Dynamic modulation of upper airway function during
sleep: a novel single-breath method
Jason P. Kirkness, Alan R. Schwartz, Susheel P. Patil, Luis E. Pichard, Jason J. Marx,
Philip L. Smith and Harmut Schneider
J Appl Physiol 101:1489-1494, 2006. First published 6 July 2006;
doi: 10.1152/japplphysiol.00173.2006
You might find this additional info useful...
This article cites 30 articles, 18 of which you can access for free at:
http://jap.physiology.org/content/101/5/1489.full#ref-list-1
This article has been cited by 9 other HighWire-hosted articles:
http://jap.physiology.org/content/101/5/1489#cited-by
Updated information and services including high resolution figures, can be found at:
http://jap.physiology.org/content/101/5/1489.full
This information is current as of June 8, 2013.
Journal of Applied Physiology publishes original papers that deal with diverse area of research in applied
physiology, especially those papers emphasizing adaptive and integrative mechanisms. It is published 12 times a
year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright
© 2006 the American Physiological Society. ISSN: 8750-7587, ESSN: 1522-1601. Visit our website at
http://www.the-aps.org/.
Downloaded from http://jap.physiology.org/ by guest on June 8, 2013
Additional material and information about Journal of Applied Physiology can be found at:
http://www.the-aps.org/publications/jappl
J Appl Physiol 101: 1489 –1494, 2006.
First published July 6, 2006; doi:10.1152/japplphysiol.00173.2006.
Innovative Methodology
Dynamic modulation of upper airway function during sleep:
a novel single-breath method
Jason P. Kirkness,1,2 Alan R. Schwartz,1 Susheel P. Patil,1 Luis E. Pichard,1
Jason J. Marx,1 Philip L. Smith,1 and Harmut Schneider1
1
Johns Hopkins Sleep Disorders Center, Baltimore, Maryland; and 2School of Anatomy
and Human Biology, University of Western Australia, Perth, Western Australia, Australia
Submitted 9 February 2006; accepted in final form 17 June 2006
sleep apnea; critical pressure; upper airway occlusion; pathophysiology
sleeping (2), in anesthetized subjects (5, 11, 12), and in
paralyzed subjects (9). These protocols, however, require monitoring pressure-flow relationships over multiple nasal pressure
levels for an extended period of time to determine Pcrit.
In previous studies, investigators have evidence that Pcrit is
not a static measure of upper airway function but rather that it
can vary dynamically over the respiratory cycle. Employing an
isolated upper airway preparation in animal, investigators have
demonstrated marked increases in upper airway collapsibility
during expiration compared with inspiration (4, 15, 16, 23–25,
28). In humans, a similar approach for assessing upper airway
properties over multiple breaths and pressure (17) has demonstrated increases in upper airway collapsibility during expiration compared with inspiration. Nevertheless, appropriate
methods for assessing the dynamic changes in upper airway
function within a single respiratory cycle have not yet been
developed for humans.
To examine the dynamic modulation of upper airway function during sleep, we devised a novel approach for measuring
the Pcrit within a single breath in tracheostomized sleep apnea
patients. Our approach was based on recent methods administering air directly into the trachea, which abolished OSA (18).
During TTI, we found that the upper airway regulated the
release of insufflated airflow from the trachea because airflow
varied throughout the respiratory cycle. This finding led us to
hypothesize that monitoring tidal pressure-flow relationships
during TTI would provide a dynamic assessment of changes in
upper airway function throughout the respiratory cycle. We
further examined whether the development of pharyngeal occlusion within a breath influenced the dynamic modulation of
upper airway flow during TTI in sleeping apneic patients.
METHODS
(OSA) is a common disorder associated with upper airway obstruction during sleep, leading to
recurrent arousals and oxyhemoglobin desaturations. In previous studies, our laboratory has demonstrated that upper airway
obstruction is related to increases in pharyngeal collapsibility
during sleep, as determined by measurements of upper airway
critical pressures (Pcrit) during sleep (6, 7, 19 –22, 26). The
Pcrit is established empirically by varying the upstream nasal
pressure and by determining the pressure at which the upper
airway occludes. Several protocols for determining Pcrit during inspiration have been utilized in spontaneously breathing
OBSTRUCTIVE SLEEP APNEA
Address for reprint requests and other correspondence: J Kirkness, Div. of
Pulmonary and Critical Care Medicine, The Johns Hopkins Asthma and
Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (e-mail:
jason_kirkness@jhmi.edu).
http://www. jap.org
Subjects
Five tracheostomized patients with concomitant OSA referred to
the Johns Hopkins Sleep Disorders Center were also recruited for this
study if they had non-rapid eye movement (NREM) apnea-hypopnea
index ⬎20 episodes/h (with a capped tracheostomy) and were free of
cardiorespiratory insufficiency (daytime hypercapnia or hypoxemia
and evidence of right or left heart failure) and significant pulmonary
disease. In these subjects, tracheostomy had been performed either
because patients could not use nasal continuous positive airway
pressure (CPAP; n ⫽ 4) or were refractory to treatment with nasal
CPAP (n ⫽ 1). The demographic and anthropometric description of
these subjects have been described previously (18). The protocol was
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
8750-7587/06 $8.00 Copyright © 2006 the American Physiological Society
1489
Downloaded from http://jap.physiology.org/ by guest on June 8, 2013
Kirkness, Jason P., Alan R. Schwartz, Susheel P. Patil, Luis E.
