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Te
ynx
ynx
Genioglossus
Epiglolti
Th
24 Pathophysiology ofObstructive Sleep Apnea
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tory motor output to respiratory pump muscles,
or “obstructive” events, which are composed of
respiratory efforts against a closed upper airway.
However, as we discuss below, most cyclical
sleep-disordered breathing events are driven by
anomalies in both anatomical and neurochemical
control of upper airway and/or chest wall respiratory musculature [14].
In short, the process is initiated because the
wakeful state provides compensatory neuronal
activation of dilator muscles in an anatomically
compromised collapsible pharynx; accordingly,
when this activation is lost at sleep onset, the airway narrows and/or collapses. However, the tendency to result (or not to result) in repeated
cyclical apneas is the end product of multiple
compensatory processes that vary markedly
among and within individuals. Concepts have
continued to evolve as we learn more about the
neurophysiological mechanisms governing control of respiratory rhythm and its coupling with
upper airway control and states of consciousness
and applying these principles to human patients
during sleep.
We will discuss the pathophysiology of OSA
in three steps. First we detail the varied structural
and functional determinants of an anatomical
predisposition for airway closure, an absolutely
essential component for OSA.The second essential component is sleep. This section emphasizes
the effects of the sleeping state on mechanisms
underlying both obstructive and central apnea
and ventilatory instability. Finally, we attempt to
integrate anatomical decits with mechanisms
underlying central neurochemical control of
breathing stability and compensatory neuromuscular control of upper airway caliber, to explain
the repetitive nature of OSA.
293
nsor palatini
Levator palatini
s
Genu of mandible
Geniohyoid
Hyoid bone
yrohyoid
Thyroid cartilage
Fig. 24.1 Anatomy of the upper airway and the important muscles controlling the airway patency
Nasophar
Velopharynx
Oropharynx
Hypophar
palate to the tip of the uvula), oropharynx (from
the tip of the uvula to the tip of the epiglottis),
and hypopharynx (from the tip of the epiglottis to
the level of the vocal cords) (Fig. 24.1). The
human pharynx can be considered as a collapsible tube that is uniquely susceptible to collapse
due to the presence of a oating hyoid bone, a
longer airway, and a less direct route for inspired
air to travel when compared to other mammals.
The presence of soft tissues and bony structures,
which increase extraluminal tissue pressures surrounding the upper airway, can predispose the
pharynx to collapse. In contrast, the actions of
pharyngeal dilator muscles maintain pharyngeal
patency due to reex pathways from the central
nervous system and within the pharynx. The
presence of these opposing forces suggest that
increased pharyngeal collapsibility is due to
alterations in anatomically imposed mechanical
loads and/or in dynamic neuromuscular responses
to upper airway obstruction during sleep [15].
24.1.2.1 Anatomical Determinants
ofUpper Airway inOSA
The pharyngeal airway is a complex structure
that serves several purposes, including speech,
swallowing, and respiration. The human pharynx
is composed of more than 20 muscles and divided
into four sections that include the nasopharynx
(from the nasal turbinates to the start of the soft
palate), velopharynx (from the start of the soft
Unique Anatomy oftheHuman Airway
The upper airway is a complex structure required
to perform deglutition, vocalization, and respiration. In the human, this structure must also perform tightly controlled and complex motor
behaviors required for speech. Upper airway
obstruction in sleep is most prevalent in the
human in part because the hyoid bone, a key
anchoring site for pharyngeal dilator muscles is
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K. Gunhan
not rigidly attached to skeletal structures [16]. In
other mammals, the hyoid bone is attached to the
styloid processes of the skull. Thus, the human
pharynx has no rigid support except at its extreme
upper and lower ends where it is anchored to
bone (upper) and cartilage (larynx); therefore,
pharyngeal cross-sectional area will vary with
lumen pressure. Humans depend critically on the
coordinated actions and interactions of over 20
skeletal muscles that dilate and stent open the
oropharynx.
Beyond the hyoid arch, it is also pointed to the
anatomical changes in the adult human upper airway during the evolutionary development of
speech as a potential major contributor to OSA
[17]. Specically, the gradual decent of the larynx to a position greatly inferior to the oropharynx separated the soft palate from the epiglottis
in which the tongue encroaches signicantly on
the available space.
