Examining the Effect of Salbutamol Use in Asthma and/or Exercise Induced Bronchoconstriction Whilst Exercising in Ozone Air Pollution
Phase: PHASE4
Conditions: Asthma and/or Exercise Induced Bronchoconstriction, Ozone Air Pollution
Sponsor: University of British Columbia

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Examining the Effect of Salbutamol Use in Asthma and/or EIB 
Whilst Exercising in Ozone Air Pollution 
Principal Investigator: Dr. Michael Koehle (MD, PhD) 
Graduate Student: Ben Stothers (BKin) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Introduction 
 
Physical activity has been recognized as an important component of a healthy lifestyle. 
This is especially true in developed regions of the world where sedentary behaviour has been 
associated with health conditions such as type 2 diabetes, hypertension, mood disorders, and 
certain types of cancer (De Rezende et al., 2014). As the world’s population continues to develop, 
industrialization and urbanization have led to a larger number of people living in areas with 
increased ambient air pollution (Barbera et al., 2010). Exposure to air pollutants, such as 
particulate matter and ozone, have been associated with increased mortality and hospitalization 
due to cardiovascular and respiratory disease (Brunekreef & Holgate, 2002). This presents a 
potential issue because increased ventilation during exercise results in a proportionate increase in 
the amount of inhaled air pollution (Carlisle & Sharp, 2001). This issue is particularly relevant for 
individuals with asthma and/or exercise induced bronchoconstriction (EIB) who are more sensitive 
to respiratory irritants such as ozone (Guarnieri & Balmes, 2014). b2 agonists, including 
salbutamol, are commonly prescribed to this population and their use is increased in regions with 
higher levels of ozone pollution (Pepper et al., 2020). However rodent studies have indicated 
potential negative consequences of b2 agonists including increased protein leakage and lung 
inflammation (Henriquez et al., 2019). Therefore, further research is required on the effects of 
using b2 agonists in ozone air pollution by people with asthma and/or EIB. 
 
Background 
 
Ozone gas is produced when volatile organic compounds and gases from the NOX family 
found in smog react with ultraviolet (UV) radiation from the sun. This means that ozone pollution 
is more prominent during sunny weather due to increased levels of UV radiation (Sillman, 2003). 
As a result, when the weather is nice and people are more inclined to exercise outside, ozone 

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pollution levels are at their highest. The World Health Organization classifies ozone as a 
respiratory irritant and recommends that one-hour exposures to ozone should not exceed 100 parts 
per billion (ppb) (WHO, 2018). However, there are a few issues with this recommendation when 
considering individuals with asthma and/or EIB. Firstly, highly populated areas where ozone 
pollution is an issue are not able to keep ozone levels below 100 ppb so people with asthma and/or 
EIB may be exposed to one-hour doses higher than this. For example, ozone levels can reach an 
hourly average concentration above 200 ppb during September at 3pm in Mexico City (Huerta et 
al., 2004). Secondly, people with asthma and/or EIB are more sensitive to respiratory irritants so 
ozone levels at 100 ppb have a larger effect on this population than individuals without respiratory 
disease. Finally, increased ventilation during exercise increases the amount of inhaled air pollution, 
thereby also increasing the dose of ozone 
 
A study by Kreit et al. showed that people with asthma exercising in ozone had larger 
decrements in pulmonary function compared to healthy controls (1989). A potential explanation 
for this is that ozone exacerbates existing airway narrowing in people with EIB and/or asthma 
during exercise by influencing both the autonomic nervous system and the immune system. The 
airways have heavy vagal afferent innervation in the form of unmyelinated C-fibers. Ozone can 
trigger transient receptor potential ankyrin 1 (TRPA1) receptors on these C-fibers leading to 
increased parasympathetic output from the medulla to the airways resulting in bronchoconstriction 
(Taylor-Clark, 2020). Ozone has a standard redox potential of +2.07 V making it one of the most 
powerful known oxidants. As a result, inhaled ozone creates oxidative stress by either oxidative 
destruction of biomolecules or the formation of free radicals (Mustafa, 1990). This oxidative stress 
initiates an immune response in the form of airway inflammation (Mustafa, 1990).  