Pichard, Jason J. Marx, Philip L. Smith, and Harmut Schneider.
Dynamic modulation of upper airway function during sleep: a novel
single-breath method. J Appl Physiol 101: 1489 –1494, 2006. First
published July 6, 2006; doi:10.1152/japplphysiol.00173.2006.—To
examine the dynamic modulation of upper airway (UA) function
during sleep, we devised a novel approach to measuring the critical
pressure (Pcrit) within a single breath in tracheostomized sleep apnea
patients. We hypothesized that the UA continuously modulates airflow dynamics during transtracheal insufflation. In this study, we
examine tidal pressure-flow relationships throughout the respiratory
cycle to compare phasic differences in UA collapsibility between
closure and reopening. Five apneic subjects (with tracheostomy) were
recruited (2 men, 3 women; 18 –50 yr; 20 –35 kg/m2; apnea-hypopnea
index ⬎20) for this polysomnographic study. Outgoing airflow
through the UA (face mask pneumotachograph) and tracheal pressure
were recorded during brief transtracheal administration of insufflated
airflow via a catheter. Pressure-flow relationships were generated
from deflation (approaching Pcrit) and inflation (after Pcrit) of the UA
during non-rapid eye movement sleep. During each breath, UA
function was described by a pressure-flow relationship that defined the
collapsibility (Pcrit) and upstream resistance (Rus). UA characteristics
were examined in the presence and absence of complete UA occlusion. We demonstrated that Pcrit and Rus changed dynamically
throughout the respiratory cycle. The UA closing pressure (4.4 ⫾ 2.0
cmH2O) was significantly lower than the opening pressure (10.8 ⫾
2.4 cmH2O). Rus was higher for deflation (18.1 ⫾ 2.4 cmH2O 䡠 l⫺1 䡠 s)
than during inflation (7.5 ⫾ 1.9 cmH2O 䡠 l⫺1 䡠 s) of the UA. Preventing
occlusion decreases UA pressure-flow loop hysteresis by ⬃4 cmH2O.
These findings indicate that UA collapsibility varies dynamically
throughout the respiratory cycle and that both local mechanical and
neuromuscular factors may be responsible for this dynamic modulation of UA function during sleep.
Innovative Methodology
1490
DYNAMIC MODULATION OF UPPER AIRWAY FUNCTION
approved by the Johns Hopkins Institutional Review Board, and
informed consent was obtained from each patient.
Conceptual Approach
Experimental Apparatus
Polysomnography. Standard polysomnographic monitoring was
performed during all study protocols, and it included monitoring of
electroencephalograms (C3-A2, C3-O1), left and right electrooculograms, submental electromyogram (EMG), and electrocardiogram
Fig. 1. Schematic of the relationship between tracheal pressure (Ptrach) and
upper airway flow (V̇ua). The upper airway is occluded (A) when Ptrach is
lower than the critical closing pressure (Pcrit). When transtracheal insufflation
(TTI) is applied at a constant flow rate (V̇in), Ptrach reaches and equilibrium
point (E) in the absence of respiration. As Ptrach changes during tidal
breathing, V̇ua rises and falls along the pressure-flow relationship throughout
inspiration (B) and expiration (C).
J Appl Physiol • VOL
Experimental Protocols
Assessment of tidal pressure-flow loops. Sleep was initiated while
nasal pressure was kept at atmospheric pressure. During periodic obstructive apneas, we administered TTI at flow rates between 9 and 16 l/min
through a capped tracheostomy, as previously described (18). At this flow
rate, a stable breathing pattern during stable stage 2 NREM sleep was
obtained that was characterized by upper airway closure and reopening in
each breath as previously demonstrated (18) and illustrated in Fig. 2.
During this stable breathing pattern, five representative breaths were
taken to determine upper airway properties.
Effect of upper airway occlusion on upper airway collapsibility. To
assess whether differences in closing and opening were due to upper
airway hysteresis, we increased the TTI flow rate by 0.5–5 l/min
during stable sleep. As the end-expiratory Ptrach pressure increased
and the tidal inspiratory pressure swings decreased, the Ptrach during
inspiration did not fall below Pcrit, thereby preventing upper airway
closure throughout the entire respiratory cycle. Upper airway properties were determined during the airway deflation [approaching critical
closing pressure (Pclose)] and airway inflation [after critical closing
pressure (Popen)] segments of the pressure-flow relationship both in
the presence and absence of upper airway occlusion.
