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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 -4 -4
Bronchogenic carcinoma -6 -6
Lymphoma -8 -8
Other metastatic disease
Vascular FIGURE 50-3 Flow–volume curves: upper airway obstruction. A,
Right-sided aortic arch Normal flow–volume curve. B, Variable intrathoracic obstruction
Double aortic arch due to a tracheal tumor. C, Variable extrathoracic obstruction due
Innominate artery syndrome to a laryngeal tumor. D, Fixed upper airway obstruction due to
Aberrant left pulmonary artery large tracheal tumor. Solid line ⫽ air; dotted line ⫽ helium. Note the
Tracheal abnormalities improvement in both inspiratory and expiratory flow with helium.
Neuromuscular
Vocal cord dysfunction
Foreign body aspiration
Trauma
tool for the diagnosis of upper airway obstruction.26–35
Inhalation
Smoke/burn Examples of normal and pathologic flow–volume curves are
Chemical 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
common than obstructive disease of the lower airway, such lung volume decreases, flow becomes effort-independent
as asthma or chronic obstructive pulmonary disease and determined by the balance between lung recoil and flow
(COPD). Unfortunately, the clinical presentation of the two resistance in progressively smaller airways. During forced
may be very similar (dyspnea and noisy breathing), so that inspiration, flow is effort dependent throughout, with the
the less common diagnosis of upper airway obstruction may peak value occurring at midinspiration. Peak expiratory
be missed if a careful clinical evaluation and appropriate flow rate is considerably larger than peak inspiratory flow
testing are not performed. A missed diagnosis, particularly rate because of the effects of lung elastic recoil. However, at
in the context of acute or severe upper airway obstruction, 50% of vital capacity, forced inspiratory flow (FIF50) is
may have devastating consequences for the patient as somewhat greater than forced expiratory flow (FEF50), due
appropriate treatment may be delayed beyond the point of in part to normal expiratory dynamic compression of the
severe airway compromise and respiratory arrest. airways. Thus, the normal FIF50/FEF50 ratio is slightly
A hallmark clinical feature of upper airway obstruction is greater than 1.
dyspnea with stridor, a loud, constant-pitch inspiratory Obstructing lesions of the upper airways may be either
sound that indicates obstruction of the extrathoracic airway. fixed or variable; that is, lesions produce narrowing that
Severe extrathoracic or variable intrathoracic large airway varies with pressures acting across the airways during inspi-
obstruction may also cause expiratory prolongation and a ration and expiration (Figure 50-4). In the case of variable
wheeze-like sound, making it difficult to distinguish from intrathoracic large airway obstruction (see Figure 50-3B),
disease of the lower airways. Other symptoms associated during expiration, pleural pressure is more positive than
with upper airway obstruction include cough, hoarseness, intratracheal pressure, leading to dynamic compression of
dysphagia, and orthopnea, depending upon the location and the airway and thereby increased airway narrowing and
nature of the obstructing lesion. Although it is beyond the reduced expiratory flow. However, during inspiration, there
scope of this chapter to provide an exhaustive description of is a net distending pressure across the large airway, so that
causes of upper airway obstruction, a list of common patency of the lumen tends to increase, yielding a relative
pathologies is provided in Table 50-1. preservation of inspiratory flow rate. The FIF50/FEF50 ratio
will therefore be well above 1, typically in the range of 2 to 3.
PHYSIOLOGIC TESTING FOR UPPER AIRWAY In the case of variable extrathoracic upper airway
OBSTRUCTION obstruction (see Figure 50-3C), the pressure surrounding
Forced expiratory and inspiratory spirometry with recording the airway is atmospheric, so that during inspiration, there
of the flow–volume curve is the most important physiologic is a net negative transmural pressure, which tends to worsen
Physiology of the Upper Airway and Upper Airway Obstruction in Disease 585
Ptr < Patm Ptr < Patm and increased breath sounds can be heard during both
0 – 0 0
+ 0 inspiration and expiration, again due to turbulent flow
– + resulting from fixed airway obstruction.
– – – + + + Turbulence due to airway narrowing can be reduced by
Ppl < Ptr Ppl < Ptr 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-
Inspiration Expiration tion of an increase with helium of more than 50% in either
peak expiratory or inspiratory flow.34 Heliox administration
FIGURE 50-4 Forces acting across the airways that determine is also a useful, albeit temporary, therapeutic adjunct in the
spirographic patterns in cases of variable intrathoracic and extra-
clinical management of upper airway obstruction.
