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Original research
Effects of inhaled bronchodilators on lung function and cycling performance in female athletes with and without exercise-induced bronchoconstriction Sarah Koch a , Derin Karacabeyli a , Ciaran Galts b , Martin J. MacInnis a , Benjamin C. Sporer c , Michael S. Koehle a,c,∗ a
School of Kinesiology, University of British Columbia, Canada Faculty of Science, University of British Columbia, Canada c Faculty of Medicine, University of British Columbia, Canada b
a r t i c l e
i n f o
Article history: Received 13 June 2014 Received in revised form 18 July 2014 Accepted 31 July 2014 Available online xxx Keywords: Ergogenic effect Asthma Doping Sex-differences Athlete care
a b s t r a c t Objectives: Inhaled 2 -agonists may cause differential effects on lung function and athletic performance in female compared to male athletes. The objective of this study was to compare the effects of inhaled 2 agonists on lung function and cycling performance between female athletes with and without exerciseinduced bronchoconstriction and with previously published data on men. Design: Double-blind crossover randomized controlled trial. Methods: Twenty-one female athletes (6 with exercise-induced bronchoconstriction and 15 without exercise-induced bronchoconstriction) performed a simulated 10-km time-trial on a cycle ergometer 60 min after the inhalation of either 400 g of salbutamol or placebo. Forced expiratory volume in 1 s, was measured immediately before and 30 min after inhalation. Performance was measured by mean power output over the duration of the time trial. Results: After salbutamol inhalation, Forced expiratory volume in 1 s improved significantly in athletes with exercise-induced bronchoconstriction (M (SD) = 6.1% (47.6)) and athletes without exerciseinduced bronchoconstriction (4.0% (3.1); p ≤ 0.02). Mean power output was significantly decreased after salbutamol use (204 W (21)) compared to placebo (208 W (17); p = 0.047), regardless of airway hyperresponsiveness. Relative to placebo, salbutamol significantly increased mean oxygen consumption (46.9 mL kg−1 min−1 (5.9) vs. 44.8 mL kg−1 min−1 (4.0); p = 0.049) and significantly decreased cycling economy (72.8 W L−1 min−1 (6.8) vs. 76.4 W L−1 min−1 (4.3); p = 0.01). Conclusions: The inhalation of salbutamol induced a significant increase in lung function in female athletes, but this increased lung function did not translate to improved exercise performance. © 2014 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.
1. Introduction Exercise-induced bronchoconstriction (EIB), the transient narrowing of the airways following exercise, affects many endurance athletes.1 For example, 17% of cyclists competing at the 2004 and 2008 Olympics treated EIB-symptoms (e.g. coughing, chest tightness and dyspnea) with inhaled 2 -agonists (IBAs).1 Inhaled 2 -agonists act on the adrenergic 2 -receptors, which are located primarily in the lungs but also in the heart and the skeletal muscles. In the lung, IBAs act as bronchodilators by inducing smooth muscle relaxation in the cells surrounding the airways.2 In the heart and
∗ Corresponding author. E-mail address: [email protected] (M.S. Koehle).
skeletal muscles, IBAs vasodilate the arteries; therefore increasing blood flow. Interestingly, athletes treating their EIB-symptoms with IBAs have won a disproportionately greater percentage of individual Olympic medals compared to athletes without EIB.1,3 Pluim et al.4 and Kindermann5 concluded in their meta-analyses that IBAs do not have a significant effect on endurance performance in athletes without EIB. In agreement with this conclusion, our research group recently demonstrated that despite a significant improvement in lung function following IBA use, cycling performance in trained male cyclists was not affected regardless of bronchial hypersensitivity.6 Despite the fact that sex-based anatomical differences in the airways and lungs cause differing respiratory responses to exercise in men and women, female athletes have been generally overlooked
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Please cite this article in press as: Koch S, et al. Effects of inhaled bronchodilators on lung function and cycling performance in female athletes with and without exercise-induced bronchoconstriction. J Sci Med Sport (2014), http://dx.doi.org/10.1016/j.jsams.2014.07.021
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in the research on the effects of IBAs on athletic performance.7,8 Dysanapsis refers to the altered relationship between airway size and lung volume.9–11 When matched for lung size, women have smaller airway luminal areas and decreased conducting airway diameters compared to men.12 Furthermore, women have smaller lung volumes, smaller maximal expiratory flow rates and decreased diffusion surfaces relative to men.8,13 During heavy exercise, endurance-trained women were more likely to develop expiratory flow limitation (EFL) compared to endurance-trained men (90% vs. 43%, respectively).14 In addition, the work required to breathe (i.e. work of breathing, WOB) was significantly greater during highintensity cycling in female athletes compared to male athletes.14 Since, according to Poiseuille’s law, airway diameter affects airflow by the fourth power, an IBA-induced bronchodilatory effect in women could lead to greater relative improvements in lung function and athletic performance compared to men. The primary aim of this study was to investigate the effects of IBAs on lung function and athletic performance in trained female endurance athletes with and without EIB. By adhering to the study design of our previous investigations on the effects of IBAs on cycling performance in male athletes,6 we also aimed to compare the effects of IBAs between female and male athletes. We hypothesized that female athletes with EIB would demonstrate a significant bronchodilatory response to inhaled salbutamol, which would translate to improved ventilatory capacity and time-trial performance, while female athletes without EIB would not benefit from an ergogenic effect of inhaled salbutamol.
cart (ParvoMedics). A time-trial course (RacerMate Inc.) was displayed on a screen, with distance, cadence, and gearing information displayed throughout each time-trial. Every 2-km, athletes rated dyspnea and perceived exertion (RPE) for their legs on a 0–10 Borgscale.17 The main outcome variable was mean power output over the duration of the 10-km time-trial. Secondary outcome variables were cycling economy (ratio of mean power output and mean oxygen consumption (VO2 ) maintained over the 10-km time-trial in W L−1 min−1 ),18 respiratory exchange ratio (RER), heart rate (HR), VO2 , minute ventilation (VE ), tidal volume (VT ), respiratory rate (rr), dyspnea and RPE. To assess for a possible time-effect of salbutamol on the outcome variables, these parameters were averaged for each 2-km interval. All data are presented as means (SD). The effects of drug treatment and EVH status were tested with repeated-measures analysis of variance (ANOVA) tests. Post hoc analyses were performed using Tukey’s HSD test. To compare the effects of salbutamol on lung function and time-trial performances between women and men (from a previously collected dataset with an identical protocol6 ), the percent change of all parameters between the salbutamol and the placebo time-trials were calculated and then analyzed using one-way ANOVA tests. Statistical analyses were completed using SPSS (IBM, Version 22.0, Armonk, NY, USA) and statistical significance was accepted when p < 0.05. Funding organizations were not involved in the data collection, analysis or interpretation.
