COPD: Journal of Chronic Obstructive Pulmonary Disease, 7:428–437
ISSN: 1541-2555 print / 1541-2563 online
c 2010 Informa Healthcare USA, Inc.
Copyright DOI: 10.3109/15412555.2010.528087
ORIGINAL RESEARCH
Lung Hyperinflation and Its Reversibility in Patients
with Airway Obstruction of Varying Severity
Athavudh Deesomchok1 ([email protected]), Katherine A. Webb1 ([email protected]), Lutz Forkert1
([email protected]), Yuk-Miu Lam2 ([email protected]), Dror Ofir1 ([email protected]), Dennis Jensen1
([email protected]), and Denis E. O’Donnell1 ([email protected])
1 Department
of Medicine, Queen’s University & Kingston General Hospital, Kingston, Ontario, Canada
of Community Health and Epidemiology, Queen’s University, Kingston, Ontario, Canada
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2 Department
ABSTRACT
The natural history of lung hyperinflation in patients with airway obstruction is unknown.
In particular, little information exists about the extent of air trapping and its reversibility to
bronchodilator therapy in those with mild airway obstruction. We completed a retrospective
analysis of data from individuals with airway obstruction who attended our pulmonary function
laboratory and had plethysmographic lung volume measurements pre- and post-bronchodilator
(salbutamol). COPD was likely the predominant diagnosis but patients with asthma may have
been included. We studied 2,265 subjects (61% male), age 65 ± 9 years (mean ± SD) with a postbronchodilator FEV1 /FVC <0.70. We examined relationships between indices of airway obstruction and lung hyperinflation, and measured responses to bronchodilation across subgroups
stratified by GOLD criteria. In GOLD stage I, vital capacity (VC) and inspiratory capacity (IC)
were in the normal range; pre-bronchodilator residual volume (RV), functional residual capacity
(FRC) and specific airway resistance were increased to 135%, 119% and 250% of predicted, respectively. For the group as a whole, RV and FRC increased exponentially as FEV1 decreased,
while VC and IC decreased linearly. Regardless of baseline FEV1 , the most consistent improvement following bronchodilation was RV reduction, in terms of magnitude and responder rate.
In conclusion, increases (above normal) in airway resistance and plethysmographic lung volumes were found in those with only minor airway obstruction. Indices of lung hyperinflation
increased exponentially as airway obstruction worsened. Those with the greatest resting lung
hyperinflation showed the largest bronchodilator-induced volume deflation effects. Reduced air
trapping was the predominant response to acute bronchodilation across severity subgroups.
INTRODUCTION
Traditionally, the progression of respiratory impairment in
susceptible smokers is charted by the accelerating rate of decline in FEV1 over time (1). This approach, while useful and
convenient, gives only limited information about the relentless
Keywords COPD, Bronchodilator response, Lung volumes,
Disease severity
Correspondence to: Denis E. O’Donnell
102 Stuart Street
Kingston, ON
Canada K7L 2V6
phone: 1–613-548–2339
fax: 1–613-549–1459
email: [email protected]
428 December 2010
deterioration of respiratory mechanics that characterizes chronic
obstructive pulmonary disease (COPD). Progressive lung hyperinflation is another salient aspect of physiological deterioration
that until recently has been neglected and is the main focus of
this study. Given the clear association between lung hyperinflation, dyspnea, exercise intolerance (2), and mortality (3, 4), as
well as its partial reversibility to treatment, there is considerable
interest in evaluating the clinical utility of this physiological
“biomarker” in COPD.
One reasonable hypothesis, recently reiterated by Peter
Macklem (5), is that the progressive decrements in FEV1 largely
reflect the erosion of vital capacity (VC) as a consequence of
increasing residual volume (RV). In other words, FEV1 decline
mirrors the evolution of lung hyperinflation. Earlier small physiological studies have attested to remarkable heterogeneity in
the pathophysiology of mild COPD. Thus, there is evidence
that significant peripheral airway closure, maldistribution of
COPD: Journal of Chronic Obstructive Pulmonary Disease
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ventilation, disruption of ventilation-perfusion relations and air
trapping can exist (in highly variable combinations) in smokers
with minimal or no reduction in FEV1 (6–8). We have recently
reported that resting lung volumes [RV, functional residual capacity (FRC) and total lung capacity (TLC)] were consistently
increased in small groups of patients with significant exertional
dyspnea who met criteria for Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I COPD (9, 10). The
existence of air trapping in patients with ostensibly mild airway
obstruction has potentially important clinical implications that
remain to be studied (11).
