Sleep Breath (2012) 16:473–481

DOI 10.1007/s11325-011-0528-7

ORIGINAL ARTICLE

Analysis of anatomical and functional determinants

of obstructive sleep apnea
Kensaku Aihara & Toru Oga & Yuka Harada & Yuichi Chihara & Tomohiro Handa &
Kiminobu Tanizawa & Kizuku Watanabe & Takefumi Hitomi & Tomomasa Tsuboi &
Michiaki Mishima & Kazuo Chin

Received: 19 November 2010 / Revised: 7 April 2011 / Accepted: 4 May 2011 / Published online: 15 May 2011
# Springer-Verlag 2011

Abstract OSA (AHI≥15 events/h), neck circumference and R20

Purpose Craniofacial abnormalities have an important role were predominantly related to AHI, whereas for non-to-
in the occurrence of obstructive sleep apnea (OSA) and mild OSA (AHI<15 events/h), age and expiratory reserve
may be particularly significant in Asian patients, although volume were the predominant determinants. In obese
obesity and functional abnormalities such as reduced lung subjects (BMI≥25 kg/m2), alveolar–arterial oxygen ten-
volume and increased airway resistance also may be sion difference, position of the hyoid bone, and R20 were
important. We conducted simultaneous analyses of their significantly associated with AHI, whereas age alone was
interrelationships to evaluate the relative contributions of a significant factor in nonobese subjects (BMI<25 kg/m2).
obesity, craniofacial structure, pulmonary function, and Conclusions Aside from age and obesity, anatomical and
airway resistance to the severity of Japanese OSA because functional abnormalities are significantly related to the
there are little data in this area. severity of Japanese OSA. Predominant determinants of
Methods A cross-sectional observational study was per- AHI differed depending on the severity of OSA or the
formed on 134 consecutive Japanese male patients. A sleep magnitude of obesity.
study, lateral cephalometry, pulmonary function tests, and
impulse oscillometry (IOS) were performed on all patients. Keywords Obstructive sleep apnea . Obesity .
Results Age, body mass index (BMI), position of the Cephalometry . Pulmonary function . Impulse oscillometry
hyoid bone, and proximal airway resistance on IOS
(R20) were significantly related to the apnea/hypopnea
index (AHI) (p<0.05) in multiple regression analysis. Introduction
Subgroup analysis showed that, for moderate-to-severe
Obstructive sleep apnea (OSA) is characterized by repeti-
tive episodes of upper airway obstruction. The critical
Electronic supplementary material The online version of this article
pathophysiological feature of OSA is sleep-related narrow-
(doi:10.1007/s11325-011-0528-7) contains supplementary material, ing or closure of the upper airway at the level of the
which is available to authorized users. pharynx [1, 2]. Anatomical abnormality is an important risk
K. Aihara : Y. Harada : Y. Chihara : T. Handa : K. Tanizawa : factor for OSA, and most patients with OSA have
K. Watanabe : M. Mishima craniofacial abnormalities such as a small mandible,
Department of Respiratory Medicine, enlarged tongue, enlarged soft palate, inferior displacement
Graduate School of Medicine, Kyoto University,
of the hyoid bone, and imbalance between soft tissue
Kyoto, Japan
volume and bony enclosure size [3–5]. Dempsey et al. [6]
T. Oga (*) : T. Hitomi : T. Tsuboi : K. Chin analyzed the interactive effects of obesity and craniofacial
Department of Respiratory Care and Sleep Control Medicine, structure on sleep-disordered breathing and reported that
Graduate School of Medicine, Kyoto University,
body mass index (BMI) and cephalometric dimensions
54 Kawahara, Shogoin, Sakyo-ku,
Kyoto 606-8507, Japan equally contributed to the elevated apnea/hypopnea index
e-mail: [email protected] (AHI). However, a recent study showed that craniofacial
474 Sleep Breath (2012) 16:473–481

