J Appl Physiol 119: 266–271, 2015.
First published June 5, 2015; doi:10.1152/japplphysiol.00455.2014.
The effect of increased lung volume in chronic obstructive pulmonary disease
on upper airway obstruction during sleep
Paolo Biselli,1,2 Peter R. Grossman,1 Jason P. Kirkness,1 Susheel P. Patil,1 Philip L. Smith,1
Alan R. Schwartz,1 and Hartmut Schneider1
1
Johns Hopkins Sleep Disorders Center, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and
Allergy Center, Baltimore, Maryland; and 2Hospital Universitário, University of Sao Paulo, São Paulo, Brazil
Submitted 29 May 2014; accepted in final form 31 May 2015
upper airway obstruction; COPD; obstructive sleep apnea; inspiratory
flow limitation; lung volume
CHRONIC OBSTRUCTIVE PULMONARY disease (COPD) stands as a
leading cause of death, disability, and reduced quality of life.
While dyspnea on exertion remains the major reason for
impaired quality of life, disturbed sleep and morning fatigue
represent the second most common complaints in these patients
(3, 18). While obstructive sleep apnea (OSA) is a well-recognized source for sleep disturbances and morning fatigue in
patients with COPD, other markers of COPD, such as lung
hyperinflation (20), increased respiratory efforts (9, 12, 26),
alterations in gas exchange (6, 15, 21, 27, 34), and inspiratory
flow limitation, have also been associated with sleep disturbances. Understanding how these factors produce sleep distur-
Address for reprint requests and other correspondence: H. Schneider, Johns
Hopkins Sleep Disorders Center, Division of Pulmonary and Critical Care
Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview
Circle, Baltimore, MD 21224 (e-mail: [email protected]).
266
bances may allow investigators to develop specific strategies
for preventing and treating sleep disturbances in patients with
COPD.
Inspiratory flow limitation is a hallmark of upper airway
obstruction, which occurs in individuals with impaired mechanical properties of the upper airways (10, 25). The mechanical properties of the upper airway is best quantified by determining the critical closing pressure (Pcrit) during a neural
passive condition (passive Pcrit) (19, 25). Our laboratory has
recently shown that the passive Pcrit predicts sleep apnea
disease susceptibility and rises with increasing body mass
index (BMI) and age (19). Moreover, our laboratory and others
recently demonstrated that increases in lung volume reduce the
passive Pcrit in normal individuals and in patients with sleep
apnea (23, 31, 32). The effect of increasing lung volumes in
patients with COPD on mechanical properties of the upper
airway has not been shown.
Upper airway obstruction elicits compensatory responses
that help to prevent hypoventilation. Specifically, the inspiratory duty cycle [proportion of inspiratory time (TI) to respiratory cycle length] increases in response to upper airway obstruction, and this rise in TI is at the expense of the expiratory
time (TE) (5, 14, 28). Patients with COPD, however, often
exhibit long TE to cope with expiratory flow limitation and
intrinsic positive end-expiratory pressure (11, 13). It is possible
that the presence of expiratory flow limitation impairs duty
cycle response to upper airway obstruction in patients with
COPD. In the present study, we recruited COPD patients and
BMI, age, sex, and apnea hypopnea index (AHI) matched
individuals to determine 1) passive Pcrit and 2) respiratory
timing responses to experimentally induced upper airway obstruction. We hypothesize that 1) COPD patients have a lower
passive Pcrit (and thus lower risk for upper airway obstruction)
in association with elevations in lung volume; and that 2)
compensatory timing responses to upper airway obstruction are
reduced in COPD patients compared with normal individuals;
and 3) that the reduction in timing responses are in proportion
to the degree of expiratory flow limitation [forced expiratory
volume in 1 s (FEV1)].