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Salbutamol is a short-acting b2 agonist that works by binding to b2 adrenergic receptors 
leading to increased sympathetic output to the lungs resulting in bronchodilation. Typically, 
individuals with EIB will take salbutamol 15 minutes before exercising (Jartti, 2001). This is 
potentially beneficial when exercising in ozone because it would counter the increased 
parasympathetic output caused by ozone exposure. However, a study conducted by Gong et al. 
showed that inhaled salbutamol did not decrease ozone-related pulmonary function impairment in 
healthy individuals compared to placebo after exercising in ozone (1988). This suggests that the 
primary mechanism of impaired lung function due to ozone may be related to inflammation rather 
than bronchoconstriction. It is not known if ozone exacerbates bronchoconstriction specifically in 
people with asthma and/or EIB exercising in ozone, but since bronchoconstriction could occur 
anyway in this population during exercise, regardless of ozone, b2 agonists may still be beneficial.  
 
A potential issue of salbutamol use in ozone relates to its effect on inflammation 
(Henriquez et al., 2019). Recent rodent studies by Henriquez et al. have shown that inflammatory 
cytokine levels, after exposure to ozone, are higher in rodents that were given a b2 agonist 
compared to placebo (2019). This could potentially be related to salbutamol’s known ability to 
increase fluid transport across the alveolar membrane (Perkins et al., 2006). However, it is not 
known if b2 agonist use in humans would have the same effect. If the same effect does indeed 
occur in humans, it is also unknown whether Increases in inflammation greater in asthma/EIB 
compared to healthy individuals. It is important to learn if salbutamol use exacerbates airway 
inflammation because chronic airway inflammation in people with asthma has been related to 
airway remodelling that increases the severity of future asthma attacks (Brightling et al., 2012). 
As a result, significant increases in airway inflammation, despite potential improvements in 

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immediate pulmonary function, may be a reason for contraindication of salbutamol use in people 
with asthma and/or EIB when exercising in ozone air pollution. 
Objective 
• Determine if using salbutamol before exercising in ozone air pollution is harmful for 
individuals with asthma and/or EIB because of increased airway inflammation. 
 
Hypothesis 
• People with asthma and/or EIB who take salbutamol before exercising in ozone will have 
improved pulmonary function but higher levels of inflammation after exercise compared 
to placebo medication. 
 
Methods 
Sample and Recruitment 
 
The target population for this study is individuals with asthma and/or EIB living in urban 
environments. The predicted sample representing this population will be people with asthma 
and/or EIB living in the Greater Vancouver area. The sample will be recruited by self-selection 
sampling. This will be accomplished through the use of posters on public advertising boards 
around campus at the University of British Columbia (UBC). A virtual form of the poster will also 
be posted on the UBC School of Kinesiology website and the in the UBC psychology graduate 
student council’s newsletter.  The poster and online advertisement will outline, in lay language, 
the purpose of the study, inclusion and exclusion criteria, the design of the study, the potential 
benefits and risks to the participants, and contact information to enroll in the study. Participants 
who hear of this study through word of mouth may also contact the research team if interested. 
 
Table 1. List of study inclusion and exclusion criteria 

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Inclusion Criteria 
Exclusion Criteria 
1) Have asthma and/or EIB related airway 
narrowing during exercise  
 
2) Able to perform maximal exercise 
3) Between 18 to 50 years of age 
4) Able to communicate sufficiently 
using the English language 
1) Use inhaled corticosteroids 
2) History of smoking 
3) Chronic respiratory disease other than 
asthma or EIB 
 
4) Upper respiratory tract infection within 
the last 4 months 
 
5) Pregnant or potentially pregnant 
6) Allergy to salbutamol 
 
 
As shown in Table 1 above, there are four inclusion criteria for this study. The first 
criterion, diagnosed with asthma and/or EIB, represents the population of interest for this study. 
During the first lab visit, participants will perform a eucapnic voluntary hyperpnea test (see 
Procedures section) to be screened for airway narrowing triggered by exercise. The second 
inclusion criterion, able to perform maximal exercise, reduces the risk of physical harm by 
preventing participants who may be harmed by exercising from participating. Participants will be 
screened for this ability on the first day by filling out the physical activity readiness questionnaire 
(PAR-Q+). The third inclusion criterion, between 18 and 50 years of age, reduces the risk of 
physical harm by preventing people with age-related risks to ozone exposure from participating in 
the study. Compared to adults, the developing lungs of children and young adults are more 
susceptible to the oxidative stress of ozone which can cause life-long decrements in lung function 
(Goldizen et al., 2016). For this reason, only adults aged 18 and older will be included. Older 
adults, age greater than 65  years, are more susceptible to ozone-induced health effects compared 
to younger adults due to decreased physiological, metabolic, and compensatory processes 
(Shumake et al., 2013). An upper age limit of 50 years was chosen because we want to test a 