structure and obesity contributed differently to OSA the Brinkman index was calculated by the following
between Caucasian and Asian patients [7]. In addition, formula:
Dempsey et al. pointed out some additional factors that
might explain elevations in the AHI and speculated that Brinkman index ¼ number of cigarettes smoked per day
functional abnormalities such as impaired neural control of
 number of smoking years:
upper airway muscles and ventilatory instability, which
may cause increased airway resistance, might be candidates
[6]. Arterial blood gas analysis, including arterial partial
It has been shown that pharyngeal patency in OSA pressure of oxygen (PaO2) and arterial partial pressure of
patients is lung volume dependent [8, 9], and previous carbon dioxide (PaCO2), was performed with patients’
reports indicated a significant correlation between a breathing room air at rest in the supine position at 19:00.
reduced lung volume and nocturnal obstructive apnea and Alveolar–arterial oxygen tension difference (A-aDO2) was
desaturation [10, 11]. Increased upper airway resistance calculated according to the standard formula, using the
also was shown to play a role in the pathogenesis of OSA respiratory exchange ratio of 0.8.
[12, 13] through the association with increased susceptibil-
ity of airway narrowing and collapse [2, 14]. Thus, in Polysomnography
addition to anatomical abnormalities, functional abnormal-
ities such as reduced lung volume and increased airway Diagnosis of OSA was confirmed by polysomnography
resistance have been shown to play important roles in the (SomnoStar pro, Cardinal Health, Dublin, OH, USA), which
pathogenesis of OSA. was started at 22:00 and ended at 6:00 the following morning.
Obesity, the most important risk factor for OSA, is Surface electrodes were attached using standard techniques to
known to affect craniofacial structures [15], lung volume obtain an electrooculogram, electromyogram of the chin, and
[16], and airway resistance [17, 18]. However, given the 12-lead electroencephalograph. Sleep stages were defined
substantial number of nonobese OSA patients in Japan according to the criteria of Rechtschaffen and Kales [20].
[19], we hypothesized that there would be significant Ventilation was monitored by inductive plethysmography
relationships between OSA and anatomical and functional (Respitrace QDC, Viasys Healthcare, Palm Springs, CA,
factors as well as obesity, reflecting a multi-factorial USA). Airflow was monitored by a nasal air pressure
pathophysiological feature of OSA. Therefore, in the transducer (PTAFlite, Pro-Tech Services Inc., Mukilteo,
present study, we simultaneously analyzed the interrela- WA, USA) and supplemented by an oronasal thermal sensor
tionships among craniofacial structure, pulmonary func- (Sleepmate Technologies, Midlothian, VA, USA). Arterial
tion, airway resistance, obesity, and OSA to investigate the oxygen saturation (SpO2) was monitored continuously with
relative contributions of these factors to the severity of a pulse oximeter (Adult Flex System, Nonin Medical,
OSA. Plymouth, MN, USA).
Apnea was defined as the complete cessation of
airflow and hypopnea as a clear decrease in airflow of
Materials and methods 30% or more lasting for 10 s or more, accompanied by a
decrease in SpO2 of at least 4% [21]. All AHI values were
Study subjects expressed as the number of episodes of apnea and
hypopnea per hour over the total sleep time. The lowest
We performed a cross-sectional observational study of SpO2 during sleep and the percentage of time of SpO2
134 consecutive Japanese male patients who visited the 90% during sleep also were calculated in each patient.
Sleep Unit of Kyoto University Hospital between January OSA severity was defined by the AHI as follows: non-
2009 and February 2010 for evaluation of OSA. None OSA (AHI<5), mild OSA (5≤AHI<15), moderate OSA
had been previously diagnosed with or treated for OSA. (15≤AHI<30), and severe OSA (AHI≥30).
Patients with pulmonary diseases such as asthma or
chronic obstructive pulmonary disease and who were Cephalometry
diagnosed as having central sleep apnea were excluded.
This study was approved by the Kyoto University A lateral cephalogram was obtained for each subject. The
Graduate School and Faculty of Medicine Ethics Com- cephalograms were taken on image plates (ST-VI, Fuji
mittee, and informed consent was obtained from all Medical Systems, Tokyo, Japan) with the subject in the
patients. A sleep study, lateral cephalometry, pulmonary sitting position at a film focus distance of 2 m, with a left to
function tests, and impulse oscillometry (IOS) were right view. Exposures were made at 75 kV and 320 mA at
performed on all patients. To establish smoking history, the end-expiratory phase during quiet breathing through the
Sleep Breath (2012) 16:473–481 475

nose, and a cephalostat was used to keep the subject’s head dicular plane from G to VL); N–Ba, the length of the
in a position such that the Frankfort horizontal line was cranial base (distance between N and Ba); S–N, the length
parallel to the floor during exposure. Images of the of the anterior cranial base (distance between S and N);
cephalograms were digitized and input into a computer, ANS–PNS, the length of the hard palate (distance between
previewed and processed for sharp visibility of both the soft ANS and PNS); PNS–Ba, bony nasopharynx (distance
tissues and bony structures, and printed out through a between PNS and Ba); PNS–P, the length of the soft palate
computed radiography system (FCR Profect CS, Fuji (distance between PNS and P); PNS–V, the length of the
Medical Systems). A total of 22 variables related to both pharyngeal airway (distance between PNS and V); MPT,
craniofacial skeletal and soft tissue morphology were greatest thickness of the soft palate; TGL, the length of the
measured as angular (degrees), linear (millimeters), or area tongue (distance between V and TT); TGH, height of the
(square centimeters) by a single observer in a single-blind tongue (linear distance along the perpendicular bisector of
manner. Images were analyzed using Image J software (US the V–TT line to the tongue dorsum); Me–Go, the length of
NIH, Bethesda, MD, USA). Every measurement was made the mandible (distance between Me and Go); MP–H,
by the same observer, who had no knowledge of the clinical vertical position of the hyoid bone (linear distance along
status of the patient. the perpendicular plane from H to MP); H–VL, antero-
The cephalometric landmarks and reference lines are posterior position of the hyoid bone (linear distance along
defined in Table 1 and illustrated anatomically in Fig. 1. the perpendicular plane from H to VL); AW1, upper
The following angles and dimensions were measured: SNA, oropharyngeal airway caliber (narrowest part of the airway
antero-posterior position of the maxilla in relation to the between PNS and P); AW2, lower oropharyngeal airway
anterior cranial base (angle between S–N and N–A); SNB, caliber (narrowest part of the airway between P and Go);
antero-posterior position of the mandible in relation to the airway area, dimensions of the oropharynx (area outlined
anterior cranial base (angle between S–N and N–B); ANB, by the inferior border of the nasopharynx, the posterior
relative position of the mandible to the maxilla (angle surface of the soft palate and tongue, the line parallel to the
between N–A and N–B); facial axis, vertical position of the palatal plate through the point V, and the posterior
mandible in relation to the skull (angle between Pt–Gn and pharyngeal wall); tongue area, dimensions of the tongue
N–Ba); G–VL, antero-posterior position of the chin in (area outlined by the dorsal aspect of the tongue surface and
relation to the vertebra (linear distance along the perpen- lines that join TT, G, H, and V); and the lower face cage,

