CHAPTER 8
Clinical exercise testing
J. Roca, R. Rabinovich
Servei de Pneumologia i Allèrgia Respiratòria (ICT), Institut d’Investigacions Biomèdiques August Pi i
Sunyer (IDIBAPS), Hospital Clı́nic, Universitat de Barcelona, Barcelona, Spain.
Correspondence: J. Roca, Servei de Pneumologia, Hospital Clı́nic, Villarroel 170, Barcelona 08036,
Spain.
Impairment of exercise tolerance in chronic respiratory disorders, in particular chronic
obstructive pulmonary disease (COPD), has important implications on health-related
quality of life [1–3], hospitalisation rate [4, 5] and survival [6, 7]. Consequently, exercise
testing is progressively being considered an essential component in the routine clinical
assessment of these patients’ functional status.
Exercise intolerance results when a subject is unable to sustain a required work rate
sufficiently long for the successful completion of the task. The physiological cause, most
commonly, is an oxygen demand that exceeds the O2 conductance capability of the
oxygen transport chain. This is usually seen in physically fit individuals [8]. However, a
limited potential for oxygen utilisation at mitochondrial level must also be considered as
a factor of exercise limitation in healthy sedentary subjects [9–12]. The consequence of
exercise intolerance is a perception of limb fatigue, breathlessness or even, in some
conditions, frank pain. Exercise intolerance is the hall mark of range of cardiovascular,
respiratory and other systemic diseases, of which congestive heart failure (CHF) and
COPD are the most prominent.
Cardiopulmonary exercise testing (CPET) is a unique tool to assess the limits and
mechanisms of exercise tolerance. It also provides indices of the functional reserve of the
organ systems involved in the exercise response, with inferences for system limitation at
peak exercise. Moreover, CPET is useful for establishing the profiles and adequacy of the
system responses at submaximal exercise. Several studies [13, 14] have shown that the
functional reserve (i.e. aerobic capacity) of patients with COPD and interstitial lung
disease is not accurately predicted from resting lung function indexes.
The appropriateness of the integrated systemic responses are best studied utilising
incremental exercise testing, either as a ramp or small work-rate increments each of short
duration. CPET has been classically built around the rapid ramp-incremental exercise
test (performed on a cycle-ergometer or motorised treadmill), breath-by-breath
monitoring of cardiopulmonary variables (e.g. O2 uptake, CO2 output, ventilation,
heart rate) and formulation of graphical clusters of response profiles that optimise
estimation of key parameters, such as peak O2 uptake (V9O2) and the lactate threshold
and the characterisation of pertinent response profiles (e.g. V9O2–oxygen pulse, minute
ventilation–carbon dioxide production (V9E–V9CO2))
This provides a convenient means of: 1) determining whether the magnitude and
pattern of response of particular variables is normal with respect to other variables or to
work rate; 2) establishing a subject’s limiting or maximum attainable value for
physiological variables of interest; and 3) establishing exercise intensity domains, such as
the transition between moderate and heavy intensity exercise. It is important to
recognise, in this context, the difference between submaximal and maximal exercise
Eur Respir Mon, 2005, 31, 146–165. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005.
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CLINICAL EXERCISE TESTING
levels. In submaximal exercise, the components of the O2 transport pathway can provide
adequate O2 flux between the air and the mitochondria. Mitochondrial oxidative
capacity has not been reached, symptoms are usually tolerable and muscle fatigue has not
occurred, or at least may be insufficient to impair performance appreciably. Figures 1
and 2 indicate the characteristics of different types of exercise protocols described in the
V 'O2 L·min-1
a)
4
b)
l
l
l
ll
ll
l
ll
l
ll l
ll
l l
l
l
ll
2
ll l
l
l
l l l l l l ll l l
l
l l ll l l l l
l
ll
l
ll ll l l l
l
l
l
l l l l l l l l l l l ll l l l l l l
l
l llll
0
l
l
l
l
l l
ll
l
l
l
l
l
l
l
l
l
Time
Time
Fig. 1. – Response of oxygen uptake (V9O2) to: a) a series of constant-work rate exercise tests, from moderate to
heavy exercise; and b) a ramp-incremental test. Note that peak oxygen uptake (??????) is not different between
the protocols (a and b). There was no evidence of plateau in oxygen uptake response (maximum O2 uptake).
Steady-state oxygen uptake was observed at moderate intensity constant-work rate exercise (a). Reproduced with
permission from [113].
2000
n
V 'O2 mL·min-1
1600
n
1200
s
l
s
s
s
800
n
l
l
l
l
l
l
l
s
l
l
s
l
l
l
l
l
l
l
l
400 n
l
0
0
1
2
3
4
6
7
5
Time min
8
9
10
11
Fig. 2. – Mean oxygen uptake (V9O2) profiles of the eight chronic obstructive pulmonary disease patients during
four different clinical exercise protocols (mean¡sem): incremental cycling (#); incremental shuttle ($); six-
minute walk test (+); and stairs climbing (%).
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J. ROCA, R. RABINOVICH
text. At maximal exercise, symptoms have caused the patient to stop exercising. At this
stage, one or more of the following possibilities exist:
1) Limits to O2 transport have been reached and maximal V9O2 (V9O2,max) attained;
under such conditions, breathing 100% O2, for example, could increase V9O2,max [15].
2) Mitochondrial oxidative capacity has been reached and again the subject would be
considered to be at V9O2,max, but adding O2 would not raise V9O2.
3) Maximal exercise has occurred at a level that does not require maximal O2 transport
or maximal oxidative capacity and here exercise has been limited by unusually severe
symptoms. Under these conditions a plateau in O2 (V9O2,max) has not been reached and
the appropriate term is peak, rather than V9O2,max.
Subjects with lung disease often experience exercise intolerance at extremely low work
rates. There are many kinds of lung disease, however, and in any one patient the
structural and functional severity of the disease may range from the barely discernible to
the very severe. As a result, responses to exercise in patients with lung disease do not
show the tight stereotypical pattern of normal subjects. However, despite the widespread
clinical use of CPET, it does not typically provide a substantial improvement in primary
diagnostic power over the more classical clinical tools/assessments (e.g. spirometry).
What CPET can do, however, is: 1) reveal specific abnormalities that occur only when
support systems are stressed by exercise (e.g. dynamic hyperinflation in COPD); and 2)
provide a functional frame of reference for assessing the efficacy of interventions targeted
to ameliorate such abnormalities (e.g. bronchodilators for dynamic hyperinflation).
More recently, test paradigms designed to quantify endurance performance have evolved
and other exercise protocols, described below, have also become popular. It is of note,
however, that CPET is now highly developed in this regard and it is the accepted "gold
standard".
Responses to exercise in health and disease
There is nothing intrinsically different in the direction of the overall system response to
exercise comparing normal subjects and patients with lung diseases. Thus, as a patient
exercises harder, O2 consumption, CO2 production, ventilation and cardiac output all
increase to fulfill increased muscle bioenergetic requirements, as they do in the normal
subject [16], but peak levels attained are less, more so with increasing severity of the
disease. What may be different from normal in lung diseases regarding exercise responses
include: 1) resting function; 2) physical deconditioning; 3) the intensity and duration of
exercise that can be performed, and the relationship between intensity/duration and
symptom development; 4) the specific responses of the heart and lungs/chest wall to a
given exercise load in terms of rate, magnitude and performance limits; 5) the relative
importance of each part of the O2 and CO2 transport pathway in contributing to any
limitation of exercise that is found; 6) the relative importance of peripheral and
respiratory muscle fatigue; and 7) metabolic accompaniments of exercise, in particular
lactate release and accumulation, and high energy phosphate levels.
Pulmonary response to exercise in healthy subjects
It is well known that ventilation and cardiac output markedly increase during exercise
to match O2 transport with augmented cellular O2 requirements [17] (fig. 3). Since
ventilation increases to a higher relative extent than pulmonary blood flow, the ratio of
total alveolar ventilation to blood flow (overall V9A/Q9 ratio) rises rather substantially.
At moderate levels of exercise, the dispersion of the V9A/Q9 distributions does not change
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Pulmonary function
(ventilation and gas exchange)
Blood O2 carrying capacity
Cardiovascular system
(cardiac output and regional distribution of blood flow)
Muscle capillary O2 transfer capacity
Mitochondrial oxidative capacity
(cellular O2 utilisation)
Fig. 3. – Major elements of the O2 transport/O2 utilisation pathway. Integrated effects of all steps involved to
move oxygen from air to mitochondria are essential to determine the maximum capacity of the system. In
disease, nonuniformity of ventilation/perfusion ratios in the lung and/or metabolism/perfusion ratios in the
peripheral tissues may be of considerable importance.
