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Pulmonary Medicine Abstract

Journal Menu Volume 2012 (2012), Article Full-Text PDF
ID 824091, 13 pages
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Assessing Exercise Limitation Using
Citations to this Journal Cardiopulmonary Exercise Testing
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Michael K. Stickland,1,2 Scott J. Butcher,3,4 Darcy D.
Contact Information Marciniuk,4 and Mohit Bhutani1
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Editorial Board 1Pulmonary Division, Department of Medicine, 8334B
· Aberhart Centre, University of Alberta, Edmonton, AB,
Editorial Workflow Canada T6G 2B7
· 2Centre for Lung Health, Covenant Health, Edmonton, AB,
Free eTOC Alerts Canada
· 3School of Physical Therapy, University of Saskatchewan,
Publication Ethics Saskatoon, SK, Canada
· 4Division of Respiratory, Critical Care and Sleep Medicine
Reviewers Acknowledgment and Airways Research Group, University of Saskatchewan,
· Saskatoon, SK, Canada
Submit a Manuscript
Received 29 June 2012; Accepted 26 September 2012
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Subscription Information Academic Editor: Denis O’Donnell
· Copyright © 2012 Michael K. Stickland et al. This is an
· Copyright © 2012 Michael K. Stickland et al. This is an
Table of Contents open access article distributed under the Creative
Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium,
Open Special Issues provided the original work is properly cited.
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Published Special Issues Abstract
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Special Issue Guidelines The cardiopulmonary exercise test (CPET) is an important
physiological investigation that can aid clinicians in their
evaluation of exercise intolerance and dyspnea. Maximal
oxygen consumption ( ) is the gold-standard measure
of aerobic fitness and is determined by the variables that
define oxygen delivery in the Fick equation ( = cardiac
output × arterial-venous O2 content difference). In healthy
subjects, of the variables involved in oxygen delivery, it is
the limitations of the cardiovascular system that are most
responsible for limiting exercise, as ventilation and gas
exchange are sufficient to maintain arterial O2 content up
to peak exercise. Patients with lung disease can develop a
pulmonary limitation to exercise which can contribute to
exercise intolerance and dyspnea. In these patients,
ventilation may be insufficient for metabolic demand, as
demonstrated by an inadequate breathing reserve,
expiratory flow limitation, dynamic hyperinflation, and/or
retention of arterial CO2. Lung disease patients can also
develop gas exchange impairments with exercise as
demonstrated by an increased alveolar-to-arterial O2
pressure difference. CPET testing data, when combined
with other clinical/investigation studies, can provide the
clinician with an objective method to evaluate
cardiopulmonary physiology and determination of exercise
intolerance.

1. Introduction
The cardiopulmonary exercise test (CPET) is an important
physiological investigation that can aid clinicians in their
diagnostic evaluation of exercise intolerance and dyspnea
[1, 2]. Although cardiac and pulmonary etiologies are the
most common causes for dyspnea and exercise intolerance
[3, 4], neurological, metabolic, hematologic, endocrine, and
psychiatric disorders can all contribute. The data gathered
from a CPET can provide valuable information to
differentiate between these causes [5], as progressive
incremental exercise testing provides the most
comprehensive and objective assessment of functional
impairment and yields information about the metabolic,

cardiovascular, and ventilatory responses to exercise. In

cardiovascular, and ventilatory responses to exercise. In
addition to assisting in the diagnosis of dyspnea and
exercise intolerance, CPETs can be used for a broad range
of other applications such as determining disease severity,
exercise prescription for rehabilitation, assessing the
effectiveness of pharmacological agents, or in the
assessment for lung transplant (see Table 1).

Table 1: Indications for

cardiopulmonary exercise testing.

Algorithms exist to help identify CPET patterns of known

clinical diagnosis [6], and typical clinical responses have
been detailed previously [1]. However, in order for
clinicians to interpret CPET results, a thorough
understanding of the cardiopulmonary responses to
exercise is needed. The purpose of this paper is to provide
the clinician with an overview of the physiological
responses to exercise as well as the processes used to
evaluate the mechanism(s) for exercise intolerance.

2. Cardiovascular Response to Exercise

Maximal oxygen consumption ( ) is a measure of the
capacity for aerobic, and exercise is determined by the
variables found in the Fick equation:

where is the cardiac output (the product of heart rate and

stroke volume) and and are the contents of
arterial and mixed venous blood, respectively. From this
equation, it is evident that the factors that influence
would include cardiac function, oxygen carrying capacity,
and the ability of the tissues to extract oxygen.
In healthy subjects, of the variables involved in oxygen
delivery, it is the limitations of the cardiovascular system
that are most responsible for limiting [7].
Ventilation and gas exchange are usually sufficient to
maintain arterial ( ), and therefore arterial
saturation ( ) and are also maintained up to
maximal workload [8]. Numerous studies have shown that
can be increased through exercise training [9, 10].
While peripheral adaptation occurs with training that will
increase peripheral O2 extraction [11], the primary
mechanism for training-induced improvements in is
mechanism for training-induced improvements in is
an increase in cardiac output secondary to an augmented
stroke volume response to exercise [12]. Indeed, many
studies have shown positive cardiac adaptation with
exercise training [13–17]. The increased stroke volume
response with exercise results in a reduced submaximal
heart rate with exercise training; however, peak heart rate is
generally unaffected by training [12]. Experimental studies
have demonstrated that improvements in O2 delivery will
positively affect . As an example, Stray-Gundersen et
al. showed that both peak cardiac output and could
be increased by 20% in untrained dogs by performing
pericardiectomy [18]. This effect is due to increased
ventricular filling and thus an increased cardiac output.
Conversely, a reduction in peak cardiac output will lead to a
lower . This is highlighted by studies in normal
humans showing beta blockade reduces by
decreasing both maximal heart rate and stroke volume [19].
These examples from experimental studies demonstrate the
close link between peak cardiac output and in health.

