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ARTICLE IN PRESS
Respiratory Medicine (2006) 100, 1896–1906
REVIEW
Respiratory muscle energetics during exercise in
healthy subjects and patients with COPD$
Giorgio Scanoa,b,, Michela Grazzinia,b, Loredana Stendardia,b,
Francesco Gigliottia,b
a
Department of Internal Medicine, Respiratory Disease Section, University of Florence, Italy
Fondazione Don C. Gnocchi, IRCCS, Pozzolatico, Florence, Italy
b
Received 20 September 2005; accepted 24 February 2006
KEYWORDS
Blood flow;
Mechanics;
Muscle fatigue
Summary The energy expenditure required by the respiratory muscles during
exercise is a function of their work rate, cost of breathing, and efficiency. During
exercise, ventilatory requirements increase further exacerbating the potential
imbalance between inspiratory muscle load and capacity. High level of exercise
intensity in conjunction with contracting respiratory muscles is the reason for
respiratory muscle fatigue in healthy subjects. Available evidence would suggest
that fatigue of the diaphragm and other respiratory muscles is an important
mechanism involved in redistribution of blood flow. Reflex mechanisms of
sympathoexcitation are triggered in fatigued diaphragm during heavy exercise
when cardiac output is not sufficient to adequately meet the high metabolic
requirements of both respiratory and limb musculature. It is very likely that local
changes in locomotor muscle blood flow may occur during exhaustive endurance
exercise and that changes may have important effect on O2 transport to the working
locomotor muscles and, therefore, on their fatigability. In a condition when the
respiratory muscles receive their share of blood flow at the expense of limb
locomotor muscles, minimizing mechanical work of breathing and therefore its
metabolic cost allows a greater amount of cardiac output to be available to be
delivered to working limb muscles. Malfunction in any of the multiple components
responsible for circulatory flow and O2 delivery will limit the blood supply therefore
inhibiting the supply of O2 and the energy substrate to the contracting muscles.
Studies are needed to overcome these limitations.
& 2006 Elsevier Ltd. All rights reserved.
$
Presented in part to the European Respiratory Society Annual Congress, 8 September, 2004,Glasgow, UK.
Corresponding author. Department of Internal Medicine, Section of Clinical Immunology, Allergology and Respiratory Disease,
University of Florence, Viale Morgagni 87, 50134 Firenze, Italy. Tel.: +39 055 4296 414; fax: +39 055 412867.
E-mail address: [email protected] (G. Scano).
0954-6111/$ - see front matter & 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rmed.2006.02.030
ARTICLE IN PRESS
Respiratory muscle energetics during exercise in healthy subjects and patients with COPD
1897
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Mechanical work rate, energy cost of breathing, and efficiency of respiratory muscles
Healthy subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Patients with COPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Exercise-induced respiratory muscle fatigue . . . . . . . . . . . . . . . . . . . . . . . . . . .
Healthy subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Do respiratory muscles fatigue during exercise in patients with COPD ? . . . . . . .
Respiratory muscle blood flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ventilatory-locomotor muscle blood flow competition during exercise . . . . . . . . . . .
Healthy subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Patients with COPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Interaction between ventilatory and circulatory mechanics during exercise in COPD . .
Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
A large body of scientific information on the
respiratory muscles during exercise has been
published since 1954. We present the accumulate
knowledge with particular emphasis on researches
publishes in the last 5–10 years. We updated
previous treatments on traditional topics such as
energetics and fatigability of the respiratory
muscles, and locomotor-respiratory muscle blood
flow competition. A MEDLINE search of articles
published between 1954 and 2005 was undertaken.
The energetics of the respiratory muscles has been
approached on the interplay between the energy
available for work, the work performed, and the
efficiency of the respiratory system. We restricted
our presentation to healthy human adults exercising at sea level and patients with COPD, a disease
state that compromises the energy supply, increases the work of breathing and decreases the
respiratory muscle efficiency.
We tried to answer the following question: (i)
does respiratory muscle fatigue affect alveolar
ventilation (VE); (ii) may work and cost of breathing
of primary and accessory respiratory muscles
compete with locomotor muscles to blood supply
and oxygen uptake; (iii) what is the role of
abnormality of O2 transport and utilization on the
limitation of exercise tolerance in patients with
COPD?
