European Respiratory Society (ERS) Task Force Report
Recommendations on the Use of Exercise Testing in Clinical Practice
Members of the Task Force: Paolo Palange, Susan A. Ward (Chairmen); Kai-Hakon
Carlsen, Richard Casaburi, Charles G. Gallagher, Rik Gosselink, Luis Puente-Maestu,
Denis E. O’Donnell, Annemie M. Schols, Sally Singh, Brian J. Whipp.
ON-LINE SUPPLEMENT
NORMAL RESPONSE PROFILES IN CPET
This section addresses key CPET-derived response profiles characteristic of
“normal” healthy subjects, and their functional basis, whose value in diagnosis,
prognosis and/or the assessment of interventions is identified in the subsequent sections.
For simplicity, we use cycle ergometry as our frame of reference.
1
INCREMENTAL EXERCISE TESTS
Cycle ergometers and motorized treadmills are widely used for CPET. The
former is often preferred, however, because of: its lower cost, smaller space
requirements, being less prone to movement artifacts and, perhaps most crucially,
providing more accurate quantification of work rate (WR) [e.g. 1, 2, 3].
Electromagnetically-braked models are more flexible, as WR imposed by the cycle itself
can be independent of pedaling frequency over quite a wide range. It is conventional
practice to select the WR incrementation rate (ΔWR/Δt) so that the tolerable limit (tLIM)
2
is reached within ~10 (8-12) min [4]. This period provides sufficient data density to
allow discrimination of pertinent response profiles and parameters (e.g. lactate
threshold: see 1.3), while constraining the test duration so as to promote subject
compliance. For a young adult of average “aerobic” fitness, a ΔWR/Δt of 15-20
Watts/min is often used; for a patient with cardiac or pulmonary disease, this may be 5
Watts/min or less, depending on the severity of the disease [e.g. 1, 2, 3].
In young children, however, use of the rapid-incremental test format is less
widespread than in adults, and doubt has been expressed as to how to optimally measure
exercise tolerance (i.e. as V’O2 peak) [5]. Cooper has reported that short bouts of highintensity exercise may represent a more natural way of studying children, rather than
repeated stepwise exercise testing [5]. Also, special consideration needs to be given to
factors such as age, gender, growth and physical performance. It has been maintained
that, in children, it is preferable to employ running rather than cycling as the test
modality, partly because of cycle mechanics, but also because (as in adults) the use of
muscle groups will differ between running and cycling [6]. As a slow increase of speed
and inclination for incremental treadmill tests may bore children, Cooper has therefore
suggested that more-rapid protocols might be preferable [5].
1.1
V’O2 peak
V’O2 peak is simply the highest V’O2 value achieved on the incremental, or
other high-intensity, test designed to bring the subject to the limit of tolerance. With
good subject effort, i.e. when the subject exercises to the limit of tolerance, V’O2 peak
is closely reflective of the subject’s "maximum" V’O2 (V’O2 max) – considered to be
the “gold-standard” index of exercise tolerance (or intolerance). But whether or not the
V’O2 peak actually corresponds to the V’O2 max depends on whether V’O2 can be
3
demonstrated not to continue to increase with further increases in WR (i.e. the V’O2
“plateau” criterion) [7]; if it cannot, the value should be reported as V’O2 peak. The
index is taken to reflect the attainment of a limitation at some point(s) in the O2
conductance pathway from the lungs to the site of the mitochondrial O2 consumption at
the cytochrome-oxidase terminus of the electron transport chain; i.e. via the convective
flows of O2 into the lungs and through the vasculature, and the diffusive O2 flows across
the pulmonary and muscle capillary beds [e.g. 8, 9]. However, in some diseases,
premature termination of a test can arise from perceptual influences, such as dyspnea,
angina or claudicating pain.
Consideration of the normalcy (or otherwise) of V’O2 peak should certainly take
account of age, gender, height and body mass [10-14]. It is usual practice to normalize
values for body mass (as ml/min/kg). A strong case can be made for normalizing to
whole-body or leg fat-free mass [15-19] in conditions such as obesity or those associated
with muscle wasting (e.g. COPD or the frail elderly) - or, failing that, scaling to the
subject’s height rather than weight [3, 12, 14, 15]. The normal value in young healthy
adults is commonly in the region of 35-40 ml/min/kg but can be considerably lower in
chronically sedentary subjects [e.g. 3] and in excess of 80 ml/min/kg in young elite
endurance athletes [e.g. 16]. Also, as the mass-specific V’O2 max is higher in small than
in large subjects, it has been suggested that it is more appropriate for V’O2 max to be
scaled to mass0.67 [16] or even to separate mass and height exponents [20]. Although
these practices are currently not in widespread use, at least in adult populations, it is
recommended that their use in CPET be evaluated.
With regard to patient populations, V’O2 peak values of less than about 14
ml/min/kg suggest a very poor prognosis for patients with chronic heart failure (CHF)
[21, 22]. However, it should be borne in mind that chronic inactivity, consequent to the
4
symptomology of the disease process(es), is likely also to be contributory. Furthermore,
a “normal” V’O2 peak can, in some instances, be compatible with disease-related
abnormality, if the pre-existing value were to have been extremely high; e.g. as could
occur in a highly-trained endurance athlete who develops incipient heart disease.