Table 1 Definitions of cephalometric landmarks and reference lines

S Sella, midpoint of the fossa hypophysealis

N Nasion, anterior point at the frontonasal suture
ANS Anterior nasal spine, most anterior point of the nasal spine
PNS Posterior nasal spine, most posterior point of the nasal spine
A Deepest anterior point in the concavity of the anterior maxilla
B Deepest anterior point in the concavity of the anterior mandible
Cd Medial condylar point of the mandible
Cd′ A point that Pg projects onto the perpendicular line to the Cd–A line at the Cd point
Go Gonion, a mid-plane point at the gonial angle located by bisecting the posterior and inferior borders of the mandible
Me Menton, most inferior point of the chin bone
Ba Basion, most posteroinferior point on the clivus
G Most posterior point on the symphysis of the mandible
Pg Prognathion, most anterior point on the symphysis of the mandible
P Lowest point of the soft palate
TT Most anterior point of the tip of the tongue
H Most anterosuperior point of the hyoid bone
V Most antero-inferior point of the epiglottic fold
Pt Intersection of the posterior pharyngeal wall and most inferior margin of the foramen rotundum
Gn Gnathion, the most antero-inferior point of body chin
NL Nasal line, a line through ANS and PNS
MP Mandibular plane, a plane constructed from Me through Go
VL A line across C3 and C4
476 Sleep Breath (2012) 16:473–481

measured first in the sitting position and then in the supine

position, fulfilling standard recommendations [24], as
previously reported in detail elsewhere [25, 26]. In short,
rectangular mechanical impulses containing the whole
frequency spectrum were applied to the respiratory system
through a mouthpiece while the patient was breathing
quietly. The resulting pressure and flow signals were
analyzed for amplitude, and the impedance (Z) represents
the total mechanical load of the subject’s respiratory system
from which the resistance (R) and the reactance (X) of the
respiratory system can be derived. The frequency range of
the signal was from 5 to 35 Hz. The impedance at 5 Hz
(Z5) represents the impedance of the total respiratory
system. In the present study, we used respiratory resistance
at 5 and 20 Hz (R5 and R20) as indices of total and
proximal airway resistance, respectively. In IOS, low
frequency oscillations are transmitted to the lung periphery,
while those at frequencies ≥20 Hz are thought to be damped
out before reaching the peripheral airways [27]. The
reactance at 5 Hz (X5) may be determined by homogeneous
distribution of ventilation, effective ventilation capacity,
and compliance of the lung and chest wall. These indices
Fig. 1 Cephalometric landmarks and reference lines. For definitions, see have been shown to be useful for the evaluation of upper
Table 1. Shaded area indicates cross-sectional area of the tongue. Dark- airway patency in OSA [12, 13].
stained area indicates cross-sectional area of the airway. Lower face
cage was defined as a trapezoid formed by Cd–A–Pg–Cd′ (dotted lines)
Statistics

the maxillomandibular enclosure size of the upper airway All statistical analyses were performed using StatView
(cross-sectional area of the trapezoid enclosed by Cd–A– version 5.0 for Windows (Abacus Concepts, Berkeley, CA,
Pg–Cd′). Upper airway anatomical balance was assessed by USA). Continuous variables are expressed as means ±
the ratio between the tongue area and lower face cage as standard deviation (SD). Intra-observer agreement for the
described in a previous study [5]. cephalometric measurements was evaluated by the intra-
class correlation coefficient (ICC) [28]. The natural
Pulmonary function tests logarithm of the AHI was used as the dependent variable
since the absolute values were not distributed normally.
Pulmonary function tests were performed in the sitting Chi-square tests were used to compare dichotomous
position using CHESTAC (Chest M.I. Inc., Tokyo, Japan). variables and unpaired Student’s t tests were used to
Subjects underwent spirometric testing according to the compare continuous data between two groups. Relation-
recommended method [22]. Residual volume (RV) and total ships between two variables were analyzed by Pearson’s
lung capacity (TLC) were measured by the closed circuit correlation coefficient tests. Stepwise multiple regression
helium method, and diffusing capacity for carbon monoxide analyses were performed to identify variables that could
(DLCO) was measured using a single-breath technique. best explain AHI. A p value less than 0.05 was considered
to indicate statistical significance.
IOS

The assessment of respiratory impedance was performed by Results

IOS (Masterscreen IOS-J, Jaeger, Wurzburg, Germany).
IOS is different from the classical forced oscillation Relative contributions of obesity, craniofacial structure,
technique (FOT) because an impulse rather than a pseudo- pulmonary function, and IOS measurements to AHI
random noise signal is applied by the loudspeaker. Data in all subjects
processing is also different between IOS and FOT. But IOS
yields respiratory system resistance and reactance values Patient characteristics and polysomnographic data are shown
similar to those provided by FOT [23]. Subjects were in Table 2. The study group of 134 patients comprised 19
Sleep Breath (2012) 16:473–481 477