Mechanical work rate, energy cost of
breathing, and efficiency of respiratory
muscles
The energy expenditure required by the respiratory
muscles during exercise depends upon exercise-
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1897
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1900
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1904
induced changes in several types of mechanical
work by the respiratory muscles1: (i) volumedependent work against elastic forces in the tissue
of the lung and chest wall. During heavy exercise a
reduction in dynamic compliance and changes in
end expiratory lung volume affect the amount of
elastic work1; (ii) work to overcome inspiratory and
expiratory flow resistance which rises disproportionally at very heavy work rates1; (iii) it is likely
that extra work will be performed during deformation of the rib cage and abdominal walls in heavy
exercise2; (iv) a small amount of work is expended
to compress and expand gas during expiration and
inspiration, respectively.
Healthy subjects
The work of breathing is the product of respiratory
muscle pressure and lung volume. During quiet
breathing through the nose, the work of breathing
amounts to about 1 cal/min [ ¼ 0.42 kpm/min0.069 W ¼ 4.18 J/min ¼ 0.12 cal/l of VE,3 and the
maximal potential work per breath is 24 cal/min.
With increasing VE, the work of breathing increases
because of the pressure–volume and pressure-flow
characteristics of the respiratory system. During
voluntary hyperventilation at 60–70 l/min of VE,
the work of breathing is 12–50 cal/min, whereas
during exercise, for VE ¼ 140 l/min, the work of
breathing is 120 cal/min, i.e., four-fold lower than
available maximal inspiratory power, and close to
the maximal voluntary VE.4
Because the metabolism of the respiratory
muscles is primarily aerobic, their rate of energy
expenditure is equal to their oxygen consumption
(VO2). For the same work of breathing, VO2
increases with increasing the breathing resistance
and is the lowest during isocapnic hyperventilation.5 This is because of the isometric work of the
ARTICLE IN PRESS
1898
postural muscles which do not contribute to thorax
expansion, and because of the work for gas
compression and decompression. Separate measure
of diaphragm power output (Wdi) indicates that the
relationship of Wdi to VO2 with increasing breathing
resistance is much lower than that for all inspiratory muscles.6 A likely explanation is that the
diaphragm acts mainly as flow generator, whereas
rib cage muscles and abdominal muscles develop
the pressure to displace the rib cage and abdomen,
respectively.7–9
A recent approach1,10 provides reasonable
estimate of both ventilatory work and work
expended in chest wall stabilization by the
respiratory muscles during exercise. This is
achieved by reproducing at rest esophageal
work of breathing, pressures–time integral of the
diaphragm, breathing pattern, end-expiratory
lung volume and VE that they generate during
moderate and maximal intensity exercise (70%
and 100% VO2max, respectively). One limitation of
this approach is, however, that it does not mimic
the phasic activation of the respiratory muscles
during exercise, nor it includes the energy
expended for postural activity, and/or locomotorrelated action of these muscles, e.g., increase in
tonic activity of the abdominal muscles during the
transition from walking to jogging.2 Another limitation is that the postural muscles, synergistic
muscles and upper limb muscles which consume
O2 may be used without necessarily inflating
directly the thorax. All this explains the difficulty
of measuring the VO2 of the respiratory muscles.
Nevertheless, Aaron et al.10 showed that during
moderate exercise the O2 cost per litre of VE
remains fairly constant from 60 to 110 l/min of VE,
averaging 1.5–2 ml VO2/l/min of VE, then it rises
sharply to 3 ml VO2/l/min of VE as VE rises hence
corresponding to 10–15% of total VO2 (VO2tot), i.e.,
300–600 ml/min. Therefore, with incremental exercise as VE rises and O2 cost per l/min of VE
increases with hyperventilation the O2 cost of
breathing requires a greater proportion of the rise
in VO2tot. This is likely to occur in elite athletes
and older individuals because the high level of
required VE causes expiratory flow limitation and
puts the inspiratory muscles close to their maximal
capacity for pressure generation. The study of
Aaron et al.10 also shows that at maximal levels of
exercise at a time when the slope of the relationship between VO2tot and work load is falling, the
VO2 of the respiratory muscles rise to 35–45%VO2tot
(see Table 3 in Aaron et al.10). Not in line with Otis
‘‘critical useful VE’’ (VEcrit) this increase was too
small to require that all the increase in VO2tot be
devoted to hyperventilation (see below). The level
G. Scano et al.
of VE would have had to be 225 l/min for this
critical level to be achieved. Similar data were
obtained by Cibella et al.11 who calculated the O2
cost of breathing (VO2resp) according to the
equation:
VO2 resp ¼ Wrs=4:825E,
where Wrs is the respiratory muscles power, E is the
efficiency, and 4.825 is the caloric equivalent of
1 ml of oxygen. The slopes DWrs/DVE and DVO2resp/DVE increased, while the slope DVO2tot/DVE
decreased with increasing VE, indicating that
the additional energy uptake per unit increase in
VE diminishes with increasing VE. When DVO2resp/
DVE ¼ DVO2tot/DVE any further increase in
VE will result in less energy (O2) for doing
useful external work because the respiratory
muscles will use all the additional O2 provided by
the increased VE. At sea level, VEmax did not
exceed the critical VE (VEcrit) i.e., the critical
value at which any increase in VE is not useful in
terms of energetics because the gain of O2 is less
than that required for respiratory muscle power.
