Clinical trial NCT05087693
Conditions: Asthma and/or Exercise Induced Bronchoconstriction Ozone Air Pollution
Keywords: Asthma Exercise Induced Bronchoconstriction Salbutamol Ozone
Sponsor: University of British Columbia
Start date: 2021-11-01; Completion date: 2023-08-31
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Salbutamol use is increased in areas with high levels of ozone pollution and the potential consequences of this are not well known. The purpose of this study is to examine the effect of salbutamol on lung function and inflammation in people with asthma and/or EIB exercising in ozone air pollution. To examine this, we are planning a randomized cross over trial where people with asthma and/or EIB complete sub maximal exercise in four conditions on four separate days. The four condition are: ozone + salbutamol, filtered air + salbutamol, ozone + placebo medication, and filtered air + placebo medication.

Detailed description:

Arms: arm 1: Participants will be doing sub-maximal exercise (60% of VO2max for 30 minutes) on a cycle ergometer while inhaling 170ppb ozone after inhaling 200ug of salbutamol. arm 2: Participants will be doing sub-maximal exercise (60% of VO2max for 30 minutes) on a cycle ergometer while inhaling filtered air after inhaling 200ug of salbutamol. arm 3: Participants will be doing sub-maximal exercise (60% of VO2max for 30 minutes) on a cycle ergometer while inhaling 170ppb ozone after inhaling placebo medication. arm 4: Participants will be doing sub-maximal exercise (60% of VO2max for 30 minutes) on a cycle ergometer while inhaling filtered after inhaling placebo medication.
Interventions: intervention 1: Salbutamol intervention 2: Placebo medication intervention 3: Ozone intervention 4: Filtered Air intervention 5: Exercise
Intervention descriptions: intervention 1: Inhaling 200ug of salbutamol intervention 2: Inhaling placebo medication intervention 3: Breathing 170ppb ozone intervention 4: Breathing filtered air intervention 5: Cycling at 60% of VO2max on a cycle ergometer

Protocol documents:
Prot_SAP_000.pdf: 
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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 


Page 18 of 23 
 Version 6 (January 28th 2022) 
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). 
https://www.who.int/news-room/fact-sheets/detail/ambient-(outdoor)-air-quality-and-
health 
Anderson, S. D., Argyros, G. J., Magnussen, H., & Holzer, K. (2001). Provocation by eucapnic 
voluntary hyperpnoea to identify exercise induced bronchoconstriction. British journal of 
sports medicine, 35(5), 344-347. 
 
Anderson, S. D., Lambert, S., Brannan, J. D., Wood, R. J., Koskela, H., Morton, A. R., & Fitch, 
K. D. (2001). Laboratory protocol for exercise asthma to evaluate salbutamol given by 
two devices. Medicine and science in sports and exercise, 33(6), 893-900. 
 
Arora, P., & Ansari, S. H. (2019). Role of various mediators in inflammation of asthmatic 
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ATS. (2005). ATS/ERS recommendations for standardized procedures for the online and offline 
measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J 
Respir Crit Care Med, 171(8), 912-930. 
 
Balmes, J. R. (1993). The role of ozone exposure in the epidemiology of asthma. Environmental 
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Barbera, E., Curro, C., & Valenti, G. (2010). A hyperbolic model for the effects of urbanization 
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Barnes, P. J., & Liew, F. Y. (1995). Nitric oxide and asthmatic inflammation. Immunology 
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Beltz, N. M., Gibson, A. L., Janot, J. M., Kravitz, L., Mermier, C. M., & Dalleck, L. C. (2016). 
Graded exercise testing protocols for the determination of VO2max: historical 
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Bjermer, L., Alving, K., Diamant, Z., Magnussen, H., Pavord, I., Piacentini, G., ... & Usmani, O. 
(2014). Current evidence and future research needs for FeNO measurement in respiratory 
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Brightling, C. E., Gupta, S., Gonem, S., & Siddiqui, S. (2012). Lung damage and airway 
remodelling in severe asthma. Clinical & Experimental Allergy, 42(5), 638-649. 
 
Brunekreef, B., & Holgate, S. T. (2002). Air pollution and health. The lancet, 360(9341), 1233-
1242. 
 
Burggraaf, J., Westendorp, R. G. J., Schoemaker, R. C., Sterk, P. J., Cohen, A. F., & Blauw, G. 
J. (2001). Cardiovascular side effects of inhaled salbutamol in hypoxic asthmatic 
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Carlisle, A. J., & Sharp, N. C. C. (2001). Exercise and outdoor ambient air pollution. British 
journal of sports medicine, 35(4), 214-222. 
 
Cerqueira, É., Marinho, D. A., Neiva, H. P., & Lourenço, O. (2020). Inflammatory effects of 
high and moderate intensity exercise—A systematic review. Frontiers in physiology, 10, 
1550. 
 