[18–20] but the V9A/Q9 ratios at the mean of both ventilation and perfusion distributions
markedly increase due to the higher overall V9A/Q9 ratio. Consequently, the efficiency of
the lung as an O2 and CO2 exchanger improves at these exercise levels. Mixed venous
oxygen partial pressure falls dramatically during exercise because the relative increase in
V9O2 is considerably greater than that of cardiac output, and mixed venous carbon
dioxide partial pressure levels rise equally remarkably. Arterial PO2 levels generally
remain unchanged until extremely high levels of exercise are undertaken. Arterial PCO2
levels are also relatively stable until the appearance of high blood lactate levels generates
acidosis, even more ventilation, and thus a fall in Pa,CO2 levels. The alveolar–arterial O2
gradient (AaPO2), however, progressively increases with the level of exercise, reaching
values of 20–30 mmHg close to maximal exercise (VO2 peak) in average subjects, and
even greater (up to 40 mmHg or more) in some elite athletes [21]. Such an increase in
AaPO2 indicates inefficiency of pulmonary gas exchange during heavy exercise that is
even more apparent in other animal species, such as the horse [22]. It has been shown
that the increase in the AaPO2 during exercise is due, in part, to VA9/Q9 mismatching [18–
20] but it is mostly explained by alveolar-end capillary O2 diffusion limitation [19, 23].
Experimental studies suggest that development of subclinical pulmonary oedema [19, 24]
may explain the deterioration of pulmonary gas exchange during heavy exercise in elite
athletes.
Pulmonary response in lung diseases
In COPD patients, resting levels of V9E are abnormally high but, during exercise, the
slope between V9E and work rate is normal. For a given level of V9E during exercise, tidal
volume (VT) tends to be lower and respiratory rate (f) higher in patients than in healthy
subjects [25, 26]. Moreover, the O2 cost of breathing per unit ventilation is higher in
COPD patients than in healthy subjects. Impaired respiratory mechanics requires more
effort to move a given volume of air. Peak exercise VT is strongly related to vital capacity
in these patients [27]. They adopt two strategies during exercise to increase V9E [25]:
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4
3
2
Flow L·s-1
1
0
-1
-2
-3
-4
-5
0
1
2
3
Volume L
4
5
Fig. 4. – The resting maximal flow–volume curve from a chronic obstructive pulmonary disease patient is
represented by the solid line. The solid smallest loop corresponds to tidal volume at rest and the dashed curve
indicates tidal volume at maximal exercise. During exercise, end-inspiratory and end-expiratory lung volumes are
increased (dynamic hyperinflation) and expiratory flow limitation is seen over most of expiration. Reproduced
with permission from [113].
1) end-expiratory lung volume (EELV) increases, allowing higher maximum expiratory
flow rates (fig. 4). This dynamic hyperinflation does not occur in normal humans, who
show a fall in EELV during exercise [25]; and 2) inspiratory flow rate increases, so that
inspiratory time decreases and more time is available for expiration [25].
Impaired respiratory mechanics (dynamic hyperinflation) seems to play a major role
limiting exercise tolerance in these patients. During exercise in COPD, a balance is struck
between the need for ventilation and the high cost of breathing. The most common endresult is a small raise in arterial PCO2 and similar fall in Pa,O2. However, unless
pulmonary carbon monoxide transfer capacity (DL,CO) is severely impaired (v50%
predicted value), Pa,O2 does not fall during exercise, and may even increase in some
subjects. Studies using the multiple inert gas elimination technique in COPD show that
VA/Q mismatch is usually unaltered from that at rest, that shunts do not develop, and
that diffusion limitation also does not occur [28]. This is even the case when COPD is
severe [28]. In milder disease, there is evidence that small improvements in VA/Q
relationships may occur on exercise [29, 30], providing a partial reason for improvement
in arterial PO2. However, it is not infrequently observed that when the patient with
COPD is encouraged to maximal effort, sudden hypoxaemia and hypercapnia can
develop just before the patient quits exercising [28].
In a variety of chronic respiratory disorders, such as interstitial lung diseases (ILD)
and pulmonary vascular diseases (PVD), abnormally high resting levels of V9E and
normal slope between V9E and work rate during exercise are commonly observed, but not
dynamic hyperinflation, as seen in COPD patients. They do not change EELV
significantly during exercise [31]. Oxygen cost of breathing per unit ventilation is
increased in patients with ILD because the increased elastic recoil requires more
inspiratory muscle activity. They show a strong linear relationship between peak exercise
VT and vital capacity [31], suggesting that differences in peak VT are mainly due to
abnormal respiratory mechanics. During exercise, patients with ILD generally show
typical and substantial blood-gas changes, even at moderate effort. While arterial PCO2 is
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generally unaffected [31], Pa,O2 falls in almost all patients [32–34], sometimes severely, as
does mixed venous PO2. It is this profound degree of arterial hypoxaemia (and not
respiratory mechanics) that mostly limits exercise tolerance in ILD [35–38]. Worsening of
V9A/Q9 mismatching and shunt does not play a relevant role in exercise-induced
hypoxaemia seen in these patients [32]. Therefore, the blood gas changes on exercise are
mostly the consequence of: 1) insufficient increase of alveolar ventilation relative to the
rise in Pa,CO2; and 2) secondary effects from the fall in mixed venous PO2 causing a fall in
arterial PO2 [39]. Also, O2 diffusion limitation is seen in most ILD patients during
exercise, further adding to the hypoxaemia [32]. The presence of O2 diffusion limitation
in these patients despite the relatively low cardiac output at peak exercise (v10 L?min-1)
is likely related to the combination of: 1) an abnormally low mixed venous PO2; 2) a short
capillary transit time; and 3) some increased interstitial resistance for the diffusion of O2
from the alveolar gas to the capillary blood caused by the large collagen deposits there.
Exercise-induced hypoxaemia in patients with PVD has been found to be largely due to
the fall in mixed venous PO2, because there is no systematic change in V9A/Q9
relationships nor does diffusion limitation develop [32].
Haemodynamic responses to exercise in health and disease
In healthy subjects, cardiac output (Q9T) shows a linear increase in relation to O2
uptake during exercise. Likewise, both stroke volume and heart rate (HR) also increase
as V9O2 increases. In well-trained subjects, up to five-fold increase (y25 L?min-1) in Q9T at
peak exercise can often be seen. Systolic pulmonary pressure increases during exercise,
but pulmonary vascular resistance falls because of vascular recruitment. At systemic
levels, systolic pressure increases, but not diastolic pressure. It is of note, however, that
elite athletes at peak exercise show a potent sympathetic vasoconstriction at systemic
level inducing massive redistribution of cardiac output, which ensures preferential
perfusion to active skeletal muscle (due to local exercise-induced vasodilator effects)
while preserving blood flow and O2 delivery to essential organs such as the brain [40]. It
has been reported that in well-trained cyclists during maximal exercise, respiratory
muscles subvert blood flow that otherwise would have been directed to limb muscles. In
these subjects, unloading the respiratory system with proportional assist ventilation
resulted in an increase in both leg blood flow and leg vascular conductance [41, 42]. This
phenomenon is not seen in chronic respiratory patients because they are unable to reach
such extreme levels of O2 uptake during exercise but despite this they may show increased
O2 cost of breathing per unit ventilation [43].
In chronic respiratory diseases, pulmonary vascular abnormalities are present well
before frank heart failure occurs. There is pulmonary hypertension often even evident at
rest, and usually during exercise. The increase in pressure per unit increase in cardiac
output is some three times greater in these patients than in the normal subjects.
Contrary to the normal subjects in whom pulmonary vascular resistance normally falls
during exercise due to a combination of vascular recruitment and distension in the lungs,
in COPD, vascular resistance remains constant or may even rise. The vascular
destruction or obstruction that is well-known to occur in these diseases, together with
some distortion and also hypoxic vasoconstriction are the reasons underlying these
physiological abnormalities. Eventually, as the diseases progress, the right heart will
hypertrophy and ultimately fail, and clinically significant cor pulmonale will be present.