There is evidence that lung hyperinflation at rest is partially reversible to bronchodilator therapy and that lung deflation
may in turn form the basis for improved respiratory symptoms
(12–15). Indeed, it can be argued that improvement in FEV1 following bronchodilator treatment mainly reflects recruitment of
VC as a result of reduced air trapping (i.e., reduced RV). Thus,
it is known that FEV1 /FVC ratio remains unaltered (or even decreases) after bronchodilator treatment at least in more advanced
COPD (12–14). The pattern of bronchodilator reversibility in patients with milder airway obstruction (i.e., expired flow versus
lung volume effects) is less well studied and will be examined
in this study.
The main objectives of this study were to: 1) examine relations between increasing airway obstruction and changes in
static lung volume components; 2) determine the nature and
extent of physiological impairment in patients with milder airflow obstruction; and 3) determine if the pattern of change in
airway function (i.e., flow versus volume response) following
acute bronchodilator inhalation would differ in mild and severe
airway obstruction.
We therefore conducted a retrospective analysis of a cohort
of individuals from our pulmonary function laboratory database
in whom plethysmographic lung volume measurements before
and after a bronchodilator were available. Although our study
population was likely comprised predominantly of patients with
COPD, we cannot exclude the possibility that some patients with
other obstructive airways diseases (i.e., asthma) were included
since complete information on smoking history and clinical
diagnosis was not available.
METHODS
Subjects and Design
This observational study involved a retrospective analysis of
pulmonary function test records collected between May 1992
and April 2008 at the Kingston General Hospital’s Pulmonary
Function Laboratory. Patients selected from this database were
referred for comprehensive pulmonary function tests with reversibility testing. Selection criteria included: males and females 40–80 years of age; body mass index 14–55 kg/m2 ;
post-bronchodilator FEV1 /FVC < 0.7; availability of postbronchodilator static lung volumes (by body plethysmography);
and the absence of a referral diagnosis of any lung disease other
than COPD.
In the case of repeated follow-up testing within a patient,
only the first visit meeting eligibility criteria was used in the
analysis. For analysis, subjects were stratified by GOLD stage
(16). Since risk of harm to patients was minimal and obtaining
patient informed consent impracticable, strict safeguards to ensure confidentiality of personal health data were implemented.
The Queen’s University and Affiliated Teaching Hospitals Research Ethics Board approved the use of this data and waived
the need for patient informed consent.
A group of our previously studied (17, 18), age-matched
(40–80 yrs), healthy non-smokers were used as control subjects to test the validity of the pulmonary function predictive
equations used in this analysis.
Procedures
Pulmonary function testing (spirometry, body plethysmography, single-breath diffusing capacity) was conducted by experienced respiratory therapists/technicians using automated pulmonary function testing equipment (2130 spirometer with 6200
Autobox DL or V6200 Autobox; SensorMedics, Yorba Linda,
CA) in keeping with current recommended standards (19–21).
Patients were required to withdraw from all short-acting and
long-acting bronchodilators for at least 4 and 12 hours, respectively. Reversibility testing (spirometry, body plethysmography)
was performed using salbutamol 200 mcg by metered dose inhaler; post-dose measurements were performed 20-min after
inhalation. Predicted normal values were those used in the laboratory at the time of testing (22–25); predicted IC was calculated
as predicted TLC minus predicted FRC, predicted ERV was calculated as predicted FRC minus predicted RV.
