Athletes are more susceptible toexercise-induced bronchoconstriction (EIB) than the general population 1.Roughly 8% of all competing Olympic athletes suffer from EIB, making it themost common medical condition among elite athletes. Indeed, at the 2004 and 2008 Olympicgames, an average of 17% of cyclists and 25% of triathletes were approved bythe International Olympic Committee to treat their asthma with inhaledadrenergic B2-agonists (IBAs) 2.
Exercise acts as atrigger of EIB, due to the hyperpnoea associated with exercise, causing thenarrowing of the airways. Therefore, endurance athletes are more at-risk due tothe provocative nature of repeated hyperpnoea in unfriendly, irritant filledenvironments. There are many pharmaceutical andnon-pharmaceutical treatment strategies that exist for EIB.
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Short-acting B2-agonistsand long-acting B2-agonists are used as preventive or acutetreatments for EIB 3. Inhaled salbutamol, a short-acting B2-agonist,is the most common therapy used among elite athletes. However, elite athletesmust be aware of inhaled salbutamol’s existence on the World-Anti-Doping Agency(WADA) prohibited list. In fact, more changes have been made to the status ofinhaled salbutamol on the WADA prohibited list than to any other substance inthe last 50 years 3. IBAs, such as salbutamol, act onadrenergic B2-receptors which are distributed in the lungs, heartand skeletal muscles 2.
IBAs relax the smooth muscles surrounding theairways, causing bronchodilation, increased heart rate and increased blood flowin the coronary and skeletal arteries. All these aid on relieving asthmasymptoms, such as coughing, wheezing and chest tightness. Therefore, theseagents act as powerful bronchodilators by decreasing obstructions in theairways 3; however, they also have the potential to affect physiologicalfactors that can limit athletic performance.
Due to this, all IBAs are on theWADA prohibited list, except inhaled salbutamol (Maximum: 1600 µg/day, withoutexceeding 800 µg in 12 hours), formoterol and salmeterol 3. Interestingly, asthmatic athletes tendto be more successful at major sporting events compared to non-asthmaticathletes 4,5. In the 2008 Beijing Olympic games, only 17%of the cyclists were asthmatic, but these athletes won 29% of the individualmedals available 2. Several studies have investigated the potentialperformance-enhancing effects of IBAs in asthmatic and non-asthmatic athletes,but a mechanism to explain the differences in Olympic success between athleteswith and without asthma remains unclear. 2In non-asthmatic athletes, studies havefound that IBAs have no effect on VO2max , anaerobic threshold,strength performance, blood lactate, peak power and rate of perceived exertion(RPE) even when supra-therapeutic doses of salbutamol were inhaled 6,7.
However, the odd study has seen an improvement in endurance cycling performancewhen taking supra-therapeutic doses of salbutamol 8, indicatingthat this route ofadministration does not exclude the possibility of an ergogenic effect of IBAs 8.Therefore,many studies have investigated the effect of IBAs on non-asthmatic,well-trained individuals, but it’s likely that the effects are more pronouncedin participants who suffer from asthma given their impaired lung function 2.Hence, in 2013, a study from Koch et al 2 investigated the effect ofinhaled salbutamol on lung function and time-trial performance in well-trainedathletes with and without EIB 2. What were the keyfindings? The study screened seventy-fiveexperienced male cyclists and triathletes between 19 and 40 years of age. Theparticipants performed two simulated 10 km time-trials on a cycle ergometer 60minutes after the inhalation of either 400 µg of salbutamol or a placebo 2.The performance outcomes measured included, mean power output relative to bodyweight, heart rate, oxygen consumption, tidal volume, minute ventilation,respiratory rate, dyspnoea and RPE.Of the 75 athletes screened, only 49athletes managed to complete the study. Of these 49 athletes, 14 were asthmaticand 35 were not.