thoracic upper airway obstruction. Patm ⫽ atmospheric pressure;
Ppl ⫽ pleural pressure; Ptr ⫽ tracheal pressure. 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
airway narrowing and reduce inspiratory flow. In contrast, prominent when the patient is supine. Airway obstruction
during expiration, the positive pressure within the airway can worsen with the chest wall relaxation that occurs on the
produces a transmural distending pressure and reduces the induction of anesthesia, so that preoperative and postopera-
extent of narrowing, resulting in increased expiratory rela- tive airway management in such patients requires careful
tive to inspiratory flow. Thus, the FIF50/FEF50 ratio will be attention. The positional variation of large airway obstruc-
less than 1. tion can be evaluated by assessing changes in peak flow rates
The anatomy of many upper airway lesions, however, during seated versus supine spirometry.36
is such that the degree of obstruction is not materially In the context of acute, severe extrathoracic upper air-
influenced by the pressures acting across the airway, with way obstruction (eg, epiglottitis, foreign body aspiration, or
resultant comparable reductions in both inspiratory and acute laryngeal injury), inspiratory intrathoracic driving
expiratory flow (see Figure 50-3D). In this case, the FIF50/ pressures may become extremely negative, and this, in turn,
FEF50 ratio may be close to 1. may lead to the development of “negative-pressure pul-
From Figure 50-3, it can be seen that inspection of the monary edema.”37,38 This is believed to be due to a combi-
flow–volume curve and recognition of the characteristic nation of increased venous return leading to increased
changes in pattern are crucial to the recognition of upper pulmonary blood volume and negative pericapillary intersti-
airway obstruction. It is important to emphasize that one tial tissue pressure caused by large negative intrapleural
cannot rely solely upon tabular data from simple spirometry pressures, resulting in forces that favor fluid transudation
to exclude the diagnosis of upper airway obstruction. into the interstitium. In some patients, left ventricular
Because flow in the medium and small airways contributes (LV) dysfunction is believed to also contribute because
significantly to forced expiratory volume in 1 second of increased LV wall transmural pressure, that is, afterload,
(FEV1), substantial large airway obstruction may be present resulting from the negative intrapleural pressure. Manage-
before significant changes in FEV1 occur. When concomi- ment of this condition primarily involves management of
tant airway disease, such as COPD, is present, the sensitiv- the upper airway obstruction.
ity of spirometry for the detection of upper airway
obstructing lesions is even lower. Peak expiratory flow rate PATHOPHYSIOLOGY OF UPPER AIRWAY
is much more sensitive for the presence of expiratory large COLLAPSE DURING SLEEP: OBSTRUCTIVE
airway obstruction, and a hallmark finding in tabular data is SLEEP APNEA
a reduction in peak expiratory flow rate (as percent pre-
dicted) that is out of proportion to other changes in flow CLINICAL DESCRIPTION
rates, particularly FEV1. However, assessment of the inspira- OSA is characterized by repeated episodes of upper airway
tory flow pattern is also crucial. obstruction during sleep. This important condition is highly
The characteristic flattening of the flow–volume curve in prevalent in the adult population, being estimated to affect
upper airway obstruction reflects the presence of pathologic 2 to 9% of women and 4 to 15% of men, depending on
flow limitation. Flow limitation is defined as a state in which the precise definitions used and the population under
increasing effort does not result in increasing airflow. Thus, study.39,40 OSA also occurs in the pediatric age group,
flow is reduced and constant over a range of lung volumes, although with considerably lower prevalence. OSA is associ-
producing the flattened shape of the curves depicted in ated with considerable morbidity, increased health care
Figure 50-3. The turbulent flow occurring in the context of resource utilization, and, probably, increased mortal-
a high driving pressure during inspiration is responsible for ity.12,13,40–42 Apneic episodes are characterized by upper air-
producing the sound of stridor in extrathoracic airway way closure and progressively increasing respiratory efforts
obstruction. As noted above, intrathoracic obstruction can driven by chemoreceptor and mechanoreceptor stimuli,
result in prolonged expiratory flow and low-pitched wheeze, which then provoke arousal from sleep and reopening of the
586 Sleep Disordered Breathing
airway. These events result in sleep fragmentation, repetitive with an oronasal thermistor or through nasal pressure
hypoxemia, and swings in heart rate, blood pressure, and (currently the method of choice), determination of respira-
cardiac output, which are responsible for the clinical seque- tory effort with inductance plethysmography, piezoelectric
lae of OSA. The latter include excessive daytime sleepiness, sensors or mercury strain gauges around the thorax and
impaired concentration, cognitive functions and memory, abdomen or with an esophageal balloon (typically reserved
and mood disturbances. There is a rapidly growing body of for research studies or special clinical cases), determination
data linking OSA to increased cardiovascular risk, including of body position with mercury switch or video recording,
hypertension, cardiac ischemic events, arrhythmia, cere- recording of sound (snoring) with a microphone, and
brovascular accidents, congestive heart failure, and pul- detection of periodic limb movements with leg electromyo-
monary hypertension. Severe OSA can also be associated graphic electrodes. A typical polysomnographic tracing from
with changes in ventilatory control and hypoventilation a patient with severe OSA is shown in Figure 50-5.
during wakefulness, typically in the context of underlying The raw data tracings from the sleep study are scored by a
lung dysfunction. There is also growing evidence of a link technologist to identify sleep–wake state for each consecutive
between OSA and asthma. These issues are discussed further 30-second period (epoch) of the night, according to standard
below and in a subsequent chapter. criteria.43 The respiratory signals are scored to identify apneas
OSA should be suspected clinically in patients with a (⬎10 seconds of complete cessation of airflow) and hypop-
history of heavy habitual snoring and excessive daytime neas (event lasting ⬎10 seconds, with reduced airflow associ-
sleepiness. Sleep testing is performed to establish the ated with oxygen desaturation and/or brief arousal from
diagnosis. The current “gold standard” test is complete sleep), and whether these are obstructive or central in nature
overnight polysomnography performed in a sleep laboratory. (associated or not with ongoing respiratory effort during
This test involves recording of the electroencephalogram, events).44 Summary data are generated in both tabular and
electrooculogram and submental electromyogram for graphic form to describe the physiology of sleep, breathing,
sleep–wake staging, pulse oximetry, determination of airflow and other events through the night (Figure 50-6). Although
OC
OC
EMG
C4-A1
C3-A2 Arc
EKG
LEGS + 100.0
+ 90.0
+ 80.0
SaO2
Flow
Chest(respitrace)
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
Ap C
Hp C
Ap M
with airflow and respiratory effort channels, to establish the
Ap O diagnosis.