Sites ofAirway Collapse
Studies using nasal pharyngoscopy, computed
tomography and magnetic resonance imaging, or
pharyngeal pressure monitoring have shown that
one or more sites within the oral pharyngeal
region are usually where closure occurs in most
subjects with OSA, and this region is also smaller
in OSA patients versus controls even during
wakefulness [18]. Although the retropalatal
region of the oropharynx is the most common site
of collapse, airway narrowing is a dynamic process, varying markedly among and within subjects and often includes the retroglossal and
hypopharyngeal areas [19].
Soft Tissue andBony Structure
Abnormalities
The recent use of quantitative imaging techniques
has allowed advances that reveal important differences in both craniofacial and upper airway
soft tissue structures in the OSA patient. The
reduced size of cranial bony structures in the
OSA patient include a reduced mandibular body
length, inferior positioned hyoid bone, and retro
position of the maxilla, all of which compromise
the pharyngeal airspace [20]. Airway length,
from the top of the hard palate to the base of the
epiglottis, is also increased in OSA patients, perhaps reecting the increased proportion of collapsible airway exposed to collapsing pressures
[21]. As expected, these craniofacial dimensions
are primarily inherited, as the relatives of OSA
patients demonstrated retroposed and short mandibles and inferiorly placed hyoid bones, longer
soft palates, wider uvulas, and higher narrower
hard palates than matched controls [22].
Enlargement of soft tissue structures both
within and surrounding the airway contributes
signicantly to pharyngeal airway narrowing in
most cases of OSA.An enlarged soft palate and
tongue would encroach on airway diameter in the
anterior-posterior plane, while the thickened pharyngeal walls would encroach in the lateral plane.
Volumetric time overlapped magnetic resonance
imaging (MRI) or computer tomography (CT)
images strongly implicate the thickness of the
lateral pharyngeal walls as a major site of airway
compromise, as the airway is narrowed primarily
in the lateral dimension in the majority of OSA
patients [22]. Furthermore, treatment with CPAP,
weight loss, or mandibular advancement all show
increases in the lateral pharyngeal dimensions
[22]. There are many potential causes of lateral
wall thickening in OSA patients. First, as shown
in both humans and rodent models, obesity is a
major contributor to airway compression through
increased area and volume of pharyngeal fat
deposits [23]. This excess fat deposition has also
been observed under the mandible and within the
tongue, soft palate, or uvula. Obesity also gives
rise to excess fat-free muscular tissue, thereby
increasing the size of many upper airway structures and compressing the lateral airway walls. In
children with OSA, tonsillar and adenoid hypertrophy form the major anatomical contributors to
airway narrowing [23].
Obesity andLung Volume
Obesity also contributes indirectly to upper airway narrowing, especially in the hypotonic airway present during sleep, because lung volumes
are markedly reduced by a combination of
increased abdominal fat mass and the recumbent
posture. In turn, the reduced lung volume reduces
the “tug” on the trachea induced by the traction
24 Pathophysiology ofObstructive Sleep Apnea
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295
exerted via mediastinal structures by negative
intrathoracic pressures and by the diaphragm
descent, thereby further increasing the thickness
of the lateral pharyngeal walls and narrowing the
airway [24].
Airway Edema andSurface Tension
Surface tension of the liquid lining the mucosa
affects collapsibility of the upper airway in the
same way as it has been well documented in the
lung’s airways [25]. A higher surface tension in
the upper airway wall of OSA patients has been
reported using a method that quanties surface
tension as the force required to separate two surfaces bridged by a droplet of the liquid under
study. Furthermore, in limited studies, surfactant
therapy in OSA patients was shown to signicantly reduce airway collapsibility and improve
apnea–hypopnea index (AHI) by 20–30% [26].