METHODS
Subjects
Subjects were recruited from a pool of individuals participating in
a trial examining the effect of sleep on COPD outcomes. A total of 96
COPD patients and 41 non-COPD smokers received a previous sleep
study and were available for our study. From this group, a total of 36
subjects were recruited (Table 1). Both men (n ⫽ 12) and women (n ⫽
6) who were diagnosed with COPD [FEV1/forced vital capacity
(FVC) ⬍ 70%] were individually matched for age, sex, BMI and AHI
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Biselli P, Grossman PR, Kirkness JP, Patil SP, Smith PL,
Schwartz AR, Schneider H. The effect of increased lung volume in
chronic obstructive pulmonary disease on upper airway obstruction
during sleep. J Appl Physiol 119: 266 –271, 2015. First published June
5, 2015; doi:10.1152/japplphysiol.00455.2014.—Patients with
chronic obstructive pulmonary disease (COPD) exhibit increases in
lung volume due to expiratory airflow limitation. Increases in lung
volumes may affect upper airway patency and compensatory responses to inspiratory flow limitation (IFL) during sleep. We hypothesized that COPD patients have less collapsible airways inversely
proportional to their lung volumes, and that the presence of expiratory
airflow limitation limits duty cycle responses to defend ventilation in
the presence of IFL. We enrolled 18 COPD patients and 18 controls,
matched by age, body mass index, sex, and obstructive sleep apnea
disease severity. Sleep studies, including quantitative assessment of
airflow at various nasal pressure levels, were conducted to determine
upper airway mechanical properties [passive critical closing pressure
(Pcrit)] and for quantifying respiratory timing responses to experimentally induced IFL. COPD patients had lower passive Pcrit than
their matched controls (COPD: ⫺2.8 ⫾ 0.9 cmH2O; controls: ⫺0.5 ⫾
0.5 cmH2O, P ⫽ 0.03), and there was an inverse relationship of
subject’s functional residual capacity and passive Pcrit (⫺1.7
cmH2O/l increase in functional residual capacity, r2 ⫽ 0.27, P ⫽
0.002). In response to IFL, inspiratory duty cycle increased more
(P ⫽ 0.03) in COPD patients (0.40 to 0.54) than in controls (0.41 to
0.51) and led to a marked reduction in expiratory time from 2.5 to 1.5
s (P ⬍ 0.01). COPD patients have a less collapsible airway and a
greater, not reduced, compensatory timing response during upper
airway obstruction. While these timing responses may reduce hypoventilation, it may also increase the risk for developing dynamic
hyperinflation due to a marked reduction in expiratory time.
Upper Airway Obstruction in COPD
Table 1. General demographics
Controls
COPD Patients
P Value
n
Anthropometry
Age, yr
Height, cm
Weight, kg
BMI, kg/m2
Sex
Lung volumes
FEV1, liters
FEV1/FVC, %
TLC, liters
RV, liters
FRC, liters
RV/TLC, %
Polysomnography
TST, min
Sleep efficiency, %TST
NREM, %TST
Stage 1
Stage 2
Stage 3
REM, %TST
Total AHI, events/h
NREM AHI, events/h
REM AHI, events/h
%Hypopnea NREM
%Hypopnea REM
Arterial SaO2, %
Average baseline value
Average low value
18
18
50.3 ⫾ 1.6
170.0 ⫾ 2.7
97.9 ⫾ 6.6
31.6 ⫾ 1.6
12M; 6 F
57.1 ⫾ 1.9
174.2 ⫾ 2.1
86.5 ⫾ 4.1
28.6 ⫾ 1.2
12M; 6 F
⬍0.05
NS
NS
NS
NS
3.1 ⫾ 0.2
79 ⫾ 1.2
5.9 ⫾ 0.3
1.9 ⫾ 0.1
2.8 ⫾ 0.2
33.8 ⫾ 1.8
1.9 ⫾ 0.2
54 ⫾ 2.6
6.7 ⫾ 0.2
3.0 ⫾ 0.2
4.0 ⫾ 0.2
45.5 ⫾ 2.4
⬍ 0.05
⬍0.05
⬍ 0.05
⬍0.05
⬍ 0.05
⬍0.05
365.6 ⫾ 10.7
86.9 ⫾ 2.0
84.7 ⫾ 1.5
19.2 ⫾ 2.4
60.2 ⫾ 2.5
5.2 ⫾ 1.8
15.3 ⫾ 1.5
28.9 ⫾ 8.1
27.8 ⫾ 8.1
36.1 ⫾ 7.7
76.9 ⫾ 6.1
73.3 ⫾ 7.3
353.7 ⫾ 15.9
79.4 ⫾ 3.0
83.9 ⫾ 1.9
27.1 ⫾ 5.2
50.8 ⫾ 4.3
6.0 ⫾ 2.3
16.1 ⫾ 1.9
28.9 ⫾ 8.6
28.2 ⫾ 8.6
33.3 ⫾ 10.0
75.9 ⫾ 6.7
62.2 ⫾ 8.6
NS
⬍0.05
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
96.4 ⫾ 0.4
91.5 ⫾ 0.7
93.9 ⫾ 0.5
90.2 ⫾ 0.6
⬍0.05
NS
Values are averages ⫾ SE of main demographic parameters for both groups;
n, no. of subjects. COPD, chronic obstructive pulmonary disease; BMI, body
mass index; M, male; F, female; FEV1, forced expiratory volume in 1 s; FVC,
forced vital capacity; TLC, total lung capacity; RV, residual volume; FRC,
functional residual capacity; TST, total sleep time; NREM, non-rapid eye
movement; REM, rapid eye movement; AHI, apnea hypopnea index; SaO2,
arterial O2 saturation; NS, nonsignificant.