Reference values for V’O2 peak in children that include considerations of age
and gender have been developed for incremental cycle ergometry [23, 24]. Interestingly,
these values do not differ significantly from those produced by Åstrand using a different
exercise protocol [25]. Also, Krahenbuhl et al have produced predictive equations for
age-dependent V’O2 peak in healthy sedentary children [26], based on a meta-analysis
of 66 studies on aerobic capacity that included 5793 boys and 3508 girls.
1.2
V’O2 -WR slope
Apart from a short initial lag-phase, imposed by the V’O2 response “kinetics”
(i.e. an index of the speed with which a new steady state is reached), V’O2 typically
increases linearly with time and therefore WR throughout the incremental test [27, 28].
Because of these kinetics, the V’O2 response at any particular WR during the
incremental test will be lower than the steady-state V’O2 value at that same WR (Fig 1)
[29]. Put another way, at a given V’O2 (including the peak value) WR will be higher on
the incremental test than for the steady-state requirement. This becomes functionally
important when interpreting peak WR, as shown (Fig 1). Thus, it is not advisable to use
peak WR as a reliable surrogate for V’O2 peak, especially in an interventional context
where one might expect V’O2 kinetics to be speeded and V’O2 peak increased.
INSERT FIGURE 1
5
In normal subjects, the slope of the linear phase of the V’O2-WR relationship
(ΔV’O2/ΔWR) is the same as that determined from a series of discrete sub-L constantload (or constant-WR) steady-state tests, i.e. ~9-12 ml/min/Watt for cycle ergometry
[13, 30-34] (Fig 2, panel 1). It may therefore be used to provide an approximate index
of work efficiency if the substrate mixture being oxidized is assumed [27] (see 1.1).
Accordingly, ΔV’O2/ΔWR is relatively independent of age, gender, fitness and body
mass. The lack of influence of body mass on this slope in obese subjects and athletes
with high lower-limb muscularity is only the case if pedaling frequency constrained to
be relatively constant, therefore not influencing the O2 cost of moving the legs per se.
However, the position of the V’O2-WR relationship will be displaced upwards in
proportion to mass, as the O2 cost of “unloaded” cycling (V’O2(0)) is mass-dependent:
V’O2(0) (ml/min) = 5.8 body mass (kg) + 151 [12, 30]. In some disease conditions,
ΔV’O2/ΔWR may be abnormally low (e.g. ~8 ml/min/Watt or less), either over the entire
tolerable
range
(e.g.
peripheral
vascular
occlusive
disease;
hypertrophic
cardiomyopathy) or as the tolerable limit is approached (e.g. ischemic heart disease) [e.g.
3, 31, 35]. In the latter case, caution is needed to ensure that estimates of ΔV’O2/ΔWR are
confined to regions of the V’O2-WR relationship which are appropriately linear, i.e. a
single value over the entire range will blur important features of the response.
1.3
Lactate threshold (L)
The lactate threshold is the highest WR (or, more properly, V’O2) at which
arterial [lactate] ([L-]a) is not systematically increased. It is thus an important functional
demarcator of exercise intensity: sub-L WRs can be designated “moderate”, as they can
normally be comfortably sustained for prolonged periods. Supra-L WRs, in contrast,
may be termed “heavy” or “very heavy” as they lead to more-rapid fatigue, with [L-]a
6
(and [H+]a) being increased in both cases but only increasing inexorably throughout the
exercise in the latter (see 2). While controversy still surrounds the precise mechanisms
underlying L, the available evidence demonstrates that the [L-]a increase during
exercise is O2-dependent, e.g. being reduced with experimentally-induced hypoxic or
anemic hypoxia at a particular level of V’O2, and increased with hyperoxia [reviewed in
1, 3, 29, 36].
As for V’O2 peak, L is dependent on age, gender, body mass and fitness [e.g. 3].
It is also common practice to normalize L values for body mass (e.g. ml/min/kg), and
(as for V’O2 peak) a case can be made for normalizing to fat-free mass. Normal values for
L in young healthy adults lie in the region of 15-25 ml/min/kg, and may be 50
ml/min/kg or more in elite endurance athletes; values below 11 ml/min/kg suggest a
poor prognosis in patient with CHF [21]. While, on average, L occurs at ~ 50% of
V’O2 peak in normal subjects, the range is very large, i.e. extending from ~ 40 to 80%
[12, 37].
Rigorous non-invasive estimation of L requires the demonstration of an
augmented V’CO2 in excess of that produced by aerobic metabolism, reflecting
additional non-metabolic CO2 released from bicarbonate (HCO3-) buffering of protons
(H+) associated with L- accumulation - but which is not attributable to hyperventilation
[38-42]. The V’CO2-V’O2 relationship below L is often well characterized by a linear
function (except in the very initial stages of the incremental phase, where there is a
period of transient CO2 accumulation in the rapidly-exchanging body CO2 stores), with
a slope (S1) normally below but close to 1 (Fig 2, panel 2), and the respiratory
exchange ratio (RER) increasing modestly (Fig 2, panel 8). Above L, the V’CO2-V’O2
relationship steepens (RER increasing at a greater rate (Fig 2, panel 8)), and is often
essentially linear over about half the WR range between L and V’O2 peak (with a slope
7
S2) to the point at which “respiratory compensation” for the metabolic acidemia
(respiratory compensation point, RCP) becomes evident. At higher WRs, the slope
increases further, reflecting the influence of compensatory hyperventilation on CO2
clearance. The point of [L-]a increase has been demonstrated to coincide with the point
at which the extrapolated S1 and S2 components intersect (i.e. the “V-slope” criterion)
[39] (Fig 2, panel 2). For those instances when the V’CO2-V’O2 relationship cannot
reliably be partitioned into two clearly linear segments, the point at which a unit tangent
(i.e. ΔV’CO2/ΔV’O2 = 1) impacts on the curve may be used as an alternative [43].
