The effects of air pollution and inhaled salbutamol
on lung function and athletic performance in
asthmatic and non-asthmatic athletes
Application for the CASEM Research Grant
Submission Date: May 1st 2013
Principal Investigator: Michael S. Koehle, MD, PhD, Dip.
Sport Med
PhD Student:
Sarah Koch, MSc
Contact Information:
Environmental Physiology Laboratory
Divison of Sport Medicine
School of Kinesiology
University of British Columbia
210 – 6081 University Boulevard
Vancouver, B.C.
V6J 1Z1
Phone:
Email:
604 822 9331
[email protected]
Conflict of Interests:
None
1
Introduction
Overview of proposed study
Major Games in cities known for high levels of air pollution such as Athens 2004, Beijing
2008, and Delhi 2010 have raised concerns regarding athlete health and performance.1-4 At
the upcoming Olympic Games in Rio de Janeiro (2016) and the Pan Am Games held in
Toronto, ON, (2014), air pollution will also be a concern.
The detrimental effects of acute and chronic air pollution on cardiovascular and respiratory
health are described in a large body of scientific literature.5,6 Ironically, athletes, who tend to
follow a healthy lifestyle, are at a greater risk of cardiorespiratory symptoms and illnesses
triggered by air pollution.7-9 Physical activity leads to the release of epinephrine (the fightor-flight hormone). Epinephrine induces a widening of the airways to facilitate the
increased ventilation required to sustain the physical demands placed by the exercise bout.
Increased inhalation of polluted air through widened airways facilitates the travel of
pollutants deeper into the bronchial tree, where they trigger responses such as coughing,
wheezing and chest tightness. Ultimately, this air pollution exposure impairs lung
function10-12 and athletic performance.9,13,14 The acute treatment of choice for these asthmalike symptoms is the inhalation β2-agonists (IBA), which mimics epinephrine.15 In addition
to the natural bronchodilation due to the exercise-induced release of epinephrine, IBAs
induce a further widening of the airways. Theoretically, inhaled β2-agonists relieve
respiratory distress in the short-term, but IBAs may also increase the amount of pollutants
traveling into deeper areas of the bronchial tree, where they can cause structural and
functional damage in the long term.6,16-18 Thus, although IBA are routinely used in
symptomatic athletes in high pollutant environments, there is no evidence that they help,
and in fact a significant risk that they could affect health, performance or both. The purpose
2
of this study is to investigate the effects of IBA-use in the treatment of respiratory
symptoms triggered by air pollution exposure on athletic performance and lung health in
elite athletes.
Air pollution and respiratory symptoms in athletes
In Olympic athletes, asthma is the most common chronic health condition (prevalence:
8%),19 and endurance athletes are the most likely group of athletes to be diagnosed with
exercise-induced asthma.19,20 Exercise-induced asthma (EIA) and exercise-induced
bronchoconstriction (EIB) are the terms used to describe the transient narrowing of the
airways that follows vigorous exercise.20 While EIA is used to describe symptoms and signs
of asthma provoked by exercise, EIB describes the reduction in lung function after exercise
(or an exercise test).20 Interestingly, the prevalence of EIB, asthma and low resting lung
function is particularly high for athletes who train and compete in an environment with
high particulate matter (PM) emissions, exceeding that of the non-athletes and the lowpollutant-exposed athlete.8 The cause of EIB is likely the thermal and osmotic consequences
of water evaporation that results from humidifying large volumes of air in a short period of
time, resulting in the release of inflammatory mediators, which causes the contraction of
airway smooth muscle.21 The inhalation of air pollutants has been shown to act as an
additional trigger for the release of inflammatory mediators from airway cells22 and to
worsen the asthmatic response.23 Exercise leads to an increased deposition fraction
(fraction of inhaled particles remaining in the lungs after inhalation) of PM.24 For example,
the fractional deposition of PM with a diameter of 0.1 μm (PM0.1) is increased 4.5-fold during
mild exercise (mean ventilation rate of 38 L min-1) compared to rest.10 For PM2.5, it has been
estimated that 9% of the inhaled pollutants are deposited in the lungs with 6% reaching the
3
alveolar region.25 Thus, exercise appears to act as a catalyst for the harmful effects of PM
inhalation on cardiorespiratory health in the athlete.
