J Appl Physiol 118: 255–264, 2015.
First published November 26, 2014; doi:10.1152/japplphysiol.00400.2014.
Heliox breathing equally influences respiratory mechanics and cycling
performance in trained males and females
Sabrina S. Wilkie,1 Paolo B. Dominelli,1 Benjamin C. Sporer,2,3 Michael S. Koehle,1,2
and A. William Sheel1
1
School of Kinesiology, University of British Columbia, Vancouver, Canada; 2Division of Sports Medicine, Faculty
of Medicine, University of British Columbia, Vancouver, Canada; and 3Canada Sport Institute Pacific, Vancouver, Canada
Submitted 12 May 2014; accepted in final form 25 November 2014
exercise; expiratory flow limitation; sex differences; ventilatory limitations to exercise
a substantial reserve exists for
increasing minute ventilation (V̇E) during heavy exercise (16,
23). Here, the flow-volume and pressure-volume responses are
substantially lower than the mechanical constraints imposed by
the properties of the airways, chest wall, and the capacity for
generating pressure by the respiratory musculature. Conversely, the high metabolic and ventilatory requirements observed in highly trained males are associated with significant
expiratory flow limitation (27). Expiratory flow limitation
occurs when, for a given operational lung volume, flow plateaus despite increasing intrapleural pressures (26). To alleviate expiratory flow limitation, operational lung volumes typically increase, which, due to the shape of the maximal expiratory flow-volume curve, permits higher expiratory flow and
IN HEALTHY UNTRAINED HUMANS
Address for reprint requests and other correspondence: A. W. Sheel, 6108
Thunderbird Blvd., Vancouver, BC, Canada V6T 1Z3 (e-mail: [email protected]).
http://www.jappl.org
greater ventilation (23). This relative hyperinflation places the
lungs on the less compliant aspect of the pressure-volume
curve, which increases the mechanical work of breathing and
reduces the mechanical efficiency of the now shortened inspiratory muscles (17, 38). The increased work of breathing is
likely linked to both the relative hyperinflation and expiratory
flow limitation. The resultant higher work of breathing and
fatigued diaphragm are associated with a redistribution of
blood flow away from the locomotor muscles (21, 44), reductions in exercise performance (7, 22), and leg fatigue (42). The
interrelationships between the respiratory system and the cardiovascular system, muscular fatigue, and exercise performance have been studied almost exclusively in male subjects.
There is now evidence suggesting that endurance-trained
females are more susceptible to expiratory flow limitation
during exercise (20, 32) and that for a given V̇E, women have
a higher work of breathing compared with males (19, 20, 49).
The higher tendency for expiratory flow limitation and a
greater work of breathing in females can be attributed to
sex-based differences in airway size. When matched for total
lung volume, females have smaller airways and smaller luminal areas of the large conducting airways compared with males
(31, 34, 45). Specifically, we have previously shown that males
have greater (14 –25%) luminal areas of the large and central
airways (trachea, generation 0 through generation 2 and several
of the segmental airways) that are not accounted for by differences in lung size (45). The chief sites of airway resistance
(⬃80%) in healthy individuals are the larger airways (up to the
7th generation), where turbulent airflow is predominate and the
Reynolds number is high under exercising conditions of elevated ventilation (46). As such, the high resistive work of
breathing in females performing heavy exercise (19) can, in
large part, be explained by narrower airways.
Given that resistance to airflow is inversely proportional
to airway radius to the fourth power, females with the same
size lungs as males will have higher airway resistance due
to a smaller airway radius and thus will have lower expiratory flows. Low-density gas mixtures such as helium-oxygen
(HeO2) could aid in understanding the physiological relevance
of the aforementioned sex-based differences. Helium has a
density that is approximately one-third that of nitrogen. Breathing HeO2 is expected to reduce airway resistance and increase
flow primarily as a result of a decrease in turbulence within the
larger airways (10, 47). McClaran et al. (33) used HeO2 to
increase the size of the maximal flow-volume envelope and
consequently reduce the amount of expiratory flow limitation
during heavy exercise in competitive male cyclists. Moreover,
the work of breathing is significantly reduced when inspiring
HeO2 during maximal exercise despite an increase in ventila-
8750-7587/15 Copyright © 2015 the American Physiological Society
255
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Wilkie SS, Dominelli PB, Sporer BC, Koehle MS, Sheel AW.
Heliox breathing equally influences respiratory mechanics and
cycling performance in trained males and females. J Appl Physiol
118: 255–264, 2015. First published November 26, 2014;
doi:10.1152/japplphysiol.00400.2014.—In this study we tested the
hypothesis that inspiring a low-density gas mixture (helium-oxygen;
HeO2) would minimize mechanical ventilatory constraints and preferentially increase exercise performance in females relative to males.
Trained male (n ⫽ 11, 31 yr) and female (n ⫽ 10, 26 yr) cyclists
performed an incremental cycle test to exhaustion to determine
maximal aerobic capacity (V̇O2max; male ⫽ 61, female ⫽ 56
ml·kg⫺1·min⫺1). A randomized, single-blinded crossover design was
used for two experimental days where subjects completed a 5-km
cycling time trial breathing humidified compressed room air or HeO2
(21% O2:balance He). Subjects were instrumented with an esophageal
balloon for the assessment of respiratory mechanics. During the time
trial, we assessed the ability of HeO2 to alleviate mechanical ventilatory constraints in three ways: 1) expiratory flow limitation, 2)
utilization of ventilatory capacity, and 3) the work of breathing. We
found that HeO2 significantly reduced the work of breathing, increased the size of the maximal flow-volume envelope, and reduced
the fractional utilization of the maximal ventilatory capacity equally
between men and women. The primary finding of this study was that
inspiring HeO2 was associated with a statistically significant performance improvement of 0.7% (3.2 s) for males and 1.5% (8.1 s) for
females (P ⬍ 0.05); however, there were no sex differences with
respect to improvement in time trial performance (P ⬎ 0.05). Our
results suggest that the extent of sex-based differences in airway
anatomy, work of breathing, and expiratory flow limitation is not great
enough to differentially affect whole body exercise performance.
256
Work of Breathing, Performance, and Sex Differences
tion (5). However, the HeO2-induced reduction in the work of
breathing is inconsistent between studies (4). Reducing turbulent airflow and increasing the maximal flow-volume envelope,
which in turn lowers the mechanical work of breathing, has
also been shown to improve treadmill running performance in
health (50) and chronic obstructive pulmonary disease (14). To
this end, we investigated whether experimentally alleviating
pulmonary system constraints with HeO2 would differentially
improve lung mechanics and exercise performance between
men and women. We hypothesized that inspiring HeO2 would
reduce the work of breathing and improve exercise performance to a greater degree in endurance-trained females relative
to males.
METHODS
Wilkie SS et al.
and operated using commercially available software (VeloTron 3D,
version 3, RacerMate). During the TT, subjects watched a monitor
displaying their distance covered and cadence. During the test the
experimenter did not verbally encourage subjects. The exact bike
set-up (seat and handle-bar positions) on day 2 was recorded and
subjects were required to ride in the identical position on day 3 and
warm-up for the same duration.
