose administrations of formoterol, 9 µg, terbutaline, 0.5 mg, or placebo, all administered as dry powder (Turbuhaler; AstraZeneca; Lund, Sweden). Randomized treatment sequences were generated in balanced blocks containing all six possible combinations by a computer program at AstraZeneca, Lund. Each sequence corresponded to a patient number that was allocated sequentially as the children were eligible for the study. No child was randomized to more than one treatment sequence. After baseline measurements, a standardized exercise test was performed at each visit. All visits were performed at approximately the same time of the day (± 3 h). Study days were separated by washout periods of at least 48 h. The median time of the randomized part of the study was 12 days (range, 4 to 35 days) with the washout periods averaging 6 days rather than the minimum required 2 days, a time period sufficiently eliminating carryover effects in a study with single doses of compounds of at most 24 h in duration.
Spirometry was performed and results accepted as per American Thoracic Society (ATS) standards18 (Jaeger MasterScreen; E Jaeger GmbH; Würzburg, Germany) with the children in a sitting position wearing a nose clip. FEV1 and maximal mid-expiratory flow (MMEF25–75) were recorded before exercise (baseline), after exercise (1 min, 3 min, and 5 min), and after administration of study drug (1 min, 3 min, 5 min, 10 min, 15 min, 20 min, 30 min, and 60 min) [Fig 1 ]. Baseline spirometry was performed in triplicate. Baseline FEV1 (the highest of three measurements) should be at least 70% of predicted normal value and was not allowed to vary > 15% between study days. Asthma symptoms were not recorded.
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The exercise test was performed according to the ATS guidelines,21 consisting of a standardized treadmill test, breathing absolutely dry, room temperature air from a facemask with a septum preventing nasal breathing. Workload was adjusted until submaximal pulse (180 ± 5 beats/min) as monitored by radio telemetry. The decline in lung function values after exercise was calculated as the change from baseline to the minimum value within 5 min after exercise in percentage of the baseline value. Study medication was administered 5 min after exercise but only if the child showed at least a 15% drop in FEV1 after exercise (Fig 1). Otherwise, FEV1 was monitored at 10 min and 15 min after exercise. If the drop then was at least 10%, the visit was rescheduled. If the drop in FEV1 also at the subsequent visit was < 15%, the child was withdrawn from the study (Fig 1).
Statistics
The primary outcome parameter was FEV1 5 min after drug administration. FEV1 and MMEF25–75 from different time points (3 min, 5 min, 10 min, and 60 min after drug administration) were compared between the treatments using analysis of variance models with treatment, period, and patient as factors. Data were log-transformed prior to analysis. Each time point was analyzed separately. Carryover effects for predose FEV1 were investigated graphically. The baseline value of the study day and the predose value (5 min after exercise) were both used as covariates in the analysis. Time to recovery (time from drug administration until FEV1 had reached within 5% of baseline FEV1) was compared between active treatments using Wilcoxon signed rank-sum test. The central tendency of time to recovery is presented by median. All tests were two sided at a 5% significance level. The efficacy analysis included all randomized patients with values from at least 2 study days.
The number of patients was based on experience from previous studies141522 with exercise tests in children, indicating that 24 patients would give an 80% chance to detect a difference of 8% (corresponding to approximately 0.2 L) between any two treatments. This assumes a two-sided test at a 5% significance level. However, since the actual design had not previously been used, the study could be considered a pilot study.
Results
Patients Enrolled
One hundred twenty-one children were screened for the study. Thirty-four children fulfilled inclusion criteria, but 4 children declined participation and 4 children were excluded due to poor compliance. Twenty-six children were randomized to a treatment sequence at the second visit. Each treatment sequence was applied to four children, and two sequences (formoterol-terbutaline-placebo and placebo-formoterol-terbutaline) were each applied to one additional child. Three randomized children were withdrawn, all due to insufficient drop in FEV1 after exercise; of these, two children only performed one treatment visit and were excluded from the analysis due to lack of data, and one child performed 2 study days (formoterol and terbutaline) and was included in the analysis. Eight children had to reschedule at least one visit due to insufficient drop in FEV1 at the first attempt. Baseline characteristics of the randomized patients are shown in Table 1
. Asthma severity ranged from mild-to-moderate persistent asthma according to Global Initiative for Asthma guidelines.23
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Discussion
Both formoterol and terbutaline provided relief from EIB, with statistically significantly larger improvements than placebo at all time points (3 min, 5 min, 10 min, and 60 min after drug administration), as measured by both FEV1 and MMEF25–75. The primary outcome parameter, FEV1 at 5 min, showed no difference between formoterol and terbutaline. At 5 min after dosing, the mean increase from each predrug baseline was 62% of the maximum increase for each drug. The median recovery times for formoterol, terbutaline, and placebo were 5.0 min, 7.4 min, and 44 min, respectively.