Statistical analysis
Values are reported as means ±SD unless otherwise specified. A p-value of < 0.05 was considered significant in all
analyses. A chi-square test for homogeneity was used to assess the differences between the proportions of gender within
the entire cohort and each GOLD stage. Differences between
means across genders were examined using the unpaired ttest. Frequency distributions were analyzed for normality using the one-sample Kolmogorov-Smirnov test. Non-normal distributions were further examined for skewness (symmetry) or
kurtosis (peakedness) which were considered significant if the
skewness or kurtosis coefficients were >2. Comparisons across
GOLD stages were analyzed using ANOVA; post-hoc testing of
significant variables was performed using t-tests with Bonferroni adjustment for multiple comparisons.
Bronchodilator responsiveness. To avoid bias from differences in baseline measurements, changes in FEV1 and various
lung volumes were assessed and compared as percentages of
predicted normal values (%pr) (26, 27). The occurrence of a
positive bronchodilator response was evaluated as frequency
statistics and compared using a chi-square test. A positive response cut-off for FEV1 of at least 10%predicted was selected
after considering consensus statements and outcomes of previous studies (12, 26, 27).
COPD: Journal of Chronic Obstructive Pulmonary Disease
December 2010
429
Subject characteristics
Sex, %male∗
Age, years
Height, cm
Body mass index, kg/m2
Post-bronchodilator FEV1 , L
Post-bronchodilator FEV1 , %predicted
Post-bronchodilator FEV1 /FVC, %
Pre-bronchodilator pulmonary function:
FEV1 , %predicted
FEV1 /FVC, %
FEF25–75, %predicted
FEF50, %predicted
TLC, %predicted
SVC, %predicted
IC, %predicted
IC/TLC, %
FRC, %predicted
RV, %predicted
RV/TLC, %
ERV, %predicted
sRaw, %predicted
SVC-FVC difference, L
DLCO , %predicted
DLCO /VA, %predicted
VA, % predicted TLC
TLC-VA difference, L
Healthy Controls (n = 128)
GOLD I (n = 620)
GOLD II (n = 1,129)
GOLD III/IV (n = 516)
50.0
63 ± 10
168 ± 9
26.4 ± 3.8
—
—
—
59.4
65 ± 10
166 ± 9
27.9 ± 5.3a
2.33 ± 0.61a
93 ± 10a
64 ± 5a
58.4
65 ± 9
166 ± 9
28.0 ± 6.1a
1.63 ± 0.43b
65 ± 8b
58 ± 8b
68.0
65 ± 9
167 ± 9
26.4 ± 6.2b
1.00 ± 0.28c
39 ± 8c
45 ± 10c
114 ± 16
75 ± 5
91 ± 32
84 ± 36
103 ± 11
112 ± 14
105 ± 18
47 ± 8
102 ± 19
95 ± 19
34 ± 7
123 ± 55
148 ± 55
0.16 ± 0.21
106 ± 21
113 ± 17
89 ± 11
0.84 ± 0.51
91 ± 9a
64 ± 6a
44 ± 14a
39 ± 13a
111 ± 13a
100 ± 12a
99 ± 18a
41 ± 8a
119 ± 24a
135 ± 32a
45 ± 8a
89 ± 47a
250 ± 122a
0.14 ± 0.18a
89 ± 23a
94 ± 25a
90 ± 12a
1.15 ± 0.61a
60 ± 10b
58 ± 8b
28 ± 10b
23 ± 10b
107 ± 17b
78 ± 13b
77 ± 17b
33 ± 8b
132 ± 30b
162 ± 43b
55 ± 9b
70 ± 38b
383 ± 183b
0.18 ± 0.20b
77 ± 21b
96 ± 27a
76 ± 13b
1.79 ± 0.86b
35 ± 8c
46 ± 10c
15 ± 6c
11 ± 5c
116 ± 22c
62 ± 13c
57 ± 16c
24 ± 7c
166 ± 40c
218 ± 62c
67 ± 8c
61 ± 34c
643 ± 321c
0.25 ± 0.24c
60 ± 19c
86 ± 32b
64 ± 14c
3.10 ± 1.23c
Values are means ± SD unless otherwise specified.
∗ p < 0.05 difference across GOLD groups by chi-square analysis.
a,b,c,d GOLD group means with different letters are significantly different from each other after Bonferroni adjustment for multiple comparisons (p <
0.05).
