Pathophysiology of Pediatric Obstructive Sleep Apnea

Eliot S. Katz1 and Carolyn M. D’Ambrosio2

1
Division of Respiratory Diseases, Department of Medicine, Children’s Hospital, and Harvard Medical School, Boston, Massachusetts; and 2Division
of Pulmonary Diseases, Department of Medicine, Tufts–New England Medical Center, and Tufts Medical School, Boston, Massachusetts

Sleep-disordered breathing is a common and serious cause of meta- the development of OSA, although they do not completely
bolic, cardiovascular, and neurocognitive morbidity in children. The account for the pattern of sleep-disordered breathing. This
spectrum of obstructive sleep-disordered breathing ranges from indicates a role for other determinants of airway patency such
habitual snoring to partial or complete airway obstruction, termed as neuromuscular activation, ventilatory control, and arousal
obstructive sleep apnea (OSA). Breathing patterns due to airway threshold. At sleep onset, airway muscle activity is reduced,
narrowing are highly variable, including obstructive cycling, in- ventilatory variability increases, and an apneic threshold slightly
creased respiratory effort, flow limitation, tachypnea, and/or gas below eupneic levels is observed in non-REM sleep. Airway
exchange abnormalities. As a consequence, sleep homeostasis collapse is offset by pharyngeal dilator activity in response to
may be disturbed. Increased upper airway resistance is an essen-
hypercapnia and negative lumenal pressure. Ventilatory over-
tial component of OSA, including any combination of narrowing/
shoot results in sudden reduction in airway muscle activation,
retropositioning of the maxilla/mandible and/or adenotonsillar
contributing to obstruction during non-REM sleep. Most chil-
hypertrophy. However, in addition to anatomic factors, the stability
of the upper airway is predicated on neuromuscular activation, ven- dren with severe OSA will be able to sustain stable breathing
tilatory control, and arousal threshold. During sleep, most children during a large portion of sleep, consistent with successful neu-
with OSA intermittently attain a stable breathing pattern, indicating romuscular compensation. Respiratory control mechanisms
successful neuromuscular activation. At sleep onset, airway muscle modulate ventilation and pharyngeal dilator activation. Arousal
activity is reduced, ventilatory variability increases, and an apneic from sleep contributes to ventilatory instability and, thus,
threshold slightly below eupneic levels is observed in non-REM obstructive cycling. Paroxysmal reductions in pharyngeal dilator
sleep. Airway collapse is offset by pharyngeal dilator activity in re- activity related to central REM sleep processes likely account
sponse to hypercapnia and negative lumenal pressure. Ventilatory for the disproportionate severity of OSA observed during REM
overshoot results in sudden reduction in airway muscle activation, sleep.
contributing to obstruction during non-REM sleep. Arousal from This review focuses on the pathophysiology of OSA in
sleep exacerbates ventilatory instability and, thus, obstructive cy- otherwise normal children. Comprehensive reviews comparing
cling. Paroxysmal reductions in pharyngeal dilator activity related to OSA in children with infants (1) and adults (2) have been
central REM sleep processes likely account for the disproportionate published elsewhere.
severity of OSA observed during REM sleep. Understanding the
pathophysiology of pediatric OSA may permit more precise clinical
phenotyping, and therefore improve or target therapies related to CLINICAL OBSERVATIONS
anatomy, neuromuscular compensation, ventilatory control, and/or
arousal threshold. To appreciate the factors that contribute to airway collapse, it is
helpful to contrast the breathing patterns during sleep in chil-
Keywords: children; sleep-disordered breathing dren with and without OSA. Normative data from several, large
samples of nonsnoring, normal children indicate that (1) ob-
The essential feature of obstructive sleep apnea (OSA) in chil-
structive apneas and hypopneas rarely occur; (2) inspiratory
dren is increased upper airway resistance during sleep. Airway
flow limitation and respiratory effort–related arousals are un-
narrowing may be due to craniofacial abnormalities and/or soft
common; (3) oxygen saturation rarely drops below 90%, even
tissue hypertrophy. The resultant breathing patterns during
during normal 10- to 15-second respiratory pauses following
sleep are highly variable, but include obstructive cycling, in-
sighs or movements; and (4) during non-REM sleep, respiratory
creased respiratory effort, flow limitation, tachypnea, and/or gas
rate decreases and end-tidal CO2 increases 3–4 mm Hg (3–7).
exchange abnormalities. Consequently, sleep disruption occurs,
Thus, despite ethnic differences in these studies the findings
ranging from visible electrocortical arousal to subtle autonomic
were remarkably similar, indicating the rarity of sleep-disordered
activation. The threshold level of obstruction leading to in-
breathing in normal children.
terference with sleep homeostasis has not been established.