Table 2 Clinical characteristics and polysomnographic data on 134 Table 3 Stepwise multiple regression analysis to predict AHI
patients (n=134)

Age (years) 56.5±14.5 r2

BMI (kg/m2) 26.5±4.2
Age (years) 0.08
Neck circumference (cm) 40.2±3.2
BMI (kg/m2) 0.09
Smoking history (current/ex/never) 37/70/27
Neck circumference (cm) –
Brinkman index 528±603
PaO2 (kPa) –
AHI (events/h) 26.0±22.5
A-aDO2 (kPa) –
Logarithmic AHI 2.8±1.3
Tongue area (cm2) –
Minimum SpO2 (%) 79.0±10.5
PNS–P (mm) –
SpO2 <90% time/TST (%) 14.8±21.4
TGL (mm) –
PaCO2 (kPa) 5.6±0.5
MP-H (mm) 0.05
PaO2 (kPa) 11.4±1.5
ERV (L) –
A-aDO2 (kPa) 1.6±1.5
%ERV (% pred) –
Data presented as mean ± SD R5 (kPa/L/s) –
BMI body mass index, AHI apnea/hypopnea index, TST total sleep Z5a (kPa/L/s) –
time, PaCO2 arterial partial pressure of carbon dioxide, PaO2 arterial R5a (kPa/L/s) –
partial pressure of oxygen, A-aDO2 alveolar–arterial oxygen tension
difference R20a (kPa/L/s) 0.06
Cumulative r2 0.28

non-OSA, 32 mild OSA, 37 moderate OSA, and 46 severe AHI apnea/hypopnea index, BMI body mass index, PaO2 arterial
partial pressure of oxygen, A-aDO2 alveolar–arterial oxygen tension
OSA patients. Regarding cephalometric measurements, intra- difference, ERV expiratory reserve volume
observer agreement was excellent (ICC ranged from 0.92 to a
In the supine position
0.99) for all variables except for ANB and TGL, which had
good intra-observer agreement (ICC=0.82 in ANB and 0.83
in TGL). We investigated the associations between anthro- Relative contributions of obesity, craniofacial structure,
pometric variables, arterial blood gas data, cephalometric pulmonary function, and IOS measurements to the AHI
parameters, pulmonary function, IOS measurements, and based on the severity of OSA
AHI. The AHI had a significant positive correlation with age
(r=0.26, p=0.003), BMI (r=0.32, p=0.0002), neck circum- We then compared the predominant determinants of AHI
ference (r=0.33, p=0.0001), and A-aDO2 (r=0.37, p< between 83 moderate-to-severe (AHI≥15) and 51 non-
0.0001) and a negative correlation with PaO2 (r=−0.31, p= to-mild (AHI<15) OSA subjects. The clinical character-
0.0003) (Table E1). Examination of cephalometric param- istics and polysomnographic data for these patients are
eters showed that the AHI had a significant positive shown in Table 4. The BMI and neck circumference were
correlation with the tongue area (r=0.18, p=0.04), PNS– significantly higher, and the PaO2 was significantly lower
P (r=0.30, p=0.0004), TGL (r=0.23, p=0.008), and MP– in moderate-to-severe OSA than in non-to-mild OSA (p=
H (r=0.28, p=0.001) (Table E2). Regarding pulmonary 0.007, 0.002, and 0.004, respectively). As we did for the
function, there was a significant negative correlation overall group of 134 patients, we performed stepwise
between the AHI and only with the expiratory reserve multiple regression analyses to account for AHI in the
volume (ERV) (r=−0.28, p=0.001) and %ERV (r=−0.24, moderate-to-severe and the non-to-mild groups, using the
p=0.007) (Table E3). The results of IOS measurements preselected variables that were significantly related to
revealed that the AHI had a significant positive correlation AHI. They included BMI, neck circumference, PaO2, A-
with R5 (r=0.22, p=0.01) in the sitting position and Z5 (r= aDO2, R5 and R20 in the sitting position, and Z5, R5, and
0.19, p=0.03), R5 (r=0.24, p=0.006), and R20 (r=0.25, p= R20 in the supine position in moderate-to-severe OSA
0.004) in the supine position (Table E3). and included age, PaCO2, VC, ERV, FEV1, RV/TLC, and
Stepwise multiple regression analysis was performed to %DLCO in non-to-mild OSA. In moderate-to-severe OSA,
examine the relationships with AHI using the preselected neck circumference and R20 in the supine position on
variables that were significantly related to AHI in the above IOS (r 2 = 0.11 and 0.10, respectively) significantly
analyses (Table 3). Age, BMI, MP–H by cephalometry, and explained 21% of the variance in AHI. By contrast, in
R20 in the supine position on IOS significantly explained non-to-mild OSA, age and ERV (r2 = 0.19 and 0.10,
28% of the variance in AHI [r2 (coefficient of determina- respectively) significantly explained 29% of the variance
tion)=0.08, 0.09, 0.05, and 0.06, respectively]. in AHI.
478 Sleep Breath (2012) 16:473–481