Flow, volume, and pressure. Ventilatory and mixed expired metabolic parameters were collected using a customized metabolic cart
consisting of two independent pneumotachographs (model 3813, Hans
Rudolph, Kansas City, MO) to measure inspiratory and expiratory
flow, and calibrated O2 and CO2 analyzers (model S-3-A/I and model
CD-3A, respectively, Applied Electrochemistry, Pittsburgh, PA). Carbon dioxide could not be measured during the HeO2 trials due to He
interfering with the infrared signal used by the CO2 analyzer to
determine CO2 concentration. The pneumotachographs were independently calibrated using a 3-liter calibration syringe for both room air
and HeO2. We wished to “unload” the respiratory system as much as
possible via heliox. As such external resistance was maintained
constant between the room air and heliox experiments, volumes were
obtained by numerical integration of the flow signals. Due to the lower
heat capacity of He and its higher thermal conductivity relative to N2,
a low-resistance spirometry filter (PDS8505, Roxon, Vancouver, BC,
Canada) was placed before the expired pneumotachograph, and the
heater was increased to 43°C. The filter and elevated temperature were
used to prevent moisture build-up on the pneumotachograph causing
false measures of flow rates. The spirometry filter was present in both
trials to maintain a consistent set-up and external resistance. Heliox
expired ventilation was temperature corrected off-line during subsequent data analysis to take into account the vapor pressure of water at
43°C. The humidified gases were inspired via a two-way breathing
valve connected to a continuously filled 200-liter meteorological
balloon (1197–25, VacuMed, Ventura, CA) via a water-filled basin.
Esophageal pressure (PES) was measured with a balloon-tipped
catheter (no. 47-9005-RO, Ackrad, Trumbull, CT) placed in the lower
third of the esophagus (12). After the balloon was inserted, all the air
was evacuated by pulling back on a syringe plunger until the plunger
returned to a nonvacuum position. One milliliter of air was injected in
order to partially inflate the balloon and catheter as per manufacturer
specifications. Validity of the balloon pressure was checked by having
the subjects perform the dynamic occlusion test (8). Mouth pressure
(PM) was measured via a port in the mouthpiece, and transpulmonary
pressure was taken as the difference between PM and PES. Separately
calibrated pressure transducers were used to measure PES and PM
(Validyne, MCI-10, Northridge, CA). All raw data during the exercise
test were recorded continuously at 200 Hz (PowerLab/16SP model
ML 796, ADInstruments, Colorado Springs, CO) and stored on a
computer for subsequent analysis (LabChart v7.1.3, ADInstruments).
Metabolic data were obtained 30 s prior to the completion of each
kilometer interval. Heart rate (S610i, Polar Electro, Kempele, Finland) was recorded at rest, and throughout the incremental and TT
tests.
Mechanics of breathing. We assessed the ability of HeO2 to
alleviate mechanical ventilatory constraints during the TTs in three
ways. First, we determined the degree of expiratory flow limitation
(18, 28), whereby FVC and graded FVC maneuvers were performed
pre- and postexercise when breathing room air and when breathing
heliox to account for thoracic gas compression and bronchodilation as
we have previously described (18). These considerations are important for two reasons. First, the maximal expiratory flow-volume curve
is based on flow and volume measured at the mouth, which does not
account for thoracic gas compression. Second, exercise is associated
with significant bronchodilation, which serves to increase the maximal
expiratory flow-volume curve. Expiratory flow limitation during exercise can be falsely detected or overestimated if gas compression and
bronchodilation are not taken into account. All maneuvers were
superimposed and aligned to maximal lung volume, whereby the
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Subjects. Twenty-one healthy subjects (11 males, 10 females)
volunteered to participate in this study. All subjects were current
competitive cyclists or triathletes who participated in regional, national, and international competitions with a range of racing accomplishments. Subjects were free of cardiopulmonary disease, were
nonsmoking, and possessed normal pulmonary function. Prior to the
study, all subjects provided written informed consent after all procedures and risks were fully explained. All procedures received institutional ethical approval and conformed to the Declaration of Helsinki.
Experimental protocol. Testing took place over three visits (range:
1 wk to 1 mo). Exercise training regimes were kept consistent
throughout testing, and subjects were instructed to refrain from
caffeine for 4 h and to avoid strenuous exercise 24 h prior to testing.
On the first visit, anthropometric and resting pulmonary function
measures were obtained prior to an incremental cycle test to exhaustion to determine maximal aerobic capacity (V̇O2max). Once sufficiently recovered from the incremental test, a familiarization 5-km
simulated time trial (TT) was performed. Based on previous work, the
familiarization TT also served to ensure subsequent testing would
elicit reproducible cycle exercise performances and that subjects were
accustomed to performing respiratory maneuvers during strenuous
exercise (48). A randomized single-blinded crossover design was used
for the two experimental TTs and testing occurred at similar times of
day. On the second and third visits, subjects were instrumented with
an esophageal balloon for the assessment of breathing mechanics. The
order of the 5-km TTs was randomized with subjects breathing either
humidified compressed room air or HeO2 (20.87–21.04% O2:balance
He). Ratings of sensory responses for breathlessness and leg discomfort were recorded during the incremental test and every kilometer
during the TTs using a 10-point category ratio scale (9).
Pulmonary function. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1.0), FEV1.0/FVC, and peak expiratory flow
were determined using a portable spirometer (Spirolab II, Medical
International Research, Vancouver, BC) according to recommended
guidelines (1) while breathing room air. Subjects were also familiarized with the graded FVC and inspiratory capacity maneuvers for
subsequent testing of breathing mechanics (18).
Incremental exercise test. All exercise was performed on a cycle
ergometer (VeloTron Pro, RacerMate, Seattle, WA). Following a
self-selected warm-up, the incremental exercise test started at 260 W
for males and 160 W for females, with the workload increasing
stepwise by 30 W every 3 min until pedaling cadence fell below 60
revolutions/min despite verbal encouragement.
Time trial exercise. Following a self-selected warm-up similar to
day 1, both TTs began at a still start with subjects in the same position.
The initial gearing combination chosen by each subject on day 2 was
used again at the start of day 3, but subjects were allowed to adjust the
gears throughout each TT. Upper body position was also standardized
such that subject’s hands were to remain on the brake-hoods at all
times during testing. The straight, flat 5-km TT course was created
•
Work of Breathing, Performance, and Sex Differences
Table 1. Resting pulmonary function and maximal exercise
values
FVC, liters
FVC, %predicted
FEV1.0, liters
FEV1.0, % predicted
FEV1.0,/FVC, %
PEF, l/s
PEF, %predicted
Male
Female
5.7 ⫾ 0.7 (4.5–6.6)
108 ⫾ 8 (96–118)
4.5 ⫾ 0.6 (3.6–5.6)
102 ⫾ 11 (82–118)
81 ⫾ 4 (76–85)
11.2 ⫾ 1.3 (9.8–13.0)
112 ⫾ 11 (99–130)
4.3 ⫾ 0.7 (3.0–5.5)*
111 ⫾ 11 (85–125)
3.5 ⫾ 0.6 (2.5–4.4)*
106 ⫾ 9 (94–122)
82 ⫾ 4 (76–88)
7.5 ⫾ 1.1 (5.6–9.0)*
102 ⫾ 15 (78–123)
Values are means ⫾ SD (range). FVC, forced vital capacity; FEV1.0, forced
expired volume in 1 s; PEF, peak expiratory flow. *Significantly different
between males and females, P ⬍ 0.05.