Despite the 2–3-fold increase in vascular resistance and high pulmonary artery pressures,
it is remarkable that even in advanced lung disease the heart can pump essentially
normally as a function of filling pressure, as shown from the limited data available.
At peak exercise, systemic O2 delivery is clearly below normal level [25]. While the
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obvious culprit is impaired pulmonary function, it is not always through a reduction in
oxygen saturation in arterial blood that systemic O2 delivery is primarily reduced, since
despite V9A/Q9 inequality and reduced effective alveolar ventilation, hypoxaemia may
not necessarily provoke a marked fall in arterial O2 content [25]. It is well accepted that
cardiac output at peak exercise is always well below normal levels. However, in COPD
patients as in normal subjects, cardiac output increases linearly in relation to oxygen
uptake as work rate increases during incremental exercise, such that cardiac output at a
given submaximal O2 uptake [44] is close to the expected normal value. It should be
noted, however, that the rise in cardiac output during exercise is usually achieved
through a higher heart rate and lower stroke volume than in healthy subjects.
Since total ventilation, cardiac output and exercise intensity remain closely coupled in
COPD as in health, the inability to raise ventilation appears as the principal governor of
the O2 transport process: a low ceiling on ventilation means a low ceiling on cardiac
output and thus on systemic O2 delivery. It should be mentioned that the mechanisms
that couple ventilation to cardiac output during exercise are still not well understood.
Montes de Oca et al. [45] proposed that the large pleural pressure swings observed
during exercise can be paramount to constrain left ventricular function, thus limiting
both peak cardiac output and exercise tolerance in very severe COPD patients. The
coupling between whole-body O2 uptake and cardiac output during exercise implies that
the O2 difference between arterial and mixed venous blood and the fractional O2
extraction are normal or near normal [11, 46]. The cardiac response to exercise in patients
with ILD is similar to the description for COPD patients. In contrast, patients with PVD
show different cardiac response to exercise. Certainly, at peak exercise cardiac output is
lower. More importantly, however, the slope of the relationship between V9O2 and
cardiac output appears different. This suggests that for any given degree of exercise (i.e.
V9O2), cardiac output in patients with PVD does not increase as much as in controls or
patients with COPD or ILD. This abnormal behaviour is likely related to the increased
after-load of the right ventricle [47–49]. As expected, patients with PVD have, at rest,
pulmonary artery hypertension and increased pulmonary vascular resistance. Compared
with patients with COPD and ILD, patients with PVD show, by far, the worse
haemodynamic situation. During exercise, pulmonary artery pressure increases in direct
proportion to the increase in cardiac output and reaches extremely high values. This
indicates the lack of pulmonary vascular reserve. In fact, the pathologically elevated
pulmonary vascular resistance seen at rest does not change substantially during exercise.
Muscle oxygen utilisation in health and disease
It has been reported that well-trained males show O2 supply dependency of maximum
O2 uptake [8], indicating that mitochondrial capacity does not constitute the rate limiting
factor for maximum exercise performance. In contrast, data from healthy sedentary
subjects [9, 10] strongly suggest that muscle mitochondrial function is a limiting step for
maximum O2 uptake (fig. 5). Studies including direct measurements of cell PO2
saturation during exercise, breathing different inspiratory oxygen fraction (FI,O2),
further indicates that sedentary subjects do not show O2 supply dependency of V9O2,max
[12]. The plasticity of skeletal muscle during a high-intensity physical training
programme [50] fully accounts for the differences alluded to between athletes and
sedentary subjects. The scenario is far more complex in patients with COPD. Femoral
blood flow (Qleg) measurements in patients with moderate-to-severe airflow limitation
[11, 51] have shown, as for cardiac output, a marked reduction in leg blood flow at peak
exercise. However, leg blood flow (and leg O2 delivery) [11, 52] at a given submaximal
whole-body O2 uptake (and leg V9O2) is above normal, which may indicate increased
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Maximum V 'O2,leg L·min-1
0.8
1.0
0.6
s
0.13
s
s
n
0.4
n
0.21
n
1.0
0.21
0.13
0.2
0.0
0
400
Peak power g
800
1200
Fig. 5. – Quadriceps maximal oxygen uptake (V9O2,leg) (y-axis) plotted against maximum work rate (x-axis)
(mean¡sem) in healthy subjects (') and in chronic renal patients (&) breathing 13%, 21% and 100% inspired
O2 concentrations (inspiratory oxygen fraction (FI,O2) 0.13, 0.21 and 1.0, respectively). While chronic renal
patients increased V9O2,max and maximum work rate (Wmax) proportionally to the FI,O2 increase, indicating
O2 supply dependency of V9O2,max, healthy sedentary subjects did not show any relationship between exercise
performance and changes in O2 transport (and in cell oxygenation) suggesting that mitochondrial capacity,
but not O2 transport, was limiting V9O2,max. Reproduced with permission from [12].
peripheral muscle O2 demand. Moreover, poor muscle capillary network in these patients
[53] seem to suggest that low peripheral O2 diffusion capacity may also contribute to
exercise-induced cell hypoxia, even in the absence of arterial hypoxaemia. Increased
lactate production [11, 54–56] is responsible for the fall in muscle pH, which, in turn, may
play a role in determining exercise intolerance in these patients [56]. Premature lactic
acidosis during exercise in COPD patients has been associated with reduced oxidative
enzyme concentrations in the lower limb muscles [54, 55] that can be, at least partly,
reversed by physical training.
Several studies [11, 57, 58] exercising different muscle groups in heterogeneous groups
of COPD patients have consistently shown lower cellular bioenergetic status (31PNuclear magnetic resonance spectroscopy) and lower pHi than those seen in healthy
sedentary controls at equivalent levels of exercise. There is evidence [11] suggesting that
muscle deconditioning plays a major role to explain the disturbances of skeletal muscle
bioenergetics in COPD patients. Recent lines of evidence indicate that intrinsic skeletal
muscle dysfunction may be present in patients with COPD, as well as in other chronic
disorders, such as CHF [59–61]. Abnormal redox status [59–62] plays a central role
prompting muscle mass wasting particularly in susceptible subsets of COPD patients.
Factors determining exercise performance: integrated response
It is presently well accepted that the level of exercise tolerance is set by the integrity of
each of the functions involved in the O2 transport/O2 utilisation system, as well as by
proper interactions among all of the physiological responses alluded to above [63].
Complex integrative pathways both at whole body level and at cellular level have been
identified. Since not only intracellular pH [64], but also cell PO2 [65] has been shown to
modulate mitochondrial function, O2 transport (cell PO2) and O2 utilisation
(mitochondrial capacity) cannot be analysed as separate systems.
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Also of major interest are the events surrounding peak or maximal V9O2 and the
physiological basis of why peak or maximal V9O2 is reduced as it almost always is in disease.
In this regard, it must be noted that the amount of V9O2 achieved by a given patient is not
only set by the intrinsic characteristics of the system, it also depends on several other factors
that modulate the physiological response of the whole body, such as: 1) environmental
conditions (altitude above sea level, FI,O2); 2) amount of exercising muscle mass (cycling,
walking, localised quadriceps exercise); and 3) type of exercise protocol (incremental,
endurance test, 6-min walking distance test (6MWT), shuttle test, etc.) (fig. 2). Since the
catabolic capacity of the myosin ATPase is such that it outstrips by far the capacity of the
respiratory system to deliver energy aerobically, exercise tolerance (V9O2,max) is determined
by the capacity of the O2 transport/O2 utilisation system rather than by the muscle’s
contractile machinery. Two physiological muscle properties (muscle strength and muscle
fatigability) may modulate functional performance of the patient in daily life activities, as
well as during clinical exercise testing. Muscle strength is defined as the force generated by a
muscle. It is determined by the number and type of motor units recruited; whereas muscle
fatigue has been defined as a loss of contractile functions (force, velocity, power or work)
that is caused by prolonged exercise and is reversible by rest. Factors involved in muscle
fatigue are complex, mainly: 1) contractile machinery; 2) muscle respiratory capacity; and
3) redox status of the muscle. In practical terms, it may be useful to consider two different
scenarios (V9O2,peak and V9O2max) (fig. 1). These are the following:
1. A peak V9O2 has been reached without evidence of V9O2 plateauing. This is perhaps
the commonest outcome in the clinical setting. Taken as it is, one cannot say
whether this peak V9O2 is limited by O2 supply, mitochondrial oxidative capacity, or
perhaps neither (i.e. symptoms are so severe that neither O2 supply nor
mitochondrial function have been fully exploited). In these circumstances, it will
be useful to identify the V9O2 at which the transition from moderate to heavy
exercise took place (lactate threshold) and evaluate the organ system responses
(ventilation, gas exchange, heart rate, etc.) during submaximal exercise and at peak
V9O2. Despite not having information about the capacity of the system (a plateau of
O2 uptake was not identified), we will know about: 1) the physiological burden
imposed by exercise; and 2) the reserve of the system depending upon the location
of the transition from moderate to heavy exercise.
