Role of expiratory flow limitation in determining
lung volumes and ventilation during exercise
STEVEN R. MCCLARAN, THOMAS J. WETTER,
DAVID F. PEGELOW, AND JEROME A. DEMPSEY
John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine,
University of Wisconsin-Madison, Madison, Wisconsin 53706
McClaran, Steven R., Thomas J. Wetter, David F.
Pegelow, and Jerome A. Dempsey. Role of expiratory flow
limitation in determining lung volumes and ventilation dur-
ing exercise. J. Appl. Physiol. 86(4): 1357–1366, 1999.—We
determined the role of expiratory flow limitation (EFL) on the
ventilatory response to heavy exercise in six trained male
cyclists [maximal O2 uptake ⫽ 65 ⫾ 8 (range 55–74)
ml · kg⫺1 · min⫺1] with normal lung function. Each subject
completed four progressive cycle ergometer tests to exhaus-
tion in random order: two trials while breathing N2O2 (26%
O2-balance N2 ), one with and one without added dead space,
and two trials while breathing HeO2 (26% O2-balance He),
one with and one without added dead space. EFL was defined
by the proximity of the tidal to the maximal flow-volume loop.
With N2O2 during heavy and maximal exercise, 1) EFL was
present in all six subjects during heavy [19 ⫾ 2% of tidal
volume (VT ) intersected the maximal flow-volume loop] and
maximal exercise (43 ⫾ 8% of VT ), 2) the slopes of the
ventilation (⌬V̇E ) and peak esophageal pressure responses to
added dead space (e.g., ⌬V̇E/⌬PETCO2, where PETCO2 is end-
tidal PCO2) were reduced relative to submaximal exercise, 3)
end-expiratory lung volume (EELV) increased and end-
inspiratory lung volume reached a plateau at 88–91% of total
lung capacity, and 4) VT reached a plateau and then fell as
work rate increased. With HeO2 (compared with N2O2 ) breath-
ing during heavy and maximal exercise, 1) HeO2 increased
maximal flow rates (from 20 to 38%) throughout the range of
vital capacity, which reduced EFL in all subjects during tidal
breathing, 2) the gains of the ventilatory and inspiratory
esophageal pressure responses to added dead space increased
over those during room air breathing and were similar at all
exercise intensities, 3) EELV was lower and end-inspiratory
lung volume remained near 90% of total lung capacity, and 4)
VT was increased relative to room air breathing. We conclude
that EFL or even impending EFL during heavy and maximal
exercise and with added dead space in fit subjects causes
EELV to increase, reduces the VT, and constrains the increase
in respiratory motor output and ventilation.
dead space; helium-oxygen; feedback inhibition; respiratory
muscle loading/unloading
THE HYPERVENTILATORY response to high-intensity exer-
cise has been attributed to one or more neurohumoral
stimuli (4, 6, 16). There is also some indirect evidence
that these ventilatory responses may be influenced by
the mechanical constraints presented by the airways
and/or inspiratory muscles, at least in many highly fit
subjects capable of achieving higher than normal maxi-
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http://www.jap.org 8750-7587/99 $5.00 Copyright r 1999 the American Physiological Society
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mal metabolic rates and minute ventilations (V̇E ) (17,
28). Significant amounts of expiratory flow limitation
during moderate through maximal exercise have been
observed in highly fit healthy subjects, including young
and elderly adult men and women (13, 17, 28, 32). Tidal
volume (VT ) has also been shown to reach a plateau and
to fall as work intensity and ventilation increase during
heavy exercise (6, 8). Furthermore, ventilatory re-
sponses to added inspired CO2 or hypoxia are reduced
in slope during heavy exercise compared with light- to
moderate-intensity exercise (4, 17). These reductions in
the ventilatory response to superimposed chemical
stimuli occurred during very high work rates, where
the expiratory portion of the tidal flow-volume loop
intersected the maximal flow-volume envelope, the
end-expiratory lung volume (EELV) was increasing,
and pressure generated by the inspiratory muscles
often exceeded 80% of the maximal dynamic capacity of
the inspiratory muscles for pressure generation (17).
We asked whether the expiratory flow limitation
incurred at high levels of V̇E may have been responsible
for the reduced ventilatory response to chemical stimuli.
We studied highly trained subjects who experienced
significant expiratory flow limitation during heavy
exercise and used dead space breathing as a means of
increasing the chemoreceptor drive to breathe (29, 36).
We also used a low-density HeO2 inspirate to reduce
airway flow resistance to increase the maximal avail-
able flow-volume envelope and thereby eliminate expi-
ratory flow limitation during tidal breathing. This
approach allowed us to determine whether expiratory
flow limitation and its associated effects on EELV and
end-inspiratory lung volume (EILV) were responsible
for any observed changes in the ventilation and breath-
ing pattern in response to increasing exercise intensity
and superimposed chemical stimuli.
METHODS
Six competitive male cyclists [maximal O2 uptake (V̇O2max) ⫽
65 ⫾ 8 ml · kg⫺1 · min⫺1] were recruited to participate in the
study. Pulmonary function tests of all subjects were within
the normal predicted range (Table 1), and no subject had any
history of cardiovascular or lung disease. All procedures were
approved by the Human Subjects Committee Institutional
Board of the University of Wisconsin-Madison, and informed
consent was obtained. The physical characteristics of the
subjects (means ⫾ SD) were as follows: age ⫽ 34 ⫾ 16 yr,
height ⫽ 1.73 ⫾ 0.10 m, weight ⫽ 74.5 ⫾ 3.9 kg.
Resting pulmonary function tests. Vital capacity (VC),
inspiratory capacity (IC), and forced expiratory volume in 1 s
were determined using a water-sealed spirometer (model
13.5L, Warren E. Collins, Braintree, MA). Resting thoracic
1357
1358 CONSTRAINT OF EXERCISE HYPERPNEA
Table 1. Resting lung volumes and flow rates
Measured % Predicted
Lung volumes, liters
TLC 6.74 ⫾ 0.44 105 ⫾ 12
VC 5.20 ⫾ 0.59 108 ⫾ 18
RV 1.55 ⫾ 0.39 99 ⫾ 19
FRC 3.06 ⫾ 0.36 100 ⫾ 18
Flow rates
FEV1 , liters 4.28 ⫾ 0.66 108 ⫾ 18
FEV1 /FVC, % 84.1 ⫾ 6.4 97 ⫾ 20
Peak flow, l/s 9.80 ⫾ 0.96 97 ⫾ 22
MEF50 , l/s 6.17 ⫾ 0.59 110 ⫾ 25
Values are means ⫾ SD; n ⫽ 6. TLC, total lung capacity; VC, vital
capacity; RV, residual volume; FRC, functional residual capacity;
