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Meakins-Christie Laboratories and Respiratory Division, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada H2X 2P2
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Koulouris, Nickolaos G., Ioanna Dimopoulou, Päivi
Valta, Richard Finkelstein, Manuel G. Cosio, and J. Milic-Emili.
Detection of expiratory flow limitation during exercise in COPD
patients. J. Appl. Physiol. 82(3):
723-731, 1997.
The negative expiratory pressure (NEP) method was
used to detect expiratory flow limitation at rest and at different
exercise levels in 4 normal subjects and 14 patients with chronic
obstructive pulmonary disease (COPD). This method does not require
performance of forced expirations, nor does it require use of body
plethysmography. It consists in applying negative pressure (
5
cmH2O) at the mouth during early expiration and comparing the flow-volume curve of the ensuing expiration with that of the preceding control breath. Subjects in whom
application of NEP does not elicit an increase in flow during part or
all of the tidal expiration are considered flow limited. The four
normal subjects were not flow limited up to 90% of maximal exercise
power output
(
max).
Five COPD patients were flow limited at rest, 9 were flow limited at
one-third max, and 12 were flow limited at two-thirds
max. Whereas
in all patients who were flow limited at rest the maximal
O2 uptake was below the normal
limits, this was not the case in most of the other patients. In
conclusion, NEP provides a rapid and reliable method to detect
expiratory flow limitation at rest and during exercise.
negative expiratory pressure; chronic obstructive pulmonary
disease; exercise performance; dynamic hyperinflation
INTRODUCTION THE HIGHEST PULMONARY ventilation that a subject can
achieve is ultimately limited by the highest flow rates that can be
generated. Most normal subjects do not exhibit expiratory flow
limitation, even during maximal exercise (2, 10, 13). In contrast, patients with chronic obstructive pulmonary disease (COPD) may exhibit
expiratory flow limitation at rest or at low work rates, as first
suggested by Potter et al. (25). They observed that patients with
severe COPD often breathe tidally along their maximal expiratory
flow-volume curve and suggested that this reflects the presence of
expiratory flow limitation (i.e., inability to further increase flow at
a given lung volume). By use of this approach, expiratory flow
limitation has been extensively studied in COPD patients at rest and
during exercise (1, 10, 17, 28). In many instances, however, the flows
obtained during tidal breathing actually exceeded those of the maximal
expiratory flow-volume curve (1, 10, 25). Several
explanations for this phenomenon have been offered: The first
explanation involves thoracic gas compression artifacts. In nearly all
previous studies, the flow-volume loops were obtained from measurements
of expired gas volume, although Ingram and Schilder (14) pointed out
that, to avoid gas compression artifacts, volume should be measured
with a body plethysmograph. The second explanation is incorrect
alignment of tidal and maximal expiratory flow-volume curves. Such
alignment is usually made on the assumption that the total lung
capacity (TLC) does not change during exercise and, hence, that changes
in inspiratory capacity (IC) reflect changes in end-expiratory lung
volume (EELV). Although several investigators have reported that TLC
does not change with exercise (21, 28, 32), others found that
it increases (11). Furthermore, this approach is based on the
assumption that during exercise the subjects can perform a truly
maximal inspiration. During exercise, however, some COPD patients may be incapable of performing IC maneuvers. The third explanation is the
effect of previous volume and time history. The maximal flows that can
be achieved during expiration depend on the volume and time history of
the preceding inspiration (4, 6, 9, 18). Because, by definition, the
previous volume and time history varies between tidal breathing and
maximal inspiration, it follows that assessment of flow limitation on
the basis of comparison of tidal and maximal flow-volume curves may
lead to erroneous conclusions, even if the measurements are done with a
body plethysmograph. The fourth explanation is the effect of muscular
exercise on lung mechanics. Exercise may result in bronchodilatation
and other changes in lung mechanics, which may affect tidal and maximal flow-volume curves (2, 28).
Assessment of expiratory flow limitation may also be based on
comparison of tidal flow-volume curves with those obtained during partial forced expirations. In this way, the previous volume history is
kept constant. The previous time history should also be kept constant.