2. A plateau in V9O2 at maximal exercise is clearly identified such that the subject
achieved his/her maximum exercise (maximum O2 uptake) capacity in that
particular setting or there is physiological evidence that they are very close to
maximum. In this circumstance, two situations may be faced:
2.1. V9O2,max is the result of having reached mitochondrial oxidative capacity. In this
scenario, the key concept is that acute increases in O2 supply to the mitochondria
would not lead to any further increase in V9O2,max. In other words, no O2 supply
dependency is observed by giving 100% O2 to breath or by blood transfusion.
2.2. V9O2,max is the result of having reached limits to the supply of O2. In this
circumstance, one or more components of the integrated O2 transport system
(the lungs, heart and blood vessels, blood and muscles) has reached maximal
capacity for the given conditions and it can be tested experimentally by
augmenting any one of the components alluded to above.
Clinical indications and exercise protocols
There is a range of indications for CPET. It is useful, for example, in the diagnosis of a
range of disease conditions, namely: exercise-induced asthma, cardiac ischaemia,
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foramen ovale patency with development of right-to-left shunt during exercise, and
McArdle’s syndrome [66]. In addition, CPET provides information on dysfunction,
monitoring or prognostic value in a wide range of conditions. However, an adequate
identification of the clinical problem requiring study should be considered a necessary
prelude to CPET, as should an appropriate assessment of the patient by: 1) medical history;
2) physical examination; 3) chest radiograph; 4) pulmonary function testing; and 5)
electrocardiogram (ECG). The clinical problem that prompts the CPET and the specific
aims of the test (i.e. assessment of exercise tolerance, analysis of pulmonary gas exchange
during exercise, etc.) determine both the type of exercise protocol to be used and the
variables to be considered in the interpretation of the test. Assessment of exercise tolerance
and potential limiting factors constitutes the most important indication of CPET. This is
particularly important to evaluate dyspnoea, but also to assess the degree of impairment in
several chronic diseases. Appropriate use of CPET allows the investigator: 1) to quantify
the degree of abnormal limitation and to discriminate among causes of exercise intolerance;
2) to differentiate between dyspnoea of cardiac or pulmonary origin when respiratory and
cardiac diseases co-exist; and 3) to analyse unexplained dyspnoea when initial pulmonary
function impairment does not provide conclusive results.
A second area of indication of CPET is pre-operative assessment in different
conditions, namely, major abdominal surgery in elderly patients [67, 68]. Also, CPET are
indicated in lung cancer resectional surgery and lung volume reduction surgery.
Information on predicted post-operative lung function: 1) helps to modulate the amount
of lung parenchyma to be resected; and 2) determines the type of peri-operative strategy
needed to prevent post-surgical complications. Resting pulmonary function tests are
considered adequate to evaluate patients with low risk (forced expiratory volume in one
second w2 L and DL,CO within the reference limits) of post-surgical complications [69–
74]. However, CPET play a pivotal role in the evaluation of patients with moderate-tohigh risk [72, 73, 75, 76]. Assessment of patients included in transplantation programmes
(lung, heart) also constitutes an indication for CPET.
CPET should always play a central role assessing candidates before the rehabilitation
programme and in the subsequent modulation of the exercise prescription, whereas
simpler tests (i.e. 6MWT) are useful for monitoring during the rehabilitation programme.
Finally, assessment of impairment-disability also constitutes a central indication of
CPET. It is now well accepted that CPET provides different and relevant information in
impairment-disability evaluation [77–79], compared to resting cardiopulmonary
measurements [80]. Consequently, CPET constitutes a key tool in this area.
Exercise protocols
The goal of CPET protocols is to stress the organ systems involved in the exercise
response in a controlled manner. For this reason the testing generally involves exercising
large muscle groups, usually the lower extremity muscles. A key requirement is that
exercise stimulus must be quantifiable in terms of the external work and power
performed. The appropriateness of the integrated systemic responses to the tolerable
range of work rates is best studied utilising incremental exercise testing. This provides a
smooth incremental stress to the subjects so that the entire range of exercise intensities
can be spanned in a short period of time. The recommended incremental exercise testing
protocol, usually electronically-braked cycle ergometry with constant pedalling
frequency, of 60 rpm is recommended. Equivalent results are obtained when work
rate is either increased continuously (ramp test) or by a uniform amount each minute (1min incremental test) until the patient is limited by symptoms (he/she cannot cycle
w40 rpm) or is not able to continue safely. The increment size should be set according to
155
J. ROCA, R. RABINOVICH
the characteristics of the patient in order to obtain y10 min duration of the incremental
part of the protocol. This may represent incremental rates of 10–20 W per minute in a
healthy sedentary subject or less in a patient. Sufficient density of data to be acquired in a
test lasting v20 min from start to finish, including: 1) measurements at rest; 2) 3 min of
unloaded exercise; 3) incremental exercise (y10 min); and 4) 2 min recovery, at least.
Standard noninvasive CPET carried out whilst breathing room air (FI,O2=0.21) involves
acquisition of breath-by-breath expired O2 and CO2 concentrations (expiratory oxygen
fraction and expiratory carbon dioxide fraction, respectively), work rate, expired airflow,
HR and systemic arterial pressure as primary variables. ECG and pulse oximetry should
be continuously monitored during the test. It is useful to establish a sense of the patient’s
exercise-related perceptions during the exercise test and at the point when the subject
discontinues exercise. This includes exertion, dyspnoea, chest-pain and skeletal muscle
effort. Quantifying these perceptions should be done using standardised rating
procedures (Borg scale, visual analogue scale (VAS) etc.).
Proper evaluation of pulmonary gas exchange in patients with lung disease requires
assessment of arterial respiratory blood gases [81]. In these cases, arterial cannulation
(preferentially radial, or brachial) is needed (Pa,O2 and Pa,CO2 measurements and
calculation of AaPO2) [81, 82]. This also provides information on acid-base status (pH,
Pa,CO2 and base excess) and allows continuous monitoring of systemic arterial blood
pressure during the test. However, while "arterialised venous blood" (e.g. from the dorsum
of the heated hand) gives good values for PCO2 and pH it is not appropriate for PO2.
Furthermore, estimation of arterial respiratory blood gases through expired O2 and CO2
profiles or "transcutaneous" electrodes and pulse oximetry should not be used as indices of
arterial PO2 and PCO2 during exercise [83–85]. It is important to recognise that arterial
blood sampling immediately after exercise does not provide an adequate assessment of
blood gas values at peak exercise. However, while pulse oximetry does not indicate arterial
PO2, it does provide valuable information on oxyhaemoglobin saturation during exercise.
If the ergometer used in the CPET is a motor driven treadmill, then the Balke’s
protocol [81, 86] is considered the most appropriate for its simplicity. The speed of the
treadmill is kept constant (3–3.5 mph) during the protocol while the slope is
progressively increased (1–2% min-1). It is of note, however, that the assessment of
the relationships between oxygen uptake and external work rate is more accurately
carried out using a cyclo ergometer than using a treadmill.
Alternative protocols can be considered for specific purposes [87]. Simpler tests, such
as step tests or timed distance walks (i.e. 6MWT or 12 min-walk) are widely used and
they can provide measures of exercise tolerance but are not as useful in diagnosis as
incremental tests [88–90]. The timed walking tests have been extensively used in the
clinical evaluation of patients with chronic cardiopulmonary disorders mainly because of
their simplicity. A present, these tests are recognised to add prognostic information
useful to the staging of patients with COPD [4, 7], primary pulmonary hypertension [91]
and congestive heart failure [92]. Timed walking tests have shown to be sensitive to
changes after interventions such as inhaled bronchodilators [93], volume reduction
surgery [94] and pulmonary rehabilitation [95, 96]. The 6MWT, for example, is currently
performed in a large number of rehabilitation programmes. Recent studies [97] suggest
that encouraged 6MWT is a strenuous protocol that evaluates sustainable exercise
performance; that is critical power. The 6MWT and the incremental cycling protocols
should be considered complementary tests.
