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Meakins-Christie Laboratories, McGill University Clinics, Montreal, Quebec, Canada H2X 2P2
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Kayser, Bengt, Pawel Sliwinski, Sheng Yan, Mirek Tobiasz,
and Peter T. Macklem. Respiratory effort sensation during exercise
with induced expiratory-flow limitation in healthy humans. J. Appl. Physiol. 83(3): 936-947, 1997.
Nine healthy subjects (age 31 ± 4 yr) exercised with and
without expiratory-flow limitation (maximal flow ~1 l/s). We
monitored flow, end-tidal PCO2, esophageal (Pes) and gastric pressures, changes in end-expiratory lung
volume, and perception (sensation) of difficulty in breathing. Subjects
cycled at increasing intensity (+25 W/30 s) until symptom limitation.
During the flow-limited run, exercise performance was limited in all
subjects by maximum sensation. Sensation was equally determined by
inspiratory and expiratory pressure changes. In both runs, 90% of the
variance in sensation could be explained by the Pes swings (difference
between peak inspiratory and peak expiratory Pes). End-tidal
PCO2 did not explain any variance in
sensation in the control run and added only 3% to the explained variance in the flow-limited run. We conclude that in healthy subjects,
during normal as well as expiratory flow-limited exercise, the pleural
pressure generation of the expiratory muscles is equally related to the
perception of difficulty in breathing as that of the inspiratory
muscles.
dynamic hyperinflation; chronic obstructive pulmonary disease; breathlessness; exercise limitation
INTRODUCTION THE HYPERPNEA OF EXERCISE leads to the
sensation that breathing is becoming difficult and that it requires
progressively increasing effort as exercise workload increases (10).
The determinants of this sensation are still not well defined, although
the sensation of effort is shared by virtually all skeletal muscles as
their power output increases (10, 13). Because the larger part of the
work of breathing during exercise is performed by inspiratory muscles,
most studies of exercise-induced difficulty in breathing have
concentrated on inspiration, and inspiratory effort was found to be an
important determinant of the degree of difficulty in breathing sensed
during exercise (10, 13). Expiratory effort has not received much
attention so far. Although much of the work of expiration is performed
by elastic energy stored during inspiration by breathing above
functional residual capacity (FRC), there are important reasons to
postulate that expiratory muscles may play an important role in
respiratory-effort sensation in exercise.
In the first place, expiratory resistive loading increases the
sensation of difficulty in breathing in resting humans, and this is
linearly related to expiratory mouth pressure changes (5). Furthermore,
the magnitude of sensation change per unit mouth pressure change is the
same for expiratory as for inspiratory loading (5). Second, although
expiratory muscles are relaxed in normal humans during quiet breathing,
these muscles are immediately recruited at the onset of exercise, even
at very low workloads, when they contribute significantly to
ventilation. Third, exercise hyperpnea leads to an increase in tidal
volume (VT) originating in
part from a decrease in end-expiratory lung volume
(EEVL) below FRC by
recruitment of abdominal muscles, decreasing end-expiratory abdominal
volume. In addition to contributing actively to expiratory flow, the expiratory muscles thus contribute to the work of inspiration by storing elastic energy in the respiratory system by breathing out
below FRC.
On the basis of these observations, we hypothesized that in addition to
inspiratory ventilatory parameters, expiratory activity is an important
determinant of the overall perception of difficulty in breathing in
healthy subjects during exercise. We therefore subjected normal
subjects to two exercise challenges and related inspiratory as well as
expiratory ventilatory parameters to the degree of difficulty in
breathing perceived by the subjects. The first exercise was performed
without any special manipulation of expiratory muscles. To amplify
expiratory muscle recruitment, the second exercise was performed while
the subject was flow limited during expiration by means of a Starling
resistor in the expiratory line of the breathing circuit. This
intervention greatly increased expiratory pressures compared with
control, allowing us to study the effect of additional expiratory
muscle recruitment. The specific purpose of the study was to quantify
the importance of expiratory pressure generation in the perception of
difficulty in breathing.
METHODS
) was measured with a heated pneumotachograph
(Fleish no. 3) and a differential pressure transducer (Validyne).
Changes in lung volume (VL) were
measured by a bag-in-box system (bag volume ~150 liters) and vital
capacity (VC) maneuvers. End-tidal PCO2(PETCO2)
was monitored by a CO2 analyzer (Ametek CD-3A). In seven subjects esophageal (Pes) and gastric pressure
(Pga) were measured by conventional balloon-catheter systems
and differential pressure transducers (Validyne).