Data Analysis
For periods of insufflation during upper airway obstruction breaths
were randomly selected for analysis from periods of stable stage 2
101 • NOVEMBER 2006 •
www.jap.org
Downloaded from http://jap.physiology.org/ by guest on June 8, 2013
In the present study, we employed a novel method to determine the
inspiratory and expiratory upper airway properties in sleep apnea patients
(with tracheostomy) within a single breath. Our approach was based on
our previous findings that the upper airway remained in a flow-limited
condition during TTI administration (18). Flow limitation was defined by
the relationship between Pcrit and downstream pressure, such that the
downstream pressure remained less than Pcrit. The sleep apnea patients in
the present study also demonstrated a similar pressure regimen with the
downstream nasal pressure (atmospheric) being less than the Pcrit (which
was positive) throughout the respiratory cycle (18). Under these circumstances, the rate of flow leaking out the upper airway was not influenced
by changes in the downstream (nasal) pressure, and it remained unchanged when subatmospheric nasal pressure was applied (18). Thus the
upper airway remained in a flow-limited condition in these apneic
patients throughout the respiratory cycle.
Under flow-limited conditions, airflow should be linearly related to the
gradient between the upstream [tracheal pressure (Ptrach)] and Pcrit (6, 7,
20, 22, 26). In patients with sleep apnea, our laboratory has previously
demonstrated that the upper airway can occlude when tracheal pressure is
lower than Pcrit (18). During occlusion, tracheal insufflation will lead to
a rise in tracheal pressure (see pressure-flow relationship; Fig. 1, segment
A) and flow will not discharge out the upper airway until Ptrach exceeds
a Pcrit (Fig. 1). Thereafter, airflow will increase linearly with the rise in
Ptrach (Fig. 1, segment B) until the level of flow discharging out the upper
airway (V̇ua) equals the insufflation flow rate (V̇in). This point (Fig. 1,
point E) represents the steady-state or equilibrium position for the
respiratory system during tracheal insufflation. During tidal breathing,
Ptrach will rise and fall above and below this equilibrium position.
Because Ptrach varies throughout the respiratory cycle, V̇ua will also
vary, as described by the pressure-flow relationship (Fig. 1, see inspiration and expiration, segments A, B, and C). This curve can be used to
describe upper airway function in terms of its collapsibility (Pcrit) and
upstream resistance (Rus), as previously described (26). Our major goal
was to describe the dynamic modulation of upper airway function as the
upper airway inflates and deflates throughout the respiratory cycle.
(modified V2 lead). Arterial oxygen saturation was also monitored
(Biox 3700, Ohmeda, Boulder, CO). Body position was monitored
visually with infrared video cameras so that patients could be maintained supine throughout the protocol.
Pressure upstream of collapse (Ptrach). In the tracheostomized
sleep apnea patients, Ptrach was measured in the trachea via Shiley
tracheostomy tube (Mallinckrodt, St. Louis, MO) inserted before the
experimental protocol. An external cap was affixed to the tracheostomy tube, and sealed ports were made in the cap for inserting an
insufflation cannula and a Luer stub adapter connected to a pressure
transducer (Gould-Statham, Oxnard, CA).
V̇ua and nasal pressure. Nasal pressure was measured at an outlet
of the tight-fitting face mask and monitored with pressure transducers.
Nasal pressure was adjusted with a modified CPAP device (CPAP,
Medizin fuer Artz und Patient, Martiris-reid, Germany) that could be
used to switch pressures from one level to the other over a range from
5 to ⫺15 cmH2O, as previously described (20). V̇ua was monitored
with a pneumotachometer (model 300A, Hans Rudolph, Kansas City,
MO) affixed to a tight-fitting face mask (Respironics, Murryville, PA).
The pneumotachometer was connected to a 2-cmH2O differential
pressure transducer (model DP45–28, Validyne Engineering,
Northridge, CA).
TTI. The apparatus employed for delivering TTI was previously
described (18). In brief, an air compressor and flow regulator were used
to insufflate air through an ⬃3-m length of oxygen extension tubing
(Baxter, Valenica, CA) and a transtracheal catheter (SCOOP catheter,
Transtracheal Systems, Denver, CO). A mass flowmeter (Matheson,
Secaucus, NJ) and a solenoid were connected in series to monitor the
level of V̇in and to direct flow to the patient or atmosphere, respectively.
Ptrach was continuously monitored, and the signal was digitized by a
microcomputer. The computer controlled the direction of flow (Labview,
National Instruments, Austin, TX) through the solenoid based on the
Ptrach level. When this pressure remained below a threshold (⬍20
cmH2O), airflow was applied to the patient. When Ptrach exceeded this
limit, the TTI flow was diverted by the solenoid to atmosphere.