Various sleep-disordered breathing patterns have been de-
The pathophysiology of OSA in children is a complex inter-
scribed in children, suggesting that distinct clinical phenotypes
action between an airway predisposed toward collapse and
may exist. The spectrum of obstructive breathing ranges from
neuromuscular compensation. Anatomic measures of the air-
persistent nonapneic/hypopneic, habitual snoring to frank, in-
way lumen, soft tissue, and skeleton are of critical importance to
termittent occlusion seen in OSA. Habitual snoring has been
reported in 3–12% of the general pediatric population, although
only 1–3% will have OSA (8–10). Children with habitual snoring
(Received in original form July 31, 2007; accepted in final form September 14, 2007) lack apnea, hypopnea, respiratory effort–related arousals, and
Supported by grant NIH/NHLBI HL073238 and grant MO1 RR02172 to Child- gas exchange abnormalities. This suggests that neuromuscular
ren’s Hospital, Boston, General Clinical Research Center by the National Center compensation was successful at attaining stable breathing dur-
for Research Resources, National Institutes of Health (to E.S.K.). ing sleep, and that any increased respiratory effort remained be-
Correspondence and requests for reprints should be addressed to Eliot S. Katz, low the threshold level for arousal. Nevertheless, children with
M.D., Division of Respiratory Diseases, Mailstop 208, Children’s Hospital, Boston, habitual snoring may still have recognizable breathing abnormal-
300 Longwood Avenue, Boston, MA 02115. E-mail: eliot.katz@childrens.
ities during sleep including inspiratory flow limitation, increased
harvard.edu
respiratory effort and tachypnea (11, 12), and evidence of subtle
Proc Am Thorac Soc Vol 5. pp 253–262, 2008
DOI: 10.1513/pats.200707-111MG alterations in sleep homeostasis (11). A related polysomno-
Internet address: www.atsjournals.org graphic pattern, termed obstructive hypoventilation, features
254 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 5 2008

snoring, stable increased respiratory effort, and hypercapnia, Skeletal

but not frank apnea, hypopnea, or respiratory arousal (13). Children with craniofacial dysmorphology involving hypoplasia
The upper airway resistance syndrome is characterized by or retropositioning of the mandible or maxilla frequently have
brief, repetitive respiratory effort–related arousals during sleep OSA. The contribution of skeletal abnormalities to the devel-
in the absence of overt apnea, hypopnea, or gas exchange ab- opment of OSA in otherwise normal children is controversial.
normalities (14) Children with upper airway resistance syn- Arens and coworkers reported that no measures of maxillary
drome arouse with less respiratory effort than do children with and mandibular width, length, or volume differed between pa-
OSA or habitual snoring, suggesting a possible etiologic role for tients with OSA and normal control subjects (30). However,
diminished arousal threshold (15). Finally, children with OSA cephalometric studies in children with OSA, which evaluate
manifest recurrent episodes of partial or complete airway ob- both size and relative position of the facial skeleton, frequently
struction. During non-REM sleep, obstructive events are gen- report narrower maxilla (35), mandibular retrognathia (32, 36),
erally accompanied by an initial decrease in respiratory effort, longer lower facial height (32, 36, 37), and caudal placement of
followed by a graded increase. In REM sleep, the respiratory the hyoid bone (38). A referral bias may explain some of the
effort is more variable and may increase or decrease during an differences in data between the sleep and dental clinics in the
obstruction. Increased upper airway resistance is correlated various studies cited above. It is reasonable to conclude that
with the severity of OSA in children (16). In addition to adeno- craniofacial skeletal abnormalities may contribute to the de-
tonsillar hypertrophy, causes of airway narrowing include allergic velopment of OSA in some otherwise normal children. Age and
rhinitis, turbinate hypertrophy, deviated septum, and maxillary sex may also be an important determinant of OSA in children,
constriction (17). based on a report that prepubertal males and females have
Most children with severe OSA are able to maintain normal similar airway lengths, but postpubertal males have longer
sleep state distribution, particularly REM and slow wave sleep, airways than do females (39). In adults, airway length has been
despite intermittent obstruction (18, 19). However, subtle associated with increased airway collapsibility and there is
abnormalities of sleep microstructure have been reported (18, a male predominance of OSA (40).