Abbreviations: DLCO , diffusing capacity of the lung for carbon monoxide; ERV, expiratory reserve volume; FEF25–75 , forced mid-expiratory flow;
FEF50, forced expiratory flow at 50% of forced vital capacity; FEV1 , forced expiratory volume in 1 s; FRC, functional residual capacity; FVC, forced
vital capacity; IC, inspiratory capacity; RV, residual volume; sRaw, specific airway resistance; SVC, slow vital capacity; TLC, total lung capacity; VA,
alveolar volume.
120
Lung volume (% predicted TLC)
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Table 1.
100
80
IC
60
ERV
RV
40
20
0
pre
Normal
pre post
GOLD I
pre post
GOLD II
pre post
GOLD III/IV
Figure 1. Pre- and post-bronchodilator static lung volumes are shown for each GOLD stage group compared with an age-matched healthy
control group. Residual volume (RV) and functional residual capacity (FRC) increased progressively as GOLD stage worsened. Total lung
capacity increased in GOLD stage I in conjunction with a preserved inspiratory capacity (IC), vital capacity (VC) and expiratory reserve volume
(ERV). IC and VC then decreased progressively in GOLD stages II and III/IV.
430
December 2010
COPD: Journal of Chronic Obstructive Pulmonary Disease
160
RV (%predicted)
FVC (%predicted)
RESULTS
Of the 2,265 subjects included in this analysis, 1,378 (61%)
were male and 887 (39%) were female. Pre-bronchodilator DLCO
measurements were available in 2,167 of the included subjects. As there were only 74 patients with a post-bronchodilator
FEV1 < 30%predicted and the presence of chronic respiratory
failure could not be confirmed, GOLD stages III and IV were
combined into one larger (n = 516) severe-to-very severe group
for evaluation in this analysis. There was a similar mean age
of 65 yrs within each gender group. GOLD stage distribution
was relatively similar in men and women, with the majority
in each gender meeting stage II criteria (48 and 53%, respectively). Measurements across age- and height-matched GOLD
stage subgroups are reported in Table 1. Lung volume components are summarized in Figure 1.
Measurements from our healthy control group (Table 1) indicated good validity of predictive equations for the majority
GOLD stage:
III/IV
II
I
500
120
100
80
60
400
300
200
100
40
20
volume-FEV1 relationship. All model fitting was examined using residual analysis and regression diagnostics were performed
to identify possible outliers and influential observations.
600
140
0
50
100
0
150
0
50
100
150
1600
200
sRaw (%predicted)
1400
DLCO (%predicted)
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Because no recognized criteria are available, we arbitrarily
selected a similar cut-off of at least 10% predicted for IC and
other measured lung volumes. A change of this magnitude falls
outside the 95% confidence interval for these measurements, as
well as outside the coefficient of variation for repeated measurements, in COPD (28, 29). In addition, we have previously
estimated that an increase in IC of ∼10%predicted (or ∼0.3 L)
results in clinically important improvements in exertional dyspnea intensity (i.e., reductions of at least 0.5 Borg Scale units)
and in exercise endurance (i.e., increases of 20% or more) in
moderate to severe COPD (14, 28).
Regression models. Post-bronchodilator measurements expressed as %pr were used for regression analyses evaluating
the effect of worsening airflow obstruction (FEV1 ) on lung volumes, specific airway resistance (sRaw) and diffusing capacity
(DLCO ). We first evaluated whether the relationship was linear
or non-linear using Box-Cox transformation (30). Regardless of
linearity/nonlinearity, we used GOLD stage grouping as a categorical variable for FEV1 and performed a two-way ANOVA
(with interaction) using GOLD stage grouping and sex as categorical variables. A significant interaction term (sex∗GOLD)
would indicate a difference between men and women in the
150
100
50
1200
1000
800
600
400
200
0
0
0
50
100
FEV1 (%predicted)
150
0
50
100
FEV1 (%predicted)
150
Figure 2. Relationships between forced vital capacity (FVC), residual volume (RV), diffusing capacity of the lung (DLCO ) and specific airway
resistance (sRaw) are shown against FEV1 (all measurements expressed as% of predicted normal values). FVC changed linearly with FEV1 ,
RV and sRaw both increased exponentially as FEV1 decreased, and DLCO decreased as FEV1 decreased.
