Defining Phenotypic Causes of Obstructive
Identification of Novel Therapeutic Targets
Danny J. Eckert1,2, David P. White1, Amy S. Jordan1,3, Atul Malhotra1, and Andrew Wellman1
1Division of Sleep Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts;2Neuroscience Research Australia and the
School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia; and3Melbourne School of Psychological Sciences,
University of Melbourne, Parkville, Victoria, Australia
Rationale: The pathophysiologic causes of obstructive sleep apnea
Objectives: To define carefully the proportion of key anatomic and
nonanatomic contributions in a relatively large cohort of patients
with OSA and control subjects to identify pathophysiologic targets
for future novel therapies for OSA.
20–65 years were studied on three separate nights. Initially, the
apnea-hypopnea index was determined by polysomnography fol-
lowed by determination of anatomic (passive critical closing pres-
sure of the upper airway [Pcrit]) and nonanatomic (genioglossus
muscle responsiveness, arousal threshold, and respiratory control
stability; loop gain) contributions to OSA.
stantially among participants. A total of 36% of patients with OSA
had a low arousal threshold, and 36% had high loop gain. A total of
airway was more collapsiblein patientswith OSA (Pcrit, 0.3 [21.5 to
noncollapsible upper airway similar to many of the control subjects
(Pcrit, 22 to 25 cm H2O). In these patients, loop gain was almost
twice as high as patients with a Pcrit greater than 22 cm H2O (25.9
[28.8 to 24.5] vs. 23.2 [24.8 to 22.4] dimensionless; P ¼ 0.01).
A three-point scale for weighting the relative contribution of the
traits is proposed. It suggests that nonanatomic features play an
important role in 56% of patients with OSA.
nonanatomic traits are also present in most patients with OSA.
Keywords: respiratory physiology; arousal; muscle; upper airway path-
ophysiology; sleep-disordered breathing
Obstructive sleep apnea (OSA) is a common breathing disorder
characterized by repetitive narrowing and closure of the upper air-
way during sleep (1). OSA is associated with major adverse health
outcomes including increased cardiovascular risk (2). The first-line
treatment for OSA, continuous positive airway pressure (CPAP),
is highly efficacious in reducing sleep-disordered breathing events.
However, about half of all patients with OSA who try CPAP
therapy are either completely intolerant or only partially adherent
(3). Accordingly, new treatments for OSA are clearly required.
If new treatments for OSA are to be effective,understanding the
various underlying causes is essential (4, 5). Key pathophysiologic
causes likely include (1) an anatomically compromised or collaps-
ible upper airway (high passive critical closing pressure of the upper
airway [Pcrit]) (6); (2) inadequate responsiveness of the upper-
airway dilator muscles during sleep (minimal increase in EMG
activity to negative pharyngeal pressure) (7, 8); (3) waking up pre-
maturely to airway narrowing (a low respiratory arousal threshold)
(9–13); and (4) having an oversensitive ventilatory control system
(high loop gain) (13–15). Indeed, small physiologic studies have
demonstrated interventions that lower Pcrit (16–18), increase the
electrical activity to genioglossus (19, 20), increase the arousal
threshold (9), or lower loop gain (21, 22) can reduce OSA severity.
However, these important pathophysiologic traits have not been
measured collectively in afflicted individuals. This study aimed to
quantify carefully each of these phenotypic traits in a relatively
large cohort of patients with OSA and a group of healthy control
subjects. We hypothesized that the relative contribution of each
(Received in original form March 8, 2013; accepted in final form May 21, 2013)
Supported by NIH 5R01HL048531. The authors have also received funding sup-
port from the AHA (0840159N, 10SDG3510018); the ARC (60702); the NHMRC
of Australia (510392, 1049814); and the NIH (RO1 102231, R01 HL090897,
NIH K24 HL 093218, NIH P01 HL 095491, NIH R01HL110350, and NIH R01
HL085188). The Harvard Catalyst is funded by UL1 RR 025758-01. A modified
continuous positive airway pressure machine was provided by Philips Respironics
and was used to obtain the physiologic measurements performed in this study.
Author Contributions: D.J.E. wrote the manuscript and all of the authors contrib-
uted to the final version. D.J.E., A.S.J., and A.W. contributed to experimental de-
sign and collected and analyzed the data. A.M. contributed to experimental
design and data interpretation. D.P.W. was responsible for the study conception,
design, and data interpretation.