Indeed, Wellman et al. (31) showed that in normal subjects the flows
attained during a partial forced expiratory maneuver depend on the
previous time history, similar to the maximal forced vital capacity
(FVC) maneuver (4). Whereas normal subjects may be trained to produce
partial FVC maneuvers with previous volume and time history similar to
that of the preceding tidal breaths, this is seldom feasible in most
patients with COPD, especially during exercise.
From the above considerations, it appears that detection of expiratory
flow limitation on the basis of comparison of tidal with maximal
flow-volume curves is questionable. Recently, however, an alternate
approach [negative expiratory pressure (NEP) method] has
been introduced (16, 30). This method does not require performance of
FVC maneuvers on the part of the patient, nor does it require use of a
body plethysmograph. It consists in applying a negative pressure at the
mouth during a tidal expiration and comparing the ensuing expiratory
flow-volume curve with that of the previous control expiration.
Accordingly, with this method the volume and time history of the
control and test expiration is the same. The NEP technique has been
previously applied and validated in mechanically ventilated patients in
the intensive care unit by concomitant determination of isovolume
flow-pressure relationships (30). It has also been used in stable COPD
patients at rest (16). The present investigation is designed to test the feasibility of using this method during exercise in COPD patients and normal subjects and to assess the implications of flow limitation on exercise performance. We have also assessed expiratory flow limitation by comparison of tidal with maximal expiratory flow-volume curves.
METHODS Four normal subjects and 14 patients with COPD ranging from mild to
severe were studied. Their anthropometric characteristics and lung
function data are given in Table 1. All
COPD patients, who were recruited from the respiratory outpatient
clinic, were in a stable clinical and functional state at the time of
the study and had no contraindications for exercise testing. None had a history of obstructive sleep apneas (OSA) or any evidence of upper airway obstruction. Routine spirometry was performed with a calibrated dry spirometer (1070 system, Medical Graphics, Minneapolis, MN), and
thoracic gas volumes were determined with a body plethysmograph (P. K. Morgan, Kent, UK). The predicted normal values for spirometric measurements were those of Morris and co-workers (20), and for thoracic
gas volumes the values of Goldman and Becklake were used (8). The study
was approved by the local Ethics Committee. All subjects gave informed
consent.
Table 1.
Anthropometric and lung function data of normal subjects and COPD
patients
n
Age, yr
Height, cm
Weight, %pred
Gender
FVC, %pred
FEV1, %pred
FEV1/FVC, %
IC, %pred
FRC, %pred
TLC, %pred
RV, %pred
Normal subjects
4
32 ± 3
177 ± 8
94 ± 6
2M, 2F
106 ± 7
108 ± 5
83 ± 4
COPD
patients
14
64 ± 9
166 ± 8
117 ± 20
10M, 4F
78 ± 20
58 ± 20
53 ± 11
80 ± 22
149 ± 37
117 ± 16
173 ± 42
Values are means ± SD. IC, inspiratory capacity; FRC, functional
residual capacity; TLC, total lung capacity; RV, residual volume;
FEV1, forced expired volume in 1 s; FVC, forced vital capacity; COPD, chronic obstructive pulmonary disease; %pred, percentage of predicted.
Figure 1 depicts the experimental setup
used to assess expiratory flow limitation. A flanged plastic mouthpiece
is connected to a Fleisch no. 3 or 4 pneumotachograph (Fleisch,
Lausanne, Switzerland) and a T tube. One side of the T tube is open to
the atmosphere, and the other side is equipped with a one-way pneumatic
valve that allows for the subject to be rapidly switched to negative pressure generated by a vacuum cleaner (Hoover Heavy Duty Portapower, model S7065-060, Hoover, Dayton, OH). The pneumatic valve
(occlusion valve setup, series 9300, Hans Rudolph, Kansas City, MO)
consists of an inflatable balloon connected to a gas cylinder filled
with helium and a manual pneumatic controller (Hans-Rudolph control switch 9301). The latter permits remote-control balloon deflation, which is accomplished quickly (30-60 ms) and quietly, allowing rapid exposure to negative pressure during expiration (NEP). The NEP
(usually set at about 5
cmH2O) (16) could be adjusted with a potentiometer (Powerstat, Superior Electric, Bristol, CT).