De Rezende, L. F. M., Lopes, M. R., Rey-López, J. P., Matsudo, V. K. R., & do Carmo Luiz, O. 
(2014). Sedentary behavior and health outcomes: an overview of systematic 
reviews. PloS one, 9(8), e105620. 
 
Evans, C. M., Kim, K., Tuvim, M. J., & Dickey, B. F. (2009). Mucus hypersecretion in asthma: 
causes and effects. Current opinion in pulmonary medicine, 15(1), 4. 
 
Gaber, H. R., Mahmoud, M. I., Carnell, J., Rohra, A., Wuhantu, J., Williams, S., ... & Peacock, 
W. F. (2019). Diagnostic accuracy and temporal impact of ultrasound in patients with 
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medicine, 6(3), 226. 
 
Giles, L. V., & Koehle, M. S. (2014). The health effects of exercising in air pollution. Sports 
Medicine, 44(2), 223-249. 
 
Goldizen, F. C., Sly, P. D., & Knibbs, L. D. (2016). Respiratory effects of air pollution on 
children. Pediatric pulmonology, 51(1), 94-108. 
 
Gomes, E. C., Allgrove, J. E., Florida-James, G., & Stone, V. (2011). Effect of vitamin 
supplementation on lung injury and running performance in a hot, humid, and ozone-
polluted environment. Scandinavian journal of medicine & science in sports, 21(6), e452-
e460. 
 
Gong Jr, H., Bedi, J. F., & Horvath, S. M. (1988). Inhaled albuterol does not protect against 
ozone toxicity in nonasthmatic athletes. Archives of Environmental Health: An 
International Journal, 43(1), 46-53. 
 
Gotshall, R. W. (2002). Exercise-induced bronchoconstriction. Drugs, 62(12), 1725-1739. 
Guarnieri, M., & Balmes, J. R. (2014). Outdoor air pollution and asthma. The Lancet, 383(9928), 
1581-1592. 
 
Guenette, J. A., Chin, R. C., Cory, J. M., Webb, K. A., & O'Donnell, D. E. (2013). Inspiratory 
capacity during exercise: measurement, analysis, and interpretation. Pulmonary 
medicine, 2013. 
 
Guenette, J. A., Dominelli, P. B., Reeve, S. S., Durkin, C. M., Eves, N. D., & Sheel, A. W. 
(2010). Effect of thoracic gas compression and bronchodilation on the assessment of 


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expiratory flow limitation during exercise in healthy humans. Respiratory physiology & 
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Henriquez, A. R., Snow, S. J., Schladweiler, M. C., Miller, C. N., Dye, J. A., Ledbetter, A. D., ... 
& Kodavanti, U. P. (2019). Exacerbation of ozone-induced pulmonary and systemic 
effects by β 2-adrenergic and/or glucocorticoid receptor agonist/s. Scientific reports, 9(1), 
1-17. 
 
Huerta, G., Sansó, B., & Stroud, J. R. (2004). A spatiotemporal model for Mexico City ozone 
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Hull, J. H., Ansley, L., Price, O. J., Dickinson, J. W., & Bonini, M. (2016). Eucapnic voluntary 
hyperpnea: gold standard for diagnosing exercise-induced bronchoconstriction in 
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Jartti, T. (2001). Asthma, asthma medication and autonomic nervous system 
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Khalili, B., Boggs, P. B., & Bahna, S. L. (2007). Reliability of a new hand-held device for the 
measurement of exhaled nitric oxide. Allergy, 62(10), 1171-1174. 
 
Kreit, J. W., Gross, K. B., Moore, T. B., Lorenzen, T. J., D'Arcy, J. A. M. E. S., & Eschenbacher, 
W. L. (1989). Ozone-induced changes in pulmonary function and bronchial 
responsiveness in asthmatics. Journal of applied physiology, 66(1), 217-222. 
 
Lippmann, M. (1989). Health effects of ozone a critical review. Japca, 39(5), 672-695. 
 
Lougheed, M. D., Fisher, T., & O’Donnell, D. E. (2006). Dynamic hyperinflation during 
bronchoconstriction in asthma: implications for symptom perception. Chest, 130(4), 
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Malinovschi, A., Janson, C., Holmkvist, T., Norbäck, D., Meriläinen, P., & Högman, M. (2006). 
Effect of smoking on exhaled nitric oxide and flow-independent nitric oxide exchange 
parameters. European Respiratory Journal, 28(2), 339-345. 
 