3. Results 2. Methods Twenty-seven female cyclists and triathletes, aged between 19 and 39 years, were screened. Athletes with a maximal oxygen consumption (VO2max ) ≥ 50 mL kg−1 min−1 were included. All athletes had to have a racing history of at least one year and were participating in or training for races during the data collection. Participants were free of cardiopulmonary disease (excluding controlled asthma) and were not pregnant. The University of British Columbia Clinical Research Ethics Board provided ethical approval (H09-01154) conforming to the Declaration of Helsinki, and written informed consent was obtained from all subjects prior to data collection. On the screening visit, bronchial hyper-responsiveness was assessed using a eucapnic voluntary hyperpnea (EVH) test.15 Lung function was measured with spirometry16 (TrueOne 2400; ParvoMedics, Sandy, UT, USA), and the highest forced expiratory volume in 1 s (FEV1 ) from three maneuvers was used as baseline. Athletes then hyperventilated dry gas (5% CO2 ) for 6 min and repeated spirometry at 3-, 5-, 15- and 20-min posthyperventilation. A decrease in FEV1 ≥ 10% relative to baseline was classified as EVH+.15 VO2max was determined using a cycle ergometer (Velotron Dynafit Pro, RacerMate Inc., Seattle, WA, USA). The test began at 0 W, and work rate increased by 0.5 W s−1 until cycling cadence was 0.05, range: −1.2 to −19.6%). Neither the severity of bronchial hyperresponsiveness assessed by the percent decrease in FEV1 in the EVH test (r = −0.092, p > 0.05), nor fitness levels assessed by VO2max on the assessment day (r = 0.423, p > 0.05), correlated with the change in mean power output after the two time trials. However, the percent change in mean power output positively correlated with the percent change in minute ventilation between the two time trials
Fig. 2. Time-effect of salbutamol on cycling and cardiovascular parameters in 2 km-intervals.
Please cite this article in press as: Koch S, et al. Effects of inhaled bronchodilators on lung function and cycling performance in female athletes with and without exercise-induced bronchoconstriction. J Sci Med Sport (2014), http://dx.doi.org/10.1016/j.jsams.2014.07.021
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Table 1 Performance parameters measured during the 10-km time trials in female athletes with a positive (EVH+) and a negative (EVH−) eucapnic voluntary hyperpnea (EVH) challenge. Parameter
Total (N = 21) Mean (SD)
Power (W) Salbutamol 204 (21)a Placebo 208 (17) VO2 (mL kg−1 min−1 ) 46.9 (5.9)b Salbutamol 44.8 (4.0) Placebo Economy (W L−1 min−1 ) 72.8 (6.8)c Salbutamol Placebo 76.4 (4.3) RER 0.99 (0.07) Salbutamol 1.01 (0.07) Placebo Heart rate (b min−1 ) 169 (12) Salbutamol 166 (11) Placebo Ventilation (L min−1 ) 95.7 (15.9) Salbutamol 94.2 (15.7) Placebo −1 Respiratory rate (b min ) 46 (9) Salbutamol Placebo 46 (10) Tidal volume (L) 2.12 (0.28) Salbutamol 2.12 (0.39) Placebo
EVH− (N = 15) Range 167–238 173–240
Mean (SD) 207 (20) 210 (15)
EVH+ (N = 6) Range 167–238 183–240
Mean (SD) 197 (25) 201 (22)
Range 168–227 173–228
36.0–58.9 35.7–51.3
47.8 (6.0) 45.9 (3.6)
36.0–58.9 39.3–51.3
44.8 (5.5) 42.0 (3.7)
40.4–55.3 35.7–46.5
60.4–82.3 69.8–83.7
72.9 (6.8) 75.5 (4.1)
60.4–82.3 69.8–83.7
72.5 (7.4) 78.6 (4.6)
69.8–83.3 73.4–83.7
0.81–1.07 0.86–1.10 142–181 142–182
0.99 (0.08) 1.01 (0.07) 165 (12) 164 (10)
0.81–1.07 0.86–1.10 142–181 145–180
0.97 (0.08) 1.02 (0.08) 178 (4) 170 (15)
0.87–1.06 0.90–1.10 170–181 142–182
70–122 64–128
97.5 (16.7) 96.2 (14.0)
70–122 72–128
91.1 (14.0) 89.2 (20.1)
74–111 64–120
34–63 27–61
46 (10) 46 (11)
34–63 27–61
45 (4) 46 (7)
40–51 38–56
1.72–2.97 1.69–3.21
2.16 (0.32) 2.20 (0.42)
1.72–2.97 1.70–3.21
2.04 (0.14) 1.93 (0.21)
1.87–2.21 1.69–2.21
EVH: eucapnic voluntary hyperpnea, RER: respiratory exchange ratio; VO2 : oxygen consumption. a Mean power output was significantly decreased in the salbutamol time-trial compared to the placebo time-trial, p = 0.047. b Mean oxygen consumption was significantly increased in the salbutamol time-trial compared to the placebo time-trial, p = 0.049. c Cycling economy was significantly decreased in the salbutamol time-trial compared to the placebo time-trial, p = 0.010.