INSERT FIGURE 2
The second criterion for L discrimination derives from the recognition that V’E
during moderate exercise responds to clear the CO2 load presented to the lungs rather
than to the requirement for pulmonary O2 exchange [reviewed in 44, 45]. Arterial PCO2
(PaCO2) is therefore regulated close to control levels, with any consequent changes in
arterial PO2 (PaO2) traversing the relatively flat upper reaches of the oxy-hemoglobin
dissociation curve [reviewed in 46]. As is the case for V’CO2, V’E at L therefore also
starts to increase at a greater rate - while maintaining its proportionality to V’CO2, such
that the V’E-V’CO2 relationship retains its sub-L slope [3, 30, 47] (Fig 2, panel 3). As
a result, alveolar (i.e. end-tidal) PCO2 (PETCO2) and PaCO2 do not fall and the
ventilatory equivalent for CO2 (V’E/V’CO2) does not increase over this region (Fig 2,
panels 4 and 6). In contrast, as V’E is now of necessity increasing at a greater rate than
V’O2, the ventilatory equivalent for O2 (V’E/V’O2)) and end-tidal PO2 (PETO2) both start
to increase (Fig 2, panels 4 and 6). That is, as long as V’E is not constrained from
increasing as a result of respiratory-mechanical dysfunction, there will be the onset of
8
hyperventilation relative to O2 at L, but not to CO2 - despite a falling arterial pH (pHa).
It is only above the RCP that hyperventilation relative to CO2 also develops, with
V’E/V’CO2 starting to increase and PETCO2 to fall. The reasons for this apparently
sluggish recruitment of respiratory compensation the rapid-incremental test remain to be
elucidated [reviewed in 44, 45].
1.4
Oxygen pulse-V’O2 relationship
HR normally increases reasonably linearly with respect to V’O2 (Fig 2, panel 5)
with a slope that is an inverse function of fitness, to attain values at peak exercise
(HRmax) which are close to the predicted HRmax (HRmaxpred) [e.g. 9, 16]. Thus, the
HR reserve (HRR, = HRmaxpred - HRmax) is essentially zero. A demonstrable HRR in
normal subjects is often taken as a marker of poor effort on the test - although the large
standard deviation on the maximum HR (approx 10 min-1) makes this a “soft” criterion
value. Furthermore, in elderly hypertensive subjects, for example, this can also be
reflective of the influence of beta-adrenergic blockade therapy.
A plot of V’O2 as function of HR yields a linear V’O2-HR relationship with a
negative intercept on the V’O2 axis (Fig 3, right). Consequently, the O2-pulse rises
hyperbolically as WR increases (Fig 2, panel 5; Fig 3, right) [29].
INSERT FIGURE 3
The O2-pulse has important interpretational value, as it is defined as the product
of the stroke volume and the arterio-venous O2 content difference (CaO2 - C v O2) derived from the well-known “Fick Equation” i.e. as
V’O2 = Q’ (CaO2 - C v O2) = HR  SV  (CaO2 - C v O2)
(1)
9
then,
V’O2/HR = SV (CaO2 - C v O2) = O2-pulse
(2)
However, it is important to not to be too-readily tempted to interpret the O2-pulse
profile as a function of either one of these variables in isolation. Only if it is possible to
make a reasonable assumption regarding the change (or not) in one of the defining
variables, may one interpret the non-invasive O2-pulse profile to reflect that of the
alternative variable. This is difficult to determine directly and requires an invasive
procedure.
If the O2-pulse fails to increase with increasing WR as peak exercise is
approached, then the product of SV and the arterio-venous O2 content difference has to
be constant. This may be because each is constant, or because one is increasing while
the other decreases. Apparent flatness in the O2-pulse profile should be considered with
care, however. That is, normal subjects who are simply unfit have a shallower V’O2-HR
relationship, and hence the curvature of the O2-pulse profile will also be shallow appearing to be flat when, in fact, it may not be [e.g. 3, 30] (Fig 4). For the O2-pulse
profile to be truly flat, there must be a change in the local V’O2-HR slope as a result of
HR accelerating relative to V’O2, such that over this region the V’O2-HR slope
extrapolates back to the origin of the plot (Fig 4, left). When this does occur, the
continued increase in V’O2 is HR-dependent [e.g. 3].