The results showed that thirty minutes after salbutamol-use,the mean forced expiratory volume (FEV1) increased by 4.7% comparedto 2.9% after the inhalation of the placebo. The improvement in lung functiondue to salbutamol was significantly greater in the asthmatic athletes (7.0%)compared to non-asthmatic athletes (2.7%).However, when focusing on the effectthat salbutamol has on time-trial performance, mean power output after salbutamol-usewas not significantly different from the mean power output produced in the placebogroup.
Indeed, the inhalation of salbutamol caused 18 athletes to increase meanpower output by more than 1%, however 17 athletes had a decrease in mean poweroutput by more than 1%. Furthermore, no correlation was found between fitnesslevel, assessed VO2max on the screening day and the differencebetween mean power output between the two time-trials. Salbutamol didn’t seem to affect fatiguein either of the two time-trials, as neither EVH+ or EVH- perceived adifference in RPE. Likewise, neither EVH+ or EVH- perceived a difference indyspnoea during the two time-trials. Therefore, salbutamol did not affecttime-trial performance in asthmatic athletes or non-asthmatic athletes despiteseeing a significant improvement in FEV1. This study therefore, supportsprevious literature that demonstrated significant improvement in lung functionafter the inhalation of IBAs in non-asthmatic athletes without any effects onathletic performance 2. As this study was the first of its kind,the findings on asthmatic athletes are novel. Athletes with asthma had asignificantly greater bronchodilatory response to inhaled salbutamol, however,this greater response did not affect power output, exercise ventilation, RPEand dyspnoea during the time-trial.
How could the studyhave been improved? There is limited data tosuggest whether exercise performance is affected in athletes with no history ofEIB. Performance can improve considerably when focusing on time-trials toexhaustion when asthmatic patients receive inhaled corticosteroids, which islargely due to an improvement in lung function and protection againstbronchoconstriction 9. Therefore, it’s assumed that athletes with apositive hyperpnoea challenge will experience an improved endurance performanceif they inhale salbutamol prior to exercise.
However, this study reports thatthe inhalation of 400 µg salbutamol prior to a 10-km time-trial performance didnot influence cycling performance in athletes with an EVH positive challenge 2.A possible limitation is that the 10-km time-trial was completed in laboratoryconditions, which has been shown to be an environment that is not provocativefor EIB and perhaps in a more provocative environment this study may havereported a performance detriment in EVH positively challenged athletes 1.Therefore, the study may have been improved by using an environmental chamberto decrease the humidity, due to dry air being more provocative to EIB 20.
This would allow for a more provocative environment as the dry air wouldincrease the burden on the lower airways in conditioning the inspired air,possibly increasing the benefit of inhaled salbutamol. The effects of IBAs onathletic performance have been investigated in male athletes in multiplestudies, however, despite sex-based pulmonary anatomical differences causingdiffering respiratory responses to exercise 3, highlytrained female participants have been overlooked. Women on average have smallerlung sizes, lung volumes, maximal expiratory flow rates and decreased diffusionsurfaces 3. Therefore, due tothese anatomical differences, female athletes may benefit more from the use ofIBAs compared to male athletes; thus, IBAs could lead to greater relativeimprovements in FEV1 and athletic performance. Consequently, thefindings from the current study should not be generalised to female athletes. Futurestudies should focus on the effects of IBAs on female athletes to see if thefindings of this current study can be applied to women.
Whilst there were no differences in theperformance parameters between the two time-trials, the study could have beenimproved by adding a familiarisation time-trial. Adding a familiarisation time-trialwould allow for the learning effect, typically sufficient pacing information isgained from the first time-trial to enable participants to adopt an appropriatepacing strategy in the subsequent trials 10,11. Also, feedback suchas distances, cadences and gears were visible to the athlete during the 10-kmtime-trial. It has been seen that different pacing strategies can emergedepending on the sources of information available to the athletes 12.Therefore, the negative results may be due to athletes concentrating on aconsistent pacing strategy rather than seeing no effect of inhaledsalbutamol.