Obesity, Leptin, andInammation
Central, or visceral, obesity is associated with the
greatest risk for OSA [27]. This suggests that factors other than pure mechanical load may contribute
to the pathogenesis of respiratory disturbances during sleep. The concept is now emerging that visceral
fat depots, which represent a rich source of humoral
mediators and inammatory cytokines, can impact
on neural pathways associated with respiratory control [28]. Perhaps the most well-studied adipocytederived factor affecting respiratory control is leptin,
which was initially determined to have a primary
role of binding to receptors in the hypothalamus to
reduce satiety and increase metabolism. Leptin can
also act as a respiratory stimulant, and impairment
of the leptin signaling pathway, as occurs in leptinresistant or leptin-decient states of obesity, causes
respiratory depression in mice, and is associated
with obesity hypoventilation syndrome in humans
[29]. Even though obesity and OSA are associated
with elevated circulating levels of leptin, if centers
in the brain impacting on respiratory control act in a
similar leptin-resistant manner to hypothalamic
regions controlling appetite and metabolism, then
impaired leptin signaling in the CNS may contribute to respiratory depression as predicted in murine
studies [19].
In addition to respiratory control, animal studies show leptin is also critical in lung development and affects the distribution of muscle ber
types in the diaphragm. However, as yet there is
no direct evidence that impaired leptin signaling
can impact on the control of respiratory muscles
of the upper airway, although it may play a role in
nocturnal hypoventilation, particularly in REM
sleep where respiration is markedly depressed in
leptin-decient mice [19].
24.1.2.2 Mechanical Determinants
ofUpper Airway Patency
Mechanical determinants of airway caliber of the
human pharynx in sleep are similar to those regulating caliber of any collapsible tube [18]. Other
well-known biological examples in respiratory
physiology include intrathoracic airway collapse
upon forced exhalation, collapse of pulmonary
capillaries in the lung apex, and collapse of alae
nasi at high inspiratory ow rates. A Starling
resistor model developed by Schwartz and colleagues consists of a collapsible tube with a
sealed box interposed between two rigid segments [28, 30]. The critical closing pressure (P
)
crit
of the passive airway is dened as the pressure
inside the airway (Pin) at which the airway collapses. The pressure gradient during airow
through the system is dened by P
remains independent of P
with increasing P
P
and P
upstream
, as the differential between
crit
decreases, inspiratory airow
crit
downstream
, P
upstream
crit
. Therefore,
, and
limitation will eventually develop, and when the
Pus falls below P
, complete airway occlusion
crit
occurs (Fig. 24.2). Effective therapy for sleep
apnea requires that the Pus to P
pressure differ-
crit
ential be widened, and this can be accomplished
by either:
1. Increasing in Pus with appropriate amounts of
CPAP applied at the airway opening or
2. Decreasing P
via either reducing the col-
crit
lapsing pressures on the airway (e.g., weight
loss or alteration of cranial-facial anatomy or
increasing lung volume) or by augmenting
“active” neuromuscular control of airway
tone [30].
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Rigid tube
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Sealed box
Collapsible segment
P
in
Upstream
P
us
Fig. 24.2 Starling resistor model of obstructive sleep
apnea. In the Starling resistor model, the collapsible segment of the tube is bound by an upstream and downstream
segment with corresponding upstream pressure (Pus),
downstream pressure (Pds), and upstream resistance and
downstream resistance. Airway occlusion occurs when
the surrounding tissue pressure (P
ryngeal muscles and pharyngeal and submucosal fat,
mucosal edema, etc.) becomes greater than the intraluminal pressure (Pin), resulting in a transmural pressure of
zero. In this model of the upper airway, Pus is atmospheric
at the airway opening, and Pds is the tracheal pressure. The
critical closing pressure of the collapsible airway (P
represented by Pin. When the P
than Pus and Pds, ow through the tube occurs. When Pds
falls during inspiration below P
limitation occurs and is independent of further decreases
in Pds. Under this condition, the pharynx is in a state of
partial collapse, and maximal inspiratory airow varies
linearly as a function of the difference between Pus and
P
. Finally, when Pus falls below P
crit
completely occluded
P
out
out
is signicantly lower
crit
crit
crit
Downstream
P
ds
) (composed of pha-
) is
crit
, inspiratory airow
, the upper airway is
24.1.2.3 Neuromuscular Control
ofUpper Airway Dynamics
inSleep
Clearly the effects of airway anatomy on airway
collapsing pressure in a hypotonic airway are a
critical determinant of obstructive apnea.