Table 4 Comparison of clinical

characteristics and polysomno- AHI≥15 (n=83) AHI<15 (n=51) p value
graphic data between groups
based on the severity of OSA Age (years) 57.6±12.3 54.7±17.4 0.26
BMI (kg/m2) 27.2±4.6 25.2±3.2 0.007
Neck circumference (cm) 40.9±3.5 39.1±2.3 0.002
Smoking history (current/ex/never) 18/46/19 9/24/18 0.18
Data presented as mean ± SD.
Unpaired t tests were performed Brinkman index 578±595 446±613 0.22
except for the chi-square test for AHI (events/h) 38.1±20.6 6.5±4.4 <0.0001
smoking history Logarithmic AHI 3.5±0.5 1.5±1.2 <0.0001
BMI body mass index, AHI Minimum SpO2 (%) 74.5±10.4 86.3±5.0 <0.0001
apnea/hypopnea index, TST total SpO2 <90% time/TST (%) 22.9±23.7 1.6±2.4 <0.0001
sleep time, PaCO2 arterial par-
tial pressure of carbon dioxide, PaCO2 (kPa) 5.6±0.5 5.7±0.4 0.32
PaO2 arterial partial pressure of PaO2 (kPa) 11.1±1.4 11.9±1.5 0.004
oxygen, A-aDO2 alveolar–arteri- A-aDO2 (kPa) 1.9±1.4 1.0±1.5 0.0008
al oxygen tension difference

Relative contributions of obesity, craniofacial structure, IOS (r2 =0.08, 0.10, and 0.07, respectively) significantly
pulmonary function, and IOS measurements to AHI based accounted for 25% of the variance in AHI. In contrast, in
on the magnitude of obesity nonobese subjects, age alone was significantly related to
AHI (r2 =0.25).
We then compared the predominant determinants of AHI
between 79 obese (BMI≥25) and 55 nonobese (BMI<25)
subjects. The clinical characteristics and the polysomno- Discussion
graphic data on these patients are shown in Table 5. There
was a trend for more current smokers or ex-smokers to be We simultaneously analyzed the interrelationships between
present among the obese subjects. Neck circumference and OSA and obesity, anatomical abnormalities measured by
the mean AHI were significantly higher, and the PaO2 was cephalometry, and functional abnormalities measured by
significantly lower in obese subjects than in nonobese pulmonary function testing and IOS. By multiple regression
subjects (p<0.0001, p=0.002, and p<0.0001, respectively). analysis, we found that age, BMI, MP-H by cephalometry,
We also performed stepwise multiple regression analyses and R20 on IOS significantly contributed to AHI. In
to account for AHI in obese and nonobese subjects using addition, separate analyses revealed that significant deter-
the preselected variables that were significantly related to minants of OSA differed between moderate-to-severe OSA
AHI. They included BMI, neck circumference, PaO2, A- and non-to-mild OSA and between obese subjects and
aDO2, PNS–P, TGL, MP-H, ERV, and R5 and R20 in the nonobese subjects.
sitting and supine positions in obese subjects and age and In addition to age and obesity (BMI), an anatomical
A-aDO2 in nonobese subjects. In obese subjects, A-aDO2, abnormality (inferior displacement of the hyoid bone) and a
MP-H by cephalometry, and R20 in the sitting position on functional abnormality (increased proximal airway resis-

Table 5 Comparison of clinical

characteristics and polysomno- BMI≥25 (n=79) BMI<25 (n=55) p value
graphic data between groups
based on the magnitude of obesity Age (years) 55.9±13.2 57.3±16.3 0.58
BMI (kg/m2) 28.9±3.7 22.9±1.4 <0.0001
Neck circumference (cm) 41.7±3.0 38.1±2.2 <0.0001
Smoking history (current/ex/never) 19/44/16 8/26/21 0.02
Data presented as mean ± SD.
Unpaired t tests were performed Brinkman index 611±618 408±566 0.054
except for the chi-square test for AHI (events/h) 31.0±25.6 18.9±14.6 0.002
smoking history Logarithmic AHI 3.0±1.2 2.5±1.3 0.03
BMI body mass index, AHI Minimum SpO2 (%) 77.1±11.5 81.8±8.2 0.009
apnea/hypopnea index, TST total SaO2 <90% time/TST (%) 20.7±25.5 6.3±8.2 <0.0001
sleep time, PaCO2 arterial par-
tial pressure of carbon dioxide, PaCO2 (kPa) 5.6±0.5 5.6±0.4 0.47
PaO2 arterial partial pressure of PaO2 (kPa) 10.9±1.5 12.0±1.4 <0.0001
oxygen, A-aDO2 alveolar–arteri- A-aDO2 (kPa) 2.1±1.4 0.9±1.4 <0.0001
al oxygen tension difference
Sleep Breath (2012) 16:473–481 479