Correspondence and requests for reprints should be addressed to Danny J. Eckert,
Ph.D., Neuroscience Research Australia, PO Box 1165, Randwick, New South
Wales, Australia, 2031. E-mail: email@example.com
Am J Respir Crit Care Med
Copyright ª 2013 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201303-0448OC on May 30, 2013
Internet address: www.atsjournals.org
Vol 188, Iss. 8, pp 996–1004, Oct 15, 2013
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
Previous studies have established that there are likely mul-
tiple causes of obstructive sleep apnea (OSA). However,
most of these studies were limited to investigating one
mechanism in isolation, involved relatively small numbers of
participants, and were not performed using detailed physi-
ologic measurements. Accordingly, before the current study,
the proportion of patients with OSA in whom nonanatomic
pathophysiologic features are present was unknown.
What This Study Adds to the Field
This is the largest comprehensive physiologic study to date
showing that the causes of OSA are multifactorial and not
just anatomically driven. One or more nonanatomic path-
ophysiologic traits are present in 69% of patients with OSA.
We propose a three-point (Passive critical closing pressure
of the upper airway, Arousal threshold, Loop gain, and
Muscle responsiveness [PALM]) scale to help guide future
investigation aimed at developing novel targeted therapies
for OSA according to pathophysiologic characterization.
trait would vary among patients, with the emergence of different
phenotypic subgroups. In identifying and characterizing these sub-
groups, the ultimate goal is to provide insight for the development
of novel therapeutic approaches that target underlying mechanisms
in individual patients with OSA. Some of the results of these studies
have been previously reported in abstract form (23–25).
Informed written consent, as approved by the Partners’ Healthcare
Institutional Review Board, was obtained in 90 men and women (69
patients with OSA who had been treated with CPAP for >3 months
and 21 healthy control subjects). Other than OSA, defined as an apnea-
hypopnea index (AHI) greater than 10 events per hour of sleep, par-
ticipants were healthy and were not taking any medications known to
affect sleep or the other parameters measured in the study. Data
addressing separate aims involving a small number of participants from
the current study have been previously reported (26, 27).
Measurements and Equipment
Polysomnography. Electroencephalograms, electrooculograms, and sur-
face submentalis EMGs were applied to enable sleep staging and score
arousals (28, 29). Chest and abdominal motion bands, a position monitor,
finger pulse oximetry, and airflow monitoring (thermistor plus nasal
pressure) were also applied to enable respiratory event detection accord-
ing to standard criteria (30).
Key physiologic measurements. Two Teflon-coated stainless steel fine-
wire intramuscular electrodes (Cooner Wire Company, Chatsworth,
CA) with 2 mm of Teflon removed from the tip were inserted into
the largest upper-airway dilator muscle, the genioglossus, by a 25-gauge
needle 3 to 4 mm on either side of the frenulum to a depth of approx-
imately 1.5 cm after surface anesthesia (4% lidocaine HCl) to create
a bipolar EMG recording. Both nostrils were decongested (0.05% oxy-
metazoline HCl). The clearer nostril was anesthetized (4% lidocaine
HCl) and an epiglottic pressure (Pepi) catheter (model MCP-500; Millar,
Houston,TX) wasadvanced1 to2 cmbelowthebaseofthetongueunder
direct visualization. The catheter was taped to the nostril and passed
through a port in a CPAP mask (Gel Mask; Philips Respironics, Murrys-
Hans Rudolf Inc.,KansasCity,MO)anddifferential pressuretransducers
(Validyne Corporation, Northbridge, CA) for measurement of airflow
and mask pressure.
Participants were studied on three separate occasions approximately
1 week apart. Initially, patients withheld their CPAP use for a single
night and a standard overnight sleep study was performed to quantify
Figure 1. (A)Exampleofacontinuouspos-
itive airway pressure (CPAP) drop high-
lighting the variables of interest for
calculation of Pcrit, genioglossus mus-
cle responsiveness, and the respiratory
arousal threshold. (B) Determination of
loop gain from a CPAP drop. (1) Before
the drop, the patient’s airway is open
and ventilation is at eupnea. (2) When
CPAP is dropped, the upper airway nar-
rows and limits ventilation. (3) As a result,
CO2increases and, in many individuals,
activates and stiffens the pharyngeal
muscles and increases ventilation slightly
(although it typically remains below eup-
nea). In this schematic example, the distur-
bance is a change in ventilation of 21.4
L/min. (4) The response to this disturbance
is determined by reopening the airway with
CPAP and measuring the ventilatory over-
shoot, which is 4.2 L/min. Therefore, the
loop gain is 4.2 O 21.4 ¼ 23 (i.e., for
every liter per minute reduction in ventila-
tion, there is a threefold increase in ventila-
tory drive). (5) After the airway is reopened
and the excess CO2is blown off, ventilation
returns back to eupnea. Refer to the text
and reference (27) for further detail. GG ¼
genioglossus; MTA ¼ 100 millisecond
moving-time-average of the rectified raw
electromyographic activity; Pepi ¼ epi-
glottic pressure; Pcrit ¼ critical closing
pressure of the upper airway; Pmask ¼
Eckert, White, Jordan, et al.: Defining Phenotypes in Obstructive Sleep Apnea997
4 hours on the diagnostic night. On the two physiology nights (random
order), subjects were studied between approximately 10:30 PM and
5:00 AM while lying in the supine posture on therapeutic CPAP for
the patients with OSA or at least 4 cm H2O in the control subjects.