(r = 0.474, p = 0.03). None of the additional cardiovascular parameters were altered by the salbutamol treatment (Table 1). The ratings of perceived dyspnea and leg fatigue did not differ across conditions for any time point. When we compared our data from the current study with those from the identical protocol in 49 male athletes,6 the effects of salbutamol on FEV1 30 min after inhalation were similar with 4.6% (4.7) in women and 6.1% (4.7) in men, p > 0.05. There were no differences in the percent changes in power output maintained during the two time trials between men (−0.4% (3.4)) and women (−2.1% (6.1); p > 0.05); however, there was a significant interaction between VO2 and sex (p = 0.03) as well as is in cycling economy and sex (p = 0.002). In men, mean VO2 was similar in the salbutamol (55.9 mL kg−1 min−1 (6.4)) and placebo (56.1 mL kg−1 min−1 (6.5); p > 0.05) time-trials, but in women VO2 was significantly increased after salbutamol compared to placebo (Table 1). In addition, cycling economy was similar in the salbutamol (72.2 W L−1 min−1 (5.5)) and placebo (72.3 W L−1 min−1 (5.5); p > 0.05) time-trials in men, but in women cycling economy was significantly decreased after the inhalation of salbutamol compared to placebo (Table 1). There were no differences in the percent changes in mean VE and VT in the two time trials between male (VE : −0.02% (9.2); VT : 0.18% (7.8)) and female athletes (VE : 1.01% (9.5); VT : 0.47% (8.4); p > 0.05 for both comparisons). For the salbutamol and the placebo time-trials, dyspnea and the perceived exertion for leg fatigue were higher in women compared to men; however, the differences were small and were not statistically significant (supplemental online Fig. S1). 4. Discussion The purpose of this study was to investigate the effects of IBAs on lung function and 10-km cycling time-trial performance in trained female EVH+ and EVH− athletes. The major findings of this project are fourfold: (1) there was a significant increase in FEV1 in trained female athletes after the inhalation of 400 g of salbutamol,
regardless of their EVH status; (2) despite this significant increase in lung function after the inhalation of salbutamol in female athletes, mean power output maintained over the duration of a 10-km cycling time-trial was significantly decreased; (3) there were no differences in the response to 400 g of salbutamol on lung function between male and female athletes; and (4) in the salbutamol time-trial, mean power output and cycling economy were significantly reduced and mean VO2 was significantly increased in female athletes, but not in males. Multiple studies on male athletes have shown a significant improvement in lung function after IBA-use without an effect on athletic performance.6,19,20 This is the first study to report a significant increase in lung function after IBA-use with a concomitant decrease in athletic performance in both EVH+ and EVH− female athletes. The reduced mean power output in the salbutamol time-trial in female athletes, representing a potential ergolytic effect of salbutamol in female athletes, could be explained by an over-stimulation of the adrenergic 2 -system impairing athletic performance. Seventeen female athletes reported either one or a combination of the following salbutamol side-effects: tremor, noticeable increase in resting heart rate, or a feeling of restlessness. In our previous study with men,6 who were heavier and exposed to the identical dose of salbutamol (i.e. had a lower dose of salbutamol per kilogram of body-weight), mean VO2 was not increased in the salbutamol time-trial and side-effects of salbutamol were reported in only 5 out of 49 athletes. The increased salbutamol dose per kilogram of body-weight may also be responsible for the trend for higher heart rates (especially in the first 8 km of the time-trial) observed in female athletes after IBA-use compared to male athletes. In contrast to this hypothesis, Sporer et al.21 did not find a dose-response relationship with regards to VO2 and HR when trained male cyclists were exposed to increasing doses (200 g, 400 g and 800 g) of IBA 15 min prior to a simulated 20-km cycling time-trial.
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One proposed ergogenic mechanism of IBAs is bronchodilation, which could improve VE during exercise and thereby increase oxygen uptake. The EVH+ and EVH− female athletes of this study demonstrated significantly increased mean VO2 during the salbutamol time-trial without any effects on VE and an average decrease in performance of 4 W. Accordingly, female EVH+ and EVH− athletes in the present study showed a decreased economy during the salbutamol time-trials. The increase in VO2 in female athletes is in contrast to the findings of our study in male athletes6 and other studies investigating the effects of IBAs on performance and VO2 in male athletes.19–21 At first glance, this may appear to have a negative impact on performance; however, it could be argued that a greater contribution of the aerobic system to power output could result in the sparing of anaerobic reserves thereby providing an advantage in a sprint finish. Indeed, RER was statistically lower for the 0–2-km interval and consistently lower after salbutamol use throughout the 10-km time-trial indicating a proportionally greater contribution of aerobic metabolism to power generation after salbutamol use. However, the performance enhancing impact of this finding was not demonstrated given that there was no enhanced finish observed in the final 2 km (Fig. 2) even with similar RPE between the two conditions. In a comparable study, Kalsen et al.22 recently reported a significant improvement in swim ergometer sprint performance but not in exhaustive swim performance after a supratherapeutic dose of IBAs in both trained male and female swimmers with and without airway hypersensitivity. The authors suggested that the much shorter ergometer test relied more on anaerobic metabolism than the exhaustive swim test, thus explaining their divergent findings.22 In the current study, the time-trials lasted between 15:50 and 19:30, which represent more of an aerobic challenge than the swim ergometer test done by Kalsen et al.22 Another difference between the Kalsen et al.22 study and ours was the medication dosage. The IBA-dose administered by Kalsen et al.22 (1600 g salbutamol; 200 g salmeterol and 36 g formoterol) was substantially higher compared to the 400 g salbutamol in our study. This supra-therapeutic dose of IBAs increased respiratory muscle strength in the asthmatic and non-asthmatic swimmers.22 Thus, in a much shorter (i.e. anaerobic) exercise challenge, an ergogenic effect of IBAs on cycling performance in female athletes might be observed. A second proposed ergogenic mechanism of IBAs is the reduction of WOB during exercise. An IBA-induced bronchodilation could delay or prevent the onset of expiratory flow limitation (EFL), reduce WOB and potentially enhance athletic performance. Due to anatomical sex-differences in the respiratory system, trained female athletes have been shown to be at greater risk of developing EFL, leading to an increased oxygen cost of breathing.14,23 Furthermore, asthmatics have been shown to develop mechanical respiratory limitations during high-intensity exercise more frequently than non-asthmatics.24,25 In the present study, the mean VE -rates of the female athletes were in a range (>90 L min−1 ) where WOB in endurance-trained women is significantly greater than in men.14 Comparing the findings in women to our previous study in men,6 there were no differences in VE between the salbutamol and placebo time trials in women or men. Furthermore, there were no statistically significant differences in ratings of dyspnea between the men and women. Both of these parameters are very indirect indications of WOB, but they seem to indicate that IBA may not significantly impact the WOB discrepancy between women and men, and between asthmatics and non-asthmatics. A limitation of this study is the relatively low number of EVH+ athletes. However, the ergolytic effect of IBAs on 10-km timetrial performance was independent of EVH− status. Both, EVH+ and EVH− athletes presented with a similar range and distribution of performance increases and decreases as shown in Fig. 1.