COPD: Journal of Chronic Obstructive Pulmonary Disease
December 2010
431
of pulmonary function measurements but underestimated our
laboratory’s normative values by at least 5% for FEV1 , VC,
IC, ERV, sRaw, DLCO and DLCO /VA. Comparisons between the
GOLD I group and this age-matched control group showed that
all pre-bronchodilator pulmonary function measurements expressed as%predicted were significantly different (p < 0.0005)
between groups except for VA and the SVC-FVC difference,
which were similar.
except sRaw%pr in which females had higher sRaw (interaction
p = 0.0003). RV%pr increased in association with worsening
sRaw%pr (r = 0.66, p < 0.0005), FEV1 /FVC (r = −0.62, p <
0.0005),FEV1 %pr (r = −0.60, p < 0.0005) and FEF25–75%pr
(r = −0.46, p < 0.0005). RV and FRCincreased together (r =
0.90, p < 0.0005).
The DLCO -FEV1 relation was nonlinear (squared) with wide
scatter (Figure 2)while the relation between DLCO corrected for
alveolar volume (VA) and FEV1 was poor. As FEV1 worsened,
single-breath VA decreased linearly (r = 0.65, p < 0.0005) and
the TLC-VA difference increased exponentially.
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Frequency distributions of pulmonary function
measurements
Pre- and post-bronchodilator measurements expressed
as%predicted showed normal distributions for: FEV1 , FVC,
IC, SVC and TLC; as well as the IC/TLC, FRC/TLC and
RV/TLC ratios. These measurements were also normally distributed within each GOLD stage subgroup. Positive skewness
(significantly longer right tail) was shown in FEF50, FRC, RV,
ERV, sRaw and DLCO . However, the skewed distributions for
the group as a whole were largely combinations of normally
distributed GOLD subgroups, each with different means.
Bronchodilator reversibility
The magnitude of pre- to post-dose change in lung function
measurements across GOLD stages is shown in Table 2 and Figure 3a. There was a small but significant (p < 0.0005) increase
in post-bronchodilator FEV1 in all GOLD subgroups; however,
this increase was significantly smaller in stage III/IV than either
I or II. FEV1 /FVC changes were not consistent across subgroups
with a small increase of 0.4% (p = 0.002), no change (p = 0.97),
and a decrease of 1.4% (p < 0.0005) in stages I, II and III/IV,
respectively.
The magnitude of the FEV1 response correlated significantly
with the FVC response (r = 0.67, p < 0.0005). In all GOLD
groups, the RV response was greatest in magnitude; however, the
magnitude of reduction in RV became greater as GOLD stage
worsened (III/IV>II>I; p < 0.0005). Bronchodilator-induced
reductions in RV%pr correlated with increases in FEV1 %pr (r
= −0.39, p < 0.0005) and sRaw%pr (r = 0.48, p < 0.0005);
reductions in RV and FRC were strongly related (r = 0.81, p <
0.0005).
Relationships with worsening airway
obstruction
There was a linear relation between FEV1 %pr and FVC%pr
(r = 0.84, p < 0.0005) (Figure 2), SVC%pr (r = 0.79, p <
0.0005) and IC%pr (r = 0.67, p < 0.0005). Relations between FEV1 and each of sRaw (Figure 2), RV (Figure 2),
FRC and TLCwere curvilinear (exponential), each measurement expressed as%predicted. These relationships were unaffected by gender (i.e., non-significant GOLD∗sex interaction),
Table 2.
