CHAPTER 50
PHYSIOLOGY OF THE UPPER
AIRWAYS AND UPPER AIRWAY
OBSTRUCTION IN DISEASE
R. John Kimoff
T he upper airway is a complex structure that serves
as the conduit from the external environment to the
intrathoracic airways and lungs. The anatomic regions of
the upper airway (Figure 50-1) include the nasal cavity,
nasopharynx, velopharynx behind the soft palate, orophar-
ynx, hypopharynx, and larynx. This conduit has a variety
of functions, including the filtering and conditioning of
air, olfaction, mastication and deglutition, phonation,
coughing, and protection of the lower airways and lungs
from large particulate material.1–6 This chapter focuses on
the physiology and pathophysiology of the respiratory-
related functions of the upper airway. The discussion of
other upper airway functions is limited to their interaction
with respiratory function.
ANATOMY AND PHYSIOLOGY
OF THE UPPER AIRWAY
NOSE
To enter the upper airway, air flows rapidly upward through the
anterior nares or nasal vestibules, which are 1 cm–diameter
channels in the anterior portion of the nose. Coarse
hairs or vibrissae within the vestibules serve to filter larger
particulate matter. The air then encounters the nasal sep-
tum, which divides the nasal passage into two fossae. The
lateral walls of the fossae contain irregular projections
known as the turbinates, which create turbulent flow and
reduce flow rate. This prolongs contact of the inspired air
with the nasal mucosa, which at this level is richly supplied
with a system of subepithelial capillaries and venous
sinusoids, along with submucosal glands and goblet cells.
The rich vascularization of the mucosa provides for
humidification and temperature conditioning of the
inspired air. Production of a mucous layer by glandular
structures provides for trapping of particulate matter.
Nasal secretions produced by the highly vascular mucosa are
rich in immunoglobulins, cytokines, and other cytolytic
substances, and there is extensive mucosal production of
nitric oxide by the nose and paranasal sinuses; all of these
have potent antimicrobial activity. There is thus consider-
able filtering, temperature conditioning, and humidification
of the air traversing the nasal fossae, which have an impor-
tant protective function for the lower airways.
Although the nose accounts for over 50% of upper airway
flow resistance in normal, awake persons, it is the preferred
route of breathing during resting ventilation. As ventilatory
drive increases, some dilatation of the nares and vasocon-
striction of the nasal mucosa may help to reduce airflow
resistance, but as demands increase, the mouth opens and
the lower-resistance oropharyngeal route is recruited,
although at the cost of reduced conditioning of the inspired
air. Other functions of the nose include olfaction and a con-
tribution to phonation, in that the nose acts as a resonating
chamber for some components of speech.
PHARYNX
This structure consists of the nasopharynx, oropharynx, and
hypopharynx. Inspired air exits the nasal passages posteri-
orly through 2.5 ⫻1.5 cm openings known as the choanae
and enters the nasopharynx. The nasopharynx extends from
the choanae down to the lower margin of the soft palate. The
segment of the nasopharynx immediately behind the soft
palate has been termed the velopharynx. The mucosa of the
posterior nasopharyngeal wall contains a collection of lym-
phoid tissue termed the single pharyngeal or adenoid tonsil.
This structure can hypertrophy and produce nasal obstruc-
tion, which often contributes to obstructive sleep apnea
(OSA) in children. As with the palatine tonsils between
the anterior and posterior tonsillar pillars lower down, the
adenoid tends to involute after puberty.
The muscular structures in the wall of the nasopharynx
and soft palate play a major role in speech, swallowing, and
breathing. These muscles act to partition airflow between
the oral and nasal routes, particularly under conditions of
increased ventilatory drive. The palatal muscles are also
important in the maintenance of airway patency.
582 Sleep Disordered Breathing
FIGURE 50-1 Anatomy of the upper airway.
The oropharynx lies behind the oral cavity and extends
from the soft palate superiorly to the tip of the epiglottis
inferiorly. The lateral walls include the anterior (palatoglos-
sal) and posterior (palatopharyngeal) tonsillar pillars, which
merge superiorly into the soft palate and between which lie
the fossae of the palatine tonsils. The posterior pharyngeal
wall is largely composed of the pharyngeal constrictor mus-
cles, whereas the posterior aspect or base of the tongue lies
anteriorly. This structure serves as the main conduit for both
solids and liquids from the mouth to the esophagus and for
the flow of air through to the larynx. The coordination of
these various neuromuscular functions is achieved through
reflex control involving neural afferents in the pharyngeal
mucosa; these project to pontomedullary centers, which
integrate this information and regulate swallowing and
respiratory functions.
Swallowing is characterized by initial elevation of the lar-
ynx, followed by active contraction of the oropharynx, lead-
ing to shortening and constriction of the pharynx to actively
propel food toward the esophagus. The normal coordination
of this action in humans is such that swallowing occurs
almost exclusively during late expiration in seated humans
and is accompanied by respiratory inhibition, that is, pro-
longation of expiratory time, and other processes, such as
vocal cord closure and laryngeal elevation, that assist in
protecting the laryngeal aperture.7–9
In contrast to the passage of food during swallowing, air-
flow through the oropharynx is passive, being driven by the
negative intrathoracic pressure generated by the respiratory
pump muscles. However, whereas the nasal and laryngeal
segments of the upper airway are supported by bony and
cartilaginous structures, the pharynx is a collapsible mus-
cular tube. There is clear evidence that the stability and
patency of this structure during breathing depend upon
tonic and phasic activation of muscles surrounding the
airway, which act to stiffen and dilate the pharynx during
inspiration.10–13 These muscles include the genioglossus
muscle, which positions and stabilizes the tongue, palatal
muscles such as the tensor and levator palatini and the
palatoglossus and palatopharyngeus muscles, and muscles
that stablilize the hyoid bone, such as the geniohyoid and
sternohyoid muscles. If the dilating musculature is not
sufficiently activated, collapse of this segment will occur
during inspiration, due to a suction effect of the negative
intraluminal pressure associated with inspiratory airflow.
Thus, in generating inspiratory impulses, the brainstem res-
piratory controller produces a sequential wave of respiratory
muscle activation, with initial activation of pharyngeal dila-
tors, which stiffen and dilate this conduit. Subsequently,
laryngeal activation leads to opening of the glottic aper-
ture, chest wall muscle activation that stiffens and
expands the chest wall, and diaphragmatic activation.14–16
Pharyngeal caliber is also modulated by important reflex
mechanisms that regulate within-breath levels of phasic
muscle activation. Both tonic and phasic activity of pharyn-
geal dilators and the protective reflexes are reduced during
sleep, which leads to increased airflow resistance during
sleep in normal subjects and can contribute to collapse of
the upper airway in patients with OSA.
The hypopharynx extends downward from the upper
margin of the epiglottis to the lower border of the cricoid
cartilage, serving as the conduit from the oropharynx to the
laryngeal inlet and esophagus. The piriform recesses lie on
each side of the hypopharynx. These recessess serve to
direct food boluses down and away from the larynx in tran-
sit to the esophagus. During swallowing, as noted above,
there is laryngeal constriction and a movement of the
epiglottis in order to protect the laryngeal aperture.
LARYNX
The structure of the larynx, and in particular the cartilagi-
nous skeleton and musculature, is illustrated in Figure 50-2,
which also illustrates the action of the musculature on glot-
tic patency.3,17–19 In addition to the thyroid, cricoid, and ary-
tenoid cartilages, the epiglottic cartilage, which descends to
protect the laryngeal aperture during swallowing, is also
considered to be part of the laryngeal apparatus. The larynx
plays an integral role in all upper airway functions, includ-
ing respiration, phonation, cough, swallowing, and vomit-
ing. As with the pharyngeal structures, these activities are
initiated and coordinated by brainstem centers, with modu-
lation by afferent neural inputs from the airway itself. In the
case of the larynx, there is a rich sensory array of mucosal
sensory receptors, which respond to changes in airflow,
pressure, temperature, and laryngeal position. Impulses
from these receptors are conveyed centrally through the
superior laryngeal nerve to modulate laryngeal function and
breathing pattern. Motor innervation of the laryngeal mus-
culature is conveyed through the recurrent laryngeal nerves,
with the exception of the cricothyroid muscle, which is sup-
plied by the external branch of the superior laryngeal nerve.
The recurrent laryngeal nerves arise from the vagus nerve
within the thorax and travel superiorly along the media-
stinal structures to the larynx. On the right, the recurrent
laryngeal nerve arises at the level of the subclavian artery,
 Physiology of the Upper Airway and Upper Airway Obstruction in Disease
FIGURE 50-2 Laryngeal skeleton and musculature, illustrating the
actions of the major muscles.
and on the left, the nerve arises at the level of the aortic
arch. Disease processes, including intrathoracic disease, that
disrupt the recurrent laryngeal nerve therefore lead to
vocal cord paralysis and laryngeal dysfunction, which has
implications for all of the other functions of the larynx.
Although protective closure of the larynx during swal-
lowing is part of the integrated deglutition process, there is
also a more basic laryngeal protective response called the
“glottic closure reflex.” This is characterized by a short-
latency activation of the adductor muscles to rapidly close
the glottic aperture in response to stimulation of the laryn-
geal mucosa by tactile or chemical stimuli. This is therefore
a critical response that protects against aspiration of foreign
material into the upper airway. It is of note that, in contrast
to the situation in many mammalian species, the human
reflex is not crossed, so that damage to the superior laryn-
geal nerve on one side can result in failure of ipsilateral vocal
fold closure, thereby increasing the risk of aspiration.17
Although the glottic closure reflex represents a crucial pro-
tective mechanism, the response may become exaggerated in
some disease conditions, leading to laryngospasm or pro-
longed glottic closure following withdrawal of the inciting
stimulus.
With respect to the respiratory function of the larynx,
during inspiration the posterior cricoarytenoid muscle, the
only vocal cord abductor muscle, is activated to widen
the glottic aperture.18,19 There is simultaneous activation of
the cricothyroid muscle, which acts to lengthen the vocal
fold. The concurrent lengthening and abduction of the
583
folds lead to an increase in glottic cross-sectional area, thus
reducing resistance to inspiratory airflow. The posterior
cricoarytenoid muscle relaxes during expiration, whereas
the cricothyroid muscle may remain active, to maintain the
length of the cords. Under some conditions, there is active
contraction of the adductor muscles to narrow the aperture
and produce expiratory “braking.” This strategy is adopted
in an attempt to maintain end-expiratory lung volume. This
occurs, for example, in neonates with respiratory distress
syndrome and is manifested as expiratory grunting due to
glottic closure. An extreme instance of prolonged glottic
closure appears to occur in apnea of prematurity, in which
experimental evidence has demonstrated that apneas are
associated with active glottic closure.20
In some patients, laryngeal function becomes disturbed
such that there is intermittent inspiratory closure of the
vocal cords. This condition has been variously termed vocal
cord dysfunction syndrome, paradoxical vocal cord motion,
and laryngismus stridulus.21–23 The clinical presentation
may mimic both asthma and organic upper airway obstruc-
tion and may be acute and lead to endotracheal intuba-
tion. Spirometric flow–volume curves are very helpful in
making the diagnosis (see below). A substantial proportion
of affected individuals also have asthma; patients without
asthma are often women who have been misdiagnosed as
asthmatic. This syndrome typically occurs in the absence of
any evident structural laryngeal disease, and the mecha-
nisms responsible are unclear. However, psychogenic factors
appear to play a role as the dysfunction is intermittent, may
be worse in times of emotional stress, and, even if sustained
during wakefulness, tends to disappear during sleep.
Furthermore, psychiatric disorders are common among
affected individuals. Treatment approaches include patient
education, psychotherapy as needed, and referral to a speech
pathologist.
The larynx also plays a major role in phonation.
Although sound can be produced passively by creating air-
flow through the larynx, the generation of speech or song
requires finely controlled activation of laryngeal muscles.
These muscles act to shape and position the vocal cords to
generate speech and modulate the spatial relationship
between the cricoid and thyroid cartilages to vary the pitch
of the sound produced. Further modulation of sound is
produced superiorly in the pharynx and nasal cavity.
Breathing during speech is characterized by rapid inspiration,
followed by prolonged expiration, during which the subglot-
tic pressure is maintained relatively constant as the fine
motor actions of the laryngeal apparatus produce sound.24
Stuttering appears to represent an example of an altered
interaction between laryngeal and respiratory function
during speech, the mechanisms for which remain poorly
understood.25
CLINICAL PHYSIOLOGY OF UPPER AIRWAY
OBSTRUCTION
CLINICAL DESCRIPTION
Obstruction of the upper airway can occur in various clini-
cal contexts and disease states, although it is much less
584 Sleep Disordered Breathing