Air pollution and athletic performance
The exposure to increased levels of air pollution has been shown to impair key parameters
of athletic performance and athletic performance directly.9,11-13 For example, decreased
work capacity and endothelial function, along with an elevated pulmonary arterial pressure
were observed in a maximal 6-min cycle ergometer bout that immediately followed a 20min high-PM exposure bout.9 Research performed in our laboratory showed a significantly
attenuated exercise-induced bronchodilation (change in forced expiratory volume in 1
second, FEV1) from baseline, and a significantly increased heart rate during a 20-km cycling
time-trial following a 60-min exposure to high PM.12 Preliminary data from a second study
in our laboratory show a significant increase in the perceived effort to breathe, and a
significant increase in oxygen consumption (VO2) in young healthy males when cycling at
50% of maximum heart rate for 30 minutes in diesel exhaust (DE), compared to filtered air
(FA). It is possible that the increased oxygen consumption was required to overcome
respiratory distress, caused by the inhaled pollutants, to maintain the ventilation rates
necessary for the required exercise bout.26
Air pollution and treatment of asthma symptoms in athletes
At the 2004 (Athens) and 2008 (Beijing) Summer Olympics, an average of 24.9% of the
triathletes and 17.2% of the cyclists were approved by the World Anti-Doping Agency
(WADA) to use IBAs.19 Similarly to epinephrine, β2-agonists act on adrenergic β2-receptors
that are primarily distributed in the lungs, but are also present in the heart and skeletal
muscles.15 In the heart, β2-agonists increase both heart rate and contractility. Due to its
4
vasodilating effects, β2-agonists can also increase blood flow in the coronary and skeletal
arteries.15
To treat asthma symptoms in polluted air, higher dosages of IBAs, taken in shorter intervals
are needed.27 An increase in dose and frequency of IBAs is critical, because of receptor
down-regulation and desensitization.28 When taken in polluted air by athletes, IBA may set a
vicious cycle in motion. To this date, little is known about the damage air pollutants cause
deep in the bronchial tree (where pollutants would not reach without the additional
bronchodilating effect of IBA) and the downstream effects on athletic performance and
cardiorespiratory health. It is likely that lung function and athletic performance will be
further impaired and that respiratory symptoms will be aggravated. Higher doses of IBA
may be required to treat these respiratory symptoms, as the removal of particles in mucus
via coughing is more difficult from the smaller airways because of fewer mucus glands.
These higher doses could further exacerbate respiratory symptoms, as described above.
Thus the widely-used strategy of administering IBA in athletes training and competing in
high pollution environments, is both untested, and potentially disadvantageous.
Objectives, specific hypotheses of proposed research and practical implications of
anticipated outcomes
The purpose of the proposed study is to investigate the short-term effects of IBA treatment
in elite athletes in response to asthma symptoms triggered by diesel exhaust (DE) on
athletic performance and cardiorespiratory health. The proposed study is designed based
on the following objectives and hypotheses:
5
Objective 1: To investigate the effects of short-duration DE-exposure on athletes’ respiratory function. We are especially interested in traditional spirometry
measures (i.e. forced expiratory volume in one second (FEV1), forced vital
capacity (FVC), and the ratio of FEV1/FVC) and newer respiratory
measurement techniques (work of breathing (WOB) and expiratory flow
limitation (EFL)) to assess lung health.
Hypothesis 1: There will be a decrease in lung function (decrease in: FEV1, FVC, FEV1/FVC;
increase in: WOB and EFL) and an increase in respiratory symptoms in
athletes when exposed to DE compared to clean, filtered air (FA).
Objective 2:
To assess the immediate effects of IBA-use in the treatment of respiratory
symptoms and impaired lung function due to air pollution exposure.
Hypothesis 2: Lung function (decreased: FEV1, FVC, FEV1/FVC; increased: WOB and EFL)
will be improved and the prevalence of respiratory symptoms will be
decreased immediately after IBA use in DE.
Objective 3: To assess the effects of IBA use in the treatment of respiratory symptoms and
impaired lung function due to air pollution exposure after the cessation of
exercise, up to 3 hours after the IBA-treatment.
Hypothesis 3: Lung function will be impaired (decreased: FEV1, FVC, FEV1/FVC; increased:
WOB and EFL) and the prevalence of respiratory symptoms will be increased
three hours after IBA-use in DE.
6
Project methodology
A randomized, double-blind, placebo-controlled, crossover design will be used. Athletes will
be tested following IBA (inhalation of 200μg of salbutamol) and placebo use (drug
condition), while exercising or at rest (exercise condition), and in filtered air (FA) or
polluted air (PA) (PM2.5 of 300 g/m3; pollution condition). A level of PM2.5 of 300 g/m3
corresponds to levels observed on high temperature, high humidity days in Rio de Janeiro.
Each subject will visit the laboratory on five different occasions (see Figure 1).
Subjects
Fifteen non-asthmatic and fifteen asthmatic athletes (15 males and females each; n = 30),
19- 40 years of age will be recruited for the study. Subjects will be excluded if they have any
history of uncontrolled respiratory or cardiac disease.