Because we expected very rapid changes in Pes and Pga during the
flow-limited run, we specifically matched the response characteristics
of the flow- and pressure-sensing systems so that there was no time
delay among , Pes, and Pga during very rapid step
changes in these signals. We chose step changes over variable-frequency
oscillations because they allowed us to mimic the effects of the very
sudden pressure changes that we observed during the experimental runs (up to 600 cmH2O/s). At these
rates there was no delay between the flow and pressure signals. All
devices were calibrated before each experimental run.
During both exercise runs, the subjects were asked to rate difficulty
in breathing on a modified Borg scale with a range from 0 to 10 (Ref.
2, Table 1). The precise wording used with
the subjects was the following: "Please rate the difficulty of
breathing during the exercise using the scale shown on the oscilloscope where 0 indicates no effort at all and 10 the maximum tolerable level
possible." The scale was shown on a piece of a transparency placed
over the cathode ray tube of an oscilloscope positioned in front of the
subject. A variable resistor in series with a 9-V battery and fitted
with a lead into the oscilloscope was mounted on one of the handlebars
of the cycle in a convenient position. The subject rated his or her
effort of breathing during both exercise runs on the oscilloscope by
manually changing the voltage signal to a discrete level corresponding
to one shown on the Borg scale (Table 1) whenever he or she felt that
it changed. Because the purpose of the study concerned the effect of
expiratory muscle recruitment on the global perception of difficulty in
breathing and because of practical reasons, no distinction between
inspiratory and expiratory sensation was sought. By the same token, no
rating of overall or leg effort was performed.
|
,
VL, Pes, Pga,
PETCO2, and perceptual
signals were amplified by an eight-channel amplifier (model 7758B, Hewlett-Packard), passed through a 12-bit analog-to-digital converter, and recorded by a computer at a 200-Hz sampling rate.
In the control run the subjects could expire freely into the bag-in-box
system. During the flow-limited run, a Starling resistor was put on the
expiratory line of the breathing circuit. The Starling resistor
consisted of a collapsible rubber tube contained in a Plexiglas
chamber. The chamber was pressurized by connecting it with a tube to
the expiratory side of the valve system near the mouthpiece. Mouth
pressure was thus relayed to the chamber that compressed the tube,
rendering expiratory flow independent of pressure at ~1 l/s.
Exercise protocol.
The subjects sat upright on an electrically braked cycle ergometer.
During the control run, after 2-3 breaths were recorded at rest,
the subjects started cycling until the air in the bag-in-box was
exhausted. In the flow-limited run the subjects would first do a VC
maneuver, take 2-3 normal breaths, and then start cycling. Initial
cycling intensity was 25 W and was increased by 25 W every 30 s. The
reasons for choosing this particular exercise protocol were twofold.
First, because expiratory flow-limitation was expected to lead to
dynamic hyperinflation, we wanted to be able to estimate changes in
absolute VL. We did this by use
of a bag-in-box system in which the volume content of the bag (~150
liters) set the maximum exercise duration. Second, we wanted to
minimize possible effects of respiratory muscle fatigue induced by
increased breathing efforts on the perception of difficulty in
breathing. Therefore, the exercise duration had to be minimized. The
rapid increment in exercise intensity did not allow a steady state of
gas exchange to be reached but was still sufficient to elicit a sizable
ventilatory drive and a substantial ventilation. In the control run the
subject stopped cycling and came off the mouthpiece when the air in the bag-in-box was exhausted. In the flow-limited run the subject continued
cycling until he or she indicated that the effort of breathing was
maximal and that he or she could no longer continue. After a couple of
more breaths the subject was allowed to stop cycling and, at the same
time, the expiratory-flow limitation was bypassed by a system of valves
so that the subject could expire normally again while remaining on the
bag-in-box system. With intervals of 4-5 breaths, the subjects
then performed four to six additional VC maneuvers to track changes in
total gas volume contained in the breathing circuit (i.e., lungs,
bag-in-box, and tubing) because of changes in respiratory quotient that
occurred during the exercise run.
Data analysis and statistics.