Bronchodilator reversibility: pre- to post-bronchodilator changes
FEV1 , L
%
%predicted
FEV1 /FVC,%
%predicted
FEF50, L/s
%predicted
TLC, L
%predicted
SVC, L
%predicted
IC, L
%predicted
FRC, L
%predicted
RV, L
%predicted
sRaw, mmHg/L/s ∗ L
%predicted
GOLD I (n = 620)
GOLD II (n = 1,129)
GOLD III/IV (n = 516)
0.15 ± 0.18
7±9
5.8 ± 6.8a
0.4 ± 3.7
1 ± 5a
0.13 ± 0.32
3 ± 8a
−0.06 ± 0.25
−1 ± 4a
0.15 ± 0.21
4 ± 6a
0.13 ± 0.26
5 ± 10a
−0.18 ± 0.29
−6 ± 9a
−0.21 ± 0.33
−6 ± 10a
−3.0 ± 3.6
−71 ± 85a
0.14 ± 0.16
11 ± 12
5.5 ± 6.0a
0.0 ± 4.0
0 ± 6a
0.07 ± 0.22
2 ± 6b
−0.12 ± 0.30
−2 ± 5b
0.20 ± 0.25
6 ± 7b
0.16 ± 0.26
6 ± 9a,b
−0.28 ± 0.34
−9 ± 11b
−0.32 ± 0.38
−15 ± 18b
−4.4 ± 4.8
−105 ± 115b
0.10 ± 0.12
13 ± 14
3.9 ± 4.1b
−1.4 ± 4.4
−2 ± 6b
0.03 ± 0.11
1 ± 3c
−0.15 ± 0.36
−2 ± 5b
0.27 ± 0.27
7 ± 7c
0.20 ± 0.26
7 ± 9b
−0.33 ± 0.43
−10 ± 13c
−0.42 ± 0.47
−19 ± 22c
−5.7 ± 7.0
−137 ± 185c
ANOVA p-value
< 0.0005
< 0.0005
< 0.0005
< 0.0005
< 0.0005
0.002
< 0.0005
< 0.0005
< 0.0005
Values are means ± SD.
= post- minus pre-bronchodilator change.
a,b,c,d means with different letters are significantly different from each other after Bonferroni adjustment for multiple comparisons (p < 0.05).
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December 2010
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Figure 3. Bronchodilator-induced changes in lung volumes are shown as (A) measured changes expressed as % of predicted normal and (B)
frequencies of a positive response defined as at least a 10 % of predicted improvement in that measurement. As GOLD stage worsened, the
FEV1 response became less important while other lung volume responses increased progressively.
Using the ATS criteria of at least a 12% and 200 mL improvement in FEV1 (31), the frequency of a positive response
was 22.6%, 28.6% and 16.7% in the GOLD I, II and III/IV subgroup, respectively. The frequency of a positive bronchodilator response assessed by an improvement of at least 10%pr in
each lung volume measurement across GOLD stages is shown
in Figure 3b; again, there were fewer FEV1 responders in the
GOLD III/IV subgroup. The frequency of a positive RV response was greater than for any other lung volume within
each GOLD stage subgroup, but increased progressively across
GOLD stages (p < 0.0005). The frequency of a positive response determined by spirometry alone or in combination with
plethysmographically-determined lung volumes is shown in
Figure 4. By considering changes in SVC and/or RV in addition
to FEV1 , a larger proportion of each GOLD subgroup showed
a positive response to a bronchodilator, especially in GOLD
stage III/IV. Reductions in sRaw by at least 10%predicted were
seen in 84, 86 and 85% of subjects in GOLD I, II and III/IV,
respectively.
DISCUSSION
The main findings of this study were as follows: 1) RV, FRC
and TLC were significantly increased above predicted values
in GOLD I; by contrast, VC and IC were largely preserved; 2)
for the whole group, the relation between increasing airflow obstruction and decreasing VC and IC was linear, whereas indices
of lung hyperinflation increased exponentially; 3) reduced air
trapping (reduced RV) was the most consistent response to a
bronchodilator across severity subgroups.