FEV1 , forced expiratory volume in 1 s; FVC, forced vital capacity;
peak flow, maximal expiratory flow; MEF50 , maximal expiratory flow
after exhalation of 50% of VC. Predicted values are based on age and
height (1).
gas volume for the determination of functional residual
capacity (FRC) was determined using Boyle’s law in a Collins
body plethysmograph (20). Total lung capacity (TLC) was
calculated as the sum of the FRC measurement from the body
box and the IC from spirometry. Residual volume was deter-
mined using an inert gas with a 10-s breath-hold dilution
test (5).
Flow, volume, pressure, and gas measurements. All mea-
surements have been described previously (27). Inspired and
expired flow rates were measured separately by dual pneumo-
tachographs (model 3800, Hans Rudolph). Volumes were
determined by computer integration of the flow signals.
Volume calibration was performed for each inspiratory gas
with various steady-state flows and verified by brief collec-
tions in a calibrated Tissot instrument.
Esophageal pressure (Pes) was measured with a 10-cm
latex balloon positioned in the lower one-third of the esopha-
gus. Mouth pressure and Pes were connected to a Validyne
transducer (model MP45-871, ⫾300 cmH2O). Pressure and
flow signals were determined to be in phase up to 12 Hz.
Inspired and expired gases were sampled at the mouth and in
a mixing chamber via an O2 analyzer (model S-3A, Applied
Electrochemistry) and a CO2 analyzer (model LB-2, Beck-
man). All signals were sent through an analog-to-digital
board (Techmar Labmaster PGH, Scientific Solutions, Solon,
OH) and sampled on a computer (PC Tailor 486 Dx2/50) at
75 Hz.
Protocol. Each subject completed an initial progressive
incremental exercise test on an electromagnetically braked
cycle ergometer (Elma). After a warm-up period (2–4 min),
the first workload was set at 150–250 W (⬃40–50% of V̇O2 max)
with an increase of 50 W every 2.5 min until exhaustion. After
a 20-min rest, the subjects repeated their highest workload
for as long as possible to ensure a plateau in O2 uptake. With
use of the criteria initially suggested by Taylor et al. (37), all
six subjects were observed to reach a plateau in V̇O2 max
(⬍150-ml increase in O2 ) during the last two workloads. After
the initial test, four progressive exercise tests were conducted
on separate days, with a minimum of 48 h between tests.
Each progressive test utilized the last six workloads of the
initial test. The following test conditions were applied in
random order: 1) N2O2 (26% O2-balance N2 ) with no added
dead space, 2) N2O2 with 1 liter of dead space, 3) HeO2 (26%
O2-balance He) with no added dead space, and 4) HeO2 with 1
liter of dead space. We used 26% O2 in the inspirate for all
conditions to prevent hypoxemia during rebreathing of added
dead space. As measured by ear oximeter (model 47201A,
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Hewlett-Packard), the range in Hb saturation was 96.7 ⫾ 0.3
to 98.2 ⫾ 0.4% during all four trials.
Added dead space and apparatus resistance. During the
added dead space trials, subjects breathed through a piece of
tubing placed between the mouthpiece and the Hans Rudolph
valve. Measured by water displacement, the total dead space
of the added section of tubing was 870 ml and the valve dead
space was 115 ml.
The HeO2 and N2O2 mixtures were warmed and humidi-
fied. Mesh screens were added to the inspiratory and expira-
tory tubing during the HeO2 trial to attain external appara-
tus resistance identical to that during the N2O2 trial.
Apparatus resistance was 0.80, 0.99, and 1.49 cmH2O · l⫺1 · s
during the N2O2 trials and 0.90, 1.00, and 1.50 cmH2O · l⫺1 · s
with HeO2 at flow rates of 3.1, 5.8, and 8.5 l/s, respectively.
Thus, with the added external resistances, the He effect was
limited only to reducing the subject’s internal airway resis-
tance. A piece of tubing identical in length and resistance was
added to the inspiratory and expiratory lines during the trials
in which no dead space was added to maintain comparable
circuit resistance relative to the trials in which dead space
was added.
Determination of expiratory flow limitation. Each subject
performed a minimum of three to five voluntary maximal
flow-volume loop (MFVL) maneuvers during the N2O2 and
HeO2 trials before and immediately after exercise, with the
largest loop accepted. A maximal IC measurement was ob-
tained during the last 20 s of each 2.5-min workload. Accept-
able IC trials during exercise required that peak inspiratory
Pes match that obtained at rest. A mean of 10–20 tidal
breaths taken at the end of each workload were averaged
(using a computer averaging program) to provide a represen-
tative tidal flow-volume and pressure-volume loop for that
workload. The EELV was determined by subtracting the
maximal IC for each workload from the TLC as measured at
rest (20). EILV was calculated as the sum of EELV and VT.
Flow limitation for each workload was computed as the
percentage of the expiratory tidal flow-volume loop for each
workload that intersected the expiratory boundary of the
maximal flow-volume loop. We used the peak Pes obtained
during the maximal IC maneuver to estimate the capacity of
the inspiratory muscles to generate pressure (Pcap,i ) for each
workload.
Prediction equations. We selected prediction equations for
resting lung function from cross-sectional studies that re-
flected the background of our subject population, namely,
those that included subjects who were of the same age, did not
smoke, were Caucasian, and resided primarily in the United
States (1).
Statistical analysis. All comparisons between group mean
values and response slopes were evaluated using a Friedman
repeated-measures ANOVA on ranks. Student-Newman-
Keuls post hoc test was used to determine where differences
occurred. Significance for all tests was set at P ⱕ 0.05.
RESULTS
Resting pulmonary function tests. The group mean
values of the resting lung volumes and maximal flow
rates are shown in Table 1. All values for lung volumes
and flow rates were not different (P ⬎ 0.05) from
predicted values for age- and height-matched men.
Ventilatory response to exercise and added dead space.
Figure 1 shows the ventilatory response to progressive
exercise. With N2O2 breathing, there was a linear
increase in V̇E with increasing work rate during sub-
maximal exercise and hyperventilation during heavy
 CONSTRAINT OF EXERCISE HYPERPNEA 1359