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relatively homogenous group with a reduced risk of occult medical conditions that may confound 
the findings. Furthermore, we have a long track record of conducting exercise and exposure studies 
in this age group without incident. As a result, only adults under the aged 50 and younger will be 
included. The final communication criteria, able to communicate sufficiently using the English 
language, ensures that participants will be able to fully understand the risks of the study and have 
any questions answered. 
 
As shown in Table 1 above, there are six exclusion criteria. The first exclusion criterion, 
regular use of inhaled corticosteroids, prevents the effects of corticosteroid medication on fraction 
of exhaled nitric oxide (FeNO) measurement, a measure of lung inflammation (see 
Measures/Instruments section), from biasing the study results. Inhaled corticosteroids are a type 
of medication that are prescribed to some people with asthma which decreases FeNO (Bjermer et 
al., 2014). The second exclusion criterion, history of smoking, prevents the influence of smoking 
history on FeNO measurement from biasing the study results. People who regularly smoke, or used 
to smoke, were shown to exhibit 30-60% lower levels of FeNO (Malinovschi et al., 2006). The 
third exclusion criterion, chronic respiratory disease other than asthma or EIB, prevents the 
influence of other chronic respiratory diseases on spirometry measures from biasing study results. 
Spirometry is a method of measuring pulmonary function (see Measures/Instruments section) and 
can be used to diagnose multiple different obstructive and restrictive respiratory diseases because 
of recognizable changes in spirometry measures such as forced expiratory volume in 1 second 
(FEV1), forced vital capacity (FVC), and FEV1/FVC (Morris, 1976). The fourth exclusion 
criterion, upper respiratory tract infection in the last four months, prevents the influence of upper 
respiratory tract infections on FeNO measurements from biasing the study results. Upper 
respiratory tract infection can increase FeNO by 50-150% for up to four weeks after infection 

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(Bjermer et al., 2014). Finally, the exclusion of pregnant or potentially pregnant individuals 
prevents potential ozone-related complications during pregnancy. Exposure to ozone during 
various stages of pregnancy has been associated with increased chances of premature birth, 
stillbirth, and preeclampsia (Salam et al., 2005). The sixth exclusion criteria, allergic to salbutamol, 
avoids physical harm from exposing people who are allergic to salbutamol to this medication. 
 
Sample size was calculated using data from previous studies that examined changes in 
FEV1 in people with EIB. Two studies by Anderson et al., in 2001 used a similar crossover 
design and found a detectable difference of 12% reduction in FEV1 with a standard deviation of 
14%. Calculation for a crossover design based on analysis of variance F-tests using these values 
with a power of 0.8 and an alpha level of 0.05 led to a sample size of 24 subjects. Previous data 
from FeNO in an asthmatic population where considered to make sure this sample size would be 
appropriate for FeNO measurement. Changes in FeNO measurements biased on a study by Niu 
et al., in 2018 showed a larger effect size than FEV1 so the sample size based on FEV1 
measurement is more conservative. 
  
Measures/Instruments 
 
The two independent variables in this study are ozone pollution status and medication 
(salbutamol) status. Both independent variables will have a nominal level of measurement with 
two levels. The two levels of ozone air pollution are: 170 ppb ozone and room air. Room air in the 
lab where data collection will be done has low levels of ozone (typically less than 10 ppb) and 
other pollutants. While wearing nose clips, participants will be exercising on a stationary bike 
breathing in air from a mouthpiece that is connected to a sealed chamber. The sealed chamber will 
contain an ACT-5000 ozone generator (ACT-series, 2021). The ozone generator will either be 
turned on or off depending on the allocated treatment. The concentration of ozone will be 