The unique features of this database are the inclusion of a
large population who met the criteria for mild airway obstruction and the availability of reliable pre- and post- bronchodilator
plethysmographic lung volumes. Given that these patients were
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Figure 4. The frequency of a significant bronchodilator response (change of at least 10% predicted) is shown when only spirometric measurements are taken into account (FEV1 alone, FVC alone or combination of FEV1 and FVC) (top). By considering plethysmographic lung volume
(RV and SVC) improvements in addition to spirometric FEV1 , greater rates of reversibility were uncovered (bottom). When volumes were taken
into account, the frequency of a positive bronchodilator response increased with worsening GOLD stage.
referred to a specialized pulmonary unit for assessment, it is
reasonable to assume that respiratory symptoms were present in
the majority. The three subgroups stratified by GOLD criteria
were well matched for age and height and had similar sex representation (i.e., 30–40% female). We validated our pulmonary
function normative reference values in a control group of ageand height-matched non-smokers. Plethysmographic lung volumes in our control group were well within the normal range
as predicted for the reference population, whereas spirometric
volume measurements in the control sample tended to exceed
the predicted normal values.
Mild airway obstruction
Individuals fitting GOLD I criteria (average postbronchodilator FEV1 of 93% predicted) had evidence of significant respiratory impairment which included increased lung
hyperinflation, increased specific airway resistance (to 250%
predicted) and reduced mid-volume expiratory flow rates (to
39% predicted) (all pre-bronchodilator values). RV was 0.73 or
35% above the predicted value, on average. The presence of an
increased RV signifies increased air trapping due to enhanced
airway closure during full expiration.
There is no consensus with respect to a definition of air
trapping but a RV exceeding the predicted value by more than
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December 2010
20% is generally thought to be significant. A greater than normal
RV has previously been reported in our own studies in GOLD I
patients (9, 10), as well as in an earlier (1966) Canadian study in
younger male smokers who had symptoms of chronic bronchitis
(32). Not surprisingly, the increased RV correlated well with
increased airway resistance and inversely with other measures
of reduced expiratory flow rates.
FRC was similarly increased by an average of 0.75 or 19%
above predicted normal in this group. In numerical terms, the increase in FRC was mainly explained by the increase in RV with
preservation of ERV. Increased FRC values correlated inversely
with FEV1 . Mechanistically, it could not be determined whether
the increased FRC was due to the effects of increased lung compliance or to heterogeneous alterations in the mechanical time
constants for gas emptying, or both. An earlier physiological
study showed that smokers with COPD with preserved FEV1
and FVC had measurable increases in static lung compliance
(7). It is therefore conceivable (but unproven) that alteration of
the elastic properties of the lung contributed to the consistent
increases in TLC and FRC that were present in the GOLD I
group.
In keeping with previous physiological studies (9, 10), the
VC and IC in the GOLD I group were not reduced in the face
of consistent increases in RV and FRC, respectively. This was
explained by the accompanying increase in TLC. Derived ratios
COPD: Journal of Chronic Obstructive Pulmonary Disease
(RV/TLV, IC/TLC and FRC/TLC) were also all within the expected ranges. The clinical relevance of increased air trapping
of this magnitude in GOLD I is unknown but it is reasonable
to assume that this may be linked to development of respiratory
symptoms such as exertional dyspnea in some individuals (9,
10).
DLCO measurements were lower than in the healthy control
group but varied widely. We could not control for the potential
effects of active tobacco smoking (33). However, the finding
that approximately 20% of the GOLD I subgroup had a DLCO
<70%predicted suggests that the surface area for gas exchange
was abnormal in some. Recent small studies have shown that
ventilation-perfusion disequilibrium and a widened alveolar to
arterial O2 tension gradient occur in the majority of patients
with mild COPD (34, 35).
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The continuum of lung hyperinflation
Relations between increasing airway obstruction
(FEV1 %predicted) and decreasing VC and IC (all postbronchodilator) were linear in this population. By contrast, the
relations between increasing airway obstruction and increasing
RV, FRC and TLC were exponential. Thus, there was a
disproportionate increase in indices of lung hyperinflation
as FEV1 and VC worsened to a critically reduced value. In
general, these data support the conclusion that progressive
decline in FEV1 in part reflects the concomitant reduction in
VC as a result of an increased RV.
However, it seems that at the extremes of airway obstruction,
RV and related volume components rise more precipitously in
tandem with sharper increases in sRaw and increases in the
TLC-VA difference. The disparity between worsening spirometry and increasing hyperinflation is not surprising given the
fact that FEV1 gives little information about the physiological
determinants of air trapping such as peripheral airway function,
the heterogeneity of mechanical time constants within the lungs
and breathing pattern (36, 37).