The methodology could have been improvedby adding a power calculation. Power analysis can be used to calculate theminimum sample size required so that a given effect size can be detected. Thepower calculation can also calculate what percentage is required to see asignificant improvement in performance. Furthermore, the study does not commenton whether a warm-up was present. Including a warm-up comes with benefits andlimitations, a warm-up will allow the athletes to cycle at their maximaltime-trial performance but also may induce a refractory period during thetime-trial and bronchoconstriction may not be evident for this reason. Another limitation is the relatively lownumber of EVH+ cyclists compares to EVH- cyclists. However, the ergogeniceffect of inhaled salbutamol on 10-km time-trial performance was independent ofEVH status. Indeed, both EVH- and EVH+ athletes presented similar performanceincreases and decreases.
Therefore, while adding more EVH+ cyclists wouldincrease the power and reliability of the study, the results would most likelyhave remained the sameTherefore, whilst the results of Koch etal 2 are novel, the study does come with some limitations. Thisstudy would have benefited from experimenting with an environmental chamber toallow for a more provocative environment for EIB and by using female athletesto focus on whether inhaled salbutamol would have a greater effect due to thedifferences in pulmonary anatomy. Future studies should take these limitationsinto consideration. Does salbutamol make a difference atall? There is no compelling evidence thatsalbutamol and other IBAs can increase performance in healthy athletes 1,2,3,6,7,13,14,18,19.
However, in spite of this, salbutamol required a “declaration of use inaccordance with the International Standard for Therapeutic Use Exemptions”under the 2010 WADA Prohibited List, which has since been relaxed in the 2011edition to a maximum use of 1600 µg over 24 hours when taking by inhalation.Whilst Koch et al 2 focused on a therapeutic dose of 400 µg, recentstudies have since been concentrating on a supra-therapeutic dose up to themaximum threshold of 1600 µg. Even though there doesn’t seem to be anergogenic effect for salbutamol at low or moderate doses 1,2, thereis potential for the maximally allowed daily dose of 1600 µg of inhaledsalbutamol to be ergogenic in elite athletes 3. Dickinson et al 13investigated the impact of the acute inhalation of 1600 µg on endurance runningperformance and reported that despite an increase in VE of 10 L/min at everykilometre over a 5-km cycling time-trial, inhalation did not lead to animprovement in running performance. Furthermore, only a limited number ofstudies have examined the salbutamol elimination in urine of inhaled doses ashigh as 1600 µg and have reported urine concentrations close to the WADA upperlimit of 1000 ng.ml-1 13.Thisstudy demonstrated thepossibility of a urinary salbutamol concentration above the threshold of 1000 ng.ml-1.
However,whilst the WADA prohibited list threshold is 1000 ng.ml-1,salbutamolshould only be reported as an adverse analytical finding (AAF) when detected ata concentration greater than 1200 ng.ml-1 14.Therefore, on this basis, this study would not warrant any sample to bereported as an AAF.
In a secondstudy by Dickinson et al 14 investigating the ergogenic effect of long-term use of highdosage salbutamol, found that inhaling 1600 ?g daily over 6 weeks does notresult in significant improvements in peak oxygen consumption, 3-km runningperformance or a one-repetition maximum for bench and leg press 14.To what extent these results from Dickinson et al 13-14 can beextrapolated to elite athletes is debatable due to a small sample size (n = 7) 13,low cardiovascular fitness levels 13,14 and a heterogeneous athleticbackground of the participants 14. In contrast to these findings,are the results from a study combining maximal doses of multiple IBAs inswimmers with and without airway hyperresponsiveness 15.