Table 50-1 Causes of Upper Airway Obstruction A 8 B 8

6 6
Infectious FEF50
Flow 4 Flow 4
Acute epiglottitis (L/s) (L/s)
2 2
Laryngotracheobronchitis (croop)
Ludwig’s angina 0 V ol (L ) 0 V ol (L )
Retropharyngeal abscess -2 -2

Allergic/immune -4 -4
Edema associated with anaphylaxis -6 -6
Angioneurotic edema FI F50
-8 -8
Relapsing polychondritis 8 8
Rheumatoid arthritis C D
6 6
Sjögren’s syndrome (adenopathy) Flow Flow
4 4
Wegener’s granulomatosis (L/s) (L/s)
2 2
Tumors
Benign 0 V ol (L ) 0 V ol (L )
Malignant -2 -2

Laryngeal carcinoma
Bronchogenic carcinoma
Lymphoma
Other metastatic disease
Vascular
Right-sided aortic arch
Double aortic arch
Innominate artery syndrome
Aberrant left pulmonary artery
Tracheal abnormalities
Neuromuscular
Vocal cord dysfunction
Foreign body aspiration
Trauma
Inhalation
Smoke/burn
Chemical
common than obstructive disease of the lower airway, such
as asthma or chronic obstructive pulmonary disease
(COPD). Unfortunately, the clinical presentation of the two
may be very similar (dyspnea and noisy breathing), so that
the less common diagnosis of upper airway obstruction may
be missed if a careful clinical evaluation and appropriate
testing are not performed. A missed diagnosis, particularly
in the context of acute or severe upper airway obstruction,
may have devastating consequences for the patient as
appropriate treatment may be delayed beyond the point of
severe airway compromise and respiratory arrest.
A hallmark clinical feature of upper airway obstruction is
dyspnea with stridor, a loud, constant-pitch inspiratory
sound that indicates obstruction of the extrathoracic airway.
Severe extrathoracic or variable intrathoracic large airway
obstruction may also cause expiratory prolongation and a
wheeze-like sound, making it difficult to distinguish from
disease of the lower airways. Other symptoms associated
with upper airway obstruction include cough, hoarseness,
dysphagia, and orthopnea, depending upon the location and
nature of the obstructing lesion. Although it is beyond the
scope of this chapter to provide an exhaustive description of
causes of upper airway obstruction, a list of common
pathologies is provided in Table 50-1.
PHYSIOLOGIC TESTING FOR UPPER AIRWAY
OBSTRUCTION
Forced expiratory and inspiratory spirometry with recording
of the flow–volume curve is the most important physiologic
-4 -4
-6 -6
-8 -8
FIGURE 50-3 Flow–volume curves: upper airway obstruction. A,
Normal flow–volume curve. B, Variable intrathoracic obstruction
due to a tracheal tumor. C, Variable extrathoracic obstruction due
to a laryngeal tumor. D, Fixed upper airway obstruction due to
large tracheal tumor. Solid line ⫽ air; dotted line ⫽ helium. Note the
improvement in both inspiratory and expiratory flow with helium.
tool for the diagnosis of upper airway obstruction.26–35
Examples of normal and pathologic flow–volume curves are
shown in Figure 50-3. Normally, there is an initial rapid rise
in expiratory flow to a peak value that is dependent on
effort, lung elastic recoil, and flow in the large airways. As
lung volume decreases, flow becomes effort-independent
and determined by the balance between lung recoil and flow
resistance in progressively smaller airways. During forced
inspiration, flow is effort dependent throughout, with the
peak value occurring at midinspiration. Peak expiratory
flow rate is considerably larger than peak inspiratory flow
rate because of the effects of lung elastic recoil. However, at
50% of vital capacity, forced inspiratory flow (FIF50) is
somewhat greater than forced expiratory flow (FEF50), due
in part to normal expiratory dynamic compression of the
airways. Thus, the normal FIF50/FEF50 ratio is slightly
greater than 1.
Obstructing lesions of the upper airways may be either
fixed or variable; that is, lesions produce narrowing that
varies with pressures acting across the airways during inspi-
ration and expiration (Figure 50-4). In the case of variable
intrathoracic large airway obstruction (see Figure 50-3B),
during expiration, pleural pressure is more positive than
intratracheal pressure, leading to dynamic compression of
the airway and thereby increased airway narrowing and
reduced expiratory flow. However, during inspiration, there
is a net distending pressure across the large airway, so that
patency of the lumen tends to increase, yielding a relative
preservation of inspiratory flow rate. The FIF50/FEF50 ratio
will therefore be well above 1, typically in the range of 2 to 3.
In the case of variable extrathoracic upper airway
obstruction (see Figure 50-3C), the pressure surrounding
the airway is atmospheric, so that during inspiration, there
is a net negative transmural pressure, which tends to worsen
 Physiology of the Upper Airway and Upper Airway Obstruction in Disease
Ptr < Patm Ptr < Patm
0 – 0 0
+ 0
– +
– – – + + +
Ppl < Ptr Ppl < Ptr
– +
– – + +
Inspiration Expiration
FIGURE 50-4 Forces acting across the airways that determine
spirographic patterns in cases of variable intrathoracic and extra-
thoracic upper airway obstruction. Patm ⫽ atmospheric pressure;
Ppl ⫽ pleural pressure; Ptr ⫽ tracheal pressure.
airway narrowing and reduce inspiratory flow. In contrast,
during expiration, the positive pressure within the airway
produces a transmural distending pressure and reduces the
extent of narrowing, resulting in increased expiratory rela-
tive to inspiratory flow. Thus, the FIF50/FEF50 ratio will be
less than 1.
The anatomy of many upper airway lesions, however,
is such that the degree of obstruction is not materially
influenced by the pressures acting across the airway, with
resultant comparable reductions in both inspiratory and
expiratory flow (see Figure 50-3D). In this case, the FIF50/
FEF50 ratio may be close to 1.
From Figure 50-3, it can be seen that inspection of the
flow–volume curve and recognition of the characteristic
changes in pattern are crucial to the recognition of upper
airway obstruction. It is important to emphasize that one
cannot rely solely upon tabular data from simple spirometry
to exclude the diagnosis of upper airway obstruction.
Because flow in the medium and small airways contributes
significantly to forced expiratory volume in 1 second
(FEV1), substantial large airway obstruction may be present
before significant changes in FEV1 occur. When concomi-
tant airway disease, such as COPD, is present, the sensitiv-
ity of spirometry for the detection of upper airway
obstructing lesions is even lower. Peak expiratory flow rate
is much more sensitive for the presence of expiratory large
airway obstruction, and a hallmark finding in tabular data is
a reduction in peak expiratory flow rate (as percent pre-
dicted) that is out of proportion to other changes in flow
rates, particularly FEV1. However, assessment of the inspira-
tory flow pattern is also crucial.
The characteristic flattening of the flow–volume curve in
upper airway obstruction reflects the presence of pathologic
flow limitation. Flow limitation is defined as a state in which
increasing effort does not result in increasing airflow. Thus,
flow is reduced and constant over a range of lung volumes,
producing the flattened shape of the curves depicted in
Figure 50-3. The turbulent flow occurring in the context of
a high driving pressure during inspiration is responsible for
producing the sound of stridor in extrathoracic airway
obstruction. As noted above, intrathoracic obstruction can
result in prolonged expiratory flow and low-pitched wheeze,
585
and increased breath sounds can be heard during both
inspiration and expiration, again due to turbulent flow
resulting from fixed airway obstruction.
Turbulence due to airway narrowing can be reduced by
administration of a helium–oxygen (Heliox) mixture, which
is less dense than air. This can be used diagnostically in
cases where it is unclear whether changes in flow–volume
curves are due to large airway obstruction. The standard cri-
terion for identifying a large airway component is the detec-
tion of an increase with helium of more than 50% in either
peak expiratory or inspiratory flow.34 Heliox administration
is also a useful, albeit temporary, therapeutic adjunct in the
clinical management of upper airway obstruction.
Mediastinal masses may cause intrathoracic large airway
obstruction that varies with body position. Owing to gravi-
tational factors, intrathoracic large airway obstruction
resulting from anterior mediastinal masses may be more
prominent when the patient is supine. Airway obstruction
can worsen with the chest wall relaxation that occurs on the
induction of anesthesia, so that preoperative and postopera-
tive airway management in such patients requires careful
attention. The positional variation of large airway obstruc-
tion can be evaluated by assessing changes in peak flow rates
during seated versus supine spirometry.36
In the context of acute, severe extrathoracic upper air-
way obstruction (eg, epiglottitis, foreign body aspiration, or
acute laryngeal injury), inspiratory intrathoracic driving
pressures may become extremely negative, and this, in turn,
may lead to the development of “negative-pressure pul-
monary edema.”37,38 This is believed to be due to a combi-
nation of increased venous return leading to increased
pulmonary blood volume and negative pericapillary intersti-
tial tissue pressure caused by large negative intrapleural
pressures, resulting in forces that favor fluid transudation
into the interstitium. In some patients, left ventricular
(LV) dysfunction is believed to also contribute because
of increased LV wall transmural pressure, that is, afterload,
resulting from the negative intrapleural pressure. Manage-
ment of this condition primarily involves management of
the upper airway obstruction.
PATHOPHYSIOLOGY OF UPPER AIRWAY
COLLAPSE DURING SLEEP: OBSTRUCTIVE
SLEEP APNEA
CLINICAL DESCRIPTION
OSA is characterized by repeated episodes of upper airway
obstruction during sleep. This important condition is highly
prevalent in the adult population, being estimated to affect
2 to 9% of women and 4 to 15% of men, depending on
the precise definitions used and the population under
study.39,40 OSA also occurs in the pediatric age group,
although with considerably lower prevalence. OSA is associ-
ated with considerable morbidity, increased health care
resource utilization, and, probably, increased mortal-
ity.12,13,40–42 Apneic episodes are characterized by upper air-
way closure and progressively increasing respiratory efforts
driven by chemoreceptor and mechanoreceptor stimuli,
which then provoke arousal from sleep and reopening of the
586 Sleep Disordered Breathing