, flow.
Airflow was measured with the heated Fleisch pneumotachographs
connected to a differential pressure transducer (Validyne MP45, ±2
cmH2O). This is one of the most
symmetrical transducers available, with a common-mode rejection ratio
of 70 dB at 30 Hz (7). The response of the pneumotachographs,
calibrated with a rotameter, was linear over the experimental range of
flows. Pressure at the airway opening (Pao) was measured through a side
port on the mouthpiece using a differential pressure transducer
(Validyne MP45, ±88 cmH2O). With this system there was no appreciable shift or alteration in
pressure amplitude up to 20 Hz. The breathing assembly had a dead space
of 220 and 410 ml with Fleisch pneumotachographs no. 3 and 4, respectively, and the corresponding pressure-flow relationships were
characterized by the following equations: P = 0.16 + 0.312 and P = 0.17 + 0.222, where P
is pressure (in cmH2O) and
is flow (in l/s). The Fleisch no. 4 pneumotachograph was used only by the normal subjects. In two normal
subjects and two COPD patients we also measured the esophageal pressure
(Pes), as previously described in detail (3). The flow and pressure
signals were amplified (model 8085, Hewlett-Packard, Waltham, MA) and
sampled simultaneously at a rate of 100 Hz using a computer data
acquisition system with a built-in 16-bit analog-to-digital converter
(AT-Codas, DATAQ Instruments, Akron, OH). Collected data were stored on
a computer disk for subsequent analysis. Volume was obtained by
numerical integration of the flow signal. The flow signal was corrected
for any offset on the basis of the assumption that inspired and expired
volume of the preceding control breath were the same (24). This
analysis was made using ANADAT data analysis software (ANADAT 5.1, RHT-InfoDat, Montreal, Quebec, Canada).
max),
O2 uptake
(O2 max),
ventilation, and heart rate were determined (Table
2). The predicted normal values for
O2 max and maximal
heart rate were those of Jones and Campbell (15). On the study day,
each subject underwent steady-state constant workload tests at
one-third and two-thirds
max at least 2 h after eating or drinking coffee. During these tests the patients breathed room air through the equipment assembly while wearing noseclips (Fig. 1). Measurements were also made at rest with subjects seated on the bicycle ergometer in the same position as during exercise. Each subject performed an initial 10- to 15-min trial run of
resting breathing to become accustomed to the apparatus and procedure.
The time course of Pao, flow, and volume, together with the
corresponding flow-volume loops, were continuously monitored on the
computer screen. After regular resting breathing had been achieved, the
maximal expiratory flow-volume curves were measured. Because flows
during FVC depend markedly on previous time and volume history (4), the
maneuvers were standardized by using a rapid inspiration to TLC from
resting EELV without an end-inspiratory pause. After resting breathing
was resumed, a series of three to five test breaths were performed in
which NEP (5 cmH2O) was applied during early expiration and maintained throughout the ensuing
exhalation (Fig. 2). Then the subjects were
asked to perform three IC maneuvers at intervals of ~30 s.
Subsequently, the external workload was set first at one-third and next
at two-thirds
max. After a
constant breathing pattern had been reached at each workload, NEP was
applied in a manner similar to that during resting breathing. Subsequently, at both levels of exercise, the patients were asked to
perform three IC maneuvers at intervals of ~30 s. At each exercise level it was assumed that TLC was reached with the highest IC (21, 32),
and this IC was used to place the tidal within the maximal flow-volume
loop. In the normal subjects, similar experiments were also carried out
at 90% max.