Data acquisition. All physiological signals were amplified and recorded continuously on a polygraph recorder (Grass recorder, Astromed,
Warwick, RI). Signals from the analog amplifiers were also digitized at
100 Hz and stored on optical disk for offline analysis (DI-200 A/D board
and Windaq/200 software, Dataq Instruments, Akron, OH).
Innovative Methodology
DYNAMIC MODULATION OF UPPER AIRWAY FUNCTION
1491
NREM sleep in all experimental conditions. V̇in was utilized as a
reference level for each individual. Upper airway function was characterized for each respiratory cycle by analyzing the relationship
between V̇ua and Ptrach. Linear segments of the pressure-flow relationship were identified for the deflation and inflation segments of the
pressure-flow loops. Least squares linear regression (Excel, Microsoft,
Redmond, WA) was performed on pressure-flow data obtained from
both the deflation and inflation segments (correlation coefficients
ranged from 0.75 to 0.99 for inflation and deflation limbs). Regression
equations were then used to derive Pclose, Popen, and Rus for the
deflation and inflation segments (14), as previously described (22). Upper
airway hysteresis was calculated as the difference between the mean
end-expiratory and end-inspiratory pressures at the level of the insufflated
flow. ANOVA (generalized linear model) with Tukey’s post hoc
comparisons were utilized to test differences between Pclose, Popen,
and Rus between the occluded upper airway and the unoccluded upper
airway condition. A value of P ⬍ 0.05 was considered significant.
RESULTS
Effect of TTI on Breathing Pattern in OSA
In Fig. 2, the effects of TTI on breathing patterns are
illustrated in a patient with OSA during NREM sleep. Baseline
breathing patterns off TTI (Fig. 2, middle) during spontaneous
breathing were characterized by periodic obstructive apneas
(Fig. 2, V̇ua) with augmenting Ptrach swings, oxyhemoglobin
desaturations, and arousals from sleep (not shown). In contrast,
TTI at ⬃15 l/min (Fig. 2, right and left) stabilized the breathing
pattern, diminished Ptrach pressure swings, and abolished
oxyhemoglobin desaturations and arousals. In each subject,
TTI was able to abolish periodic apneas and stabilize breathing
patterns, as previously reported (18). During TTI, airflow
discharged out the upper airway, and it fluctuated around the
equilibrium TTI flow rate during tidal breathing. As Ptrach
fluctuated during tidal breathing, V̇ua increased as Ptrach rose
during expiration, and decreased as Ptrach fell during inspiration, consistent with the conceptual pressure-flow relationship
J Appl Physiol • VOL
shown in Fig. 1. Of note, while V̇ua fell to zero, it never
became negative, despite further decreases in Ptrach during
midinspiration, suggesting an occluded upper airway at this
point in the respiratory cycle.
Upper Airway Pressure-Flow Relationships During TTI
Tidal fluctuations in Ptrach and V̇ua are further illustrated in
an expanded recording from a single patient during TTI administration in Fig. 3. As Ptrach fell and approached atmospheric pressure during inspiration, the level of V̇ua discharging out the upper airway also fell. In fact, with further decreases in Ptrach during inspiration, upper airway flow ceased,
indicating that the upper airway had closed (Pclose; Fig. 3)
during this portion of the respiratory cycle. As Ptrach began to
rise again, airflow resumed out the upper airway (Popen; Fig.
3). As Ptrach varied throughout the respiratory cycle, exhaled
airflow contributed to a rise in V̇ua above the TTI level during
expiration, whereas inhalation from the TTI source accounted
for a fall in V̇ua below the TTI level during inspiration.
In Fig. 4A, Ptrach vs. V̇ua loops are generated for the
five-breath recording example in Fig. 3. Each breath in the
Fig. 3. Raw data recording of Ptrach and V̇ua during a period on TTI (dotted line)
during stable non-rapid eye movement sleep. The upper airway critical pressure
during closing (Pclose) and opening (Popen) are indicated by the arrows.
101 • NOVEMBER 2006 •
www.jap.org
Downloaded from http://jap.physiology.org/ by guest on June 8, 2013
Fig. 2. Raw data recording of Ptrach and V̇ua
during periods with TTI ON and OFF in non-rapid
eye movement sleep. When TTI was OFF (middle), periodic apneas were observed (zero flow,
augmented Ptrach, and decreased oxygen desaturations). When TTI was ON (right and left), the
apneas were abolished and flow fluctuated around
an equilibrium level (see dashed line, which indicates TTI flow rate level). The equilibrium point
(E) of the pressure-flow loop from Fig. 1. is
represented. Note that during the period with TTI
ON, V̇ua is ⬎0 l/min during phasic respiration.
SaO2, arterial oxygen saturation.