airway. These events result in sleep fragmentation, repetitive
hypoxemia, and swings in heart rate, blood pressure, and
cardiac output, which are responsible for the clinical seque-
lae of OSA. The latter include excessive daytime sleepiness,
impaired concentration, cognitive functions and memory,
and mood disturbances. There is a rapidly growing body of
data linking OSA to increased cardiovascular risk, including
hypertension, cardiac ischemic events, arrhythmia, cere-
brovascular accidents, congestive heart failure, and pul-
monary hypertension. Severe OSA can also be associated
with changes in ventilatory control and hypoventilation
during wakefulness, typically in the context of underlying
lung dysfunction. There is also growing evidence of a link
between OSA and asthma. These issues are discussed further
below and in a subsequent chapter.
OSA should be suspected clinically in patients with a
history of heavy habitual snoring and excessive daytime
sleepiness. Sleep testing is performed to establish the
diagnosis. The current “gold standard” test is complete
overnight polysomnography performed in a sleep laboratory.
This test involves recording of the electroencephalogram,
electrooculogram and submental electromyogram for
sleep–wake staging, pulse oximetry, determination of airflow
with an oronasal thermistor or through nasal pressure
(currently the method of choice), determination of respira-
tory effort with inductance plethysmography, piezoelectric
sensors or mercury strain gauges around the thorax and
abdomen or with an esophageal balloon (typically reserved
for research studies or special clinical cases), determination
of body position with mercury switch or video recording,
recording of sound (snoring) with a microphone, and
detection of periodic limb movements with leg electromyo-
graphic electrodes. A typical polysomnographic tracing from
a patient with severe OSA is shown in Figure 50-5.
The raw data tracings from the sleep study are scored by a
technologist to identify sleep–wake state for each consecutive
30-second period (epoch) of the night, according to standard
criteria.43 The respiratory signals are scored to identify apneas
(⬎10 seconds of complete cessation of airflow) and hypop-
neas (event lasting ⬎10 seconds, with reduced airflow associ-
ated with oxygen desaturation and/or brief arousal from
sleep), and whether these are obstructive or central in nature
(associated or not with ongoing respiratory effort during
events).44 Summary data are generated in both tabular and
graphic form to describe the physiology of sleep, breathing,
and other events through the night (Figure 50-6). Although

Stage 1 Stage 1 Wake Stage 1 Stage 2 Stage 1 Stage 2 Stage 2

OC
OC
EMG
C4-A1

C3-A2 Arc

EKG
LEGS + 100.0

+ 90.0

+ 80.0
SaO2

Flow

Chest(respitrace)

Obstructive Apnea Obstructive Hypopnea w Obstructive Hypopnea

Abdomen(respitrace)

Snore
Snore Snore

FIGURE 50-5 Representative tracing from a polysomnographic recording in a patient with obstructive sleep apnea, showing three sequen-
tial obstructive events, one apnea and two hypopneas. Note that the severity of event-associated oxygen desaturation correlates with the
extent of flow reduction during these events. The flow signal is a nasal pressure recording, with inspiration in the upward direction, and
illustrates the upper airway flow limitation (flattening) during hypopneas. Note the partial rib cage paradox in the thoracic respiratory
inductance plethysmography signal.
 Physiology of the Upper Airway and Upper Airway Obstruction in Disease 587

Stage 4 the polysomnogram therefore provides extensive physiologic

STAGING Stage 3
Stage 2
information, which is useful in the clinical setting, this is a
Stage 1
Wake
time- and cost-intensive testing procedure of limited availa-
Rem bility. Owing to the prevalence of OSA and issues of limited
21:00 22:00 23:00 00:00 01:00 02:00 03:00 04:00 05:00 access to full polysomnography, there is a growing reliance
on simplified tests that record oximetry alone, or oximetry
RESPIRATORY

Ap C
Hp C
Ap M
with airflow and respiratory effort channels, to establish the
Ap O diagnosis.
Hp O
UAWR

21:00 22:00 23:00 00:00 01:00 02:00 03:00 04:00 05:00

MECHANISMS OF UPPER AIRWAY COLLAPSE
OXIMETRY

100
DURING SLEEP
As described above, the pharyngeal airway can be consid-
50
21:00 22:00 23:00 00:00 01:00 02:00 03:00 04:00 05:00 ered as a collapsible tube, the patency of which is deter-
1000
mined by a balance between forces tending to close the
SNORING

airway, such as intraluminal suction pressure during breath-

-1000 ing, and forces acting to maintain airway patency, notably
21:00 22:00 23:00 00:00 01:00 02:00 03:00 04:00 05:00
the activation of upper airway dilator muscles. The current
Supine
BODY POS

Prone
Left
Right
Upright
Out of Bed
21:00 22:00 23:00
FIGURE 50-6 Composite hypnogram from a patient with severe
obstructive sleep apnea and hypopnea. Individual apneas and
hypopneas are indicated by vertical bars on the “Respiratory”
graph. The patient was awake from 1:45 am to 3:15 am, so that
no respiratory disturbance occurred during that time. Note that
in this patient the severity of respiratory disturbance is influenced
by sleep stage and body position. Oxygen desaturation is more
severe during rapid eye movement (REM) than during non-
REM sleep, in part due to increased length of events related to
increased arousal threshold during REM. During stage 2, non-
REM sleep apneas predominate when the patient is supine
(eg, 10 pm), whereas hypopneas predominate when the patient
is on the side (eg, 1 am), due to gravitational effects on upper air-
way caliber. This results in positional effects on event-associated
oxygen desaturation.
broad conception of OSA pathophysiology is that upper air-
way anatomic dimensions are reduced in affected patients,
00:00 01:00 02:00 03:00 04:00 05:00 leading to compensatory activation of upper airway dilators.
Muscle activity is therefore adequate during wakefulness to
maintain airway patency, but at sleep onset, when upper
airway tonic and phasic activity are reduced and protective
reflexes are inhibited, airway closure supervenes.12,13,42
The evidence supporting these concepts, as well as other
potential factors contributing to the pathophysiology of
OSA, is considered in the following sections. A schematic of
the mechanisms contributing to upper airway collapse dur-
ing sleep is shown in Figure 50-7.
Upper Airway Anatomy in OSA Upper airway collapse dur-
ing sleep in OSA occurs predominantly in the retropalatal and
retroglossal airway, that is, the velopharynx and oropharynx.

Factors Affecting Upper Airway Calibre FIGURE 50-7 Schematic of mechanisms

contributing to upper airway collapse during
Patency Collapse sleep in obstructive sleep apnea.