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confirmed using an electrochemical ozone sensor that will be set up in the chamber. 
Electrochemical ozone sensors have been validated using linear association models that have 
reported R2 values of 0.98 (Afshar-Mohajer et al., 2018). For the salbutamol condition, participants 
will take two puffs from a meter dose inhalers (MDI) designed to deliver 100 µg of salbutamol per 
puff or a trainer MDI for the placebo condition. To ensure reliability of the dose delivered 
participants will be told standardized instruction for using an MDI. Adhering to these instructions 
increases the consistency of the dose delivered (Sanchis et al., 2013). In addition, an aerochamber 
will be attached to the MDI which further increases dose consistency (Newman, 2004). Medication 
status will have two levels: 200 µg of salbutamol and placebo salbutamol. 
 
The main two dependent variables are spirometry and FeNO. Both dependent variables 
will have a ratio level of measurement. Pulmonary function will be measured using spirometry 
which includes multiple measures taken from a single test (Miller et al., 2005). Conceptually, a 
spirometry test involves taking a maximal inspiration followed by a maximal expiration held for 
six seconds then using data collected from that maneuver to create different measures of pulmonary 
function (Miller et al., 2005). Measures taken from spirometry tests include FEV1, FVC, and mid 
volume forced expiratory flow (FEF25-75). FEV1 is the maximal amount of air that can be expired 
in one second, FVC is the maximal volume of air that can be expired, and FEF25-75 is the rate of 
expiration between 25% and 75% of FVC (Miller et al., 2005). For pre and post exercise 
measurements, spirometry will be measured twice and the attempt with the highest values will be 
used. A series of FVC maneuvers with graded expiratory efforts, to account for thoracic gas 
compression, can be used to generate maximal expiratory flow-volume (MEFV) curves before and 
after an exercise intervention (Guenette et al., 2010). Tidal flow-volume loops (FVL) during 
exercise can be plotted within the MEFV curves using inspiratory capacity (IC) maneuvers were 

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participants take a maximal inspiration after a normal breath out (Guenette et al., 2013). 
Spirometry is the gold-standard for measuring pulmonary function and has a high level of face 
validity and content validity (Miller et al., 2005). Spirometry can be used to diagnose different 
respiratory diseases because changes in FEV1, FVC, and FEF25-75 match how one would expect 
these values to change based on the nature of the diseases (Miller et al., 2005).  When taking 
spirometry measurements, it is important to ensure the participants maximally inhale and exhale 
to get an accurate reading. This can be accomplished by conducting a few practice measurements 
on an orientation day.  
 
Airway inflammation will be measured using FeNO. FeNO is defined as the fraction of 
exhaled nitric oxide in expired air which acts as a biomarker for airway inflammation (Barnes & 
Liew, 1995). FeNO will be measured using a NObreath-v2 FeNO monitor. When taking a FeNO 
measurement, participants will breathe at a steady rate for ten seconds into the mouthpiece of the 
FeNO monitor (Bjermer et al., 2014). For pre and post exercise measurements FeNO will be 
measured four times in a row. The first measurement will be thrown out and the last three will be 
averaged and recorded. We chose to throw away the first measurement because the first FeNO 
reading on our device tends to be much lower than subsequent readings. FeNO has high convergent 
validity shown by strong correlation with other markers of airway inflammation including 
bronchoalveolar lavage fluid eosinophil counts, airway hyperresponsiveness, and bronchial biopsy 
eosinophil score (Khalili et al., 2007). Since FeNO can be influenced by other variables it is 
important to control for these variables as much as possible. This can be done by excluding people 
who smoke and have recently had an upper respiratory tract infection. Participants will also be 
asked to avoid the following foods that are high in nitrates 12 hours before each lab visit including 
(rocket, spinach, lettuce, radish, beetroot, Chinese cabbage, turnips, cabbage, green beans, leeks, 

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spring onion, cucumber, carrot, potato, garlic, sweet pepper, green pepper) which can artificially 
elevate FeNO measurements (Bjermer et al., 2014). In addition, participants will be asked to avoid 
alcohol consumption 24 hours before each visit (ATS, 2005), and asked to avoid drinking and 
eating one hour before the test (ATS, 2005). 
 