As increases with incremental exercise, the variables in

the Fick equation will eventually reach their upper limits,
and as a result, a plateau of the will occur. The plateau
in oxygen consumption despite an increase in workload is
defined as a person’s . However, many subjects,
particularly clinical patients, do not demonstrate this
plateau in [20], for a variety of reasons which may
include intolerable symptoms of breathing discomfort
(dyspnea), muscular fatigue, chest pain, and so forth, [20,
21]. If a plateau is not seen, then the highest achieved,
termed the , is used as an estimate of [20, 22].
These values represent the maximal oxygen consumption
and can be expressed in L/min or indexed by body weight
and expressed in mL/min/kg [20]. Of note, the best
adjustment for body size is not known and many
estimations exist [20]. Various reference equations have
been provided (see [1] for list) to evaluate , and
previous guidelines [1] define a of predicted
as low and abnormal (see later section on evaluating
for further discussion).

The limitation of the cardiovascular system is well accepted

as being the point where healthy subjects reach their
[23, 24]. Thus, if a subject reaches their maximum
predicted heart rate (HR) for age (i.e., peak HR > 85% of
predicted [1]), it would be reasonable to conclude based on
predicted [1]), it would be reasonable to conclude based on
the cardiac response that they have reached their .
However, this should not be used as a single determinant
of , as there is considerable between-subject
variability in maximal heart rate [25]. As well, clinical
conditions and medications, especially beta blocker use, can
affect the HR response to exercise [20–22]. Thus, in the
setting of a reduced , (i.e., <85% of predicted [1]),
reaching maximal HR suggests maximal subject effort and
that a cardiac limitation may exist; however, this must be
confirmed by examining additional variables (see later
section).
Oxygen pulse is the amount of oxygen consumed by the
tissue per heart beat (i.e., /heart rate) [26]. By
modifying the variables in the Fick equation, the O2 pulse
is calculated as follows:

With O2 pulse, the assumption is that the O2

difference widens in a predictable manner, and therefore
examination of the O2 pulse can provide information about
the stroke volume response to exercise [26]. In the setting
of a low , a reduced O2 pulse would indicate a low
stroke volume response to exercise. However, as O2 pulse is
calculated using HR, the value is subject to the same
assumptions regarding the HR response to exercise, and
therefore the considerable between-subject variability in
maximal heart rate [25] can translate to substantial
variability in O2 pulse response to exercise.
In summary, the is determined by the variables that
define oxygen delivery by the Fick equation. While
anything that alters components of the Fick equation can
alter , studies in health have demonstrated that it is
the cardiac output response and more specifically the stroke
volume response to exercise that limit , and thus in
the normal healthy subject, is limited by the
cardiovascular system.

3. Ventilatory Response to Exercise

As previously mentioned, increases during exercise as
governed, by the Fick equation. With increasing O2
consumption there is an increase in production (
). The relationship between PaCO2, , and alveolar
ventilation ( ) is governed by the alveolar ventilation
ventilation ( ) is governed by the alveolar ventilation
equation [27]:

PaCO2 is reported in mmHg (and assumed to be equal to

alveolar PCO2), while both and are reported in
L/min [28]. is always given at 0°C, 760 mmHg, dry
(STPD); and PaCO2 are reported under body
temperature, ambient pressure and saturated with water
vapor (BTPS) [28]. The is a conversion factor
], where = body temperature (273 is
0°C converted to °Kelvin). is used to adjust to body
temperature and pressure and is equal to 863 mmHg at sea
level and at normal body temperature of 37°C [27, 29]. As
highlighted in (4) in the following section, can be
derived from (minute ventilation) and (physiologic
dead space ventilation).
Assuming does not change with exercise, (3)
demonstrates that in order to maintain PaCO2 at normal
resting values, must increase with exercise because of
the increased CO2 production. Thus in health, the normal
response from rest to mild/moderate exercise is an increase
in ventilation that is commensurate with metabolic demand
(termed exercise hyperpnea), and therefore PaCO2 should
be unchanged from rest to mild/moderate exercise.
Practically, subjects often hyperventilate prior to exercise
(or at low levels of exercise in the laboratory), and therefore
it is common to see PaCO2 rise to a more normal value
with mild/moderate exercise. Once past ventilatory
threshold, increases disproportionally relative to
metabolic demand and PaCO2 drops below resting values
(i.e., hyperventilation). PaCO2 typically falls to 30–35
mmHg at peak exercise, and a peak PaCO2 of 35–38 mmHg
indicates a borderline effective alveolar hyperventilation,
while a PaCO2 in excess of 38 mmHg suggests the absence
of a compensatory hyperventilatory response [30]. Thus,
PaCO2 values obtained with incremental exercise allow for
the determination of the adequacy or appropriateness of
ventilation during exercise.
End-tidal CO2 (PETCO2) can be used to estimate PaCO2.
At rest PETCO2 is less than PaCO2 (and correspondingly
end-tidal O2, PETO2 more than alveolar PO2, PAO2) due
to dilution of gas from poorly perfused alveoli (i.e., dead
space). Using end-tidal values to predict alveolar pressures
has the potential of underestimating PaCO2; however, in
the healthy lung at rest, dead space is extremely low, and
the healthy lung at rest, dead space is extremely low, and
PETCO2 is a good approximation of PaCO2 [28]. With
exercise there is an increase in tidal volume ( ), and
mixed venous , such that the within-breath
fluctuations of alveolar gas composition are greater [31].
With the rapid increase in alveolar volume on inspiration
during exercise, end-inspiratory PCO2 is well below the
mean alveolar PCO2, whereas during expiration, alveolar
PCO2 increases toward mixed venous PCO2 more rapidly
than at rest as the increased CO2 production of exercise is
evolved into a lung volume becoming smaller as expiration
continues [32]. The latter factor results in PETCO2 being
higher than mean PaCO2 during exercise [33], and
therefore PETCO2 has the potential to overestimate PaCO2
at peak exercise. In patients with lung disease who generally
have a blunted tidal volume response to exercise, and a
relatively low peak metabolic rate, the within-breath
fluctuations of alveolar PCO2 are likely less than what
would be seen in health. Rather, a larger issue in lung
disease is the increased dead space ventilation and likely
underestimation of PaCO2 using PETCO2. Jones et al.
developed a prediction equation to calculate PaCO2 from
PETCO2 during exercise [PaCO2 = 5.5 + (0.90 × PETCO2)
− (0.0021 × tidal volume)] [32]; however, it is worth noting
that this equation was developed with subjects exercising
up to 50% . Further, it was suggested that the
equation should not be used in patients with abnormal
pulmonary function nor in children [32]. Thus, there are
limitations with using PETCO2 as a prediction of PaCO2
that need to be considered when interpreting CPET data.
Arterialized blood can also be used to predict PaCO2 with
reasonable accuracy [34, 35] but is practically more difficult
as compared to PETCO2.