Hp O
UAWR
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
Prone
Left
broad conception of OSA pathophysiology is that upper air-
Right
Upright
Out of Bed
way anatomic dimensions are reduced in affected patients,
21:00 22:00 23:00 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
FIGURE 50-6 Composite hypnogram from a patient with severe
obstructive sleep apnea and hypopnea. Individual apneas and maintain airway patency, but at sleep onset, when upper
hypopneas are indicated by vertical bars on the “Respiratory” airway tonic and phasic activity are reduced and protective
graph. The patient was awake from 1:45 am to 3:15 am, so that reflexes are inhibited, airway closure supervenes.12,13,42
no respiratory disturbance occurred during that time. Note that The evidence supporting these concepts, as well as other
in this patient the severity of respiratory disturbance is influenced potential factors contributing to the pathophysiology of
by sleep stage and body position. Oxygen desaturation is more
severe during rapid eye movement (REM) than during non- OSA, is considered in the following sections. A schematic of
REM sleep, in part due to increased length of events related to the mechanisms contributing to upper airway collapse dur-
increased arousal threshold during REM. During stage 2, non- ing sleep is shown in Figure 50-7.
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- Upper Airway Anatomy in OSA Upper airway collapse dur-
way caliber. This results in positional effects on event-associated ing sleep in OSA occurs predominantly in the retropalatal and
oxygen desaturation. retroglossal airway, that is, the velopharynx and oropharynx.
There is abundant evidence that the airway dimensions are course of obstructive apnea. These reductions in lung
reduced in OSA patients in comparison with normal control volume would therefore contribute to reduced upper airway
subjects. Techniques that have been used to study airway caliber, further increasing the predisposition to collapse.
size include cephalometry, fluoroscopy, acoustic reflection,
videoendoscopy, computed tomography, and magnetic Mechanical Properties of the Upper Airway The cross-
resonance imaging (MRI). The accumulated data indicate sectional area of the pharynx is determined by the interac-
that both reductions in the dimensions of the bony cranio- tion between the mechanical characteristics of this
facial framework and increases in the size of soft tissue structure, that is, compliance of the wall, and the transmural
structures surrounding the airway may contribute to pressure.12,13 The passive mechanical properties of the upper
reduced airway dimensions. Alterations in craniofacial airway in OSA have received considerable attention.
proportions that have been described include reduced Schwartz and colleagues54,55 have modeled the upper airway
length of the mandibular ramus, inferior positioning of as a Starling resistor and produced an extensive literature
the hyoid bone, and retroposition of the maxilla.45 In addi- assessing the collapsibility of the pharyngeal airway under
tion to circumferential narrowing, increased airway length passive conditions. This typically involves the application
may also be a factor. Increased distance between the hyoid of a range of positive and negative airway pressures, with
bone and the mandibular plane found in cephalometric extrapolation from steady-state pressure–flow relationships
studies and increased airway length found in a recent MRI to determine the pressure associated with airway closure, or
modeling analysis appear to be associated with an increased critical pressure, Pcrit. During sleep, Pcrit values are about
likelihood of upper airway collapse.46 ⫺13 cm H2O in normal subjects, about ⫺6 cm H2O in snor-
Increases in soft tissue dimensions that have been found ers, and about ⫺2 cm H2O in patients with predominantly
in imaging studies include enlargement of the soft palate, obstructive hypopnea; in apneic patients, the upper airway
tongue, parapharyngeal fat pads, and lateral pharyngeal closing pressure is positive, often in the range ⫹10 to
walls. These increases contribute to anatomic narrowing ⫹15 cm H2O. Isono and colleagues56 have studied the
and may also contribute to increased tissue pressure, which static properties of the human pharynx under conditions
favors airway collapse. The increased tissue volume proba- of general anesthesia and muscle paralysis. These authors
bly reflects changes that also affect mechanical characteris- found that for OSA versus control subjects, the average and
tics of the tissues, leading to altered airway biomechanics maximal velopharyngeal cross-sectional areas were smaller,
(see below). Several mechanisms appear to contribute to closing pressures were higher, and area–pressure compliance
these soft tissue changes. Upper airway edema has been curves were shifted down and to the right, indicative of
found clinically, histologically, and by MRI scanning.47–49 increased collapsibility. Other authors have also shown
This may result from upper airway trauma during obstruc- reduced distensibility of the upper airway in OSA.
tive events, hypoxemia, systemic inflammation, or a combi- Collectively, these data point to the presence of a smaller,
nation of factors. Mucosal edema improves with nasal more collapsible, and less distensible, that is, less compliant,
continuous positive airway pressure (CPAP) treatment of airway in OSA.