The opposite did occur at altitude when VEmax
exceeded VEcrit so that any further increase in VE
did not provide oxygen available to exercising
muscles unless respiratory muscles operate anaerobically. Unlike Margaria et al.12 who found VEcrit
being lower than VEmax in sedentary individuals
the data by Cibella et al.11 are in line with those of
Aaron et al.10 showing that VEcrit should be higher
in the fitter subject.
High levels of VO2resp may occur at relatively
lower level of VE in healthy fit elderly subjects
because aging reduces elastic lung recoil and
therefore the flow volume loop, and because a
stiffen chest wall increases VO2resp in healthy
elderly at any given level of hyperpnea.13 Peak
values of 15% of VO2tot represent the upper limits
at maximal VO2resp.14,15 At maximal voluntary VE
VO2resp amounts to 485–613 cal/min.4
Efficiency (E) is PV0 /VO2 (where P is pressure and
0
V is flow). Therefore, VO2 is proportional to P when
V0 is constant; the increase in V0 should be
associated with proportional increase in E. Efficiency is greatest at 20% velocity of shortening,
thereafter it decreases.16 Efficiency depends on the
specific type of work. The efficiency is optimized if
fast contracting muscle fibers contract rapidly
against light load. In contrast, slow contracting
muscles are more efficient when they develop
tension. In general, respiratory muscles are rather
fast muscles that reduce efficiency when they are
required to contract slowly against resistive heavy
work. Cala et al.17 showed that for the same work
rate and pressure–time product the VO2 against
ARTICLE IN PRESS
Respiratory muscle energetics during exercise in healthy subjects and patients with COPD
resistive breathing is greater than VO2 against
elastic breathing; it is likely that less efficient fast
fibres are recruited by respiratory and fixator
muscles while breathing against a resistor. MilicEmili and Petit18 have indicated that efficiency
varies between 0.19 and 0.20; also, the greater
respiratory muscles efficiency in supine position is
likely to be due to less activity of postural muscles
and a better configuration of the diaphragm which
requires less activation. As to the expiratory
muscles it seems that they have a major influence
on the VO2, i.e, the efficiency in overcoming the
expiratory resistive load is less than that for
inspiratory loads.19
Patients with COPD
Because COPD increases several types of mechanical work of the respiratory muscles, their rate of
work is 10–12 times greater than in healthy
subjects at rest and even greater at low level of
voluntary hyperventilation. Between 20 and 30 l/
min of VE, the respiratory power output is between
20 and 40 kg m/min in COPD. At that power output,
VE is 120–160 l/min in healthy subjects. Efficiency
progressively decreases being higher at 20–40 l/min
of VE than at 100–180 l/min of VE. VO2resp
increases remarkably and steeply during the modest increase in VE that these patients are able to
achieve during voluntary hyperventilation because
of low efficiency.20,21
Early reports on ventilatory cost of exercise in
COPD patients showed similar increase in VO2
and disproportionaly greater increase in VE
compared to controls for a given work load,
indicating a higher O2 cost of breathing in
patients.21 Because of the high VO2resp (35–40%
of VO2tot) less O2 was available for the nonrespiratory muscles. It was suggested that the O2
cost of increased VE during exercise could be an
important factor limiting the physical performance
of patients with COPD.21
An elevated VO2resp may reflect increased work
of breathing as well as a decreased efficiency of the
respiratory muscles; therefore it has been postulated22 that the decrease in inspiratory effort with
pressure support (PS) during exercise would be
associated with a corresponding reduction in O2
cost of breathing as measured by the difference in
VO2 between control and PS trials. Failure to
demonstrate any difference in VO2 [713(53) vs.
733(58) ml/min, respectively] was thought to be
due to the fact that the anticipated reduction in
the O2 cost of breathing relative to VO2tot was too
small to be detected.22
1899
Exercise-induced respiratory muscle
fatigue
Healthy subjects
In this section, we update the effects of strenuous
exercise on the respiratory muscles. We will not
consider the global inspiratory muscle fatigue
induced by breathing against a high inspiratory
resistance during exercise. With regard to this
topic, in an elegant paper Sliwinski et al.23 showed
alteration in breathing pattern accompanied by a
substantial different pattern of respiratory muscle
activity. There appear to be two general causes of
diaphragmatic fatigue induced by endurance exercise namely, one cause attributable to the force
production by the diaphragm it self and a second
due to the effects of whole body exercise per se.