Breathing pattern and lung volume response to exer-

cise and added dead space. The breathing pattern
during progressive exercise is shown in Fig. 2 and the
lung volumes in Fig. 3. During N2O2 breathing without
and with added dead space, there was a progressive
parallel increase in breathing frequency and VT during
submaximal exercise (Fig. 2). During heavy exercise,
VT reached a peak and then fell at maximal exercise
during N2O2 breathing (Fig. 2B), with breathing fre-
quency accounting for all the increases in V̇E. EELV
was reduced at the onset of exercise, was maintained at
these reduced levels during moderate-intensity sub-
maximal exercise, and then rose during heavy and
maximal exercise to approximate resting FRC (Fig. 3A).
EILV showed a progressive increase during submaxi-
mal exercise, eventually reaching a plateau at 89–
91% of TLC during heavy and maximal exercise
(Fig. 3B).
Adding dead space increased VT at all exercise inten-
sities, accounting for most of the ventilatory response
(Fig. 2B). Breathing frequency also increased with
added dead space during mild and moderate exercise
but then was unchanged or decreased slightly at heavy
Fig. 1. Relationship between minute ventilation (V̇E ) and end-tidal
PCO2 (PETCO2) during 6 incremental exercise workloads [52, 65, 74, 88,
95, and 100% of maximal O2 consumption (V̇O2 max), n ⫽ 6] when
subjects were breathing N2O2 (26% O2-balance N2 ) with no added
dead space (ds), N2O2 with 1 liter of dead space, HeO2 (26%
O2-balance He) with no added dead space, and HeO2 with 1 liter of
dead space. Solid lines, ventilatory response to added dead space
during N2O2 breathing; dashed lines, ventilatory response to added
dead space during HeO2 breathing. * Significantly different ventila-
tory response slope to added dead space from all 4 submaximal
workloads with N2O2 and all 6 workloads with HeO2 (see Table 2),
P ⱕ 0.05. ⫹ Significantly higher than N2O2 breathing at same
workload, P ⱕ 0.05.

and maximal exercise. Table 2 shows the response

slopes of V̇E and the nadir of inspiratory pressure to
added dead space all expressed per Torr change in
end-tidal PCO2 (PETCO2). The slope of the ventilatory
response to added dead space (⌬V̇E/⌬PETCO2) was sim-
ilar during the first four workloads of N2O2 but was sig-
nificantly reduced during heavy and maximal exercise
(Table 2, Fig. 1).