However, several lines of evidence also support
neuromuscular factors as signicant determinants
of airway collapsibility in sleep. First, tonic and
phasic EMG activity of pharyngeal airway dilator
muscles (genioglossus and tensor palatine) is
progressively reduced from wakefulness to
NREM to REM sleep and further inhibited coincident with the “phasic” eye movement events in
REM [31]. This powerful effect of state has been
adequately documented in tracheostomized animal models and recently has been demonstrated
in OSA patients in whom the potentially confounding, compensatory responses to sleep-
K. Gunhan
induced changes in upper airway resistance,
negative pressure, PaCO2, and respiratory motor
output were controlled through the use of either
CPAP or positive pressure controlled mechanical
ventilation [32]. These state effects on the neuromuscular control of the upper airway likely
explain, along with reductions in lung volume
why P
is never positive in the waking state,
crit
even in OSA patients.
Second, neuromuscular factors also play a signicant role in the dynamic breath-to-breath and
intrabreath regulation of upper airway caliber,
through changes in proprioceptive and chemoreceptor feedback. During inspiration, the passive
pharynx narrows as intraluminal pressure is progressively reduced because of energy lost in
overcoming frictional airway resistance and
increases in ow velocity secondary to the
Bernoulli effect operating in a reduced lumen
size [18]. This collapsing effect of a reduced
luminal pressure is opposed during inspiration by
a reduction in dynamic compliance, i.e., collapsibility, of the airway achieved via reex activation of pharyngeal dilator muscles. In turn, the
reex activation occurs in response to negative
pressure airway mechanoreceptors located principally in the larynx and to a lesser extent in the
supercial layers of the pharyngeal wall, with
their afferent projections located in the superior
laryngeal nerve, and also in glossopharyngeal
and trigeminal nerves [11]. Large changes in negative pressure in the isolated upper airway trigger
a dual protective reex, which restores airway
patency by both activating airway dilators (to
reduce airway compliance) while inhibiting diaphragm EMG activity (which minimizes intraluminal negative pressure) (Fig. 24.3). Vagally
mediated feedback inuences on laryngeal,
tongue, and hyoid muscle via pulmonary stretch
receptors also protect against airway collapse as
the rate of lung ination is slowed in the face of
increased airway resistance, thereby reexly activating upper airway motor neurons.
Finally, chemoreceptor inuences also have
substantial effects on upper airway muscle
recruitment, and in the case of CO2, upper airway
motor neurons relative to phrenic motor neurons
have been shown to have a substantially higher
a
b
Genioglossus
Lung
volume
y-related activity
24 Pathophysiology ofObstructive Sleep Apnea
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297
sleep. One approach has been to model the upper
Diaphragm
airway as a collapsible tube (i.e., a Starling resistor) as mentioned above. The relationship of
pressure and ow through collapsible tubes has
been well dened in the pulmonary and systemic
circulation, the intrathoracic airways, and more
recently the upper airway. In the Starling resistor
model (Fig.24.2), the collapsible segment of the
tube is bound by an upstream and downstream
segment with the corresponding upstream pres-
Genioglossus
electromyogram
Inspiration
Respirator
Tonic activity
sure (Pus), downstream pressure (Pds), and
Fig. 24.3 (a) Contraction of the diaphragm and chest
wall muscles leads to the generation of subatmospheric
pressures in the thoracic cavity and airow into the lungs.
For effective lung ventilation, however, this airow must
pass through an open upper airspace. Activation of the
pharyngeal muscles, such as the genioglossus muscle of
the tongue, helps keep the upper airspace open for effective passage of air. Pharyngeal muscle activation acts to
enlarge the airspace. Importantly, reduced pharyngeal
muscle tone in sleep can reduce the size of the upper airspace and even promote complete airway obstruction.
This tendency for airway collapse is exacerbated by
increased weight of the tongue or neck (e.g., caused by
obesity), an already anatomically narrow upper airway
(e.g., caused by adenotonsillar hypertrophy), or the supine
sleeping position. (b) The pharyngeal muscles exhibit
respiratory-related activity superimposed upon a background of tonic activity. The background tonic muscle
tone contributes to baseline airway size and stiffness. The
increased pharyngeal muscle activity during inspiration
enlarges and further stiffens the airspace to resist the subatmospheric collapsing pressures generated during
inspiration
threshold for inhibition (via hypocapnia) and
activation (via hypercapnia) [33].