This holding pressure was increased during sleep to eliminate any sign
of inspiratory airflow limitation, according to the epiglottic-airflow re-
lationship, as required in both groups.
Swallows and tongue protrusions against the top teeth were per-
formed before sleep to determine maximal genioglossus EMG activity
for each participant (31). After stable non-REM sleep was established,
progressive CPAP drops for up to 3 minutes were applied to induce
varying degrees of upper-airway collapse using a modified CPAP de-
vice capable of delivering 6 20 cm H2O (Philips Respironics) for mea-
surement of (1) Pcrit (6), (2) genioglossus muscle responsiveness (7),
and (3) the respiratory arousal threshold (32). Steady-state loop gain
was measured on a separate night also using CPAP drops (21, 27) as
Data Analysis and Statistical Procedures
CPAP compliance history was measured objectively by inbuilt compliance
meter. To determine the Pcrit in each participant, linear regression was
three to five after each CPAP drop if the breaths were flow-limited (33).
Raw genioglossus EMG was rectified, moving-time-averaged (100 milli-
seconds), and expressed as a percentage of maximum activity (31). Linear
regression was performed between peak genioglsssus EMG versus nadir
epiglottic pressure for each artifact-free breath before arousal or sudden
restoration of airflow during CPAP drops. Genioglossus muscle respon-
siveness was defined as the slope of the relationship between these two
variables (7). The respiratory arousal threshold was defined as the average
nadir epiglottic pressure immediately before cortical arousal (.3 seconds
of high frequency activity on the EEG) for all CPAP drops lasting greater
than or equal to 10 seconds that terminated in an arousal and had greater
than or equal to 2 cm H2O decrement in epiglottic pressure in the pre-
ceding 30 seconds (9, 32). Figure 1A shows an example of a CPAP drop
highlighting how each of these three pathophysiologic traits was defined.
Loop gain was quantified as the ventilatory response to a disturbance in
ventilation (21, 27). The disturbance was produced by the CPAP drop, as
shown in the schematic diagram in Figure 1B.
Similar to previous studies that characterized the various sleep-
disordered breathing severities according to Pcrit (6, 34), to provide
pathophysiologic insight Pcrit was separated into four categories: (1)
control subjects with a highly negative Pcrit (,25 cm H2O); (2) con-
trol subjects and patients with OSA with overlapping Pcrit values
(,25 to 22 cm H2O); and patients with OSA with (3) moderately
(22 to 12 cm H2O) to (4) highly collapsible upper airways (.12 cm
H2O). Poor genioglossus muscle responsiveness was defined as a less
than 0.1% of maximum increase in EMG activity per centimeter of
water of negative epiglottic pressure. Awakening to greater than 215 cm
H2O of negative epiglottic pressure constituted a low respiratory
arousal threshold as previously defined (9). High loop gain was de-
fined as less than 25, based on physiologic insight from a previous
intervention study (21) and model simulations (27).
For each outcome variable where the distribution of the delta be-
tween conditions was normally distributed (according to a Shapiro-
Wilk test), statistical comparisons were performed using Student paired
t tests. Nonnormally distributed data were compared using a nonpara-
metric Mann-Whitney test. Analysis of variance was used to compare
phenotypic traits between Pcrit groups (SigmaPlot, San Jose, CA).
Group data are reported as mean 6 SD or median with interquartile
range for nonnormally distributed variables. Statistical significance was
defined as P less than 0.05.
Four of the control subjects and 11 of the patients with OSA did
not complete all three nights of the protocol and were excluded
from data analysis. Reasons for incomplete data included the di-
agnosis of OSA in one of the control subjects, and insufficient
sleep in three of the control subjects and six of the patients with
OSA. The remaining five patients with OSA were excluded be-
cause of the presence of central respiratory events, failure to at-
tend, uncontrolled hypertension, use of an antidepressant, and
a technical problem. Anthropometric, baseline sleep, and CPAP
compliance characteristics for the 75 participants that completed
all three nights are displayed in Table 1.