Table 2. Slope of ventilatory and Pes

responses to added dead space
⌬V̇E/⌬PETCO2 , ⌬Pes/⌬PETCO2 ,
l/Torr cmH2O/Torr

%V̇O2max N2O2 HeO2 N2O2 HeO2

52 ⫾ 4 5.8 ⫾ 4.2 5.3 ⫾ 5.6 2.3 ⫾ 2.2 1.8 ⫾ 2.1

65 ⫾ 5 7.1 ⫾ 6.8 5.6 ⫾ 6.6 2.8 ⫾ 2.2 1.7 ⫾ 2.0
74 ⫾ 5 7.4 ⫾ 8.2 4.2 ⫾ 4.5 2.0 ⫾ 1.9 1.3 ⫾ 1.7
88 ⫾ 5 6.3 ⫾ 6.6 3.6 ⫾ 2.3 2.1 ⫾ 1.9 1.2 ⫾ 1.6
95 ⫾ 4 1.9 ⫾ 2.0* 2.4 ⫾ 1.2 0.6 ⫾ 1.6† 1.1 ⫾ 1.6 Fig. 2. Relationship between breathing frequency (A) and tidal
100 1.1 ⫾ 1.6* 3.1 ⫾ 1.8 0.1 ⫾ 1.2† 1.4 ⫾ 1.6 volume (VT, B) and V̇E during incremental exercise (n ⫽ 6) when
subjects were breathing N2O2 (26% O2-balance N2 ) with no added
Values are means ⫾ SD; n ⫽ 6. N2O2 , 26% O2-balance N2 ; HeO2 , dead space, N2O2 with 1 liter of dead space, HeO2 (26% O2-balance
26% O2-balance He; V̇E, minute ventilation; PETCO2 , end-tidal PCO2 ; He) with no added dead space, and HeO2 with 1 liter of dead space.
Pes, maximum inspiratory esophageal pressure. * Significantly differ- * Significantly different from N2O2 with no added dead space, P ⱕ
ent from other N2O2 and all HeO2 workloads, P ⱕ 0.05. † Significantly 0.05. ⫹ Significantly different from N2O2 with 1 liter of dead space,
different from other N2O2 and all HeO2 workloads, P ⱕ 0.05. P ⱕ 0.05.

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1360 CONSTRAINT OF EXERCISE HYPERPNEA

Fig. 3. Relationship between end-expiratory lung volume (EELV) as

percentage of total lung capacity (TLC, A) and end-inspiratory lung
volume (EILV) as percentage of TLC (B) to V̇E at rest (n) and during 6
incremental exercise workloads (52, 65, 74, 88, 95, and 100% of
V̇O2 max, n ⫽ 6) when subjects were breathing N2O2 (26% O2-balance
N2 ) with no added dead space, N2O2 with 1 liter of dead space, HeO2
(26% O2-balance He) with no added dead space, and HeO2 with 1 liter
of dead space. * Significantly different from all 4 submaximal work-
loads with N2O2 and no added dead space, P ⱕ 0.05. ⫹ Significantly
different from all 4 submaximal workloads with N2O2 and 1 liter of
dead space, P ⱕ 0.05.

and maximal work intensities, respectively, accounting

for the reduced ventilatory response to added dead
space. The EILV increased slightly with added dead
space at all work rates, accounting for most of the
increase in VT. Small reductions in EELV also occurred
with added dead space but only at light-intensity
exercise (Fig. 3).
Expiratory flow limitation during exercise. Ensemble-
averaged tidal flow-volume loops for rest and submaxi-
mal (74% of V̇O2 max), heavy (95% of V̇O2 max), and maxi-
mal exercise, along with the postexercise maximal
voluntary flow-volume loop during N2O2 breathing with
and without added dead space are shown in Fig. 4A.
Expiratory flow limitation was nonexistent in all sub-
jects without and with added dead space through the
first three workloads. Without added dead space, all six
subjects showed significant expiratory flow limitation
during heavy (19 ⫾ 2% of VT ) and maximal exercise
(43 ⫾ 8% of VT ), when V̇E exceeded 120 l/min. With the
increased ventilatory response to added dead space,
four subjects showed significant expiratory flow limita-
Fig. 4. Response to progressive exercise (n ⫽ 6). A: group mean tidal
flow-volume loops at rest and moderate (74% of V̇O2 max), near-
maximal (95% of V̇O2 max), and maximal exercise plotted relative to
group mean maximal voluntary flow-volume loop during N2O2 breath-
ing (26% O2-balance N2 ). Solid lines, N2O2 with no added dead space;
dashed lines, N2O2 with 1 liter of dead space. > and <, Flow rate
response to added dead space. B: group mean tidal pressure-volume
loops during moderate, near-maximal, and maximal exercise during
N2O2 breathing. Solid lines, N2O2 with no added dead space; dashed
lines, N2O2 with 1 liter of dead space. > and <, Pressure response to
added dead space.
tion during the fourth workload (12 ⫾ 4% of VT ) and all
six subjects showed significant expiratory flow limita-
tion during heavy (36 ⫾ 9% of VT ) and maximal
exercise (45 ⫾ 7% of VT ).

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 CONSTRAINT OF EXERCISE HYPERPNEA 1361