OSA.48 Increased deposition of fat in the upper airway in During active breathing, the transmural pressure across
obese patients contributes to narrowing, particularly in the the pharynx is another major determinant of cross-sectional
region of the parapharyngeal fat pads, but elsewhere in the area. The transmural pressure is determined by the balance
upper airway as well.45 Weight gain is also associated with between the intraluminal pressure, which is negative during
increased amounts of fat-free tissue, some of which is mus- inspiration, and the extraluminal or tissue pressure. The
cle, such that obesity may contribute to increased upper air- latter is determined by the volume and mechanical charac-
way muscle mass. The latter may also be due to loading with teristics of tissues surrounding the airways and by the level
hypertrophy or muscle injury and edema, which is discussed of activation of surrounding constrictor and dilator muscles.
further below. Genetic factors probably also play a role in Muscle activation will be considered in the following
determining soft-tissue volume, in a manner analogous to section. No direct measurements have been made of inter-
craniofacial structure. stitial tissue pressure in humans, although measurements
in anesthetized pigs showed positive extraluminal pressures
Lung Volume Effects on Upper Airway Size Studies in that correlated with airway obstructive events. The occur-
both humans and animals have shown that upper airway rence of airway collapse under passive conditions without
caliber is influenced by changes in lung volume, such that negative intraluminal pressure54,55 suggests that positive
decreased lung volume is associated with decreased upper tissue pressures probably also exist in humans.
airway dimensions and increased airflow resistance.50–52 Surface tension contributes to pharyngeal collapsi-
This appears to be due to effects of tracheal tug on upper air- bility.12,57,58 This may be particularly important at the point
way length and/or wall characteristics.51,52 OSA patients where generation of an opening pressure is required to
appear to have greater lung volume dependence of upper separate mucosal surfaces that have come into contact
airway caliber than normal subjects.53 Assumption of during complete airway collapse. However, surface forces
the recumbent position is associated with reduced end- will also influence the distensibility of the rounded pha-
expiratory lung volume, and obese patients have particularly ryngeal structure throughout the respiratory cycle. Upper
marked reductions in supine functional residual capacity. airway surface lining fluid from OSA subjects shows
Furthermore, lung volume may also decrease during the increased surface tension in comparison with that of fluid
Physiology of the Upper Airway and Upper Airway Obstruction in Disease 589
from control subjects.58 Topical application of artificial muscles in OSA versus control subjects. Furthermore, even
surfactant renders the upper airway less collapsible and in normal individuals, there is a decrease in the activity of
can produce reductions in the severity of obstructive events this reflex at sleep onset. Thus, an important modulating
during sleep in OSA patients.57 influence on upper airway caliber is attenuated during sleep,
and this is believed to predispose to upper airway collapse.
Neural Control of Pharyngeal Motor Activity As dis- The afferent inputs to the negative pressure reflex arise
cussed earlier in this chapter, the tonic and phasic activation from the mucosa of the oropharynx and larynx.66–68 The
of dilatory musculature surrounding the pharyngeal airway importance of mucosal afferents to upper airway motor con-
is critical to the prevention of airway collapse as negative trol has been demonstrated in studies involving topical
intraluminal pressure during inspiration causes a decrease in application of anesthetic to interfere with mucosal sensory
transmural pressure. Results from several groups have indi- receptor activity. Topical upper airway anesthesia leads to
cated that the activity of upper airway dilators is greater in reduced dilator muscle activity and increased pharyngeal
OSA patients than in normal subjects, and this is believed to airflow resistance during wakefulness and sleep and can
represent a compensatory mechanism for the inherent induce apnea and hypopnea in normal subjects, increase the
anatomic compromise of the airway in such patients.59,60 frequency of obstructive events in snorers, and lead to
There are several major inputs influencing the activation delayed end-apneic arousal and increased apnea duration in
of pharyngeal dilator muscles by the brainstem respiratory OSA subjects.67–69 Recently, we showed the presence of an
controller.13,61–63 As noted above, the normal integrated pat- impairment in mucosal mechanosensory function in the
tern of central respiratory output is such that there is preac- oropharynx of snorers and OSA patients, which partially
tivation of upper airway musculature before activation of the improved in OSA patients following CPAP treatment.67 The
lower pump muscles occurs.14,15 Perturbations in this pat- severity of oropharyngeal sensory impairment correlates
tern, with delayed activation of upper airway dilators in rela- with the latency of the palatoglossus and genioglossus
tion to chest wall and diaphragm activation, have been muscle reflex responses to pulses of negative pressure
reported in some patients with OSA, and this is believed to delivered to the upper airway, as described by Mortimore
contribute to upper airway instability.15 Central output to and Douglas.70 Therefore, the afferent neural impairment
upper airway motor neurons is also influenced by chemo- appears to contribute to impaired dilator reflex responsive-
receptor stimulation, so that fluctuations in carbon dioxide ness, which probably has important implications for upper
level may destabilize output to the dilator muscles. airway function. Additional studies using endoscopic
Most important for sleep apnea, however, is the influence sensory testing have also demonstrated impaired laryngeal
of sleep-related decrements in pharyngeal motor output. sensation in OSA patients versus controls.68 Within the
Whereas the upper airway may be narrowed during wakeful- OSA group, there appeared to be two subgroups, one
ness in OSA, obstruction occurs only during sleep, empha- with normal sensation and another with abnormal sensa-
sizing the importance of state-dependent influences on tion, the severity of which correlated with the apnea–
upper airway control. Sleep onset in normal subjects is ini- hypopnea index. Thus, in some patients, an impairment
tially associated with reduced tonic and phasic activity of the of mucosal sensory function appears to contribute to
genioglossus, geniohyoid, and palatal muscles. However, OSA pathophysiology.