An unexpected result was that the drop in lung function before drug administration on the formoterol day was statistically significantly smaller than on the placebo day with the drop on the terbutaline day in-between. Baseline antiinflammatory treatment was unchanged, and the analysis revealed no period or carryover effect, so this appears a chance finding and probably reflects the natural variation in severity of bronchial hyperresponsiveness. As a result, the outcome of the analyses of FEV1 and MMEF25–75 depended on the choice of reference point. If using baseline as reference, formoterol would be favored. If, instead, using the predose value as reference, terbutaline with its larger room for improvement would be favored. The primary analysis used both the baseline and the predose values as covariates. According to this, no statistical difference between formoterol and terbutaline was observed 5 min after dosing. This result of no statistically significant difference between formoterol and terbutaline was also seen when analyzing the response in FEV1 at 5 min in percentage of maximum increase.
We applied EIB as a model of a very common clinical situation in which asthmatic children require relief. EIB involves a different pathology from that observed in acute severe attacks of asthma or severe chronic asthma, the mechanism of action being dominated by acute mediator release and short-term effects and less by changes in the underlying chronic inflammatory reaction. In addition to FEV1 we also measured MMEF25–75, which is more related to small airway function and may be more sensitive than FEV1.24 MMEF25–75 showed changes consistent with FEV1.
Our findings are in line with previous reports123457 in acute and chronic asthma in both adults and children and with a study of methacholine-induced bronchoconstriction in adults, showing similar onset of action of formoterol and salbutamol. These findings are supported by our previous report6 of the effect of formoterol and terbutaline in young preschool children using a model of cold-air induced hyperventilation. We chose lung function measurement as the only outcome measure since symptoms are poor predictors of bronchoconstriction after exercise in children.25 Previous studies891011 have attested to a favorable tolerability of formoterol at high doses in adults and children. Similar numbers of standard dose inhalations of formoterol (4.5 µg) and terbutaline (0.5 mg) gave less systemic activity from formoterol.
EIB is a cardinal symptom in pediatric asthma affecting social and physical development and quality of life more so than in adults. Asthma management strategies today generally recommend the use of SABAs 15 min before exercise. This may be well suited for the scheduled activities of adult life, but it is insufficient for most children. Typically, children exercise spontaneously multiple times during a day, and such repeated pretreatment is a challenge to compliance. Prolonged protection should be preferred to enhance the child’s physical activity. However, regular use of an LABA could induce tolerance with cross-tolerance to bronchodilators used as rescue treatment.1626 The induced tolerance reduces the advantage of prolonged protection against EIB. Indeed, it is advised not to use regular LABAs as monotherapy, and the available evidence does not show convincing additive clinical effect16 or protection against exacerbations27 from regular LABAs added to ICS. However, intermittent use of formoterol would be less prone to the development of tolerance and takes full advantage of the effect of the adrenergic symptom relief. This will provide the child with a rapid relief and long-term protection against EIB on occasions where the primary antiinflammatory control has failed to protect the child. This approach may eventually prove more successful for the management of childhood asthma than current options for relief.
In conclusion, this study shows a similar acute bronchodilatory effect from formoterol and terbutaline during EIB in children with persistent asthma. This proposes the usefulness of formoterol for relief therapy in pediatric asthma management.
Footnotes
Abbreviations: ATS = American Thoracic Society; EIB = exercise-induced bronchoconstriction; FeNO = exhaled nitric oxide; ICS = inhaled corticosteroid; LABA = long-acting ß2-agonist; MMEF25–75 = maximal mid-expiratory flow; SABA = short-acting ß2-agonist
Mr. Bengtsson is an employee of AstraZeneca. Dr. Nielsen has within the last 3 years received honoraria for lectures and attendance at pediatric advisory boards for AstraZeneca, GlaxoSmithKline, and Merck. Dr. Bisgaard has within the last 3 years received honoraria for lectures and attendance at pediatric advisory boards for Aerocrine, Altana, AstraZeneca, GlaxoSmithKline, and Merck. Dr. Bisgaard holds no stock options in the pharmaceutical industry in the respiratory field. Dr. Bisgaard owns a world patent for an inhaler device but receives no royalty. The COPSAC clinical research unit has in the last 3 years received research grants from the following industry partners in increasing order: Aerocrine, Merck, GSK, and AstraZeneca.
Received for publication June 13, 2005. Accepted for publication October 24, 2005.
References
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