Transdiaphragmatic pressure (Pdi) was algebraically calculated (Pga 
Pes). Even though the sampling rate was 200 Hz, because pressure changes were as large and as rapid as 600 cmH2O/s at zero-flow time points
during the flow-limited run (i.e., up to 3 cmH2O between two
analog-to-digital conversions), zero-flow time points were calculated
by identifying zero-flow crossings with a best fit nonlinear
interpolation technique. The time points thus calculated were then used
to calculate the corresponding pressures by using the same
interpolation technique. Peak inspiratory and expiratory pressures were
identified from the raw signals. Calculations were done by using
end-inspiratory, end-expiratory, peak inspiratory, peak expiratory, and
pressure-swing (
; i.e., the absolute pressure change from peak
inspiratory to peak expiratory pressure) amplitudes.
VL was obtained from the
bag-in-box system. Minute expiratory ventilation
(E),
VT, breathing frequency (f), inspiratory time (TI),
expiratory time (TE), and
total breath time (TT) were
calculated from the integrated signal corrected for drift.
Because the Borg scale consists of discrete steps, all statistical
calculations were done by using the values of the various measured and
calculated variables obtained at those time points where the Borg
rating of the perception of difficulty in breathing was increased by
the subject. Zero (i.e., no sensation of difficulty in breathing,
whatsoever) on the Borg-scale rating was excluded from the analysis.
Correlations between variables were performed with the Pearson test.
Single- and multiple-linear regression analyses were performed on the
individual data as well as on the pooled data. The dependent variable
was the Borg-scale rating, and all other variables were independent.
Because in the pooled-data set distributions were skewed by a greater
number of low Borg ratings, a log transformation was performed to
obtain a normal distribution. All models included a constant, but these
are not shown in the results for reasons of clarity. Our strategy was aimed at identifying the least number of independent variables giving
the highest r2.
Care was taken not to include interdependent variables within the same
model and to ensure normal distribution and linearity of the final
chosen predictors. Results were considered significant at the
P < 0.05 level.
RESULTS
), times, and perception of
difficulty in breathing.
All subjects were able to exercise in the control run until the air in
the bag-in-box was exhausted, whereas the flow-limited run was
invariably limited by the development of intense perception of
difficulty in breathing. Perception of difficulty in breathing during
the control run increased to an average Borg-scale rating of 3.9 ± 0.4 (i.e., close to "somewhat severe"; Table 1), whereas, when
flow was limited, perception of difficulty in breathing reached a
rating of 10 in all subjects but one, who stopped at a rating of 9 (mean 9.9 ± 0.1). The Borg-scale rating increased
nonlinearly with by the subjects on the
cycle ergometer, as shown in Fig. 1.
Maximum (max) reached in the
control run was 211 ± 8 W, corresponding to a 4.2 ± 0.2-min
exercise duration. Conversely, max reached during the
flow-limited run amounted to 141 ± 9 W, corresponding to a 2.8 ± 0.2-min exercise duration.
) of
subjects on cycle ergometer. Nos. in upper left of each
panel designate individual subjects. Bottom
right, mean data; solid lines and solid symbols,
flow-limited run; dashed lines and open circles, control run.
Pattern of ventilation. As shown in Fig. 2, expiratory-flow limitation led to an increase in both peak (
Ipeak)
and mean inspiratory flow. The former was double (5.6 l/s) that during
the control run (2.7 l/s) at 75% of reached in the
control run (max,c). As expected,
TE was prolonged, decreasing
duty cycle from 0.37-0.40 to 0.22-0.28 (not shown) and
increasing TT at
<50% of control. However, when, during flow
limitation, reached 50% max,c,
breath time was identical to control and was reduced compared with
control at higher values of max,c. Conversely, f was
less than control during flow limitation at values of
max,c <50% and greater at higher values.
VT initially increased during
flow limitation and was somewhat greater than control. It then leveled
off and subsequently fell to 60% of control at 75%
max,c. Thus, on average, during the flow-limited run,
breathing started out slower and deeper but, as exercise intensity
increased, became rapid and shallow. This resulted in a
reduced E at exercise workloads >25%
max,c.
E) in 2 conditions. Closed symbols, flow-limited run; open symbols, control
run. of subjects on cycle ergometer is expressed as
% reached during control run (max,c; determined by air content of bag-in-box).
During flow limitation, on average exercise was symptom limited at 75%
max,c.
Pressures. In Fig. 3, end-inspiratory (EIPes) and end-expiratory Pes (EEPes), as well as peak inspiratory (Pesmin) and peak expiratory Pes (Pesmax), are shown for the two experimental conditions. More negative end-expiratory pressure during the flow-limited run reflects an increase in EEVL and the consequent increase in elastic load on the inspiratory muscles. End-inspiratory pressures were also more negative during the flow-limited run, indicating increased end-inspiratory VL. There was marked recruitment of expiratory muscles during flow limitation so that average Pesmax exceeded 40 cmH2O at 75%
max,c, with individual values >50
cmH2O in three subjects.