5
Further assessment in female athletes during a race simulation with a sprint finish including measurements such as blood lactate and peak power is recommended to investigate the effects of IBAs on athletic performance further from a metabolic point of view. 5. Conclusions In female EVH+ and EVH− cyclists, FEV1 was improved after the inhalation of 400 g of salbutamol. Despite this increase in lung function, cycling performance during a 10-km time-trial was decreased regardless of the athletes’ EVH status. A significantly increased mean VO2 and a decreased cycling economy after the inhalation of salbutamol in female athletes, but not in male athletes, may indicate an overstimulation of women’s adrenergic 2 -system due to an increased salbutamol dosage compared to men (relative to body weight). Practical implications • In contrast to previous studies on male athletes, the inhalation of 400 g of salbutamol might have an ergolytic effect in female cyclists, possibly due to an overstimulation of the adrenergic 2 system. • Warm-up is often neglected but important strategy in the management if EIB. In this study, all athletes performed a self-selected, 20-min warm-up prior to the time-trials. In the presence of this warm-up, there appears to be no benefit of salbutamol to cyclists with EIB in terms of symptoms or performance. If the subjects had not warmed up, the potential for a greater effect of salbutamol might exist. • The inhalation of 400 g of salbutamol prior to exercise led to an ergolytic effect on cycling economy and induced a high incidence of side-effects such as tremor, restlessness and increased resting heart rate in female athletes; these potentially deleterious factors should be taken under consideration when managing female athletes with EIB. Acknowledgements This study was funded by World Anti-Doping Agency (WADA) and the Natural Science and Engineering Research Council (NSERC). We would like to thank all study participants for their time and commitment to participate in our research. Furthermore we would like to thank Gudni K. Rosenkjaer for his help in the data extraction from the time-trial text files. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jsams.2014.07.021. References 1. Fitch KD. An overview of asthma and airway hyper-responsiveness in Olympic athletes. Br J Sports Med 2012; 46(6):413–416. 2. Davis E, Loiacono R, Summers RJ. The rush to adrenaline: drugs in sport acting on the beta-adrenergic system. Br J Pharmacol 2008; 154(3):584–597. 3. McKenzie DC, Fitch KD. The asthmatic athlete: inhaled Beta-2 agonists sport performance doping. Clin J Sport Med 2011; 21(1):46–50. 4. Pluim B, de Hon O, Staal J et al. Beta2-agonists and physical performance: a systematic review and meta-analysis of randomized controlled trials. Sports Med 2011; 41(1):39–57. 5. Kindermann W. Do inhaled 2-agonists have an ergogenic potential in nonasthmatic competitive athletes? Sports Med 2007; 116(3):95–102. 6. Koch S, Macinnis MJ, Sporer BC et al. Inhaled salbutamol does not affect athletic performance in asthmatic and non-asthmatic cyclists. Br J Sports Med 2013. http://dx.doi.org/10.1136/bjsports-2013-092706.
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7. Sheel AW, Guenette JA. Mechanics of breathing during exercise in men and women: sex versus body size differences? Exerc Sport Sci Rev 2008; 36(3):128–134. 8. Harms CA. Does gender affect pulmonary function and exercise capacity? Respir Physiol Neurobiol 2006; 151(2–3):124–131. 9. Green M, Mead J, Turner JM. Variability of maximum expiratory flow-volume curves. J Appl Physiol 1974; 37(1):67–74. 10. Mead J. Dysanapsis in normal lungs assessed by the relationship between maximal flow, static recoil, and vital capacity. Am Rev Respir Dis 1980; 121(2):339–342. 11. Martin TR, Castile RG, Fredberg JJ et al. Airway size is related to sex but not lung size in normal adults. J Appl Physiol 1987; 63(5):2042–2047. 12. Sheel AW, Guenette JA, Yuan R et al. Evidence for dysanapsis using computed tomographic imaging of the airways in older ex-smokers. J Appl Physiol 2009; 107(5):1622–1628. 13. Sheel AW, Richards JC, Foster GE et al. Sex differences in respiratory exercise physiology. Sports Med 2004; 34(9):567–579. 14. Guenette JA, Witt JD, McKenzie DC et al. Respiratory mechanics during exercise in endurance-trained men and women. J Physiol 2007; 581(Pt. 3):1309–1322. 15. Anderson SD, Argyros GJ, Magnussen H et al. Provocation by eucapnic voluntary hyperpnoea to identify exercise induced bronchoconstriction. Br J Sports Med 2001; 35(5):344–347. 16. Miller MR, Hankinson J, Brusasco V et al. Standardisation of spirometry. Respir Eur J 2005; 26(2):319–338.
17. Borg G. Psychophysical scaling with applications in physical work and the perception of exertion. Scand J Work Environ Health 1990; 16(Suppl. 1):55–58. 18. Lansley KE, Winyard PG, Bailey SJ et al. Acute dietary nitrate supplementation improves cycling time trial performance. Med Sci Sports 2011; 43(6): 1125–1131. 19. Meeuwisse WH, McKenzie DC, Hopkins SR et al. The effect of salbutamol on performance in elite nonasthmatic athletes. Med Sci Sports Exerc 1992; 24(10):1161–1166. 20. Sue-Chu M, Sandsund M, Helgerud J et al. Salmeterol and physical performance at −15 ◦ C in highly trained nonasthmatic cross-country skiers. Scand J Med Sci Sports 1999; 9(1):48–52. 21. Sporer BC, Sheel AW, McKenzie DC. Dose response of inhaled salbutamol on exercise performance and urine concentrations. Med Sci Sports Exerc 2007; 40(1):149–157. 22. Kalsen A, Hostrup M, Bangsbo J et al. Combined inhalation of beta2-agonists improves swim ergometer sprint performance but not high-intensity swim performance. Scand J Med Sci Sports 2013. http://dx.doi.org/10.1111/sms.12096. 23. McClaran SR, Harms CA, Pegelow DF et al. Smaller lungs in women affect exercise hyperpnea. J Appl Physiol 1998; 84(6):1872–1881. 24. Johnson BD, Scanlon PD, Beck KC. Regulation of ventilatory capacity during exercise in asthmatics. J Appl Physiol 1995; 79(3):892–901. 25. Haverkamp HC, Dempsey JA, Miller JD et al. Gas exchange during exercise in habitually active asthmatic subjects. J Appl Physiol 2005; 99(5):1938–1950.