Ensemble-averaged tidal pressure-volume loops for

submaximal, heavy, and maximal exercise during N2O2
breathing with and without added dead space are
shown in Fig. 4B. As exercise intensity increased, there
was a progressive decrease in nadir tidal inspiratory
pressures and increase in peak tidal expiratory pres-
sures. There was a significant response of inspiratory
(nadir) and expiratory (peak) pressures to added dead
space (⌬Pes/⌬PETCO2) during submaximal exercise, and
these response slopes were reduced during heavy and
maximal exercise (Table 2, see Fig. 6).
Effect of the available maximal flow-volume envelope
on expiratory flow limitation during exercise. We used
HeO2 to increase the size of the MFVL and, in turn,
reduce the amount of expiratory flow limitation during
exercise. The averaged MFVL with the ensemble rest
and submaximal (74% of V̇O2 max), heavy (95% of V̇O2 max),
and maximal exercise loops placed within the MFVL for
the HeO2 trials are shown in Fig. 5A. HeO2 significantly
increased maximal volitional expiratory flow rates at
75, 50, and 25% of VC by 2.7, 2.7, and 0.9 l/s, respec-
tively, compared with N2O2. Throughout exercise, expi-
ratory flow limitation was nonexistent in all subjects
with no added dead space. With added dead space,
there was some measurable, but minimal, expiratory
flow limitation during HeO2 breathing in three subjects
(10 ⫾ 14% of VT ) only at maximal exercise. Thus HeO2
eliminated or significantly reduced expiratory flow
limitation during heavy and maximal exercise relative
to N2O2 (Fig. 4A).
Effect of reducing expiratory flow limitation via HeO2
on ventilation, breathing pattern, and lung volume
response to exercise and added dead space. The ventila-
tory response was unaltered with HeO2 relative to N2O2
breathing during the same submaximal exercise work-
loads up to 85% of V̇O2 max. At heavy workloads with
HeO2 breathing, further hyperventilation occurred (i.e.,
increased V̇E/CO2 output ratio and decreased PETCO2)
because of a higher VT and breathing frequency (Figs.
1 and 2). With HeO2 breathing, the ventilatory response
slope to added dead space (⌬V̇E/⌬PETCO2; Fig. 1, Ta-
ble 2) was unchanged and similar to that with N2O2
breathing over the first four workloads. At heavy and
maximal exercise intensities, the mean ventilatory
response to added dead space with HeO2 breathing was
reduced slightly but not significantly (P ⬎ 0.05) com-
pared with lower workloads and was greater than the
response slope during heavy and maximal exercise Fig. 5. Response to progressive exercise (n ⫽ 6). A: group mean tidal
with N2O2 breathing (Table 2, Fig. 1). The increased flow-volume loops at rest and moderate (74% of V̇O2 max), near-
⌬V̇E/⌬PETCO2 response with added dead space during maximal (95% of V̇O2 max), and maximal exercise plotted relative to
heavy and maximal exercise with HeO2 vs. N2O2 breath- group mean maximal voluntary flow-volume loop during HeO2 breath-
ing was entirely due to an increased gain in breathing ing (26% O2-balance He). Solid lines, HeO2 with no added dead space;
dashed lines, HeO2 with 1 liter of dead space. > and <, Flow rate
frequency (data not shown). response to added dead space. B: group mean tidal pressure-volume
With HeO2 breathing, VT rose linearly with increas- loops during moderate, near-maximal, and maximal exercise during
ing exercise intensity up to heavy exercise and then HeO2 breathing. Solid lines, HeO2 with no added dead space; dashed
reached a plateau but did not fall during heavy and lines, HeO2 with 1 liter of dead space. > and <, Pressure response to
added dead space.
maximal exercise as V̇E exceeded 130–140 l/min. These
higher VT values during HeO2 breathing (with no
added dead space and with added dead space) in heavy remained at ⬃90% of TLC and unchanged from that
and maximal exercise occurred because EELV re- during N2O2 breathing.
mained reduced and below FRC rather than increased Ensemble-averaged tidal pressure-volume loops for
(as occurred during N2O2 breathing), whereas EILV submaximal, heavy, and maximal exercise and the

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1362 CONSTRAINT OF EXERCISE HYPERPNEA

slope of the ⌬Pes/⌬PETCO2 during HeO2 with and with-

out added dead space are shown in Fig. 5B. With
increases in exercise intensity, added dead space caused
a substantial decrease in peak inspiratory pressures.
The slope of maximal inspiratory pressure to added
dead space (⌬Pes/⌬PETCO2) was not significantly differ-
ent during submaximal, heavy, and maximal exer-
cise with HeO2 (Table 2, Fig. 6). Thus, similar to the
gain of the ventilatory response with HeO2 breathing,
the slope of maximal inspiratory pressure to added
dead space remained unchanged with increasing exer-
cise intensity and during heavy and maximal exercise
was significantly higher than with heavy and maximal
exercise during N2O2 breathing (Table 2). Peak tidal
expiratory Pes increased proportionately with increas-
ing exercise intensity, although added dead space had
little effect on expiratory Pes during HeO2 breathing at
any workload (Fig. 5).
Ratings of dyspnea. During the N2O2 and HeO2
breathing with or without added dead space, dyspnea
ratings increased slightly and progressively over the
initial three workloads and then more steeply ap-
proached a maximal rating of 9–10 during heavy and
maximal exercise intensities (Fig. 7). Added dead space Fig. 7. Perception of dyspnea during increasing exercise with and
caused increased dyspnea ratings at most workloads without added dead space and during N2O2 (air) and HeO2 (Heliox)
coincident with an increasing PETCO2, V̇E, and expira- breathing.
tory flow limitation, and this occurred with N2O2 and
HeO2 breathing. Dyspnea ratings at a specific workload
and with or without added dead space were not signifi-
cantly influenced by HeO2 breathing, even though V̇E
was higher and flow limitation was reduced during the
HeO2 trials.
DISCUSSION