Johnson et al.24 were the first to demonstrate
objectively that the diaphragm muscle is susceptible to exercise-induced low-frequency fatigue,
especially when exercise intensity progressed beyond 85% of VO2max and was of endurance type.
This study showed that diaphragmatic force output,
and exercise intensity were likely factors contributing to the fatigue. Babcock et al.25 examined
the role that diaphragmatic pressure generation
played in the fatigue process independent of the
whole body exercise effect. The effect of voluntarily mimicking at rest the diaphragm power output
(509781 cm H2O/min, threshold) for a similar time
period that subjects achieved during exercise at
86–93%VO2max did not result in fatigue of the
diaphragm. By contrast, diaphragmatic power output in excess of the threshold did result in fatigue:
as shown by a significant fall in diaphragmatic
power output to bilateral phrenic nerve stimulation
(BPNS). Thus, the available data show: (i) a
substantial influence of endurance exercise on
diaphragm fatigue; (ii) a significant reduction of
the amount of diaphragm force output required to
cause fatigue during endurance exercise; and (iii)
on the other hand, the effect of whole body
endurance exercise per se did not elicit fatigue in
non-exercising muscle of the hand. It has been
therefore postulated that acidification of the
diaphragm via uptake of circulating lactate in
conjunction with a contracting diaphragm accounted for most of the exercise-induced diaphragm fatigue. A major contribution of
diaphragm work per se to exercise-induced diaphragm fatigue would be expected to occur only at
high levels of metabolic requirement during which
diaphragmatic pressure generation exceeds this
fatigue threshold. In a second study Babcock
et al.26 unloaded partially the diaphragm via
ARTICLE IN PRESS
1900
pressure assist ventilation (PAV). PAV reduced work
of breathing by 40–50% and VO2tot by 10–15% below
control, and prevented diaphragm fatigue at all
BPNS frequencies and time points post exercise.
These findings are consistent with the notion that
the workload endured by the diaphragm is a critical
determinant of exercise-induced diaphragm fatigue. Thus, while the force output of the diaphragm
experienced during exercise was not sufficient to
cause fatigue in the absence of locomotor muscle
force output, it was critical to the development of
diaphragmatic fatigue in the presence of whole
body exercise.
Available evidence would suggest24–27 that fatigue of the diaphragm and other respiratory muscles
is an important mechanism involved in redistribution of blood flow. Development of diaphragm
fatigue during exercise is a function of the
relationship between the magnitude of the diaphragm work and the adequacy of its blood supply:
the less the blood flow available, the less the
diaphragm work required to produce fatigue.
Imbalance of muscle force output vs. blood flow
and/or oxygen transport availability to the diaphragm which favors fatigue appears to occur
during exhaustive endurance exercise only when
either the relative intensity of the exercise exceeds
85% VO2max24 or arterial hypoxemia is present.27
G. Scano et al.
that the diaphragm adapts to chronic loading and
that the degree of adaptation correlates with the
severity of COPD. According to Levine et al.31 these
adaptations include larger proportion of type I
fiber, lesser proportion of type IIa and the same
proportion of type IIb fibers in the costal diaphragm
of patients compared to controls. Each fiber type
had also higher succinate dehydrogenase activity
and mitochondrial oxidative capacity leading to
increased aerobic ATP generating capacity. In a
further paper Levine et al.32 found that type I fibers
generated lower force than did type II fibers. They
also found an exponential relationship between the
proportion of type I fibers and FEV1 accounting for
discrepancies with observations that the diaphragm
of subjects with less severe COPD did not differ
from those of controls with respect to the proportion of type I fibers. These authors believe that
fiber type adaptations found in the diaphragm of
COPD patients may represent an example of fast to
slow fiber type transformation elicited by longterm respiratory muscles loading. It is the authors’
hypothesis that this diaphragm remodeling associated with COPD is characterized by trade-off of
decreases in force generating capacity for increase
in fatigue resistance.32
Respiratory muscle blood flow
Do respiratory muscles fatigue during
exercise in patients with COPD ?