Normal Anatomic Configuration Reduced Dimensions

(bony structure, soft tissue)
Traction on UA Lung Volume Reduced EELV, Less Traction
Normal Surface Tension Increased
Lower Airway Collapsibility (Pcrit) Higher

Less Negative Intraluminal Pressure More Negative

Less Positive Extraluminal Tissue Pressure More Positive
Adaptation Increased Dilator Muscle Injury, Dysfunction
Activation
Mild Sleep-related decrements in Marked vs. Heightened
muscle activity Compensatory Levels During W
Normal Sleep-related Dilator Reflex Responses Blunted (latency, amplitude)
Decrement
Absent Denervation (Sensory, Motor) Neural, Muscular Dysfunction
Absent Inflammation, Edema Altered Airway Calibre,
Tissue Characteristics,
Neuromuscular fxn
588 Sleep Disordered Breathing
There is abundant evidence that the airway dimensions are
reduced in OSA patients in comparison with normal control
subjects. Techniques that have been used to study airway
size include cephalometry, fluoroscopy, acoustic reflection,
videoendoscopy, computed tomography, and magnetic
resonance imaging (MRI). The accumulated data indicate
that both reductions in the dimensions of the bony cranio-
facial framework and increases in the size of soft tissue
structures surrounding the airway may contribute to
reduced airway dimensions. Alterations in craniofacial
proportions that have been described include reduced
length of the mandibular ramus, inferior positioning of
the hyoid bone, and retroposition of the maxilla.45 In addi-
tion to circumferential narrowing, increased airway length
may also be a factor. Increased distance between the hyoid
bone and the mandibular plane found in cephalometric
studies and increased airway length found in a recent MRI
modeling analysis appear to be associated with an increased
likelihood of upper airway collapse.46
Increases in soft tissue dimensions that have been found
in imaging studies include enlargement of the soft palate,
tongue, parapharyngeal fat pads, and lateral pharyngeal
walls. These increases contribute to anatomic narrowing
and may also contribute to increased tissue pressure, which
favors airway collapse. The increased tissue volume proba-
bly reflects changes that also affect mechanical characteris-
tics of the tissues, leading to altered airway biomechanics
(see below). Several mechanisms appear to contribute to
these soft tissue changes. Upper airway edema has been
found clinically, histologically, and by MRI scanning.47–49
This may result from upper airway trauma during obstruc-
tive events, hypoxemia, systemic inflammation, or a combi-
nation of factors. Mucosal edema improves with nasal
continuous positive airway pressure (CPAP) treatment of
OSA.48 Increased deposition of fat in the upper airway in
obese patients contributes to narrowing, particularly in the
region of the parapharyngeal fat pads, but elsewhere in the
upper airway as well.45 Weight gain is also associated with
increased amounts of fat-free tissue, some of which is mus-
cle, such that obesity may contribute to increased upper air-
way muscle mass. The latter may also be due to loading with
hypertrophy or muscle injury and edema, which is discussed
further below. Genetic factors probably also play a role in
determining soft-tissue volume, in a manner analogous to
craniofacial structure.
Lung Volume Effects on Upper Airway Size Studies in
both humans and animals have shown that upper airway
caliber is influenced by changes in lung volume, such that
decreased lung volume is associated with decreased upper
airway dimensions and increased airflow resistance.50–52
This appears to be due to effects of tracheal tug on upper air-
way length and/or wall characteristics.51,52 OSA patients
appear to have greater lung volume dependence of upper
airway caliber than normal subjects.53 Assumption of
the recumbent position is associated with reduced end-
expiratory lung volume, and obese patients have particularly
marked reductions in supine functional residual capacity.
Furthermore, lung volume may also decrease during the
course of obstructive apnea. These reductions in lung
volume would therefore contribute to reduced upper airway
caliber, further increasing the predisposition to collapse.
Mechanical Properties of the Upper Airway The cross-
sectional area of the pharynx is determined by the interac-
tion between the mechanical characteristics of this
structure, that is, compliance of the wall, and the transmural
pressure.12,13 The passive mechanical properties of the upper
airway in OSA have received considerable attention.
Schwartz and colleagues54,55 have modeled the upper airway
as a Starling resistor and produced an extensive literature
assessing the collapsibility of the pharyngeal airway under
passive conditions. This typically involves the application
of a range of positive and negative airway pressures, with
extrapolation from steady-state pressure–flow relationships
to determine the pressure associated with airway closure, or
critical pressure, Pcrit. During sleep, Pcrit values are about
⫺13 cm H2O in normal subjects, about ⫺6 cm H2O in snor-
ers, and about ⫺2 cm H2O in patients with predominantly
obstructive hypopnea; in apneic patients, the upper airway
closing pressure is positive, often in the range ⫹10 to
⫹15 cm H2O. Isono and colleagues56 have studied the
static properties of the human pharynx under conditions
of general anesthesia and muscle paralysis. These authors
found that for OSA versus control subjects, the average and
maximal velopharyngeal cross-sectional areas were smaller,
closing pressures were higher, and area–pressure compliance
curves were shifted down and to the right, indicative of
increased collapsibility. Other authors have also shown
reduced distensibility of the upper airway in OSA.
Collectively, these data point to the presence of a smaller,
more collapsible, and less distensible, that is, less compliant,
airway in OSA.
During active breathing, the transmural pressure across
the pharynx is another major determinant of cross-sectional
area. The transmural pressure is determined by the balance
between the intraluminal pressure, which is negative during
inspiration, and the extraluminal or tissue pressure. The
latter is determined by the volume and mechanical charac-
teristics of tissues surrounding the airways and by the level
of activation of surrounding constrictor and dilator muscles.
Muscle activation will be considered in the following
section. No direct measurements have been made of inter-
stitial tissue pressure in humans, although measurements
in anesthetized pigs showed positive extraluminal pressures
that correlated with airway obstructive events. The occur-
rence of airway collapse under passive conditions without
negative intraluminal pressure54,55 suggests that positive
tissue pressures probably also exist in humans.
Surface tension contributes to pharyngeal collapsi-
bility.12,57,58 This may be particularly important at the point
where generation of an opening pressure is required to
separate mucosal surfaces that have come into contact
during complete airway collapse. However, surface forces
will also influence the distensibility of the rounded pha-
ryngeal structure throughout the respiratory cycle. Upper
airway surface lining fluid from OSA subjects shows
increased surface tension in comparison with that of fluid
 Physiology of the Upper Airway and Upper Airway Obstruction in Disease
from control subjects.58 Topical application of artificial
surfactant renders the upper airway less collapsible and
can produce reductions in the severity of obstructive events
during sleep in OSA patients.57
Neural Control of Pharyngeal Motor Activity As dis-
cussed earlier in this chapter, the tonic and phasic activation
of dilatory musculature surrounding the pharyngeal airway
is critical to the prevention of airway collapse as negative
intraluminal pressure during inspiration causes a decrease in
transmural pressure. Results from several groups have indi-
cated that the activity of upper airway dilators is greater in
OSA patients than in normal subjects, and this is believed to
represent a compensatory mechanism for the inherent
anatomic compromise of the airway in such patients.59,60
There are several major inputs influencing the activation
of pharyngeal dilator muscles by the brainstem respiratory
controller.13,61–63 As noted above, the normal integrated pat-
tern of central respiratory output is such that there is preac-
tivation of upper airway musculature before activation of the
lower pump muscles occurs.14,15 Perturbations in this pat-
tern, with delayed activation of upper airway dilators in rela-
tion to chest wall and diaphragm activation, have been
reported in some patients with OSA, and this is believed to
contribute to upper airway instability.15 Central output to
upper airway motor neurons is also influenced by chemo-
receptor stimulation, so that fluctuations in carbon dioxide
level may destabilize output to the dilator muscles.
Most important for sleep apnea, however, is the influence
of sleep-related decrements in pharyngeal motor output.
Whereas the upper airway may be narrowed during wakeful-
ness in OSA, obstruction occurs only during sleep, empha-
sizing the importance of state-dependent influences on
upper airway control. Sleep onset in normal subjects is ini-
tially associated with reduced tonic and phasic activity of the
genioglossus, geniohyoid, and palatal muscles. However,
phasic muscle activity tends to recover as sleep is estab-
lished, whereas muscles with a predominantly tonic pattern
of activation tend to show further losses of activity as sleep
deepens.13,42 It is therefore believed that reduced tonic acti-
vation is an important factor contributing to upper airway
collapse. However, both phasic and tonic muscle activity
may be potently inhibited during rapid eye movement
(REM) sleep,64 accounting in part for the increased severity
of OSA during REM versus non-REM sleep. A key observa-
tion in OSA patients is that the fall in upper airway dilator
electromyographic activity associated with sleep onset
appears to be substantially greater than in controls.65 Thus,
upper airway dilator activity is greater during wakefulness,
representing a compensation for upper airway size and
mechanics, but appears to be lost at sleep onset.
The activity of upper airway dilators is also modulated
by reflex inputs. The available evidence indicates that the
most important local stimulus for activation of these mus-
cles is intrapharyngeal negative pressure.13,66 Reflex activa-
tion by pulses of negative pressure applied to the upper
airway has been described for the genioglossus, levator
palatini, and palatoglossus muscles. This negative pressure
reflex is impaired for the levator palatini and palatoglossus
589
muscles in OSA versus control subjects. Furthermore, even
in normal individuals, there is a decrease in the activity of
this reflex at sleep onset. Thus, an important modulating
influence on upper airway caliber is attenuated during sleep,
and this is believed to predispose to upper airway collapse.
The afferent inputs to the negative pressure reflex arise
from the mucosa of the oropharynx and larynx.66–68 The
importance of mucosal afferents to upper airway motor con-
trol has been demonstrated in studies involving topical
application of anesthetic to interfere with mucosal sensory
receptor activity. Topical upper airway anesthesia leads to
reduced dilator muscle activity and increased pharyngeal
airflow resistance during wakefulness and sleep and can
induce apnea and hypopnea in normal subjects, increase the
frequency of obstructive events in snorers, and lead to
delayed end-apneic arousal and increased apnea duration in
OSA subjects.67–69 Recently, we showed the presence of an
impairment in mucosal mechanosensory function in the
oropharynx of snorers and OSA patients, which partially
improved in OSA patients following CPAP treatment.67 The
severity of oropharyngeal sensory impairment correlates
with the latency of the palatoglossus and genioglossus
muscle reflex responses to pulses of negative pressure
delivered to the upper airway, as described by Mortimore
and Douglas.70 Therefore, the afferent neural impairment
appears to contribute to impaired dilator reflex responsive-
ness, which probably has important implications for upper
airway function. Additional studies using endoscopic
sensory testing have also demonstrated impaired laryngeal
sensation in OSA patients versus controls.68 Within the
OSA group, there appeared to be two subgroups, one
with normal sensation and another with abnormal sensa-
tion, the severity of which correlated with the apnea–
hypopnea index. Thus, in some patients, an impairment
of mucosal sensory function appears to contribute to
OSA pathophysiology.
Although the mechanisms underlying impaired upper
airway sensation remain unclear, histologic studies have
demonstrated neural changes consistent with injury and
repair that could represent the basis for mucosal sen-
sorineural dysfunction.49,68 An accumulating body of data
points to the presence of significant cellular inflammation
in upper airway tissue.49,68 As noted above, this may be
related to tissue injury resulting from vibration-associated
trauma, hypoxemia, or other factors, including the state
of systemic inflammation, which has been associated with
both OSA and obesity. Inflammatory mechanisms or
mechanical trauma may account for the neural injury
observed in the upper airway mucosa, although further
investigation is required to establish the precise mechanisms