with eighteen subjects without COPD. In addition, subset analysis was
done on 12 COPD patients and 12 controls, matched by their mechanical upper airway properties (Passive Pcrit) and BMI. Subjects
using respiratory depressants, sedatives or oral steroids were excluded. The subjects were also screened for unstable cardiovascular
disease, uncontrolled hypertension, recent oropharyngeal surgery,
neurological disorders, renal and hepatic insufficiency, current pregnancy, bleeding disorders, psychiatric issues, a mean resting O2
hemoglobin saturation of ⬍88% and allergies to lidocaine. Written
informed consent was obtained from each participant for this study,
which was approved by the Johns Hopkins Medical Institution Human
Investigations Review Board.
Experimental Techniques
Pulmonary function testing. Standard techniques for pulmonary
function testing (CPL Lung Function Analyzer; W.E. Collins, Braintree MA.) were conducted the morning after the diagnostic sleep study
(2). The FEV1 and the FVC were determined using spirometry.
Functional residual capacity (FRC) was measured using multiplebreath closed-circuit helium dilution, with slow vital capacity and
expiratory reserve volume determined at the end of the procedure.
Residual volume (RV) was calculated by subtracting the expiratory
reserve volume from FRC. Total lung capacity could then be found by
adding slow vital capacity to RV.
Polysomnography. Standard diagnostic techniques were employed
to determine baseline sleep characteristics. To monitor and stage
sleep, electroencephalograph electrodes were placed at F3-A2, C3-
Biselli P et al.
267
A2, and O1-A2, in addition to submental electromyogram electrodes
and left and right electroculogram electrodes. Respiratory events were
scored using impedance thoracoabdominal belts to gauge respiratory
effort, a nasal cannula was used to quantify airflow, and pulse
oximetry was used to monitor hemoglobin oxygen saturation. Apneas
were defined as cessation of breathing for 10 s, while hypopneas were
scored when a 30% reduction in airflow was accompanied by ⱖ4%
oxygen desaturation. Standard polysomnographic methods and scoring rules were utilized to stage sleep and classify sleep-disordered
breathing events, according to the 2007 recommended scoring guidelines set forth by the American Academy of Sleep Medicine (1).
Respiratory physiology setup. In addition to standard polysomnographic techniques, the subject was fitted with a gel mask attached to
a custom designed continuous positive airway pressure unit capable of
delivering pressures between ⫺20 and ⫹20 cmH2O (Resmed, Bella
Vista, NSW, Australia). Airflow was measured with a pneumotachograph (model 4830, 0-400 l/min; Hans Rudolph, Kansas City, MO).
Flow and pressure were acquired at a sampling rate of 100 Hz. All
physiological signals were acquired and monitored on a computer
station using Somnologica software (Medcare, Buffalo, NY).
Study Protocol
Initially, subjects underwent a diagnostic sleep study for determining severity of sleep-disordered breathing, which was required for
matching individuals by AHI and anthropometric data (see Table 1).
In addition, pulmonary function tests were performed the day after the
sleep study to determine total lung volumes and disease status. We
then performed a follow-up sleep study within a 2- to 4-wk period to
determine the patients’ mechanical upper airway properties (passive
Pcrit) and the compensatory timing responses to upper airway obstruction. The procedures for Pcrit determination have been detailed
earlier (24) and are illustrated in Fig. 1 and briefly described below.