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Wanger, J. A. T. S. (2005). Standardisation of spirometry. European respiratory 
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Morris, J. F. (1976). Spirometry in the evaluation of pulmonary function. Western Journal of 
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Mustafa, M. G. (1990). Biochemical basis of ozone toxicity. Free Radical Biology and 
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Nerenberg, K. A., Zarnke, K. B., Leung, A. A., Dasgupta, K., Butalia, S., McBrien, K., ... & 
Canada, H. (2018). Hypertension Canada’s 2018 guidelines for diagnosis, risk 
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Newman, S. P. (2004). Spacer devices for metered dose inhalers. Clinical 
pharmacokinetics, 43(6), 349-360. 
 
Niu, Y., Chen, R., Xia, Y., Cai, J., Lin, Z., Liu, C., ... & Kan, H. (2018). Personal Ozone 
Exposure and Respiratory Inflammatory Response: The Role of DNA Methylation in the 
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ICF_001.pdf: 
University of British Columbia 
School of Kinesiology 
 
Faculty of Education 
 
Rm. 3031, Biological Sciences Building 
 
6270 University Blvd. 
 
Vancouver, B.C., Canada V6T 1Z4 
 
Tel: (604) 822-9331 Fax: (604) 822-9451 
 
Version 10 (February 14th 2022)                  Ethics ID Number: H21-01080 
Page 1 of 12 
SUBJECT INFORMATION AND CONSENT FORM 
 
Examining the Effect of Salbutamol Use in Asthma and/or EIB 
Whilst Exercising in Ozone Air Pollution 
 
 
Principal Investigator:   
Michael Koehle MD PhD 
School of Kinesiology 
Division of Sports Medicine 
Faculty of Medicine  
 
 
 
 
University of British Columbia 
 
 
 
 
604 822 9331 
 
 
Co-Investigators: 
 
William Sheel, PhD 
 
 
 
 
Nadine Borduas-Dedekind, PhD 
 
 
 
 
= 
 
 
 
 
 
 
 
 
 
Bennett Stothers (BKin) 
 
 
 
 
 
 
Sponsors: 
 
 
UBC Faculty of Education 
 
 
 
 
Natural Sciences and Engineering Research Council 
 
 
 
 
  
 
Emergency Telephone Number: (604) 788-7268 (24-hour, 7-days a week phone number)  
 
 
Contact Person: Ben Stothers 
School of Kinesiology 
The University of British Columbia 
Email: ben.stothers@ubc.ca 
Telephone: (604) 240-7188 
 
 
 
 
 
 
 
 
 
 


University of British Columbia 
School of Kinesiology 
 
Faculty of Education 
 
Rm. 3031, Biological Sciences Building 
 
6270 University Blvd. 
 
Vancouver, B.C., Canada V6T 1Z4 
 
Tel: (604) 822-9331 Fax: (604) 822-9451 
 
Version 10 (February 14th 2022)                  Ethics ID Number: H21-01080 
Page 2 of 12 
1. INVITATION 
 
You are being invited to take part in this research study because you have asthma and or exercise 
induced bronchoconstriction (EIB) and are between 19 and 50 years of age. If you are allergic to 
salbutamol (also known as Ventolin), pregnant, have a history of smoking, use inhaled 
corticosteroid medication, had an upper respiratory tract infection in the last four weeks, or have 
a chronic respiratory disease other than asthma or EIB you are not eligible for this investigation. 
 
 
2. YOUR PARTICIPATION IS VOLUNTARY 
 
Your participation in this study is completely voluntary. You have the right to refuse 
participation in this study. Should you choose to participate, you may choose to withdraw from 
the study at any time without penalty. Before you decide, it is important for you to understand 
what the research involves. This consent form will tell you about the study, why the research is 
being done, what will happen to you during the study and the possible benefits, risks and 
discomforts.  
If you wish to participate, you will be asked to sign this form. If you do decide to take part in this 
study, you are still free to withdraw at any time and without giving any reasons for your 
decision.  
If you do not wish to participate, you do not have to provide any reason for your decision not to 
participate nor will you lose the benefit of any medical care to which you are entitled or are 
presently receiving.  
Please take time to read the following information carefully and to discuss it with your family, 
friends, and doctor before you decide.  
 
 
3. WHO IS CONDUCTING THIS STUDY? 
 
This study is funded by the UBC Faculty of Education and the Natural Sciences and Engineering 
Research Council of Canada (NSERC). 
 
 
4. BACKGROUND 
 
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. As the world’s population continues to become more developed, more people are 
living in areas with increased ambient air pollution. Exposure to air pollutants, such as ozone 


University of British Columbia 
School of Kinesiology 
 
Faculty of Education 
 
Rm. 3031, Biological Sciences Building 
 
6270 University Blvd. 
 
Vancouver, B.C., Canada V6T 1Z4 
 
Tel: (604) 822-9331 Fax: (604) 822-9451 
 
Version 10 (February 14th 2022)                  Ethics ID Number: H21-01080 
Page 3 of 12 
gas, have been associated with increased mortality and hospitalization due to heart and lung 
disease. This presents a potential issue because increased breathing rates during exercise result in 
an increased amount of inhaled air pollution. 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. Salbutamol is a medication commonly prescribed to this 
population and its use is increased in regions with higher levels of ozone pollution. However, 
rodent studies have indicated a potential for negative consequences of salbutamol use in ozone 
air pollution including increased protein leakage and lung inflammation.  
 