The purpose of this study was to determine whether

Fig. 6. Relationship between esophageal pressure (Pes) as percent-
age of capacity of inspiratory muscles to generate pressure (Pcap,i ) and
PETCO2 during 6 incremental exercise workloads (52, 65, 74, 88, 95,
and 100% of V̇O2 max, n ⫽ 6) when subjects were breathing N2O2
(26% O2-balance N2 ) with no added dead space, N2O2 with 1 liter of
dead space, HeO2 (26% O2-balance He) with no added dead space,
and HeO2 with 1 liter of dead space. Solid lines, Pes/Pcap,i response
to added dead space during N2O2 breathing. Dashed lines, Pes/Pcap,i
response to added dead space during HeO2 breathing. ⫹ Significantly
different from all 4 submaximal workloads with N2O2 and all 6
workloads with HeO2 (see Table 2), P ⱕ 0.05.
mechanical constraints affected the ventilatory re-
sponse and breathing pattern of heavy exercise. In the
presence of significant expiratory flow limitation dur-
ing heavy and maximal exercise, we observed an attenu-
ated ventilation and reduction in the nadir of inspira-
tory Pes in response to added dead space relative to
that obtained during submaximal exercise. With the
removal of expiratory flow limitation via HeO2 breath-
ing, the gain of the ventilatory response to added dead
space was maintained throughout all exercise intensi-
ties. Further comparisons of N2O2 to HeO2 trials re-
vealed that 1) when expiratory flow limitation was
reduced with HeO2 (heavy and maximal exercise), V̇E
was increased, but V̇E was not affected by HeO2 at
submaximal workloads where no expiratory flow limita-
tion was observed during the N2O2 trial; 2) HeO2
reduced expiratory flow limitation during heavy and
maximal exercise and reduced EELV with no effect on
EILV; thus the reduced EELV with HeO2 prevented the
fall in VT during heavy and maximal exercise; and 3)
HeO2 increased the gain of the reduction in peak
inspiratory Pes with added dead space during heavy
and maximal exercise. We believe that these correlative
findings, together with the observed effects of the HeO2
breathing, demonstrate that the occurrence of expira-
tory flow limitation, even when less than one-half of the