involved.
Pharyngeal Muscle Function in OSA There is accumu-
lating evidence that OSA is associated with changes in the
structure and function of the upper airway dilator muscles.
Some of these changes appear to be adaptive in nature,
whereas others are more consistent with injury and may lead
to impaired contractile function, thus contributing to upper
airway dysfunction. As noted above, upper airway dilator
590 Sleep Disordered Breathing
activity is increased in OSA patients during wakefulness.
Whereas sleep-related decrements in upper airway muscle
activity contribute to upper airway collapse, the termination
of obstructive events is associated with massive activation of
upper airway dilators, which, it should be noted, occurs
under hypoxic conditions. Thus, the evidence suggests that,
overall, upper airway muscle activity is substantially
increased in OSA. This raises the possibility that these mus-
cles could undergo secondary changes as a direct conse-
quence of their increased activity level.71 Skeletal muscle is
well recognized to alter its phenotype in order to adapt to
the prevailing demands placed upon it, thereby maximizing
muscle efficiency. Properties such as muscle fiber size, con-
tractile protein isoform profile, and metabolic enzyme con-
tent can be readily modified, with resultant changes in
muscle performance. However, when excessive contractile
demands are placed upon muscle, it is well documented
that the structural integrity of the muscle cell can be
physically disrupted by the forces produced during muscle
contraction. This activity-induced injury is particularly
prominent when the forces opposing muscle contraction
result in muscle lengthening during activation, or so-called
eccentric contraction.71,72
Eccentric contractions of upper airway dilator muscles
have been demonstrated during airway occlusion and
progressive hypercapnia in anesthetized cats.73 Because
similar events occur in human OSA, it has been hypothe-
sized that eccentric contractions also occur in pharyngeal
dilators in this condition,71 through at least two possi-
ble mechanisms: (1) muscles that are mechanically linked
could contract against one another, as has been demon-
strated for the sternohyoid and geniohyoid muscles during
airway occlusion in anesthetized animals, and (2) large
negative intraluminal pressures associated with pharyngeal
obstruction, which could act to forcibly lengthen the oppos-
ing dilator muscles.71,72
Petrof and colleagues,72 using the English bulldog, which
suffers from OSA, found that the sternohyoid muscle, an
important upper airway dilator muscle, showed evidence of
fiber-type shift but also changes consistent with activity-
induced muscle injury, consisting of abnormal fiber mor-
phology (central nucleation, fissured and moth-eaten
appearance), inflammatory cell infiltrates, and increased
amounts of connective tissue. Muscle injury was also found
in the geniohyoid muscle, another pharyngeal dilator. A
subsequent MRI study using the bulldog model74 showed
changes consistent with muscle edema or fibrosis in four of
five pharyngeal muscles examined. These changes were not
seen in limb muscles or in control animals. Thus, there is
compelling evidence for muscle injury in this animal model
of OSA.
Studies on human OSA tissues have also shown evidence
of both adaptation and injury. Several smaller studies have
shown histologic changes consistent with injury.71 However,
studies by Series and colleagues75,76 on the musculus uvulae
muscle did not show pathologic evidence of injury but
demonstrated an increase in the proportion of fast-twitch
(type IIa) fibers and the activity of enzymes of anaerobic
metabolism in OSA patients. The force-generating capacity
of the muscle was the same in OSA patients and control
subjects when normalized for muscle cross-sectional area,
but in a subsequent study, changes in the musculus uvulae
muscle correlated with upper airway collapsibility. Patients
with the most easily collapsible upper airway also showed
the greatest increases in force production, type IIa fiber
prevalence, anaerobic metabolism, and susceptibility to
muscle fatigue. Carrera and Barbé77 studied genioglossus
muscles from OSA patients and from controls; they also
reported a shift to type II fiber type and specifically demon-
strated increased fatigability of the genioglossus muscle in
OSA. Thus, even in the absence of morphologic injury,
adaptive changes induced by the contraction history of
the upper airway muscles may also have adverse functional
consequences.
In the discussion on pharyngeal motor control in the pre-
ceding section, it was noted that there is evidence for an
upper airway afferent neuropathy in OSA, based on both
sensory testing data and pathologic findings. There is evi-
dence to suggest that there may, in fact, be a more diffuse
upper airway neuropathy in OSA that also affects efferent
nerves and may lead to muscle denervation. Woodson and
colleagues47 reported demyelination in upper airway tissue
specimens. Histologic evidence of motor denervation, such
as fiber type grouping and grouped atrophy, has also been
found in several recent studies.50,78 In a recent study of
human upper airway surgical specimens from OSA and con-
trol subjects, we demonstrated increased nerve tissue prolif-
eration within the muscle compartment, revealed by specific
antibody to neural tissue (PGP 9.5), and also found groups
of myocytes expressing neural cell adhesion molecule, a
sensitive marker of muscle denervation.49 These findings
suggest that denervation-related changes may contribute to
upper airway muscle function in OSA.
As discussed above, the edema and inflammatory cell
infiltration of the upper airway mucosa described by several
groups suggest that inflammatory mechanisms may con-
tribute to upper airway dysfunction in OSA, leading, for
example, to neuropathic changes.49 In the study just cited
from the author’s laboratory,49 we demonstrated increased
inflammatory cell infiltration in OSA upper airway muscle.
Furthermore, preliminary data from our laboratory have
revealed increased expression of tumor necrosis factor-␣ and
interleukin-1␣ in muscle tissue from patients with severe
OSA versus those with mild OSA. It is now well established
that cytokines can lead directly to muscle dysfunction.79
Thus, inflammatory changes in the upper airway may
alter muscle function directly by this means or conceivably
by contributing to neuropathy, which, in turn, may lead to
muscle denervation. It is likely that muscle adaptation
and injury are ongoing in a dynamic process in OSA, that
different muscle groups within the upper airway may be
affected differently, and that the extent of change and phys-
iologic consequences for muscle function may vary between
OSA patients. Further work will be required to further elu-
cidate the contribution of upper airway muscle denervation
and injury to the pathophysiology of this disorder, as well as
to determine whether muscle changes may represent a
potential therapeutic target in OSA.
 Physiology of the Upper Airway and Upper Airway Obstruction in Disease
OSA and Ventilatory Control There is a growing
understanding of the effects of chemoreceptor sensitivity
and ventilatory control instability on the pathogenesis of
periodic breathing and central apnea.80,81 Differences in the
control of breathing between wakefulness and sleep (eg, the
higher ventilatory setpoint and ventilatory chemosensitivity
during wakefulness) lead to respiratory instability during
the transition from wakefulness to sleep, accounting for
apneas and hypopneas, which may be seen at sleep onset in
normal subjects. Furthermore, recent work has shown that
ventilatory responses are heightened at the instant of arousal
from sleep in comparison to stable wakefulness.62 Thus,
instability of the sleep–wake state per se may destabilize
breathing. The state changes associated with apneas and
hypopneas, that is, microarousal at the termination of
events, followed by the rapid return to sleep, therefore
represent a situation of inherently unstable respiratory con-
trol. Numerous investigators have postulated that altered
chemoreceptor sensitivity or instability of other respiratory
control mechanisms may therefore contribute to the patho-
genesis of OSA. An early observation in support of this
hypothesis was the occurrence of periodic breathing during
sleep immediately following tracheostomy for OSA.82
A large body of data has been generated concerning
changes in classic chemoreceptor responses in OSA,
although there have been rather inconsistent findings. Some
authors have reported heightened hypoxic sensitivity, which
was postulated to contribute to respiratory instability,
whereas others have reported blunted hypoxic sensitivity.83
Hypercapnic ventilatory responsiveness has been reported
to be normal or decreased in OSA and, if reduced, may
improve following treatment with nasal CPAP.83
Recently, Younes and colleagues used proportional assist
ventilation (PAV) to evaluate ventilatory control stability in
OSA patients.84 With the upper airway stabilized during
sleep by nasal CPAP, increasing levels of PAV (controller
gain) were applied up to the point at which periodic breath-
ing was elicited. It was found that patients with severe
OSA were much more susceptible to the development of
periodic breathing than patients with mild-to-moderate
OSA, indicating increased endogenous loop gain in the
severe group. The mechanisms underlying this ventilatory
instability, and its precise role in the pathogenesis of OSA,
remain to be established.
Although the role of changes in chemoreceptor sensitiv-
ity in the pathogenesis of OSA remains unclear, there is
strong evidence that severe OSA may produce secondary
changes in ventilatory control, namely hypoventilation dur-
ing wakefulness. This occurs in a subset of OSA patients
who appear to be the group at risk for decompensation and
respiratory failure in the context of intercurrent medical ill-
ness, or in some cases simply because of inexorable progres-
sion of the changes associated with sleep-disordered
breathing. Most patients with OSA and daytime hypoxemia
and/or hypercapnia have some underlying lung dysfunction,
such as COPD or obesity-related or neuromuscular restric-
tive impairment.83,85,86 OSA patients with hypercapnia have
been described as demonstrating impaired ventilatory recov-
ery after apnea.87 This may represent a blunting or failure of
591
load compensation mechanisms in such patients and may
contribute to a “resetting” of the chemoreceptors, leading to
awake hypoventilation. Daytime blood gases typically
improve dramatically or normalize following effective treat-
ment of OSA, supporting the concept that the nocturnal
respiratory disturbance leads to the development of awake
hypoventilation.
OSA and Asthma There is growing evidence of a link
between OSA and asthma. In a recent study at McGill,88 26
consecutive refractory asthmatic subjects were evaluated in
comparison with 21 age-matched and gender-matched con-
trol subjects with moderate asthma. The prevalence of OSA
in both groups was dramatically increased over population
normal values, with a tendency for OSA to be more preva-
lent among subjects with severe asthma (16/26, 62%) than
among those with moderate asthma (10/21, 48%) and for
OSA to be somewhat more severe among the refractory
asthma group. These findings, together with evidence from
other case series, suggest that OSA may contribute to wors-
ened asthma control. For example, Chan and colleagues89
studied nine patients with severe asthma and snoring or
OSA who suffered frequent nocturnal asthma attacks despite
maximum bronchodilator therapy. CPAP treatment of upper
airway obstruction during sleep improved asthma control,
as reflected in asthma symptoms, bronchodilator use, and
peak flow rates.
There are several mechanisms by which OSA and asthma
could interact. There is evidence that stimulation of upper
airway mechanoreceptors during snoring and apneas can
lead to reflex bronchoconstriction. Alternatively, gastro-
esophageal reflux occurs frequently in OSA patients and is a
well-recognized exacerbating factor in asthma. Treatment of
asthma with corticosteroids may contribute to OSA by
increasing obesity and/or pharyngeal myopathy.90 Finally, as
noted above, there are considerable data documenting upper
airway inflammation in OSA and growing evidence that this
plays a role in OSA pathophysiology. The links between rhi-
nosinus inflammation and lower airway inflammation in
asthma are well documented (termed the “united airway
hypothesis”). It may therefore be that pharyngeal involve-
ment represents part of a continuum of airway inflammatory
involvement. There may thus be a reciprocal interaction
between these disease processes, such that worsening of
OSA may contribute to worsened asthma control and vice
versa. This concept is supported by the clinical data cited
above concerning the effects of OSA treatment on asthma
control. Research efforts are ongoing to further evaluate the
mechanisms of the OSA–asthma interaction and to more
systematically assess the effects of OSA treatment on asthma
control.
PHYSIOLOGIC ASPECTS OF DIAGNOSTIC TESTING
FOR OSA
In recent years, recording of nasal pressure has emerged
as a sensitive indicator of upper airway narrowing.
Introduction of a standard nasal oxygen cannula into the
nares, with connection of the tubing end to a differential
pressure transducer referenced to atmosphere, provides for
592 Sleep Disordered Breathing