 
5. WHAT IS THE PURPOSE OF THIS STUDY? 
 
The purpose of this study is to investigate the influence of salbutamol use on lung function and 
inflammation in people with asthma and/or EIB when exercising in ozone air pollution. 
 
 
6. WHO CAN PARTICIPATE IN THIS STUDY? 
 
You may be able to participate if you: 
• Are between 18 and 50 years of age 
• Have asthma and/or EIB related airway narrowing during exercise (this will be confirmed 
on the first lab visit) 
• Are able to perform maximal exercise 
• Are able to communicate sufficiently using the English language  
 
In total a minimum of 24 participants will be recruited.  
 
 
7. WHO SHOULD NOT PARTICIPATE IN THIS STUDY? 
 
You should not participate if you: 
• Are allergic to salbutamol (also known as Ventolin) 
• Are pregnant or potentially pregnant 
• Have a history of smoking 
• Had an upper respiratory tract infection within the last 4 weeks 
• Have a chronic respiratory disease other than asthma or EIB  
 
 
 
 
 
 
 


University of British Columbia 
School of Kinesiology 
 
Faculty of Education 
 
Rm. 3031, Biological Sciences Building 
 
6270 University Blvd. 
 
Vancouver, B.C., Canada V6T 1Z4 
 
Tel: (604) 822-9331 Fax: (604) 822-9451 
 
Version 10 (February 14th 2022)                  Ethics ID Number: H21-01080 
Page 4 of 12 
8. WHAT DOES THIS STUDY INVOLVE? 
 
This is a maximal exercise study design where you will complete both room air and ozone 
conditions after taking either a placebo or an asthma medication. This design has two 
independent variables (air quality and medication) and two dependent variables (lung function 
and lung inflammation). The two levels of the air quality variable are room air and ozone 
containing air. The air quality variable will be double blinded. The two levels of the medication 
variable will be salbutamol and placebo medication. The medication variable will be double 
blinded. This study will involve five visits to the lab separated by a minimum of 48 hours. There 
are pre-lab visit restrictions described below in section 9 related to food to avoid 12 hours before, 
medication, supplements and exercise. After providing informed written consent, we will ask 
you to complete a questionnaire regarding your medical history and physical activity levels 
(PAR-Q+) to ensure it is safe for you to exercise. The first visit will be a screening day where 
you will do test breathing test (EVH test) and a maximal exercise (VO2max test). The EVH test 
will determine the degree of airway narrowing that occurs during exercise. The VO2max test is a 
maximal exercise test that will be used to standardize exercise intensity in subsequent visits. 
Days 2-5 will be experimental days involving lung function (spirometry), lung inflammation 
(FeNO) measurement, blood pressure measurement, and symptom  rating (breathlessness, cough, 
sore throat, headache, chest pain, and chest tightness) before and after doing moderate intensity 
exercise for 30 minutes. Before exercise you will inhale either placebo or real salbutamol. 
During exercise you will be breathing air from a tube connected to a sealed chamber that will 
contain room air or air with ozone. Over the course of the four experimental days you will 
exercise under four different conditions: (salbutamol + ozone), (salbutamol + room air), (placebo 
+ ozone), and (placebo + room air). The order of these conditions over the four experimental 
days will be determined by a random number generator in an Excel spreadsheet. The testing will 
take place in Room 118 of the Medical Sciences Block C building located at 2176 Health 
Sciences Mall. The first day should take about 2 hours and days 2-5 should take about 2.5 hours 
each for a total of 12 hours. 
 
If you decide to join this study: 
 
Specific procedures day 1 
 
On day 1 you will re-read and sign this consent form in addition to a PAR-Q+ questionnaire. 
You will then do a EVH test which simulates breathing during exercise. After the EVH test you 
will take 200µg (two puffs) of salbutamol, wait 15 minutes, do a self-selected warm up on a 
stationary bike, and then complete a maximal exercise test (VO2max test). Overall this day may 
last up to 2 hours. 
 