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-V) curves from representative normal
subject at rest and at 3 levels of exercise, expressed as a fraction of
maximal power output
(max). Zero
volume represents end-expiratory lung volume at rest. In each instance,
-V loops of 2 consecutive breathing cycles are shown:
that of a test breath during which negative expiratory pressure (NEP)
of 5 cmH2O was applied
during expiration and that of preceding control breath. NEP was applied during early expiration (1st arrow) and maintained throughout expiration (2nd arrow). In all instances, NEP elicited a sustained increase in flow, reflecting absence of expiratory flow limitation. Dotted line, expiratory -V curve obtained during
forced vital capacity maneuver.
Principle of NEP method and data analysis. The NEP method to detect expiratory flow limitation has been previously described in detail (16, 30). It is based on the principle that in the absence of preexisting flow limitation the increase in pressure gradient between the alveoli and the airway opening caused by NEP should result in increased expiratory flow (Fig. 2). By contrast, in flow-limited subjects, application of NEP should enhance dynamic airway compression downstream from the flow-limiting segments without substantial effect on pressure or flow upstream. Under these conditions, expiratory flow does not change with NEP, except for a brief flow transient (i.e., spike), which in our experiments should mainly reflect a sudden reduction in volume of the compliant oral and neck structures. To a lesser extent, however, enhanced dynamic airway compression and a small artifact due to the common-mode rejection ratio of the system for measuring flow may also contribute to the flow transients. In this connection, it should be noted that the flow spikes can be regarded as a characteristic marker of flow limitation (16, 30). On the basis of the above considerations, our analysis essentially consists in comparing the expiratory flow-volume curve obtained during a control breath with that obtained during the subsequent expiration in which NEP is applied. Subjects in whom application of NEP did not elicit an increase in flow during part or all of the tidal expiration were considered flow limited. By contrast, subjects in whom flow increased with NEP throughout the control tidal volume (VT) range were considered not flow limited. In agreement with a previous study (16), application of NEP was not associated with unpleasant sensations or cough, nor was there any evidence of upper airway collapse. Indeed, with NEP the expiratory flow increased (reflecting absence of flow limitation) or did not change (reflecting presence of flow limitation). There was no instance in which application of NEP resulted in a sustained decrease in expiratory flow. Flow limitation was also assessed by comparison of tidal with maximal expiratory flow-volume curves based on expired volume (13). Hereafter this method is called the "conventional" method. Patients in whom, at comparable lung volumes, flows during tidal expiration were similar to or higher than those obtained during the FVC maneuver were considered "flow limited" (16, 25). Statistical analysis was made using Dunnett's test of multiple comparisons and unpaired t-test, where appropriate. P
0.05 was taken as
significant. Values are means ± SD.
RESULTS
Figure 2 depicts flow-volume loops obtained at rest and at three levels
of steady-state exercise in a representative normal subject. In all
instances the application of NEP resulted in increased expiratory flow
over the entire range of control tidal volume (VT), indicating absence of
expiratory flow limitation up to 90% max. Also shown
in Fig. 2 is the maximal expiratory flow-volume curve obtained at rest.
In all instances the latter exceeded those used to sustain resting and
exercise ventilation. With increasing exercise level, the
end-inspiratory lung volume (EILV) increased while the EELV tended to
decrease. Similar results were found in the other three normal subjects
studied. In all instances the results were reproducible with repeated
NEP tests. The average values of EILV and EEVL during exercise of
the four normal subjects are depicted in Fig.
3.
max in 4 normal
subjects. EILV and EELV, end-inspiratory and end-expiratory lung
volume; IRV, inspiratory reserve volume;
VT, tidal volume. 
, Average
values; bars, SE. P < 0.05, significant change relative to EELV at rest.
Figure 4 illustrates flow-volume loops of
COPD patient 4 at rest and during
exercise. In all instances, the application of NEP did not elicit an
increase in flow, except for a transient increase (i.e., spike)
coincident with NEP application. This transient mainly reflects
reduction in volume of the airways and heralds flow limitation (see
METHODS). Thus, according to NEP,
this patient had expiratory flow limitation at rest as well as during
exercise. Also shown in Fig. 4 is the maximal expiratory flow-volume
curve. The tidal expiratory flows largely exceeded the maximal flows at
rest and during exercise. Thus, according to the conventional method
for detecting flow limitation, this patient would also be classified as
flow limited. In this patient, EILV and EELV increased progressively
with increasing exercise load. Similar results were found in
patients 2, 5, 8, and
14.