Constant-work rate protocols can result in steady-state responses when work rate is of
moderate intensity. In contrast, constant work rate of high intensity for the individual
typically results in continually changing values in most variables of interest. Consequently,
attainment of, or failure to attain, a steady-state V9O2 during a constant-load test can be used
to determine if a particular task is sustainable by the individual. During a constant-work
156
CLINICAL EXERCISE TESTING
rate protocol, the period of dynamic adjustment to a constant-work rate test provides
information regarding the dynamic behaviour of lung function, haemodynamics and tissue
O2 utilisation. However, there is to date virtually no information on the confidence limits,
reproducibility and predictive value of the derived parameters in patient populations.
Consequently, the utility of quantifying dynamic responses to constant-work rate exercise in
clinical exercise testing remains to be established. The constant-work rate protocols are,
however, useful to assess the impact of a given intervention on the system responses to
exercise (i.e. bronchodilator therapy) [98]. Alternatively, the use of high intensity constantwork rate to assess exercise-induced asthma has been traditionally used in the clinical
setting, but it might be progressively substituted [99].
Testing procedures
Cardiopulmonary exercise testing should be conducted only by adequately trained
personnel with a basic knowledge of exercise physiology. Technicians familiar with normal
and abnormal responses during exercise and trained in cardiopulmonary resuscitation
(CPR) should be present throughout the test. CPET should be performed under the
supervision of a physician who is appropriately trained to conduct exercise tests and in
advanced CPR. The degree of subject supervision needed during the test can be determined
by the clinical status of the subject being tested and the type of exercise protocol. While it is
preferable for the physician to be present during the test, if not he/she must be readily
available to respond as needed. Additional roles for the physician are the evaluation of the
patient immediately before the test and the interpretation of the results.
Patient preparation
At the time of scheduling, the subject should be instructed to adhere to his/her usual
medical regimen; he/she should not to eat for at least 2 h before the test, avoid cigarette
smoking and caffeine, and dress appropriately for the exercise test. A brief history (with
detailed inquiries about the medications) and physical examination should be done to
rule out contraindications to testing. Results of recent resting pulmonary function tests,
as a minimum forced spirometry, should be available for patients in whom pulmonary
disease is suspected.
On arrival at the CPET laboratory, a detailed explanation of the testing procedure and
equipment should be given to the patient outlining risks and potential complications as
described below. The subject should be told how to perform the exercise test and the
testing procedure should be demonstrated if needed. The patient should be encouraged to
ask questions to reduce any anxiety. The patient needs to become familiar with the
equipment. If the treadmill is used, time is provided for several practice trials of starting
and stopping until the patient feels confident. If the cycle ergometer is used, the seat
height is adjusted so that the subject’s legs are almost completely extended when the
pedals are at the lowest point and the cycling rhythm practiced. Before the test, the ECG
electrodes are carefully placed and secured after preparing the skin to ensure good
recordings (if necessary, the area of the electrodes placement should be shaved). A
sphygmomanometer cuff is placed on the upper arm. The mouthpiece and noseclip are
then tried and the position adjusted until adopting a comfortable position. The patient is
informed that it is acceptable to swallow with the mouthpiece in place and that he/she
must signal any unexpected difficulty by the signal "thumbs down". The patient is advised
to point to the site of discomfort if chest or leg pain is experienced.
157
J. ROCA, R. RABINOVICH
During the test, the patient is encouraged to carry on with a regular pedalling cadence.
Symptoms and degree of discomfort are periodically checked (see below safety
precautions). Good communication with the patient throughout the whole procedure
increases the subject’s confidence and predisposes to good effort. During recovery, the
patient is told to continue to pedal, without external work load (or walk at a slow pace on
the treadmill), for at least 2 min during recovery in order to prevent fainting and to
accelerate lactate removal. At the point when the subject discontinues exercise, after
removal of the mouthpiece, the physician should ask for symptoms (type and intensity)
that prompted the patient to stop exercise. If blood gas analysis is done, a last blood
sample is taken at 2 min of recovery. If the test does not provide adequate diagnostic
information because of premature termination or inadequate cooperation of the patient,
it should be repeated after a resting period of 30–45 min.
Although CPET may be considered to be a safe procedure, risks and complications
have been reported. Good clinical judgment should be paramount in defining indications
and contraindications for exercise testing [100]. Cardiac (bradyarrhythmias, ventricular
tachycardia, myocardial infarction, heart failure, hypotension and shock) and
noncardiac (musculoskeletal trauma, severe fatigue, dizziness, fainting, body aches)
complications of CPET have been reported. Consequently, during the test, the personnel
should be alert to any abnormal event. The indications to stop the test must be clearly
established and known by all the personnel involved in testing. These indications include
symptoms such as: 1) acute chest pain, 2) sudden pallor, 3) loss of coordination, 4)
mental confusion, and 5) extreme dyspnoea; and signs such as: 1) depression of ST
segment w0.1 mV (less specific in females), 2) T-wave inversion, 3) sustained ventricular
tachycardia, and 4) fall in systolic pressure either below the resting value or y20 mmHg
below its highest value during exercise testing. Relative indications to stop the test are: 1)
polymorphic and/or frequent premature ventricular beats; and, 2) hypertension
(w250 mmHg systolic, w130 mmHg diastolic). If the exercise test has been stopped for
one of the above-listed reasons, the patient should be monitored in the CPET laboratory
until symptoms or ECG modifications have completely cleared. Admission to hospital
for longer observation or more often for complementary investigation will be necessary
in very rare cases. If necessary, intensive care can be administered on site. Full
cardiopulmonary resuscitation equipment should be available in the CPET laboratory.
Interpretation strategies
The greatest diagnostic potential and impact on the clinical decision making process of
exercise testing should rely not on the utility of any one individual measurement,
although some are obviously more important than others, but rather on their integrated
use. Identification of a cluster of responses characteristic of different diseases is often
useful. The major portion of the interpretation strategy is focused on CPET results
generated during maximal, symptom-limited, incremental exercise testing. This is
currently the most popular, albeit not the exclusive protocol. Often, insufficient attention
is paid to trending phenomena as the work rate progresses from submaximal to peak
levels. To facilitate this type of analysis, the results should be formatted in an appropriate
manner. Figure 6 displays data obtained in a normal subject performing cycle ergometry,
using an ergometer that utilises an "assist" to provide an actual zero-watt work rate at
"unloaded" pedalling. Figures 6a–d provide, in addition to the peak V9O2, the variables
commonly used to provide an indirect estimation of the lactate threshold. That is,
identification of the O2 uptake at which the transition between moderate to heavyintensity exercise occurs. Figure 6e (O2 uptake versus work rate) reflects the exercise
158
CLINICAL EXERCISE TESTING
e)
1.5
nn
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n
nn
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n
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1.0
P ET,O2 mmHg
c)
RER
d)
135
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125
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115
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105
100
0.0
1.4
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1.2
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V 'O2 L·min-1
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60
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n
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V 'O2 L·min-1
2.0
46
44
42
40
38
36
34
32
30
2.5
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n
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n
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50
100 150
Work rate W
200
250
f) 150
n
125
100
V 'E L·min-1
55
50
45
40
35
30
25
20
0.0
2.0
1.5
n
nnn
nn
n
nn
*
2.5
n
75
50
25
0
0.0
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160
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100
80
0.0
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V 'CO2 L·min-1
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2.5
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14
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6
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1.0
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VT L
V 'E/V 'O2
b)
nn
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fc beats·min-1
0.0
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2.5
P ET,CO2 mmHg
V 'CO2 L·min-1
a)
0
25
50
75 100
V 'E L·min-1
125
150
Fig. 6. – Exercise performance in a healthy sedentary male subject. The basic plots for the interpretation of
cardiopulmonary exercise testing are reported. In plots a–d, in addition to peak oxygen uptake (V9O2), the
variables commonly used to indirectly estimate lactic threshold (LT) are given. That is, the V9O2 at which the
transition from moderate to high intensity exercise occurs is identified (vertical dashed line). The expected LT
for a healthy subject (55% of predicted V9O2,peak) is indicated in plots a) to d) by a small arrow (continuous
line). Predicted V9O2,peak is indicated in a) by an arrow (dashed line). In plot e), V9O2 versus work rate reflects
the exercise efficiency and limits of exercise tolerance of the subject; with the expected peak exercise performance
represented by the asterisk. Plots f) and h) indicate minute ventilation (V9E) versus carbon dioxide uptake
(V9CO2) and tidal volume (VT) versus V9E, respectively; these two plots describe the characteristics of the
ventilatory response during submaximal and peak exercise. Finally, plot g) presents characteristics of the
haemodynamic response to exercise with estimated peak heart rate represented by the asterisk and predicted
peak O2 pulse by the arrow. PET,O2: end-tidal pressure of oxygen; PET,CO2: end-tidal pressure of carbon dioxide;
RER: respiratory exchange ratio. Reproduced with permission from [113].