Lung Function Measurement (Spirometry): 
Lung function will be measured as per the guidelines of the American Thoracic Society (ATS). 
The baseline measurements involve using a machine (called a spirometer) to measure your 
breathing function (spirometry). This will involve taking a series of breaths (at rest) as instructed 


University of British Columbia 
School of Kinesiology 
 
Faculty of Education 
 
Rm. 3031, Biological Sciences Building 
 
6270 University Blvd. 
 
Vancouver, B.C., Canada V6T 1Z4 
 
Tel: (604) 822-9331 Fax: (604) 822-9451 
 
Version 10 (February 14th 2022)                  Ethics ID Number: H21-01080 
Page 5 of 12 
by the investigators. You will exhale into a machine that measures the amount of air that you 
breathe out. Standard measures of pulmonary function will be measured.  
 
Eucapnic Voluntary Hyperpnea Test (EVH test): 
The EVH test is the most commonly used test to assess exercise-induced airway narrowing in 
athletes. After three lung function tests (see above), you will breathe a dry gas mixture (5% CO2, 
21% O2, balanced with N2) for 6 min. During those 6 min you will be asked to increase your 
breathing rate and volume, similar to how you breathe during intense exercise. The purpose is to 
simulate the breathing pattern you would use while training or competing at a high intensity. 
Following this 6 min period, you will repeat the lung function testing that you already performed 
at the beginning of the test. This test will indicate if you have asthma related airway narrowing 
during exercise. - 
 
Maximal Exercise Test (VO2max test): 
We will ask you wear appropriate exercise attire for the cycling exercise. Before the cycling test 
begins, you will perform a 5-minute self-selected warm up on a stationary bike. Following the 
warm up, you 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 you feel you can no longer continue 
or until you can no longer maintain a cadence of 60 rpm. We will ask you to perform a large 
breath in until your lungs are completely full at the end of each stage of exercise. This allows us 
to assess your lung volumes. During all exercise bouts, you will be breathing on a standard 
mouthpiece while wearing a nose clip to monitor breathing.  
 
Specific procedures days 2-5 
 
Days 2-5 will involve taking either placebo medication or salbutamol, waiting 15 minutes and 
then doing pre-exercise measures. Pre-exercise measures include spirometry, lung inflammation 
(FeNO) measurement, blood pressure measurement, and rating of breathlessness.  You will then 
exercise for 30 minutes at 60% of your VO2max while breathing in room air or air that contains 
ozone. During all exercise bouts, you will be breathing from a standard mouthpiece while 
wearing a nose clip to monitor breathing. We will ask you to perform a large breath in until your 
lungs are completely full periodically during exercise. This allows us to assess your operating 
lung volumes. Immediately after exercise, blood pressure, symptoms, FeNO, and spirometry will 
be measured. These measures will be repeated again after 30 minutes and 1 hour after exercise. 
These 4 days will be separated by a minimum of 48 hours. Each visit should take roughly 2.5 
hours. 
 
Lung Function Measurement (Spirometry): 
Same at day 1 described above. 
 
Lung Inflammation Measurement (FeNO): 
Nitic oxide (NO) is produced by the epithelial cells lining your airway and is related to the level 
of airway inflammation. When there is a larger amount of airway inflammation more NO is 


University of British Columbia 
School of Kinesiology 
 
Faculty of Education 
 
Rm. 3031, Biological Sciences Building 
 
6270 University Blvd. 
 
Vancouver, B.C., Canada V6T 1Z4 
 
Tel: (604) 822-9331 Fax: (604) 822-9451 
 
Version 10 (February 14th 2022)                  Ethics ID Number: H21-01080 
Page 6 of 12 
produced and there is a larger amount of NO in the air you breath out. Measuring the fraction of 
exhaled NO (FeNO) is a common technique used to measure airway inflammation in people with 
asthma. To do this you will take a big breath in and then exhale slowly into a FeNO monitor for 
10 seconds. During these 10 seconds the FeNO monitor will guide you on how fast you should 
exhale. 
 
Blood Pressure Measurement 
We will wrap a blood pressure cuff around your upper arm. A machine will then briefly inflate 
and then deflate this cuff. 
 
Rating of breathlessness (dyspnea) measurement 
We will show you a rating scale from one to ten and ask you how severe your feeling of 
breathlessness is. 
 
 
9. WHAT ARE MY RESPONSIBILITIES? 
 
Avoid alcohol consumption 24 hours before each visit 
 
Avoid eating or drinking 1 hour before each visit 
 
Foods to avoid 12 hours before each visit: 
-Rocket, Spinach, Lettuce, Radish, Beetroot, Chinese cabbage, Turnips, Cabbage, Green beans, 
Leeks, Spring onion, Cucumber, Carrot, Potato, Garlic, Sweet pepper, Green pepper. 
 
Medication: 
-No leukotriene modifier medication (such as montelukast or Singulair) 24 hours before each 
visit. 
-No short-acting beta agonists (such as salbutamol or Ventolin) 8 hours before each visit.  
-No long-acting beta agonists (such as salmeterol or Serevent) 48 hours before each visit. 
-No anti-histamines 72 hours before each visit. 
 