INSERT FIGURE 4
1.5
V’E-V’CO2 slope and V’E/V’CO2
There are two ineluctable considerations of the relationship between V’E and
V’CO2 during muscular exercise: (a) that ventilation is a control variable with respect to
10
the regulation of PaCO2 and pHa, and (b) that the ventilatory response during exercise is
demonstrably a highly linear function of V’CO2 over a wide range of metabolic rate
[reviewed in 44, 45, 48] (Fig 2, panel 3), with a slope (m, = ΔV’E/ΔV’CO2) in healthy
young adults of ~25 (when V’E and V’CO2 are reported in l/min) [34, 49, 50] and a
small positive V’E intercept (c) of ~3-5 l/min [49] (Fig 3, left), i.e.:
V’E = m  V’CO2 + c
(3)
The slope estimation must, of course, be confined to that region of the V’E-V’CO2
relationship which is discernibly linear, i.e. not including the often curvilinear region
above the RCP within which PaCO2 is reduced to provide respiratory compensation for
the metabolic acidosis. However, in disease states characterized by disturbances in
PaCO2 regulation and/or pulmonary gas exchange function, linearity below RCP should
not be assumed a priori.
It is important to recognize, therefore, that the V’E-V’CO2 slope alone is not the
decisive variable with respect to PaCO2 and pH regulation, as apparent from the mass
balance equation:
V’E = (863  V’CO2)/PaCO2 (1-VD/VT)
(4)
where 863 is the constant which corrects for the different conditions of reporting the
ventilatory volumes (BTPS, saturated, at a body temperature of 37oC) and the metabolic
rate under “standard”, dry conditions (STPD) and also the transformation of the fractional
concentration of CO2 to its partial pressure; and VD/VT is the physiologic dead space/tidal
volume ratio Hence,
V’E/V’CO2 = 863/PaCO2 (1-VD/VT)
(5)
or, alternatively
PaCO2 = 863/(V’E/V’CO2) · (1-VD/VT)
(6)
11
Consequently, as shown in equations 6 & 7, it is the ventilatory equivalent for
CO2 that is the crucial CO2-linked variable with respect to PaCO2 and pH regulation.
Note that the V’E-V’CO2 slope (m) differs from the actual value for V’E/V’CO2 during
exercise by the influence of the V’E intercept (c), which is rarely considered in this
context; i.e.
V’E/V’CO2 = m + c/ V’CO2
(7)
The ventilatory equivalent therefore declines hyperbolically as V’CO2 increases
over this region (Fig 2, panel 4), projecting to an asymptote with the value (i.e. at high
levels of V’CO2) equal to the slope of the linear V’E-V’CO2 relationship (i.e. m) [51]
(Fig 3, left). V’E-V’CO2 typically does not attain the asymptotic level as WR increases
owing to a hyperventilatory influence of the lactic acidosis and/or developing
hypoxemia (or even the apparent increase in VD/VT associated with a right-to-left
shunt). Consequently, while there is relatively little difference between the minimum
value of V’E/V’CO2 (V’E/V’CO2 min) during the test and the slope m in relatively fit
subjects with a high L and RCP (the term c/V’CO2 becomes disappearingly small (eq.
7)), the difference can be more marked in sedentary subjects in whom L and RCP occur
at a relatively low levels of V’CO2. This should be borne in mind when interpreting
V’E/V’CO2 at specific points on the incremental test. The V’E/V’CO2 at L
(V’E/V’CO2@L) and V’E/V’CO2min have both been proposed to provide non-invasive
indices of ventilatory inefficiency [48, 52].
The decrease in V’E/V’CO2 over the moderate WR range (Fig 2, panel 4; Fig 3,
left) - over which PaCO2 is normally regulated at or close to resting levels - therefore
reflects the operation of an exquisite control system that provides the appropriate level
of ventilation for the CO2 exchange rate even as the functional efficiency of the lung
improves, in this regard, as reflected by the declining VD/VT (Fig 5). Furthermore, as
12
the VD/VT declines to, or close to, a constant value at high WRs [48, 53-56], the
subsequent increase in V’E/V’CO2 (Fig 3, left) reflects the provision of respiratory
compensation for the metabolic acidosis, i.e. PETCO2 and, more importantly, mean
alveolar (P A CO2) (an estimator of PaCO2 in normal subjects [57-58]) fall (Fig 5).
INSERT FIGURE 5
In hyperventilatory conditions (e.g. metabolic acidaemia, arterial hypoxemia),
both ΔV’E/ΔV’CO2 (i.e. the slope m) and V’E/V’CO2 are increased, reflecting the
greater V’E requirement for PaCO2 regulation; and less in hypoventilatory conditions
(e.g. with blunted chemosensitivity). In a similar sense, both ΔV’E/ΔV’CO2 and
V’E/V’CO2 are increased when VD/VT is high (e.g. in the elderly and in COPD).
Recognizing the exercise-related complexities of PaCO2 and VD/VT response in many
cardiopulmonary diseases, interpretation of these CO2 linked ventilatory relationships
should be undertaken with caution. Certainly, unless constancy of PaCO2 can be
confidently assumed (or, better still, demonstrated), their interpretation solely in terms
of ventilatory efficiency is not warranted.
1.6
Breathing reserve
Breathing reserve (BR) provides an index of the proximity of the actual level of
exercise ventilation at the limit of tolerance (V’E max) to the maximal level achievable,
characterized as the subject’s maximum voluntary ventilation (MVV), usually at rest
(MVV is either measured directly or estimated from the subject’s forced expiratory
volume in one second (FEV1), although it should be recognized that the conditions
under which these two indices are not strictly comparable). BR can be defined either in
13
relative terms as V’E max as a percentage of MVV (i.e. V’E max  100/MVV) or in
absolute terms as the difference between the MVV and the V’E max (MVV - V’E max)
[e.g. 1, 3] (again, it should be noted that MVV and V’E max are measured under quite
different conditions: see Ref. 59 for discussion). As V’E max in normal subjects is
higher with greater levels of fitness (i.e. V’O2 peak) and MVV is, to a large extent,
independent of fitness, BR will be correspondingly reduced.