20, 21). Obstructive events occur disproportionately in REM
sleep and are rare during slow wave sleep (19). Dayyat and
coworkers demonstrated that obese children with OSA had Pharyngeal Soft Tissues and Lumen
more obstructive events in the supine position, whereas ob- Children with OSA have larger adenoids, tonsils, and soft pal-
structive events in nonobese children with OSA were more ates compared with normal control subjects (30) (Figure 1).
severe in the prone or side positions (22). This suggests that Consequently, the pharyngeal airway is smaller in OSA as
there are important physiological differences between obese measured under sedation by MRI (30) and using paralysis with
and nonobese airways. Lateral positioning has been shown to endoscopy (31). In sedated, young children (4.8 6 2.1 yr; range,
increase the size of the airway by both magnetic resonance 1.9–9.3 yr), there was a positive linear correlation between the
imaging (MRI) (23) and endoscopy (24). The degree of neck tonsil and adenoid volume and the AHI (r2 5 0.26), but there
flexion was not quantified in these studies, and may also affect was no such correlation with airway volume (30). In unsedated,
airway collapsibility, but these data are not available in children. older children (9.5 6 1.2 yr; range, 7–12 yr), the tonsil cross-
Insight into the pathophysiology of pediatric OSA can also sectional area (CSA) (r2 5 0.44), soft palate CSA (r2 5 0.39),
be derived from treatment studies. The importance of increased oropharyngeal volume (r2 5 0.27), and ratio of the retropalatal
upper airway resistance is evident by the improvement in OSA airway to soft palate CSA (r2 5 0.49) strongly correlated
in selected populations after turbinectomy (17), septal repair (tonsils and palate) or inversely correlated (ratio of retropalatal
(17), administration of intranasal corticosteroids (25), and rapid airway to soft palate) with the obstructive AHI (33). The
maxillary expansion (26). Also, children with persistent OSA parapharyngeal fat pad did not significantly contribute to apnea
after an adenotonsillectomy are more likely to have enlarged severity in either the young (30) or older (33) children. Re-
turbinates, a deviated septum, and/or retroposition of the man- markably, in older children, a multiple linear regression analysis
dible (27). Two large studies have documented persistent OSA indicated that 74.3% of the variance in obstructive AHI could
in otherwise normal children with adenotonsillar hypertrophy be explained by the tonsil and soft palate CSAs (33). A corre-
after adenotonsillectomy. Tauman and colleagues reported com- lation with apnea severity was observed with the younger children’s
plete normalization of patients with OSA after adenotonsillec- combined adenotonsillar volume (30), but not with the older
tomy (apnea–hypopnea index [AHI] , 1) in only 25% of children’s combined adenotonsillar CSA (33). Cephalometric
patients, with 46% having persistent mild OSA (1 , AHI , data similarly indicate that younger children have larger soft
5), and 29% having at least moderate OSA (AHI . 5) (28). tissues relative to the facial skeleton than do older children (41).