The inspiratory muscles are faced with an increased
load in patients with COPD. During exercise the
ventilatory requirement increases further exacerbating the potential imbalance between inspiratory
muscle load and capacity. For these reasons
patients with COPD may be particularly prone to
the development of inspiratory muscle fatigue
during exercise. Evidence of overt central or
contractile fatigue of the diaphragm, however,
has not been provided.28–30 Mador et al.30 studied
COPD patients who exercised maximally relative to
their capacity of reaching a VO2 greater than peak
VO2 obtained during a preliminary maximal incremental cycle exercise test. Transdiaphragmatic
twitch pressure (Pditw) measured after exercise
was not significantly different from baseline at any
time point post exercise (10, 30 and 60 min). In two
patients Pditw had a persistent 410% fall post
exercise potentially indicative of contractile fatigue of the diaphragm. The study also shows that,
despite a significant increase in blood lactate post
exercise, the majority of patients did not develop
fatigue of the diaphragm. The authors concluded
Rochester and Bettini33 assessed respiratory muscles blood flow by application of the Fick principle
VO2 ¼ Q ðCa2CvÞO2 ,
where Q is blood flow and (Ca–Cv)O2 is the
arterovenous oxygen content difference. They
showed in anestethized dogs that inspiring through
an inspiratory resistance led to much bigger
increase in diaphragm VO2 than that occurring
during unobstructed hyperventilation. Furthermore, diaphragm VO2 was linearly related to
diaphragm inspiratory pressure–time index and to
diaphragm electrical activity. At the highest level
of effort, diaphragm O2 requirements were met by
increasing diaphragm blood flow, but diaphragm O2
extraction plateaued. This and other studies34 have
shown that the pattern of contraction is a major
determinant of diaphragm blood flow which is in
fact linked to the level of respiratory muscle
activity.33–36 Negative pleural pressure holds the
vessels open, whereas abdominal positive pressure
compresses intramuscular vessels (increase in
vascular resistance) thereby producing an effect
of Starling resistance.35 Metabolic and neural
factors, and autoregulation are also involved on
ARTICLE IN PRESS
Respiratory muscle energetics during exercise in healthy subjects and patients with COPD
blood perfusion of the respiratory muscles such as
the diaphragm.6,36–38
In experimental animals, respiratory muscle
blood flow is measurable and since muscle VO2
and cardiac output usually change together a good
estimate of O2 requirement can be derived from
blood flow measurements. In dog whose total mass
of the respiratory muscles is 5–6% of total body
weight the highest diaphragm blood flow is about
265 ml/100 g/min,6,35,39 and in pony a similar
increase in perfusion of the diaphragm and rib
cage muscles often approximate the perfusion of
locomotor muscles during maximal exercise.40 In a
70 kg man respiratory total muscle mass would
correspond to 3–5 kg, but total blood flow to the
respiratory muscles remains to be defined.
Sexton and Poole41 reported that emphysema
increases blood flow in the diaphragm, intercostal
and abdominal muscles of exercising hamster,
supporting the contention that emphysema increases the energetic requirements of the diaphragm. Diaphragm blood flow, however, was far
below that found in hind limbs skeletal muscles.
Whether this reflects the presence of blood flow
limitation in respiratory muscles, or alternatively a
blood flow reserve in the locomotor muscle or a
regulatory effect remained to be defined.
In patients with emphysema the strength of
contraction may limit further increase in perfusion.5 Estimate of blood flow of the respiratory
muscles, based on the Fick principle, in patients is
prevented by lack of data on O2 extraction ratio
[O2ER: (CaO2–CVO2/CaO2)]. The question whether
in COPD patients O2ER of the respiratory muscles is
constant during exercise as in skeletal limb
muscles42 is far from being answered.
Ventilatory-locomotor muscle blood flow
competition during exercise
Healthy subjects
The hypothesis has recently been put forward that
the metabolic cost of breathing required by
respiratory muscles and stabilizing muscles of the
chest wall limit the blood flow available for the
locomotor muscles, thereby limiting their power
output.43 By using thermo-dilution technique to
study leg blood perfusion,44 Harms et al.43 have
shown in elite athletes during control maximal
exercise (VO2 85–90% pred: 55–74 ml/kg/min) and
exercise with inspiratory muscle work, either
reduced via PAV, or increased via graded
resistive loads, an inverse relationship between
1901
work of breathing on the one hand, and leg blood
flow and VO2legs % control on the other. With
respiratory unloading, while VO2tot decreased
VO2leg (%VO2tot) increased. In that study the direct
relationship of leg vascular resistance with norepinephrine spill over implied an increased muscle
sympathetic nerve activity and vasoconstriction
with respiratory muscles loading and vasodilatation
with unloading. In a further study Harms et al.45
found that with respiratory muscles loading, total
blood flow did not change while leg blood flow
decreased from 77% to 71% as did VO2 secondary to
increase in leg vascular resistance.45 In contrast,
with respiratory unloading leg blood flow (85%) and
leg VO2 (87%) increased in concomitance with
decrease in leg vascular resistance. Blood flow of
the respiratory muscles was assumed to be ¼ 4.4 l/
min calculated as the difference between 26.5 l/
min in control and 22.3 l/min by extrapolating
respiratory muscles flow at zero work load. In turn,
the respiratory muscles receive their share of
blood flow at expense of limb locomotor muscles
under condition in which total cardiac output and
artero-venous O2 content difference are at maximal levels.45
The influence of respiratory muscle work and leg
blood flow on VO2 is trivial during submaximal
exercise (50% and 75% VO2max) when the 50–70%
increase in work of breathing is too small to
activate sympathetic vasoconstrictor efferent output because of the lack of diaphragm fatigue.46
Minimizing mechanical work of breathing and
therefore the metabolic cost of breathing allows
for a greater share of cardiac output to be available
for delivery to working limb muscles. A reduction in
respiratory muscles energy stores minimizes sensory inputs and discomfort from chest wall and
lung, reducing the potential for dyspnea or leg
effort.47 Given the high demand for oxygen and
blood flow by the respiratory muscles during
maximal exercise, and its effect on peripheral
cardiovascular system, Harms et al.47 hypothesized
that work of breathing during strenuous exercise
(90% VO2max) would impair exercise performance.