Screening day
Eucapnic voluntary hyperpnea: To test for exercise-induced bronchoconstriction in all
subjects, we will use the eucapnic voluntary hyperpnea test.29 The highest FEV1 value from
the baseline spirometry will serve as the reference value. Subjects will be required to
breathe dry air with added CO2 (5%) at a high frequency and deep inhalations to provoke
EIB. Subjects will ventilate 30 times their baseline FEV1 volume for 6 min.29 Subjects will
repeat spirometry 3 min, 5 min, 15 min and 20 min post-hyperventilation. A decrease in
FEV1 of 10% or greater below the baseline value will be considered a positive EVH test.
Maximal Exercise Text: A graded exercise test with a step-protocol will be performed to
measure peak oxygen consumption (VO2peak) and peak heart rate (HRpeak) on a Velotron
cycle ergometer. The test protocol for women and men will starting at a workload of 100
7
and 160 Watts, respectively, and resistance will increase by 30 Watts every 3 minutes until
the subject reaches volitional exhaustion, a plateau in oxygen consumption, an RER ≥ 1.15, or a heart rate greater than their maximal predicted.
Pulmonary function: Pulmonary function will be measured by spirometry following the
guidelines of the American Thoracic Society.30 Spirometry will be assessed prior to exercise,
immediately following exercise, 60 and 120 minutes following exercise. Standard measures
of pulmonary function will be assessed, including FEV1, FVC, and FEV1/FVC.
Test days II and III
Expiratory flow limitation (EFL) and work of breathing (WOB): By assessing inspiratory
and expiratory flow volumes and rates, we will be able to assess EFL and WOB.31 In addition
to traditional spirometry, these are sensitive assessments of lung function that will provide
us with a deeper insight into the effects of air pollution exposure on lung health in athletes.
A reduction in WOB due to IBA use could reduce the oxygen cost for breathing, and thus
possibly improve athletic performance. The work of breathing and EFL will be determined
by taking the integral of an ensemble average of several tidal breaths to form the average
trans-pulmonary pressure-tidal volume loop.32 Work of breathing for a single breath will
then be multiplied by the frequency of breathing to determine the work done per minute by
the respiratory muscles.
Rest and exercise intervention: Prior to entering the Air Pollution Exposure Chamber
(APEC), athletes’ lung functions will be assessed (spirometry, EFL and WOB, see Figure 2). Upon entering the APEC athletes will inhale a dose of salbutamol (200 μg) or placebo, which
will be administered via a metered dose inhaler (MDI) connected to a spacer. During the 60-
8
min rest period after the drug treatment, resting measures will be collected (see Table 1).
Athletes will start their graded exercise tests 60-min after the drug intervention. The
exercise test will start at a resistance of 0 Watts. The resistance will then be increased by 30
Watts every 2.5-min until volitional exhaustion is reached. All exercise will be performed on
a Velotron cycle ergometer. By controlling for exercise intensity during the graded exercise
test, we will be able to compare WOB and EFL at a given exercise intensity to assess the
effect of salbutamol.
Table 1: Timing of parameters assessed prior, during and after the exercise test.
Timing of Parameter Assessment
Assessed Parameters
prior entering the APEC
expiratory flow limitation (EFL)
15min after the IBA treatment
work of breathing (WOB)
60min after the IBA treatment
forced vital capacity (FVC)
immediately after the completion of the
forced expired volume in 1s (FEV1)
graded exercise test (~ 30min)
ratio of FEV1/FVC (FEV1/FVC)
60 and 120min after completion of the
exercise test (~ 150 and 210min)
Parameters continuously assessed during rest
periods and during the exercise test:
heart rate (HR)
oxygen consumption (VO2)
in APEC, post treatment (0min – 60min)
carbon dioxide consumption (VCO2)
during graded exercise test (60min- ~90min)
oxygen saturation (SpO2)
post graded exercise test (~ 90min – 210min)
minute ventilation (VE)
tidal volume (Vt)
respiratory rate (RR)
expiratory flow limitation (EFL)
work of breathing (WOB)
rating of perceived exertion for
breathing and legs RPEB/RPEL
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Statistical considerations
Data analysis will be completed using SPSS software (version 21.0). Two sets of analyses
will be performed: those for the variables measured during exercise (for example: HR, VE,
RR, HR, Vt and VO2, EFL, WOB), and those for the pre- and post-testing variables
(spirometry, WOB and EFL). The exercise data will be divided into the numbers of exerciseintensity stages ridden by each subject and compared among the eight conditions (DEsalbutamol-rest,
DE-salbutamol-exercise,
DE-placebo-rest,
DE-placebo-exercise,
FA-
salbutamol-rest, FA-salbutamol-exercise, FA-placebo-rest, and FA-placebo-exercise) using
repeated measures ANOVA. For the pre- and post-testing parameters, values will be
compared at the 5 time-points (pre-treatment, 60min-post-treatment, immediately postexercise, 60-min-post-exercise and 120 min-post exercise) among the eight conditions using
repeated measures ANOVA. Significant main or interaction effects will be further analyzed
using Tukey’s HSD post-hoc tests. Significance will be set at α = 0.05.