However, a subject’s BR is not a single constant value but is dependent on the
actual exercise protocol used. That is, the value that V’E attains values at the end of an
incremental (or constant-load) test will depend not only on metabolic rate, PaCO2 and
VD/VT, but also the rate at which CO2 is being evolved from body stores through
buffering of metabolic acid - this is a function of the rate at which the [HCO3-]
decreases and not the amount by which it has decreased [41]. As rapid work rate
incrementation rates yield commensurately-rapid rates of [HCO3-] decrease, maximum
V’E will therefore be higher than with tests employing slower work rate increases [41] with a consequently-lower breathing reserve. A BR which is “minimal”, zero or negative
is suggestive of a “ventilatory limitation” to exercise tolerance; a negative BR can occur as
a result of exercise-induced bronchodilatation associated with increased catecholamine
production in a subject with some ongoing bronchoconstriction (i.e. the resting MVV is
now not appropriate as the frame of reference).
Some elite young endurance athletes and “athletic” elderly subjects can also
demonstrate a low or absent of BR at end-exercise, in this case reflecting an
inadequately-high MVV for the ventilatory demands of the extreme metabolic rates that
can be achieved.
14
1.7 End-expiratory lung volume
The end-expiratory lung volume (EELV) plays an important role in the
ventilatory response to exercise - especially its pattern of response. In normal subjects,
EELV typically decreases with increasing WR by as much as 0.5-1.0 l below functional
residual capacity (FRC) [e.g. 59-61]. This not only improves the mechanical advantage
of the inspiratory muscles, but the consequently-increased inspiratory capacity (IC)
provides a greater scope for the tidal volume (VT) to operate on the relatively linear
component of the thoracic volume-pressure (i.e. compliance) curve; this maintains a low
elastic work of breathing [e.g. 59-61]. Normally, therefore, VT makes the predominant
contribution to the V’E response, except at very high WRs where further increases in
V’E rely largely on breathing frequency (Fig 2, panel 7).
In contrast, in conditions such as COPD, the increased regional mechanical time
constants of, especially, the lung (i.e. increased airflow resistance and compliance (low
lung recoil)) predispose both to expiratory airflow limitation and an increase in EELV
during exercise (i.e. impairing the spontaneous emptying rate often to an extent that
FRC is not re-attained by the time for the next inhalation). The increase in EELV tends
to ameliorate the flow limitation as it allows the expiration to proceed at a higher
volume-specific limiting airflow. Thus, EELV increases throughout high-intensity
exercise in spite of expiratory muscle activity [e.g. 59, 60, 62-65] - attempts to increase
flow by further expiratory “effort” are typically counter-productive in patients with
COPD. As this “dynamic hyperinflation” progresses, with an associated reduction in IC,
not only are there increased demands on the inspiratory muscles but the scope for VT
increase is reduced, being constrained by end-inspiratory lung volume encroaching onto
the flatter upper reaches of the compliance curve. In elderly subjects (i.e. ostensibly
normal, but with the age-related reductions of lung recoil increasing the pulmonary-
15
mechanical time constant(s)), for example, EELV often declines over the moderate WR
range but subsequently tends to increase back towards, or often beyond, resting levels
[61, 66] as the pulmonary time constants become inadequate for the flow demands.
Direct measurement of EELV is not straightforward, especially during exercise.
However, an indirect approach pioneered by O’Donnell and colleagues that is becoming
widely used requires subjects to perform an IC maneuver at a selected point in the
exercise test [64, 65], since TLC remains essentially unaltered during exercise [67, 68].
It is more usual that serial IC measurements are taken during symptom-limited constantload tests, rather than in incremental tests; in the latter, the negative impact of the
maximal maneuver on subsequent data profiles is likely to outweigh the advantages of
tracking EELV.
Exercise inspiratory capacity [64, 69] and graphical analysis of tidal breathing
exercise in comparison with maximal resting flow-volume loops [e.g. 59-61, 69, 70]
may be better indices of ventilatory limitation than BR. Both IC and flow-volume loops
can be recorded with reasonable accuracy during exercise [69, 71, 72]. (Fig 6)
INSERT FIGURE 6
1.8
Arterial O2 saturation
Arterial O2 saturation is normally well maintained throughout the tolerable WR
range, in the region of ~97-98% for young adults but at progressively lower values with
increasing age (largely as a consequence of the lung-recoil related changes in regional
ventilation/perfusion (V’A-Q’) distribution) [e.g. 66]. However, it is not uncommon for:
(a) highly-fit endurance athletes, (b) the “athletic” elderly, and (c) women to exhibit
arterial desaturation and abnormal widening of the alveolar-arterial PO2 difference
16
(P(A-a)O2) as peak WRs are approached [e.g. 73-75]. This has been argued to reflect
pulmonary capillary transit-time limitations (determined by the capillary “capacitanceto-conductance” ratios) resulting from the recruited pulmonary-capillary volume
becoming inadequate for the high levels of pulmonary blood flow and, in addition, to
increasing regional V’A/Q’ dispersion [e.g. 73-75].