Pesmin was more negative,
reflecting both hyperinflation and increased inspiratory flow rates.
max,c. 
, Peak expiration; 
, end expiration; 
, peak inspiration; 
, end inspiration. Starling, Starling resistor, flow-limited run.
Pga fluctuations during the control run were of modest amplitude and not very different from one workload to another. During the flow-limited run, there was a dramatic increase in abdominal expiratory muscle activity, as evidenced by the large increases in peak expiratory Pga (Pgamax), reaching >60 cmH2O in several subjects. During the control run, Pdi at end inspiration increased from an average of 7 to 22 cmH2O. The increase in end-expiratory Pdi from 0 to 7 cmH2O indicates that a passive Pdi due to stretching of the diaphragm occurred during expiration below FRC secondary to abdominal muscle recruitment. During the flow-limited run, end-inspiratory Pdi was greater than during the control run at all exercise levels, reaching an average of 27 cmH2O at 75%
max,c. Because FRC increased in all subjects but one,
the increase in end-expiratory Pdi during the flow-limited run was not
because of passive stretching of the diaphragm and must therefore
represent preinspiratory activity to overcome the threshold load due to dynamic hyperinflation. Only during midexpiration did we observe a Pdi
of zero during flow-limited exercise. Compared with the large changes
in Pga and Pes induced by the flow limitation, the changes in Pdi were
of relatively small amplitude.
Absolute VL.
As shown in Fig. 4, a shift in apparent
VL occurred during the
flow-limited run, as measured by the bag-in-box system. This was both
because of changes in EEVL as
well as an increase in body CO2
stores caused by CO2 retention, as
evidenced by an increase in
PETCO2 in seven out of nine
subjects. Assuming no changes in residual volume, we used
the VC maneuvers before and after exercise to correct for the shift
because of CO2 retention, allowing
an estimation of the increase in
EEVL at the end of exercise in
the flow-limited run. As can be seen in Fig. 4, VC
maneuvers 2-5 were not
different in amplitude (i.e., VC going from total lung capacity to
residual volume) but shifted with respect to baseline.
When corrected for this CO2
retention-induced shift, in all subjects but one the expiratory
flow-limitation led to dynamic hyperinflation, with an average increase
of EEVL of 1.4 ± 1.0 liters
(range 0-2.9 liters) during the flow-limited run. However, because
of the unknown effects of changes of
PETCO2 on
EEVL during the exercise,
EEVL could not be used as an
independent variable in the regression analysis. Because the lack of
air in the bag-inbox system at the end of the control run prevented
any VC maneuvers, we have no accurate estimates of
EEVL in those conditions, although the increase in EEPes during the control run would indicate a
decrease of EEVL.
PETCO2. In the flow-limited run, PETCO2 increased to higher levels, leading to significant CO2 retention in seven of the nine subjects (Fig. 5). In six subjects PETCO2 increased above 50 Torr. The reason for the increase in PETCO2 was, of course, the decrease in
E, as shown in Fig. 2, and
therefore a decrease in alveolar ventilation. At the end of exercise
this effect was aggravated by the decrease in
VT and the increase in f. One
subject (subject 2) reacted
differently compared with the others to the expiratory-flow limitation.
This subject adopted a very low initial f of 7 breaths/min and only
increased f to 12 breaths/min at the end of the run, when he reached
nine on the Borg scale and indicated that he could not endure the run any longer. He showed some dynamic hyperinflation early in the run but
then was able to maintain his
EEVL near FRC by prolonging expiratory time. Nevertheless, his pressure swings were sizeable, and
his PETCO2 increased
steadily to reach >60 Torr at end exercise.
of subjects on cycle ergometer. Nos. in
upper left of each panel designate individual subjects. Bottom right,
mean data; solid lines and open circle, flow-limited run; dashed lines
and solid circle, control run.