4. Dead Space Ventilation

As shown in (4), total expired minute ventilation ( ),
measured at the mouth, consists of both alveolar ventilation
( ) and physiologic dead space ventilation ( ):

Alveolar ventilation is the amount of effective ventilation

that participates in gas exchange. Physiological dead space
is ventilation that does not participate in gas exchange and
consists of anatomical dead space such as the conducting
airways, as well as alveolar dead space which are unperfused
alveoli. Physiological dead space can be calculated as a
fraction of total ventilation using the Enghoff modification
[36] of the Bohr [37] dead space equation:
[36] of the Bohr [37] dead space equation:

where PECO2 represented the mean PCO2 in the expired

air. Examining this equation, dead space ventilation (i.e.,
ratio) would be zero if mean expired PCO2 was
equal to arterial PCO2. Conversely, significant dead space
results in expiration of gas that is more similar to inspired
PCO2 (i.e., sections of the lung that did not participate in
gas exchange and therefore have a ), which has
the effect of diluting the expired air and reducing PECO2
relative to PaCO2. Of note, many metabolic carts typically
calculate a dead space/tidal volume ratio ( / ratio, i.e.,
dead space per breath), using the same equation as listed in
(5). However, these calculations are often based on a PaCO2
that is predicted from PETCO2, and therefore significant
caution should be taken in interpreting values that
are not derived using direct PaCO2 measurement.

5. Breathing Pattern Response to Exercise

The precise matching of alveolar ventilation with metabolic
rate during exercise is achieved by increasing minute
ventilation. This increase is accomplished by increases in
both tidal volume and breathing frequency. The increased
tidal volume slightly increases airway dead space, due to
tethering effects of the lung parenchyma on airway lumen
size. However, the relative tidal volume increase exceeds
this effect, and the dead space to tidal volume ratio
decreases during exercise from resting values of ~0.35 to
~0.20, translating into more efficient ventilation [1].
During low-to-moderate intensity exercise, both tidal
volume and breathing frequency increase roughly in
proportion to exercise intensity, whereas at higher
intensities, tidal volume reaches a plateau and further
increases in ventilation are accomplished by increases in
breathing frequency alone [1].
Increases in breathing frequency are accomplished by
reducing both the inspiratory ( ) and expiratory times (
). However, the ratio of inspiratory time to total breath
cycle duration ( ), the duty cycle ( ), increases
only slightly during exercise (~0.40 at rest to ~0.50 during
high-intensity exercise) [38]. The increase in tidal volume is
achieved by reducing the end-expiratory lung volume
(EELV) below the functional residual capacity (achieved by
activating expiratory muscles) and increasing the end-

inspiratory lung volume (see later section on EELV

inspiratory lung volume (see later section on EELV
determination) [38]. At lower exercise intensities, increases
in ventilation are mostly achieved through tidal volume
changes, rather than just increasing breathing frequency,
which would increase dead space ventilation and
compromise effective alveolar ventilation. To minimize the
work of breathing during heavier exercise, tidal volume
increases only to ~70% of the vital capacity [39], as above
this lung volume, lung compliance decreases markedly and
the respiratory pressure production required for a given
change in volume is very large, leading to exaggerated
respiratory discomfort (i.e., dyspnea) [40].

6. Ventilatory Efficiency
Ventilatory efficiency is typically evaluated by the
responses to exercise, and as the term implies, it provides
information about the effectiveness of minute ventilation
for a given metabolic rate. Importantly, ventilatory
efficiency has been shown to be decreased in several clinical
conditions including chronic obstructive pulmonary
disease (COPD), pulmonary arterial hypertension (PAH)
[41, 42], and in heart failure [43]. In patients with PAH
[42] and chronic heart failure [43], the ratio is
predictive of mortality. Importantly, when is
elevated it is important to understand the underlying
physiological mechanism for the increased relative to
metabolic rate. As shown in (4), would be elevated
because of an increase in dead space and/or alveolar
ventilation. In pulmonary arterial hypertension, the
characteristic response is of pronounced hyperventilation at
rest and with incremental exercise likely because of
stimulation of receptors in the lung secondary to high
vascular pressures [44]. In this condition, the enhanced
response to exercise is secondary to greater as
demonstrated by a low PaCO2 (or PETCO2) throughout
exercise [41, 42]. Patients with chronic heart failure (CHF)
also show an exaggerated response to exercise
[43]; however, PaCO2 can appear normal in these patients
[45], indicating that the increased is secondary to
enhanced dead space ventilation.
Lung diseases associated with airflow limitation and/or a
loss of elastic recoil can lead to altered ventilation/perfusion
( ) matching in the lung [46]. As a result of the
reduction in matching, physiological dead space is
increased, and therefore and will be
increased with incremental exercise as compared to controls
[47]. In these patients is exaggerated while PaCO
[47]. In these patients is exaggerated while PaCO2
is normal or perhaps even elevated, indicating that the
increased for a given metabolic rate is secondary to
increased dead space. This reduction in ventilatory
efficiency can further compromise exercise tolerance and
potentiate dyspnea in patients with obstructive lung disease
as their ventilatory reserve is already reduced, and therefore
they have both an inability to increase because of
airflow limitation, plus a need to have a greater for a
given metabolic rate because of altered matching and
the associated increased dead space ventilation. These
examples highlight how the and PaCO2 responses
to exercise can be used to differentiate between pathologies
and mechanisms of dyspnea.