Innovative Methodology
1492
DYNAMIC MODULATION OF UPPER AIRWAY FUNCTION
V̇ua-Ptrach relationship inscribed practically superimposable
counterclockwise loops. During inspiration, V̇ua decreased
linearly with the decline in Ptrach (see segment B), and it
ultimately ceased despite further decreases in Ptrach below
Pcrit (see segment A). As Ptrach rose in late inspiration, V̇ua
remained zero (V̇ua ⫽ 0), indicating the upper airway remains
closed for this portion of the respiratory cycle (see segment X)
until V̇ua was reestablished as Ptrach exceeded Popen (Fig.
4A). The sloped portions of the V̇ua-Ptrach loops are represented by linear regression lines constructed from the V̇uaPtrach segments obtained for each breath. These regression
lines were used to calculate Pcrit during phase 1 (Pclose) and
phase 2 (Popen) of the V̇ua-Ptrach loops, as illustrated in Fig. 4B.
Upper Airway Tidal Pressure-Flow Loops
Fig. 5. Individual subject pressure-flow loops for periods with (left; condition
1) and without (right; condition 2) upper airway occlusion.
was comparable to the occluded upper airway condition for the
deflation segment (4.0 ⫾ 2.1 to 18.3 ⫾ 2.2 l/min; both P ⬎ 0.3
compared with the occluded upper airway conditions) and for the
inflation segment (5.8 ⫾ 3.1 to 18.3 ⫾ 2.1 l/min; both P ⬎ 0.4
compared with the occluded upper airway conditions). Of note, in
both the occluded and unoccluded conditions, Popen and Pclose
the upper airway occurred at positive pressures in each subject
(Fig. 5, conditions 1 and 2). These findings confirmed that the
upper airway remained flow limited during TTI administration,
Table 1. Group mean data for TTI flow rates and breathing
mechanics during occluded upper airway (condition 1) and
unoccluded upper airway (condition 2) states
Fig. 4. V̇ua and Ptrach tidal pressure-flow signals (top) for breaths shown in
Fig. 3 inscribe counterclockwise loops (dotted line and arrow). TTI flow rate
(dashed line; V̇in) intersects the pressure-flow loop at the equilibrium point (E).
Expiration is above and inspiration below the equilibrium level. During inspiration, critical closing (Pclose) and reopening (Popen) are seen in the early and late
phase of the loops (see text for details). The regression line for the linear portions
of the pressure-flow curves (bottom) were used to determine the upstream resistance (Rus), Pclose, and Popen of the loops. The difference in Ptrach at the V̇in
level was used for the measurement of upper airway pressure-flow hysteresis.
J Appl Physiol • VOL
TTI, l/min
Closing
Pcrit, cmH2O
Rus, cmH2O䡠l⫺1䡠s
Opening
Pcrit, cmH2O
Rus, cmH2O䡠l⫺1䡠s
Hysteresis, cmH2O
P Value
Condition 1
Condition 2
11.9⫾1.2
14.0⫾1.2
0.07
4.4⫾2.0
18.1⫾2.4
4.6⫾2.0
19.2⫾3.5
0.7
0.7
10.8⫾2.4*
7.5⫾1.9*
4.3⫾0.6
7.1⫾2.6*
22.0⫾5.7
3.0⫾0.4
⬍0.01
⬍0.04
⬍0.05
Values are means ⫾ SE. TTI, transtracheal insufflation; Pcrit, critical pressure;
Rus, upstream resistance. *P ⬍ 0.05, upper airway opening vs. closing.
101 • NOVEMBER 2006 •
www.jap.org
Downloaded from http://jap.physiology.org/ by guest on June 8, 2013
The data obtained from tidal pressure-flow loops are illustrated
in Fig. 5 and summarized in Table 1 for TTI flow rates associated
with the presence and absence of upper airway occlusion. Loops
were analyzed from steady-state periods of breathing at a TTI
flow rate of 11.9 ⫾ 1.2 l/min for the occluded upper airway
condition and at a TTI flow rate of 14.0 ⫾ 1.2 l/min (P ⬎ 0.07)
for the unoccluded upper airway condition. In the occluded upper
airway condition, the range of V̇ua for the linear portions of the
pressure-flow loops used was 2.4 ⫾ 0.8 to 17.9 ⫾ 3.8 l/min for the
closing limb and 2.5 ⫾ 0.8 to 17.3 ⫾ 4.0 l/min for the opening
limb. In the unoccluded upper airway condition, the V̇ua range
Innovative Methodology
DYNAMIC MODULATION OF UPPER AIRWAY FUNCTION
1493
Mechanism for Within-Breath Changes in Upper
Airway Properties
because the downstream pressure at the nose remained less than
Pcrit throughout the respiratory cycle (see Conceptual Approach).
Within-breath modulation of upper airway properties. For
both the occluded upper airway and unoccluded upper airway
conditions, Pclose was significantly lower than Popen (Table 1
and Fig. 6A). Similarly, there was a decrease in Rus from the
deflation limb to the inflation limb of the upper airway pressure-flow relationship (Table 1, Fig. 6B).