-V curves, as in Fig. 2, from
patient 4 with chronic obstructive
pulmonary disease (forced expired volume in 1 s = 33% predicted). In
all instances, there was no change in expiratory flow with NEP, except
for a flow transient (spike) at onset of NEP application. Such
relationships indicate presence of expiratory flow limitation at rest
and during exercise. Insp, inspiration.
Figure 5 depicts results obtained in COPD
patient 1, who, according to the NEP
test, was not flow limited at rest but became flow limited at one-third
and two-thirds
max. At rest the
tidal flows were essentially superimposed on the maximal expiratory flow-volume curve, whereas during exercise the tidal flows exceeded the
maximal expiratory flow-volume curve. Thus at rest the patient would be
classified as flow limited with the conventional method but not flow
limited with the NEP test. During exercise, flow limitation was
detected with both methods. However, at one-third max, flow
limitation with NEP encompassed only the last 30% of
VT, whereas the maximal
expiratory flow-volume curve was superimposed with a larger fraction of
the tidal expiratory flow-volume curve (~70%
VT). In this patient, EILV was
close to TLC even at rest, and during exercise there was little change
in EELV or VT.
-V curves, as in Fig. 2, from
patient 1 with chronic obstructive
pulmonary disease (forced expired volume in 1 s = 45% predicted). With
NEP, flow increased at rest but not during exercise, indicating that
expiratory flow limitation was present at both levels of exercise but
not at rest. With conventional test, patient would be classified as
flow limited at rest and during exercise.
Figure 6 depicts the time course of flow,
volume, Pao, and Pes during a control breath and the subsequent
expiration with NEP, together with the corresponding flow-volume and
Pes-volume loops, at rest in a COPD patient who was flow
limited and in a normal subject. In the flow-limited patient, the time
course of flow, volume, and Pes was not affected by NEP, except for the characteristic initial flow transient. Apart from the latter, the
flow-volume and Pes-volume loops obtained with NEP were essentially the
same as in the preceding control breath. This indicates that NEP did
not elicit changes in respiratory muscle activity. By contrast, in the
non-flow-limited subject, the increase in flow elicited by NEP was
associated with a slower increase in Pes at any given time during
expiration (Fig. 6Ba). An increase
in flow would per se be expected to result in more negative Pes at any given time of expiration because of
1) increased pressure dissipations due to the Newtonian resistance of the chest wall,
2) decreased elastic recoil pressure
of the chest wall due to faster lung deflation, and
3) increased antagonistic pressure
exerted by the breaking action of the inspiratory muscles, which are
active during expiration (19, 27). That is, during pliometric
contraction the force exerted by a muscle increases with increased
velocity of lengthening (19). With NEP, Pes at any given volume was
more negative than during the control expiration (Fig.
6Bb). Apart from
mechanisms 1 and
3, this phenomenon was also related to
the postinspiratory activity of the inspiratory muscles (PIIA) (19,
27). Indeed, even if the magnitude and rate of decay of PIIA were the
same with and without NEP, Pes at any given lung volume should be lower with NEP, because, as a result of faster exhalation, PIIA has less time
to decay. Thus, also in the subject without flow limitation, there was
no evidence that NEP elicited appreciable changes in activity of the
respiratory pump muscles. Similar results were found in the other two
subjects in whom Pes was measured.
According to the NEP results, our 14 COPD patients could be subdivided
into four groups: 1) flow limited
from rest (n = 5), 2) flow limited from one-third
max
(n = 4),
3) flow limited from two-thirds
max
(n = 3), and
4) not flow limited up to two-thirds max
(n = 2). Assessment of flow limitation
based on comparison of tidal with maximal flow-volume curves yielded
different results (Table 3). With the
conventional method, nine COPD patients would have been classified flow
limited at rest, whereas with NEP flow limitation was present in only
five of the COPD patients. Similarly, at one-third
max, 12 patients
were flow limited according to the conventional method but only 9 were
flow limited with NEP. Furthermore, one patient who was not flow
limited according to the conventional method was found to be flow
limited with NEP. Thus, at one-third
max,
consistent results were obtained with the two methods in only 8 patients, whereas consistent results were found in 10 patients at
two-thirds max.