7. Ventilatory Reserve
Traditionally, ventilatory reserve has been evaluated by
examining how closely the peak minute ventilation on a
CPET ( ) approaches the greatest volume of gas that
can be breathed per minute by voluntary effort, termed the
maximal voluntary ventilation (MVV). Previous guidelines
state that breathing reserve [
] should be >15% at
peak exercise [1]. This method provides a general
approximation of ventilatory capacity, with little analysis
required. Ventilatory reserve depends on two main factors:
ventilatory demand and ventilatory capacity [46, 48].
Ventilatory demand is dependent on metabolic demand,
body weight, mode of testing, dead space ventilation as well
as neuroregulatory and behavioral factors [48]. Ventilatory
capacity is affected by mechanical factors such as airflow
limitation and operating lung volumes, ventilatory muscle
function, genetic endowment, aging, and disease [48].
Ventilatory capacity can also be affected by
bronchoconstriction or bronchodilation [48]. Thus, a
reduction in ventilatory reserve may be explained by
increased ventilatory demand (such as during heavy
exercise in an athlete or with inefficient ventilation) and/or
reduced ventilatory capacity (typically due to airflow
limitation).
Importantly, there are limitations to determining MVV
which can affect determination of ventilatory reserve, and
further, there are mechanical differences between voluntary
hyperventilation at rest and exercise-induced hyperpnea.
When performing an MVV at rest, subjects often
hyperinflate, which can increase work of breathing relative
to the same ventilation during exercise [46, 49–51]. In
addition, MVV is subject to patient effort, and with poor
to the same ventilation during exercise [46, 49–51]. In
addition, MVV is subject to patient effort, and with poor
effort the MVV can be low and the calculated ventilatory
reserve falsely reduced. Because of the difficulties in
measuring MVV, it is often predicted based on FEV1
(typically FEV1 multiplied by 35–40) [48, 52], and as with
any prediction equation, there is variance around the
accuracy of this prediction. Most importantly, using only
the breathing reserve does not provide any information
about the mechanism of ventilatory constraint (i.e., is there
evidence of expiratory flow limitation or hyperinflation?)
[46]. It is for these reasons that examining expiratory flow
limitation and operating lung volumes has evolved as the
preferred technique to examine a ventilatory limitation to
exercise.

8. Expiratory Flow Limitation

To evaluate the degree of ventilatory constraint during
exercise, the degree of expiratory flow limitation (EFL) can
be examined by plotting the exercise flow-volume loop
relative to the maximal flow [46]. This relationship can
provide information about the degree of expiratory flow
limitation, operating lung volumes, as well as breathing
strategies used with incremental exercise. The degree of EFL
during exercise has been previously expressed as a percent
of that meets or exceeds the expiratory boundary [48,
53, 54]. The presence of EFL promotes dynamic
hyperinflation and intrinsic positive end-expiratory
pressure with increased work of breathing, functional
impairment of inspiratory muscle strength, increased
sensations of dyspnea, and adverse effects on
hemodynamics [55, 56]. When the degree of expiratory
flow limitation becomes significant (>40–50% ), EELV
typically increases [48, 53, 57, 58].
Many of the modern metabolic carts allow for evaluation of
EFL by plotting exercise tidal breathing within a maximal
flow-volume loop. However, there is no clear consensus
regarding the quantification of EFL. Johnson et al. [48]
suggested an evaluation criteria regarding EFL and
inspiratory capacity (IC); however, this had not been
widely adopted clinically. Instead, most typically categorize
EFL as an “all or none” criteria. Importantly, it is not
unusual for a normal young (<35 yrs) subject of average
fitness and no lung disease to have EFL of <25% of at
peak exercise [48, 49, 59, 60]. Thus, the clinical significance
of some EFL occurring at or close to peak exercise is
unclear.

By definition, EFL requires the demonstration of an

By definition, EFL requires the demonstration of an
increase in transpulmonary pressure with no increase in
expiratory flow [56]. As well reviewed recently by Calverley
and Koulouris [56], the comparison of tidal breathing
relative to the maximal flow volume loop has its limitations
including (1) thoracic gas compression artifact; to reduce
these errors volume should be measured using a body
plethysmograph instead of the typical Pneumotach. (2)
Incorrect alignment of the tidal breathing curve within the
maximal flow-volume loop. (3) The previous volume and
time history of a spontaneous tidal breath is different than
the flow-volume curve derived from the maximum forced
vital capacity; there is not a single maximum flow volume
curve, but rather a family of curves which are dependent on
the time course of the preceding forced vital capacity [56,
61–63]. (4) Mechanics and time-constant inequalities are
different in tidal versus maximal flow-volume curves. (5)
Exercise may cause bronchodilation/bronchoconstriction.
(6) The technique requires good patient cooperation/effort.
Guenette et al. [64] recently demonstrated that failure to
account for gas compression and exercise-induced
bronchodilation results in a significant overestimation of
EFL. As a result of these limitations, the use of plotting tidal
breathing relative to the maximal flow-volume loop to
detect/quantify EFL has been questioned [56], although
many of these potential limitations can be avoided or
minimized with the use of standardized techniques.
As an alternative, the negative expiratory pressure method
has been advocated for the detection of EFL. As the name
implies, with this technique a small negative pressure (i.e.,
suction of −3 to −5 cm H2O) is given during expiration
[56]. This method is based on the principle that in the
absence of EFL, an increase in the pressure gradient
between the alveoli and the mouth would increase flow,
whereas with EFL increasing the pressure gradient would
not increase flow [56]. This technique has been used during
exercise to demonstrate EFL in lung disease [65–67];
however, it does not allow for quantification of severity of
EFL and has not been adopted during widespread clinical
practice.