Please cite this article in press as: Koch S, et al. Effects of inhaled bronchodilators on lung function and cycling performance in female athletes with and without exercise-induced bronchoconstriction. J Sci Med Sport (2014), http://dx.doi.org/10.1016/j.jsams.2014.07.021
ARTICLE IN PRESS Journal of Science and Medicine in Sport xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Science and Medicine in Sport journal homepage: www.elsevier.com/locate/jsams
Original research
Effects of inhaled bronchodilators on lung function and cycling performance in female athletes with and without exercise-induced bronchoconstriction Sarah Koch a , Derin Karacabeyli a , Ciaran Galts b , Martin J. MacInnis a , Benjamin C. Sporer c , Michael S. Koehle a,c,∗ a
School of Kinesiology, University of British Columbia, Canada Faculty of Science, University of British Columbia, Canada c Faculty of Medicine, University of British Columbia, Canada b
a r t i c l e
i n f o
Article history: Received 13 June 2014 Received in revised form 18 July 2014 Accepted 31 July 2014 Available online xxx Keywords: Ergogenic effect Asthma Doping Sex-differences Athlete care
a b s t r a c t Objectives: Inhaled 2 -agonists may cause differential effects on lung function and athletic performance in female compared to male athletes. The objective of this study was to compare the effects of inhaled 2 agonists on lung function and cycling performance between female athletes with and without exerciseinduced bronchoconstriction and with previously published data on men. Design: Double-blind crossover randomized controlled trial. Methods: Twenty-one female athletes (6 with exercise-induced bronchoconstriction and 15 without exercise-induced bronchoconstriction) performed a simulated 10-km time-trial on a cycle ergometer 60 min after the inhalation of either 400 g of salbutamol or placebo. Forced expiratory volume in 1 s, was measured immediately before and 30 min after inhalation. Performance was measured by mean power output over the duration of the time trial. Results: After salbutamol inhalation, Forced expiratory volume in 1 s improved significantly in athletes with exercise-induced bronchoconstriction (M (SD) = 6.1% (47.6)) and athletes without exerciseinduced bronchoconstriction (4.0% (3.1); p ≤ 0.02). Mean power output was significantly decreased after salbutamol use (204 W (21)) compared to placebo (208 W (17); p = 0.047), regardless of airway hyperresponsiveness. Relative to placebo, salbutamol significantly increased mean oxygen consumption (46.9 mL kg−1 min−1 (5.9) vs. 44.8 mL kg−1 min−1 (4.0); p = 0.049) and significantly decreased cycling economy (72.8 W L−1 min−1 (6.8) vs. 76.4 W L−1 min−1 (4.3); p = 0.01). Conclusions: The inhalation of salbutamol induced a significant increase in lung function in female athletes, but this increased lung function did not translate to improved exercise performance. © 2014 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.
1. Introduction Exercise-induced bronchoconstriction (EIB), the transient narrowing of the airways following exercise, affects many endurance athletes.1 For example, 17% of cyclists competing at the 2004 and 2008 Olympics treated EIB-symptoms (e.g. coughing, chest tightness and dyspnea) with inhaled 2 -agonists (IBAs).1 Inhaled 2 -agonists act on the adrenergic 2 -receptors, which are located primarily in the lungs but also in the heart and the skeletal muscles. In the lung, IBAs act as bronchodilators by inducing smooth muscle relaxation in the cells surrounding the airways.2 In the heart and
∗ Corresponding author. E-mail address: [email protected] (M.S. Koehle).
skeletal muscles, IBAs vasodilate the arteries; therefore increasing blood flow. Interestingly, athletes treating their EIB-symptoms with IBAs have won a disproportionately greater percentage of individual Olympic medals compared to athletes without EIB.1,3 Pluim et al.4 and Kindermann5 concluded in their meta-analyses that IBAs do not have a significant effect on endurance performance in athletes without EIB. In agreement with this conclusion, our research group recently demonstrated that despite a significant improvement in lung function following IBA use, cycling performance in trained male cyclists was not affected regardless of bronchial hypersensitivity.6 Despite the fact that sex-based anatomical differences in the airways and lungs cause differing respiratory responses to exercise in men and women, female athletes have been generally overlooked
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Please cite this article in press as: Koch S, et al. Effects of inhaled bronchodilators on lung function and cycling performance in female athletes with and without exercise-induced bronchoconstriction. J Sci Med Sport (2014), http://dx.doi.org/10.1016/j.jsams.2014.07.021
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in the research on the effects of IBAs on athletic performance.7,8 Dysanapsis refers to the altered relationship between airway size and lung volume.9–11 When matched for lung size, women have smaller airway luminal areas and decreased conducting airway diameters compared to men.12 Furthermore, women have smaller lung volumes, smaller maximal expiratory flow rates and decreased diffusion surfaces relative to men.8,13 During heavy exercise, endurance-trained women were more likely to develop expiratory flow limitation (EFL) compared to endurance-trained men (90% vs. 43%, respectively).14 In addition, the work required to breathe (i.e. work of breathing, WOB) was significantly greater during highintensity cycling in female athletes compared to male athletes.14 Since, according to Poiseuille’s law, airway diameter affects airflow by the fourth power, an IBA-induced bronchodilatory effect in women could lead to greater relative improvements in lung function and athletic performance compared to men. The primary aim of this study was to investigate the effects of IBAs on lung function and athletic performance in trained female endurance athletes with and without EIB. By adhering to the study design of our previous investigations on the effects of IBAs on cycling performance in male athletes,6 we also aimed to compare the effects of IBAs between female and male athletes. We hypothesized that female athletes with EIB would demonstrate a significant bronchodilatory response to inhaled salbutamol, which would translate to improved ventilatory capacity and time-trial performance, while female athletes without EIB would not benefit from an ergogenic effect of inhaled salbutamol.