Similarly, Guilleminault and coworkers reported that 45% of Thus, the contributions of soft tissue structures to the patho-
children with OSA had persistent OSA after adenotonsillec- physiology of OSA may vary with the age of children (see
tomy (27). Together, these studies indicate that adenotonsillar below, CRANIOFACIAL DEVELOPMENT).
hypertrophy is only one of several important determinants of Dynamic inspiratory airway narrowing during tidal breathing
OSA in children. was much greater in children with OSA compared with normal
control subjects (mean age, 4.3 6 2.3 yr; age range, 2–7.2 yr [42];
mean age, 9.7 yr; age range, 0.5–19 yr [34]) (see Figure 1). This
ANATOMY indicates that patients with OSA have either greater lumenal
pressure oscillations due to increased upper airway resistance
Children with OSA have narrower pharyngeal airways com- and/or an increase in airway compliance. Nasal resistance mea-
pared with control children during wakefulness (29), sedation sured by anterior rhinometry is reported to be increased in
(30), and paralysis (31). This has been demonstrated by ceph- children with OSA compared with control subjects (16). Even in
alometry (32), acoustic reflection (29), endoscopy (31), and asymptomatic children, adenotonsillar size correlates with in-
MRI (30, 33, 34). However, anatomic comparison between creased inspiratory airway narrowing at the nasopharynx (43).
children with OSA and children with habitual snoring has not During tidal breathing, the narrowest airway segment occurs
yet been performed. at the site of overlap between the tonsil and adenoid in both
Katz and D’Ambrosio: Pathophysiology of Pediatric OSA 255

Figure 1. Top: Three-year-old normal control male subject. Sagittal images from various points in the respiratory cycle show no significant change
in airway diameter at the level of the hypopharynx (arrows in image 1) or nasopharynx (arrowheads in image 2). Bottom: Eleven-year-old male
patient with obstructive sleep apnea (OSA). Sagittal images from various points of the respiratory cycle demonstrate airway collapse at the level of
the hypopharynx (arrows in images 1 and 2). The palatine tonsils (P in image 2) are enlarged and are seen to move inferiorly and medially during the
respiratory cycle to obstruct the airway (image 2). The adenoids are enlarged (A in images 1 and 2). Modified by permission from Reference 34.

younger and older children (33, 44). The site of airway narrow- increasingly negative airway pressures to sustain minute venti-
ing during obstructive events in children with OSA has been lation, which results in airway collapse at multiple sites.
measured during sedation, paralysis, and sleep by multiple
techniques, including endoscopy and imaging studies. Direct
visualization of the airway during paralysis in normal children Craniofacial Development
requires negative pressure to collapse the airway (31). This At birth, the face is about 40% of adult size, increasing to 65%
technique demonstrates obstruction at the level of the soft at 3 years of age, and is only completed after puberty. Facial
palate (54%), tonsil (15%), or the tongue (31%) (31). By con- growth is influenced principally by genetic factors, but environ-
trast, children with OSA under paralysis obstructed predomi- mental inputs may also contribute, including route of breathing.
nantly at the level of the adenoids (57%), soft palate (29%), and Considerable evidence supports the view that upper airway
tonsil (14%) (31). Importantly, children with OSA also had obstruction and mouth breathing induce morphologic skeletal
increased collapsibility at the level of the soft palate and retro- changes in the maxilla and mandible. Importantly, adverse cranio-
glossal area, indicating a generalized increased collapsibility of facial development may be at least partially reversible after
the pharynx compared with normal control subjects (31). Using treatment (37, 45, 46).
cine MRI during sedation, Donnelly and coworkers reported A cross-sectional MRI study, in a convenience sample of
that (1) intermittent or fixed hypopharyngeal airway collapse children that excluded serious illnesses, reported that the soft
was observed in 81% of children with OSA, but in none of the tissues and facial skeleton grew linearly and in proportion to
normal control subjects; and (2) patients with OSA were more each other between 1 and 11 years of age (47). By contrast,
likely to have intermittent airway collapse at the level of the a longitudinal cephalometric study in normal children reported
nasopharynx (34). Thus, airway narrowing likely necessitates that the airway soft tissues grow more rapidly than the skeleton
256 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 5 2008

between 3 and 5 years of age, resulting in pharyngeal airway inflammatory changes to the upper airway includes the in-
narrowing during this interval (41). This is consistent with the creased expression of leukotriene receptors in tonsillar tissue
reported peak prevalence of OSA in children. from children with OSA compared with children with recurrent
Mouth-breathing children habitually lower their mandible, throat infections (56). Also, treatment studies using intranasal
which may influence dentoalveolar morphology, resulting in corticosteroids (25), leukotriene receptor antagonists (57), or
a high-arched palate, narrow maxilla, retrognathia, and increased both (58), result in a reduction in OSA severity.