They validate their hypothesis by showing that
loading the respiratory muscles resulted in curtailed performance, increased VO2, and decreased
VE/VO2, whereas unloading the respiratory muscles
lengthened exercise tolerance, reduced dyspnea
and leg effort, and decreased VO2. The authors also
argue that the fatigue of the diaphragm may have
influenced its performance promoting: (i) greater
use of accessory muscles that may have led to chest
wall distortion; (ii) mechanical inefficiency of
breathing; (iii) greater work of breathing; and (iv)
increased metabolic and blood flow demand by the
ARTICLE IN PRESS
1902
respiratory muscles. In turn, it appears that
respiratory muscle fatigue must occur for unloading
in order to improve performance. This might
explain why other studies have not found a
significant effect of respiratory muscle unloading
on exercise capacity.48–50
An important observation is that respiratory
muscle fatigue during heavy exercise could impair
limb work capacity due to blood flow redistribution
even when cardiac output is not near maximal
level.26 Babcock et al.26 postulated that reflex
mechanisms of sympathoexcitation are triggered by
metaboreceptors in the diaphragm as the muscle
begins to accumulate metabolic end-products during heavy exercise when cardiac output is not
sufficient to adequately meet the high metabolic
requirements of both respiratory and limb musculature. To test this hypothesis St. Croix et al.51
fatigued the diaphragm by imposing high intensity
contraction and high duty cycle to healthy subjects. Fatigue caused a time-dependent increase in
muscle sympathetic nerve activity (MSNA) in the
resting legs despite a corresponding increase in
systemic blood pressure (inhibitory feedback from
systemic baroreceptors are associated with increase in arterial blood pressure). MSNA was
thought to be due to type IV nerve ending
stimulation of the diaphragm. In a following study
MSNA was found to be accompanied by significant
decreases in limb vascular conductance and limb
blood flow along with an increased mean arterial
pressure and heart rate.52 A high MSNA has also
been referred to a metaboreflex during high
intensity and high frequency contractions of the
expiratory muscles.53 What it still not clear is
whether this mataboreflex is solely responsible for
the vasoconstrictor effects of respiratory muscles
on limb muscles vasculature being sufficiently
powerful to override the local vasodilator effect
from circulating metabolites and compromise blood
flow to exercising muscles .
The appropriate exercise conditions, sufficient to
elicit a significant vasoconstrictor effect from the
diaphragm to the limb muscle vasculature, might
also occur in chronic heart failure patients even at
moderate exercise intensities of submaximal exercise when cardiac output is abnormally low,54,55
or COPD.56 In these cases respiratory muscle
unloading may be especially beneficial to enhancement of exercise performance.47
To summarize, it is very likely that local changes
in locomotor muscle blood flow may occur during
exhaustive endurance exercise and that changes
may have important effect on O2 transport to the
working locomotor muscles and, therefore, on their
fatigability.