tance) were significantly related to OSA. Obesity and age suggested that the consequences of craniofacial abnormal-
have been considered to be the characteristic risk factors for ities are more severe in Japanese than in Caucasian OSA
OSA [29]. On the other hand, certain forms of craniofacial patients [3], craniofacial abnormalities were not significant-
abnormalities measured by cephalometry [3–5], reduced ly related to AHI in both moderate-to-severe and non-to-
lung volume [8–11], and increased upper airway resistance mild OSA groups in the present study after adjustment for
[12, 13] also have been suggested as predisposing factors other risk factors, although further study is needed.
for upper airway obstruction during sleep. Although these Moreover, that age independently correlated with non-to-
factors may be significantly affected by age and obesity mild OSA but not moderate-to-severe OSA may partly
[15–17, 30, 31], the relative contributions of anatomical support the evidence that with increasing age, OSA
and functional abnormalities, age, and obesity to OSA have prevalence increases but that its severity does not [19, 29].
remained to be elucidated. Our findings indicate that OSA Another subgroup analysis showed that in obese sub-
is the result of independent interrelationships among jects, A-aDO2, the distance between the hyoid bone and
anatomical abnormalities, functional abnormalities, age, mandible, and airway resistance were predominantly related
and obesity, which reflects a multi-factorial pathophysio- to AHI. Recent studies suggested that subclinical lung
logical feature of OSA. injury may be present in OSA possibly through local
We found that, compared with pulmonary function, oxidative stress in the alveolus [35, 36]. Although the
airway resistance on IOS was related more closely to magnitude of the injury might not be great, given the effect
AHI. Structurally, the pharyngeal airway is surrounded by of ventilation–perfusion inequality due to obesity [16],
soft tissue, which is enclosed by bony structures and is A-aDO2 can be significantly related to AHI in obese OSA
caudally pulled by the thorax. As has been suggested, an subjects. The position of the hyoid bone is correlated with
imbalance between the amount of soft tissue and the size of accumulations of adipose tissue in pharyngeal regions, and
the surrounding bony structures [32] and decreased thoracic its inferior displacement may give rise to the posterior
traction [33] due to a reduced lung volume may result in relocation of the tongue and reduce upper airway patency
increased tissue pressure surrounding the pharyngeal [3, 37, 38]. Abdominal fat is likely to have direct effects on
airway and decreased longitudinal tension of the pharyn- the downward movement of the diaphragm and is associ-
geal airway wall, leading to increased upper airway ated with increased airway resistance through the reduction
resistance. Moreover, airway resistance was shown to in lung volume [16, 39]. Our results may also imply the
increase when the body position changed from a sitting to importance of abundant parapharyngeal and intraabdominal
a supine position [34]. In nonobese subjects, the falls in distribution of adipose tissue in obese subjects. Addition-
lung volume in a supine position are likely to lead to ally, in nonobese subjects, age alone had a significant
increased airway resistance, while in obese subjects in a relationship with the AHI. The unexplained variance by age
supine position, such falls are smaller than in nonobese may be related to structural or functional abnormalities that
subjects and can only partly explain an increase in airway were not measured, indicating the complicated pathogenesis
resistance [34]. Hence, there must be additional causes and of OSA in lean individuals.
sites of increased airway resistance in obese subjects. Our Unfortunately, the four crucial features in our study
results showed the importance and usefulness of demon- account for only 28% of the variance in AHI. There are
strations of increased airway resistance on IOS in explain- several possible explanations. Firstly, various determinants
ing the severity of OSA. of OSA, not limited to obesity, might be characteristic in
In one subgroup analysis, predominant determinants of Japanese subjects. Secondly, all of our anatomical and
AHI differed depending on the severity of OSA. In functional measurements were obtained during wakeful-
moderate-to-severe OSA, neck circumference and airway ness, which may have limited relevance to the sleeping
resistance were predominantly related to AHI, whereas in state. Furthermore, some cephalometric measurements,
non-to-mild OSA, age and ERV were predominantly related including that of the position of the hyoid bone, may be
to AHI. There was no overlap in those factors that were affected by muscle contraction required for central occlu-
significantly associated with AHI, indicating a different sion of the jaw. Thirdly, we did not evaluate the degree of
pathogenesis of the disease between moderate-to-severe ventilatory control stability. It is termed “loop gain”, whose
versus non-to-mild OSA. Asians were reported to have increase is suggested to play an important role in the
more severe OSA than Caucasians even when the BMI was pathogenesis of OSA [40, 41]. Additional assessments
similar between the two groups [7]. Our results indicate the might have explained a certain proportion of the residual
importance of increased fat deposition adjacent to the upper variance in AHI.
airway rather than total body fat volume in Japanese As a limitation, the present study had a small sample size
individuals with moderate-to-severe OSA, which may (especially non-OSA subjects) with only male subjects
partially explain this difference. Although it has been from one university hospital, which might have limited the
480 Sleep Breath (2012) 16:473–481