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 CONSTRAINT OF EXERCISE HYPERPNEA
VT is flow limited, is an important determinant of
EELV, VT, and respiratory motor output and ventila-
tion during heavy exercise.
Measurement of flow limitation. We used the proxim-
ity of the tidal breath to the maximal voluntary flow-
volume loop (obtained immediately after exercise) to
estimate the onset and degree of expiratory flow limita-
tion incurred during exercise. During voluntary forced
expiratory maneuvers, pleural pressures (Ppl) are suffi-
ciently high so as to compress intrathoracic gas, and
when flow rate and volume are measured at the airway
opening (as we did), this ‘‘external’’ measurement of
volume displacement will underestimate the true di-
mensions of the maximal expiratory flow-volume enve-
lope (15). Accordingly, we may have overestimated the
onset and/or magnitude of expiratory flow limitation
during exercise. On the other hand, previous studies
utilizing an independent measurement of the maximal
effective transpulmonary pressure (Pmax ) during expira-
tion showed close agreement during heavy and maxi-
mal exercise between the degree of expiratory flow
limitation as estimated from the tidal vs. maximal
flow-volume envelope with that determined from the
proximity of the tidal expiratory pressure to the Pmax (9,
17, 30). Furthermore, the expiratory Pes values we
observed during heavy and maximal exercise were in
excess of 20 cmH2O over a significant portion of expira-
tion, and these values were previously shown to approxi-
mate Pmax in normal subjects (19, 30). We believe, then,
that our measurements of the proximity of the tidal to
the maximal voluntary flow-volume envelope are rea-
sonably accurate estimates of significant expiratory
flow limitation, especially during heavy and maximal
exercise, where the tidal flow-volume envelope showed
time and volume courses similar to the voluntary
maximal flow-volume loop with which they were com-
pared (9, 17, 34).
Nonetheless, our estimates did not identify true flow
limitation in the classic sense, i.e., demonstrate a
further change in transpulmonary pressure with no
increase in expiratory flow rate (22). Indeed, as ex-
plained below (see Flow ‘‘limitation’’ and its compensa-
tory responses are on a continuum), during heavy
exercise there appeared to be many more instances
where maximal expiratory flow and pressure were
achieved over only a portion of the VT range at low lung
volumes. We believe that these instances of ‘‘impend-
ing’’ complete flow limitation have substantial signifi-
cance in the regulation of EELV and exercise hyper-
pnea.
Effects of expiratory flow limitation. Many studies
have utilized an added chemical stimulus to examine
the control of ventilation during exercise (4, 8, 17, 29,
33, 36). The significant ventilatory response we ob-
served to added dead space during moderate exercise
(Fig. 3) is consistent with previous studies that showed
a vigorous ventilatory response to added inspired CO2
(8) and an increased VT with added dead space (29, 33,
36) in normal subjects throughout exercise. However,
our observations of a significantly attenuated ventila-
tory response to added dead space during heavy exer-
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1363
cise (vs. moderate-intensity exercise) agree only with
those studies in which endurance-trained runners were
used as subjects (4, 17). Johnson and co-workers (17)
investigated the correspondence of significant expira-
tory flow limitation with the reduced ventilatory re-
sponse to added chemical stimuli. They showed some
increase in V̇E with added CO2 as long as there was
room under the MFVL for increases in flow rate but a
greatly attenuated or even no increase in V̇E in the
presence of significant expiratory flow limitation. Al-
though Clark and co-workers (4) did not measure
expiratory flow limitation, they found that the attenu-
ated ventilatory response to added inspired CO2 in
endurance-trained men only occurred at a high ventila-
tory demand (⬎120 l/min), where in our experience
some degree of expiratory flow limitation would likely
occur in most subjects. We also note that some highly
trained subjects have been reported to have exception-
ally large MFVL and, therefore, may not experience
expiratory flow limitation even at very high ventilatory
requirements (2).
As workload increased, we showed a progressive
parallel increase in breathing frequency and VT during
submaximal exercise followed at higher workloads by a
decreasing contribution of VT as breathing frequency
accounted for most of the increases in V̇E during heavy
exercise (Fig. 2). Notably, this decreasing relative con-
tribution of VT to increases in V̇E began at a workload
where no significant expiratory flow limitation was
evident, suggesting that flow limitation was not manda-
tory. However, despite the lack of expiratory flow
limitation when the decreasing contribution of VT
began, EILV had risen above 85% of TLC (Fig. 3B). It
would appear, therefore, that, to prevent lung volumes
from encroaching on the stiffer portion of the lung and
chest wall pressure-volume curves, increasing breath-
ing frequency may have been the best available option
for increasing V̇E. Furthermore, as our subjects pro-
gressed from heavy to maximal exercise, we observed a
substantial rise in EELV (Fig. 3A), presumably caused
by the onset of significant expiratory flow limitation.
With an EILV at 90% of TLC, we also showed that VT
actually decreased at maximal exercise relative to
heavy exercise (Fig. 4B). Again, this suggests a mechani-
cal constraint on VT, in that further increases in EILV
(⬎90% of TLC) do not appear to be an available option.
The effects of increasing flow limitation on ventilation,
breathing pattern, and lung volumes were also re-
flected in a reduced gain of the ventilatory response to
added dead space.
The use of HeO2 provided us with an important tool
to test experimentally the correlative evidence ob-
tained during exercise with air breathing and with
added dead space, as summarized above. We noted that
HeO2 breathing was without significant effect on the
ventilatory response to added dead space when expira-
tory flow limitation was not present. However, when
flow limitation was eliminated by breathing HeO2
during heavy and maximal exercise intensities, hyper-
ventilation ensued and the slopes of the ventilatory
response to added dead space increased and approxi-
1364 CONSTRAINT OF EXERCISE HYPERPNEA
mated the response gains observed during moderate
exercise. Increases in EELV and reductions in VT with
heavy-intensity exercise and with added dead space
were also prevented when expiratory flow limitation
was eliminated via HeO2.
We interpret these correlations between expiratory
flow limitation and reduced ventilatory response slopes,
along with the observed effects of HeO2 breathing, to
mean that when significant expiratory flow limitation
is incurred during heavy exercise, EELV will increase,
EILV will rise to within 10% of TLC, and increases in
VT and V̇E will be constrained. What began then as a
resistive load on expiration resulted in an increasing
elastic load on inspiration. Indeed, the combination of
increased EELV (which reduces the capacity for pres-
sure generation by the inspiratory muscles) and the
high volumes reached at EILV means that pressure
generation by the inspiratory muscles often reaches
80–90% of their dynamic capacity during maximal
exercise in highly trained individuals. These data
suggest then that the regulation of lung volume be-
comes a critical determinant of the breathing pattern
and the ventilatory response to heavy and maximal
exercise in the presence of expiratory flow limitation.
Although we commonly refer to the maximal VT
achieved in exercise as a fraction of VC for use as a
reference standard in comparing subjects (6, 8, 28), in
view of the importance of a changing EELV, it would be
more appropriate to use VT/IC as the regulated vari-
able.
Additional mechanical constraints on the ventilatory
response. We have attributed the constraint of the
ventilatory response during heavy exercise and to
increased dead space to expiratory flow limitation and
its sequelae of effects on hyperinflation and increased
elastic inspiratory loads (see above). However, there
are other potential mechanical constraints that occur