159
J. ROCA, R. RABINOVICH
efficiency and the limits of exercise tolerance of the subject. Figure 6f (ventilation versus
CO2 output) and figure 6h (tidal volume versus ventilation) characterise aspects of the
ventilatory response during submaximal and maximal exercise. However, some
investigators find the relationship between V9E and V9O2 during such tests to be
useful. Finally, figure 6g, which plots heart rate (and O2 pulse) versus O2 uptake, is
informative with respect to the characteristics of the haemodynamic response to exercise.
The next step is to choose adequate reference values to establish patterns of normal or
abnormal response. Available reference values and present limitations in this particular
issue are discussed below. Relatively few studies have evaluated the sensitivity, specificity
and predictive value of patterns of measurements in distinguishing among different
clinical entities. Even more importantly, the precise role of clusters of variables
commonly used in the decision making process in well identified diseases (i.e. evaluation
of ILD, pre-operative evaluation for resection lung cancer surgery, etc.) is insufficiently
known. For the future, studies addressing the use of likelihood ratios might be even more
useful to clinicians than sensitivity/specificity, since likelihood ratios refer to actual test
results before disease status is known. This shift to an evidence-based approach for
CPET interpretation will hopefully provide important answers to clinically relevant
questions that are not immediately available.
Selection of appropriate reference values is an important step to establish patterns of
normal or abnormal response to exercise stress. An initial analysis of available data on
healthy subjects [88, 89, 101–111] clearly indicated that only some of these studies [89,
103, 105–107] fulfil minimum requirements to be considered as candidates to be used in
the clinical setting. Blackie et al. [105] cover a limited age span (from 55–80 yrs) and
Bruce et al. [107] provide data obtained with treadmill in a population of rather
physically fit people. Hence, the analysis of potential studies in healthy sedentary people,
providing prediction equations for V9O2,peak obtained with cycling incremental exercise
testing, is then even more reduced to three sets [102, 106, 112]. Reference values estimated
by fairbarn et al. [106] are consistently higher than those provided by Jones et al. [102],
both in males and females. Predicted values by Wasserman et al. [89] and Hansen et al.
[112] are closer either to Jones et al. [102] or to Fairbarn et al. [106], depending upon the
values of height-weight of the subject in whom the equations are used. The characteristics
of the presently available prediction equations for peak O2 uptake (and peak work rate)
clearly impose limitations to the interpretative strategy. Moreover, except for HR in the
study of Fairbarn et al. [106] the profile of response in healthy sedentary subjects (i.e.
from submaximal to peak exercise results) are not available. Further, adequate
prediction equations for the most important variables obtained from the same group of
reference subjects are not currently available.
Summary
The role of the O2 transport/O2 utilisation system determining maximum O2 uptake
has been analysed in an integrative manner. The system responses to exercise in
healthy subjects (athletes and sedentary) and in common pulmonary diseases have
been examined. Finally, basic principles of exercise testing and interpretation of the
results have been reviewed.
Keywords: Aerobic capacity, cardiopulmonary exercise testing, endurance, lactic
threshold, oxygen uptake, work rate.
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References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
Ferrer M, Alonso A, Morera J, et al. Chronic obstructive pulmonary diseases stage and healthrelated quality of life. The quality of life of chronic obstructive pulmonary disease study group.
Ann Intern Med 1997; 127: 1072–1079.
Jones PW. Health status measurement in chronic obstructive pulmonary disease. Thorax 2001;
56: 880–887.
ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166: 111–
117.
Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E. Predictive factors of
hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 1999; 159: 158–164.
Garcia-Aymerich J, Farrero E, Felez MA, et al. Risk factors of readmission to hospital for a
COPD exacerbation: a prospective study. Thorax 2003; 58: 100–105.
Gerardi DA, Lovett L, Benoit-Connors ML, et al. Variables related to increased mortality
following out-patient pulmonary rehabilitation. Eur Respir J 1996; 9: 431–435.
Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and
exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004; 350: 1005–
1012.
Richardson RS, Noyszewski EA, Kendrick KF, Leigh JS, Wagner PD. Myoglobin O2
desaturation during exercise. Evidence of limited O2 transport. J Clin Invest 1995; 96: 1916–1926.
Roca J, Agustı́ AGN, Alonso A, Barberá JA, Rodriguez-Roisı́n R, Wagner PD. Effects of training
on muscle O2 transport at VO2max. J Appl Physiol 1992; 73: 1067–1076.
Cardus J, Marrades RM, Roca J, et al. Effects of FIO2 on leg VO2 during cycle ergometry in
sedentary subjects. Med Sci Sports Exerc 1998; 30: 697–703.
Sala E, Roca J, Marrades RM, et al. Effects of endurance training on skeletal muscle bioenergetics
in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159: 1726–1734.
Sala E, Noyszewski EA, Campistol JM, et al. Impaired muscle oxygen transfer in patients with
chronic renal failure. Am J Physiol Regul Integr Comp Physiol 2001; 280: R1240–R1248.
Weisman IM, Zeballos RJ. Cardiopulmonary exercise testing. Pulmonary Critical Care Update
Series 1995; 11: 1–9.
Sue DY. Exercise testing in the evaluation of impairment and disability. Clin Chest Med 1994;
15: 369–387.
Knight DR, Schaffartzik W, Poole DC, Hogan MC, Bebout DE, Wagner PD. Effects of hyperoxia
on maximal leg O2 supply and utilization in men. J Appl Physiol 1993; 75: 2586–2594.
Wasserman K, Hansen JE, Sue DY, Whipp BJ, Casaburi R. Principles of Exercise Testing and
Interpretation. 2nd Edn. Philadelphia, Lea & Febiger, 1994.
Agustı́ A, Cotes J, Wagner PD. Responses to exercise in lung diseases. In: Roca J, Whipp B, eds.
Clinical Exercise Testing. Eur Respir Mon 1997; 2 (no. 6): 32–50.
Gale GE, Torre-Bueno J, Moon RE, Salzman HA, Wagner PD. Ventilation-perfusion inequality
in normal humans during exercise. J Appl Physiol 1985; 58: 978–988.
Wagner PD, Gale GE, Moon RE, Torre-Bueno JE, Stolp BW, Saltzman HA. Pulmonary gas
exchange in humans exercising at sea level and simulated altitude. J Appl Physiol 1986; 61: 260–270.
Hammond MD, Gale GE, Kapitan KS, Ries A, Wagner PD. Pulmonary gas exchange in humans
during exercise at sea level. J Appl Physiol 1986; 60: 1590–1598.
Dempsey JA, Hanson PG, Henderson KS. Exercise-induced arterial hypoxemia in healthy subjects
at sea level. J Physiol (London) 1984; 355: 161–175.
Wagner PD. Hypoxia: the Adaptions. Sutton JR, Coates G, Remmers JE, eds. Toronto, BC
Decker Inc., 1999, pp. 142–147.
Hammond MD, Gale GE, Kapitan KS, Ries A, Wagner PD. Pulmonary gas exchange in humans
during normobaric hypoxic exercise. J Appl Physiol 1985; 58: 978–988.
161
J. ROCA, R. RABINOVICH
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
Wagner PD, Sutton JR, Reeves JT, Cymerman A, Groves BM, Malconian MK. Operation Everest
II: pulmonary gas exchange during a simulated ascent of Mt Everest. J Appl Physiol 1987;
63: 2348–2359.
Gallagher CG. Exercise limitation and clinical exercise testing in chronic obstructive pulmonary
disease. Clin Chest Med 1994; 15: 305–326.