257
Wilkie SS et al.
mance we utilized t-test procedures and the magnitude-based inferences approach and precision of estimation (90% confidence limits) to
detect small effects of practical importance for cyclists (24, 25). The
magnitude of the percent change in power was interpreted using 0.3%
(smallest effect) of the within-athlete indoor cycling variation of
power (coefficient of variation) (1.9% or 1.31 W) (39, 48) as a
threshold for small differences in the change in power between the
trials (25). Therefore the smallest worthwhile change in power is
0.57%, and the smallest worthwhile change in time is 0.21% (1.04 s)
for a coefficient of variation of 0.7% (39, 48). The practical interpretation of an effect is deemed “unclear” when the magnitude of change
is substantial and when the confidence interval (precision of estimation) could result in positive and negative outcomes. The level of
significance was set at P ⬍ 0.05 for all statistical comparisons. Values
are presented as means ⫾ SD unless otherwise noted.
RESULTS
Subject characteristics and incremental exercise. Descriptive characteristics and maximal exercise data are summarized
in Table 1. Normal pulmonary function was present in all
subjects relative to normative values (3). Subjects were of
comparable age (males: 31 ⫾ 5 yr; females: 26 ⫾ 5 yr), but
males were taller (180 ⫾ 7 vs. 168 ⫾ 7 cm) and heavier (74 ⫾
7 vs. 60 ⫾ 6 kg) (P ⬍ 0.05). Females possessed aerobic
capacities that were greater than males when expressed as
%predicted V̇O2max (29). However, both sexes had similar
competitive racing experience.
Effect of HeO2 on the cardiopulmonary response to exercise.
Across both TTs (room air and HeO2) males had a higher V̇O2,
V̇E, and tidal volume relative to females (P ⬍ 0.05) (Table 2).
The frequency and timing of breathing and heart rate were
unaffected by gas composition, and there were no sex differences (P ⬎ 0.05). The effect of HeO2 on V̇E was variable
between subjects and was nonsignificant (P ⬎ 0.05), although
there was a tendency for V̇E to increase (⫹3–10 l/min) in both
males and females. There was no effect of sex or inspirate on
Table 2. Maximal exercise values
V̇O2max,
ml·kg⫺1·min⫺1
V̇O2max, l/min
V̇O2max, %predicted
V̇CO2, l/min
RER
V̇E, l/min, STPD
fb, breaths/min
VT, liters, BTPS
Heart rate, beats/min
Heart rate,
%predicted
Peak power, W
Peak power, W/kg
Total time, s
Leg discomfort,
Borg units
Breathing
discomfort, Borg
units
Male
Female
60.8 ⫾ 3.8 (55.3–67.0)
4.5 ⫾ 0.40 (3.8–5.0)
134 ⫾ 11 (118–151)
4.9 ⫾ 0.40 (4.1–5.4)
1.11 ⫾ 0.03 (1.07–1.15)
140 ⫾ 12 (118–163)
58 ⫾ 14 (34–78)
2.88 ⫾ 0.50 (2.35–4.01)
193 ⫾ 16 (178–233)
55.8 ⫾ 3.2 (51.8–61.3)*
3.3 ⫾ 0.36 (2.9–3.9)*
163 ⫾ 12 (147–182)*
3.6 ⫾ 0.40 (3.1–4.2)*
1.08 ⫾ 0.04 (1.03–1.13)
101 ⫾ 14 (84–133)*
57 ⫾ 9 (46–72)
2.10 ⫾ 0.40 (1.44–2.75)*
185 ⫾ 12 (168–204)
102 ⫾ 8 (94–122)
361 ⫾ 24 (320–410)
4.9 ⫾ 0.4 (4.5–5.5)
725 ⫾ 142 (525–1013)
96 ⫾ 6 (83–105)
283 ⫾ 34 (250–340)*
4.8 ⫾ 0.4 (4.3–5.6)
836 ⫾ 224 (601–1217)
9.0 ⫾ 0.6 (8.0–10.0)
7.5 ⫾ 1.9 (5.0–10.0)
8.5 ⫾ 0.7 (7.0–9.0)
7.3 ⫾ 1.7 (5.0–9.0)
Values are means ⫾ SD (range). V̇O2max, maximal oxygen consumption;
V̇CO2, carbon dioxide production; RER, respiratory exchange ratio; V̇E, minute
ventilation; fb, frequency of breathing; VT, tidal volume. *Significantly different between males and females, P ⬍ 0.05.
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highest flows at a given volume represented the outer boundary of the
maximal expiratory flow-volume curve. The magnitude of flow limitation was calculated as the volume of tidal breath overlapping the
maximal expiratory flow-volume curve divided by the tidal volume.
End-expiratory reserve lung volume (ERV) was calculated by subtracting the resting inspiratory capacity from FVC with the assumption that total lung capacity remains constant throughout exercise (28).
End-inspiratory point (EIP), as an index of end-inspiratory reserve
lung volume, was calculated by adding ERV to tidal volume relative
to FVC. Inspiratory capacity maneuvers were considered acceptable
when peak inspiratory esophageal pressure matched those obtained at
rest. Operational lung volumes were expressed as %FVC as we have
previously described (20). Second, we determined ventilatory capacity (V̇ECAP) (12, 28) by using measured breathing parameters (duty
cycle, tidal volume, and operational lung volume) and assumed that
the subjects ventilated along their maximal expiratory flow-volume
curve allowing for the determination of minimal expiratory time and
subsequently maximal breathing frequency. Calculated V̇ECAP is the
product of maximal breathing frequency and tidal volume and reflects
the maximal expiratory flow an individual is theoretically capable of
attaining for their chosen breathing pattern. We then related the
measured V̇E during the TT to V̇ECAP (V̇E/V̇ECAP). A reduction in
V̇E/V̇ECAP during the HeO2 TT would reflect a reduced fractional usage
of the maximal ventilatory capacity and a reduction of mechanical
constraints. Last, the work of breathing was determined from transpulmonary pressure loops using Campbell diagrams where the muscular work was separated into resistive and elastic with the sum
reflecting the total mechanical work (19). When nitrogen is replaced
with He as a backing gas, airflow remains more laminar, thereby
allowing greater flows. As such, a reduction in mechanical constraints
when breathing HeO2 would be reflected in a lowering of the resistive
work of breathing. It is important to note that He has a higher viscosity
than air, which will increase flow resistance when flow is laminar (i.e.,
the small airways). Given that the small airways contribute minimally
to total resistance, any HeO2-induced increases in viscosity resistance
would be masked by the substantial reduction in the main sites of
resistance (i.e., the medium- and larger-sized airways) where airflow
is predominantly turbulent rather than laminar.
Statistical analysis. A sample size of 9 per group was determined
(G*Power; http://www.gpower.hhu.de) using ␣ ⫽ 0.05, a power of
80%, and an expected difference of 2% in time-to-completion of the
5-km time trials (room air vs. heliox). Our estimates of sample size are
primarily based on previously published cycle performance tests (48).