Effects of occlusion on upper airway pressure-flow hysteresis. Pclose did not differ between the occluded airway and
unoccluded airway conditions (Fig. 6A). In contrast, Popen decreased by 3.7 ⫾ 0.9 cmH2O from the occluded upper airway to
the unoccluded upper airway condition (Fig. 6A). There was no
difference in Rus for the deflation limb of the pressure-flow curve
between the occluded upper airway and unoccluded upper airway
conditions, whereas Rus for the inflation limb increased significantly by 14.5 ⫾ 4.6 cm H2O䡠l⫺1 䡠s in the unoccluded upper
airway compared with the occluded upper airway condition (Table 1). At the TTI level, the inflation segment of pressure-flow
loop was displaced further to the right in the occluded upper
airway compared with the unoccluded upper airway condition
(4.3 ⫾ 0.6 vs. 3.0 ⫾ 0.4 cmH2O in the occluded upper airway vs.
the unoccluded upper airway condition; P ⬍ 0.05; Table 1).
DISCUSSION
This paper describes a novel method for assessing the
physiological properties of the upper airway continuously on a
breath-by-breath basis during tracheal insufflation. We found
that the collapsibility was reduced and the Rus increased during
upper airway deflation compared with inflation of tidal pressureflow loops. Moreover, preventing upper airway occlusion did not
alter the critical closing (upper airway deflation) properties.
Rather, it led to a decrease in Popen and a increase in the Rus
during reopening (upper airway inflation). Our findings indicate
that upper airway properties change dynamically within a breath
in sleeping apneic individuals as a function of the respiratory
phase and the state of airway patency. These data suggest that
the upper airway is more stable in the early compared with late
phase of inspiration and that, once the upper airway has
occluded during sleep, it is much harder to reopen.
J Appl Physiol • VOL
Limitations
There are three main limitations of our present study. First, our
study lacked EMG monitoring of upper airway muscles; therefore, we did not examine the relationship between Pcrit and
neuromuscular activity. Nevertheless, the phasic modulation of
upper airway dilator activity is well documented, as is the relationship between early inspiratory activation and reductions in
upper airway collapsibility. Of note, when tidal pressure-flow
loops were generated during TTI administration in deeply anesthetized subjects, no significant hysteresis was observed (13),
101 • NOVEMBER 2006 •
www.jap.org
Downloaded from http://jap.physiology.org/ by guest on June 8, 2013
Fig. 6. Group mean Pcrit (A) and Rus (B) of the closing and opening limbs of
the tidal pressure-flow loop for the occluded upper airway (condition 1; F) and
unoccluded upper airway (condition 2; E) conditions. *P ⬍ 0.05.
Dynamic changes in upper airway function may be related to
the mechanical changes in tracheal traction, lung inflation,
and/or surface tension throughout the respiratory cycle. Reciprocal changes in Pcrit and Rus have previously been observed
in the isolated feline upper airway with caudal traction on the
trachea (15, 25, 28). Increases in inspiratory effort produce
caudal traction on the trachea (29), which decreases Pcrit and
increases Rus (15, 28). Consistent with animal studies, we
found increasing effort (decreasing Ptrach) led to a decrease in
Pcrit and increase in Rus, whereas decreasing effort lead to a
increase in Pcrit and decrease in Rus. Mechanical effects of
caudal tracheal traction can account for decreased Pcrit and
increased Rus as effort increases in the early compared with the
latter part of inspiration. The stabilizing effect of caudal
tracheal traction is likely offset by lower lung volumes in early
inspiration than late inspiration, which would increase therapeutic CPAP requirements (8). Thus dynamic changes in upper
airway function within a single breath can be best attributed to
alterations in tracheal traction rather than lung volume, and the
effects of tracheal traction on upper airway collapsibility may
be underestimated with this current method.
In addition to the stabilizing effect of tracheal traction during
early inspiration, surface tension can account for hysteresis in
opening and closing Pcrit within a breath. The development of
upper airway occlusion within a breath was associated with
substantial increase in Pcrit hysteresis (⬃4 cmH2O). This
finding is best explained by surface forces that develop when
mucosal surfaces are opposed and adhere to one another
(10 –12). In previous studies, our laboratory has shown that a
30% change in the surface tension of the liquid lining the upper
airway decreases the difference between Popen and Pclose by
2 cmH2O (11), consistent with observed differences between
Popen and Pclose pressures during sleep (1). Our present
findings confirm that surface forces contribute an ⬃2-cmH2O
increase in the Popen compared with Pclose. Our within-breath
method for determining Popen and Pclose allows us to conclude that surface forces account for approximately one-half of
the hysteresis between Popen and Pclose.