lower facial height. This constellation of findings has been termed
the ‘‘long face syndrome,’’ and is similar to the reported cepha- VISCOELASTIC MECHANICS
lometric findings in children with OSA (32, 36, 37). Thus, not only
does upper airway obstruction predispose to OSA, but it also has The upper airway is a compliant tube, the cross-sectional area
an adverse effect on craniofacial development, posing an in- and shape of which are nonlinearly dependent on the transmural
creased future risk of OSA. pressure, termed the ‘‘tube’’ law (Figure 2). As the lumenal pres-
Long-term follow-up studies of children with OSA after ade- sure becomes more negative, the airway size decreases until
notonsillar removal indicate an increased incidence of snoring, a ‘‘buckling’’ point is reached, at which the airway markedly
increased respiratory effort, and OSA (48, 49), suggesting re- collapses. Thus, there is a narrow, highly compliant range over
sidual craniofacial narrowing. However, normalization of some which small changes in pressure produce large changes in airway
cephalometric measures after treatment of upper airway ob- cross-sectional area. This has important implications in the path-
struction in children with OSA has been reported (37, 45, 46). ophysiology of OSA, resulting in rapid airway closure. Con-
Resolution of both open bites and cross-bites was observed versely, the rapid opening of the airway after an apnea/hypopnea
2 years after tonsillectomy in most patients (46). A resolution of may yield a ventilatory overshoot producing respiratory insta-
mandible and maxillary inclination abnormalities, and lower face bility and, thus, obstructive cycling.
height, was observed 5 years after an adenotonsillectomy in The viscoelastic properties of the airway in children have
children with OSA (37). Thus, relief of upper airway obstruction been evaluated during anesthesia under complete paralysis (31).
during periods of rapid facial growth may normalize dentofacial The mean airway closing pressure is greater for children with
abnormalities that predispose to OSA. If treatment is initiated in OSA compared with control subjects, 13.5 6 4.3 and 27.4 6
younger children (before 6 yr of age), the long-term dentoalveo- 4.9 cm H2O, respectively (31) (see Figure 2). Children with OSA
lar development is more likely to normalize (46). have higher airway compliance than do control subjects near the
closing pressure, contributing to greater airway instability. Post
Obesity mortem analysis demonstrated that the passive airway closing
The prevalence of childhood obesity has tripled since the early pressure was 20.7 6 2 cm H2O, indicating that neuromuscular
1980s, and is presently estimated to be 16%. The risk of OSA in compensation must be active in the living infant (59). However,
obese children is high at 36% (50), and may exceed 60% if the airway opening pressure was much higher, 15 6 2.4 cm
habitual snoring is present (51). Most obese children with OSA H2O, likely indicating hysteresis due to surface forces (59).
will also have adenotonsillar hypertrophy (51). Surgical removal Extension of the neck decreased the closing pressure, thereby
of enlarged tonsils and adenoids in obese children with OSA stabilizing the airway (59). Neck extension is a compensatory
results in a marked improvement of the AHI, but 76% have strategy often observed in children with OSA to mitigate the
residual OSA (52). There is no consistent relationship between severity of OSA.
pediatric OSA and measures of fat distribution (53). Although
imaging studies specific to obese children have not been per- FLOW MECHANICS
formed, adult studies indicate that increased deposition of fat in
the parapharyngeal fat pads near and within the soft palate Starling Resistor Model
contributes to airway obstruction. Obese individuals also have Airflow through the upper airway has the mechanical properties
lower lung volumes, increasing both airway collapsibility and of a Starling resistor (60–63). The essential features of this
gas exchange abnormalities. model are a collapsible segment dividing upstream (nasal) and
downstream (tracheal) segments with fixed resistances. The
PATHOLOGY lumenal pressure at which airway collapse occurs is termed
the critical closing pressure (Pcrit). In humans, the Pcrit is an
Chronic vibratory stress on the airway soft tissues could ad- index of both the viscoelastic and neuromuscular properties of
versely affect pharyngeal dilator function by inducing patho- the pharynx. When downstream pressure is above the Pcrit,
logical changes to nerves, muscles, or sensory innervation. De
Vuono and coworkers performed blinded, histologic analysis on
palatopharyngeal biopsies in mouth-breathing children with ade-
notonsillar hypertrophy undergoing tonsillectomy (54). Patients
were categorized into three groups, OSA, habitual snoring, and
normal, based on nocturnal polysomnography. Histopatholog-
ical findings were similar between the groups, indicating that it
is unlikely that a primary or secondary neuromyopathy is an
important determinant of OSA (54).