G. Scano et al.
Patients with COPD
Malfunction in any of the multiple components
responsible for circulatory flow and O2 delivery will
limit the blood supply therefore inhibiting the
supply of O2 and the energy substrate to the
contracting muscles.57 Patients with COPD characteristically show poor exercise performance
indicated by a marked reduction in both peak
cardiac output response, pulmonary O2 uptake and
work rate at peak exercise.58–60 However, the
relationship between whole body O2 uptake and
work rate is normal and the O2 uptake for a given
submaximal work rate in these patients is similar to
that seen in healthy sedentary subjects.61 Recently,
other evidence suggests42,60,62–65 that skeletal
muscle dysfunction should also be considered as
playing a role in the limitation of exercise
tolerance in COPD. There is also evidence that
whole body fractional O2 extraction may be less
than normal in some patients with COPD42,60
indicating either impaired O2 uptake by exercising
muscles and/or abnormal redistribution of blood
flow during exercise. Unlike athletes during extreme exercise,45,47 leg blood flow and leg O2
delivery at a given submaximal whole-body O2
uptake is normal in these patients.42,66 Finally,
recent evidence demonstrates that an early increase in femoral venous blood lactate levels
during exercise is not correlated with reduced O2
delivery to the lower limb.42 This provides further
support for a biochemical abnormality that may be
considered a hallmark of muscle dysfunction in
COPD.
On the other side, Macklem67 had shown the
vicious circle between hyperventilation and lactic
acidosis in patients with chronic heart failure and
suggested that O2 demands of the respiratory
muscles may be a major fraction of total O2
decline. In the face of hypoxemia and decreased
cardiac output, the O2 demand of the respiratory
muscles may deprive the rest of the body of O2, or
alternatively the O2 may be diverted from the
muscles to the rest of the body.67 Furthermore,
Field et al.68 showed in patients with COPD weaned
from artificial VE a reduced ventilatory efficiency
and increased work of breathing, which resulted in
substantial increases in VO2resp. In the presence of
an impaired O2 delivery system, the O2 demands of
the respiratory muscles may be excessive. As a
result, ‘‘either other body tissues are robbed of
much needed O2 supplies, or otherwise the inspiratory muscles are deprived resulting in an
inability to maintain an adequate VE’’.68 Thus,
competition between locomotor and ventilatory
muscles for the available supplies of energy
ARTICLE IN PRESS
Respiratory muscle energetics during exercise in healthy subjects and patients with COPD
aggravated by inadequate cardiac pumping capacity, might limit O2 supply.
The concept of respiratory-peripheral muscle
competition has been bolstered by Richardson et
al.56 in patients with severe COPD. They showed
that both 100%O2 and unloading of ventilatory
muscles with helium increased peak work output
during two-legged exercise. Oxygen, but not
helium resulted in 2.2-fold increase in one-legged
exercise (knee extensor muscle) specific power
output (10 vs. 4 W/kg) than during whole body
exercise. Improved power output with O2 probably
occurred because of greater blood perfusion and
energy supply. The effect with helium during whole
body exercise was due to unloading the respiratory
muscles with fall in muscle output. Helium, however, did not improve the performance of the knee
extensor muscle because of the lower level of VE in
a condition where blood flow competition between
the respiratory and peripheral skeletal muscles is
not likely. The beneficial effect of oxygen also
suggests that the respiratory system is not the sole
constraint to oxygen consumption. This study
provide also the evidence of a skeletal muscle
metabolic reserve during whole body exercise in
this population. In turn, Richardson et al. maintain
that the major limitation to exercise performance
in patients who exercise beyond the lactate threshold is notably an inadequate O2 supply.
Simon et al.69 have recently reported that for a
work load between 20 and 40 W, VO2leg, leg blood
flow and artero-venous O2 content difference
reached a plateau in one of two groups of COPD
patients. Because VO2tot kept rising in both groups
the relationships of VO2tot with VO2leg, leg blood
flow, and artero-venous O2 content difference at
peak exercise were lower in the ‘‘plateau’’ group.
Despite similar respiratory function at baseline,
greater VE, leg vascular resistance and dyspnea at
submaximal exercise suggest greater mechanical
respiratory constraint in the ‘‘plateau’’ group.
Assuming that cardiac output kept rising (according
to the ‘Fick’s principle) a competition in blood flow
between peripheral and ventilatory muscles should
be considered in the plateau group. In turn,
competition between ventilatory and locomotor
muscles for the available energy supplies increases
with increasing work of breathing.
Competition is an important factor in the early
appearance of anaerobic threshold and it can
markedly aggravate a situation already compromised by a reduction in cardiac output and tissue
perfusion at high exercise work load. Respiratory
muscle stress associated with mild hypoxia70 or
isocapnic hyperventilation71 causes mild increase in
lactic acid (1 mmol/l). Pulmonary vascular disease
1903
that accompany COPD may decrease blood flow to
exercising respiratory muscles and decrease their
aerobic exercise capacity. Does this increase the
contribution of the respiratory muscles to increasing blood lactate levels? Study in large animals
showed that the diaphragm does not produce lactic
acid during maximal exercise.72,73 In patients with
COPD voluntary hyperventilation against a background of constant work load exercise at the
anaerobic threshold brings VE to the same levels
as during progressive exercise, but peak lactic acid
only modestly increases well below the levels
attained during progressive exercise.74 Despite
the correlation between the increased level of
airway obstruction and the increased level of
lactate, the increased volitional VE was associated
with an increase in blood lactate of only 0.5 mEq/l.