cart (ParvoMedics). A time-trial course (RacerMate Inc.) was displayed on a screen, with distance, cadence, and gearing information displayed throughout each time-trial. Every 2-km, athletes rated dyspnea and perceived exertion (RPE) for their legs on a 0–10 Borgscale.17 The main outcome variable was mean power output over the duration of the 10-km time-trial. Secondary outcome variables were cycling economy (ratio of mean power output and mean oxygen consumption (VO2 ) maintained over the 10-km time-trial in W L−1 min−1 ),18 respiratory exchange ratio (RER), heart rate (HR), VO2 , minute ventilation (VE ), tidal volume (VT ), respiratory rate (rr), dyspnea and RPE. To assess for a possible time-effect of salbutamol on the outcome variables, these parameters were averaged for each 2-km interval. All data are presented as means (SD). The effects of drug treatment and EVH status were tested with repeated-measures analysis of variance (ANOVA) tests. Post hoc analyses were performed using Tukey’s HSD test. To compare the effects of salbutamol on lung function and time-trial performances between women and men (from a previously collected dataset with an identical protocol6 ), the percent change of all parameters between the salbutamol and the placebo time-trials were calculated and then analyzed using one-way ANOVA tests. Statistical analyses were completed using SPSS (IBM, Version 22.0, Armonk, NY, USA) and statistical significance was accepted when p < 0.05. Funding organizations were not involved in the data collection, analysis or interpretation.
3. Results 2. Methods Twenty-seven female cyclists and triathletes, aged between 19 and 39 years, were screened. Athletes with a maximal oxygen consumption (VO2max ) ≥ 50 mL kg−1 min−1 were included. All athletes had to have a racing history of at least one year and were participating in or training for races during the data collection. Participants were free of cardiopulmonary disease (excluding controlled asthma) and were not pregnant. The University of British Columbia Clinical Research Ethics Board provided ethical approval (H09-01154) conforming to the Declaration of Helsinki, and written informed consent was obtained from all subjects prior to data collection. On the screening visit, bronchial hyper-responsiveness was assessed using a eucapnic voluntary hyperpnea (EVH) test.15 Lung function was measured with spirometry16 (TrueOne 2400; ParvoMedics, Sandy, UT, USA), and the highest forced expiratory volume in 1 s (FEV1 ) from three maneuvers was used as baseline. Athletes then hyperventilated dry gas (5% CO2 ) for 6 min and repeated spirometry at 3-, 5-, 15- and 20-min posthyperventilation. A decrease in FEV1 ≥ 10% relative to baseline was classified as EVH+.15 VO2max was determined using a cycle ergometer (Velotron Dynafit Pro, RacerMate Inc., Seattle, WA, USA). The test began at 0 W, and work rate increased by 0.5 W s−1 until cycling cadence was 0.05, range: −1.2 to −19.6%). Neither the severity of bronchial hyperresponsiveness assessed by the percent decrease in FEV1 in the EVH test (r = −0.092, p > 0.05), nor fitness levels assessed by VO2max on the assessment day (r = 0.423, p > 0.05), correlated with the change in mean power output after the two time trials. However, the percent change in mean power output positively correlated with the percent change in minute ventilation between the two time trials
Fig. 2. Time-effect of salbutamol on cycling and cardiovascular parameters in 2 km-intervals.
Please cite this article in press as: Koch S, et al. Effects of inhaled bronchodilators on lung function and cycling performance in female athletes with and without exercise-induced bronchoconstriction. J Sci Med Sport (2014), http://dx.doi.org/10.1016/j.jsams.2014.07.021
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Table 1 Performance parameters measured during the 10-km time trials in female athletes with a positive (EVH+) and a negative (EVH−) eucapnic voluntary hyperpnea (EVH) challenge. Parameter
Total (N = 21) Mean (SD)
Power (W) Salbutamol 204 (21)a Placebo 208 (17) VO2 (mL kg−1 min−1 ) 46.9 (5.9)b Salbutamol 44.8 (4.0) Placebo Economy (W L−1 min−1 ) 72.8 (6.8)c Salbutamol Placebo 76.4 (4.3) RER 0.99 (0.07) Salbutamol 1.01 (0.07) Placebo Heart rate (b min−1 ) 169 (12) Salbutamol 166 (11) Placebo Ventilation (L min−1 ) 95.7 (15.9) Salbutamol 94.2 (15.7) Placebo −1 Respiratory rate (b min ) 46 (9) Salbutamol Placebo 46 (10) Tidal volume (L) 2.12 (0.28) Salbutamol 2.12 (0.39) Placebo
EVH− (N = 15) Range 167–238 173–240
Mean (SD) 207 (20) 210 (15)
EVH+ (N = 6) Range 167–238 183–240
Mean (SD) 197 (25) 201 (22)
Range 168–227 173–228
36.0–58.9 35.7–51.3
47.8 (6.0) 45.9 (3.6)
36.0–58.9 39.3–51.3
44.8 (5.5) 42.0 (3.7)
40.4–55.3 35.7–46.5
60.4–82.3 69.8–83.7
72.9 (6.8) 75.5 (4.1)
60.4–82.3 69.8–83.7
72.5 (7.4) 78.6 (4.6)
69.8–83.3 73.4–83.7
0.81–1.07 0.86–1.10 142–181 142–182
0.99 (0.08) 1.01 (0.07) 165 (12) 164 (10)
0.81–1.07 0.86–1.10 142–181 145–180
0.97 (0.08) 1.02 (0.08) 178 (4) 170 (15)
0.87–1.06 0.90–1.10 170–181 142–182
70–122 64–128
97.5 (16.7) 96.2 (14.0)
70–122 72–128
91.1 (14.0) 89.2 (20.1)
74–111 64–120
34–63 27–61
46 (10) 46 (11)
34–63 27–61
45 (4) 46 (7)
40–51 38–56
1.72–2.97 1.69–3.21
2.16 (0.32) 2.20 (0.42)
1.72–2.97 1.70–3.21
2.04 (0.14) 1.93 (0.21)
1.87–2.21 1.69–2.21
EVH: eucapnic voluntary hyperpnea, RER: respiratory exchange ratio; VO2 : oxygen consumption. a Mean power output was significantly decreased in the salbutamol time-trial compared to the placebo time-trial, p = 0.047. b Mean oxygen consumption was significantly increased in the salbutamol time-trial compared to the placebo time-trial, p = 0.049. c Cycling economy was significantly decreased in the salbutamol time-trial compared to the placebo time-trial, p = 0.010.