Correlates of perception of difficulty on breathing. In Table 2, the Pearson correlations between perception of difficulty in breathing and the various measured and calculated variables are shown. The first value shown for each variable corresponds to the mean ± SE of the individual correlations; the correlation of the pooled-data set is then shown in parentheses. The r values of the control run data are shown in the middle column, and those of the flow-limited run are shown in the far right-hand column. We chose to consider r values of 0.70 and greater to be relevant. In the control run the variables that correlated with the Borg scale with an r value >0.70 ranked in the following order:
E, peak inspiratory flow
(Ipeak),
Pesmax, Pes,
VT,
Pesmin, end-expiratory Pga, EIPes,
end-inspiratory Pga, and
PETCO2. During flow limitation, these variables were, in order, Pes,
Pesmax,
Pgamax, PETCO2, EIPes, Pga,
Pesmin,
Ipeak,
E,
Epeak,
and f. The r values for two variables
directly related to abdominal muscle use, namely,
Pgamax and Pga increased
considerably between the control and the flow-limited run.
PETCO2 was weakly associated
with the perception of difficulty in breathing in the control run but
strongly during flow limitation. Pdi did not relate well to
Borg-scale rating. On the basis of these outcomes we applied multiple
linear regression analysis, with the Borg scale as the dependent
variable, aiming to obtain the highest r2 with a minimum
of variables. With regard to pressures, the best relationships were
found with Pes, which includes both inspiratory and expiratory
effort (see Tables 3 and 4). Figure 6 shows the individual relationships between the Borg scale and Pes, the lines
representing the least squares linear regression lines for the two
experimental conditions. In several subjects the relationship between
the Borg scale and Pes tended to be slightly different in the two
conditions, with significantly different intercepts in three subjects
(subjects 2,
6, and
7). There were no significant differences in slopes. For the pooled data there was no significant difference in slope or intercept between the two conditions. As is
shown in Fig. 6, the relationship between
PETCO2 and the Borg score
was not the same in the two conditions. In several subjects, increases
in Borg rating occurred without an increase in
PETCO2.
PETCO2 had a negative slope
when included in the relationship between dyspnea and Pes for the control run and did not reach significant
P values. For the control run it was
therefore excluded from the final model. However, when all individual
data were pooled for both the flow-limited run and the combined data,
inclusion of PETCO2
significantly improved the relationships
(P < 0.001). The variance in
perception of difficulty in breathing rating in the pooled-data set
explained by the equations in Table 2 thus amounted to 79% for the
control run, 82% for the flow-limited run, and 83% for the combined
data. In an analysis of the data on an individual basis in the control run, Pes by itself could explain, on average, 90% of the variance of perception of difficulty in breathing. In two subjects,
PETCO2 significantly
improved the relationship between Pes and perception of difficulty
in breathing during the control run. In the flow-limited run, when
PETCO2 was added to the
model, significant T-values were
reached only in four of the seven subjects. The additional explained
variance in perception of difficulty in breathing was small (from a
mean of 92 to 95%). For the combined data per individual, the
additional explained variance in the Borg rating by adding
PETCO2 to the equation was
5%.
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Pes;
left) and perception of difficulty
in breathing and PETCO2
(right). Bottom right, mean data; solid lines and solid circles,
flow-limited run; dashed lines and open circles, control run.
Regression coefficients. In multiple regression analysis, when all independent variables in a model are expressed in the same units, the standardized regression coefficients (
) indicate the relative importance of the variables at
stake. In the pooled-data set, when only
Pesmin and
Pesmax (both log transformed to
achieve normal distributions) were included in the model, in the
control run, of Pesmin was 0.61 and that of Pesmax was 0.56. In the flow-limited run these amounted to 0.28 and 0.67, respectively.
In the pooled data, of Pesmax was again higher then
that of Pesmin (0.66 vs. 0.31). Because the scale of the inspiratory and expiratory pressures is the
same (cmH2O), these coefficients
can be directly compared. Pesmin
and Pesmax were thus of equal
importance in the control run, whereas in the flow-limited run
expiratory pressures appeared to have a greater impact on the model
then inspiratory pressures.
DISCUSSION
As expected, in the control exercise the hyperpnea of exercise led to an increased sensation of difficulty in breathing. During the flow-limited run, the subjects experienced an increased perception for a given exercise intensity compared with the control exercise. We used the Borg scale to quantify the perception during both exercises. There were three reasons to choose the Borg scale. First, it is a widely used scale for the study of perception of difficulty in breathing during exercise, allowing direct comparison of our results to those of others. Second, because of its design it retains interval and ratio properties and, therefore, mathematical manipulation of ratings is justified (11). Third, it is easy for subjects to understand, is highly reproducible in healthy subjects (19), and yields absolute values that allow direct comparison within and between subjects. However, whether it correctly scales psychophysiological sensation, maintaining ratio properties as claimed by Borg, is uncertain, although its widespread successful use attests to its utility (11). We scaled the sensation of difficulty in breathing, which means effort, not dyspnea specifically. However, invariably it was this sensation that limited exercise duration with expiratory-flow limitation.