Passive condition: brief periods of upper airway obstruction. We
used the passive Pcrit to determine upper airway properties under a
low, hypotonic neuromuscular activity. During stable non-rapid eye
movement sleep, the nasal pressure was incrementally raised until
non-flow-limited nasal breathing was achieved. The nasal pressure
was then dropped in stepwise fashion in 1- to 2-cmH2O increments,
for five breaths at a time, until the subject’s airway occluded. A
pressure drop would be aborted and repeated if an arousal or an
increase in EMG activity without an arousal occurred. Periods of
breathing were excluded if there were arousals from stable sleep.
Upper airway collapsibility. Pressure-flow (maximal inspiratory
flow at flow-limited conditions) relationships were generated for each
subject by plotting the maximal airflow from breaths 3–5 of each
pressure drop, as previously described (30). Linear regression was
used to determine the nasal pressure at which there was zero flow,
indicating that the upper airway had occluded (passive Pcrit), as
demonstrated in Fig. 1.
Respiratory timing responses. TI, TE, the total time of each breath
(Ttot) and respiratory rate were all determined. Inspiratory duty cycle
(TI/Ttot) was reported in the non-flow-limited condition, as well as
during breaths with acute moderate to severe flow limitation, defined
as a mean peak inspiratory airflow rate of 50 –150 ml/s (Fig. 1) (28).
The change in timing parameters from baseline to upper airway
obstruction condition was used to determine individual strength in
respiratory timing responses to upper airway obstruction.
Statistical Analysis
Individual values were averaged and compared for both the COPD
and control groups using Student’s unpaired t-test. Further subgroup
analysis was performed in those with and without OSA. The changes
in duty cycle response were compared between COPD and control
subject groups with unpaired t-test. Comparisons pre- and postinduction of inspiratory flow limitation were performed using a paired
t-test. Regression analysis between FRC and passive Pcrit was per-
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Variable
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Upper Airway Obstruction in COPD
•
Biselli P et al.
Baseline (Holding pressure)
EMG (µV)
SaO2 %
Nasal Pressure
(cmH2O)
10
0
-10
100
95
5
0
5
Flow
(L/min)
ViMax
-40
RESULTS
Subject Characteristics
Demographic, anthropometric, polysomnographic, and pulmonary function statistics for all 18 COPD participants and 18
controls matched by the AHI are displayed in Table 1. Comparison of the anthropometric variables for the subjects individually matched for age (57.1 ⫾ 1.9 vs. 50.3 ⫾ 1.6 yr), sex
(12 men; 6 women), BMI (28.8 ⫾ 1.3 vs. 31.6 ⫾ 1.6 kg/m2),
and AHI (29 ⫾ 8 vs. 29 ⫾ 9 events/h) are shown in Table 1.
One-half of the subjects (7 men and 2 women from each group)
had sleep-disordered breathing with an event rate ⬎10
events/h. COPD subjects, compared with the control subjects,
had an FEV1 of 1.9 ⫾ 0.2 vs. 3.1 ⫾ 0.2 liters, and FEV1/FVC
of 54 ⫾ 0.0 vs. 79 ⫾ 1.2%. Similarly, lung volumes were
elevated in COPD patients vs. controls: total lung capacity was
6.7 ⫾ 0.2 vs. 5.9 ⫾ 0.3 liters, RV was 3.0 ⫾ 0.2 vs. 1.9 ⫾ 0.1
liters, and FRC was 4.0 ⫾ 0.2 vs. 2.8 ⫾ 0.2 liters.
Acute (Passive) Mechanical Upper Airway Properties
COPD subjects had a mean passive Pcrit of ⫺2.8 cmH2O
compared with that of ⫺0.5 cmH2O for their matched controls
(P ⫽ 0.03; unpaired t-test; Fig. 2). For the subgroup without
OSA, COPD subjects had a mean passive Pcrit of ⫺4.6 cmH2O
compared with that of ⫺0.8 cmH2O for their matched controls
(P ⫽ 0.02; unpaired t-test). For the subgroup with OSA, COPD
subjects had a mean passive Pcrit of ⫺1.0 cmH2O compared
with that of ⫺0.2 cmH2O for their matched controls (P ⫽
0.55). There was a significant association between FRC and
passive Pcrit (r2 ⫽ 0.27, P ⫽ 0.002), as illustrated in Fig. 3,
indicating that patients with higher lung volumes had lower
passive Pcrit values.