Descriptive characteristics, pulmonary function, and maximal exercise data between males and females were compared with unpaired
t-tests. All values were examined and met the assumption of being
normally distributed as assessed by a Shapiro-Wilk test. Repeatedmeasures ANOVA procedures (Statistica v6.1, StatSoft, Tulsa, OK)
were used to compare the effects of gas inspirate across the time trials.
In the case of a significant F-ratio, differences were further investigated with Tukey’s post hoc. To evaluate time trial exercise perfor-
•
258
Work of Breathing, Performance, and Sex Differences
•
Wilkie SS et al.
sensory responses (leg discomfort, dyspnea) during TT exercise (P ⬎ 0.05).
Effect of HeO2 on the mechanics of breathing. Inspiring
HeO2 significantly increased resting peak expiratory flow and
maximal expiratory flow at 50% of vital capacity for both
males and females (Table 3) but did not change FVC. Averaged over the duration of the time trials, peak expiratory flow
was higher when breathing HeO2 compared with room air in
males (room air 6.65 ⫾ 0.90 vs. HeO2 8.42 ⫾ 1.01 l/s, P ⬍
0.001) and females (room air 4.78 ⫾ 0.73, HeO2 5.52 ⫾ 0.82
l/s, P ⬍ 0.05) and the increase in peak expiratory flow during
Table 3. Change in resting expiratory flow when inspiring
HeO2 compared with room air breathing
⌬
⌬
⌬
⌬
PEF, l/s
PEF, %
FEF50% FVC, l/s
FEF50% FVC, %
Male
Female
4.04 ⫾ 1.21
35 ⫾ 11
2.46 ⫾ 1.13
38 ⫾ 16
2.07 ⫾ 0.68*
28 ⫾ 12
1.59 ⫾ 0.46*
33 ⫾ 10
Values are means ⫾ SD. ⌬ PEF, change in peak expiratory flow; ⌬ FEF50%
, change peak expiratory flow at 50% vital capacity measured in each
condition (room air, heliox). *Significantly different between males and
females, P ⬍ 0.05.
FVC
exercise was greater in males relative to females (P ⬍ 0.05).
Across all trials, ERV decreased relative to rest with the onset
of exercise and remained below resting values (P ⬍ 0.05).
Values for ERV at each kilometer are shown in Table 4 for
males and females and for both inspired gas conditions.
Breathing HeO2 resulted in lowering of ERV relative to room
air at end-exercise, and the changes were similar between men
and women. End-inspiratory lung volume was unaffected by
HeO2. The development of flow limitation was variable between subjects during TT exercise. During room air breathing,
5 males and 7 females became flow limited at some point
during the 5-km time trial, and the same subjects became flow
limited during HeO2 breathing. Three of the other male subjects and two female subjects demonstrated “impending” flow
limitation where their tidal flow-volume loop approached the
maximal flow-volume curve and developed its characteristic
shape but did not fully intersect. Of those that developed flow
limitation, the magnitude was similar between sexes during
room air breathing and HeO2 breathing. On average, the
magnitude of flow limitation was unaffected by inspiring HeO2
because flow-limited subjects increased their tidal flow-volume
loops thereby taking advantage of the heliox-induced increase
in the maximal expiratory flow-volume loop. This phenome-
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Fig. 1. Flow-volume and pressure-volume
loops during time trial exercise in representative male subject. A and B: tidal loops
obtained at rest and at 1, 3, and 5 km positioned within the maximal expiratory flow
volume curve (MEFV) breathing room air
(A) or HeO2 (B). Note that with each successive kilometer, end-expiratory lung volume increased towards resting values. C and
D: pressure-volume loops obtained at rest
and at 1, 3, and 5 km while breathing room
air (C) or HeO2 (D). Note the reduction in
size of the transpulmonary loop when
breathing HeO2 (i.e., a reduced work of
breathing) despite a larger flow-volume
loop.
Work of Breathing, Performance, and Sex Differences
•
259
Wilkie SS et al.
Table 4. Metabolic and respiratory responses during 5-km time trials
1 km
2 km
3 km
4 km
5 km
46.7 ⫾ 3.1
47.3 ⫾ 6.2
51.9 ⫾ 6.1
50.6 ⫾ 4.8
54.6 ⫾ 6.0
53.0 ⫾ 4.9
56.2 ⫾ 6.1
55.3 ⫾ 4.4
57.2 ⫾ 6.4
56.0 ⫾ 4.4
44.9 ⫾ 3.3
42.9 ⫾ 3.3*
48.0 ⫾ 4.0
45.4 ⫾ 4.4*
49.7 ⫾ 5.1*
47.9 ⫾ 5.4*
50.3 ⫾ 5.7*
48.1 ⫾ 5.7*
51.3 ⫾ 5.8*
48.9 ⫾ 6.0*
165 ⫾ 12
164 ⫾ 12
171 ⫾ 11
174 ⫾ 10
175 ⫾ 8
178 ⫾ 8
179 ⫾ 6
182 ⫾ 7
184 ⫾ 6
187 ⫾ 5
163 ⫾ 11
164 ⫾ 8
168 ⫾ 12
170 ⫾ 9
172 ⫾ 10
173 ⫾ 9
175 ⫾ 10
175 ⫾ 8
181 ⫾ 9
181 ⫾ 10
83 ⫾ 18
85 ⫾ 16
113 ⫾ 19
116 ⫾ 19
121 ⫾ 18
122 ⫾ 17
126 ⫾ 15
131 ⫾ 13
134 ⫾ 12
141 ⫾ 12
65 ⫾ 10*
66 ⫾ 9*
83 ⫾ 14*
83 ⫾ 14*
87 ⫾ 15*
89 ⫾ 17*
90 ⫾ 16*
92 ⫾ 16*
94 ⫾ 17*
97 ⫾ 18*
37 ⫾ 10
41 ⫾ 11
44 ⫾ 11
49 ⫾ 12
47 ⫾ 12
53 ⫾ 13
50 ⫾ 12
57 ⫾ 13
55 ⫾ 12
67 ⫾ 13
39 ⫾ 8
47 ⫾ 14
48 ⫾ 13
54 ⫾ 13
51 ⫾ 12
58 ⫾ 12
52 ⫾ 9
63 ⫾ 15
54 ⫾ 10
67 ⫾ 17
2.7 ⫾ 0.5
2.7 ⫾ 0.5
3.1 ⫾ 0.6
3.1 ⫾ 0.5
3.1 ⫾ 0.6
3.1 ⫾ 0.5
3.1 ⫾ 0.6
3.0 ⫾ 0.5
3.0 ⫾ 0.7
3.0 ⫾ 0.6
2.0 ⫾ 0.4*
1.9 ⫾ 0.5*
2.3 ⫾ 0.5*
2.1 ⫾ 0.5*
2.2 ⫾ 0.6*
2.1 ⫾ 0.5*
2.2 ⫾ 0.6*
2.0 ⫾ 0.5*
2.2 ⫾ 0.5*
2.0 ⫾ 0.5*
37 ⫾ 35
27 ⫾ 11
35 ⫾ 8
30 ⫾ 7
33 ⫾ 13
30 ⫾ 8
39 ⫾ 8
33 ⫾ 9†
39 ⫾ 9
33 ⫾ 13†
35 ⫾ 6
34 ⫾ 8
33 ⫾ 12
35 ⫾ 10
32 ⫾ 14
35 ⫾ 7
37 ⫾ 8
35 ⫾ 6
39 ⫾ 9
35 ⫾ 6†
88 ⫾ 7
75 ⫾ 5
87 ⫾ 6
86 ⫾ 5
80 ⫾ 3
85 ⫾ 6
91 ⫾ 5
85 ⫾ 9
88 ⫾ 6
80 ⫾ 3
86 ⫾ 4
84 ⫾ 7
82 ⫾ 3
85 ⫾ 10
79 ⫾ 3
84 ⫾ 11
87 ⫾ 5
84 ⫾ 8
88 ⫾ 1
82 ⫾ 11
0⫾0
19 ⫾ 10
26 ⫾ 3
30 ⫾ 23
35 ⫾ 20
27 ⫾ 27
32 ⫾ 10
32 ⫾ 16
48 ⫾ 24
30 ⫾ 17
0⫾0
0⫾0
21 ⫾ 10
16 ⫾ 7
41 ⫾ 33
0⫾0
36 ⫾ 17
42 ⫾ 21
30 ⫾ 19
45 ⫾ 13
323 ⫾ 51
335 ⫾ 50
302 ⫾ 42
305 ⫾ 36
309 ⫾ 37
310 ⫾ 39
307 ⫾ 37
311 ⫾ 41
323 ⫾ 42
327 ⫾ 46
217 ⫾ 39*
221 ⫾ 32*
215 ⫾ 41*
223 ⫾ 42*
212 ⫾ 40*
223 ⫾ 41*
215 ⫾ 42*
218 ⫾ 38*
232 ⫾ 44*
235 ⫾ 41*
105 ⫾ 7
105 ⫾ 7
106 ⫾ 7
107 ⫾ 6