In an acceptance of these limitations to the Borg scale, the main new finding of the present study in relation to the sensation of difficulty in breathing is that expiratory pressure is a significant contributor to the perception of dyspnea during exercise. To our knowledge this is the first study reporting this finding.
In the control run the linear regression analysis on the pooled data
showed almost identical regression coefficients () for Pesmax and
Pesmin (0.56 vs. 0.61), indicating
that they equally added to the explanation of the variance in
perception of difficulty in breathing. This is reflected in the similar
absolute amplitudes in expiratory and inspiratory changes in Pes as can
be seen in Fig. 3, top. We define
these amplitudes as the difference in pressure between the onset of
flow and the peak pressure obtained during inspiration or expiration,
e.g., the distance between the solid end-inspiration line and the
dashed peak-expiration line in Fig. 3,
top, for expiratory pleural pressure
swings. In the flow-limited run the coefficient for
Pesmax was greater than of
Pesmin (0.67 vs. 0.28, respectively). This may be explained by the much greater expiratory
changes in Pes during the flow-limited run compared with the
inspiratory swings (at end exercise; 72 vs. 30 cmH2O, respectively; see Fig. 3).
The individual linear relationships between perception and Pes were
highly significant (an average r2 of 0.90 and
0.92, for the control and flow-limited run, repectively) and did not
have a significantly different slope in the two conditions (Fig. 6). It
thus appears that the scaling between Pes and perception is the same
for inspiration and expiration. This is in agreement with the findings
of Chonan et al. (5), who found that, at rest, the relationship between
absolute mouth pressure swings and dyspnea was the same during
inspiratory and expiratory loaded breathing. It is also in agreement
with the findings of Muza et al. (15), who reported that, at rest, the
estimation of added loads on either inspiration or expiration led to
the same linear relationship between perceived magnitude and peak mouth
pressure (Fig. 3B in Ref. 15) that
linearly relates log perceived magnitude to log peak mouth
pressure, the slopes ~1 imply a linear relationship between the
untransformed variables. This leads one to the hypothesis that
the information relayed to the brain and leading to the development of
the increased sensation of difficulty in breathing, whether sensed during the inspiratory or expiratory part of the breathing cycle, arises through similar pathways and is processed in the same
way.
Pressure swings across the diaphragm did not explain much of the
variance in perception of difficulty in breathing. This finding is in
agreement with previous studies (3, 6, 7, 19) reporting that Pdi does
not relate well to effort sensation during loaded breathing. By
contrast, using Pes we could explain >90% of the variance of
perception of difficulty in breathing, both in the control and the
flow-limited run. Apart from a minor contribution from
PETCO2 in the flow-limited
run we have no data regarding the remaining 10% unexplained variance,
although part of it may obviously be due to sampling error.
The perception of difficulty in breathing gradually increases when constant-load exercise is continued for long periods (12). This increase relates to the duration of exercise, and it was speculated that this could be because of developing respiratory muscle fatigue (12). In the present experiment, muscle fatigue seems unlikely to have developed in the control run. It lasted for too short a time, and the ventilatory levels and pleural pressures that were reached were of modest amplitude. The flow-limited run only lasted 3 min, of which only the last minute introduced important additional elastic and resistive loads on the inspiratory and expiratory muscles. Measurable diaphragm fatigue is only present when exhaustion is reached after ~10 min while a subject is exercising at levels >85% maximal O2 uptake (9), and overt expiratory muscle fatigue only develops while a subject is breathing against an increased expiratory load after considerable time, when this fatigue adds to the sensation of inspiratory dyspnea (17).
Increased PETCO2 would be another plausible determinant of perception of difficulty in breathing. Most subjects showed significant CO2 retention toward the end of the flow-limited run, one subject reaching a PETCO2 value of >60 Torr. With the use of increasing PETCO2 as an indicator of adequacy of alveolar ventilation and a PETCO2 >49 Torr as indicating hypercapnic respiratory failure, several of our subjects developed respiratory failure. However, because none of the subjects showed a drop in inspiratory or expiratory pressures preceding the end of the exercise, ventilatory drive and the ability to convert drive into power were maintained throughout the exercise until the subjects voluntarily decided to stop because of maximum tolerable perception of difficulty in breathing. Interestingly, the statistical analysis showed that, compared with the importance of pleural pressure swings, as estimated from Pes, PETCO2 explained little additional variance in the sensation.