9. Inspiratory Capacity
With EFL, expiratory flow rates are independent of
expiratory muscle effort and are determined by the static
lung recoil pressure and the resistance of the airways
upstream from the flow-limited segment [60, 68, 69]. In
flow-limited patients, the mechanical time constant for lung
emptying is increased in many alveolar units, but the
emptying is increased in many alveolar units, but the
expiratory time available is often insufficient to allow EELV
to return to its original values, resulting in gas
accumulation and retention (i.e., air trapping) [60]. As
demonstrated by (3), the increased CO2 production with
exercise necessitates an increase in by increasing and
breathing frequency to maintain PaCO2. However, the
increased tidal volume in combination with diminished
expiratory time due to increased breathing frequency can
cause dynamic hyperinflation in patients with EFL [60].
Thus, the main consequence of expiratory flow limitation
during exercise is the development of dynamic
hyperinflation (DH) [47, 60].
As reviewed recently by O’Donnell and Lavenziana [60],
DH during exercise has several important consequences
including (1) a sudden increase in elastic and threshold
loads on the inspiratory muscles, leading to increased work
and O2 cost of breathing. (2) Functional inspiratory muscle
weakness by shortening the diaphragm muscle length. (3)
Reducing the ability of to expand appropriately with
exercise, leading to a mechanical limitation of ventilation.
(4) Hypoventilation and hypoxemia in more severe patients
[70]. (5) Impairment in cardiac function. In COPD
patients, was strongly related to peak tidal volume (
), which in turn was strongly related to IC at peak
exercise ( ) [71]. These results indicate that DH
blunts the tidal volume expansion with incremental
exercise, which contributes to exercise intolerance/reduced
. Consistent with the consequences of IC listed, the
IC during exercise and the rate of change in IC with
exercise (i.e., dynamic hyperinflation) are strong
determinants of exertional dyspnea and exercise intolerance
[71–73].
Dynamic hyperinflation in early exercise may be a
compensatory mechanism to increase with limited (or
minimal) respiratory discomfort [74]; however, with
increasing exercise a threshold is reached (around an
inspiratory reserve volume of 0.5 L, or within 10% of total
lung capacity), where plateaus [60, 74]. At this point the
breathing occurs at the least compliant portion of the
respiratory system’s pressure-volume curve; the diaphragm
muscle fibers are maximally shortened, and dyspnea
develops at an extremely accelerated rate because of the
disparity between the inspiratory effort and tidal volume
response [60, 74].
Recent work has shown that below this tidal volume
inflection (or plateau), dyspnea increases linearly with
inflection (or plateau), dyspnea increases linearly with
workload; however once IC drops below a critical value,
dyspnea increases abruptly and becomes the most
frequently selected reason for exercise termination
regardless of exercise protocol [75]. The rate of dynamic
hyperinflation has been shown to be correlated with
diffusion capacity (DLCO/ ) [71]. Patients with lower
DLCO would be expected to have a greater propensity to
expiratory flow limitation because of reduced lung elastic
recoil and airway tethering. Patients with a more
emphysematous clinical profile (i.e., low DLCO) have been
shown to have a greater rate of dynamic hyperinflation, less
expansion of tidal volume, greater dyspnea, and lower
as compared to patients with similar airflow
obstruction, but normal DLCO [71]. More recent work has
shown that in COPD patients it may be the progressive
erosion of resting IC with worsening airflow obstruction
and hyperinflation that represents the true operating limits
for tidal volume expansion from rest to exercise [76].
O’Donnell et al. [76] found that reductions in resting IC
were associated with the development of an increasingly
shallow, rapid breathing pattern and worsening dyspnea at
progressively lower levels of ventilation during exercise.
Importantly, regardless of the severity of airflow limitation,
once reaches the previously described threshold, there
was a steep increase in dyspnea [76]. Other recent work has
shown that it may not be the drop in IC but rather a critical
reduction in inspiratory reserve volume that causes the
plateau in and marked increase in dyspnea [77]. These
findings indicate that EFL contributes to DH, and once
EELV has increased to a critical value and/or inspiratory
reserve volume drops to a critical value, dyspnea is greatly
potentiated, resulting in substantial exercise limitation.
Serial inspiratory capacity maneuvers are used during
incremental exercise to evaluate EELV/IC progression with
exercise. The use of IC to track EELV during exercise is
based on the assumption that total lung capacity (TLC)
does not change during exercise, and that reductions in IC
represent changes in EELV (i.e., ) [78,
79]. Inspiratory capacity is determined by the degree of
hyperinflation, inspiratory muscle strength, and the extent
of intrinsic mechanical loading on the inspiratory muscles
[72]. The IC also provides information regarding the
position of the tidal volume on the respiratory system’s
pressure-volume curve [72]. The lower the IC, the closer
towards TLC the subject is breathing, which is the least
compliant portion of the respiratory system’s pressure-
volume curve. Previous work has also shown that IC
determination can be reliably obtained during exercise [72,
determination can be reliably obtained during exercise [72,
80]. When performing serial IC measurements with
incremental exercise, a good effort is required to inspire up
to TLC during each maneuver so as to ensure IC is not
becoming falsely reduced because of inadequate
inspiration. Esophageal pressure data confirms that peak
esophageal pressure (an estimate of effort) does not change
with repeated IC measurements, thereby indicating that
serial ICs are valid with incremental exercise testing [72, 73,
80]. In addition to IC maneuvers, changes in EELV during
exercise can also be tracked with newer methods such as
optoelectronic plethysmography or respiratory inductance
plethysmography [81, 82]; however, these techniques have
not been adopted widely for clinical use.