In the univariate analysis, there was statistically significant
associations between passive Pcrit values and both FRC (P ⫽
0.002) and BMI (P ⫽ 0.003). In the multivariate analysis, both
factors remained determinants for passive Pcrit level (FRC,
P ⫽ 0.021; BMI, P ⫽ 0.041; Table 2).
Acute Respiratory Timing Responses
In the subgroup of 12 patients paired for the analysis of the
timing responses, the control group had an AHI of 29.8 ⫾ 7.5
events/h and the CODP group had an AHI of 31.2 ⫾ 6.8
events/h. The average holding pressure was 8.8 ⫾ 0.8 cmH2O
in controls and 8.1 ⫾ 1.0 cmH2O in patients with COPD. The
average delta pressure required for inducing severe inspiratory
flow limitation was 6.4 ⫾ 0.8 cmH2O for controls and 7.0 ⫾
0.9 cmH2O for patients with COPD.
Pcrit - all patients
No COPD
Pcrit (cmH2O)
formed to determine the association between lung volume and upper
airway collapsibility. A P value of 0.05 was considered statistically
significant. All data are presented as means ⫾ SE, unless otherwise
stated.
Pcrit - non OSA
COPD
Controls
Pcrit - OSA
COPD
Controls
0
0
1
-1
-2
0
-2
-4
-3
3
6
-6
-4
p=0.03
-8
COPD
-1
p=0.01
-2
NS
Fig. 2. Passive critical closing pressure (Pcrit) measurements in chronic
obstructive pulmonary disease (COPD) patients and controls. The graph
represents average passive Pcrit values for COPD patients and matched
controls. Left: all patients. Middle: non-obstructive sleep apnea (OSA) patients.
Right: OSA patients. Values are means ⫾ SE. Upper airway collapsibility
(passive Pcrit) is lower in patients with COPD compared with subjects
matched for age, sex, body mass index, and respiratory disturbance index (P ⫽
0.03). This difference seems greater in nonapneic patients, but can no longer
be noticed in apneic patients. NS, nonsignificant.
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Fig. 1. Experimental protocol. Schematic diagram of the experimental protocols (top)
and polysomnographic responses (bottom)
during non-rapid eye movement sleep in an
apneic male subject. Baseline (left): nasal
pressure was adjusted to effective continuous
positive airway pressure and held for at least
3 min (holding pressure) to establish a stable
non-flow-limited breathing pattern (see flow
trace, bottom left). Passive upper airway obstruction (middle left): a series of brief (5
breaths) drops in nasal pressure from holding
pressure were performed without concomitant
activation of EMG. During these drops, upper
airway obstruction ensued, as indicated by inspiratory flow limitation as in the flow trace
below. SaO2, arterial O2 saturation; VImax, maximal inspiratory flow.
Passive Pressure Drops – Upper Airway challenge
Upper Airway Obstruction in COPD
FRC vs Pcrit
6
4
Pcrit (cmH2O)
2
0
0
1
2
3
4
5
6
7
Non-OSA Controls
-2
OSA Controls
-4
Non-OSA COPD
OSA COPD
-6
-8
y = - 1.7 x + 3.8
r2 = 0.27, p=0.002
-10
-12
FRC (L)
Respiratory timing responses were assessed by comparing
non-flow-limited condition (baseline) with periods of severe
upper airway obstruction. The peak inspiratory airflow at
baseline and severe upper airway obstruction were similar in
both groups, declining from 383 ⫾ 49 to 105 ⫾ 11 ml/s in
controls and from 387 ⫾ 47 to 111 ⫾ 12 ml/s in COPD
patients. Respiratory timing parameters during baseline, nonflow-limited breathing, and in response to severe degree of
inspiratory flow limitation are summarized in Table 3. In both
non-flow-limited and flow-limited conditions, COPD patients
and controls had similar timing indexes. While the control
group had an ⬃25% increase in the duty cycle from 0.41 to
0.51, the COPD patients had an ⬃40% increase from 0.40 to
0.55 (P ⫽ 0.03 for the comparison on the increase in the duty
cycle). TE decreased on average from 2.5 to 1.5 s in the COPD
group (P ⬍ 0.01) and in the matched controls from 2.4 to 1.8
s (P ⬍ 0.01). Ttot decreased in COPD from 4.1 to 3.3 s (P ⬍
0.05) and in the controls from 3.9 to 3.6 s (nonsignificant). TI
increased from 1.5 to 1.8 s (P ⬍ 0.01) in patients with COPD
and from 1.6 to 1.8 s in controls (P ⬍ 0.05). None of the
inspiratory or expiratory timing responses were correlated to
the level of obstruction (FEV1) in patients with COPD.