106 ⫾ 9
107 ⫾ 7
105 ⫾ 8
106 ⫾ 7
107 ⫾ 8
107 ⫾ 8
96 ⫾ 5
101 ⫾ 6
97 ⫾ 5
100 ⫾ 7
100 ⫾ 6
96 ⫾ 9
98 ⫾ 5
100 ⫾ 7
100 ⫾ 6
102 ⫾ 8
Values are means ⫾ SD. V̇O2, oxygen consumption; ERV, end-expiratory reserve lung volume; EIP, end-inspiratory point; %FVC, percent forced vital
capacity; M, male; F, female; HR, heart rate. *Significantly different between males and females, P ⬍ 0.05. †Significantly different between room air and HeO2,
P ⬍ 0.05.
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V̇O2, ml·kg⫺1·min⫺1
M
Room air
HeO2
F
Room air
HeO2
HR, beats/min
M
Room air
HeO2
F
Room air
HeO2
V̇E, l/min, STPD
M
Room air
HeO2
F
Room air
HeO2
fb, breaths/min
M
Room air
HeO2
F
Room air
HeO2
VT, liters, BTPS
M
Room air
HeO2
F
Room air
HeO2
ERV, % FVC
M
Room air
HeO2
F
Room air
HeO2
EIP, % FVC
M
Room air
HeO2
F
Room air
HeO2
%Flow limited
M (n ⫽ 5)
Room air
HeO2
F (n ⫽ 7)
Room air
HeO2
Power, W
M
Room air
HeO2
F
Room air
HeO2
Cadence, rpm
M
Room air
HeO2
F
Room air
HeO2
260
Work of Breathing, Performance, and Sex Differences
•
Wilkie SS et al.
non is displayed by a representative male (Fig. 1) and female
(Fig. 2) subject whose higher expiratory flow rates achieved
during the HeO2 TT were generated via lower transpulmonary
pressures compared with room air breathing.
Group averages for the ventilatory fractional usage (V̇E/
V̇ECAP) are shown in Fig. 3. The V̇E/V̇ECAP was decreased with
HeO2 in each woman without exception, and 9 of 11 men. The
reduction of V̇E/V̇ECAP was similar between males and females
(7–9%; P ⬎ 0.05), and values have been combined to show the
effect of gas inspirate. Table 5 shows the effect of breathing
HeO2 on the total and constituent components of the work of
breathing values averaged across the entire 5-km trials. HeO2
reduced the total work of breathing and the resistive components of breathing (P ⬍ 0.05), but there was no difference
between men and women (P ⬎ 0.05). Inspiratory and expiratory elastic work of breathing were increased in men but were
unchanged in women.
Time trial performance. Inspiring heliox was associated with
a statistically significant performance improvement of 0.7 ⫾
1.5% (3.2 s) for males and 1.5 ⫾ 1.9 % (8.1 s) for females;
however, there were no sex differences with respect to improvement in time trial performance. Figure 4 shows individual
time trial values during conditions of room air and HeO2.
Three subjects (2 men and 1 woman) were above the line of
identity; all others were below the line (indicating performance
improvement) or on the line (indicating no change in performance). Using the magnitude-based inferences approach (see
Statistical analyses), the chances the effect of inspiring HeO2
is beneficial, trivial, or harmful are 94.6%, 5.3%, and 0.1%
with regards to time trial performance, respectively. Inspiring
HeO2 was also associated with statistically significant improvements in power for males 1.61 ⫾ 0.81% (5.00 W) and
females 4.03 ⫾ 1.8 (7.90 W). There was no effect of order on
TT performance. The TT with the highest power output was
performed first for approximately half of the subjects; accordingly, test order did not appear to have an effect on performance. Both men and women equally improved their room air
time trial relative to the familiarization time trial suggesting
that the familiarization equally improved the ability to perform
time trial cycle exercise.
DISCUSSION
We tested the hypothesis that inspiring HeO2 would reduce
the work of breathing, attenuate expiratory flow limitation, and
improve exercise performance to a greater degree in endurance-trained females relative to males. The rationale for our
study was based on observations that 1) the conducting airways
are narrower in women even when matched for lung size, 2)
women have a higher propensity for flow limitation than men,
and 3) women have a higher total and resistive mechanical
work of breathing. The primary finding of this study is that
when mechanical ventilatory constraints are minimized, males
and females improve time trial exercise performance to a
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Fig. 2. Flow-volume and pressure-volume loops during time trial exercise in representative female subject. A and B: tidal loops obtained at rest and at 1, 3,
and 5 km positioned within the maximal expiratory
flow volume curve (MEFV) breathing room air (A)
or HeO2 (B). Note that with each successive kilometer, end-expiratory lung volume increased towards resting values. C and D: pressure-volume
loops obtained at rest and at 1, 3, and 5 km while
breathing room air (C) or HeO2 (D). Note the reduction in size of the transpulmonary loop when breathing HeO2 (i.e., a reduced work of breathing) despite
a larger flow-volume loop. See Fig. 1 for description
of individual lines.
Work of Breathing, Performance, and Sex Differences
Wilkie SS et al.
261
We also used the magnitude-based inferences approach to
show that the performance effect of HeO2 is meaningful. No
differences in performance between males and females were
observed. It should be emphasized that the reduction in the
work of breathing with HeO2 (see Table 5) was less than that
which can be achieved with a proportional assist ventilator
(22). The time trial improvements we observed were statistically significant and important from a performance standpoint
but were nonetheless relatively small. We attribute the moderate improvements to the fact that the muscles of respiration
were unloaded to a lesser degree in our study relative to
ventilator studies (22).