10. Pulmonary Gas Exchange

Pulmonary gas exchange is typically evaluated by alveolar-
arterial oxygen partial pressure difference (AaDO2 = PAO2
− PaO2). The stress of exercise on pulmonary gas exchange
can be highlighted by the following two equations. For a
hypothetical homogeneous lung with no
heterogeneity, the physiological definition of lung diffusion
capacity for O2 (DLO2) is [28]:

PcO2 is the mean PO2 passing through the pulmonary

capillaries, which cannot be measured and therefore is
estimated by arterial blood sampling. Assuming PcO2 =
PaO2 this equation can be rearranged to:

This physiological definition demonstrates that with the

increased O2 consumption with exercise, the lung must
increase its diffusive capacity in order to limit the increase
in AaDO2 [28]. DLO2 increases with exercise as a result of
capillary recruitment, as demonstrated by an increase in
diffusion capacity with exercise [83–88]. From this
equation it is intuitive as to how exercise may result in
impaired gas exchange in patients with lung disease,
resulting in decreased and/or increased dyspnea.
Patients with a diffusion impairment at rest from
thickening of the blood gas barrier, such as in interstitial
lung disease, would be expected to show an increase in
AaDO2 with exercise, while patients who have an inability
to recruit pulmonary capillaries and therefore increase
to recruit pulmonary capillaries and therefore increase
DLO2 because of capillary destruction (i.e., COPD) would
also increase AaDO2 with exercise. Importantly, in addition
to the impact on recruitment of diffusion capacity, lung
disease can also result in greater mismatch which can
be exacerbated with exercise, resulting in further
deterioration in gas exchange.
In health, most exercising humans show an increase in
AaDO2 with incremental exercise which reaches its peak at
[30, 89], but remains within normal limits (i.e., <35
mmHg) [1]. The AaDO2 appears greatest in endurance
athletes, and in severe cases may cause hypoxemia [30, 89],
which is somewhat counterintuitive as one would expect
endurance athletes to have an excellent cardiopulmonary
system. The increase in AaDO2 with exercise has been an
area of physiological interest and is likely explained by a
combination of mismatch [90–92] and diffusion
limitation secondarily to reduced red blood cell transit time
or the development of interstitial non-clinical edema
[90–93] and/or the recruitment of intrapulmonary
arteriovenous shunts [94, 95]. Importantly, despite the
attention given to pulmonary gas exchange in the research
literature, exercise-induced arterial hypoxemia is
uncommon in all but the most highly aerobic athletes.
Thus, further clinical followup may be warranted in
symptomatic non-athletic subjects who demonstrate an
exaggerated AaDO2 (>35 mmHg) and/or decreased PaO2
with exercise.
As measurement of PaO2 requires arterial catheterization,
most CPET studies are conducted by monitoring arterial
saturation by pulse oximetry (SpO2). While SpO2 may be
appropriate for monitoring, care should be taken when
interpreting this data. Firstly, the standard error of estimate
for SpO2 monitors is between 2% and 5% [96–98]. SpO2
monitors can also bias low when blood flow is reduced,
such as what can occur with a finger oximeter while
subjects are exercising vigorously on a cycle ergometer.
Previous work suggests that an oximeter placed on the
forehead provides the most accurate readings [97]. When
using SpO2 to evaluate gas exchange during normoxic
exercise, it is important to note that within the typical
exercise range, SaO2 values are on the flat part of the oxygen
hemoglobin dissociation curve, and within this range
relatively small changes in SaO2 are associated with large
differences in PaO2. Thus, even small uncertainties in SaO2
would have a big effect on estimated PaO2 [97]. SaO2 is
also affected by the temperature and pH changes during
exercise, and these alone can result in a SpO decrease of
exercise, and these alone can result in a SpO2 decrease of
4%-5% in the absence of any change in PaO2. Finally,
should hypoxemia develop, it is not possible to determine
if hypoxemia is secondary to an impairment in gas
exchange (i.e., increased AaDO2) or significant
hypoventilation with a corresponding drop in PAO2 and
PaO2. Previous guidelines [1] define an SpO2 of 88%
during exercise as significant hypoxemia; however, this
value does not rule out the development of a significant gas
exchange impairment, and therefore temperature-corrected
arterial blood gas data should be used if careful gas
exchange evaluation is needed.

11. CPET Interpretation

The purpose of the previous sections was to highlight the
physiological responses to exercise, and how decrements in
cardiopulmonary physiology can lead to dyspnea and
exercise intolerance. While a great deal of research has
examined cardiopulmonary physiology and exercise, these
findings still make it somewhat difficult to integrate all the
data obtained in a CPET to provide a clear clinical
interpretation of the mechanism(s) contributing to
dyspnea/exercise intolerance in symptomatic individuals.
Previous position statements have provided insight [1], and
the purpose of this section is to provide guidelines to help
clinicians evaluate CPET responses. It should be noted that
the interpretation strategy described may not apply to all
conditions and remains an evolving process. It is also
important to appreciate that there are various
contraindications to CPET (see Table 2).

Table 2: Contraindications for

cardiopulmonary exercise testing.

12. Determination of Maximal Patient Effort

Prior to full interpretation of a CPET, determination of
maximal patient effort is required. Previous guidelines [1]
list the following as evidence of maximal patient effort. (1)
The patient achieves predicted and/or a plateau in
is observed. (2) Predicted maximal work rate is
achieved. (3) Predicted maximal heart rate is achieved. (4)
There is evidence of a ventilatory limitation; that is, peak
exercise ventilation approaches or exceeds maximal
ventilatory capacity. (5) A respiratory exchange ratio (RER,

often called respiratory quotient (RQ)) greater than 1.15.