Some controversy still persists with regard to the role of the
chemosensitive respiratory centers in the sensation of breathing. According to Campbell et al. (4),
CO2 levels per se do not give rise
to a sensation of dyspnea. These authors argued that although an acute
rise of arterial CO2 does
certainly drive ventilation, in the absence of an increase in
ventilation dyspnea does not occur. In contrast, several recent studies
have indicated that a rise in arterial
CO2 tension can lead to dyspnea
without a rise in ventilation (1, 8). Part of this controversy seems to stem from semantics because the word "dyspnea" covers a broad range of symptoms in the same way that "pain" covers sensations of quite different quality (17). Although we accept that alterations in
blood CO2 tension sensed by the
chemoreceptors may contribute to breathing sensation, in the
experiments reported here its relative importance is indeed minor
compared with that of the Pes. This was so despite the fact that we
induced abnormal levels of CO2 in
the blood of our normal subjects. This finding is in agreement with the
recent findings of Clague et al. (6), who found that during
CO2 rebreathing the inspiratory
effort sensation was mainly related to the inspiratory rib cage
tension-time index, arterial CO2
tension having only a small independent effect on sensation.
Modest falls in arterial oxygen levels contribute little to the dyspnea experienced with exertion (13). In the present study we did not monitor blood oxygen levels. In the flow-limited run, the increase in PETCO2 would have induced some arterial oxygen desaturation, but its magnitude was probably small and consequently would have contributed little to the sensation of dyspnea.
The increased ventilatory demand during the exercise was met by
increases in both VT and f. In
the control run, the increase in
VT was accomplished by a
combination of a reduction in
EEVL and an increase in
end-inspiratory VL. This
strategy minimizes the shortening of the inspiratory muscles and
reduces inspiratory effort for a given
VT. During the flow-limited run,
end-expiratory volume could not be reduced, owing to the reduced
expiratory airflow, and, consequently, end inspiration occurred at an
ever higher lung volume, leading to dynamic hyperinflation. This
implies that the inspiratory muscles not only had to work against
increased elastic loads but also worked on a disadvantageous part of
the length-tension relationship, which increased the ratio of pressure required to breathe over pressure available. In addition, the decrease
in TI led to an increase in
inspiratory flow, which burdened the inspiratory muscles even more,
owing to an increased contraction velocity. When end-inspiratory lung
volume approached total lung capacity, f increased, entailing even
greater dynamic hyperinflation, forcing a reduction in
VT. During the flow-limited run,
all of these mechanisms changed the tension-time characteristics of
inspiratory and expiratory muscle activity compared with control.
However, the changes in
Ipeak,
Epeak,
or mean flows, as well as breath-time components (i.e., f,
TI,
TE,
TI/TT),
did not add much to the explanation of the variance in perception of
difficulty in breathing in the chosen model. This would argue against
an important role of changes in tension-time characteristics for
the perception of difficulty in breathing. By contrast, it would argue
in favor of a mechanism related to absolute changes in pleural
pressure.
We have no data on what receptors would have picked up such changes in the present experiment. We speculate that they are located in muscles and/or reflect corollary discharge from brain-stem respiratory centers. Certainly, the magnitude of pleural pressure swings, while not a direct measure of force produced by muscles, is nevertheless an index of muscle force. We believe that neither the diaphragm nor its drive is important for the sensation of breathing effort during exercise (Table 2). The drive to both nondiaphragmatic inspiratory muscles and expiratory muscles lumped together, or receptors within these muscles, would appear to be prime candidates for generating the sensation we measured. The neural drive to muscles is converted into force (pressure) and velocity of shortening (flow). Therefore, central corollary discharge may not correlate well with peripheral force receptors in muscles when velocity of shortening is large. This may point a way to distinguish between peripheral and central origins of respiratory sensation. Indeed, our data showing high Pearson correlation values for flow parameters as well as pressures (see Table 2) would indicate that both shortening velocity and force generation play a role in the sensation of effort and are consistent with the idea that corollary discharge from the brain stem respiratory centers to the cortex is important in breathing sensation.
The present results clearly indicate that further investigation into this field also needs to include expiratory components of respiratory activity. When this is done, our results as well as those of Muza et al. (15) and Chonan et al. (5) all show near-linear relationships between pressure swings and breathing effort sensation.