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In all our COPD patients who were flow limited from rest or one-third
max, flow
limitation at two-thirds
max
encompassed >60% of the VT
(flow-limited range 64-78%
VT; Fig. 5). In contrast, in the
three patients who became flow limited only at two-thirds max, flow
limitation at this level of exercise was 13-55% of control
VT.
The presence of flow limitation at rest implies that the increased
ventilation during exercise should be associated with dynamic pulmonary
hyperinflation (25, 26). Indeed, in our COPD patients who were flow
limited at rest, the EELV increased significantly at both exercise
levels studied (Fig. 7,
left). Similarly, in the patients
who became flow limited at one-third
max, there was a
significant increase in EELV only at two-thirds
max (Fig. 7,
middle). In contrast, in the other
patients there was no significant change in EELV over the entire
exercise range studied (Fig. 7, right).
max, and flow
limited or not flow limited at two-thirds
max.
, Average values; error bars, SE.
The five COPD patients who were flow limited from rest exhibited a
significantly lower IC (percent predicted) than the other COPD patients
(Table 4). If flow limitation is present at
rest, with a concomitant decrease in IC,
VTmax
during exercise should also be reduced. Indeed, a very low
VTmax was a
characteristic feature of the five COPD patients who were flow limited
from rest (Fig. 8). In four of these
patients the low
VTmax was
associated with a low maximal ventilation, whereas severe tachypnea was
present in the fifth patient. In all five of these patients the values of O2 max (percent
predicted) were below the normal range (<80% predicted). In
contrast, in only two of the other nine COPD patients was the
O2 max below the normal
range (77 and 78% predicted, respectively). However, there was no
significant difference in O2 max (percent
predicted) among the three groups of COPD patients (Table 4), probably
mainly reflecting the small number of patients studied.
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max of normal
subjects and 3 groups of patients with chronic obstructive pulmonary
disease. Error bars, SE. * P < 0.001, relative to FL at rest. Maximal
VT of normal subjects were
significantly higher than those of patients with chronic obstructive
pulmonary disease (
P < 0.001).
In the COPD patients who were flow limited from rest, forced expired
volume in 1 s (FEV1) and FVC
were significantly more impaired than in the other COPD patients (Table
4). Figure 9 depicts the individual values
of FEV1 (percent predicted) of the COPD patients classified according to NEP. Although four of the five
patients who were flow limited from rest had severe airway obstruction
(FEV1 < 49% predicted), one had
only moderate airway obstruction
(FEV1 = 63% predicted) (22).
Furthermore, a patient with severe airway obstruction was not flow
limited at one-third max, and another
was not flow limited even at two-thirds
max.
max, 3 who were
flow limited from two-thirds
max, and 2 who were not flow limited up to two-thirds
max.
Figure
10B
depicts the
O2 max-FEV1
relationship of the 14 COPD patients and the 4 normal subjects.
Although the correlation was highly significant, there was considerable
scatter of the data. Less scatter was found when
O2 max was correlated
with VTmax
(Fig. 10A).
O2 max-maximal
VT
(VTmax)
relationship (A) and
O2 max-FEV1
relationship (B) in 14 patients with
chronic obstructive pulmonary disease (COPD) and 4 normal subjects.
Average regression lines and 95% confidence limits are shown.
DISCUSSION
The present results indicate that NEP provides a simple and reliable
method for on-line detection of expiratory flow limitation at rest and
during exercise. Flow limitation at rest is associated with low values
of O2 max and
VTmax,
which are probably mainly due to dynamic pulmonary hyperinflation (3,
21, 26). In agreement with previous results obtained in COPD patients
at rest (16), the present study indicates that the conventional method for detecting flow limitation based on comparison of tidal with maximal
flow-volume curves is not reliable. Before further discussion of the
present results, however, some methodological considerations are
required.