generalization of the results. Moreover, we only studied obesity in Caucasian and Chinese patients with obstructive sleep
apnea. Sleep 33:1075–1080
Japanese subjects and did not directly assess inter-ethnic 8. Heinzer RC, Stanchina ML, Malhotra A, Fogel RB, Patel SR,
differences in OSA risk factors. Considering that OSA is Jordan AS, Schory K, White DP (2005) Lung volume and
highly prevalent worldwide, inter-ethnic differences in continuous positive airway pressure requirements in obstructive
OSA risk factors is an important issue. Although we sleep apnea. Am J Respir Crit Care Med 172:114–117
9. Tagaito Y, Isono S, Remmers JE, Tanaka A, Nishino T (2007)
discussed inter-ethnic differences by comparing the results Lung volume and collapsibility of the passive pharynx in patients
with previous studies, such as those of a recent study by with sleep-disordered breathing. J Appl Physiol 103:1379–1385
Lee et al. [7], further studies directly comparing OSA risk 10. Bradley TD, Martinez D, Rutherford R, Lue F, Grossman RF,
factors in different ethnic groups would more clearly Moldofsky H, Zamel N, Phillipson EA (1985) Physiological
determinants of nocturnal arterial oxygenation in patients with
elucidate those risk factors. Another limitation is that we obstructive sleep apnea. J Appl Physiol 59:1364–1368
assessed craniofacial structures only by cephalometry. Our 11. Appelberg J, Nordahl G, Janson C (2000) Lung volume and its
limited measures of craniofacial morphology may underes- correlation to nocturnal apnoea and desaturation. Respir Med
timate the actual contributions of craniofacial morphology, 94:233–239
12. Lin CC, Wu KM, Chou CS, Liaw SF (2004) Oral airway
especially of upper airway anatomical imbalance. Addi- resistance during wakefulness in eucapnic and hypercapnic sleep
tional three-dimensional, volumetric evaluations using apnea syndrome. Respir Physiol Neurobiol 139:215–224
computed tomography [42] or magnetic resonance imaging 13. Cao J, Que C, Wang G, He B (2009) Effect of posture on airway
[43] might show more sensitively the impact of anatomical resistance in obstructive sleep apnea–hypopnea syndrome by
means of impulse oscillation. Respiration 77:38–43
imbalance on the pathogenesis of OSA. 14. Dempsey JA, Veasey SC, Morgan BJ, O’Donnell CP (2010)
OSA is a multi-factorial disease in which age and Pathophysiology of sleep apnea. Physiol Rev 90:47–112
obesity play important roles. However, aside from age and 15. Mayer P, Pepin JL, Bettega G, Veale D, Ferretti G, Deschaux C,
obesity, our results indicated that both anatomical and Levy P (1996) Relationship between body mass index, age and
upper airway measurements in snorers and sleep apnoea patients.
functional abnormalities play significant roles in the Eur Respir J 9:1801–1809
pathogenesis of OSA. The severity of OSA or obesity 16. Salome CM, King GG, Berend N (2010) Physiology of obesity
appears to determine the relative contribution of these and effects on lung function. J Appl Physiol 108:206–211
abnormalities to sleep-related collapse of the upper airway. 17. Zerah F, Harf A, Perlemuter L, Lorino H, Lorino AM, Atlan G
(1993) Effects of obesity on respiratory resistance. Chest
103:1470–1476
18. Watson RA, Pride NB (2005) Postural changes in lung volumes
Role of funding sources Kazuo Chin has received grants from the and respiratory resistance in subjects with obesity. J Appl Physiol
Japanese Ministry of Education, Culture, Sports, Science and 98:512–517
Technology (nos. 20590921 and 22590760), Respiratory Failure 19. Ohdaira F, Nakamura K, Nakayama H, Satoh M, Ohdaira T,
Research Group and Health Science Research Grants (Comprehensive Nakamata M, Kohno M, Iwashima A, Onda A, Kobayashi Y,
Research on Life-Style Related Diseases including Cardiovascular Fujimori K, Kiguchi T, Izumi S, Kobayashi T, Shinoda H,
Diseases and Diabetes Mellitus) from the Ministry of Health, Labor Takahashi S, Gejyo F, Yamamoto M (2007) Demographic
and Welfare of Japan, and the Japan Vascular Disease Research characteristics of 3,659 Japanese patients with obstructive sleep
Foundation. apnea–hypopnea syndrome diagnosed by full polysomnography:
associations with apnea–hypopnea index. Sleep Breath 11:93–101
20. Rechtschaffen A, Kales A (1968) A manual of standardized
References terminology, techniques and scoring system for sleep stages of
human subjects. National Institutes of Health, Washington
21. Iber C, Ancoli-Israel S, Chesson A, Quan S (2007) The AASM
1. Hudgel DW (1992) Mechanisms of obstructive sleep apnea. Chest manual for the scoring of sleep and associated events: rules,
101:541–549 terminology and technical specifications. American Academy of
2. Ryan CM, Bradley TD (2005) Pathogenesis of obstructive sleep Sleep Medicine, Westchester
apnea. J Appl Physiol 99:2440–2450 22. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R,
3. Sakakibara H, Tong M, Matsushita K, Hirata M, Konishi Y, Suetsugu Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P,
S (1999) Cephalometric abnormalities in non-obese and obese Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D,
patients with obstructive sleep apnoea. Eur Respir J 13:403–410 Pedersen OF, Pellegrino R, Viegi G, Wanger J (2005) Stand-
4. Yu X, Fujimoto K, Urushibata K, Matsuzawa Y, Kubo K (2003) ardisation of spirometry. Eur Respir J 26:319–338
Cephalometric analysis in obese and nonobese patients with 23. Hellinckx J, Cauberghs M, De Boeck K, Demedts M (2001)
obstructive sleep apnea syndrome. Chest 124:212–218 Evaluation of impulse oscillation system: comparison with forced
5. Tsuiki S, Isono S, Ishikawa T, Yamashiro Y, Tatsumi K, Nishino T oscillation technique and body plethysmography. Eur Respir J
(2008) Anatomical balance of the upper airway and obstructive 18:564–570
sleep apnea. Anesthesiology 108:1009–1015 24. Oostveen E, MacLeod D, Lorino H, Farre R, Hantos Z, Desager
6. Dempsey JA, Skatrud JB, Jacques AJ, Ewanowski SJ, Woodson K, Marchal F (2003) The forced oscillation technique in clinical
BT, Hanson PR, Goodman B (2002) Anatomic determinants of practice: methodology, recommendations and future develop-
sleep-disordered breathing across the spectrum of clinical and ments. Eur Respir J 22:1026–1041
nonclinical male subjects. Chest 122:840–851 25. Takeda T, Oga T, Niimi A, Matsumoto H, Ito I, Yamaguchi M,
7. Lee RW, Vasudavan S, Hui DS, Prvan T, Petocz P, Darendeliler Matsuoka H, Jinnai M, Otsuka K, Oguma T, Nakaji H, Chin K,
MA, Cistulli PA (2010) Differences in craniofacial structures and Mishima M (2010) Relationship between small airway function
Sleep Breath (2012) 16:473–481 481