A total of 27 6 12 CPAP drops per subject were delivered
during sleep. Of these, 6 6 5 caused an immediate arousal
(within ,10 seconds) and 2 6 4 were excluded from the analysis
because of poor signal quality. The average reduction in the
CPAP holding level required to derive the phenotypic traits
was 6 6 2 cm H2O. All four traits could be quantified in 52
subjects, three in 22 subjects, and two in one subject. Group
and individual data for each phenotypic trait are displayed in
Figures 2 and 3. There was substantial between-subject variabil-
ity in both patients and control subjects.
Patients with OSA versus Control Subjects
Pcrit was more positive in the patients with OSA compared with
the control subjects (0.3 [21.5 to 1.9] vs. 26.2 [212.4 to 23.6];
P , 0.001) (Figure 2). Patients with a Pcrit less than 12 cm H2O
all had severe OSA (AHI .30 events per hour of sleep) (Figure
2; Table 2). Conversely, those with Pcrit values less than 25 cm
H2O did not have OSA (AHI ,10 events per hour of sleep)
(Figure 2). However, there was substantial overlap in Pcrit between
patients with OSA and control subjects in the subatmospheric
range between 22 and 25 cm H2O. AHI varied considerably
within this subgroup (Figure 2) as did the nonanatomic pheno-
typic traits (Table 2).
On average, the respiratory arousal threshold was significantly
higher (more negative) in patients with OSA versus control sub-
jects (P , 0.01) (Figure 3B). Nonetheless, approximately one-
third of patients with OSA had a low arousal threshold according
to previously defined thresholds (9) (Figure 3B). The propor-
tion of CPAP drops that caused immediate arousals (within
,10seconds)was higher inthosewitha low compared witha high
arousal threshold (23 [13–33] vs. 15 [8–22] %; P ¼ 0.02) despite
lower magnitude CPAP drops (5 [4–6] vs. 7 [6–7] cm H2O; P ,
0.01). Conversely, there was no systematic difference in the
slope of genioglossus muscle responsiveness (P ¼ 0.41) or loop
gain (P ¼ 0.68) between patients with OSA and control sub-
jects (Figures 3A and 3C). However, approximately one-third
of patients with OSA had poor muscle responsiveness (Figure
3A). Similarly, 36% of patients with OSA had a high loop gain
TABLE 1. ANTHROPOMETRIC, SLEEP, AND CPAP COMPLIANCE
Patients with OSA
(n ¼ 58)
47 6 11
35 6 6
(n ¼ 17)
38 6 12
26 6 4
Body mass index, kg/m2
Median AHI, number of
events per hour sleep
AHI range, number of
events per hour sleep
CPAP compliance, h/night
6.4 6 1.6
Definition of abbreviations: AHI ¼ apnea-hypopnea index; CPAP ¼ continuous
positive airway pressure; OSA ¼ obstructive sleep apnea.
Values are mean 6 SD or median and interquartile range in parentheses.
998AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 1882013
Group data according to Pcrit category for each of the pheno-
typic traits are displayed in Figure 4. When grouped according
to upper-airway collapsibility (Pcrit) characterization, loop gain
was almost twice as high (more negative) in patients with OSA
with a Pcrit less than 22 cm H2O versus those with a Pcrit
greater than 12 cm H2O (P ¼ 0.01) (Figure 4B). Similarly, loop
gain tended to be higher in the patients with OSA with a Pcrit
less than 22 cm H2O compared with control subjects (P ¼ 0.06)
(Figure 4B) and patients with OSA with a Pcrit greater than
12 cm H2O (P ¼ 0.07) (Figure 4B).
The findings of this study highlight the multifactorial pathophys-
iology of OSA. Upper airway collapsibility and anatomy is an im-
portant determinant of the presence or absence of OSA and its
severity. In our cohort, those with a Pcrit greater than 12 cm
H2O invariably have severe OSA, whereas those with a Pcrit be-
low 25 cm H2O do not have OSA. However, approximately one
in five of the patients with OSA required less than 22 cm H2O to
collapse their upper airway during sleep. Within the 22 to 25 cm
H2O Pcrit range, the AHI varies considerably (some individuals do
not have OSA). This finding suggests that other nonanatomic path-
ophysiologic traits are particularly important in contributing to the
presence or absence of OSA and its severity within this group.