In addition to mechanical effects, it is also possible that
phasic neuromuscular activity may account for residual differences between Popen and Pclose. Phasic EMG generally peaks
in early inspiration (27, 30), has been associated with decreased upper airway collapsibility in animals and humans (23,
24). Although we do not assess upper airway EMG activity,
current evidence suggests that phasic neuromuscular activity
may account for the remaining decrease in the early inspiratory
(closing) compared with late inspiratory (opening) Pcrit.
Innovative Methodology
1494
DYNAMIC MODULATION OF UPPER AIRWAY FUNCTION
which may have been due to the suppression of phasic upper
airway neuromuscular activity (3). Second, our sample size is
limited to a small number of sleep apnea subjects, making it
difficult to extrapolate our findings to normal individuals who
may also exhibit phasic modulation of upper airway properties.
We acknowledge that to extend our approach to the study of
normal subjects during sleep, air must be insufflated below a site
of upper airway obstruction and subatmospheric pressure must be
applied to the airway opening, such that the airway remains flow
limited (i.e., nasal pressure remains below a negative Pcrit). Third,
our measurements required TTI in tracheostomized patients, both
of which may have altered breathing patterns (17). Nevertheless,
our findings indicate that mechanical and neuromuscular effects
provide for a marked decrease in Pcrit in early inspiration, which
stabilizes upper airway patency during this portion of the respiratory cycle.
The present findings have important physiological implications
for investigating the control of upper airway function during sleep.
Our method provides an approach for examining the acute modulation of upper airway flow dynamics within and between single
breaths. Within-breath changes in upper airway properties can
provide a dynamic assessment of the mechanical (late inspiratory)
and neuromuscular (early inspiratory) components of upper airway collapsibility. Utilizing this approach, investigators can now
partition the effects of these factors. In addition, our technique
provides greater flexibility in assessing the acute effects of interventions on the dynamic modulation of upper airway function.
Extending this method to nontracheostomized subjects would
allow investigators to delineate effects of acute interventions such
as surfactant instillation, changes in lung volume or mandibular
position, and electrical or pharmacological stimulation of upper
airway neuromuscular activity. Moreover, this approach can be
adapted for studies of upper airway function in healthy apneic and
nonapneic subjects.
GRANTS
This work was supported by National Heart, Lung, and Blood Institute
Grants HL-10247, HL-37379, and HL-50381 and by National Health and
Medical Research Council Grant 353705
REFERENCES
1. Berry RB, Bonnet MH, and Light RW. Effect of ethanol on the arousal
response to airway occlusion during sleep in normal subjects. Am Rev
Respir Dis 145: 445– 452, 1992.
2. Boudewyns AN, De Backer WA, and Van de Heyning PH. Pattern of
upper airway obstruction during sleep before and after uvulopalatopharyngoplasty in patients with obstructive sleep apnea. Sleep Med 2: 309 –315, 2001.
3. Eastwood PR, Platt PR, Shepherd K, Maddison K, and Hillman DR.
Collapsibility of the upper airway at different concentrations of propofol
anesthesia. Anesthesiology 103: 470 – 477, 2005.
4. Eastwood PR, Satoh M, Curran AK, Zayas MT, Smith CA, and
Dempsey JA. Inhibition of inspiratory motor output by high-frequency
low-pressure oscillations in the upper airway of sleeping dogs. J Physiol
517: 259 –271, 1999.
5. Eastwood PR, Szollosi I, Platt PR, and Hillman DR. Comparison of
upper airway collapse during general anaesthesia and sleep. Lancet 359:
1207–1209, 2002.
6. Gleadhill IC, Schwartz AR, Schubert N, Wise RA, Permutt S, and Smith
PL. Upper airway collapsibility in snorers and in patients with obstructive
hypopnea and apnea. Am Rev Respir Dis 143: 1300 –1303, 1991.
7. Gold AR and Schwartz AR. The pharyngeal critical pressure. The whys
and hows of using nasal continuous positive airway pressure diagnostically. Chest 110: 1077–1088, 1996.
J Appl Physiol • VOL
101 • NOVEMBER 2006 •
www.jap.org
Downloaded from http://jap.physiology.org/ by guest on June 8, 2013
Implications
8. Heinzer RC, Stanchina ML, Malhotra A, Fogel RB, Patel SR, Jordan
AS, Schory K, and White DP. Lung volume and continuous positive
airway pressure requirements in obstructive sleep apnea. Am J Respir Crit
Care Med 172: 114 –117, 2005.
9. Isono S, Remmers JE, Tanaka A, Sho Y, Sato J, and Nishino T.
Anatomy of pharynx in patients with obstructive sleep apnea and in
normal subjects. J Appl Physiol 82: 1319 –1326, 1997.
10. Kirkness JP, Christenson HK, Garlick SR, Parikh R, Kairaitis K,
Wheatley JR, and Amis TC. Decreased surface tension of upper airway
mucosal lining liquid increases upper airway patency in anaesthetised
rabbits. J Physiol 547: 603– 611, 2003.