phasic muscle activity tends to recover as sleep is estab- Although the mechanisms underlying impaired upper
lished, whereas muscles with a predominantly tonic pattern airway sensation remain unclear, histologic studies have
of activation tend to show further losses of activity as sleep demonstrated neural changes consistent with injury and
deepens.13,42 It is therefore believed that reduced tonic acti- repair that could represent the basis for mucosal sen-
vation is an important factor contributing to upper airway sorineural dysfunction.49,68 An accumulating body of data
collapse. However, both phasic and tonic muscle activity points to the presence of significant cellular inflammation
may be potently inhibited during rapid eye movement in upper airway tissue.49,68 As noted above, this may be
(REM) sleep,64 accounting in part for the increased severity related to tissue injury resulting from vibration-associated
of OSA during REM versus non-REM sleep. A key observa- trauma, hypoxemia, or other factors, including the state
tion in OSA patients is that the fall in upper airway dilator of systemic inflammation, which has been associated with
electromyographic activity associated with sleep onset both OSA and obesity. Inflammatory mechanisms or
appears to be substantially greater than in controls.65 Thus, mechanical trauma may account for the neural injury
upper airway dilator activity is greater during wakefulness, observed in the upper airway mucosa, although further
representing a compensation for upper airway size and investigation is required to establish the precise mechanisms
mechanics, but appears to be lost at sleep onset. involved.
The activity of upper airway dilators is also modulated
by reflex inputs. The available evidence indicates that the Pharyngeal Muscle Function in OSA There is accumu-
most important local stimulus for activation of these mus- lating evidence that OSA is associated with changes in the
cles is intrapharyngeal negative pressure.13,66 Reflex activa- structure and function of the upper airway dilator muscles.
tion by pulses of negative pressure applied to the upper Some of these changes appear to be adaptive in nature,
airway has been described for the genioglossus, levator whereas others are more consistent with injury and may lead
palatini, and palatoglossus muscles. This negative pressure to impaired contractile function, thus contributing to upper
reflex is impaired for the levator palatini and palatoglossus airway dysfunction. As noted above, upper airway dilator
590 Sleep Disordered Breathing
activity is increased in OSA patients during wakefulness. of the muscle was the same in OSA patients and control
Whereas sleep-related decrements in upper airway muscle subjects when normalized for muscle cross-sectional area,
activity contribute to upper airway collapse, the termination but in a subsequent study, changes in the musculus uvulae
of obstructive events is associated with massive activation of muscle correlated with upper airway collapsibility. Patients
upper airway dilators, which, it should be noted, occurs with the most easily collapsible upper airway also showed
under hypoxic conditions. Thus, the evidence suggests that, the greatest increases in force production, type IIa fiber
overall, upper airway muscle activity is substantially prevalence, anaerobic metabolism, and susceptibility to
increased in OSA. This raises the possibility that these mus- muscle fatigue. Carrera and Barbé77 studied genioglossus
cles could undergo secondary changes as a direct conse- muscles from OSA patients and from controls; they also
quence of their increased activity level.71 Skeletal muscle is reported a shift to type II fiber type and specifically demon-
well recognized to alter its phenotype in order to adapt to strated increased fatigability of the genioglossus muscle in
the prevailing demands placed upon it, thereby maximizing OSA. Thus, even in the absence of morphologic injury,
muscle efficiency. Properties such as muscle fiber size, con- adaptive changes induced by the contraction history of
tractile protein isoform profile, and metabolic enzyme con- the upper airway muscles may also have adverse functional
tent can be readily modified, with resultant changes in consequences.
muscle performance. However, when excessive contractile In the discussion on pharyngeal motor control in the pre-
demands are placed upon muscle, it is well documented ceding section, it was noted that there is evidence for an
that the structural integrity of the muscle cell can be upper airway afferent neuropathy in OSA, based on both
physically disrupted by the forces produced during muscle sensory testing data and pathologic findings. There is evi-
contraction. This activity-induced injury is particularly dence to suggest that there may, in fact, be a more diffuse
prominent when the forces opposing muscle contraction upper airway neuropathy in OSA that also affects efferent
result in muscle lengthening during activation, or so-called nerves and may lead to muscle denervation. Woodson and
eccentric contraction.71,72 colleagues47 reported demyelination in upper airway tissue
Eccentric contractions of upper airway dilator muscles specimens. Histologic evidence of motor denervation, such
have been demonstrated during airway occlusion and as fiber type grouping and grouped atrophy, has also been
progressive hypercapnia in anesthetized cats.73 Because found in several recent studies.50,78 In a recent study of
similar events occur in human OSA, it has been hypothe- human upper airway surgical specimens from OSA and con-
sized that eccentric contractions also occur in pharyngeal trol subjects, we demonstrated increased nerve tissue prolif-
dilators in this condition,71 through at least two possi- eration within the muscle compartment, revealed by specific
ble mechanisms: (1) muscles that are mechanically linked antibody to neural tissue (PGP 9.5), and also found groups
could contract against one another, as has been demon- of myocytes expressing neural cell adhesion molecule, a
strated for the sternohyoid and geniohyoid muscles during sensitive marker of muscle denervation.49 These findings
airway occlusion in anesthetized animals, and (2) large suggest that denervation-related changes may contribute to
negative intraluminal pressures associated with pharyngeal upper airway muscle function in OSA.