If you need to take one of these medications within the time limit before your visit please do not 
hesitate. You can always reschedule your visit to a later date. 
 
Vitamins: 
-No vitamin E supplements for the duration of the study 
-No vitamin C supplements for the duration of the study 
-No multivitamin supplements for the duration of the study 
 
Exercise: 
-Avoid exercising 24 hours before each visit 
 


University of British Columbia 
School of Kinesiology 
 
Faculty of Education 
 
Rm. 3031, Biological Sciences Building 
 
6270 University Blvd. 
 
Vancouver, B.C., Canada V6T 1Z4 
 
Tel: (604) 822-9331 Fax: (604) 822-9451 
 
Version 10 (February 14th 2022)                  Ethics ID Number: H21-01080 
Page 7 of 12 
10. WHAT ARE THE POSSIBLE HARMS AND DISCOMFORTS? 
 
Risks related to maximal exercise: 
Some rare risks related to maximal exercise include: vomiting (2%), abnormal blood pressure, 
(less than 1%), disorders of heartbeat, or arrhythmia (0.1%), and very rare instances of heart 
attack (less than 0.001%). The percentage of risk of heart attack based on males and females who 
have been given these tests is very small (less than 0.0001%).  
 
Risks related to EVH test: 
Performing spirometry and EVH test involves exhaling forcefully into the mouthpiece of the 
spirometer and may cause some light-headedness, chest discomfort and coughing immediately 
after the procedure.  
Risks related to ozone exposure: 
Some uncommon side effect to this level of ozone exposure include: cough, throat irritation, 
pain, burning, or discomfort in the chest when taking a deep breath, chest tightness, wheezing a 
shortness of breath.  
 
Risk related to salbutamol side effects: 
Some less common side effects of salbutamol use include throat iteration (10%), and viral 
respiratory infection (7%). Some uncommon symptoms include upper respiratory tract infection 
(5%), cough (5%), and musculoskeletal pain (5%). 
 
How risks will be mitigated? 
Risk related to maximal exercise will be minimized by fill out the PAR-Q+ questionnaire which 
is designed to screen for individuals that are at higher risk of experiencing complications from 
exercise. Risks related to ozone exposure will be minimized by using a 170ppb ozone 
concentration. This concentration is much lower than in studies done on ozone previously and is 
representative of what one might find on a polluted summer day in certain cities in the real 
world. For example, ozone concentrations can reach 200ppb at 3pm in Mexico City during 
September. Risk related to salbutamol will be minimized by excluding people who are allergic to 
salbutamol and by using a dose of 200μg. This is a lower dose of salbutamol that is typically 
used for preventing exercise related asthma attacks. In the event of an emergency at least one of 
the researchers present will be trained in standard first aid and an AED will be present on site. 
The nearest emergency room is also located approximately 250 metres away at UBC hospital. 
 
 
11. WHAT ARE THE POTENTIAL BENEFITS OF PARTICIPATING? 
 
As part of your participation, you will undergo a maximal oxygen consumption measure 
(VO2max test). The results will give individuals a direct measure of cardiorespiratory fitness 
likely unavailable to them otherwise. The results of the EVH test may also provide insight into 
the current severity of the participants asthma. The results of the exercise trials in ozone may 
also provide insight into your susceptibility to ozone pollution. Other than that, there are no 


University of British Columbia 
School of Kinesiology 
 
Faculty of Education 
 
Rm. 3031, Biological Sciences Building 
 
6270 University Blvd. 
 
Vancouver, B.C., Canada V6T 1Z4 
 
Tel: (604) 822-9331 Fax: (604) 822-9451 
 
Version 10 (February 14th 2022)                  Ethics ID Number: H21-01080 
Page 8 of 12 
known direct benefits from taking part in this study. We hope that the information learned from 
this study can be used in the future to benefit individuals who are repeatedly training and 
competing in areas of increased air pollution levels to better manage any asthma-symptoms, 
cardiorespiratory risks and complications associated with exercising in polluted conditions.  
 
 
12. WHAT HAPPENS IF I DECIDE TO WITHDRAW MY CONSENT TO 
PARTICIPATE? 
 
You may withdraw from this study at any time without giving reasons. If you choose to enter the  
study and then decide to withdraw later, you have the right to request the withdrawal of your  
information collected during the study. This request will be respected to the extent possible.  
Please note however that there may be exceptions where the data will not be able to be  
withdrawn for example when it is no longer identifiable (meaning it cannot be linked in any way  
back to your identity) or where the data has been merged with other data. If you would like to  
request the withdrawal of your data, please let your study investigator know.  
 