often called respiratory quotient (RQ)) greater than 1.15.
(6) Patient exhaustion/Borg scale rating of 9-10 on a 10-
point scale.
Importantly, because of the cardiovascular adaptations
observed in athletes, these subjects often exceed predicted
and predicted maximal work rate even during
submaximal work, and therefore we would suggest that
reaching predicted or or maximum work rate should
not be evidence of a maximal effort. Based on this and new
research detailed previously on EFL and changes in IC with
exercise, we would suggest the following criteria for
determination of maximal effort.
Criteria for Maximal Effort
(1) RER ≥ 1.1.
(2) HR > 90% predicted max.
(3) Patient exhaustion/Borg scale > 9/10.
(4) Was there a plateau in ?
(5) Was there evidence of a ventilatory limitation
(breathing reserve <15% and/or significant EFL
and/or decrease in IC)?
Importantly, there is no gold standard for evaluating
maximal effort [1]. There is currently disagreement as to
whether hypoxemia is evidence of a maximal effort. As
hypoxemia can develop during submaximal exercise in
some patients (e.g., interstitial lung disease), it has been
suggested that this is not evidence of a maximal test [1],
while others have indicated that hypoxemia is indeed
confirmation of a maximal test [99].
With respect to the above-listed criteria, when more criteria
are attained during a CPET, there would be more
confidence that a maximal patient effort has been obtained.
Notably, patients often have difficulty reaching a plateau in
, and considering the between-subject variability in
maximal heart rate [25], both criteria (2) and (4) are
frequently not reached despite maximal effort. Further,
while patients may achieve exhaustion with CPET testing
(3), their Borg scale may be high, but not exceed a value of
“9” on Borg scale as defined by previous guidelines [1]. It is
also important to note that in the absence of respiratory
disease, criteria (5) is rarely obtained. Conversely, in the
presence of a significant ventilatory limitation (5), criteria
1, 2 and 4 may not be achieved despite maximal patient
effort. Severe hypoxemia/gas exchange impairment, chest
pain, ischemic ECG changes, and decreases in heart rate and
blood pressure can occur during submaximal exercise and
are not evidence of maximal effort [1], but may be very
are not evidence of maximal effort [1], but may be very
informative in the interpretation of test results.

13. Evaluation of Peak Oxygen Consumption

As is affected by age and sex, conditioning
status, and the presence of diseases or medications that can
influence its components, accurate interpretation of
exercise data requires reference values that are appropriate
for each patient (see [1] for a comprehensive list of
reference formulas). As with any criteria, the determination
of low/abnormal is somewhat arbitrary. The
American Thoracic Society/American College of Chest
Physicians statement on cardiopulmonary exercise testing
defines a of predicted as abnormal [1].
When examining long-term survival, subjects with an
absolute peak exercise capacity of >8 metabolic equivalents
(METS) regardless of age, have improved survival as
compared to subjects with a peak workload of 5–8 METS,
or below 5 METS [100]. When exercise capacity is
expressed as a % of predicted, subjects who attain a
of 75%–100% of predicted have lower survival than those
who reach of predicted, and survival is
correspondingly lower for those with a 50 to 74%
and those with a of predicted, respectively
[100]. These findings indicate that a below age-
predicted, but still within typical values (i.e., 75%–100% of
predicted), is associated with increased mortality and is
therefore clinically important.
is highly dependent on chronic physical
fitness/exercise history and can be increased with exercise
training and conversely reduced with inactivity. This is
noteworthy when evaluating a previously athletic
individual, as in these individuals a of ~100% of
predicted may represent a substantial reduction in previous
functional ability. The next section will now review how to
determine whether the exercise intolerance can be explained
by a pulmonary or cardiovascular limitation to exercise and
whether this limitation is physiological (i.e., normal) or
pathological.

14. Determining Exercise Limitation

Importantly, the data obtained from a CPET test should not
be interpreted in isolation. Rather, the interpretation
should be an integration of CPET results with other clinical
findings/investigations. In addition to the data directly
findings/investigations. In addition to the data directly
obtained from the CPET, feedback from the patient,
including reason for exercise termination, can be useful in
evaluating exercise limitation. Figure 1 provides a guideline
for CPET interpretation and classification based on
previous work [48, 53, 57, 58, 60, 70, 74].

Figure 1: Interpretation algorithm for

cardiopulmonary exercise testing. This
figure provides an outline of a CPET
interpretation strategy and suggested
classification of ventilatory limitation
based on previous work [1, 48, 53, 57,
58, 60, 70, 74]. Importantly, the data
obtained from a CPET test should not
be interpreted in isolation, but rather
results should be integrated with other
clinical findings/investigations. RER:
respiratory exchange ratio,
oxygen consumption, HR: heart rate,
SpO2: arterial saturation, BR:
breathing reserve, CV: cardiovascular,
EFL: expiratory flow limitation, :
tidal volume, EELV: end-expiratory
lung volume, PaCO2: arterial PCO2.

As detailed previously, is determined by the Fick

equation. Increases in cardiac output/blood flow result in
increased , indicating that the normal person has a
cardiovascular limitation to exercise. These subjects would
surpass their ventilatory threshold, and therefore the RER
would be expected to be >1.1, while HR should approach
age-predicted maximum. In these subjects EFL, increases in
EELV, and significant gas exchange impairment would not
develop with exercise. Subjects who, despite showing a
normal pulmonary, cardiovascular and metabolic response
to exercise, still have a low would be classified as
being deconditioned. In contrast, subjects showing ECG
changes with exercise, an exaggerated BP response to
exercise, a significant drop in BP or HR with exercise,
exaggerated response with hyperventilation, and a
very low would be suggestive of a pathological
cardiovascular limitation to exercise. Thus, a cardiovascular
limitation to exercise is the interpretation of default; that is,
in the absence of any abnormal/pathological response,
subjects are limited by their cardiovascular system.