FIGURE 50-8 Approach to Clinical Suspicion of OSA

diagnosis and management
of obstructive sleep apnea.
Polysomnography (PSG) Readily Available

No Yes

Portable PSG
Monitor

RDI < 10 RDI 10-30 RDI > 30 AHL < 10 AHL 10-30 AHL > 30

Daytime Sleepiness Daytime Sleepiness Daytime Sleepiness Daytime Sleepiness

No Yes No Yes No Yes No Yes

Stop W/U PSG Clinical F/U Treat Treat Stop W/U Consider Clinical F/U Treat Treat
Other
Dx +/or
Repeat
PSG

Treatment Decision

CPAP CPAP Alternaitve (oral

appliance surgery)
Titration PSG
PSG on Treatment
Clnical F/U
AHI < 10 AHI > 10
Persistent or
Recurrent Sx Adjust
Treatment or
Sleep Hx, F/U, PSG CPAP Trial

a semiquantitative assessment of nasal airflow. Of greater
interest is the fact that the shape of the inspiratory pressure
curve during tidal respiratory cycles shows flattening indica-
tive of flow limitation as upper airway narrowing occurs, in
the same way that forced maximal curves reveal extratho-
racic upper airway obstruction, as discussed earlier in this
chapter.91,92 This technique provides for the detection of
subtle episodes of upper airway narrowing.
Respiratory effort was traditionally measured by using an
esophageal catheter to estimate pleural pressure. This inva-
sive approach has largely been replaced by techniques
involving the use of sensors on the rib cage and abdomen to
detect respiratory effort and movement. The most sensitive
of these is respiratory inductance plethysmography, which
provides data on changes in thoracoabdominal motion
resulting from partial or complete upper airway obstruction.
Partial or complete rib cage paradoxical motion is often seen
during apneas and hypopneas and can provide confirmatory
evidence of increasing respiratory effort in the context of
upper airway obstruction.
PHYSIOLOGY OF TREATMENT APPROACHES TO OSA
There are several treatments aimed at compensating for
the anatomic predisposition to upper airway collapse.
Mandibular advancement splints, for example, act to advance
the lower jaw in relation to other craniofacial structures,
thereby increasing the anteroposterior oropharyngeal
dimension.93 This approach does not compensate for other
factors contributing to upper airway collapse during sleep,
and there are limitations to its anatomic effects. Oral appli-
ances are therefore effective in mild-to-moderate apnea but
typically do not alleviate moderate-to-severe OSA. Surgical
interventions are also aimed at compensating for reduced
upper airway dimensions. In childhood OSA, hypertrophy
of the adenoid and, to a lesser extent, the palatine tonsils is
often a major factor contributing to airway compromise, so
that adenoidectomy–tonsillectomy is a mainstay of treat-
ment for OSA in the child. Maxillomandibular advancement
surgery may be beneficial in the context of craniofacial
insufficiency, for example, the marked micrognathia associ-
ated with Pierre–Robin syndrome. This approach may also
be useful for nonobese adults with similar but more subtle
craniofacial disproportion. Surgical intervention in general,
however, has a much more limited role in adult OSA.94
Tracheostomy is highly effective as it bypasses the site of
airway obstruction. However, there are adverse social as
well as medical aspects of chronic tracheostomy, which
severely limit the applicability of this intervention. A
variety of approaches directed at reducing or stiffening
soft palate tissue have been applied to adult OSA.
These include conventional uvulopalatopharyngo-
plasty, laser-assisted uvuloplasty, radiofrequency-controlled
 Physiology of the Upper Airway and Upper Airway Obstruction in Disease
thermoablation (somnoplasty), and other procedures.
Overall, the results of these interventions have been highly
disappointing in the context of moderate-to-severe OSA.
This is undoubtedly due to the limited anatomic effects
of these interventions, combined with the role of factors
other than anatomic predisposition to upper airway collapse
during sleep.
The treatment of choice for OSA is nasal CPAP.95,96 CPAP
functions as a pneumatic splint for the upper airway. A
sealed mask is applied over the nose, and a continuous
positive pressure is applied to the mask from a blower unit
to distend the airway. The pressure required to maintain
airway patency is determined by anatomic, mechanical, neu-
romuscular, and state-dependent factors, such that a greater
pressure may be required for the supine position than for the
lateral decubitus position and during REM than during
non-REM sleep. Traditionally, CPAP titration has been per-
formed in the sleep laboratory, with manual adjustment to
determine the minimum pressure required to maintain air-
way patency in all sleep stages and body positions. This
pressure is then prescribed for home treatment. More
recently, automated CPAP devices have become available,
which continuously monitor the amplitude and contour of
airflow with a pneumotachograph in the CPAP unit. A
microprocessor then evaluates the adequacy of these signals
and adjusts the pressure to respond to inspiratory flow
limitation and/or reduced airflow. The concept is that this is
a more physiologic approach that should match the treat-
ment delivered to the dynamic changes in upper airway
caliber determined by the factors described above. An algo-
rithm for the diagnosis and management of OSA is shown in
Figure 50-8.
UPPER AIRWAY IN CENTRAL SLEEP APNEA
Central sleep apnea is encountered in a variety of clinical
conditions. It may be present as part of primary or sec-
ondary hypoventilation syndromes (hypercapnic central
apnea) due to central nervous system (CNS) lesions or
neuromuscular disease involving the respiratory muscles.
Alternatively, nonhypercapnic forms of central apnea
include idiopathic central sleep apnea and Cheyne–Stokes
respiration (CSR) during sleep, which may occur in the
setting of congestive heart failure, renal failure, or CNS
lesions.97
Although the upper airway is not believed to play a pri-
mary role in most of these conditions, there is evidence that
upper airway instability and collapse are associated with
central apnea and may contribute to its pathophysiology.
Badr and colleagues have shown, using video-endoscopy, that
upper airway collapse occurs in the context of hyperventila-
tion-induced central apnea during sleep, even in normal
subjects.98 Thus, the loss of respiratory drive due to induced
hypocapnia leads to airway closure, confirming the impor-
tance of respiratory drive to upper airway muscles in main-
taining airway patency. Conversely, there is evidence that
upper airway collapse may induce central apneas. The
clinical correlate of this is that patients with snoring and
some obstructive apneas or hypopneas during REM sleep
593
may demonstrate central events during non-REM sleep.
Furthermore, some patients with predominant central apnea
respond to nasal CPAP treatment, suggesting that upper
airway closure contributes to these events.99 These findings
may in part be explained by evidence indicating that stimu-
lation of upper airway mechanoreceptors may result in
reflex inhibition of inspiratory drive. Thus, stimulation of
laryngeal receptors in experimental animals has been
reported to induce apnea.97,100 Furthermore, we found that
inhibition of upper airway mucosal receptors with the use of
topical anesthesia resulted in increased respiratory effort
during obstructive apneas in OSA patients. This points to
the loss of an inhibitory influence on respiratory drive, with
attenuation of airway sensory receptor function.69
There has been considerable recent interest in CSR
during sleep in the setting of chronic congestive heart
failure. Sleep-disordered breathing is common among
stable heart failure patients, occurring in up to 40%,101,102
with CSR representing the most common form. CSR is
believed to both result from and lead to worsening of
heart failure through complex mechanisms and has been
shown to be associated with reduced survival for a given
level of cardiac dysfunction. Treatment with nasal CPAP
in this group leads to improvements in CSR, ventricular
function, and quality of life.102 A multicenter trial (CAN-
PAP) is currently under way to determine the effects of
CPAP on mortality in heart failure patients with CSR. The
mechanisms by which CPAP leads to improvement in CSR
remain unclear. However, recent work at McGill, involving
the forced oscillation technique to assess upper airway
patency, has demonstrated that upper airway closure is
frequent even during pure central events in heart failure
patients with CSR.103 Furthermore, overlap between OSA
and CSR has been described in this population.104
Thus, upper airway instability may also contribute to the
pathogenesis of CSR.
SUMMARY AND CONCLUSIONS
This chapter has examined the normal structure and