Phenotypic Traits: Between-Group Differences, Relationship
with AHI, and Interactions with Pcrit
There is considerable intersubject variability and overlap be-
tween patients with OSA and control subjects for each of the
four pathophysiologic traits measured in this study. As previ-
ously demonstrated (6, 16, 34–36), and consistent with the im-
portance of upper-airway collapsibility in OSA pathogenesis,
Pcrit is considerably more positive in patients with OSA com-
pared with control subjects. Similarly, the broad distribution of
Pcrit values, the widespread relationship between Pcrit and AHI,
and the sizable between-group overlap observed in the current
study are consistent with previous reports (6, 34).
An inability to mount an adequate increase in neural drive to the
collapsing pressure contributes to OSA pathogenesis (4, 8, 11).
More than one-third of the patients with OSA studied generated
less than a 0.1% increase in their maximal genioglossus activity in
response to a 1 cm H2O decrement in negative pharyngeal pres-
sure. Poor genioglossus responsiveness during sleep is particularly
common in patients with OSA with a mild to moderately collaps-
ible upper airway. Accordingly, this trait is likely to be important in
mediating the presence or absence of apnea and its severity in
these individuals. However, muscle responsiveness is not system-
atically different in patients with OSA compared with control sub-
jects. This finding is consistent with previous studies demonstrating
comparable or increased neural responsiveness to negative collapsing
Figure 2. Critical closing pressure of the upper airway (Pcrit) versus the
apnea-hypopnea index (AHI). Grey circles represent individuals with an
AHI less than 10 events per hour of sleep.
Figure 3. Phenotypic trait scatter plots for (A) slope of genioglossus
muscle responsiveness versus negative epiglottic pressure, (B) the re-
spiratory arousal threshold, and (C) loop gain. Note the large degree of
between-subject variability within patients with OSA and control sub-
jects and considerable between-group overlap for each of the patho-
physiologic parameters. Horizontal black lines represent median values.
Values above the dashed grey lines in A (more positive) and B (more
positive) indicate poor muscle responsiveness and a low arousal thresh-
old, respectively. Values below the dashed grey line in C (more negative)
indicate a high loop gain. Refer to text and Tables 2 and 3 for further
detail. *Significant difference between groups (P , 0.05). OSA ¼ ob-
structive sleep apnea; Pepi ¼ epiglottic pressure.
Eckert, White, Jordan, et al.: Defining Phenotypes in Obstructive Sleep Apnea999
pressures in patients with OSA (7, 37, 38). However, the ability to
translate upper airway neural drive to mechanical airway opening
may be compromised in some patients with OSA (7, 39–41).
Direct comparisons of the respiratory arousal threshold between
patients with OSA and control subjects have not been previously
performed. However, an increased arousal threshold in patients
with OSA is in accordance with prior between-study compari-
sons in patients with severe OSA and healthy control subjects
(42). CPAP therapy decreases the arousal threshold in patients
with severe OSA (42–45). However, the current findings indi-
cate that despite objectively documented regular CPAP use, the
arousal threshold remains higher in patients with OSA com-
pared with control subjects. Nonetheless, more than one-third
of CPAP-treated patients with OSA have a low arousal thresh-
old. In these individuals, waking up prematurely is predicted to
contribute to their OSA by disrupting sleep continuity and lim-
iting the opportunity for adequate upper airway muscle recruit-
ment to restore airflow during sleep (4, 9, 10, 12).
with OSA and nonsnoring control subjects (14, 15). However,
both of these studies concluded that loop gain is likely to be
important in OSA pathogenesis for some patients but not others
according to their degree of upper-airway collapsibility (15) or
apnea severity (14). Consistent with this notion, loop gain was
not systematically different in patients with OSA compared
with control subjects in the current study but was almost 50%
higher (more negative) in patients with a Pcrit less than 22 cm
H2O compared with those with more positive Pcrit values. Loop
gain also tended to be higher in patients with OSA than control
subjects with a similar Pcrit. This finding suggests that loop gain
is likely to be particularly important in OSA pathogenesis in
those with mild vulnerability to upper-airway collapse but less
so in those with a highly collapsible upper airway, in whom
biomechanical predisposition may prevail.
Taken together, these findings indicate that the way in which
these traits interact to cause or prevent OSA is highly complex
and likely varies considerably between individuals. The degree
of upper airway collapsibility is particularly important in medi-
ating the relative importance of each of the nonanatomic traits.
Indeed, many healthy individuals without OSA also display vul-
nerability in the nonanatomic phenotypic traits, particularly
arousal threshold. However, in the absence of an inherently col-
lapsible upper airway, these traits in and of themselves are un-
likely to cause clinically important sleep-disordered breathing.