There is some debate about whether indirect measurements of SpO2 by pulse
oximetry have a sufficiently high level of accuracy and reliability. The 95% confidence
limits of pulse-oximetric values, relative to those directly measured, have been shown to
be ~4-5% [reviewed in 1].
2
CONSTANT-LOAD EXERCISE TESTS
The incremental-type exercise test should be considered an essential prelude to
any subsequent constant-load (or more properly, constant work rate) test that might be
used to better characterize exercise intolerance, improve prognostic power, and provide
more sensitive discrimination of interventions. This is because the investigator can then
select the appropriate intensity domain within which the constant-load test is performed.
The use of constant-load tests is becoming more prominent in clinical exercise testing,
because of their relevance to characterizing: (a) the speed with which system responses
attain (or attempt to attain) a new steady state (response “kinetics”) and (b) exercise
endurance.
2.1
Response kinetics
The speed and manner in which V’O2, V’CO2, V’E respond to constant-load
exercise is highly intensity-dependent; i.e. being complicated by the sequelae of the
lactic acidosis for supra-L WRs. Below L, there is general agreement about the form of
17
these kinetics [e.g. 44, 45, 76]. There is an initial component (“phase 1”) of short duration
(i.e. 15-20 s, reflecting the muscle-to-lung vascular transit delay) and of modest absolute
amplitude; the response is usually quite abrupt from a resting baseline in the upright
position but is more sluggish when the test is conducted from a baseline of prior unloaded
(or light) exercise (Fig 7) - but, interestingly, it is also sluggish when initiated from rest in
the supine position. This early phase 1 response is followed by a more prominent “phase
2” component which has an exponential time course (Fig 7). Its rate of development can
therefore be described by a time constant (); this is quantified as the time taken to attain
63% of the steady-state response or, to a close approximation as 1.5 times the half-time of
the response [77, 78].
INSERT FIGURE 7
V’O2 is typically ~30-40 s in healthy young subjects. However, it can be as much
as 2-3 fold longer in elderly subjects, in subjects with cardiopulmonary or muscular
disease and others who are chronically sedentary [e.g. 3, 79]; in such subjects, this
“slowing” can be largely reversed by endurance training [79, 80]. These considerations
have an important impact on muscle energetics; i.e. whether the exercise can be sustained
solely through aerobic ATP resynthesis, or whether there is a requirement to supplement
this from anaerobic glycolytic sources (i.e. with its attendant lactic acidosis). This can be
quantitated in terms of the “oxygen deficit” (O2def), which may be defined as the O2
equivalent of the energy utilized for the work which did not derive from aerobic
mechanisms utilizing the increased pulmonary V’O2. For moderate exercise, the decreases
in muscle creatine phosphate (PCr) and mixed venous O2 content (in addition to a small
and usually-transitory increase in [lactate]) provide the energy resources making up the
18
deficit, the value of which may be computed as the product of the overall V’O2 (i.e.
utilizing the combined phase 1 and phase 2 responses) and the steady-state V’O2
increment (V’O2 ss) [77, 81]. While V’O2 ss naturally will increase in proportion to
the size of the applied WR step (i.e. ΔV’O2/ΔWR = ~9-11 ml/min/Watt for cycle
ergometry), it is essentially independent of factors such as fitness and age (see 1.2). This
means that subjects with a long V’O2 will have an increased demand on muscle PCr and
blood O2 stores and also transient (at the least) lactate production to supplement the aerobic
energy transfer; i.e. a larger O2def necessarily predisposes towards anaerobiosis.
V’CO2 is appreciably longer than V’O2 (Fig 7), being ~ 50-60 s in healthy
young adults [e.g. 44, 45], reflecting the influence of the high capacitance CO2 stores
(chiefly in the exercising muscle) during the exercise transient [27, 82]. During
constant-load exercise, as for incremental-type and other kinds of WR forcings, the
time course of the V’E response is in close proportion to that of V’CO2, although with a
small but discernible lag [e.g. 44, 45] (Fig 7) – undermining the view that the V’CO2
dynamics are consequent to those of V’E. Thus, V’E is ~ 60-70 s in healthy young
adults, and is responsive to experimental alterations in V’CO2: when V’CO2 is caused
to be speeded, V’E is also speeded. It is important to recognize that the close coupling
of V’E and V’CO2 means that there is a marked transient dissociation of V’E not only
with V’O2 but also with the actual metabolic CO2 production rate in the muscle. As a
result, PaO2 falls transiently during phase 2 on-transients (and increase during offtransients) [78, 83, 84] (Fig 7). Furthermore, the small kinetic dissociation between V’E
and V’CO2 results in a small transient increase of PaCO2 [78] (Fig 7), discerned to date
only for sinusoidal exercise [85] and rapid-incremental exercise [86].