Casaburi R, Petty TL. Ventilatory control in lung disease. In: Barstow TJ, Casaburi R, eds.
Principles and Practice of Pulmonary Rehabilitation. Philadelphia, WB Saunders Company, 1993,
pp. 50–65.
Gowda KS, Zintel T, McParland C. Diagnostic value of maximal exercise tidal volume. Chest
1990; 98: 1351–1354.
Dantzker DR, D’Alonzo GE. The effect of exercise on pulmonary gas exchange in patients with
severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1986; 134: 1135–1139.
Agusti AGN, Barbera JA, Roca J, Rodriguez-Roisin R, Wagner PD, Agusti-Vidal A. Hypoxic
pulmonary vasoconstriction and gas exchange during exercise in chronic obstructive pulmonary
disease. Chest 1990; 97: 268–275.
Barberà JA, Roca J, Ramirez J, Wagner PD, Ussetti P, Rodriguez-Roisin R. Gas exchange during
exercise in mild chronic obstructive pulmonary disease. Am Rev Respir Dis 1991; 144: 520–525.
Marciniuk DD, Gallagher CG. Clinical exercise testing in interstitial lung disease. Clin Chest Med
1994; 15: 287–303.
Agusti AG-N, Roca J, Rodriguez-Roisin R, Gea J, Xaubet A, Wagner PD. Mechanisms of gas
exchange impairment in idiopathic pulmonary fibrosis. Am Rev Respir Dis 1991; 143: 219–225.
Cherniack RM, Colby TV, Flint A, et al. Correlation of structure and function in idiopathic
pulmonary fibrosis. Am J Respir Crit Care Med 1995; 151: 1180–1188.
Agustı́ C, Xaubet A, Agustı́ AG-N, Roca J, Ramirez J, Rodriguez-Roisin R. Clinical and
functional assessment of patients with idiopathic pulmonary fibrosis: results of a 3 years follow-up.
Eur Respir J 1994; 7: 643–650.
Harris-Eze AO, Sridhar G, Clemens RE, Zintel TA, Gallagher CG, Marciniuk DD. Role of
hypoxemia and pulmonary mechanics in exercise limitation in interstitial lung disease. Am J Respir
Crit Care Med 1996; 154: 994–1001.
Marciniuk DD, Sridhar G, Clements RE, Zintel TA, Gallagher CG. Lung volumes and expiratory
flow limitation during exercise in interstitial lung disease. J Appl Physiol 1994; 77: 963–973.
Marciniuk DD, Watts RE, Gallagher CG. Dead space loading and exercise limitation in patients
with interstitial lung disease. Chest 1994; 105: 183–189.
Harris-Eze AO, Sridhar G, Clemens RE, Gallagher CG, Marciniuk DD. Oxygen improves
maximal exercise performance in interstitial lung disease. Am J Respir Crit Care Med 1994;
150: 1616–1622.
Wagner PD. Ventilation-perfusion inequality and gas exchange during exercise in lung disease. In:
Dempsey JA, Reed CE, eds. Muscular Exercise and the Lung. Madison, The University of
Wisconsin Press, 1977, pp. 345–356.
Rowell LB. Human Cardiovascular Control. New York, Oxford University Press, 1993.
Harms CA, Babcock MA, McClaran SR, et al. Respiratory muscle work compromises leg blood
flow during maximal exercise. J Appl Physiol 1997; 82: 1573–1583.
Harms CA, Wetter TJ, McClaran SR, et al. Effects of respiratory muscle work on cardiac output
and its distribution during maximal exercise. J Appl Physiol 1998; 85: 609–618.
Onorati P, Rabinovich RA, Mancini M, et al. Effects of proportional assist ventilation (PAV) on
limb exercise in COPD. Am J Respir Crit Care Med 2000; 161: A228.
Light RW, Mintz HM, Linden GS, Brown SE. Hemodynamics of patients with severe chronic
obstructive pulmonary disease during progressive upright exercise. Am Rev Respir Dis 1984;
130: 391–395.
Montes de Oca M, Rassulo J, Celli BR. Respiratory muscle and cardiopulmonary function during
exercise in very severe COPD. Am J Respir Crit Care Med 1996; 154: 1284–1289.
Raffestin B, Escourrou P, Legrand A, Duroux P, Lockhart A. Circulatory transport of oxygen in
162
CLINICAL EXERCISE TESTING
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
patients with chronic airflow obstruction exercising maximally. Am Rev Respir Dis 1982; 125: 426–
431.
D’Alonzo GE, Gianotti LA, Pohil RL. Comparison of progressive exercise performance of normal
subjects and patients with primary pulmonary hypertension. Chest 1987; 92: 57–62.
Mélot Ch, Naeije R, Mols P, Vandenbossche J-L, Denolin H. Effects of nifedipine on ventilation/
perfusion matching in primary pulmonary hypertension. Chest 1983; 83: 203–207.
Rubin LJ, Peter RH. Oral hydralazine therapy for primary pulmonary hypertension. N Engl J
Med 1980; 302: 69–73.
Saltin B, Gollnick PD. Skeletal muscle adaptability: significance for metabolism and performance.
In: Peachey L, ed. Handbook of Physiology, Section 10, Skeletal Muscle. Baltimore, Waberly Press
Inc., 1983, p. 555.
Maltais F, Jobin J, Sullivan MJ, et al. Lower limb metabolic and hemodynamic responses during
exercise in normal subjects and in COPD. J Appl Physiol 1998; 84: 1573–1580.
Richardson RS, Leek BT, Gavin TP, et al. Reduced mechanical efficiency in chronic obstructive
pulmonary disease but normal peak VO2 with small muscle mass exercise. Am J Respir Crit Care
Med 2004; 169: 89–96.
Jobin J, Maltais F, Doyon JF, Leblanc P, Simard PM, Simard AA. Chronic obstructive
pulmonary disease: capillarity and fiber characteristics of skeletal muscle. J Cardiopulm Rehabil
1998; 18: 432–437.
Maltais F, Simard AA, Simard C, Jobin J, Desgagnes P, Leblanc P. Oxidative capacity of the
skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with
COPD. Am J Respir Crit Care Med 1996; 153: 288–293.
Maltais F, Leblanc P, Simard C, et al. Skeletal muscle adaptation to endurance training in
patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 154: 442–
447.
Maltais F, Jobin J, Sullivan MJ, et al. Lower limb metabolic and hemodynamic responses during
exercise in normal subjects and in COPD. J Appl Physiol 1998; 84: 1573–1580.
Payen JF, Wuyam B, Levy P, et al. Muscular metabolism during oxygen supplementation in
patients with chronic hypoxemia. Am Rev Respir Dis 1993; 147: 592–598.
Mannix ET, Boska MD, Galassetti P, Burton G, Manfredi F, Farber MO. Modulation of ATP
production by oxygen in obstructive lung disease as assessed by 31P-MRS. J Appl Physiol 1995;
78: 2218–2227.
Hare JM. Nitric Oxide and excitation-contraction coupling. J Mol Cell Cardiol 2003; 35: 719–729.
Singel DJ, Stamler JS. Blood traffic control. Red blood cell vasodilation: nitric oxide and
haemoglobin help to match blood flow to metabolic demand. Nature 2004; 430: 297.
Hare JM. Nitroso-redox balance in the cardiovascular system. N Engl J Med 2004; 351: 2112–
2114.
Rabinovich RA, Ardite E, Troosters T, et al. Reduced muscle redox capacity after endurance
training in COPD patients. Am J Respir Crit Care Med 2001; 164: 1114–1118.
Wagner PD, Hoppeler H, Saltin B. Determinants of maximal oxygen uptake. In: Crystal RG,
West JB, eds. The Lung: Scientific Foundations. New York, Raven Press, 1997, pp. 2033–2041.
McCully K, Vanderborne K, Posner JD, Leigh JS. Muscle metabolism in track athletes, using 31P
magnetic resonance spectroscopy. Can J Physiol Pharmacol 1992; 70: 1353–1359.
Haseler LJ, Richardson RS, Videen JS, Hogan MC. Phosphocreatine hydrolysis during
submaximal exercise: the effect of FIO2. J Appl Physiol 1998; 85: 1463.
Wahren J, Felig P, Havel RJ, Jorfeldt L, Pernow B, Saltin B. Amino acid metabolism in McArdle’s
syndrome. N Engl J Med 1973; 288: 774–777.