The PALM Scale, Simplified Approaches, and Potential Novel
Targets for Therapy
In carefully defining each of these four pathophysiologic traits,
several key themes have emerged. In this paper we present the
anatomic and nonanatomic phenotypic traits (Table 3). The scale
provides insight into the proportion and characteristics of pa-
tients with OSA in each category. To stimulate future research,
it also highlights the potential to target new and existing therapies
based on specific mechanisms in individual patients with OSA.
scale 1. These patients have a high Pcrit, invariably have severe
OSA, and approximately two-thirds have vulnerability in one
or more of the other three phenotypic traits. Although targeting
one or more nonanatomic traits (muscle responsiveness, arousal
threshold, or loop gain) with novel therapies in these patients
may reduce OSA severity, it is highly unlikely that this approach
is sufficient to overcome the extent of upper airway collapsibility
presentinthesepatients.Accordingly, CPAPora major anatomic
intervention is likely to be required for this group of patients.
PALM scale category 2 constitutes almost three out of five of the
ible upper airway with a wide range of OSA severities, although on
average OSA is moderately severe. Within category 2, there are two
types of patients: those in whom the nonanatomic phenotypic traits
the nonanatomic traits is likely to be important in the pathogenesis.
TABLE 2. PHENOTYPIC TRAITS IN INDIVIDUALS WITH UPPER AIRWAY COLLAPSIBILITY BETWEEN 25
AND 22 cm H2O
AHI (Number of Events
per Hour of Sleep) Pcrit (cm H2O)
GG Response (% Maximum
EMG/2cm H2O Pepi)
Patients with OSA
Definition of abbreviations: AHI ¼ apnea-hypopnea index; GG ¼ genioglossus; OSA ¼ obstructive sleep apnea; Pcrit ¼
pharyngeal critical closing pressure; Pepi ¼ epiglottic pressure.
Values in bold indicate poor muscle responsiveness, a low respiratory arousal threshold, or a high loop gain.
1000AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 188 2013
In category 2a, which constitutes approximately one-third of
category 2 patients, an anatomic intervention is likely to be re-
quired. In addition to CPAP, other interventions, such as a man-
dibular advancement splint, upper airway surgery, positional
therapy, or weight loss, may be beneficial. The ability of each
to normal limits depends on the baseline upper airway collapsibil-
ity and the ability of the intervention to reduce collapsibility in
a particular individual. For example, on average, mandibular ad-
vancement therapy reduces Pcrit by 2.3 cm H2O (18), uvulopa-
latopharyngoplasty surgery by 3.3 cm H2O (17), supine to lateral
position by 2.2 cm H2O (46), and a 17% reduction in body mass
index reduces Pcrit by 7.5 cm H2O (16).
In the category 2b patients, a primarily nonanatomic interven-
tion may be beneficial. For example, oxygen therapy reduces loop
gain and OSA severity by approximately 50% in patients with
OSA with high loop gain (22), acetazolamide reduces loop gain
and OSA severity by about 50% (21), and stabilizing or increas-
ing CO2reduces OSA severity by more than 30% in patients with
high loop gain (by controller gain) (47). A roughly doubling of
genioglossus EMG activity reduces Pcrit by 1.6 cm H2O (48),
whereas a standard dose of eszopiclone increases the arousal
threshold and reduces OSA severity by approximately 45% in
patients with OSA with a low arousal threshold (9). Reductions
in AHI by these approaches may be more pronounced than in
category 2a patients, although this assumption clearly requires
investigation. The extent to which reductions in AHI may occur
with nonanatomic interventions is also likely to be influenced
importantly by the individual’s baseline upper airway collapsibil-
ity. Ultimately, a combination of an anatomic intervention (e.g.,
mandibular advancement) and a nonanatomic intervention (e.g.,
oxygen therapy) may be required to achieve complete therapeutic
use for many category 2b patients with non-CPAP approaches.
Approximately one in five patients with OSA falls into PALM
scale category 3. These patients have some vulnerability to upper
airway collapse. However, negative pharyngeal pressure is re-
quired andmany non-OSA individuals have comparablePcritval-
REM in these patients. All of the category 3 patients have one or
more of the nonanatomic traits that are likely to be contributing
importantly to their apnea pathogenesis. Therapeutic approaches
categorization to assist in optimizing patient selection and treat-
ment effectiveness needs to be assessed formally by adequately
powered targeted intervention studies.