The negative pressure reflex is an important mediator of
upper airway neuromuscular compensation. It is plausible that
mucosal inflammation or edema could impair the afferent limb
of this reflex. It is hypothesized that snoring induces a mucosal
inflammatory response resulting in swelling, affecting upper air- Figure 2. Static airway cross-sectional area versus pressure curves at the
way resistance and/or collapsibility. Blunted respiratory per- level of the soft palate for a series of children with obstructive sleep apnea
ception in children with OSA has been reported by measuring (OSA) (right) and control subjects (left). The closing pressure defined as
respiratory-related evoked potentials (55). Direct evidence of zero area is higher in OSA. Modified by permission from Reference 31.
Katz and D’Ambrosio: Pathophysiology of Pediatric OSA 257

airflow is proportional to the pressure gradient across the air- adenotonsillectomy did not decrease to the level in control
way. However, when downstream pressure falls below the Pcrit, subjects (62), or even primary snorers (60), suggesting that
flow limitation is observed. Thus, maximal airflow will vary in subtle abnormalities of anatomy or neuromuscular control re-
relation to the upstream pressure and Pcrit, but not the down- main after treatment (mean age of subjects in both studies: 8 yr
stream variables. Techniques to measure the Pcrit differ con- old; age range, 5–11 yr). In normal children, the relatively
siderably in the degree of airway neuromuscular activation. passive Pcrit was 225 cm H2O and the active Pcrit was essen-
Thus, the relative importance of the viscoelastic and neuromus- tially unmeasurable because the airway is not collapsible (62).
cular components of pharyngeal collapsibility may be estimated Between 10 and 16 years of age there is a small, but significant,
(Figure 3). increase in airway collapsibility in older children, independent
Pcrit can be measured by brief negative pressure challenges of Tanner stage (64). Under general anesthesia with muscle
via nasal mask (60, 62). Pcrit is extrapolated as the zero flow point paralysis, the mean airway closing pressure (Pclose) in normal
(x intercept) of the mask pressure versus maximal inspiratory children is 27.4 cm H2O (31). A comparison of the Pcrit (rela-
flow curve (see Figure 3). The negative pressure challenges have tively passive, 225 cm H2O, sleep) and Pclose (–7.4 cm H2O,
been of two types, termed relatively passive and active, which paralysis) in normal children indicates considerable activity of
differ in degree of neuromuscular activation allowed. The the upper airway musculature during sleep. By contrast, in
relatively passive technique consists of intermittent pressure children with OSA, the relatively passive Pcrit was 25 cm H2O,
drops of three to five breaths, followed by a return to a pressure the active Pcrit was 27 cm H2O, and the Pclose was 22 cm
sufficient to achieve non–flow-limited breathing. The relatively H2O, indicating less effective neuromuscular compensation (31, 62).
passive technique attempts to minimize the effect of neuromus- Hypercapnia increases maximal inspiratory airflow (reduces
cular activation. By contrast, the active technique uses a pro- Pcrit and slope of the mask pressure–maximal flow curve) in
gressive drop in airway pressure, allowing muscle activation (62). normal children (65), presumably also by augmenting airway
Comparing the changes in collapsibility between techniques neuromotor activity. By contrast, hypercapnia generally does
(relatively passive vs. active) provides a measure of neuromus- not decrease airway compliance in children with OSA (62).
cular activation. Empirically, many children will not demonstrate Thus, children with OSA have more collapsible airways during
a decrease in maximal flow even at very negative mask pressures, sleep at baseline, as well as impaired airflow responses to nega-
suggesting low airway compliance. In this case, it is desirable tive pressure and hypercapnia, compared with normal children.
simply to evaluate the slope of the mask pressure–maximal flow The hypercapnic ventilatory response during wakefulness and
curve as a measure of airway collapsibility, combining both sleep is similar in children with and without OSA (66, 67).
structural and neuromuscular components. Whether the impaired responses to negative pressure in children
with OSA are related to neural processing or to a phenomenon
Airflow Data secondary to impaired afferent receptors due to mucosal swell-
ing/inflammation remains to be determined.