13. CAN I BE ASKED TO LEAVE THE STUDY? 
 
You may be asked to leave the study if it is not in your best interest to continue, if you are unable 
to fulfill the requirements for the study, or for any other reason. If you are asked to leave the 
study, the reasons for this will be explained to you and you will have the opportunity to ask 
questions about this decision. The study may also be stopped at any time by the sponsor to the 
Research Ethics Board if new information rises about the safety of the study treatment. The 
reasons for study stoppage will be explained to you. 
 
14. WILL MY TAKING PART IN THIS STUDY BE KEPT CONFIDENTIAL? 
Your confidentiality will be respected. However, research records and health or other source 
records identifying you may be inspected in the presence of the Investigator or his or her 
designate by representatives of UBC Clinical Research Ethics Board for the purpose of 
monitoring the research. No information or records that disclose your identity will be published 
without your consent, nor will any information or records that disclose your identity be removed 
or released without your consent unless required by law.  
You will be assigned a unique study number as a participant in this study. This number will not 
include any personal information that could identify you (e.g., it will not include your Personal 
Health Number, SIN, or your initials, etc.). Only this number will be used on any research- 
related information collected about you during the course of this study, so that your identity will 
be kept confidential. Information that contains your identity will remain only with the Principal 
Investigator and/or designate. The list that matches your name to the unique study number that is 
used on your research-related information will not be removed or released without your consent 
unless required by law.  


University of British Columbia 
School of Kinesiology 
 
Faculty of Education 
 
Rm. 3031, Biological Sciences Building 
 
6270 University Blvd. 
 
Vancouver, B.C., Canada V6T 1Z4 
 
Tel: (604) 822-9331 Fax: (604) 822-9451 
 
Version 10 (February 14th 2022)                  Ethics ID Number: H21-01080 
Page 9 of 12 
Your rights to privacy are legally protected by federal and provincial laws that require safeguards 
to ensure that your privacy is respected and also give you the right of access to the information 
about you, if need be, an opportunity to correct any errors in this information. Further details 
about these laws are available on request to your study doctor.  
 
 
15. WHAT HAPPENS IF SOMETHING GOES WRONG? 
 
By signing this form, you do not give up any of your legal rights and you do not release the study 
doctor, participating institutions, or anyone else from their legal and professional duties. If you 
become ill or physically injured as a result of participation in this study, medical treatment will 
be provided at no additional cost to you. The costs of your medical treatment will be paid by 
your provincial medical plan.  
 
 
16. WHAT WILL THE STUDY COST ME? 
 
There will be no cost to the participant to partake in this study. However, you will be expected to 
arrange your own transportation to and from the laboratory for each visit. 
Remuneration: You will be paid $150 (Canadian dollars) for your participation in the study. 
Payments will be pro-rated ($30 for each day) if the participant withdraws from the study. No 
receipts are required to receive payment.  
 
 
17. WHO DO I CONTACT IF I HAVE QUESTIONS ABOUT THE STUDY DURING MY 
PARTICIPATION? 
 
If you have any questions or desire further information about this study before or during 
participation, or if you experience any adverse effects, you can contact Ben Stothers at 
ben.stothers@ubc.ca or (604) 240-7188. You may also contact the Principal Investigator, Dr. 
Michael Koehle, at (604) 788 7268. 
 
 
18. WHOM DO I CONTACT IF I HAVE ANY QUESTIONS OR CONCERNS ABOUT 
MY RIGHTS AS A SUBJECT? 
 
If you have any concerns about your rights as a research subject and/or your experiences while 
participating in this study, contact the Research Participant Complaint Line in the University of 
British Columbia Office of Research Ethics at 1-877-822-8598 (toll free); or by email at 
RSIL@ors.ubc.ca. Please reference the study number [H21-01080] when calling so the 
Complaint Line staff can better assist you. 
 
 


University of British Columbia 
School of Kinesiology 
 
Faculty of Education 
 
Rm. 3031, Biological Sciences Building 
 
6270 University Blvd. 
 
Vancouver, B.C., Canada V6T 1Z4 
 
Tel: (604) 822-9331 Fax: (604) 822-9451 
 
Version 10 (February 14th 2022)                  Ethics ID Number: H21-01080 
Page 10 of 12 
 
Notice of COVID-Related Risks during Research | Version A 
 
Please read this form before you consent to participate in a research study. Please also talk to the 
researcher about any concerns you have before signing the consent form or agreeing to participate. 
Remember that research participants may withdraw from a study at any time, without giving a reason.  
Contact Tracing  
The researcher may be required by public health authorities to share your contact information if there 
is a chance that you have been exposed to COVID-19 during a study visit. You will find more information 
about contact tracing on the BC Centre for Disease control website: http://www.bccdc.ca/health-
info/diseases-conditions/covid-19/self-isolation/contact-tracing. 
How does contact tracing work?  
If public health authorities ask the researcher to provide a list of people who they have been in contact 
with, the researcher will be required to share your contact details. The researcher will not share 
information about the purpose of your contact, the name of the study, or anything about the research 
topic. Your contact tracing information will be kept securely and separate from de-identified research 
records and will be deleted 30 days after your last contact with the researcher It is important to know 
that because of this your anonymity will not be preserved.  
 