and health status, dyspnea and disease control in asthma. 34. Michels A, Decoster K, Derde L, Vleurinck C, Van de Woestijne
Respiration 80:120–126 KP (1991) Influence of posture on lung volumes and impedance
26. Haruna A, Oga T, Muro S, Ohara T, Sato S, Marumo S, Kinose D, of respiratory system in healthy smokers and nonsmokers. J Appl
Terada K, Nishioka M, Ogawa E, Hoshino Y, Hirai T, Chin K, Physiol 71:294–299
Mishima M (2010) Relationship between peripheral airway 35. Lederer DJ, Jelic S, Basner RC, Ishizaka A, Bhattacharya J (2009)
function and patient-reported outcomes in COPD: a cross- Circulating KL-6, a biomarker of lung injury, in obstructive sleep
sectional study. BMC Pulm Med 10:10 apnoea. Eur Respir J 33:793–796
27. Goldman MD, Saadeh C, Ross D (2005) Clinical applications of 36. Aihara K, Oga T, Harada Y, Chihara Y, Handa T, Tanizawa K,
forced oscillation to assess peripheral airway function. Respir Watanabe K, Tsuboi T, Hitomi T, Mishima M, Chin K (2011)
Physiol Neurobiol 148:179–194 Comparison of biomarkers of subclinical lung injury in obstruc-
28. Bédard M, Martin NJ, Krueger P, Brazil K (2000) Assessing tive sleep apnea. Respir Med 105(6):939–945
reproducibility of data obtained with instruments based on 37. Guilleminault C, Riley R, Powell N (1984) Obstructive sleep apnea
continuous measurements. Exp Aging Res 26:353–365 and cephalometric roentgenograms. Am Rev Respir Dis 130:145–146
29. Young T, Shahar E, Nieto FJ, Redline S, Newman AB, Gottlieb 38. Maltais F, Carrier G, Cormier Y, Series F (1991) Cephalometric
DJ, Walsleben JA, Finn L, Enright P, Samet JM (2002) Predictors measurements in snorers, non-snorers, and patients with sleep
of sleep-disordered breathing in community-dwelling adults: the apnoea. Thorax 46:419–423
Sleep Heart Health Study. Arch Intern Med 162:893–900 39. Begle RL, Badr S, Skatrud JB, Dempsey JA (1990) Effect of lung
30. Pecora NG, Baccetti T, McNamara JA Jr (2008) The aging inflation on pulmonary resistance during NREM sleep. Am Rev
craniofacial complex: a longitudinal cephalometric study from late Respir Dis 141:854–860
adolescence to late adulthood. Am J Orthod Dentofacial Orthop 40. White DP (2005) Pathogenesis of obstructive and central sleep
134:496–505 apnea. Am J Respir Crit Care Med 172:1363–1370
31. Janssens JP (2005) Aging of the respiratory system: impact on 41. Verbraecken JA, De Backer WA (2009) Upper airway mechanics.
pulmonary function tests and adaptation to exertion. Clin Chest Respiration 78:121–133
Med 26:469–484 42. Shigeta Y, Ogawa T, Ando E, Clark GT, Enciso R (2011)
32. Watanabe T, Isono S, Tanaka A, Tanzawa H, Nishino T (2002) Influence of tongue/mandible volume ratio on oropharyngeal
Contribution of body habitus and craniofacial characteristics to airway in Japanese male patients with obstructive sleep apnea.
segmental closing pressures of the passive pharynx in patients Oral Surg Oral Med Oral Pathol Oral Radiol Endod 111:239–243
with sleep-disordered breathing. Am J Respir Crit Care Med 43. Saigusa H, Suzuki M, Higurashi N, Kodera K (2009) Three-
165:260–265 dimensional morphological analyses of positional dependence in
33. Van de Graaff WB (1988) Thoracic influence on upper airway patients with obstructive sleep apnea syndrome. Anesthesiology
patency. J Appl Physiol 65:2124–2131 110:885–890