DISCUSSION
The main findings in the present study are that COPD
patients have a less collapsible upper airway than age, sex,
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Biselli P et al.
BMI, and AHI matched control subjects, and that the passive
Pcrit inversely correlates with residual lung volume. Airway
patency was increased in patients with COPD compared with
matched controls, but this difference was much smaller and
nonsignificant in the subgroup of patients with sleep apnea,
indicating that sleep apnea disease status influences the mechanisms that mediate the lung volume and passive Pcrit relationship. Second, in contrast to our hypothesis, COPD patients
demonstrated increased rather than a decreased duty cycle
response to upper airway obstruction compared with matched
controls. This rise in duty cycle was associated with an increased respiratory rate and a marked reduction in TE, both of
which are known risk factors for dynamic hyperinflation.
Taken together, our data suggest that, while elevations in lung
volume may lower OSA susceptibility in patients with COPD,
timing responses to upper airway obstruction may promote
dynamic hyperinflation.
One of the main clinical features of COPD is a progressive
elevation of lung volume. Our patient population had a moderate degree of COPD with FEV1/FVC ranging from 50 –70%
predicted and a mean increase in FRC of 1.2 liters compared
with controls. Increases in lung volume decreases upper airway
collapsibility in normal individuals and patients with OSA (23,
31, 32). The proposed mechanism for this association is an
increase in caudal tracheal traction during inflation of the lungs
producing a stiffer, less collapsible upper airway (16). We have
now extended these findings to COPD patients with increased
lung volumes and found a similar relationship between FRC
and upper collapsibility of ⬃2 cmH2O decrease in passive Pcrit
per liter increase in FRC. A lower passive Pcrit is associated
with a lower risk for developing OSA. Thus it appears that
COPD patients with increased lung volumes have lower susceptibility to develop OSA.
We observed a lower passive Pcrit in nonapneic COPD
patients compared with their matched nonapneic controls. One
could suspect this difference to be due to an abnormally high
passive Pcrit in the control group and not due to a decrease in
passive Pcrit in the COPD group. Our laboratory has previously demonstrated that the passive Pcrit can be similar in
non-OSA and OSA individuals, while the active Pcrit is lower
in normal individuals compared with apneic patients, even
when matched by passive Pcrit (19, 25). Passive Pcrit reveals
mechanical airway properties in a nonneural activated state and
approaches the Pcrit measurements under anesthesia. In fact,
some reports during anesthesia have also shown Pcrit values
close to atmospheric, particularly when studying older patients
(7, 8). We, therefore, suggest that the difference in passive
Pcrit between nonapneic COPD patients and controls is not due
to an abnormally high Pcrit in the normal controls, but rather
due to a decreased passive Pcrit in nonapneic COPD patients.
Table 2. Passive Pcrit relationship with BMI and FRC
Model 1
FRC, cmH2O/l
BMI, kg/m2
Model 2
␤-coefficient
P value
⫺1.66 ⫾ 0.50
0.002
␤-coefficient
0.25 ⫾ 0.08
Model 3
P value
␤-coefficient
P value
0.003
⫺1.25 ⫾ 0.51
0.17 ⫾ 0.08
0.021
0.042
Values are means ⫾ SE for ␤-coefficients. Multivariate models of passive critical closing pressure (Pcrit) with BMI and/or FRC as the independent variables
are given. The ␤-coefficient of the passive Pcrit vs. FRC association decreases from ⫺1.66 ⫾ 0.50 to ⫺1.24 ⫾ 0.51 cmH2O/l when BMI is added to the regression
model.