(r = 0.474, p = 0.03). None of the additional cardiovascular parameters were altered by the salbutamol treatment (Table 1). The ratings of perceived dyspnea and leg fatigue did not differ across conditions for any time point. When we compared our data from the current study with those from the identical protocol in 49 male athletes,6 the effects of salbutamol on FEV1 30 min after inhalation were similar with 4.6% (4.7) in women and 6.1% (4.7) in men, p > 0.05. There were no differences in the percent changes in power output maintained during the two time trials between men (−0.4% (3.4)) and women (−2.1% (6.1); p > 0.05); however, there was a significant interaction between VO2 and sex (p = 0.03) as well as is in cycling economy and sex (p = 0.002). In men, mean VO2 was similar in the salbutamol (55.9 mL kg−1 min−1 (6.4)) and placebo (56.1 mL kg−1 min−1 (6.5); p > 0.05) time-trials, but in women VO2 was significantly increased after salbutamol compared to placebo (Table 1). In addition, cycling economy was similar in the salbutamol (72.2 W L−1 min−1 (5.5)) and placebo (72.3 W L−1 min−1 (5.5); p > 0.05) time-trials in men, but in women cycling economy was significantly decreased after the inhalation of salbutamol compared to placebo (Table 1). There were no differences in the percent changes in mean VE and VT in the two time trials between male (VE : −0.02% (9.2); VT : 0.18% (7.8)) and female athletes (VE : 1.01% (9.5); VT : 0.47% (8.4); p > 0.05 for both comparisons). For the salbutamol and the placebo time-trials, dyspnea and the perceived exertion for leg fatigue were higher in women compared to men; however, the differences were small and were not statistically significant (supplemental online Fig. S1). 4. Discussion The purpose of this study was to investigate the effects of IBAs on lung function and 10-km cycling time-trial performance in trained female EVH+ and EVH− athletes. The major findings of this project are fourfold: (1) there was a significant increase in FEV1 in trained female athletes after the inhalation of 400 g of salbutamol,
regardless of their EVH status; (2) despite this significant increase in lung function after the inhalation of salbutamol in female athletes, mean power output maintained over the duration of a 10-km cycling time-trial was significantly decreased; (3) there were no differences in the response to 400 g of salbutamol on lung function between male and female athletes; and (4) in the salbutamol time-trial, mean power output and cycling economy were significantly reduced and mean VO2 was significantly increased in female athletes, but not in males. Multiple studies on male athletes have shown a significant improvement in lung function after IBA-use without an effect on athletic performance.6,19,20 This is the first study to report a significant increase in lung function after IBA-use with a concomitant decrease in athletic performance in both EVH+ and EVH− female athletes. The reduced mean power output in the salbutamol time-trial in female athletes, representing a potential ergolytic effect of salbutamol in female athletes, could be explained by an over-stimulation of the adrenergic 2 -system impairing athletic performance. Seventeen female athletes reported either one or a combination of the following salbutamol side-effects: tremor, noticeable increase in resting heart rate, or a feeling of restlessness. In our previous study with men,6 who were heavier and exposed to the identical dose of salbutamol (i.e. had a lower dose of salbutamol per kilogram of body-weight), mean VO2 was not increased in the salbutamol time-trial and side-effects of salbutamol were reported in only 5 out of 49 athletes. The increased salbutamol dose per kilogram of body-weight may also be responsible for the trend for higher heart rates (especially in the first 8 km of the time-trial) observed in female athletes after IBA-use compared to male athletes. In contrast to this hypothesis, Sporer et al.21 did not find a dose-response relationship with regards to VO2 and HR when trained male cyclists were exposed to increasing doses (200 g, 400 g and 800 g) of IBA 15 min prior to a simulated 20-km cycling time-trial.
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One proposed ergogenic mechanism of IBAs is bronchodilation, which could improve VE during exercise and thereby increase oxygen uptake. The EVH+ and EVH− female athletes of this study demonstrated significantly increased mean VO2 during the salbutamol time-trial without any effects on VE and an average decrease in performance of 4 W. Accordingly, female EVH+ and EVH− athletes in the present study showed a decreased economy during the salbutamol time-trials. The increase in VO2 in female athletes is in contrast to the findings of our study in male athletes6 and other studies investigating the effects of IBAs on performance and VO2 in male athletes.19–21 At first glance, this may appear to have a negative impact on performance; however, it could be argued that a greater contribution of the aerobic system to power output could result in the sparing of anaerobic reserves thereby providing an advantage in a sprint finish. Indeed, RER was statistically lower for the 0–2-km interval and consistently lower after salbutamol use throughout the 10-km time-trial indicating a proportionally greater contribution of aerobic metabolism to power generation after salbutamol use. However, the performance enhancing impact of this finding was not demonstrated given that there was no enhanced finish observed in the final 2 km (Fig. 2) even with similar RPE between the two conditions. In a comparable study, Kalsen et al.22 recently reported a significant improvement in swim ergometer sprint performance but not in exhaustive swim performance after a supratherapeutic dose of IBAs in both trained male and female swimmers with and without airway hypersensitivity. The authors suggested that the much shorter ergometer test relied more on anaerobic metabolism than the exhaustive swim test, thus explaining their divergent findings.22 In the current study, the time-trials lasted between 15:50 and 19:30, which represent more of an aerobic challenge than the swim ergometer test done by Kalsen et al.22 Another difference between the Kalsen et al.22 study and ours was the medication dosage. The IBA-dose administered by Kalsen et al.22 (1600 g salbutamol; 200 g salmeterol and 36 g formoterol) was substantially higher compared to the 400 g salbutamol in our study. This supra-therapeutic dose of IBAs increased respiratory muscle strength in the asthmatic and non-asthmatic swimmers.22 Thus, in a much shorter (i.e. anaerobic) exercise challenge, an ergogenic effect of IBAs on cycling performance in female athletes might be observed. A second proposed ergogenic mechanism of IBAs is the reduction of WOB during exercise. An IBA-induced bronchodilation could delay or prevent the onset of expiratory flow limitation (EFL), reduce WOB and potentially enhance athletic performance. Due to anatomical sex-differences in the respiratory system, trained female athletes have been shown to be at greater risk of developing EFL, leading to an increased oxygen cost of breathing.14,23 Furthermore, asthmatics have been shown to develop mechanical respiratory limitations during high-intensity exercise more frequently than non-asthmatics.24,25 In the present study, the mean VE -rates of the female athletes were in a range (>90 L min−1 ) where WOB in endurance-trained women is significantly greater than in men.14 Comparing the findings in women to our previous study in men,6 there were no differences in VE between the salbutamol and placebo time trials in women or men. Furthermore, there were no statistically significant differences in ratings of dyspnea between the men and women. Both of these parameters are very indirect indications of WOB, but they seem to indicate that IBA may not significantly impact the WOB discrepancy between women and men, and between asthmatics and non-asthmatics. A limitation of this study is the relatively low number of EVH+ athletes. However, the ergolytic effect of IBAs on 10-km timetrial performance was independent of EVH− status. Both, EVH+ and EVH− athletes presented with a similar range and distribution of performance increases and decreases as shown in Fig. 1.