In patients with chronic airflow limitation (CAL), exercise is usually limited by shortness of breath rather than the physiological determinants that usually set the limits in healthy humans. In the present study, the subjects could not continue to exercise once they reached a Borg score of ten. Exercise was symptom limited by shortness of breath. Thus, in healthy humans, increased effort necessary to cope with increased demand on the ventilatory pump can lead to early symptom limitation of exercise performance. Although at first glance this may seem trivial, it has important implications on how we think about exercise limitation. For example, it would apply when exercising at high altitude, when ventilatory requirements for a given level of gas exchange are greatly increased beyond control levels at sea level, or at depth when increased gas density adds a resistive load and induces substantial flow limitation compared with sea level.
The present study was performed with healthy young subjects. CAL
patients show different behavior. Although they recruit expiratory muscles, both at rest and during exercise, they do not usually complain
of expiratory difficulty but rather of difficulty in breathing in (16),
possibly because the dynamic hyperinflation that is induced markedly
increases elastic work of inspiration while the inspiratory muscles are
forced to operate at disadvantageous lengths. Furthermore, during
dynamic hyperinflation when VT
approaches inspiratory capacity, E can
only increase by increasing f, further increasing
EEVL, forcing a decrease in
VT. Faced with this particularly vicious circle, it is not surprising that CAL patients complain of
shortness of breath during exercise as a difficulty in getting air in.
This difficulty is secondary to the expiratory flow-limitation that
prevents the expiratory muscles from decreasing
EEVL. It would thus appear that
in an investigation of shortness of breath, the distinction between
expiratory and inspiratory difficulty may be misleading. Expiratory
flow-limitation simultaneously increases expiratory muscle recruitment
and loads the inspiratory muscles. Thus, as our results indicate, both
inspiratory and expiratory muscle recruitement contribute equally to
the sensation of difficulty in breathing.
EEVL increased significantly during the flow-limited run (by 0-2.9 liters). Expiratory-flow limitation during exercise in healthy subjects therefore leads to significant dynamic hyperinflation. Our setup did not allow quantification of changes in EEVL during the control run, but the fact that EEPes during the control exercise was slightly higher than at rest indicates that EEVL was lower. Because EEPes in the flow-limited run, indicating the level of dynamic hyperinflation, did not relate well to breathing-effort sensation, it would appear that it was the pressure generated, necessary for breathing at those high VLs, rather then operative VL per se that triggered the increasing difficulty in breathing. However, the small absolute changes in end-expiratory pressures may have lacked sufficient statistical power for us to observe an effect, and experiments better designed to measure increases in EEVL continuously are needed to answer this question.
From Fig. 6, left, it appears that in
three subjects (subjects 2,
6, and
7) the relationship between Pes
and dyspnea was shifted to the right, with a different intercept but
similar slope during the flow-limited run compared with control. We
have no explanation for this finding. In the pooled-data set, the
relationships were not statistically different in the two conditions
(P = 0.82), having similar slope and
intercept. Although individual relationships between Pes and Borg
rating in the flow-limited run were invariably highly significant,
there was large interindividual variation with regard to the absolute
Pes reached at the various effort ratings. This would suggest that
Pes should perhaps be normalized to individual maximum values. We
made no attempt to do so. Indeed, because the large differences in
operative lung volume, in amplitude of inspiratory and expiratory flow,
and possible changes in chest wall configuration imply large
differences in pressure-generating capacity, normalization would have
posed major problems.
In conclusion, this study was designed to test the hypothesis that expiratory muscle activity, as reflected by an increase in Pes, is related to the perception of difficulty in breathing during exercise. The results clearly show that, in normal healthy subjects, during normal as well as expiratory flow-limited short-term exercise, the pressures developed by the expiratory muscles significantly contribute to this sensation. In a study of the determinants of dyspnea during exercise, it thus makes sense to include expiratory pressure as a variable and measure absolute pleural pressure swings (i.e., the difference between inspiratory and expiratory peak pressures) rather then inspiratory ventilatory parameters only.
ACKNOWLEDGEMENTS
This research was supported by the Medical Research Council of Canada and the Canadian Respiratory Health Network of Centres of Excellence Inspiraplex. B. Kayser was a recipient of a Merck-Frosst Fellowship and a grant from La Fondation Suisse pour Bourses en Medecine et Biologie.
FOOTNOTES
Address for reprint requests: B. Kayser, Dept. of Physiology, CMU, 1211 Geneva 4, Switzerland (E-mail bengt.kayser{at}medecine.unige.ch).
Received 13 May 1996; accepted in final form 10 June 1997.
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