 
Rating of symptoms (dyspnea, cough, sore throat, headache, chest pain, and chest 
tightness)  and blood pressure will also be measured. The selected symptoms were chosen because 
they have been recognized or are related to symptoms of ozone exposure (Lippmann, 1989). 
Dyspnea will be measured subjectively using a modified Borg scale that has previously been used 
to measure dyspnea and validated against other dyspnea measures (Gaber et al., 2019). The other 
symptoms will be subjective rated on a scale from 0-5. Blood pressure will be measured using an 
automated sphygmomanometer. In accordance with Hypertension Canada’s guidelines on blood 
pressure measurement, blood pressure will be measured three times and the first measure will be 
thrown away while the latter two are averaged (Nerenberg et al., 2018). 
Study Design 
 
This research design can be characterized as a placebo-controlled crossover design with 
pre-post measures. There are two independent variables: ozone pollution status and medication 
status. The two levels of ozone pollution status are 170 ppb ozone and room air. The two levels of 
medication status are 200 µg of salbutamol and placebo medication. Participants will perform 30 
minutes of submaximal exercise at 60% of their VO2max in all four conditions. These conditions 
are salbutamol + ozone, placebo + ozone, salbutamol + room air, and placebo + room air. The 
order of the conditions on the experimental days will be randomized to one of four sequences. The 
four conditions will be labelled A (ozone + inhaler A), B (ozone + inhaler B), C (room air + inhaler 
A), and D (room air + inhaler B). The researchers will not know which inhaler (A or B) is placebo 

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and which is salbutamol to facilitate blinding. The four condition sequences will be ABCD, 
BDAC, CABD, DCBA. These sequences represent a Latin Square crossover design, which is 
uniform both within periods and within sequences. In other words, each condition appears only 
once in each sequence and only once at a particular spot within the four sequences. This means 
that the sequences are balanced with respect to first order carry over effects because each condition 
precedes every other condition only once. For example, condition D is fist only once and is 
preceded by condition A, B, and C only once. FeNO, spirometry, blood pressure, and  symptom 
measures will be obtained before and immediately after, 30 minutes after, and 1 hour after exercise 
in each condition. Pre and post measures will be compared from the four conditions to examine 
how exercising in different combinations of ozone pollution and medication influence pulmonary 
function (spirometry) and inflammation (FeNO). The medication condition will be double blinded 
to control for the placebo effect and expectancy bias of the research. This will be done by having 
a placebo inhaler and a salbutamol inhaler labeled A and B by someone who is not collecting data. 
That way neither the participant nor the researcher collecting data will know whether placebo or 
real salbutamol is being used in a particular condition. The ozone condition will also be double 
blinded . This will be done by having the participant breathe air from a tube connected to a sealed 
chamber, which they will not be able to see inside, that  has an ozone generator that is controlled 
on the opposite side of the chamber. A separate researcher will be controlling the ozone chamber 
and on room are day will pretend to operate the generator for the room air conditions and actually 
operate the generator for the ozone conditions. Ozone levels will be recorded for all conditions 
and revealed to the main researcher after data collection is completed.  
 
Procedures 

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Participants will visit the lab on five occasions. It will also be expected that participants 
will take no leukotriene modifier medication (Singulair or Montelukast) 24 hours before each visit, 
no short acting beta agonists 8 hours before each visit, no long acting beta agonists 48 hours before 
each visit, and no anti-histamines 72 hours before each visit. These pre-visit restrictions control 
for potential confounding effects on the eucapnic voluntary hyperpnea (EVH) test and FeNO 
measurement. Participants will be asked to avoid supplementation with vitamin C, vitamin E, and 
multivitamins over the course of the 5 visits. This prevents changes in the response to ozone related 
to vitamin supplementation (Gomes et al., 2011). Finally, participants will be asked to avoid 
exercise 24 hours before each lab visit. This is to ensure there is no diminishment in asthma and/or 
EIB severity related to a refractory period following exercise (Stickland et al., 2012). Day one will 
be a screening day and will involve: obtaining consent, collecting height, weight, age, and sex, 
screening participants for EIB, conducting a VO2max test, and orienting participants to FeNO and 
spirometry measurement. Participants will re-read and sign a consent form in addition to reviewing 
and signing a PAR-Q+. They will then do practice spirometry and FeNO measurements to orient 
themselves to the procedure of these measures. Then, participants will complete a EVH test to 
screen for EIB. The EVH test requires participants to voluntarily hyperventilate regular air that 
has a higher than normal CO2 concentration for 6 minutes to replicate breathing during exercise. 
This mimics the stimulus that leads to airway narrowing in EIB (Hull et al., 2016). The higher than 
normal CO2 concentration prevents CO2 levels in the blood from dropping leading to loss of 
consciousness. Spirometry measures are obtained before and after EVH and compared. A 10% or 
greater decrease in FEV1 will be used to confirm the presence of EIB (Hull et al., 2016). 
Participants will then take salbutamol at the treatment dose (200𝜇g and perform a VO2max test on 
a cycle ergometer. Performing a VO2max text will allow for the exercise intensity to be standardized 