Older P, Hall A. The role of cardiopulmonary exercise testing for preoperative evaluation of the
elderly. In: Exercise gas exchange in heart disease. Wasserman K, ed. Armonk: Futura Publishing
Company, New York, 1996, pp. 287–297.
Shoemaker WC, Appel PL, Kram HB. Role of oxygen debt in the development of organ failure
sepsis, and death in high-risk surgical patients. Chest 1992; 102: 208–215.
163
J. ROCA, R. RABINOVICH
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
Marshall MC, Olsen GN. The physiologic evaluation of the lung resection candidate. Clin Chest
Med 1993; 14: 305–320.
Ferguson MK, Little L, Rizzo L, et al. Diffusing capacity predicts morbidity and mortality after
pulmonary resection. J Thorac Cardiovasc Surg 1988; 96: 894–900.
Kearney DJ, Lee TH, Reilly JJ, DeCamp MM, Sugarbaker DJ. Assessment of operative risk
in patients undergoing lung resection: importance of predicted pulmonary function. Chest 1994;
105: 753–759.
Markos J, Mullan BP, Hillman DR. Preoperative assessment as a predictor of mortality and
morbidity after lung resection. Am Rev Respir Dis 1989; 139: 902–910.
Olsen GN. The evolving role of exercise testing prior to lung resection. Chest 1989; 95: 218–225.
Boysen PS. Perioperative management of the thoracotomy patient. Clin Chest Med 1993; 14: 321–
333.
Bolliger CT, Wyser C, Roser H, Solèr M, Perruchoud AP. Lung scanning and exercise testing for
the prediction of postoperative performance in lung resection candidates at increased risk for
complications. Chest 1995; 108: 341–348.
American Thoracic Society: ATS Statement. Standards for the diagnosis and care of patients with
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152: 77–120.
Weisman IM, Zeballos RJ. Cardiopulmonary exercise testing. Pulmonary Critical Care Update
series 1995; 11: 1–9.
Oren A, Sue DY, Hansen JE, Torrance DJ, Wasserman K. The role of exercise testing in
impairment evaluation. Am Rev Respir Dis 1987; 135: 230–235.
Cotes JE, Zejda J, King B. Lung function impairment as a guide to exercise limitation in workrelated lung disorders. Am Rev Respir Dis 1988; 137: 1089–1093.
ATS Statement. Evaluation of impairment/disability secondary to respiratory disorders. Am Rev
Respir Dis 1986; 133: 1205–1209.
Zeballos RJ, Weisman IM. Behind the scenes of cardiopulmonary exercise testing. Clin Chest Med
1994; 15: 193–213.
Hansen JE. Participant responses to blood gas proficiency testing reports. Chest 1992; 101: 1240–
1244.
Clark JS, Votteri B, Arriagno RL, et al. Noninvasive assessment of blood gases. Am Rev Respir Dis
1992; 145: 220–232.
Hughes JMB. Blood gas estimations from arterialized capillary blood versus arterial puncture: are
they different? Eur Respir J 1996; 9: 184–185.
Sauty A, Uldry C, Debétaz L, Leuenberger P, Fitting J. Differences in PO2 and PO2 between
arterial and arterialized earlobe samples. Eur Respir J 1996; 9: 186–189.
Balke B, Ware RW. An experimental study of ’physical fitness’ of Air Force personnel. US Armed
Forces Med J 1959; 10: 675–678.
Make BJ. Pulmonary rehabilitation: myth or reality. Clin Chest Med 1986; 7: 519–540.
Weisman IM, Zeballos RJ. An integrated approach to the interpretation of CPET. In: Weisman IM,
Zeballos RJ, eds. Clinical Exercise Testing; Clinics in Chest Medicine. Philadelphia, WB Saunders,
1994, pp. 421–445.
Wasserman K, Hansen JE, Sue DY, Whipp BJ, Casaburi R. Principles of exercise testing and
interpretation. Philadelphia, Lea & Febiger, 1994.
Jones NL. Clinical Exercise Testing. Philadelphia, W.B. Saunders, 1980.
Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of sixminute walk test in patients with primary pulmonary hypertension. Comparison with
cardiopulmonary exercise testing. Am J Respir Crit Care Med 2000; 161: 487–492.
Willenheimer R, Erhardt LR. Value of 6-min-walk test for assessment of severity and prognosis of
heart failure. Lancet 2000; 355: 515–516.
Blosser SA, Maxwell SL, Reeves-Hoche MK, Localio AR, Zwillich CW. Is an anticholinergic
agent superior to a b2-agonist in improving dyspnea and exercise limitation in COPD? Chest 1995;
108: 730–735.
164
CLINICAL EXERCISE TESTING
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
Wilkens H, Demertzis S, Konig J, Leitnaker CK, Schafers HJ, Sybrecht GW. Lung volume reduction surgery versus conservative treatment in severe emphysema. Eur Respir J 2000; 16: 1043–1049.
Troosters T, Gosselink R, Decramer M. Short- and long-term effects of outpatient rehabilitation in patients with chronic obstructive pulmonary disease: a randomized trial. Am J Med 2000;
109: 207–212.
Lacasse Y, Wong E, Guyatt GH, King D, Cook DJ, Goldstein RS. Meta-analysis of respiratory
rehabilitation in chronic obstructive pulmonary disease. Lancet 1996; 348: 1115–1119.
Casas A, Vilaro J, Rabinovich R, et al. Encouraged six minute walking test reflects critical power
in copd patients. Chest 2005 (In press).
O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol on the ventilatory
response to exercise in chronic obstructive pulmonary disease. Eur Respir J 2004; 24: 86–94.
Anderson SD, Brannan JD. Methods for "indirect" challenge tests including exercise, eucapnic
voluntary hyperpnea, and hypertonic aerosols. Clin Rev Allergy Immunol 2003; 24: 27–54.
Fletcher GF, Froelicher VF, Hartley LH, Haskell WL, Pollack ML. Exercise standards. A
statement for health professionals from the American Heart Association. Circulation 1990;
82: 2286–2322.
Astrand PO, Rodahl K. Textbook of Work Physiology. New York, McGraw-Hill, 1986.
Jones NL, Makrides L, Hitchcock C, Chypchar T, McCartney N. Normal standards for an
incremental progressive cycle ergometer test. Am Rev Respir Dis 1985; 131: 700–708.
Jones NL, Summers E, Killian KJ. Influence of age and stature on exercise capacity during
incremental cycle ergometry in men and women. Am Rev Respir Dis 1989; 140: 1373–1380.
Blackie SP, Fairbarn MS, McElvaney NG, Wilcox PG, Morrison NJ, Pardy RL. Normal values
and ranges for ventilation and breathing pattern at maximal exercise. Chest 1991; 100: 136–142.
Blackie SP, Fairbarn MS, McElvaney NG, Morrison NJ, Wilcox PG, Pardy RL. Prediction of
maximal oxygen update and power during cycle ergometry in subjects older than 55 years of age.
Am Rev Respir Dis 1989; 139: 1424–1429.
Fairbarn MS, Blackie SP, McElvaney NG, Wiggs BR, Paré PD, Pardy RL. Prediction of heart
rate and oxygen uptake during incremental and maximal exercise in healthy adults. Chest 1994;
105: 1365–1369.
Bruce RA, Kusumi MS, Hosmer D. Maximal oxygen intake and nomographic assessment of
functional aerobic impairment in cardiovascular disease. Am Heart J 1973; 85: 546–562.
Vogel JA, Patton JF, Mello RP, Daniels WL. An analysis of aerobic capacity in a large United
States population. J Appl Physiol 1986; 60: 494–500.
Pollock ML, Bohannon RL, Cooper KHE. A comparative analysis of four protocols for maximal
treadmill stress testing. Am Heart J 1976; 92: 39–46.
Shephard RJ, Allen C, Benade AJ. The maximal oxygen intake - an international reference
standard of cardiorespiratory fitness. Bull World Health Organization 1968; 38: 757–764.
Taylor HL, Buskirk E, Henschel A. Maximal oxygen intake as an objective measure of cardiorespiratory performance. J Appl Physiol 1955; 8: 73–80.
Hansen JE, Sue DY, Wasserman K. Predicted values for clinical exercise testing. Am Rev Respir
Dis 1984; 129: S49–S50.
Roca J, Whipp BJ, eds. Clinical Exercise Testing. Eur Respir Mon 1997; 2 (no. 6).
165