11 to
40 cmH2O, which is
considerably more subatmospheric than our value of NEP (5
cmH2O). Furthermore, our subjects
were studied in the sitting position, and none had a history of OSA or
any evidence of upper airway obstruction. Not surprisingly, therefore,
we did not find any instance of airway closure in our study. This is in
agreement with a previous study in which NEP of 5
cmH2O was applied to COPD patients
at rest in the sitting and the supine position (16).
Although there was no airway collapse, application of NEP could have
resulted in increased flow resistance due to passive upper airway
narrowing. This would imply that the increase in flow with NEP observed
in our normal subjects and non-flow-limited COPD patients was in part
counterbalanced by a concomitant increase in flow resistance. In the
limit, the increase in resistance could be such that, with NEP,
expiratory flow would not change at all, and hence the NEP test would
not be valid. A similar scenario could be argued in terms of modulation
of respiratory muscle activity: in the face of NEP, the expiratory flow
could be maintained unchanged by appropriately modulating the
respiratory pump muscle activity. However, such perfect and immediate
load compensation is highly unlikely and has not been previously
reported in the vast literature dealing with respiratory loading (19).
Furthermore, our measurements of Pes indicate that NEP does not elicit
appreciable changes in activity of the respiratory pump muscles (Fig.
6). In this connection, it should be noted that in humans NEP increases
the activity of the upper airway muscles, which tends to maintain the
upper airway dilated (12). In this context, it should also
be noted that most of our subjects were also studied with different
values of NEP (range 5 to 10
cmH2O). In the non-flow-limited
subjects the increase in flow was proportional to NEP magnitude,
whereas in the flow-limited patients flow did not change indepedent of NEP value. It should be stressed that in flow-limited patients an
increase in airway resistance with NEP should not necessarily result in
decreased flow. Indeed, Valta and co-workers (30) used added expiratory
resistances to detect expiratory flow limitation and found that in
flow-limited patients expiratory flow did not change with added
expiratory resistances until this reached a critical value. Such
behavior is consistent with flow limitation. Similarly, in flow-limited
patients an increase in expiratory pump muscle activity associated with
NEP should also result in no change in expiratory flow.
Flow limitation and exercise performance.
In agreement with previous reports (2, 10, 13), we found that in normal
young subjects there is no evidence of expiratory flow limitation
during submaximal exercise (up to 90%
max). By
contrast, most of our COPD patients were flow limited at rest or during
light exercise (one-third
max). Two COPD
patients, however, were not flow limited even at two-thirds
max. In
the patients who were flow limited from rest, the values of
O2 max were
below the normal limits. This was associated with a low
VTmax (Fig.
8), probably reflecting severe dynamic pulmonary hyperinflation. If
flow limitation is present during resting breathing, any further increase in ventilation should result in enhanced pulmonary
hyperinflation, which is associated with increased inspiratory work due
to intrinsic positive end-expiratory pressure and impaired inspiratory
muscle function, and will necessarily limit
VTmax (3,
21, 26). Indeed, in these patients, pulmonary hyperinflation tended to be more pronounced not only at rest (Table 4) but also during exercise
(Fig. 7).
Whereas in all five COPD patients who were flow limited at rest the
values of O2 max were
<80% of predicted, this was the case in only two of the other nine
patients. Furthermore, in two of these nine patients,
O2 max
was 129% of predicted. This suggests that, in the patients who are not
flow limited at rest, exercise performance is not necessarily limited
by ventilatory constraints, as is the case in the patients who are flow
limited at rest. This suggests that the abnormally low values of
O2 max exhibited by two
of the COPD patients who were not flow limited at rest (77 and 78%
predicted) probably reflect physical deconditioning due to a sedentary
life (1).
Flow limitation and dynamic pulmonary hyperinflation.