In summary, the evidence to date supports
important roles for both anatomical and neural
control of dilator muscles to the regulation of
upper airway caliber in the sleeping human. The
relative contributions of these factors will vary
widely among and within individuals with, for
example, patterns of fat deposition on the one
hand and neurochemical sensitivity for dilator
muscle recruitment on the other.
24.1.3 Measurements ofPharyngeal
Collapsibility
Quantitative measurements of mechanical and
neuromuscular contributions to pharyngeal collapsibility have been difcult to derive during
upstream resistance and downstream resistance.
Occlusion occurs when the surrounding pressure
(P
) becomes greater than the intraluminal pres-
crit
sure, resulting in a transmural pressure of zero. In
this model of the upper airway, Pus is atmospheric
pressure at the airway opening and Pds is the tracheal pressure. When the P
lower than the Pus and Pds (Pus>Pds>P
is signicantly
crit
), ow
crit
through the tube follows the principles of an
Ohmic resistor. When the Pds falls during inspiration below P
(Pus>P
crit
>Pds), inspiratory air-
crit
ow limitation occurs and is independent of
further decreases in Pds. Under this condition, the
pharynx is in a state of partial collapse and maximal inspiratory airow varies linearly as a function of the difference between the Pus and P
Finally, when the Pus falls below P
(P
>Pus>Pds), the upper airway is occluded.
crit
Operationally, P
in the human upper air-
crit
.
crit
crit
way is determined by lowering the nasal pressure until inspiratory airow ceases.
Measurements of P
have been shown to dene
crit
a spectrum of upper airway obstruction from
normal breathing (P
snoring (P
range, −10 to −5 cmH2O), to
crit
obstructive hypopneas (P
< −10 cm cmH2O), to
crit
range, −5 to
crit
0 cm cmH2O) and, nally, obstructive apneas
(P
> 0 cmH2O) during sleep [26]. Patients
crit
with the upper airway resistance syndrome
(UARS), an entity characterized by ow-limited
breathing that results in arousals, has been
shown to have P
levels that are between snor-
crit
ing and hypopneas [34]. (Gold, Marcus)
Depending on the methodology, measurements
of P
reect either the contributions of anatom-
crit
ically imposed mechanical loads on the upper
airway or dynamic neuromuscular responses
that maintain upper airway patency (Fig.24.4).
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Genioglossus
48
Diaphragm
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FLOW
Collapsible
segment
MAX
K. Gunhan
P
R
N
N
P
CRIT
(mL/s)
MAX
Flow
500
400
300
200
100
= 1/slope
R
N
P
CRIT
Airflow
Lungs
Fig. 24.4 Airow into the lungs is generated by contraction of the primary respiratory muscles (e.g., diaphragm
and intercostal muscles) and modulated by contraction of
the secondary respiratory muscles (e.g., genioglossus
muscle), which helps keep the upper airway open for
effective airow. The upper airway has been modeled as a
collapsible tube where maximum airow through the collapsible segment of the pharynx (FLOW
) is deter-
MAX
24.1.4 Contribution ofAnatomic
Factors toOSA
OSA is known to be associated with alterations in
upper airway anatomy. Structural changes,
including tonsillar hypertrophy, retrognathia, and
variations in craniofacial structures, have been
linked to an increased risk of sleep apnea, presumably by increasing upper airway collapsibility [17, 35, 36]. Ethnic differences in craniofacial
features are one potential mechanistic explanation for observed differences in OSA prevalence
and severity for a given level of obesity [35].
During wakefulness, CT and MRI studies have
demonstrated increased fatty tissue deposition
and submucosal edema in the lateral walls of the
pharynx, both of which narrow the pharyngeal
lumen and may predispose to obstruction during
sleep [37].