Children with OSA have a higher Pcrit than do control subjects
(62) and children with habitual snoring (60). Pcrit correlates
with the severity of OSA, and decreases after adenotonsillec-
tomy (60). Interestingly, the Pcrit in patients with OSA after NEUROMUSCULAR COMPENSATION OF THE
UPPER AIRWAY
The upper airway lumenal dimension is determined by the
balance between the viscoelastic properties of the pharynx,
neuromuscular activity, and the transmural pressure. Upper
airway muscles that are phasically activated during inspiration
increase both the lumenal size and stiffness of the airway. The
significance of muscular modulation of airway patency in
children is suggested by the following clinical observations: (1)
apnea is observed predominantly in REM and stage 2 sleep
rather than in wakefulness or slow wave sleep; (2) although
sedated and anesthetized children with OSA have narrower and
more collapsible airways compared with normal control chil-
dren, there is considerable overlap (30, 31); and (3) during
sleep, most children with OSA intermittently attain a stable
breathing pattern, suggesting that reflex neuromuscular activa-
tion below the arousal threshold is possible. Thus, the anatomic
and viscoelastic properties of the airway are not the sole deter-
minants of airway patency.
Pharyngeal dilator muscle activity, including the genioglos-
sus, hyoglossus, and styloglossus, modulates flow through the
Figure 3. Left: Normal control child. Nasal pressure (PN) versus maximal upper airway. Although it is believed that these muscles act in
inspiratory flow (V̇Imax) is plotted subsequent to a series of negative unison, the genioglossus is the most easily measured. The ge-
pressure challenges, using the active (solid circles) and relatively passive nioglossus produces forward movement of the tongue, increasing
(open circles) techniques. The relatively passive technique minimizes oropharyngeal airway size and stiffness. Both tonic and phasic
neuromuscular activation of the upper airway and results in a critical inspiratory genioglossal activity have been noted in children (68).
closing pressure of 222 cm H2O. The active technique facilitates
pharyngeal dilator activity and resulted in a less collapsible upper airway.
Sleep State Effect
Right: Patient with obstructive sleep apnea (OSA). There is no change in
airway collapsibility between the active and relatively passive techni- During wakefulness, children with OSA have an increased
ques. Modified by permission from Reference 62. genioglossus EMG (EMGgg) compared with control children
258 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 5 2008

(68). This is thought to represent reflex activation by mucosal homeostasis. By contrast, normal children respond to loading
mechanoreceptors sensing negative airway pressure. Further, with an increased inspiratory time, and were able to sustain
applying topical anesthesia during wakefulness to the airway of loads without arousing for several minutes (74). Reflex mech-
children with and without OSA results in a greater decline in anisms that alter respiratory timing and increase pharyngeal
airway size in patients with OSA (69). Thus, mucosal mecha- dilator activity without arousal are less disruptive to sleep
noreceptor-induced pharyngeal dilator activity is more active in homeostasis.
patients with OSA (69) during wakefulness. The negative pressure reflex can be observed more directly
During the sleep onset period, the EMGgg decreases in both by experimentally lowering mask pressure. In normal children,
patients with OSA and control subjects, but more so in the for- negative pressure challenges in the range of 210 cm H2O
mer (68). This suggests that central respiratory drive and/or generally resulted in a return of the minute ventilation to
neuromuscular compensatory mechanisms are diminished dur- baseline by breath number 5 (61). Importantly, breaths without
ing the transition to sleep. The reduction in muscle activity is a visible EEG arousal tended to approach baseline minute
associated with increased airway resistance and collapsibility. ventilation without a significant overshoot, thus contributing to
As stable non-REM sleep is established over several minutes ventilatory stability. There is wide intersubject variability in
there is a divergence in the EMGgg activity between patients inspiratory EMGgg activation in response to negative pressure,
with OSA and control subjects. In normal children, the EMGgg which may represent an intermediate phenotype affecting the
remains below the wakeful baseline during stable stage 2 and expression of sleep apnea (Figure 4). The increased EMGgg
stage 4 sleep, suggesting that additional neuromuscular activity induced by negative pressure challenge is associated with in-
is not necessary with a mechanically stable airway (70). How- creased flow, increased respiratory rate, and decreased airway
ever, most children with severe OSA have a rebound increase in collapsibility (61).