Bronchodilator reversibility of lung
hyperinflation
The pattern of reversibility varied across severity subgroups.
Thus, improvement in FEV1 was more likely in those fitting
GOLD I criteria than those with more severe airway obstruction. Additional measurements of change in static lung volumes
following bronchodilator therapy added little to evaluation of
bronchodilator efficacy in those with mild airway obstruction.
Among all lung volume components, the greatest effect (in terms
of effect size and responder rate) was reduction of RV. This was
true regardless of GOLD stage. RV changes correlated inversely
with changes in FEV1 and FVC across all three groups. The
fact that FEV1 mainly changed in proportion to changes in VC
supports the idea that lung volume recruitment as a result of
reduced RV is an important contributor to improved expiratory
flow rates.
sRaw consistently decreased after bronchodilator in the majority of subjects in all GOLD groups and was correlated with
change in RV. The magnitude of this change fell within one standard deviation of the mean across groups, therefore, the clinical
significance of this improvement is unclear.
Incremental decrements in FRC and reciprocal increases in
IC also occurred as GOLD severity increased. Consistent with
results of previous studies (12, 29), the largest lung volume deflation effect was seen in those with the most severe resting lung
hyperinflation. In GOLD III/IV, the majority (64%) showed a
significant volume reduction response while fewer in this group
had an FEV1 response, i.e., 5% and 17% by ERS and ATS
criteria, respectively. The true magnitude of bronchodilator reversibility may have been underestimated in our study due to
the fact that only a single beta2-agonist bronchodilator was used
and that there was a relatively short period of withdrawal of any
long-acting bronchodilators (12 hours) prior to testing. However, the disparity in flow versus volume responses is striking
and indicates that important improvements in the mechanical
time constants for lung emptying may occur independently of
change in FEV1 . Pharmacological lung volume reduction of the
magnitude seen in GOLD stages II-IV is likely important but
the clinical relevance of smaller such changes in GOLD I is less
certain (10).
Limitations
We utilized a hospital database consisting exclusively of
caucasians where information on smoking history, respiratory
symptoms, comorbidities, medications and healthcare utilization was not available. Therefore, the generalizability of our results to a broader population of patients with COPD is unclear.
However, our study sample is representative of the population
of older individuals with airway obstruction that is not fully reversible who seek pulmonary subspecialist care. We used GOLD
fixed ratio spirometric criteria for airway obstruction which may
lead to over-diagnosis of COPD in the elderly (38,39). However,
corroborating evidence of increased air trapping, increased airway resistance and configurational changes in the expiratory
flow-volume loop (all referenced to an age-matched control
group) suggest the presence of respiratory impairment beyond
the effects of healthy aging in the GOLD I subgroup.
CONCLUSIONS AND CLINICAL
IMPLICATIONS
The novel findings of this study were as follows. Individuals
with mild airway obstruction had relatively preserved vital
and inspiratory capacities but showed consistent evidence
of increased airway resistance and air trapping. This is the
first population study to demonstrate an exponential relation
between worsening airflow obstruction and indices of lung
hyperinflation. The most consistent physiological improvement
following acute bronchodilator therapy across GOLD stages
was reduced RV. Collectively, these results provide new insights
into the possible course of physiological deterioration in COPD
and prompt the question of whether pharmacological reduction
COPD: Journal of Chronic Obstructive Pulmonary Disease
December 2010
435
of air trapping in patients with milder airway obstruction is
clinically beneficial.
15.
ACKNOWLEDGMENTS
The authors wish to acknowledge the pulmonary function
laboratory staff Cathy Muir (RRT, RCPT(P)), Denis Faubert
(B.Sc., RRT) and Robin McHardy (RCPT(P)) for their careful
attention to detail when conducting the tests reported as part of
this study.
16.
17.
Declaration of interest
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The authors report no conflicts of interest related to this
manuscript. The authors alone are responsible for the content
and writing of the paper.
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