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in subsequent trials at 60% of VO2max. A graded exercise test with a ramp protocol will be 
performed while expired gas is analyzed using a metabolic cart to measure VO2max (Beltz et al., 
2016). Participants will conduct a self-selected warm-up. Following the warm up, participants will 
start the exercise test at 75 or 100 Watts, with the workload increasing in a step-wise fashion by 
10 or 20 Watts every two minutes until they feel that they can no longer continue or until they can 
no longer maintain a cadence of 60 rotations per minute (rpm). VO2max will be considered achieved 
if three of the following four criteria are met: heart rate (HR) >90% of age-predicted maximum, 
respiratory exchange ratio >1.15, plateau of oxygen consumption per minute (VO2) with increasing 
work load, and volitional exhaustion (Beltz et al., 2016). Age-predicted maximum heart rate will 
be calculated as 220 – age (years).  
 
Participants will return to the lab on four separate occasions to complete the four exercise 
trials in a random order. During each visit, participants will take two puffs from an MDI, wait 15 
minutes, and then pre-exercise measures will be taken. Pre-exercise FeNO, blood pressure, and  
symptoms will be measured and then participants will put on a headset that includes a mouth piece 
that will be used for spirometry and will control inspired air during exercise. Pre-exercise 
spirometry will be measured and then participants will perform a self-selected warm-up. Once they 
are ready, participants will exercise at a resistance that will elicit 60% of their VO2max for 30 
minutes while breathing through a one-way valve connected to a sealed chamber. The chamber 
will either contain room air or 170 ppb ozone being generated by an ozone generator. After 5 
minutes and 25 minutes of exercise participants will do an IC. After 30 minutes are complete, post-
exercise blood pressure, symptoms, spirometry and FeNO will be measured.  All visits will be 
separated by 48 hours to prevent carryover effects from previous exposure to ozone or salbutamol. 

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This 48-hour duration was chosen because it is longer than five half-lives of salbutamol 
medication.  
 
 
Ethical Considerations 
 
Risks to participants related to physical harm for this study include: severe asthma attack, 
complications from maximal exercise, exposure to ozone, and salbutamol side effects. There will 
be a few instances during the study where participants will have a higher risk of having a severe 
asthma attack. These include the EVH test and the conditions where participants will be exercising 
in ozone. Having people with asthma and/or EIB exercise with placebo medication in the presence 
of a respiratory irritant could elicit an asthma attack (Balmes, 1993). Rescue medication, labelled 
salbutamol, the participant’s own medication and oxygen will be kept nearby in the event of an 
emergency. Participants will also be reminded that they can stop the test at any time if breathing 
becomes too difficult. Potential complications of maximal exercise include: vomiting, abnormal 
blood pressure, fainting, heartbeat disorder, and rare instances of heart attack (Gibbons et al., 
1989). To mitigate this risk, participants will fill out a PAR-Q+ on their first visit to the lab before 
signing the consent form. The PAR-Q+ is designed to screen for individuals that should speak to 
a physician before exercising (Warburton et al., 2018). Participants will be asked to immediately 
report any unusual symptoms during the test and be reminded that they may stop the test at any 
time. An automated external defibrillator (AED) will be present on site and researchers on site will 
trained in standard first aid. Potential symptoms of exposure to ozone include cough, pain with 
inspiration, and shortness of breath (Lippmann, 1989). This risk will be mitigated by using a dose 
of ozone that does not exceed real-world levels of ozone exposure. This low dose of ozone will 
reduce the risk of experiencing symptoms from ozone exposure. In addition, this means that the 