obstruction, which could act to forcibly lengthen the oppos- As discussed above, the edema and inflammatory cell
ing dilator muscles.71,72 infiltration of the upper airway mucosa described by several
Petrof and colleagues,72 using the English bulldog, which groups suggest that inflammatory mechanisms may con-
suffers from OSA, found that the sternohyoid muscle, an tribute to upper airway dysfunction in OSA, leading, for
important upper airway dilator muscle, showed evidence of example, to neuropathic changes.49 In the study just cited
fiber-type shift but also changes consistent with activity- from the author’s laboratory,49 we demonstrated increased
induced muscle injury, consisting of abnormal fiber mor- inflammatory cell infiltration in OSA upper airway muscle.
phology (central nucleation, fissured and moth-eaten Furthermore, preliminary data from our laboratory have
appearance), inflammatory cell infiltrates, and increased revealed increased expression of tumor necrosis factor-␣ and
amounts of connective tissue. Muscle injury was also found interleukin-1␣ in muscle tissue from patients with severe
in the geniohyoid muscle, another pharyngeal dilator. A OSA versus those with mild OSA. It is now well established
subsequent MRI study using the bulldog model74 showed that cytokines can lead directly to muscle dysfunction.79
changes consistent with muscle edema or fibrosis in four of Thus, inflammatory changes in the upper airway may
five pharyngeal muscles examined. These changes were not alter muscle function directly by this means or conceivably
seen in limb muscles or in control animals. Thus, there is by contributing to neuropathy, which, in turn, may lead to
compelling evidence for muscle injury in this animal model muscle denervation. It is likely that muscle adaptation
of OSA. and injury are ongoing in a dynamic process in OSA, that
Studies on human OSA tissues have also shown evidence different muscle groups within the upper airway may be
of both adaptation and injury. Several smaller studies have affected differently, and that the extent of change and phys-
shown histologic changes consistent with injury.71 However, iologic consequences for muscle function may vary between
studies by Series and colleagues75,76 on the musculus uvulae OSA patients. Further work will be required to further elu-
muscle did not show pathologic evidence of injury but cidate the contribution of upper airway muscle denervation
demonstrated an increase in the proportion of fast-twitch and injury to the pathophysiology of this disorder, as well as
(type IIa) fibers and the activity of enzymes of anaerobic to determine whether muscle changes may represent a
metabolism in OSA patients. The force-generating capacity potential therapeutic target in OSA.
Physiology of the Upper Airway and Upper Airway Obstruction in Disease 591
OSA and Ventilatory Control There is a growing load compensation mechanisms in such patients and may
understanding of the effects of chemoreceptor sensitivity contribute to a “resetting” of the chemoreceptors, leading to
and ventilatory control instability on the pathogenesis of awake hypoventilation. Daytime blood gases typically
periodic breathing and central apnea.80,81 Differences in the improve dramatically or normalize following effective treat-
control of breathing between wakefulness and sleep (eg, the ment of OSA, supporting the concept that the nocturnal
higher ventilatory setpoint and ventilatory chemosensitivity respiratory disturbance leads to the development of awake
during wakefulness) lead to respiratory instability during hypoventilation.
the transition from wakefulness to sleep, accounting for
apneas and hypopneas, which may be seen at sleep onset in OSA and Asthma There is growing evidence of a link
normal subjects. Furthermore, recent work has shown that between OSA and asthma. In a recent study at McGill,88 26
ventilatory responses are heightened at the instant of arousal consecutive refractory asthmatic subjects were evaluated in
from sleep in comparison to stable wakefulness.62 Thus, comparison with 21 age-matched and gender-matched con-
instability of the sleep–wake state per se may destabilize trol subjects with moderate asthma. The prevalence of OSA
breathing. The state changes associated with apneas and in both groups was dramatically increased over population
hypopneas, that is, microarousal at the termination of normal values, with a tendency for OSA to be more preva-
events, followed by the rapid return to sleep, therefore lent among subjects with severe asthma (16/26, 62%) than
represent a situation of inherently unstable respiratory con- among those with moderate asthma (10/21, 48%) and for
trol. Numerous investigators have postulated that altered OSA to be somewhat more severe among the refractory
chemoreceptor sensitivity or instability of other respiratory asthma group. These findings, together with evidence from
control mechanisms may therefore contribute to the patho- other case series, suggest that OSA may contribute to wors-
genesis of OSA. An early observation in support of this ened asthma control. For example, Chan and colleagues89
hypothesis was the occurrence of periodic breathing during studied nine patients with severe asthma and snoring or
sleep immediately following tracheostomy for OSA.82 OSA who suffered frequent nocturnal asthma attacks despite
A large body of data has been generated concerning maximum bronchodilator therapy. CPAP treatment of upper
changes in classic chemoreceptor responses in OSA, airway obstruction during sleep improved asthma control,
although there have been rather inconsistent findings. Some as reflected in asthma symptoms, bronchodilator use, and
authors have reported heightened hypoxic sensitivity, which peak flow rates.