Space, facilities and personnel support
Space: All test days will take place in Dr. Carlsten’s Air Pollution Exposure Laboratory (APEL). This 1000 square foot facility is located at the Chan-Yeung Center for Occupational
and Environmental Respiratory Disease (CCOERD). It has the capacity to generate and
monitor the particulate matter exposures proposed in this application.
Equipment: Exercise will be performed on a Racermate Velotron Pro cycle ergometer that
is available at the APEL. We have a complete set-up of equipment for the EVH test, which
can easily be transported to the APEL. We possess all of the equipment necessary to assess
the described metabolic parameters and respiratory (spirometry, WOB and EFL)
measurements. This includes O2 analyzers, CO2 analyzers and a pneumotach setup. All the
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procedures outlined in this proposal have been performed in our laboratories, and thus we
have the requisite ability and space to conduct this work.
Personnel support:
Dr. Michael Koehle: The principal investigator on this study will be Dr. Koehle, an Assistant
Professor in the Division of Sports Medicine and the School of Kinesiology at the University
of British Columbia. Dr. Koehle’s clinical work complements the proposed studies. Dr.
Koehle served as the medical officer coordinating the medical teams for all Nordic events at
the Vancouver 2010 Olympic Games, and has previously served as a physician on the
medical team for other National and International Games. Working with such athletes has
provided key real-world experience in elite athletic performance, athletes’ health and antidoping issues.
Dr. Christopher Carlsten: Dr. Carlsten is an academic physician and associate professor at the
Centre for Respiratory and Critical Care Medicine, Vancouver Coastal Health Research
Institute and the UBC Division of Respiratory Medicine. Board certified in both, occupational
and respiratory medicine, Dr. Carlsten is the director of the Chan-Yeung Center for
Occupational and Environmental Respiratory Disease. His research interests include
environmental respiratory disease, asthma and cardiovascular disease in relation to trafficrelated air pollution, occupational lung disease, and the interplay between exercise and
these conditions.
Dr. Jordan Guenette: Dr. Guenette is an assistant professor in the Department of Physical
Therapy at the University of British Columbia. The aim of his research is to better
understand the physiological factors that limit exercise tolerance and across the spectrum
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of health and chronic lung disease. His prior research focused on the assessment of the
mechanics of lung function during exercise in females. He has published widely in this area
and is an expert with all the respiratory mechanics techniques to be used in the proposed
study.
Relevance of the study to the field of Sport Medicine
Based on the findings of this study, the treatment of respiratory symptoms in elite athletes
who are repeatedly exposed to air pollution during training and competition can be
improved. Furthermore, strategies to prevent exacerbations of respiratory distress and a
decrease in athletic performance will be developed, which could improve the long-term
health and performance of athletes. High levels of air pollution are often present at
competition venues, especially at major games such as Beijing, Delhi, Rio de Janeiro. Sport
and Exercise Medicine Physicians involved in the care of athletes training and competing in
these conditions would benefit from novel strategies to mitigate the adverse health and
performance effects of polluted air.
12
Proposed budget
All anticipated costs are listed below. The expected final costs are estimated to be $38,500.
A portion of these costs ($24,000) to be covered by an operating grant from the Natural
Sciences and Engineering Research Council (NSERC), entitled Mechanisms of Environmental
Stress on Human Performance.
Air Pollution Exposure Laboratory (APEL):
The Air Pollution Exposure Chamber (APEC) use in the APEL and
technician cost ($100/hr):
30 participants, 4 visits of 2 hour duration/each:
$24,000
Work of Breathing and Expiratory Flow Limitation Assessment:
30 esophageal catheters to determine WOB ($80/each):
$2,400
Eucapnic Voluntary Hyperpnea Test:
Gas to assess asthma-status through EVH test:
$800
Gas Tanks:
Calibration gas and compressed air for particulate matter and filtered
air exposures in APEL:
$1,500
Participant honoraria:
$200 for each participant for a total of 5 visits:
$6,000
Spirometry:
Mouthpieces for asthma-test: 30 filters for $20 each:
Publication Costs:
$600
$700
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Figure 1: Randomized double-blind crossover study design of proposed research
Figure 1: Timing of interventions on test days II and III.