Methodologic and Future Study Considerations
The generalizability of the current findings is limited by several
features of the patient population and study design. First, the
Figure 4. Phenotypic traits according to upper
airway collapsibility (critical closing pressure of
the upper airway [Pcrit]) category. Control sub-
jects with a Pcrit less than 25 cm H2O (n ¼ 11;
65%) had a median apnea-hypopnea index
(AHI) of 2 (1–3) events per hour of sleep. Con-
trol subjects with a Pcrit between 25 and 22
cm H2O (n ¼ 6; 35%) had a median AHI of 5 (3–
9) events per hour of sleep. Patients with ob-
structive sleep apnea (OSA) with a Pcrit be-
tween 25 and 22 cm H2O (n ¼ 11; 19%)
had a median AHI of 19 (12–39) events per hour
of sleep. Patients with OSA with a Pcrit between
22 and 12 cm H2O (n ¼ 33; 58%) had a me-
dian AHI of 32 (19–56) events per hour of sleep.
Patients with OSA with a Pcrit greater than 12
cm H2O (n ¼ 13; 23%) had a median AHI of 76
(48–100) events per hour of sleep. (A) The dots
indicate the median arousal threshold, which is
higher in the OSA groups. The two control
groups have a relatively low arousal threshold,
but note how they can achieve a high level of
genioglossus (GG) muscle activity because of
their steep slope and high starting point. Thus,
combined with a relatively noncollapsible upper
airway, these individuals probably do not need
a higher arousal threshold to prevent OSA. The
patients with OSA with a Pcrit greater than 12
have a steep muscle responsiveness slope and
a high arousal threshold and thus can achieve
the greatest amount of muscle activity. How-
ever, they are limited by their highly collapsible
upper airway. The OSA group with a relatively
uncollapsible upper airway (Pcrit between 25
and 22 cm H2O) has the poorest muscle acti-
vation response, which is likely to be an issue for
this group. (B) Loop gain is substantially higher
in the patients with OSA with a Pcrit between
25 and 22 cm H2O, in which ventilatory motor output increases sixfold for every liter per minute reduction in ventilation. The other groups exhibit
only a threefold to fourfold increase and thus are much more stable. Horizontal white lines indicate median values and the grey portions of the box
plot represent the 25th and 75th centiles. *Significant difference between groups (P , 0.05).
Eckert, White, Jordan, et al.: Defining Phenotypes in Obstructive Sleep Apnea1001
patients with OSA were highly compliant with CPAP therapy.
Our goal was to minimize the confounding effects of OSA (sleep
fragmentation, hypoxemia) to determine “inherent” character-
istics of each of the pathophysiologic traits (43) rather than
disease consequences. Accordingly, the magnitude of the path-
ophysiologic traits defined in this cohort, and the proportion of
patients in each category, may vary in untreated patients. In
addition, the traits may vary over time; with aging; between sexes;
and with other events including sleep deprivation, changes in
autonomic activation, and with exposure to intermittent hypoxia.
However, the effect of CPAP treatment on each of these traits
across the spectrum of disease remains uncertain. For example,
sleep deprivation and CPAP treatment can reduce chemosensi-
tivity (43, 49). Accordingly, the proportion of patients with OSA
with loop gain abnormalities in untreated patients with OSA may
be higher than reported in the current study. Interestingly, the
proportion of patients with OSA with a low arousal threshold in
the current cohort is comparable with that of untreated patients
with OSA (9). This finding suggests that CPAP therapy may do
little to alter the arousal threshold in these individuals. Nonethe-
less, further investigation is required to characterize each of the
phenotypic traits in untreated patients, including those who are
noncompliant with CPAP therapy.
Second, data were acquired in non-REM sleep. Thus, the role
of these pathophysiologic traits in REM sleep remains unknown.
The patients with OSA studied were also predominantly obese.
Comparing pathophysiologic traits between obese and nonobese
individuals in future studies is likely to be insightful. It is also im-
portant to note that the passive Pcrit is a composite measure of
overall upper airway collapsibility during sleep. Although anat-
omy is clearly an important determinant of Pcrit, other imaging
techniques are required to assess upper airway anatomy per se.