What if I want to withdraw from the study?  
If at any time you decide to withdraw from the study, the research team will only continue to store your 
contact information for as long as required by public health authorities. Unless otherwise stated, other 
data you have contributed will be removed from the study when you withdraw. 
 
Risks of in-person contact during the research 
For research that involves in-person activities such as focus groups, interviews or observations, the 
researchers will be following safety plans that have been approved by the University. They include: safe 
use of facilities (including outdoor spaces) and experimental equipment, proof of vaccination, personal 
protective equipment, and physical distancing. The researchers in this study are vaccinated. 
 
If you are required to use public transit to get to or from a research location, this may increase your risk 
of being exposed to COVID-19. We encourage you to take all precautions, including wearing a face mask 
while in public, washing your hands, avoiding touching your face, and keeping a safe physical distance 
from others (at least 2 metres or 6 feet). Please let the researcher know if you want more information 
about the safety plans that have been put in place.  
 
What if I have COVID-19 symptoms or am diagnosed with COVID-19?   
Before every research activity, the researcher will ask each person who is present a series of questions 
about their health. The questions have been recommended by public health authorities, and ask about 
physical symptoms, if you have been in contact with people who are sick, and other questions. Based on 
your responses, the researcher will decide if it is safe to proceed with the in-person activity.  
 
Ensure that you keep the research team’s contact information (included on the consent form) so you 
can share it with public health authorities in the event that you become sick after participating in 
research.  
 
Thank you! 


University of British Columbia 
School of Kinesiology 
 
Faculty of Education 
 
Rm. 3031, Biological Sciences Building 
 
6270 University Blvd. 
 
Vancouver, B.C., Canada V6T 1Z4 
 
Tel: (604) 822-9331 Fax: (604) 822-9451 
 
Version 10 (February 14th 2022)                  Ethics ID Number: H21-01080 
Page 11 of 12 
Examining the Effect of Salbutamol Use in Asthma and/or EIB 
Whilst Exercising in Ozone Air Pollution 
 
 
SUBJECT CONSENT TO PARTICIPATE   
 
The consent form is not a contract and as such that the subject does not give up any legal rights by 
signing it.   
 
• I have read and understood the subject information and consent form. 
• I have had sufficient time to consider the information provided and to ask for advice if 
necessary. 
• I have had the opportunity to ask questions and have had satisfactory responses to my 
questions. 
• I understand that all of the information collected will be kept confidential and that the 
results will only be used for scientific objectives.  
• I understand that my participation in this study is voluntary and that I am completely free 
to refuse to participate or to withdraw from this study at any time. 
• I understand that there is no guarantee that this study will provide any benefits to me. 
 
 
I will receive a signed copy of this consent form for my own records. 
 
 
I consent to participate in this study. 
 
____________________                ____________________                               _______________ 
Subject’s Signature 
                    Printed Name 
                                           Date 
 
 
 
 
 
 
 
 
 
 
Signature of Person 
 
Printed name 
 
Study Role 
Date 
 
Obtaining Consent 
 
 
 


University of British Columbia 
School of Kinesiology 
 
Faculty of Education 
 
Rm. 3031, Biological Sciences Building 
 
6270 University Blvd. 
 
Vancouver, B.C., Canada V6T 1Z4 
 
Tel: (604) 822-9331 Fax: (604) 822-9451 
 
Version 10 (February 14th 2022)                  Ethics ID Number: H21-01080 
Page 12 of 12 
If this consent process has been done in a language other than that on this written form, with the 
assistance of an interpreter/translator, indicate: 
 
Language: _____________________ 
Was the subject assisted during the consent process in one of ways listed below? 
☐Yes ☐No 
 
If yes, please check the relevant box and complete the signature space below: 
 
☐ The consent form was read to the subject, and the person signing below attests that the 
study was accurately explained to, and apparently understood by, the subject (please check 
if subject is unable to read). 
 
☐ The person signing below acted as an interpreter/translator for the subject, during the 
consent process (please check if an interpreter/translator assisted during the consent 
process). 
 
____________________      
__________________                        ________________      
Signature of Person Assisting         Printed Name 
                                 Date 
in the Consent Discussion 
Witness Signature 
 
 
 
____________________                     ___________________                
________________ 
Investigator Signature                      Printed Name                               Date 
 
 
My signature above signifies that the study has been reviewed with the study subject by me and/or 
by my delegated staff. My signature may have been added at a later date, as I may not have been 
present at the time the subject’s signature was obtained.