Swim ergometer sprint performance and MVC was significantly improvedafter the inhalation of 1600 µgsalbutamol, 200 µg salmeterol and 36 µg formoterol, regardless of airway hyperresponsiveness. In addition, astudy investigating the inhalation of an acute salbutamol dose following aquadriceps fatigue test showed that an intermediatedose (800 ?g) of salbutamol induced a significant improvement in quadricependurance despite similar amounts of fatigue and had a positive effectregarding the capacity to maintain intermittent isometric contractions 16.Other inhaled B2-agonists, such as terbutaline, have also shown asignificant increase in maximal voluntary contraction, which has led to anenhancement in muscle strength and sprint performance 17. Therefore, while theredoes not seem to be an ergogenic effect with inhaled doses at low or moderatedoses, there is potential for a high, supra-therapeutic dose to have anergogenic effect on athletic performance. Furthermore,it’s unclear if there is a relationship between the relative IBA dose andergogenic potential 3. The maximum allowed daily use of IBAs are notnormalised by body mass in the WADA guidelines, therefore a lighter athlete maybenefit more from a greater IBA dose per kg than a heavier athlete, however, a lighter athlete may also be at agreater risk of breaching the maximum threshold when administering high dosescompared to a heavier athleteWhile a few studies haveshowed a possible ergogenic effect when inhaling the maximum amount ofsalbutamol, other studies, show no ergogenic effect. Koch et al 18 continuedfrom their previous study, but focusing on the impact that a supra-therapeuticdose had on 10-km time-trial performance.
Trained male cyclists with andwithout EIB were analysed and found that theinhalation of 1600 ?g salbutamol improved FEV1 regardless of EVH status but didnot improve 10-km time trial performance regardless of relative dose perkilogram of body weight or EVH status 17. Later that same year, Koch et al 19focused on how inhaled salbutamol affected female athletes with and withoutEIB, to allow the present study and their two previous to be applied to women.Much like their study in 2013, participants performed a simulated 10-km cyclingtime-trial after the inhalation of either 400 ?g or placebo. Despite asignificant increase in lung function after the inhalation of salbutamol infemale athletes, mean power output maintained over the duration of thetime-trial was significantly reduced.
This is the first study to report anincrease in lung function after IBA use with a decrease in athletic performance19. This reduction in mean power output represents a potentialergolytic effect of salbutamol on female athletes and could be explained by anoverstimulation of the adrenergic B2-agonist system impairingathletic performance 3. Therefore, this suggests that despite sexdifferences in pulmonary anatomy, the inhalation of 400 ?g salbutamol does notincrease cycling time-trial performance in men or women.
However, much like their previous twostudies, this study was also performed in laboratory conditions, and thereforestill has similar limitations. Due to this, Molphy et al 1investigated the effect that 400 ?g of inhaledsalbutamol on 3 km running time-trial performance in an EIB provocativeenvironment 1, in line with the notion that dry air is moreprovocative for EIB 20. Despite significantly increased heart rateand FEV1, the administration of 400 ?g of inhaled salbutamol did notimprove 3-km time-trial performance in athletes who do or do not suffer from EIB.While in general higher doses of inhaled salbutamol have shown no improvementsin athletic performance, a reason for not seeing an ergogenic effect in thisstudy could be due to the comparatively small doses used. There also remainsthe possibility that performance improvements may not have been seen becausethis study solely focused on endurance performance. Recent studies haveindicated that inhaled B2-agonists may enhance strength and powerperformance rather than endurance performance 15-17.
Recommendations andconclusions Oral B2-agonistsadministration in humans has substantial effects on muscle function 21 andexercise performance 22. Doses of inhaled B2-agonists ofsalbutamol, however, are more than 20 times smaller (100 ?g/puff) than oral (2mg per pill up to 12-20 mg/day) 16 doses. In general, most studieshaving tested the effect of inhalation of therapeutic (400 ?g), intermediate(800 ?g) or even supra-therapeutic (1600 ?g) doses of salbutamol on exerciseperformance revealed no ergogenic effect 16. These findings suggest that the currentWADA guidelines, which allows athletes to inhale up to 1600 ?g is sufficient to avoid pharmaceutical enhancementduring athletic competition. However, a dose of 1600 ?g suggests poormanagement of asthma and increases the risk of an athlete violating the currentmaximum threshold 13.
In conclusion, previous studies, such as Koch et al 2, haveshowed that small therapeutic doses of inhaled salbutamol have no effect onathletic performance, however, the odd study has found that a possibleergogenic effect of inhaled salbutamol at the maximum dose. Therefore, whilethe current WADA guidelines are sufficient, inhaled salbutamol at the maximumdose should continue to be monitored, especially during strength and powerperformances.