TABLE 3. Pcrit, AROUSAL THRESHOLD, LOOP GAIN, AND MUSCLE RESPONSIVENESS SCALE (THE PALM SCALE)
PALM Category Proportion of PatientsCategory Cut-OffsPatient Features
1 23% Pcrit greater than 12 cm H2O Highly collapsible upper airway
62% have one or more nonanatomic
traits in the vulnerable* range
23% have poor muscle responsiveness
38% have a low arousal threshold
29% have high loop gain
23% have two or more potentially
All have severe OSA: AHI ¼ 76 (53–100);
range, 31–122 events per hour;
REM/non-REM ¼ 0.8†
BMI ¼ 37 6 6; range, 28–45 kg/m2;
age ¼ 46 6 11; range, 24–60 y; 8%♀
Moderately collapsible upper airway
Overall severe OSA: AHI ¼ 32 (19–55);
wide range, 10–112 events per hour;
REM/non-NREM ¼ 1.2†
BMI ¼ 35 6 6; range, 23–46 kg/m2;
age ¼ 47 6 11; range, 20–65 y; 33%♀
Moderately collapsible upper airway;
primarily anatomically driven
None have nonanatomic traits in the
Moderately collapsible upper airway and
100% have one or more nonanatomic
traits in the vulnerable* range
52% have poor muscle responsiveness
48% have a low arousal threshold
50% have high loop gain
33% have two or more potentially
Some vulnerability to upper airway collapse
100% have one or more nonanatomic traits
in the vulnerable* range
55% have poor muscle responsiveness
45% have a low arousal threshold
70% have high loop gain
55% have two or more potentially
Overall mild-moderate OSA: AHI ¼ 19 (13–37);
range, 11–59 events per hour;
REM/non-REM ¼ 3.3†
BMI ¼ 34 6 5; range, 26–42 kg/m2;
age ¼ 47 6 12; range, 26–64 y; 27%♀
Major anatomic or mechanical
intervention likely required
2 58%Pcrit 22 to 12 cm H2O Candidate for one or a combination
of targeted therapies
2a36%Pcrit 22 to 12 cm H2O without
Anatomic intervention (e.g., CPAP,
mandibular advancement splint,
upper airway surgery, positional
therapy, or weight loss)
A combination of anatomic and
nonanatomic interventions is likely
required (e.g., mandibular
advancement splint or weight
loss plus oxygen or a sleep
2b 64% Pcrit 22 to 12 cm H2O with
3 19% Pcrit less than 22 cm H2O Candidate for one or a combination
of targeted therapies with an
increased likelihood that
nonanatomic interventions (e.g.,
oxygen or a sleep consolidation aid)
would be beneficial in these patients
Definition of abbreviations: AHI ¼ apnea-hypopnea index; BMI ¼ body mass index; CPAP ¼ continuous positive airway pressure; OSA ¼ obstructive sleep apnea; Pcrit ¼
pharyngeal critical closing pressure.
*Definitions of “vulnerable” for nonanatomic traits: poor muscle responsiveness; greater than 20.1% maximum genioglossus electromyographic activity/2cm H2O
epiglottic pressure, low arousal threshold; greater than 215 cm H2O, and high loop gain; less than 25 dimensionless. Refer to the text for further detail.
yREM/non-REM AHI ratio was only calculated in patients who had greater than 30 minutes of REM sleep during their diagnostic study (64% of PALM category 1, 58%
of PALM category 2, and 46% of PALM category 3 patients).
1002AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 188 2013
Finally, despite the complexity of the measurements per-
formedand ourcareful approach to data collection, there remain
other mechanisms that are also likely to be important in OSA
pathophysiology. These include but are not limited to surface
tension forces (50), lung volume effects (51), fluid shifts (52, 53),
body-head position (46, 54), hormonal effects (55, 56), and venti-
latory responses to transient stimuli (57). Although many of these
mechanisms may be mediated through one or more of the four
traits defined in this study, these and other currently unknown
factors must be important in either protecting against or perpet-
uating OSA for certain individuals. For example, in examining the
individual data in Table 2 of patients with OSA and control sub-
jects with similar upper airway collapsibility, overall the patients
with OSA seem to have greater vulnerability across the three
measured nonanatomic phenotypic traits. However, despite vul-
nerability in all three traits, one of the control subjects (AHI of 9.3
events per hour) does not have OSA and must be protected by
other currently unknown mechanisms. Determining these factors
is clearly an important objective for future research.
during sleep,the respiratoryarousalthreshold,andloopgain,may
also play an important role in OSA pathogenesis for certain
patients. How these and other pathophysiologic factors interact
with upper airway collapsibility and anatomy ultimately deter-
mines the presence or absence of OSA and its severity. The
scale is to provide a conceptual framework in which to stimulate
future hypothesis-driven testing of therapies that target specific
underlying mechanisms in individuals. Ultimately, novel ap-
proaches that can easily and reliably define the varying pheno-
typic traits in clinical practice are required. A simplified method
in which these traits can be acquired in a single night study is one
such approach (21, 27, 58).
Author disclosures are available with the text of this article at www.atsjournals.org.
Acknowledgement: The authors are grateful for contributions and technical sup-
port on this project provided by Erik Smales, Geoffrey Kehlman, Karen Stevenson,
Lauren Hess, Louise Dover, Pamela DeYoung, Salonee Parikh, and Scott Smith.
Barbara Toson also provided invaluable statistical advice.
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