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Fig. 3. Passive Pcrit vs. functional residual capacity (FRC) relationship. The
graph represents passive Pcrit and FRC relationship, with a linear regression
using all subject values. 䊐, Non-OSA controls; {, OSA controls; , non-OSA
COPD; } OSA COPD. There was a statistically significant association between
FRC and upper airway collapsibility (passive Pcrit) in all subjects (P ⫽ 0.002,
r2 ⫽ 0.27). Each 1-liter increase in FRC was associated with an ⬃2-cmH2O
reduction in passive Pcrit, which was similar to the relationship observed
previously in normal individuals and patients with sleep apnea (31, 32).
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Upper Airway Obstruction in COPD
•
Biselli P et al.
Table 3. Timing responses to induced flow limitation
Inspiratory Time, s
Baseline
IFL
Expiratory Time, s
Total Time, s
Duty Cycle
Respiratory Rate, breaths/min
Control
COPD
Control
COPD
Control
COPD
Control
COPD
Control
COPD
1.6 ⫾ 0.1
1.8 ⫾ 0.1*
1.5 ⫾ 0.1
1.8 ⫾ 0.1*
2.4 ⫾ 0.2
1.8 ⫾ 0.2*
2.5 ⫾ 0.3
1.5 ⫾ 0.1*
3.9 ⫾ 0.2
3.6 ⫾ 0.3
4.1 ⫾ 0.3
3.3 ⫾ 0.2*
0.41 ⫾ 0.02
0.51 ⫾ 0.02*
0.40 ⫾ 0.02
0.55 ⫾ 0.02*†
16.0 ⫾ 0.9
18.1 ⫾ 1.6
15.5 ⫾ 0.9
18.9 ⫾ 1.1*
Values are averages ⫾ SE. Timing responses are shown for 12 COPD patients and 12 controls matched by sex, BMI (30.6 ⫾ 1.3 vs. 29.8 ⫾ 2.0 kg/m2), and
passive Pcrit (⫺0.7 vs. ⫺0.7 cmH2O). IFL, inspiratory flow limitation. *P ⬍ 0.05, comparison between flow-limited condition and non-flow-limited condition.
†P ⬍ 0.05, comparison between response to flow limitation in patients with COPD and matched controls.
patients to controls for age, sleep apnea disease severity (AHI),
sex, and BMI, which are known risk factors for upper airway
collapsibility. When we analyzed only the patients without
OSA, the differences in upper airway collapsibility are even
greater than for the whole group comparison, suggesting that
we may have underestimated the effect of elevated lung volume on upper airway patency. The second strength is our
experimental design for the determination of the timing parameters in response to upper airway obstruction. In previous
studies, our laboratory has demonstrated that duty cycle increases with the severity of upper airway obstruction in a
dose-dependent fashion. We, therefore, imposed similar severity of upper airway obstruction across our study participants.
This experimental design allowed us to reduce the variability in
timing responses while observing the differential responses
between COPD patients and controls. In contrast, despite best
matching of COPD patients and controls by disease status
(AHI), age, and sex, we have only cross-sectional data on
passive Pcrit in our study participants. It is possible that we
may have underestimated the effect of lung volume on upper
airway collapsibility due to a selection bias. We also did not
measure intrinsic positive end-expiratory pressure, which is
probably present in many of our COPD patients and could be
altered by the experimentally induced flow limitation. We
acknowledge that our COPD patients were significantly older
than controls. Increased age is associated with either no change
or increase in passive Pcrit (19). We, therefore, believe that the
age difference cannot account for the lower passive Pcrit in the
COPD group. Finally, it is possible that we did not achieve a
similar neuromuscular passivity in the apneic controls vs.
apneic COPD individuals. Patients with COPD have higher
respiratory loads and, consequently, higher effort, which can
translate into stronger neurological input to both respiratory
and upper airway muscles. Although passive Pcrit measurements are designed to describe airway properties in a passive
state, we cannot exclude that some of the observed upper
airway differences reflect different upper airway muscle activation states.