was postulated to contribute to respiratory instability, There are several mechanisms by which OSA and asthma
whereas others have reported blunted hypoxic sensitivity.83 could interact. There is evidence that stimulation of upper
Hypercapnic ventilatory responsiveness has been reported airway mechanoreceptors during snoring and apneas can
to be normal or decreased in OSA and, if reduced, may lead to reflex bronchoconstriction. Alternatively, gastro-
improve following treatment with nasal CPAP.83 esophageal reflux occurs frequently in OSA patients and is a
Recently, Younes and colleagues used proportional assist well-recognized exacerbating factor in asthma. Treatment of
ventilation (PAV) to evaluate ventilatory control stability in asthma with corticosteroids may contribute to OSA by
OSA patients.84 With the upper airway stabilized during increasing obesity and/or pharyngeal myopathy.90 Finally, as
sleep by nasal CPAP, increasing levels of PAV (controller noted above, there are considerable data documenting upper
gain) were applied up to the point at which periodic breath- airway inflammation in OSA and growing evidence that this
ing was elicited. It was found that patients with severe plays a role in OSA pathophysiology. The links between rhi-
OSA were much more susceptible to the development of nosinus inflammation and lower airway inflammation in
periodic breathing than patients with mild-to-moderate asthma are well documented (termed the “united airway
OSA, indicating increased endogenous loop gain in the hypothesis”). It may therefore be that pharyngeal involve-
severe group. The mechanisms underlying this ventilatory ment represents part of a continuum of airway inflammatory
instability, and its precise role in the pathogenesis of OSA, involvement. There may thus be a reciprocal interaction
remain to be established. between these disease processes, such that worsening of
Although the role of changes in chemoreceptor sensitiv- OSA may contribute to worsened asthma control and vice
ity in the pathogenesis of OSA remains unclear, there is versa. This concept is supported by the clinical data cited
strong evidence that severe OSA may produce secondary above concerning the effects of OSA treatment on asthma
changes in ventilatory control, namely hypoventilation dur- control. Research efforts are ongoing to further evaluate the
ing wakefulness. This occurs in a subset of OSA patients mechanisms of the OSA–asthma interaction and to more
who appear to be the group at risk for decompensation and systematically assess the effects of OSA treatment on asthma
respiratory failure in the context of intercurrent medical ill- control.
ness, or in some cases simply because of inexorable progres-
sion of the changes associated with sleep-disordered PHYSIOLOGIC ASPECTS OF DIAGNOSTIC TESTING
breathing. Most patients with OSA and daytime hypoxemia FOR OSA
and/or hypercapnia have some underlying lung dysfunction, In recent years, recording of nasal pressure has emerged
such as COPD or obesity-related or neuromuscular restric- as a sensitive indicator of upper airway narrowing.
tive impairment.83,85,86 OSA patients with hypercapnia have Introduction of a standard nasal oxygen cannula into the
been described as demonstrating impaired ventilatory recov- nares, with connection of the tubing end to a differential
ery after apnea.87 This may represent a blunting or failure of pressure transducer referenced to atmosphere, provides for
592 Sleep Disordered Breathing
No Yes
Portable PSG
Monitor
RDI < 10 RDI 10-30 RDI > 30 AHL < 10 AHL 10-30 AHL > 30
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
a semiquantitative assessment of nasal airflow. Of greater thereby increasing the anteroposterior oropharyngeal
interest is the fact that the shape of the inspiratory pressure dimension.93 This approach does not compensate for other
curve during tidal respiratory cycles shows flattening indica- factors contributing to upper airway collapse during sleep,
tive of flow limitation as upper airway narrowing occurs, in and there are limitations to its anatomic effects. Oral appli-
the same way that forced maximal curves reveal extratho- ances are therefore effective in mild-to-moderate apnea but
racic upper airway obstruction, as discussed earlier in this typically do not alleviate moderate-to-severe OSA. Surgical
chapter.91,92 This technique provides for the detection of interventions are also aimed at compensating for reduced
subtle episodes of upper airway narrowing. upper airway dimensions. In childhood OSA, hypertrophy
Respiratory effort was traditionally measured by using an of the adenoid and, to a lesser extent, the palatine tonsils is
esophageal catheter to estimate pleural pressure. This inva- often a major factor contributing to airway compromise, so
sive approach has largely been replaced by techniques that adenoidectomy–tonsillectomy is a mainstay of treat-
involving the use of sensors on the rib cage and abdomen to ment for OSA in the child. Maxillomandibular advancement
detect respiratory effort and movement. The most sensitive surgery may be beneficial in the context of craniofacial
of these is respiratory inductance plethysmography, which insufficiency, for example, the marked micrognathia associ-
provides data on changes in thoracoabdominal motion ated with Pierre–Robin syndrome. This approach may also
resulting from partial or complete upper airway obstruction. be useful for nonobese adults with similar but more subtle
Partial or complete rib cage paradoxical motion is often seen craniofacial disproportion. Surgical intervention in general,
during apneas and hypopneas and can provide confirmatory however, has a much more limited role in adult OSA.94
evidence of increasing respiratory effort in the context of Tracheostomy is highly effective as it bypasses the site of
upper airway obstruction. airway obstruction. However, there are adverse social as
well as medical aspects of chronic tracheostomy, which
PHYSIOLOGY OF TREATMENT APPROACHES TO OSA severely limit the applicability of this intervention. A
There are several treatments aimed at compensating for variety of approaches directed at reducing or stiffening
the anatomic predisposition to upper airway collapse. soft palate tissue have been applied to adult OSA.