When ventilatory demand is excessive or ventilatory

When ventilatory demand is excessive or ventilatory
capacity is reduced, a ventilatory limitation to exercise can
develop. Ventilatory reserve is related to ventilatory
demand, and ventilatory capacity [46, 48]; however because
of the difficulties in determining MVV and the lack of
information provided about the mechanism of ventilatory
constraint, ventilatory reserve in isolation is a more
rudimentary evaluation of ventilatory limitation, and
determination of EFL and IC is preferable. As mentioned
previously, EFL determination also has its limitations, and
failure to account for variables such as thoracic gas
compression and exercise-induced
bronchodilation/bronchoconstriction will result in an
overestimation of EFL [64]. Since an EFL < 25% of can
occur at maximal exercise in normal subjects [48, 49, 59,
60], it is unlikely that this amount of EFL should be
considered abnormal and clinically significant. The
development of EFL for >40%–50% is abnormal and
can result in an increase in EELV [48, 53, 57, 58]. As EFL
contributes to work of breathing and functional
impairment of inspiratory muscle strength [55, 56],
significant EFL by itself would contribute to perceived
dyspnea and exercise intolerance. The development of EFL
with a decrease in IC would represent a more severe
respiratory limitation and also result in a plateau in tidal
volume expansion and potentiated dyspnea [60, 74]. In the
most severe cases, hypercapnea and hypoxemia would
develop, as ventilation is insufficient to meet metabolic
demand. In many cases, the ventilatory limitation to
exercise is so severe that the patient does not reach their
ventilatory threshold (i.e., an RER < 1.0 at peak) or age-
predicted maximum heart rate. Some subjects demonstrate
a reduction in IC with exercise despite normal lung
function and no evidence of EFL or any other mechanical
limitation. In these situations, behavioral conditions such
as anxiety should be considered. See Figure 1 for a
suggested classification of ventilatory limitation based on
previous work [48, 53, 57, 58, 60, 70, 74].
The pulmonary system can further contribute to exercise
intolerance by failing to maintain adequate arterial
oxygenation. Previous guidelines indicate a fall in SaO2 of
≥4%, SaO2 ≤ 88% or PaO2 ≤ 55 mmHg is considered
clinically significant [1]. As mentioned, SaO2/SpO2
evaluated in isolation does not allow for determination of
the underlying mechanism for hypoxemia (i.e.,
hypoventilation versus gas exchange impairment versus
lactic acidosis/hyperthermia).

Poor ventilatory efficiency (i.e., high ) can be

Poor ventilatory efficiency (i.e., high ) can be
characteristic of various cardiovascular and pulmonary
diseases. Importantly, an abnormal response may
be a signal to obtain arterial blood gases during exercise so
that PaCO2 and dead space ventilation can be directly
determined [1]. A high ratio in isolation may
contribute to dyspnea but is not likely to contribute to
exercise intolerance by itself. However, with an exaggerated
ventilatory response to exercise EFL and an increase in
EELV that may develop, and these components would
contribute to exercise intolerance.
Other patients may terminate a CPET because of alternate
issues such as back pain and knee pain. In addition, the
testing staff may terminate the exercise because of safety
concerns (ECG changes, altered BP response, etc.). In these
situations, the test would be terminated because of a
noncardiopulmonary limitation, and it is unlikely that the
patient would have reached maximal patient effort.
As a final step, the clinician should determine whether the
limitation to exercise is physiological (i.e., normal) or
pathological and needing further followup. By way of
example, a subject with a low , but otherwise normal
test, would have a physiological cardiovascular limitation to
exercise whereby the low is explained by
deconditioning. A subject with a similar , but
showing abnormal ECG or BP responses, would have a
pathological cardiovascular limitation requiring further
followup. A COPD patient who has a low , but
otherwise normal test (including a normal ventilatory
response to exercise), would have a physiological
cardiovascular limitation to exercise whereby the low
is explained by deconditioning. While in contrast, a
COPD patient who has a low but substantial EFL
and hyperinflation would have a pathological respiratory
limitation to exercise. Respiratory limitations to exercise
are typically pathological, except in the case of an athlete
with superior cardiovascular function and normal lung
function [28]. These athletes can demonstrate EFL,
increased EELV and gas exchange impairment; however,
this is an example of the cardiovascular system outgrowing
the lungs, and not pulmonary pathology [28]. Of note,
patients may demonstrate evidence of both a cardiovascular
and pulmonary limitation to exercise.

15. Summary
As reviewed in this paper, exercise represents a significant
As reviewed in this paper, exercise represents a significant
stress to the cardiopulmonary system. With exercise,
oxygen delivery and local muscle O2 extraction must
increase appropriately to meet metabolic demand.
Ventilation must similarly increase to compensate for the
increased CO2 production and maintain alveolar
ventilation, while diffusion capacity must also be
augmented to maintain arterial PO2. The normal subject
has a breathing reserve even at maximal exercise, and
therefore expiratory flow limitation and/or hyperinflation
should not occur with exercise. In addition, healthy
subjects maintain oxygenation up to peak exercise because
of an appropriate increase in diffusion capacity. The failure
to have an appropriate cardiovascular, ventilatory, or gas
exchange response to exercise can result in greater
exertional dyspnea and/or exercise tolerance. As outlined in
the paper, examining the cardiopulmonary responses to a
CPET can provide additional clinical data that is not
available through resting tests of lung and cardiac function
and can help clinicians determine mechanism(s) for
exercise intolerance and/or dyspnea.

Abbreviations
Alveolar :
Alveolar ventilation:
Arterial content:
Arterial :
Arterial saturation:
Arterial saturation by pulse oximetry:
Cardiopulmonary exercise test: CPET
production:
Diffusion capacity for carbon monoxide: DLCO
Diffusion capacity for :
End-tidal :
End-tidal :
Expiratory flow limitation: EFL
Expiratory lung volume: EELV
Expiratory time:
Heart rate: HR
Inspiratory capacity: IC
Inspiratory time:
Maximal oxygen consumption:
Maximal voluntary ventilation: MVV
Metabolic equivalents: METS
Minute ventilation:
Mixed venous content:
Peak minute ventilation:

Peak oxygen consumption:

Peak oxygen consumption:
Physiologic dead space ventilation:
Pulmonary arterial hypertension: PAH
Tidal volume:
Total breath cycle duration:
Total lung capacity: TLC
Ventilation/perfusion: .

Acknowledgment
M. K. Stickland was supported by a Heart and Stroke
Foundation of Canada New Investigator Award.

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