Implications
The present work has several clinical implications. First, we
show that elevations in lung volume are associated with a
lower Pcrit (passive Pcrit) of the upper airway. Similarly,
changes in lung volume may also affect passive Pcrit in COPD
patients. Lung volume reduction surgery (LVRS) is one treatment strategy for severe COPD. If LVRS would increase
passive Pcrit, treatment efficacy of LVRS may be impeded by
the emergence of OSA. Second, in COPD patients, brief
periods of severe upper airway obstruction elicited marked
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Although there was a difference in passive Pcrit between
nonapneic COPD patients and their matched controls, we no
longer observed this difference when comparing apneic COPD
patients to their controls. We propose several mechanisms to
explain this differential response. First, several investigators
demonstrated that passive Pcrit decreases with elevations in
lung volume, which is attributed to a caudal traction of the
upper airway (31, 33, 35). Apneic individuals have larger
tongues (29) and often narrow, high arched hard palate (17),
both of which may have blunted the stretching effect provided
by increases in lung volumes. Second, it is also possible that
elevations in lung volume lower passive Pcrit through neural
stimulation of intra- or extrapulmonary stretch receptors. Apneic individuals may have an attenuated neural response to
elevations in lung volume similar to a diminished neural
control of the upper airway in response to upper airway
obstruction (22, 25). Alternatively, similar to the Hering
Breuer reflex, which requires large inhaled volumes for eliciting the reflex response, passive Pcrit responses may also be
dependent on the degree of hyperinflation. In some apneic
COPD patients, increases in lung volumes may not have been
large enough to reduce passive Pcrit. To determine why nonapneic COPD patients have a lower passive Pcrit compared
with controls, while apneic COPD patients have similar passive Pcrit than apneic controls, mechanistic experiments involving neural and muscular activity assessment are required.
In the presence of upper airway obstruction, increasing the
duty cycle is one of the main responses to sustain ventilation.
The larger the increase in the duty cycle, the better individuals
maintain their minute ventilation (5, 28, 36). In our present
work, we observed that patients with COPD, compared with
matched controls, have a larger duty cycle increase when
challenged by upper airway obstruction. Thus COPD patients
appear to be better protected from developing hypoventilation
compared with matched controls when facing upper airway
obstruction. In contrast, patients with COPD need very long TE
to prevent dynamic lung hyperinflation. In the present work,
we observed that COPD patients, as well as controls, decreased
TE when challenged by inspiratory flow limitation. While mild
reductions in TE usually do not affect breathing mechanics, the
observed ⬃50% reduction in TE may be enough to elicit
dynamic hyperinflation. In fact, a similar reduction of TE by
using a metronome during wakefulness induced dynamic hyperinflation in patients with moderate COPD (4). Subjects with
normal lung function might well tolerate the TE reduction.
However, in subjects with COPD inspiratory flow limitation,
the observed reduction in TE may produce dynamic hyperinflation during sleep.
There are several strengths and limitations to the present
study. The first strength is our approach for matching COPD
Upper Airway Obstruction in COPD
reductions in TE to levels comparable to findings of previous
studies examining sources of dynamic hyperinflation. Dynamic
hyperinflation is known to increase work of breathing and
reduce sleep efficiency, both of which could be attributed to the
morning fatigue commonly observed in COPD patients.
15.
16.
GRANTS
This study was funded by National Heart, Lung, and Blood Institute Grant
RO1-HL-105546 and the Conselho Nacional de Desenvolvimento Científico e
Tecnológico-Brasil.
DISCLOSURES
17.
18.
19.
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
20.
21.
22.
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Author contributions: P.J.C.B., P.R.G., J.P.K., S.P.P., P.L.S., A.R.S., and
H.S. analyzed data; P.J.C.B., P.R.G., J.P.K., S.P.P., P.L.S., A.R.S., and H.S.
interpreted results of experiments; P.J.C.B., P.R.G., and H.S. prepared figures;
P.J.C.B., P.R.G., A.R.S., and H.S. drafted manuscript; P.J.C.B., J.P.K., S.P.P.,
P.L.S., A.R.S., and H.S. edited and revised manuscript; P.J.C.B. and H.S.
approved final version of manuscript; P.R.G., J.P.K., S.P.P., P.L.S., A.R.S.,
and H.S. conception and design of research; P.R.G., J.P.K., and H.S. performed experiments.
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