Mandibular advancement splints, for example, act to advance These include conventional uvulopalatopharyngo-
the lower jaw in relation to other craniofacial structures, plasty, laser-assisted uvuloplasty, radiofrequency-controlled
Physiology of the Upper Airway and Upper Airway Obstruction in Disease 593
thermoablation (somnoplasty), and other procedures. may demonstrate central events during non-REM sleep.
Overall, the results of these interventions have been highly Furthermore, some patients with predominant central apnea
disappointing in the context of moderate-to-severe OSA. respond to nasal CPAP treatment, suggesting that upper
This is undoubtedly due to the limited anatomic effects airway closure contributes to these events.99 These findings
of these interventions, combined with the role of factors may in part be explained by evidence indicating that stimu-
other than anatomic predisposition to upper airway collapse lation of upper airway mechanoreceptors may result in
during sleep. reflex inhibition of inspiratory drive. Thus, stimulation of
The treatment of choice for OSA is nasal CPAP.95,96 CPAP laryngeal receptors in experimental animals has been
functions as a pneumatic splint for the upper airway. A reported to induce apnea.97,100 Furthermore, we found that
sealed mask is applied over the nose, and a continuous inhibition of upper airway mucosal receptors with the use of
positive pressure is applied to the mask from a blower unit topical anesthesia resulted in increased respiratory effort
to distend the airway. The pressure required to maintain during obstructive apneas in OSA patients. This points to
airway patency is determined by anatomic, mechanical, neu- the loss of an inhibitory influence on respiratory drive, with
romuscular, and state-dependent factors, such that a greater attenuation of airway sensory receptor function.69
pressure may be required for the supine position than for the There has been considerable recent interest in CSR
lateral decubitus position and during REM than during during sleep in the setting of chronic congestive heart
non-REM sleep. Traditionally, CPAP titration has been per- failure. Sleep-disordered breathing is common among
formed in the sleep laboratory, with manual adjustment to stable heart failure patients, occurring in up to 40%,101,102
determine the minimum pressure required to maintain air- with CSR representing the most common form. CSR is
way patency in all sleep stages and body positions. This believed to both result from and lead to worsening of
pressure is then prescribed for home treatment. More heart failure through complex mechanisms and has been
recently, automated CPAP devices have become available, shown to be associated with reduced survival for a given
which continuously monitor the amplitude and contour of level of cardiac dysfunction. Treatment with nasal CPAP
airflow with a pneumotachograph in the CPAP unit. A in this group leads to improvements in CSR, ventricular
microprocessor then evaluates the adequacy of these signals function, and quality of life.102 A multicenter trial (CAN-
and adjusts the pressure to respond to inspiratory flow PAP) is currently under way to determine the effects of
limitation and/or reduced airflow. The concept is that this is CPAP on mortality in heart failure patients with CSR. The
a more physiologic approach that should match the treat- mechanisms by which CPAP leads to improvement in CSR
ment delivered to the dynamic changes in upper airway remain unclear. However, recent work at McGill, involving
caliber determined by the factors described above. An algo- the forced oscillation technique to assess upper airway
rithm for the diagnosis and management of OSA is shown in patency, has demonstrated that upper airway closure is
Figure 50-8. frequent even during pure central events in heart failure
patients with CSR.103 Furthermore, overlap between OSA
UPPER AIRWAY IN CENTRAL SLEEP APNEA and CSR has been described in this population.104
Thus, upper airway instability may also contribute to the
Central sleep apnea is encountered in a variety of clinical pathogenesis of CSR.
conditions. It may be present as part of primary or sec-
ondary hypoventilation syndromes (hypercapnic central SUMMARY AND CONCLUSIONS
apnea) due to central nervous system (CNS) lesions or
neuromuscular disease involving the respiratory muscles. This chapter has examined the normal structure and
Alternatively, nonhypercapnic forms of central apnea function of the upper airway, with an emphasis on the
include idiopathic central sleep apnea and Cheyne–Stokes physiologic aspects of the integration of breathing with the
respiration (CSR) during sleep, which may occur in the variety of other upper airway functions. The most serious
setting of congestive heart failure, renal failure, or CNS clinical disturbance of upper airway function is anatomic
lesions.97 or functional obstruction with airflow compromise. We
Although the upper airway is not believed to play a pri- have considered the physiologic basis for both the clinical
mary role in most of these conditions, there is evidence that presentation and approach to diagnostic testing for the
upper airway instability and collapse are associated with various forms of upper airway obstruction. Finally, we
central apnea and may contribute to its pathophysiology. have considered sleep-disordered breathing and in particular
Badr and colleagues have shown, using video-endoscopy, that OSA, a very common but, for many individuals, no less
upper airway collapse occurs in the context of hyperventila- serious form of variable extrathoracic upper airway
tion-induced central apnea during sleep, even in normal obstruction occurring during sleep. The research that
subjects.98 Thus, the loss of respiratory drive due to induced has been directed at understanding the mechanisms under-
hypocapnia leads to airway closure, confirming the impor- lying OSA has led to major advances in our knowledge of
tance of respiratory drive to upper airway muscles in main- upper airway structure and function. Although considerable
taining airway patency. Conversely, there is evidence that progress has been made, ongoing work aimed at further
upper airway collapse may induce central apneas. The elucidating the mechanisms of OSA will undoubtedly
clinical correlate of this is that patients with snoring and broaden our understanding of upper airway function in
some obstructive apneas or hypopneas during REM sleep general.
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