Based on the presence of upper airway anatomic alterations in OSA patients, it has been
proposed that structural or mechanical alterations are a primary determinant of upper airway
obstruction during sleep [10]. Recent data suggest that structural alterations in the lateral pha-
0
0
-4-8
(cmH2O)
P
N
mined by upstream nasal pressure (PN) and resistance
(RN). Airow ceases in the collapsible pharyngeal segment of the upper airway at a particular value of critical
pressure (P
way is determined by (PN−P
linear, and experimentally induced decreases in PN
decrease FLOW
collapse
). Maximum airow through the upper air-
CRIT
and ultimately elicit complete airway
MAX
)/RN. This relationship is
CRIT
ryngeal walls and tongue aggregate on a familial
basis, suggesting genetic susceptibility to OSA
[38]. In addition, experimental data in the
absence of neuromuscular activity demonstrate a
reduction in maximal pharyngeal area and elevated P
in OSA subjects compared with nor-
crit
mal subjects [30]. Furthermore, obesity, jaw
position, acromegaly, tonsillar hypertrophy, and
a smaller bony enclosure surrounding the pharynx have been demonstrated to predispose
toward pharyngeal collapsibility [10]. These
studies imply that upper airway structural differences distinguish OSA patients from normal
subjects, and may predispose to upper airway
obstruction when protective neuromuscular
mechanisms wane at sleep onset [39].
Obesity, the major risk factor for OSA, has
been linked with elevations in neck circumference and increased amounts of peripharyngeal
fat, which could narrow and compress the upper
airway [40]. Furthermore, increased parapharyngeal fat has been correlated with increased sleep
apnea severity [27]. The compressive effects of
fatty tissue deposited around the pharynx may
increase upper airway collapsibility, and possibly
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299
offset the effects of dilator muscles that maintain
airway patency. Obesity may also increase pharyngeal collapsibility through reductions in lung
volumes, particularly decreases in functional
residual capacity, which are accentuated with the
onset of sleep. Reductions in function residual
capacity may increase pharyngeal collapsibility
through reductions in tracheal traction on the
pharyngeal segment. Conversely, increases in
lung volumes result in increased tracheal traction
and stabilize the upper airway during inspiration
[41]. In OSA patients, increases in lung volumes
have been shown to decrease continuous positive
airway pressure (CPAP) requirements and OSA
severity, suggesting corresponding improvements in pharyngeal collapsibility [42, 43].
24.1.5 Contribution
ofNeuromuscular Factors
toOSA
It should be noted, however, that anatomically
imposed mechanical loads on the upper airway
might not be sufcient to produce pharyngeal
collapse during sleep. For example, women have
been shown to have a smaller pharynx and oropharyngeal junction than men, despite having a
lower prevalence of OSA [17]. Furthermore,
measurements of P
neuromuscular activity, which reect upper airway mechanical loads, demonstrate signicant
overlap between OSA and normal subjects [44].
Thus, nonstructural (i.e., neuromuscular) factors
must also play a role in protecting the upper airway. In fact, changes in upper airway neuromuscular activity during sleep were originally
described by Remmers etal., who demonstrated
that genioglossal electromyogram (EMGGG)
activity was reduced at apnea onset and increased
with arousal when airway patency was restored
[7, 45]. Subsequently, it was recognized that
upper airway obstruction could trigger a variety
of neuromuscular responses that restore upper
airway patency by recruiting muscles that dilate
and elongate the airway. Various pharyngeal
muscle groups are important in stabilizing the
upper airway throughout the respiratory cycle
under conditions of low
crit
(tonic activity, e.g., tensor palatini) and in dilating the airway during inspiration (phasic activity,
e.g., genioglossus). Pharyngeal motor output is
modulated by a number of factors that include
wake vs sleep state-dependent mechanisms, local
mechanoreceptor responses to negative pressure,
and ventilatory control mechanisms.
In OSA patients during wakefulness, elevated genioglossal and tensor palatini muscle
activity have been observed and are signicantly
lowered with the application of positive nasal
pressure [46]. In contrast, normal subjects had
lower levels of genioglossal and tensor palatini
muscle activity that were not further reduced
when positive nasal pressure was applied. These
observations suggested that increased upper airway dilator muscle activity compensates for a
more anatomically narrow upper airway in the
OSA patient. Thus, reductions in upper airway
muscle activity with sleep onset through serotonergic, cholinergic, noradrenergic, and histaminergic pathways may lead to upper airway
obstruction and have been hypothesized to be
due to the loss of a “wakefulness stimulus” that
may be greater in OSA patients than in healthy
control subjects [46].