The statistically significant improvements in performance
we observed were modest but the gains can be considered
relevant and important to competitive cyclists (24, 25). The
improvements we observed are consistent with another study
that used 5-km time trials to evaluate exercise performance (2).
What is the mechanism by which exercise performance improved with HeO2 breathing? Our study was not designed to
specifically address this question but it merits brief consideration. The respiratory muscles are known to influence exercise
performance via the triggering of a respiratory muscle
metaboreflex (11). The substantial mechanical and metabolic
demands placed on the respiratory muscles during high-intensity exercise lead to fatigue of the diaphragm and expiratory
muscles. The fatiguing contractions and high metabolic work
of the respiratory muscles lead to a sympathetically mediated
decrease in limb blood flow and O2 transport to locomotor
muscles and is associated with significant fatigue of the quadriceps muscle and decrements in exercise performance (9). The
effects of high respiratory muscle work described above occur
only during heavy exercise such as the protocol we employed
rather during than submaximal exercise.
Finally, the HeO2-related improvement we observed could
also be attributed to the increases in maximal expiratory flow
rather than decreases in airway resistance and the mechanical
work of breathing. The physics underlying the phenomenon of
expiratory flow limitation are complex and have been described in detail elsewhere (41). Briefly, one explanation relates to the contraction of expiratory muscles and the increasingly positive pleural pressure, which results in dynamic airway compression (35). An alternate explanation relates to the
Bernoulli effect whereby increases in airflow velocity cause
reductions in lateral airway pressure, which in turn narrows the
airway lumen. Breathing a less dense gas increases expiratory
flow, in part, because Bernoulli pressure is proportional to gas
density (36). In our study we observed increases in resting and
exercise peak expiratory flows, which may explain the beneficial effects of HeO2. On the other hand, we observed an
inconsistent effect of HeO2 on V̇E (⫹3–10 l/min; P ⬎ 0.05)
and the change in performance was not associated with the
change in V̇E.
Study limitations. We observed a significant improvement in
time trial performance and a reduction in mechanical constraints with HeO2. However, our approach permitted subjects
to adjust their pacing (i.e., power output, cadence) during the
time trials, which was likely influenced, in part, by perception
of effort. As such the fact that expiratory flow limitation along
with other respiratory parameters was variable may reflect the
subjects’ ability to adjust power. Our study was designed to
alleviate mechanical constraints and ascertain the effects on the
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similar degree. Our results suggest that the extent of sex-based
differences in airway anatomy, work of breathing, and expiratory flow limitation are not great enough to differentially affect
whole body exercise performance.
Mechanics of breathing and sensory responses. In our study
we were primarily concerned with innate sex-based differences
in airway anatomy and function with respect to the properties
that govern airflow under conditions of strenuous whole body
dynamic exercise. As such, we replaced nitrogen with helium
as the backing gas whereby airflow remains more laminar and
permits greater flows. Using our approach we successfully
reduced the work of breathing and V̇E/V̇ECAP with the effects of
HeO2 being similar between men and women. When both men
and women are provided additional “room” to increase expiratory flow offered by HeO2, they do so equally although we
observed considerable between-subject variation.
Any intervention that reduces central ventilatory drive, improves ventilatory mechanics, or improves respiratory muscle
function has the potential to reduce exertional dyspnea (37).
We found that the perceptual ratings of breathing were unaffected by gas inspirate and were not different between males
and females. There are inconsistent reports on the effects of
HeO2 on dyspnea (5, 6, 33), which may reflect between-study
differences in exercise intensity as well as the aerobic fitness of
the subjects. That we observed an absence of effect also speaks
to the complexities of the interactions between sensory responses and the cardiopulmonary demands of exercise. It may
be that the substantive feed-forward (i.e., so-called “central
command”) and numerous feedback mechanisms (i.e., muscle
reflexes: chemical, mechanical, thermoregulatory) necessary to
perform strenuous exercise are dominant and mask any
changes to the mechanics of breathing. Based on the recent
findings of Schaeffer et al. (43), who found significant sex
differences in the intensity and unpleasantness of exertional
dyspnea in healthy young males and females, we predicted that
HeO2 would have reduced the awareness of breathing to a
greater degree in females. We attribute a lack of difference in
sensory responses to the fact that HeO2 changed the mechanics
of breathing similarly between the sexes.
Time trial performance. To assess the effects of HeO2 on
exercise performance we used time trial tests rather than a
constant-load test. We selected a short-duration, high-intensity
test of exercise performance because it has been shown that
reducing respiratory muscle work by 60% with a proportional
assist ventilator is associated with a 14% increase in time to
exhaustion when trained cyclists exercise at near-maximal
intensities (90 –95% V̇O2max) (22). High-intensity exercise is
required because there is no effect of reducing respiratory
muscle work when subjects perform constant-load exercise at
lower levels of intensity (75% V̇O2max) (15, 30). Furthermore,
performance tests which require self-selection of pace (i.e.,
constant-distance test), such as the test used in the present
study, are known to have a low source of random error and are
appropriate for determining small changes in competitive performance (40). We included a familiarization performance trial
and randomized the order of gas inspirate in order to reduce
variation and improve our ability to detect systematic HeO2induced changes in performance. We found that exercise performance was significantly improved in highly trained males
and females when breathing HeO2 relative to room air breathing in the form of reductions in time and increases in power.
•
262
Work of Breathing, Performance, and Sex Differences
integrative response that governs exercise performance. To
determine the mechanisms for the observed improvements in
performance, future studies will need to incorporate limb blood
flow and arterial oxygenation measures into the experimental
design. We did not catheterize our subjects for the direct
assessment of leg blood flow but many of the predisposing
factors for fatigue of the respiratory muscles and ensuing
metaboreflex were present in our study, including flow limitation, a high work of breathing, and metabolic acidosis. While
we favor the metaboreflex explanation for our findings, future
invasive studies with experimental manipulation of the work of
breathing are required to confirm our hypothesis.
Wilkie SS et al.
Fig. 4. Individual and group mean time trial (TT) performance times relative
to the line of identity. Triangles are means ⫾ SE. HeO2, helium oxygen; RA,
room air; TT, time trial.
The specific heat capacity of helium is higher than that of
nitrogen. As such, respiratory heat loss could have been higher
during the heliox trials and this could have contributed to the
observed exercise performance effect. We have no measure of
body temperature or heat storage and are unable calculate the
potential effect of differences in temperature on exercise performance. However, in our study we delivered inspired gas via
a humidified system, which decreases the evaporative component of respiratory heat loss in both conditions. This would
have minimized the potential effect of a helium-associated
difference in heat loss. The absolute differences in temperature
were likely to have been relatively small between conditions
but we recognize this as a limitation to the interpretation of the
performance changes we observed.