during heavy exercise that should be considered. First,
as VT and breathing frequency increase and expiratory
time shortens with increasing exercise intensity, expira-
tion becomes active and causes reductions in EELV
below resting FRC (6, 9, 13, 32). Accordingly, expiratory
muscle work increases substantially in heavy exercise,
and if fatigue in these expiratory muscles occurs, then
this could conceivably explain at least some of the
observed increase in EELV. Although this possibility
has not been tested directly, it seems unlikely, espe-
cially during very-short-term heavy exercise, inasmuch
as continued increases in gastric pressure have been
observed as EELV increases with increasing exercise
intensity (13, 35). Furthermore, the Pes achieved dur-
ing expiration in heavy exercise at the time EELV has
begun to increase are substantially below the peak
levels of expiratory pressure that can be voluntarily
achieved under these conditions (14, 24).
Second, given the very high inspiratory flow rates
and velocity of muscle shortening achieved in heavy
exercise (and with added dead space), a significant
flow-resistive load on the inspiratory muscles must
account for at least a portion of the mechanical con-
straint on the ventilatory responses. Two types of
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evidence speak against this mechanism being a major
contributor. First, unloading of inspiratory and expira-
tory muscle work (by as much as 50–60%) with use of a
proportional-assist ventilator has shown little system-
atic effect on the ventilatory response to heavy or
maximal exercise, even in highly trained subjects with
V̇E ⬎150 l/min (10, 25). We do need to add the impor-
tant caveat for these studies that a strong behavioral
response to positive-pressure mechanical ventilation
during exhaustive exercise may override any potential
reflex feedback effects emanating from respiratory
muscle unloading. Second, previous HeO2 breathing
studies were conducted at high work rates in highly
trained women (28). Although all these subjects pro-
duced comparably high levels of inspiratory flow rate
and V̇E during exercise, not all experienced significant
expiratory flow limitation. Among these women, the
HeO2 influence on preventing the increase in EELV and
enhancing VT and V̇E (as presently shown) occurred
only in those who experienced measurable expiratory
flow limitation during air breathing.
In summary, we believe that these reports, along
with present findings, present a strong argument in
favor of 1) a significant mechanical constraint to increas-
ing VT and V̇E during heavy exercise commensurate
with the onset of expiratory flow limitation and 2) the
postulate that expiratory flow limitation leading to
relative hyperinflation is the dominant mechanical
constraint to the VT and ventilatory response to heavy
exercise.
Flow ‘‘limitation’’ and its compensatory responses are
on a continuum. The increase in EELV and the con-
strained response of V̇E to added dead space began to
occur when there was still substantial room within the
maximal flow (and pressure)-volume envelope to in-
crease expiratory and inspiratory flow rate and pres-
sure. In fact, during submaximal heavy exercise inten-
sities when the EELV began to increase and the
ventilatory response to added dead space was signifi-
cantly reduced, ⬍40% of the VT intersected the maxi-
mal flow-volume envelope. Furthermore, Ppl observed
during tidal expiration approximated normal values for
maximal, effective pressure during a brief fraction of
expiration (17, 30). Also, on the inspiratory side, we
estimated that peak Ppl would be only 60–70% of Pcap,i
(Fig. 6). As exercise intensity was increased to maxi-
mum, further increases in V̇E caused more flow limita-
tion, increased EELV, pushed inspiratory pressure closer
to Pcap,i, and caused greater reduction in and, in some
cases, even flattened the slope of the V̇E and Pes
responses to added dead space. However, even under
these circumstances, 20–30% of the maximal flow-
volume envelope remained unused.
So, given that complete physical limitation of the
airways to increased flow rate or of the inspiratory and
expiratory muscles to increased force and pressure
development is clearly not required to cause constraint
of the ventilatory response during heavy exercise, we
propose that some type of reflex inhibition of respira-
tory motor output must occur in response to even
minimal expiratory flow limitation during exercise.
 CONSTRAINT OF EXERCISE HYPERPNEA
Perhaps this proposed feedback effect is first triggered
as the subject’s airways begin to narrow and ‘‘approach’’
flow limitation during expiration, which would reflex-
ively terminate expiratory effort and initiate inspira-
tion (3, 31). Then, as EELV rises, inspiratory motor
output could be inhibited via lung stretch at high EILV.
Limited evidence in lung transplant patients is consis-
tent with some role for vagal feedback in regulating
breathing pattern during heavy exercise in humans
(34). Other indirect evidence in support of a disfacilita-
tion or inhibition of respiratory motor output occurring
during heavy exercise includes 1) the observation that
tidal expiratory flow rates at the beginning of expira-
tion do not instantaneously reach the boundary of the
MFVL (19), 2) the substantial reduction in expiratory
pressures produced during tidal breathing in maximal
exercise compared with those produced by voluntary
efforts in the resting subject for an identical flow-
volume loop (14, 24), and 3) the finding that substantial
amounts of hypoxia or hypercapnia superimposed on
maximal exercise in fit subjects (17) (Fig. 1) caused no
further increases in VT or flow rate or expiratory and
inspiratory Pes, suggesting that inspiratory and expira-
tory motor output were unresponsive to potent chemo-
receptor stimulation under conditions of complete expi-
ratory flow limitation.
Finally, it is certainly conceivable that high levels of
several types of sensory input from chemoreceptors and
from lung and chest wall mechanoreceptors may give
rise to conscious perception of respiratory muscle force
development and/or relative hyperinflation, which
would also contribute importantly to modification of
respiratory motor output (20, 26). Although we ob-
served increased dyspneic sensations in response to
added dead space, these subjective ratings were not
further influenced by superimposed HeO2 breathing.
We cannot then correlate all observed changes in
breathing pattern, EELV, and/or V̇E in response to
alterations in flow limitation with changes in percep-
tion of breathing effort. However, given the wide vari-
ety of sensory inputs associated with exhaustive exer-
cise and added chemical stimuli, it is perhaps not
unexpected that subjects were unable to consciously
discriminate all superimposed reductions in flow limita-
tion.
Summary and relevance. The mechanical constraints
to flow and volume have a significant influence on the
ventilatory response, lung volumes, and breathing pat-
tern during heavy exercise in those endurance-trained
subjects who experience expiratory flow limitation. Two
types of findings support this conclusion: 1) the reduc-
tion in the ventilatory response and increase in EELV
with added dead space as tidal expiratory airflow
intersected the MFVL in heavy exercise and 2) the
prevention of these effects on EELV, VT, and V̇E when
HeO2 breathing was used to eliminate flow limitation.
These data point to significant feedback inhibition of
respiratory motor output during heavy exercise, which
becomes evident under conditions of significant but not
complete expiratory flow limitation. These mechanical
constraints on V̇E likely explain, in part, why many
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1365
highly trained subjects show relatively little hyperven-
tilation during heavy exercise (7, 11, 12, 17). The result
is that they fail to compensate for an excessively
widened alveolar-arterial PO2 difference; thus arterial
hypoxemia occurs and systemic O2 transport and V̇O2 max
are limited.
Address for reprint requests and other correspondence: J. A.
Dempsey, Dept. of Preventive Medicine, John Rankin Laboratory of
Pulmonary Medicine, 504 N. Walnut St., Madison, WI 53706-2368.
Received 21 July 1998; accepted in final form 9 December 1998.
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