function of the upper airway, with an emphasis on the
physiologic aspects of the integration of breathing with the
variety of other upper airway functions. The most serious
clinical disturbance of upper airway function is anatomic
or functional obstruction with airflow compromise. We
have considered the physiologic basis for both the clinical
presentation and approach to diagnostic testing for the
various forms of upper airway obstruction. Finally, we
have considered sleep-disordered breathing and in particular
OSA, a very common but, for many individuals, no less
serious form of variable extrathoracic upper airway
obstruction occurring during sleep. The research that
has been directed at understanding the mechanisms under-
lying OSA has led to major advances in our knowledge of
upper airway structure and function. Although considerable
progress has been made, ongoing work aimed at further
elucidating the mechanisms of OSA will undoubtedly
broaden our understanding of upper airway function in
general.
594 Sleep Disordered Breathing
REFERENCES
1. Proctor D. Form and function of the upper airways and the
larynx. In: Macklem P, Mead J, editors. Handbook of physi-
ology. Section 3. The respiratory system, mechanics of
breathing. Bethesda, MD: American Physiological Society;
1986. p. 63–74.
2. Isaacs RS, Sykes JM. Anatomy and physiology of the upper
airway. Anesthesiol Clin North Am 2002;20:733–45, v.
3. Proctor DF. The upper airways. II. The larynx and trachea. Am
Rev Respir Dis 1977;115:315–42.
4. Doyle DJ, Arellano R. Upper airway diseases and airway man-
agement: a synopsis. Anesthesiol Clin North Am 2002;20:
767–87, vi.
5. Cauna N. Blood and nerve supply of the nasal lining. In:
Proctor DF, Anderson IB, editors. The nose. Oxford: Elsevier
Biomedical Press; 1982. p. 44–69.
6. Thach B, Brouillette R. The respiratory function of pharyngeal
musculature: relevance to clinical obstructive apnea. In:
Euler C, Lagercrantz H, editors. Central nervous control
mechanisms in breathing. Oxford: Pergamon Press; 1979. p.
483–94.
7. McFarland DH, Lund JP. Modification of mastication and
respiration during swallowing in the adult human. J
Neurophysiol 1995;74:1509–17.
8. McFarland DH, Lund JP, Gagner M. Effects of posture on the
coordination of respiration and swallowing. J Neurophysiol
1994;72:2431–7.
9. Broussard DL, Altschuler SM. Central integration of swallow
and airway-protective reflexes. Am J Med 2000;108 Suppl
4a:62S–7S.
10. Remmers JE, DeGroot WJ, Sauerland EK, Anch AM.
Pathogenesis of upper airway occlusion during sleep. J
Appl Physiol 1978;44:931–8.
11. Kuna ST, Sant’Ambrogio G. Pathophysiology of upper airway
closure during sleep. JAMA 1991;266:1384–9.
12. Wheatley JR, Amis TC. Mechanical properties of the upper
airway. Curr Opin Pulm Med 1998;4:363–9.
13. Fogel RB, Malhotra A, White DP. Sleep. 2: pathophysiology of
obstructive sleep apnoea/hypopnoea syndrome. Thorax
2004;59:159–63.
14. Strohl KP, Hensley MJ, Hallett M, et al. Activation of upper air-
way muscles before onset of inspiration in normal humans.
J Appl Physiol 1980;49:638–42.
15. Hudgel DW, Harasick T. Fluctuation in timing of upper airway
and chest wall inspiratory muscle activity in obstructive
sleep apnea. J Appl Physiol 1990;69:443–50.
16. Patrick GB, Strohl KP, Rubin SB, Altose MD. Upper airway and
diaphragm muscle responses to chemical stimulation and
loading. J Appl Physiol 1982;53:1133–7.
17. Sasaki CT, Weaver EM. Physiology of the larynx. Am J Med
1997;103:9S–18S.
18. Suzuki M, Kirchner JA. The posterior cricoarytenoid as an inspi-
ratory muscle. Ann Otol Rhinol Laryngol 1969;78:849–64.
19. Wyke B. Respiratory activity of intrinsic laryngeal muscles. An
experimental study. In: Wyke BD, editor. Ventilatory and
phonatory control systems. London: Oxford University
Press; 1974. p. 408–21.
20. Fortier PH, Reix P, Arsenault J, et al. Active upper airway closure
during induced central apneas in lambs is complete at the
laryngeal level only. J Appl Physiol 2003;95:97–103.
21. Cormier YF, Camus P, Desmeules MJ. Non-organic acute upper
airway obstruction: description and a diagnostic approach.
Am Rev Respir Dis 1980;121:147–50.
22. Newman KB, Mason UG III, Schmaling KB. Clinical features of
vocal cord dysfunction. Am J Respir Crit Care Med 1995;152
(4 Pt 1):1382–6.
23. Macklem P, Rector W, Wang K. Upper airway obstruction in
asthma. Johns Hopkins Med J 1980;147:233–7.
24. Proctor DF. Modifications of breathing for phonation. In:
Macklem PT, Mead J, editors. Handbook of physiology.
Bethesda (MD): American Physiological Society; 1986. p.
597–604.
25. Johnston S, Yan S, Sliwinski P, Macklem PT. Modified Campbell
diagram to assess respiratory muscle action in speech.
Respirology 1999;4:213–22.
26. Kryger M, Bode F, Antic R, Anthonisen N. Diagnosis of obstruc-
tion of the upper and central airways. Am J Med 1976;61:
85–93.
27. Miller RD, Hyatt RE. Evaluation of obstructing lesions of the
trachea and larynx by flow–volume loops. Am Rev Respir
Dis 1973;108:475–81.
28. Hyatt RE. Evaluation of major airway lesions using the
flow–volume loop. Ann Otol Rhinol Laryngol 1975;84
(5 Pt 1):635–42.
29. Gibson GJ, Pride NB, Empey DW. The role of inspiratory
dynamic compression in upper airway obstruction. Am Rev
Respir Dis 1973;108:1352–60.
30. Owens GR, Murphy DM. Spirometric diagnosis of upper airway
obstruction. Arch Intern Med 1983;143:1331–4.
31. Kashima HK. Documentation of upper airway obstruction in
unilateral vocal cord paralysis: flow–volume loop studies in
43 subjects. Laryngoscope 1984;94:923–37.
32. Vincken WG, Gauthier SG, Dollfuss RE, et al. Involvement of
upper-airway muscles in extrapyramidal disorders. A cause
of airflow limitation. N Engl J Med 1984;311:438–42.
33. Vincken W, Elleker G, Cosio MG. Detection of upper airway
muscle involvement in neuromuscular disorders using the
flow–volume loop. Chest 1986;90:52–7.
34. Orr JB. Helium–oxygen gas mixtures in the management of
patients with airway obstruction. Ear Nose Throat J 1988;
67:866–9.
35. Ernst A, Feller-Kopman D, Becker HD, Mehta AC. Central
airway obstruction. Am J Respir Crit Care Med 2004;169:
1278–97.
36. Hnatiuk OW, Corcoran PC, Sierra A. Spirometry in surgery for
anterior mediastinal masses. Chest 2001;120:1152–6.
37. Kanter RK, Watchko JF. Pulmonary edema associated
with upper airway obstruction. Am J Dis Child 1984;138:
356–8.
38. Kollef MH, Pluss J. Noncardiogenic pulmonary edema follow-
ing upper airway obstruction. 7 cases and a review of the
literature. Medicine (Baltimore) 1991;70:91–8.
39. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive
sleep apnea: a population health perspective. Am J Respir
Crit Care Med 2002;165:1217–39.
40. Flemons WW. Clinical practice. Obstructive sleep apnea.
N Engl J Med 2002;347:498–504.
41. Cistulli PA, Sullivan CE. Pathophysiology of sleep apnea. In:
Saunders NA, Sullivan CE, editors. Sleep and breathing.
New York: Marcel Dekker; 1994. p. 405–48.
42. Ayappa I, Rapoport DM. The upper airway in sleep: physiology
of the pharynx. Sleep Med Rev 2003;7:9–33.
43. Rechtschaffen A, Kales A. A manual of standardized terminol-
ogy, technique and scoring system for sleep stages of
human sleep. Los Angeles: Los Angeles Brain Information
Service, Brain Information Institute, UCLA; 1968.
44. Sleep-related breathing disorders in adults: recommenda-
tions for syndrome definition and measurement tech-
niques in clinical research. The Report of an American
Academy of Sleep Medicine Task Force. Sleep 1999;22:
667–89.
45. Schwab RJ. Pro: sleep apnea is an anatomic disorder. Am
J Respir Crit Care Med 2003;168:270–1.
 Physiology of the Upper Airway and Upper Airway Obstruction in Disease
46. Malhotra A, Huang Y, Fogel RB, et al. The male predisposition
to pharyngeal collapse: importance of airway length. Am
J Respir Crit Care Med 2002;166:1388–95.
47. Woodson BT, Garancis JC, Toohill RJ. Histopathologic changes
in snoring and obstructive sleep apnea syndrome.
Laryngoscope 1991;101:1318–22.
48. Ryan CF, Lowe AA, Li D, Fleetham JA. Three-dimensional
upper airway computed tomography in obstructive
sleep apnea. A prospective study in patients treated by
uvulopalatopharyngoplasty. Am Rev Respir Dis 1991;144:
428–32.
49. Boyd JH, Petrof BJ, Hamid Q, et al. Upper airway muscle inflam-
mation and denervation changes in obstructive sleep
apnea. Am J Respir Crit Care Med 2004;170:541–6.
50. Series F, Cormier Y, Desmeules M. Influence of passive
changes of lung volume on upper airways. J Appl Physiol
1990;68:2159–64.
51. Van de Graaff WB. Thoracic traction on the trachea: mecha-
nisms and magnitude. J Appl Physiol 1991;70:1328–36.
52. Rowley JA, Permutt S, Willey SJ, et al. Effect of tracheal and
tongue displacement on upper airway airflow dynamics.
J Appl Physiol 1996;80:2171–8.