11. Kirkness JP, Eastwood PR, Szollosi I, Platt PR, Wheatley JR, Amis TC,
and Hillman DR. Effect of surface tension of mucosal lining liquid on upper
airway mechanics in anesthetized humans. J Appl Physiol 95: 357–363, 2003.
12. Kirkness JP, Madronio M, Stavrinou R, Wheatley JR, and Amis TC.
Relationship between surface tension of upper airway lining liquid and
upper airway collapsibility during sleep in obstructive sleep apnea hypopnea syndrome. J Appl Physiol 95: 1761–1766, 2003.
13. Okazaki J, Isono S, Tanaka A, Tagaito Y, Schwartz AR, and Nishino T.
Usefulness of continuous oxygen insufflation into trachea for management of
upper airway obstruction during anesthesia. Anesthesiology 93: 62– 68, 2000.
14. Roberts JL, Reed WR, Mathew OP, Menon AA, and Thach BT.
Assessment of pharyngeal airway stability in normal and micrognathic
infants. J Appl Physiol 58: 290 –299, 1985.
15. Rowley JA, Permutt S, Willey S, Smith PL, and Schwartz AR. Effect
of tracheal and tongue displacement on upper airway airflow dynamics.
J Appl Physiol 80: 2171–2178, 1996.
16. Rowley JA, Williams BC, Smith PL, and Schwartz AR. Neuromuscular
activity and upper airway collapsibility. Mechanisms of action in the
decerebrate cat. Am J Respir Crit Care Med 156: 515–521, 1997.
17. Schneider H, Boudewyns A, Smith PL, O’Donnell CP, Canisius S,
Stammnitz A, Allan L, and Schwartz AR. Modulation of upper airway
collapsibility during sleep: influence of respiratory phase and flow regimen. J Appl Physiol 93: 1365–1376, 2002.
18. Schneider H, O’Hearn DJ, Leblanc K, Smith PL, O’Donnell CP,
Eisele DW, Peter JH, and Schwartz AR. High-flow transtracheal insufflation treats obstructive sleep apnea. A pilot study. Am J Respir Crit Care
Med 161: 1869 –1876, 2000.
19. Schwartz AR, Gold AR, Schubert N, Stryzak A, Wise RA, Permutt S,
and Smith PL. Effect of weight loss on upper airway collapsibility in
obstructive sleep apnea. Am Rev Respir Dis 144: 494 – 498, 1991.
20. Schwartz AR, O’Donnell CP, Baron J, Schubert N, Alam D, Samadi
SD, and Smith PL. The hypotonic upper airway in obstructive sleep
apnea: role of structures and neuromuscular activity. Am J Respir Crit
Care Med 157: 1051–1057, 1998.
21. Schwartz AR, Schubert N, Rothman W, Godley F, Marsh B, Eisele D,
Nadeau J, Permutt L, Gleadhill I, and Smith PL. Effect of uvulopalatopharyngoplasty on upper airway collapsibility in obstructive sleep apnea. Am Rev Respir Dis 145: 527–532, 1992.
22. Schwartz AR, Smith PL, Wise RA, Gold AR, and Permutt S. Induction
of upper airway occlusion in sleeping individuals with subatmospheric
nasal pressure. J Appl Physiol 64: 535–542, 1988.
23. Schwartz AR, Thut D, Gauda E, Wise RA, Permutt S, and Smith PL.
Effect of phasic neuromuscular activity (NMA) on airflow mechanics in the
isolated canine upper airway (Abstract). Am Rev Respir Dis 141: A743, 1990.
24. Schwartz AR, Thut D, Roach D, and Smith PL. Effect of hypoglossal
nerve stimulation on airflow mechanics in the isolated upper airway. Am
Rev Respir Dis 143: A405, 1991.
25. Seelagy MM, Schwartz AR, Russ DB, King ED, Wise RA, and Smith
PL. Reflex modulation of airflow dynamics through the upper airway.
J Appl Physiol 76: 2692–2700, 1994.
26. Smith PL, Wise RA, Gold AR, Schwartz AR, and Permutt S. Upper
airway pressure-flow relationships in obstructive sleep apnea. J Appl
Physiol 64: 789 –795, 1988.
27. Strohl KP, Hensley MJ, Hallett M, Saunders NA, and Ingram RHJ.
Activation of upper airway muscles before onset of inspiration in normal
humans. J Appl Physiol 49: 638 – 642, 1980.
28. Thut DC, Schwartz AR, Roach D, Wise RA, Permutt S, and Smith PL.
Tracheal and neck position influence upper airway airflow dynamics by
altering airway length. J Appl Physiol 75: 2084 –2090, 1993.
29. Van de Graaff WB. Thoracic traction on the trachea: mechanisms and
magnitude. J Appl Physiol 70: 1328 –1336, 1991.
30. White DP and Mezzanotte WS. Neuromuscular compensation in the
human upper airway. Sleep 16: S90 –S91, 1993.