Pressure-sensing mechanisms play a prominent role in modulating upper airway neuromuscular activity during wakefulness and sleep. A
negative pressure reex within the upper airway
serves to stabilize the upper airway during inspiration. At least three lines of evidence suggest
that the negative pressure reex is primarily
mediated by mechanoreceptors within the pharynx. First, there is a tight relationship between
EMGGG and pharyngeal pressure independent
of the central respiratory pattern generator within
the brainstem [47]. Second, topical anesthesia to
the pharyngeal mucosa attenuates the relationship between genioglossal muscle activity and
pharyngeal pressure with an increased number of
obstructive apneas and hypopneas during sleep in
normal subjects and loud snorers, and/or
increased duration of apneic episodes [48]. Third,
marked decreases in EMGGG activity with corresponding increases in pharyngeal collapsibility
have been observed in patients when breathing
through a tracheostomy compared to nasal
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K. Gunhan
breathing suggesting that negative pressure
within the pharynx during inspiration stabilizes
upper airway patency [11].
It is possible that OSA results from trauma to
the upper airway due to repetitive collapsing and
opening of the upper airway over time, resulting
in muscle and neuronal ber injury. Upper airway sensory pathways may be impaired in OSA
patients because temperature, two-point discrimination, and vibratory thresholds are disrupted in
OSA patients compared to normal individuals
[6]. Sensory receptor dysfunction could attenuate
the response of upper airway dilator muscles to
the markedly negative airway pressures generated during periods of upper airway obstruction.
Further evidence for sensorimotor dysfunction
and an upper airway myopathy is provided by
graded histopathologic and immunochemical
alterations in the palatopharyngeus and muscularis uvulae in OSA patients, relative to asymptomatic snorers and normal subjects [10, 16]. The
extent to which such mechanisms are important
in the pathogenesis of OSA, however, remains to
be established.
24.1.6 Contribution
ofNeuroventilatory Factors
toOSA
Ventilatory control mechanisms may also play a
role in modulating pharyngeal collapsibility
during sleep. Preactivation of the pharyngeal
dilator muscles stabilizes the upper airway
prior to the inow of air and suggests CNS
coordination between the upper airway and diaphragm. The CNS is inuenced by central and
peripheral chemoreceptors with conditions of
hypercapnia and hypoxemia increasing central
drive to the upper airway and decreasing pharyngeal collapsibility [49]. Increased hypercapnic
ventilatory responses, prolonged circulatory
times, or low oxygen stores within the body can
result in ventilatory instability that leads to the
development of periodic breathing [50]. Sleep
also unmasks a highly sensitive apneic threshold
(the PaCO2 level below which an apnea occurs)
that remains within 1–2 mmHg of the normal
waking eupneic PaCO2 level. Therefore, a brisk
ventilatory response as seen during an arousal in
the susceptible individual can result in hypocapnia that is near or at the sleeping apneic threshold
and result in a hypopnea or apnea with the reinitiation of sleep [11]. In fact, measurements of
loop gain, a measure of ventilatory control instability, have been demonstrated to be high in
patients with more severe OSA compared to
patients with mild OSA [14, 51]. In contrast, during periods of ventilatory instability, individuals
with low levels of mechanical loads on the upper
airway appear to be resistant to the development
of upper airway obstruction [52].
Nevertheless, whether alteration of loop gain
is important in the pathogenesis of upper airway obstruction or is a consequence of OSA
has not been established. OSA can develop in
normal subjects with the application of negative nasal pressure to the upper airway (lowering the Pus near or below the P
level seen in
crit
normal subjects), which reduces the transmural
pressure across the upper airway to near or
below zero, and results in upper airway obstruction with recurrent obstructive hypopneas and/
or apneas [53].