Perspectives. Our findings suggest that mechanical ventilatory constraints negatively impact exercise performance
Table 5. Work of breathing (WOB) during 5-km time trials
Total WOB, J/min
M
Room air
HeO2
F
Room air
HeO2
Resistive WOB, J/min
M
Room air
HeO2
F
Room air
HeO2
Elastic WOB, J/min
M
Room air
HeO2
F
Room air
HeO2
1 km
2 km
3 km
4 km
5 km
248 ⫾ 105
230 ⫾ 110
329 ⫾ 118
308 ⫾ 123
396 ⫾ 156
315 ⫾ 103*
425 ⫾ 107
375 ⫾ 105*
457 ⫾ 109
407 ⫾ 110*
170 ⫾ 38
154 ⫾ 52
256 ⫾ 86
226 ⫾ 99
282 ⫾ 95
232 ⫾ 106*
291 ⫾ 100
244 ⫾ 113*
338 ⫾ 86
272 ⫾ 104*
131 ⫾ 61
93 ⫾ 68
195 ⫾ 93
135 ⫾ 76*
245 ⫾ 120
148 ⫾ 66*
246 ⫾ 117
180 ⫾ 75*
273 ⫾ 67
207 ⫾ 71*
90 ⫾ 28
68 ⫾ 27
139 ⫾ 62
108 ⫾ 55*
171 ⫾ 73
112 ⫾ 54*
179 ⫾ 74
123 ⫾ 68*
206 ⫾ 69
139 ⫾ 62*
117 ⫾ 49
137 ⫾ 57
134 ⫾ 51
173 ⫾ 69
151 ⫾ 45
176 ⫾ 52
180 ⫾ 58
195 ⫾ 85
184 ⫾ 65
200 ⫾ 77
80 ⫾ 21
86 ⫾ 27
117 ⫾ 41
118 ⫾ 48
111 ⫾ 34
120 ⫾ 56
112 ⫾ 36
121 ⫾ 52
133 ⫾ 38
131 ⫾ 51
Values are means ⫾ SD. *Significantly different between room air and HeO2, P ⬍ 0.05.
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Fig. 3. Change in minute ventilation/ventilatory capacity (V̇E/V̇ECAP) when
breathing HeO2 relative to room air. Shown are mean values for the inspired
gas conditions with male and female values combined. No statistical differences were detected between males and females (P ⬎ 0.05). Inspiring HeO2
reduced V̇E/V̇ECAP at each kilometer (*P ⬍ 0.05) indicating a reduced fractional
usage of the maximal ventilatory capacity and a minimization of mechanical
constraints.
•
Work of Breathing, Performance, and Sex Differences
GRANTS
The Natural Sciences and Engineering Research Council (NSERC) of
Canada supported this study. S. S. Wilkie and P. B. Dominelli were supported
by NSERC postgraduate scholarships.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: S.S.W., P.B.D., B.C.S., M.S.K., and A.W.S. conception and design of research; S.S.W. and P.B.D. performed experiments;
S.S.W., P.B.D., B.C.S., M.S.K., and A.W.S. analyzed data; S.S.W., P.B.D.,
B.C.S., M.S.K., and A.W.S. interpreted results of experiments; S.S.W., P.B.D.,
and A.W.S. prepared figures; S.S.W., P.B.D., B.C.S., M.S.K., and A.W.S.
drafted manuscript; S.S.W., P.B.D., B.C.S., M.S.K., and A.W.S. edited and
revised manuscript; S.S.W., P.B.D., B.C.S., M.S.K., and A.W.S. approved
final version of manuscript.
REFERENCES
1. American Thoracic Society. Standardization of Spirometry, 1994 Update
American Thoracic Society. Am J Respir Crit Care Med 152: 1107–1136,
1995.
2. Amann M, Hopkins WG, Marcora SM. Similar sensitivity of time to
exhaustion and time-trial time to changes in endurance. Med Sci Sports
Exerc 40: 574 –578, 2008.
3. ATS. ATS/ERS Statement on respiratory muscle testing. Am J Respir Crit
Care Med 166: 518 –624, 2002.
4. Babb TG. Breathing He-O2 increases ventilation but does not decrease the
work of breathing during exercise. Am J Respir Crit Care Med 163:
1128 –1134, 2001.
5. Babb TG. Ventilation and respiratory mechanics during exercise in
younger subjects breathing CO2 or HeO2. Respir Physiol 109: 15–28,
1997.
6. Babb TG. Ventilatory response to exercise in subjects breathing CO2 or
HeO2. J Appl Physiol 82: 746 –754, 1997.
7. Babcock MA, Pegelow DF, Harms CA, Dempsey JA. Effects of respiratory muscle unloading on exercise-induced diaphragm fatigue. J Appl
Physiol 93: 201–206, 2002.
8. Baydur A, Behrakis PK, Zin WA, Jaeger M, Milic-Emili J. A simple
method for assessing the validity of the esophageal balloon technique. Am
Rev Respir Dis 126: 788 –791, 1982.
9. Borg GAV. Psychophysical bases of perceived exertion. Med Sci Sports
Exerc 14: 377–381, 1982.
Wilkie SS et al.
263
10. Brice AG, Welch HG. Metabolic and cardiorespiratory responses to
He-O2 breathing during exercise. J Appl Physiol 54: 387–392, 1983.
11. Dempsey JA, Romer L, Rodman J, Miller J, Smith C. Consequences of
exercise-induced respiratory muscle work. Respir Physiol Neurobiol 151:
242–250, 2006.
12. Dominelli PB, Foster GE, Dominelli GS, Henderson WR, Koehle MS,
McKenzie DC, Sheel AW. Exercise-induced arterial hypoxaemia and the
mechanics of breathing in healthy young women. J Physiol 591: 3017–
3034, 2013.
13. Dominelli PB, Guenette JA, Wilkie SS, Foster GE, Sheel AW. Determinants of expiratory flow limitation in healthy women during exercise.
Med Sci Sports Exerc 43: 1666 –1674, 2011.
14. Eves ND, Petersen SR, Haykowsky MJ, Wong EY, Jones RL. Heliumhyperoxia, exercise, and respiratory mechanics in chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 174: 763–771, 2006.
15. Gallagher CG, Younes M. Effect of pressure assist on ventilation and
respiratory mechanics in heavy exercise. J Appl Physiol 66: 1824 –1837,
1989.
16. Grimby G, Saltin B, Wilhelmsen L. Pulmonary flow-volume and pressure-volume relationship during submaximal and maximal exercise in
young well-trained men. Bull Physiopathologie Respir 7: 157–172, 1971.
17. Grimby G, Goldman M, Mead J. Respiratory muscle action inferred
from rib cage and abdominal V-P partitioning. J Appl Physiol 41: 739 –
751, 1976.
18. Guenette JA, Dominelli PB, Reeve SS, Durkin CM, Eves ND, Sheel
AW. Effect of thoracic gas compression and bronchodilation on the
assessment of expiratory flow limitation during exercise in healthy humans. Respir Physiol Neurobiol 170: 279 –286, 2010.
19. Guenette JA, Querido JS, Eves ND, Chua R, Sheel AW. Sex differences in the resistive and elastic work of breathing during exercise in
endurance-trained athletes. Am J Physiol Regul Integr Comp Physiol 297:
R166 –R175, 2009.
20. Guenette JA, Witt JD, McKenzie DC, Road JD, Sheel AW. Respiratory
mechanics during exercise in endurance-trained men and women. J
Physiol 581: 1309 –1322, 2007.
21. Harms CA, Babcock MA, McClaran SR, Pegelow DF, Nickele GA,
Nelson WB, Dempsey JA. Respiratory muscle work compromises leg
blood flow during maximal exercise. J Appl Physiol 82: 1573–1583, 1997.