This study74 suggests that the respiratory muscles
do not importantly contribute to lactic acidosis
during maximal exercise. Oelberg et al.60 found
that lactate threshold occurred at an early (lower)
O2 extraction ratio in COPD patients compared with
controls (o0.50 vs. 0.57, respectively), and was
not influenced by unloading the ventilatory muscles
whilst breathing helium. In turn, the respiratory
muscles contribute to a small extent blood lactic
acid production.
Interaction between ventilatory and
circulatory mechanics during exercise in
COPD
The mechanisms that couple VE to cardiac output
during exercise are still not well understood. On the
inspiratory side, changes in intrathoracic pressure
imposed primarily at rest in supine humans are
shown to exert effects on both left and the right
heart.75 With increasing negativity of intrathoracic
pressure, venous return increases (preload). Increasing intrathoracic negativity also implies an increase
in transmural pressure across the left ventricle
(afterload). Increases in right atrial and ventricular
filling will compromise left ventricular expansion.76
Both will compromise left ventricular stroke volume
and cardiac output. Preload effects dominate the
effect of changes in intrathoracic pressure on stroke
volume. Given the finding of reduced stroke volume
with respiratory muscle unloading during maximal
exercise, one may speculate that less negative
esophageal pressure during inspiration reduces
venous return thereby resulting in reduction in
stroke volume and cardiac output. Furthermore,
increased pulmonary vascular resistance should
increase the afterload of the right ventricle. Montes
de Oca et al.77 proposed that the large pressure
ARTICLE IN PRESS
1904
swings observed during exercise can constrain left
ventricular function, thus limiting both peak cardiac
output and exercise tolerance in patients with
severe COPD. If the work of breathing increases,
VO2resp increases and, beyond the anaerobic
threshold, this should deprive the locomotor muscles of some of their perfusion.
On the expiratory side, the mechanics of breathing may interfere with cardiovascular function.
High abdominal pressures interfere with venous
return from exercising leg muscles.78–80 The high
expiratory pleural pressure interferes with venous
return to right heart, and a high alveolar pressure
increases pulmonary vascular resistance and decreases both left heart filling and cardiac output.67
In presence of tidal flow expiratory limitation, the
expiratory muscles might develop excessive pressure in the vain attempt to increase flow; above the
anaerobic threshold the perfusion to the locomotor
and respiratory muscles provides insufficient oxygen to meet the demands.67 During activity,
patients with COPD are exposed to expiratory load
and dynamic hyperinflation as ventilatory demand
increases. These alterations can affect cardiac
function. The separate influence of dynamic hyperinflation and expiratory load on cardiac output (CO)
are not likely to be assessed in these patients. Data
in healthy subject, however, indicate that mild to
moderate expiratory load limits CO primarily
through an influence on esophageal and gastric
pressures, whereas change in lung volume appear
to minimally influence CO.81 On the other hand,
O’Donnell et al.54 have suggested that respiratory
muscle work per se is not a major determinant of
dyspnea in heart failure patients, but, rather, their
respiratory discomfort may originate in the expiratory flow limitation and hyperinflation these patients experience during even moderate-intensity
exercise.
Summary and conclusions
Lung and chest wall are highly efficient for long
duration of exercise at high intensity. The following
evidences support this conclusion:
(1) sufficient dynamic capacity of generating pleural pressure to meet or sustain ventilatory
requirements.
(2) total VO2 cost of hyperpnea (VO2resp) less than
10% VO2max.
(3) respiratory muscle fatigue does not compromise
an adequate alveolar ventilation.
(4) work and cost of breathing of primary and
accessory respiratory muscles may compete
G. Scano et al.
with locomotor muscles to blood flow supply
and O2 uptake in healthy subjects only during
very heavy exercise.
On the other hand, abnormality of O2 transport
and utilization may contribute to depressing VO2max in patients with COPD. How much of the
abnormal peripheral skeletal muscle oxidative
metabolism is related to inadequate O2 delivery
in these patients remains to be defined.
Last but not the least, can these muscle limitations be overcome? Specifically, what is the role of
respiratory muscle training (RMT) on the limitation
on exercise performance imposed by the respiratory muscles? Has specific RMT the potential to
increase exercise performance by means of delaying fatigue of the diaphragm and its associated
vasoconstrictor influences, and reducing diaphragmatic sensations during high intensity exercise?
Studies are needed to answer these questions.
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