Above L, the kinetics of V’O2, V’CO2, V’E become complicated by additional
time- and amplitude-related complexities, a detailed discussion of which is beyond the
19
scope of this article (the interested reader is referred to Refs. 45, 87 for further
discussion). Of relevance, however, is the demonstration that the supra-L WR range can
be subdivided into two domains: (a) “heavy”, for which V’O2 (and blood [lactate]) can
attain a new steady-state although more slowly and at a greater O2 cost (i.e. Δ
V’O2/ΔWR is increased) than for sub-L exercise; and (b) “very-heavy” where, for all
WRs, V’O2 is set on a trajectory to, or towards, V’O2 peak and fatigue (attained more
rapidly, the higher the WR) with blood [lactate] also increasing [87].
2.2
T-Lim criterion and “iso-time” measures
The fatigue process in the very-heavy domain in normal subjects is reflected in a
hyperbolic relationship between WR (or power (P)) and the tolerable duration of the
exercise (Fig 8) – this has been shown to be the case for cycle ergometry, treadmill
running and swimming [reviewed in 88, 89]:
(WR – CP) . tLIM = W’
(8)
where tLIM is the tolerable duration, CP is the critical power (i.e. the asymptote for this
hyperbolic relationship), and W' is the curvature constant for this relationship - with the
mechanistically-provocative unit of work. If, however, WR is plotted as a function of
1/tLIM rather than tLIM, then the relationship is linear, with a slope equivalent to W' and an
intercept at CP [90] (Fig 8):
WR = W'/tLIM + CP
(9)
CP has been shown to be the upper constancy limit of V’O2, blood [lactate] and [H+], and
hence is a crucial determinant of the endurability of a particular task. And in the context of
CPET, it is of some interest that these characteristics have recently been demonstrated to
be the case also in patients with COPD [91, 92].
20
INSERT FIGURE 8
CP has been demonstrated to occur, on average, at a blood lactate of some 4-5 mM
(i.e. the highest sustainable blood lactate) in normal subjects [90, 93]. This value can vary
markedly in different subjects, however, with values greater than 8 mM being sustainable
in some. CP occurs at approximately half the V’O2 range between L and V’O2 peak in
normal subjects [e.g. 88, 90] and at approximately 80% in patients with COPD (i.e. peak
WR and V’O2 in the latter case being limited by respiratory mechanics) [91, 92].
Furthermore, because of the hyperbolic shape of the P-t relationship, what may
appear to be a relatively small percentage increase in V’O2 peak on an incremental test can
translate to an appreciable increase in the tolerable duration of a particular constant-load
test. That is, small increases in CP can result in large increases in tolerable duration for
WRs slightly greater than the pre-training CP [94] (Fig 9). The magnitude of the apparent
improvement in such cases will, naturally, depend on the position of the pre-training work
rate on the subject’s power-duration relationship.
INSERT FIGURE 9
In the context of patient evaluation, it is important to recognize that the powerduration relationship cannot, at present, be defined by means of a single exercise test. A
minimum of 3-4 tests is required (Figs 8 & 9), each of which should be conducted on a
separate day. It is instructive, therefore, to consider what alternatives are currently
available and what they can tell us about endurance in the context of the P-t relationship.
Timed field tests (e.g. 6- and 12-minute walk tests (6-MWT, 12-MWT)) are growing in
21
popularity in large part because of their ease of administration and their potential
prognostic value (see below).
A more sophisticated, laboratory-based test is the constant-load test at 80-90%
of V’O2 peak performed to the limit of tolerance, usually with breath-by-breath
monitoring. However, the dissociation between the V’O2 achieved at a particular work
rate on an incremental-type test and that of the steady-state requirement (see 1.2 and
Fig. 1) - a necessary consequence of the kinetics of the V’O2 response dynamics means that it is preferable not to select a given percentage of the maximum work rate
attained on an incremental test for the chosen constant-load test without correcting for
this kinetic influence. As schematized in Fig. 1, while the maximum V’O2 attained on
an incremental test is largely independent of the rate at which the work rate is
incremented (except for tests of extremely long or short duration [4]), the maximum
work rate achieved is higher the higher the incrementation rate. This may readily be
corrected for by subtracting the product of the ramp slope (WR/t) and an estimated
V’O2 response time constant (or mean response time (MRT)) from the maximum work
rate achieved. For example, for a sedentary patient having undergone a 10 Watts/min
incremental test and with an “expected” MRT of one minute, 10 Watts should be
subtracted from the maximum work rate to give a more appropriate frame of reference
for the constant-load endurance test.
However, such tests provide only a single point on the patient’s P-t relationship,
the determinants of which (CP and W’) can differ markedly among subjects (see above).
For example, the relationship between the average velocity on the standard (or
encouraged) 6-MWT and the velocity-equivalent of six minutes on the P-t relationship is
not, at present, known; i.e. the implications for interpretation of distinguishing what can
possibly be done for six minutes from what is chosen to be done for six minutes. And on a
22
practical note, standardization with regard to walking-test design and conduct are
needed (e.g. pacing strategies; the timing and degree of encouragement; whether only
one test is completed on a given day).
It is becoming increasingly common to utilize a standardized time point (i.e.
“iso-time”) for comparison of physiologic responses to an intervention on a symptomlimited constant-load laboratory test (usually at the limit of tolerance for the preintervention test) [95-97]. However, the functional significance of a certain magnitude of
intervention-induced improvement will, as mentioned above, depend very much on where
the point lies within the subject’s P-t relationship: a given increase in CP will be associated
with a far greater increase in tolerable duration for a WR that lies relatively low, rather
than high, on the P-t relationship (Fig 9).