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risk related to ozone exposure would not exceed the level of risk that would occur in the daily lives 
of the participants. Participants will also have the ability to stop the exposure to ozone at any time. 
Some potential temporary side effects of salbutamol use include: nervousness, tremor, headache, 
dryness of the mouth, changes in taste or smell, cough, nausea, and dizziness. Some rare but serious 
side effects include: pounding heartbeat, chest pain, irregular heartbeat, rapid breathing, and 
confusion. Allergic reaction is rare but can result in rash, itchy tongue, severe dizziness, and 
trouble breathing (Burggraaf et al., 2001). This risk is avoided by only including participants in 
the study who have been prescribed salbutamol by their physician. A physician would not prescribe 
salbutamol if the side effects outweighed the benefits of the medication or the patient was allergic 
to the medication. If the participants do experience any serious side effects, immediate care will 
be provided by the researchers who are trained in standard first aid, and the participant will be 
taken to the nearest emergency room located approximately 250 meters away. On experimental 
days a physician will always be available to be onsite within ten minutes and at least one person 
collecting data will have a Standard First Aid with CPR/AED C certification. We have also created 
an emergency action plan and attached it to box 9.8.A of the application. This lab has a long track 
record of using this type of physician supervision with exercise studies in individuals with and 
without asthma, using higher intensity exercise, and even higher intensity exposures to air 
pollution like diesel exhaust ([H08-03055], [H09-01154], [H10-02028], [H10-00902], [H12-
00539]). These studies have all been completed without incident. To ensure informed consent, a 
consent form will be sent to any individual interested in participating with enough time for them 
to review it and contact a member of the research team if they have any questions. This consent 
form will contain: the general purpose of the study and what the participant will be expected to do, 
foreseeable risks and potential benefits, alternatives to participation, contact information of the 

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researcher, assurance that the participant can end their participation at any time, and contact 
information of the relevant research ethics board (TCPS 2, 2018). The relevant research ethics 
board for this study is the Clinical Research Ethics Board (CREB) which reviews clinical research 
done at the University of British Columbia. At the first lab visit, a printed version of the consent 
form will be provided for the participant to review and sign. Upon documenting consent there will 
be: a restatement of the study purpose and description of the study tasks, sufficient prompts to 
encourage participants to ask questions, a reminder of the participant’s right to refuse anything 
they find disturbing or uncomfortable, an assurance of their right to leave at any time without 
penalty, a statement indicating that by signing the consent form the participant is not waving any 
legal rights, and the provision of contact information of the researcher and CREB (TCPS 2, 2018). 
 
Application of Findings 
 
It is important to learn if salbutamol use exacerbates airway inflammation when exercising 
in ozone because chronic airway inflammation in people with asthma has been related to airway 
remodelling that increases the severity of future asthma attacks. In many cases, people with asthma 
and EIB are able to tolerate exercise without salbutamol use. This study will provide some 
information on whether this is a better strategy for preventing future more serious asthma attacks 
or not. This information can be used by physicians who prescribe salbutamol and by people with 
asthma and/or EIB. 
 
Knowledge Translation 
 
There are multiple stakeholders who may be interested in the results of this study including: 
clinicians, asthma and/or EIB patients, and air pollution policy makers. Publishing a paper in 
academic journals such as the European Respiratory Journal or the American Journal of 

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Respiratory and Critical Care Medicine would make this information available to clinicians and 
policy makers. Poster presentations at conferences such as the American Thoracic Society 
Conference would also enable communication of this information to clinicians and policy makers. 
Infographics that simplify the findings and recommendations could be used to communicate the 
information to non-expert stake holders such as patients with asthma and/or EIB. Web-based 
summaries, podcasts, and blogs could also be used to communicate this information to a larger 
population. 
 
 
 
 
 
 
 
 
 
 
 
 
 
References 
Afshar-Mohajer, N., Zuidema, C., Sousan, S., Hallett, L., Tatum, M., Rule, A. M., ... & Koehler, 
K. (2018). Evaluation of low-cost electro-chemical sensors for environmental monitoring 
of ozone, nitrogen dioxide, and carbon monoxide. Journal of occupational and 
environmental hygiene, 15(2), 87-98. 

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Ambient (outdoor) air pollution. (2018, May 2). World Health Organization (WHO). 
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