Pulmonary hyperinflation is defined as an increase in functional
residual capacity (FRC) above predicted normal. This may be due to an
increase in the relaxation volume
(Vr) of the respiratory system
resulting from loss of lung elastic recoil (e.g., emphysema) or to
dynamic pulmonary hyperinflation, which is said to be present when FRC
exceeds Vr (26). Predictably, the
group of patients who exhibited expiratory flow limitation at rest had,
on average, a higher FRC (percent predicted) and a lower IC (percent
predicted) than the other COPD patients (Table 4). This was probably
due to dynamic hyperinflation caused by expiratory flow limitation as
well as increased Vr. The COPD
patients who were not flow limited at rest also exhibited an increase
in FRC and a decrease in IC, although it was less pronounced than in
the other patients. In this case, the hyperinflation probably reflected
increased Vr, as well as dynamic
hyperinflation, which may be present in the absence of flow limitation.
This tends to occur when expiration is impeded (e.g., increased airway
resistance, persistent contraction of inspiratory muscles during
expiration) or when expiratory time is shortened (19, 23, 26). Lung
units with slow time constant may exhibit dynamic hyperinflation during
resting breathing in the absence of overall expiratory flow limitation.
Such regional dynamic hyperinflation may also contribute to the
increase in FRC in the COPD patients who are not flow limited at rest.
In agreement with previous studies (1, 10, 17, 21, 25, 28, 32),
we found that whereas in normal subjects there was a reduction in EELV
with exercise, this was not the case in the COPD patients in whom the
changes in EELV were mainly dictated by flow limitation. Indeed, in the
patients who were flow limited at rest the EELV increased significantly
at both levels of exercise studied (Fig. 7,
left), whereas in those who became
flow limited at one-third
max the EELV
increased significantly at two-thirds max (Fig. 7,
middle). In the remaining five
patients there was no significant change in EELV with exercise. In this
connection, it should be noted that the latter group of patients
included two individuals who were not flow limited even at two-thirds
max. Nevertheless, in both patients the EELV did not decrease with exercise,
as in normal subjects. This probably reflects the fact that during
exercise in these two patients the lung units with the lowest time
constant exhibited dynamic hyperinflation, and, as a result, the
overall EELV did not change significantly.
Pellegrino et al. (23) suggested that compression of the airways
downstream from the flow-limiting segment may elicit a flow reflex
mechanism that influences the breathing pattern by terminating
expiration prematurely, thus increasing the EELV. In this way,
ventilation may be increased with flow limitation being absent over
most of the VT, and hence flow
limitation should be found only near end expiration. Results consistent
with this hypothesis were found by Babb et al. (1) in patients with
mild-to-moderate airflow obstruction. This, however, does not appear to
be the case in our COPD patients in whom the values of
FEV1/FVC were lower than those in
the patients studied by Babb et al. (53 ± 11 vs. 74 ± 8%
predicted). Indeed, in the nine COPD patients who were flow limited
from rest or one-third
max,
flow limitation at two-thirds
max encompassed
64-78% of VT. Furthermore,
in the three patients who became flow limited only at two-thirds max, there was
no significant increase in EELV, although flow limitation was
present over 13-55% of VT. Thus in our COPD
patients the increase in EELV with exercise appears to be mainly a
passive response to expiratory flow limitation.
O'Donnell and Webb (21) showed that in COPD patients there is a close
association between the increase in EELV and the severity of dyspnea. A
similar association has been found between the degree of flow
limitation at rest and chronic dyspnea (Medical Research Council score)
(5).
In conclusion, the NEP method provides a simple and reliable method for
detecting expiratory flow limitation at rest and during exercise. The
method does not require body plethysmography or the patient's
cooperation and coordination and can be applied in any desired body
posture. In our COPD patients, flow limitation at rest was associated
with impaired exercise capacity mainly due to pulmonary hyperinflation.
ACKNOWLEDGEMENTS
The authors thank Maria Makroyanni for typing the manuscript and Dr. H. Ghezzo for help with the statistical analysis.
FOOTNOTES
Address for reprint requests: J. Milic-Emili, Meakins-Christie Laboratories, McGill University, 3626 St. Urbain St., Montreal, Quebec, Canada H2X 2P2.
Received 5 September 1995; accepted in final form 22 October 1996.
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