23
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30
FIGURE LEGENDS
Fig 1: Schematic of the V’O2 response to ramp incremental exercise (―) as a function
of time at three different work-rate (WR) incrementation rates, and the corresponding
WR profile ( - - - ). Note that V’O2max is unaffected by WR incrementation rate.
However, the influence of the V’O2 time constant ( ▬ ) results in WRmax progressively
higher, the faster the incrementation rate. (See text for details). Modified from ref 29,
with permission.
31
Fig 2: Responses to incremental exercise performed to the limit of tolerance by a healthy
subject on a cycle ergometer. Panel 1: O2 uptake (V’O2) vs. work rate; panel 2: CO2
output (V’CO2) vs. V’O2, showing the intersection of the lower S1 and upper S2
regression lines; panel 3: ventilation (V’E) vs. V’CO2, with horizontal dashed line
indicating maximum voluntary ventilation (MVV); panel 4: ventilatory equivalents for
O2 and CO2 (V’E/V’O2, V’E/V’CO2) vs. V’O2; panel 5: heart rate (HR) and O2-pulse
(V’O2/HR) vs. V’O2, with horizontal dashed line indicating predicted HRmax; panel 6:
end-tidal PCO2 and PO2 (PETCO2, PETO2) vs. V’O2; panel 7: tidal volume (VT) vs. V’E,
with horizontal dashed line indicating vital capacity (VC) and vertical dashed line
indicating MVV; panel 8: respiratory exchange ratio (RER) vs. V’O2. Solid vertical line is
the estimated lactate threshold (L). See text for further details.
Left panel
Right panel
Fig 3: Schematic of responses to an incremental cycle-ergometer exercise test
performed to the limit of tolerance. Left panel: ventilation (V’E) as a function of CO2
output (V’CO2) with V’E/V’CO2 isopleths superimposed; and V’E/V’CO2 vs. work rate
32
(W’). Note that the asymptotic value of V’E/V’CO2 approximates the slope (Sa) of the
V’E-V’CO2 relationship. Right panel: O2 uptake (V’O2) as a function of heart rate (HR)
with V’O2/HR isopleths superimposed; and V’O2/HR vs. work rate (W’). Note that the
asymptotic value of V’O2/HR approximates the slope (Sd) of the V’O2-HR relationship.
See text for further details
Fig 4: Schematic to show mechanism leading to flatness in the O2-pulse profile. Right
panel: O2-pulse (O2P) as a function of work rate (W’). Note flattening of O2-pulse at
higher work rates (relative to normal profile, which continues to increase, ─ ─ ─ ). Left
panel: heart rate (HR) as a function of O2 uptake (V’O2), with discontinuity at higher
work rates providing a steeper linear HR-V’O2 segment that superimposes on HR/V’O2
isopleth (i.e. constant O2-pulse, - - - ). See text for further details.
Fig 5: Responses to incremental exercise (15 Watts/min). Left panel: Breath-by-breath
end-tidal and flow-weighted mean alveolar PCO2 (PETCO2, P A CO2), with
corresponding values from directly-sampled arterial blood (PaCO2). Right panel:
estimated series dead space ( V̂ D) as a function of tidal volume (VT); dashed lines
represent VD/VT isopleths. P A CO2 and VD estimated from intra-breath analysis.
Reproduced from ref 56, with permission.
33
Flow (L/s)
COPD
Normal
8
6
6
4
4
2
2
RV
TLC
0
predicted
rest
exercise
8
-2
0 TLC
RV
-2
IC
-4
-4
-6
-6
6
5
4
3
Volume (L)
2
7
6
5
4
Volume (L)
3
Figure 6. Flow-volume loops showing the effects of exercise on tidal volume in a
COPD patient and in age-matched healthy subject. The large solid loops represent the
maximal limits of flow and volume, and the small inner solid loops represent resting
tidal volumes. The larger dashed loops represent the increased tidal volumes and flows
seen with exercise. The dotted line on the left panel represents the IC maneuver to TLC
which is used to anchor tidal flow-volume loops within the respective maximal loops.
Healthy subjects are able to increase both their tidal volumes and inspiratory and
expiratory flows. In COPD, expiratory flow is already maximal during resting
ventilation (for comparison, the predicted maximal flow-volume curve is also shown).
In order to increase expiratory flow further, these patients must hyperinflate.
Fig 7: Schematic representation of time course of O2 uptake (V’O2, ─ · ─), CO2 output
(V’CO2; ······) and ventilation (V’E; ──) in response to a moderate work-rate step from
rest (top panel) and unloaded pedaling (middle panel), with corresponding profiles of
34
arterial PCO2 (PaCO2; ─ ─ ─) and PO2 (PaO2; ─ · · ─). Reproduced from ref 78, with
permission.
Fig 8: Top panel: schematized relationship between power or work rate (WR) and its
tolerable duration for exercise performed above critical power. Bottom panel: linearized
form of the WR-t relationship, with the WR-intercept corresponding to critical power. See
text for details.
Fig 9: The effects of endurance training on the power-duration relationship, which results
in a given work rate being sustainable for a longer period (dashed horizontal arrow).
Dashed line: pre-training; solid line: post-training. Note increase in lactate threshold with
training. Reproduced from ref 94, with permission.