24.1.7 Interaction ofAnatomic
andNeuromuscular Factors
onPharyngeal Collapsibility
It is likely that a combination of upper airway
mechanical loads and disturbances in neuromuscular mechanisms accounts for the pathogenesis
of OSA.For example, in a group of OSA subjects,
one third of the variability in OSA severity was
ascribed to mechanical loads, suggesting that neuromuscular mechanisms accounted for the
remaining two thirds [54]. Using techniques to
partition the relative contribution of mechanical
and neuromuscular factors toward pharyngeal
collapsibility, it has been shown that OSA patients
during sleep have both an increased mechanical
load on the upper airway (passive P
impaired neuromuscular responses to upper airway obstruction (active P
Fig.24.4, a P
of approximately −5cmH2O rep-
crit
). As demonstrated in
crit
) and
crit
a
eness
24 Pathophysiology ofObstructive Sleep Apnea
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301
resents the disease threshold, above which
obstructive hypopneas and apneas occur [55]. In
normal subjects, when mechanical loads on the
upper airway lowered the P
below the disease
crit
threshold, OSA is not present. In contrast, subgroups of normal subjects elevate mechanical
loads that raised the P
above the disease thresh-
crit
old and placed them at risk of OSA, but are pro-
tected through the recruitment of neuromuscular
responses that lowered the P
below the disease
crit
threshold. The development of OSA requires a
“two-hit” defect, with defects in both upper airway mechanical and neuromuscular responses.
The summary of the above mentioned mechanisms are briey shown in two schemes below
(Fig.24.5a, b).
Obstructive
apnea
≠ Surface tension
Airway
narrowing or
collaps
Ø UA dilatatory
muscle activity
Ø UA dilatatory muscle
responsiveness
Ø Arousal threshold
Respiratory
effort
Hypoventilation
≠ UA resistance
Ø Chemosensitivity
Ø UA dilatatory muscle
activity/responsiveness
Ø Lung volume
Return to sleep
Fig. 24.5 (a) A scheme of the protective or benecence
(outside the circle) and unfavorable (inside the circle)
physiologic process that are related to the pathophysiological sequences developing in OSA. (b) A stepwise scheme
of the various pathophysiological events (inside the circle)
predisposing or aggravating the clinical ndings in the
course of OSA.Some of these events are related to each
Ø CO
≠ O
2
2
Arousal
≠ UA dilatatory muscle
activity/responsiv
Rapid reopening of UA
Hyperventilation
other, such as increasing loop gain, may decrease the
upper airway dilatory muscle activity, hence increasing
the respiratory response to arousal and prone to cyclic respiration. Dotted lines determine the potential management
approach to the current event. UA upper airway, CPAP
continuous positive airway pressure, ODD oral dental
device
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K. Gunhan
b
CPAP/ODD
Hypoventilation
Surfacant
Airway
narrowing or
collaps
Ø UA patency
Ø UA dilatatory muscle
activity/responsiveness
Ø Lung volume
Obstructive
apnea
≠ Surface tension
Respiratory effort
or Ø PO
Ø UA dilatatory muscle
responsiveness
Ø Arousal threshold
≠ PCO
2
Arousal
≠ Arousal threshold
Neuromusclar compensation
2
Return to sleep
≠ Loop gain
Fig. 24.5 (continued)
24.2 Conclusion
Obstructive sleep apnea is a common sleep disorder that can present in a variety of ways. With a
fundamental understanding of the pathophysiology of OSA, the physician can routinely integrate
questions into their review of system that will
assist in appropriate referral for polysomnography and diagnosis of the disorder. Knowledge of
common patterns of OSA may help identify
patients and guide therapy.
The pharyngeal muscles are essential for
effective lung ventilation because they help
maintain an open upper airspace for the unhindered passage of air into the lungs. Sleep, especially rapid eye movement sleep, however, causes
fundamental modications of pharyngeal muscle
Hyperventilation
tone and reex responses that in normal individuals lead to airway narrowing and hypoventilation.
In individuals with already anatomically narrow
upper airways, these effects of sleep predispose
them to inspiratory ow limitation (hypopneas),
airway closure, and OSA. Obstructive sleep
apnea is a common disorder, which is associated
with serious clinical, social, and economic
consequences.
The primary defect is probably an anatomically small or collapsible pharyngeal airway, in
combination with a sleep-induced fall in upper
airway muscle activity. Current understanding of
the pathophysiologic basis of the disorder suggests that a balance of anatomically imposed
mechanical loads and compensatory neuromuscular responses are important in maintaining
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