22. Harms CA, Wetter TJ, St Croix CM, Pegelow DF, Dempsey JA.
Effects of respiratory muscle work on exercise performance. J Appl
Physiol 89: 131–138, 2000.
23. Henke KG, Sharratt M, Pegelow D, Dempsey JA. Regulation of
end-expiratory lung volume during exercise. J Appl Physiol 64: 135–146,
1988.
24. Hopkins WG. A spreadsheet for deriving a confidence interval, mechanistic inference and clinical inference from a P value. Sportscience 11:
16 –20, 2007.
25. Hopkins WG, Batterham AM, Marshall SW, Hanin JH. Progressive
statistics. Sportscience 13: 55–70, 2009.
26. Hyatt R. Pressure-flow-volume interrelationships in man. Am Rev Respir
Dis 80: 138 –140, 1959.
27. Johnson BD, Saupe KW, Dempsey JA. Mechanical constraints on
exercise hyperpnea in endurance athletes. J Appl Physiol 73: 874 –886,
1992.
28. Johnson BD, Weisman IM, Zeballos RJ, Beck KC. Emerging concepts
in the evaluation of ventilatory limitation during exercise: the exercise
tidal flow-volume loop. Chest 116: 488 –503, 1999.
29. Jones NL, Makrides L, Hitchcock C, Chypchar T, McCartney N.
Normal standards for an incremental progressive cycle ergometer test. Am
Rev Respir Dis 131: 700 –708, 1985.
30. Krishnan B, Zintel T, McParland C, Gallagher CG. Lack of importance of respiratory muscle load in ventilatory regulation during heavy
exercise in humans. J Physiol 490: 537–550, 1996.
31. Martin TR, Castile RG, Fredberg JJ, Wohl ME, Mead J. Airway size
is related to sex but not lung size in normal adults. J Appl Physiol 63:
2042–2047, 1987.
32. McClaran SR, Harms CA, Pegelow DF, Dempsey JA. Smaller lungs in
women affect exercise hyperpnea. J Appl Physiol 84: 1872–1881, 1998.
33. McClaran SR, Wetter TJ, Pegelow DF, Dempsey JA. Role of expiratory flow limitation in determining lung volumes and ventilation during
exercise. J Appl Physiol 86: 1357–1366, 1999.
34. Mead J. Dysanapsis in normal lungs assessed by the relationship between
maximal flow, static recoil, and vital capacity. Am Rev Respir Dis 121:
339 –342, 1980.
J Appl Physiol • doi:10.1152/japplphysiol.00400.2014 • www.jappl.org
Downloaded from http://jap.physiology.org/ by 10.220.33.5 on June 16, 2017
equally in endurance-trained males and females. Healthy females exhibit greater mechanical constraints during exercise
than males (13, 20, 32), owing to their smaller lungs and
airways (34, 45). Specifically, our recent work (12) and that of
McClaran et al. (32) show that females develop significant
expiratory flow limitation which can constrain the ventilatory
response during high-intensity exercise. The higher overall
work of breathing in females during dynamic exercise is
associated with a substantially greater resistive work during
inspiration and expiration (19). In the present study we reasoned that reducing mechanical ventilatory constraints would
result in greater exercise performance gains in females. We
observed a similar improvement between males and females.
This can be attributed to at least two possibilities. First, there
is no male-female difference. The sex differences in airway
anatomy, high work of breathing, and expiratory flow limitation are of insufficient magnitude to negatively impact exercise
performance. Second, the reductions in ventilatory constraints
offered by HeO2 were modest relative to that offered by a
proportional assist ventilator. It may be that in order to determine if sex differences exist with respect to respiratory system
influences on exercise performance, a greater degree of unloading is required.
•
264
Work of Breathing, Performance, and Sex Differences
44.
45.
46.
47.
48.
49.
50.
Wilkie SS et al.
tional dyspnea: role of neural respiratory motor drive. Exp Physiol 99:
427–441, 2014.
Sheel AW, Derchak PA, Morgan BJ, Pegelow DF, Jacques AJ, Dempsey
JA. Fatiguing inspiratory muscle work causes reflex reduction in resting
leg blood flow in humans. J Physiol 537: 277–289, 2001.
Sheel AW, Guenette JA, Yuan R, Holy L, Mayo JR, McWilliams AM,
Lam S, Coxson HO. Evidence for dysanapsis using computed tomographic imaging of the airways in older ex-smokers. J Appl Physiol 107:
1622–1628, 2009.
Sheel AW, Romer LM. Ventilation and respiratory mechanics. Compr
Physiol 2: 1093–1142, 2012.
Spitler DL, Horvath SM, Kobayashi K, Wagner JA. Work performance
breathing normoxic nitrogen or helium gas mixtures. Eur J Appl Physiol
43: 157–166, 1980.
Sporer BC, McKenzie DC. Reproducibility of a laboratory based 20-km
time trial evaluation in competitive cyclists using the Velotron Pro
ergometer. Int J Sports Med 28: 940 –944, 2007.
Wanke T, Formanek D, Schenz G, Popp W, Gatol H, Zwick H.
Mechanical load on the ventilatory muscles during an incremental cycle
ergometer test. Eur Respir J 4: 385–392, 1991.
Wilson GD, Welch HG. Effects of varying concentrations of N2/O2 and
He/O2 on exercise tolerance in man. Med Sci Sports Exerc 12: 380 –384,
1980.
J Appl Physiol • doi:10.1152/japplphysiol.00400.2014 • www.jappl.org
Downloaded from http://jap.physiology.org/ by 10.220.33.5 on June 16, 2017
35. Mead J, Turner JM, Macklem PT, Little JB. Significance of the
relationship between lung recoil and maximum expiratory flow. J Appl
Physiol 22: 95–108, 1967.
36. Mink S, Ziesmann M, Wood LD. Mechanisms of increased maximum
expiratory flow during HeO2 breathing in dogs. J Appl Physiol 47:
490 –502, 1979.
37. O’Donnell DE, Ora J, Webb KA, Laveneziana P, Jensen D. Mechanisms of activity-related dyspnea in pulmonary diseases. Respir Physiol
Neurobiol 167: 116 –132, 2009.
38. Otis AB, Fenn WO, Rahn H. Mechanics of breathing in man. J Appl
Physiol 2: 592–607, 1950.
39. Palmer GS, Dennis SC, Noakes TD, Hawley JA. Assessment of the
reproducibility of performance testing on an air-braked cycle ergometer.
Int J Sports Med 17: 293–298, 1996.
40. Paton CD, Hopkins WG. Tests of cycling performance. Sports Med
489 –496, 2001.
41. Pedersen OF, Butler JP. Expiratory flow limitation. Compr Physiol 1:
1861–1882, 2011.
42. Romer LM, Lovering AT, Haverkamp HC, Pegelow DF, Dempsey JA.
Effect of inspiratory muscle work on peripheral fatigue of locomotor
muscles in healthy humans. J Physiol 571: 425–439, 2006.
43. Schaeffer MR, Mendonca CT, Levangie MC, Andersen RE, Taivassalo T, Jensen D. Physiological mechanisms of sex differences in exer-
•