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Further assessment in female athletes during a race simulation with a sprint finish including measurements such as blood lactate and peak power is recommended to investigate the effects of IBAs on athletic performance further from a metabolic point of view. 5. Conclusions In female EVH+ and EVH− cyclists, FEV1 was improved after the inhalation of 400 g of salbutamol. Despite this increase in lung function, cycling performance during a 10-km time-trial was decreased regardless of the athletes’ EVH status. A significantly increased mean VO2 and a decreased cycling economy after the inhalation of salbutamol in female athletes, but not in male athletes, may indicate an overstimulation of women’s adrenergic 2 -system due to an increased salbutamol dosage compared to men (relative to body weight). Practical implications • In contrast to previous studies on male athletes, the inhalation of 400 g of salbutamol might have an ergolytic effect in female cyclists, possibly due to an overstimulation of the adrenergic 2 system. • Warm-up is often neglected but important strategy in the management if EIB. In this study, all athletes performed a self-selected, 20-min warm-up prior to the time-trials. In the presence of this warm-up, there appears to be no benefit of salbutamol to cyclists with EIB in terms of symptoms or performance. If the subjects had not warmed up, the potential for a greater effect of salbutamol might exist. • The inhalation of 400 g of salbutamol prior to exercise led to an ergolytic effect on cycling economy and induced a high incidence of side-effects such as tremor, restlessness and increased resting heart rate in female athletes; these potentially deleterious factors should be taken under consideration when managing female athletes with EIB. Acknowledgements This study was funded by World Anti-Doping Agency (WADA) and the Natural Science and Engineering Research Council (NSERC). We would like to thank all study participants for their time and commitment to participate in our research. Furthermore we would like to thank Gudni K. Rosenkjaer for his help in the data extraction from the time-trial text files. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jsams.2014.07.021. References 1. Fitch KD. An overview of asthma and airway hyper-responsiveness in Olympic athletes. Br J Sports Med 2012; 46(6):413–416. 2. Davis E, Loiacono R, Summers RJ. The rush to adrenaline: drugs in sport acting on the beta-adrenergic system. Br J Pharmacol 2008; 154(3):584–597. 3. McKenzie DC, Fitch KD. The asthmatic athlete: inhaled Beta-2 agonists sport performance doping. Clin J Sport Med 2011; 21(1):46–50. 4. Pluim B, de Hon O, Staal J et al. Beta2-agonists and physical performance: a systematic review and meta-analysis of randomized controlled trials. Sports Med 2011; 41(1):39–57. 5. Kindermann W. Do inhaled 2-agonists have an ergogenic potential in nonasthmatic competitive athletes? Sports Med 2007; 116(3):95–102. 6. Koch S, Macinnis MJ, Sporer BC et al. Inhaled salbutamol does not affect athletic performance in asthmatic and non-asthmatic cyclists. Br J Sports Med 2013. http://dx.doi.org/10.1136/bjsports-2013-092706.
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17. Borg G. Psychophysical scaling with applications in physical work and the perception of exertion. Scand J Work Environ Health 1990; 16(Suppl. 1):55–58. 18. Lansley KE, Winyard PG, Bailey SJ et al. Acute dietary nitrate supplementation improves cycling time trial performance. Med Sci Sports 2011; 43(6): 1125–1131. 19. Meeuwisse WH, McKenzie DC, Hopkins SR et al. The effect of salbutamol on performance in elite nonasthmatic athletes. Med Sci Sports Exerc 1992; 24(10):1161–1166. 20. Sue-Chu M, Sandsund M, Helgerud J et al. Salmeterol and physical performance at −15 ◦ C in highly trained nonasthmatic cross-country skiers. Scand J Med Sci Sports 1999; 9(1):48–52. 21. Sporer BC, Sheel AW, McKenzie DC. Dose response of inhaled salbutamol on exercise performance and urine concentrations. Med Sci Sports Exerc 2007; 40(1):149–157. 22. Kalsen A, Hostrup M, Bangsbo J et al. Combined inhalation of beta2-agonists improves swim ergometer sprint performance but not high-intensity swim performance. Scand J Med Sci Sports 2013. http://dx.doi.org/10.1111/sms.12096. 23. McClaran SR, Harms CA, Pegelow DF et al. Smaller lungs in women affect exercise hyperpnea. J Appl Physiol 1998; 84(6):1872–1881. 24. Johnson BD, Scanlon PD, Beck KC. Regulation of ventilatory capacity during exercise in asthmatics. J Appl Physiol 1995; 79(3):892–901. 25. Haverkamp HC, Dempsey JA, Miller JD et al. Gas exchange during exercise in habitually active asthmatic subjects. J Appl Physiol 2005; 99(5):1938–1950.
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