53. Hoffstein V, Zamel N, Phillipson EA. Lung volume dependence
of pharyngeal cross-sectional area in patients with obstruc-
tive sleep apnea. Am Rev Respir Dis 1984;130:175–8.
54. Schwartz AR, Smith PL, Wise RA, et al. Induction of upper air-
way occlusion in sleeping individuals with subatmospheric
nasal pressure. J Appl Physiol 1988;64:535–42.
55. Gleadhill IC, Schwartz AR, Schubert N, et al. Upper airway col-
lapsibility in snorers and in patients with obstructive
hypopnea and apnea. Am Rev Respir Dis 1991;143:1300–3.
56. Isono S, Remmers JE, Tanaka A, et al. Anatomy of pharynx in
patients with obstructive sleep apnea and in normal
subjects. J Appl Physiol 1997;82:1319–26.
57. Jokic R, Klimaszewski A, Mink J, Fitzpatrick MF. Surface tension
forces in sleep apnea: the role of a soft tissue lubricant:
a randomized double-blind, placebo-controlled trial. Am
J Respir Crit Care Med 1998;157(5 Pt 1):1522–5.
58. Kirkness JP, Madronio M, Stavrinou R, et al. Relationship
between surface tension of upper airway lining liquid and
upper airway collapsibility during sleep in obstructive
sleep apnea hypopnea syndrome. J Appl Physiol 2003;95:
1761–6.
59. Mezzanotte WS, Tangel DJ, White DP. Waking genioglossal
electromyogram in sleep apnea patients versus normal
controls (a neuromuscular compensatory mechanism).
J Clin Invest 1992;89:1571–9.
60. Suratt PM, McTier RF, Wilhoit SC. Upper airway muscle activa-
tion is augmented in patients with obstructive sleep apnea
compared with that in normal subjects. Am Rev Respir Dis
1988;137:889–94.
61. Horner RL. Motor control of the pharyngeal musculature and
implications for the pathogenesis of obstructive sleep
apnea. Sleep 1996;19:827–53.
62. Horner RL. Impact of brainstem sleep mechanisms on pharyn-
geal motor control. Respir Physiol 2000;119:113–21.
63. Horner RL. The neuropharmacology of upper airway motor
control in the awake and asleep states: implications for
obstructive sleep apnoea. Respir Res 2001;2:286–94.
64. Wiegand L, Zwillich CW, Wiegand D, White DP. Changes in
upper airway muscle activation and ventilation during
phasic REM sleep in normal men. J Appl Physiol 1991;71:
488–97.
65. Mezzanotte WS, Tangel DJ, White DP. Influence of sleep onset
on upper-airway muscle activity in apnea patients versus
normal controls. Am J Respir Crit Care Med 1996;153
(6 Pt 1):1880–7.
595
66. Malhotra A, Fogel RB, Edwards J, et al. Local mechanisms
drive genioglossus activation in obstructive sleep apnea.
Am J Respir Crit Care Med 2000;161:1746–9.
67. Kimoff RJ, Sforza E, Champagne V, et al. Upper airway sensa-
tion in snoring and obstructive sleep apnea. Am J Respir
Crit Care Med 2001;164:250–5.
68. Nguyen ATD, Jobin V, Payne R, et al. Laryngeal and velopha-
ryngeal sensory impairment in obstructive sleep apnea.
Sleep. [In press]
69. Cala SJ, Sliwinski P, Cosio MG, Kimoff RJ. Effect of upper
airway anesthesia on apnea lengthening across the
night in obstructive sleep apnea. J Appl Physiol 1996;81:
2618–26.
70. Mortimore IL, Douglas NJ. Palatal muscle EMG response to
negative pressure in awake sleep apneic and control
subjects. Am J Respir Crit Care Med 1997;156:867–73.
71. Petrof BJ, Hendricks JC. Muscle factors in obstructive sleep
apnea. In: Pack AI, editor. Sleep apnea: pathogenesis,
diagnosis, and treatment. New York: Marcel Dekker; 2002.
p. 217–34.
72. Petrof BJ, Pack AI, Kelly AM, et al. Pharyngeal myopathy of
loaded upper airway in dogs with sleep apnea. J Appl
Physiol 1994;76:1746–52.
73. van Lunteren E, Haxhiu MA, Cherniack NS. Effects of tracheal
airway occlusion on hyoid muscle length and upper airway
volume. J Appl Physiol 1989;67:2296–302.
74. Schotland HM, Insko EK, Panckeri KA, et al. Quantitative mag-
netic resonance imaging of upper airway musculature in an
animal model of sleep apnea. J Appl Physiol 1996;81:
139–46.
75. Series F, Cote C, Simoneau J-A, et al. Physiologic, metabolic,
and muscle fiber type characteristics of musculus uvulae in
sleep apnea hypopnea syndrome and in snorers. J Clin
Invest 1995;95:20–5.
76. Series F, Simoneau JA, St Pierre S. Muscle fiber area distribu-
tion of musculus uvulae in obstructive sleep apnea and
non-apneic snorers. Int J Obes Relat Metab Disord 2004;24:
410–5.
77. Carrera M, Barbé F, Savelda J, et al. Patients with obstructive
sleep apnea exhibit genioglossus dysfunction that is
normalized after treatment with continuous positive airway
pressure. Am J Respir Crit Care Med 1999;159:1960–6.
78. Edstrom L, Larsson H, Larsson L. Neurogenic effects on the
palatopharyngeal muscle in patients with obstructive sleep
apnoea: a muscle biopsy study. J Neurol Neurosurg
Psychiatry 1992;55:916–20.
79. Wilcox P, Milliken C, Bressler B. High-dose tumor necrosis
factor ␣ produces an impairment of hamster diaphragm
contractility. Am J Respir Crit Care Med 1996;153:1611–5.
80. Phillipson EA, Bowes G. Control of breathing during sleep.
In: Cistulli PA, Widdicombe JG, editors. Handbook of phys-
iology. Vol 2. The respiratory system, control of breathing.
Section 3. Part 1. Bethesda, MD: American Physiological
Society; 1986. p. 649–80.
81. Dempsey JA, Smith CA, Eastwood PR, et al. Sleep-induced
respiratory instabilities. In: Pack AI, editor. Sleep apnea:
pathogenesis, diagnosis and treatment. New York: Marcel
Dekker; 2002. p. 57–98.
82. Onal E, Lopata M. Periodic breathing and the pathogenesis of
occlusive sleep apnea. Am Rev Respir Dis 1982;126:676–80.
83. Kimoff RJ, Brooks D, Horner RL, et al. Ventilatory and arousal
responses to CO2 and hypoxia during application of a
canine model of obstructive sleep apnea. Am J Respir Crit
Care Med 1997;156:886–94.
84. Younes M, Ostrowski M, Thompson W, et al. Chemical control
stability in patients with obstructive sleep apnea. Am
J Respir Crit Care Med 2001;163:1181–90.
596 Sleep Disordered Breathing
85. Bradley TD, Rutherford R, Lue F, et al. Role of diffuse airway
obstruction in the hypercapnia of obstructive sleep apnea.
Am Rev Respir Dis 2004;134:920–4.
86. Krieger J, Sforza E, Apprill M, et al. Pulmonary hypertension,
hypoxemia, and hypercapnia in obstructive sleep apnea
patients. Chest 1989;96:729–37.
87. Ayappa I, Berger KI, Norman RG, et al. Hypercapnia and ven-
tilatory periodicity in obstructive sleep apnea syndrome.
Am J Respir Crit Care Med 2002;166:1112–5.
88. Shannon J, Pepe C, Ernst P, et al. High prevalence of obstruc-
tive sleep apnea (OSA) in severe and moderate asthma.
Am J Respir Crit Care Med 2004;169:A542.
89. Chan CS, Woolcock AJ, Sullivan CE. Nocturnal asthma: role of
snoring and obstructive sleep apnea. Am Rev Respir Dis
1988;137:1502–4.
90. Yigla M, Tov N, Solomonov A, et al. Difficult-to-control
asthma and obstructive sleep apnea. J Asthma 2003;40:
865–71.
91. Montserrat JM, Farre R, Ballester E, et al. Evaluation of nasal
prongs for estimating nasal flow. Am J Respir Crit Care Med
1997;155:211–5.
92. Condos R, Norman RG, Krishnasamy I, et al. Flow limitation as
a non-invasive assessment of residual upper-airway resist-
ance during continuous positive airway pressure therapy of
obstructive sleep apnea. Am J Respir Crit Care Med
1994;150:475–80.
93. Ferguson KA. The role of oral appliance therapy in the
treatment of obstructive sleep apnea. Clin Chest Med
2003;24:355–64.
94. Li KK. Surgical management of obstructive sleep apnea. Clin
Chest Med 2003;24:365–70.
95. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of
obstructive sleep apnoea by continuous positive airway
pressure applied through the nares. Lancet 1981;1:862–5.
96. Verse T, Pirsig W, Stuck BA, et al. Recent developments in the
treatment of obstructive sleep apnea. Am J Respir Med
2003;2:157–68.
97. Bradley TD, Phillipson EA. Central sleep apnea. Clin Chest
Med 1992;13:493–505.
98. Badr MS, Toiber F, Skatrud JB, Dempsey J. Pharyngeal narrow-
ing/occlusion during central sleep apnea. J Appl Physiol
1995;78:1806–15.
99. Hoffstein V, Slutsky AS. Central sleep apnea reversed by
continuous positive airway pressure. Am Rev Respir Dis
1987;135:1210–2.
100. Lee JC, Stoll BJ, Downing SE. Properties of the laryngeal
chemoreflex in neonatal piglets. Am J Physiol 1977;233:
R30–6.
101. Bradley TD, Floras JS. Sleep apnea and heart failure: part II:
central sleep apnea. Circulation 2003;107:1822–6.
102. Sin DD, Logan AG, Fitzgerald FS, et al. Effects of continuous
positive airway pressure on cardiovascular outcomes in
heart failure patients with and without Cheyne–Stokes
respiration. Circulation 2000;102:61–6.
103. Jobin V, Rigau J, Farre R, et al. Evaluation of upper airway
patency during Cheyne–Stokes respiration using the forced
oscillation technique. Am J Respir Crit Care Med 2002;165:
A247.
104. Tkacova R, Niroumand M, Lorenzi-Filho G, Bradley TD.
Overnight shift from obstructive to central apneas in
patients with heart failure: role of PCO2 and circulatory
delay. Circulation 2001;103:238–43.