EMGgg activity during stage 2 sleep, consistent with a reflex
driven by mechano- and/or chemoreceptors (70). There is a sig-
nificant correlation between OSA severity (i.e., AHI) and
AROUSAL
EMGgg activity in all sleep stages. Finally, applying continuous
positive airway pressure to patients with OSA during sleep Arousal from sleep immediately opens the airway and normal-
results in a reduction in the EMGgg coincident with reductions izes gas exchange abnormalities. However, arousal may also be
in respiratory effort and hypercapnia (70). considered an adverse epiphenomenon that potentiates obstruc-
Obstructive events occur most frequently in children during tive cycling and interferes with sleep homeostasis (75). Arousal
REM sleep, followed by stage 2, and are rare in slow wave sleep is a graded phenomenon resulting in reflex activation of pharyn-
(19). REM sleep is a heterogeneous state with paroxysmal phasic geal dilator muscles and central nervous system activation,
processes that both increase and decrease EMGgg activity (70). ranging from visible EEG arousal to subtle autonomic changes.
Overall in REM sleep, there is a reduction in tonic and phasic The principal stimulus for arousal appears to be respiratory
EMGgg activity. However, there is a marked increase in the effort and hypercapnia, whereas hypoxemia is a poor arousing
variability of EMGgg during REM sleep in children with and stimulus. Increased respiratory effort alone may induce subtle
without OSA (70). Sudden reductions in EMGgg activity during frequency changes in the surface EEG (11, 20). This is con-
REM sleep lasting a few seconds are observed coincident with sistent with clinical studies demonstrating that snoring with
apneic and hypopneic events (70). The vulnerability of REM increased respiratory effort, but without discrete obstructive
sleep to sleep-disordered breathing may also be related to gen- events, is associated with adverse neurodevelopmental out-
eralized muscle atonia and relatively lower lung volume (71). comes (76).
Low lung volumes may influence the upper airway by decreasing The arousal threshold to negative pressure challenges is
‘‘tracheal tug,’’ and therefore increasing airway collapsibility highest in stage 4, intermediate in stage 2, and lowest in REM
(72, 73). In addition, low lung volumes decrease the oxygen re- sleep (61). A high arousal threshold may stabilize breathing by
serve and adversely affect ventilation–perfusion matching, allowing time for mechano- and/or chemoreceptor recruitment
resulting in more rapid gas exchange abnormalities. of pharyngeal dilator muscles. Marcus and coworkers have
reported that children with OSA have normal ventilatory re-
sponses to hypoxemia and hypercapnia during wakefulness (67)
Negative Pressure Reflex and stage 2 sleep (66). However, children with OSA have de-
Collapse of the upper airway reduces minute ventilation and creased arousal responsiveness (that is, require a greater stimulus)
induces a compensatory increase in respiratory effort. This re- during sleep to respiratory loading and hypercapnia, compared
sults in large negative lumenal pressure changes during inspi- with normal control subjects (66, 74). The etiology of the in-
ration. The negative pressure reflex consists of airway mucosal creased arousal threshold to respiratory stimuli has not been
mechanoreceptor–induced activation of pharyngeal dilator mus- established, and may be a secondary phenomenon. However,
cles. This mechanism decreases airway collapsibility, resulting the arousal threshold to acoustic stimuli does not differ between
in increased minute ventilation. Children who successfully aug- the two groups, suggesting that children with OSA do not have
ment airflow early during airway collapse may be spared the a global arousal deficit (77).
progression to apneas or hypopneas that would be more likely Children with severe OSA have a visible EEG arousal with
to result in sleep disruption. only 50% of obstructive events (15, 78) and often have a normal
The negative pressure reflex has been studied in children sleep state distribution (19). However, evidence of autonomic
using inspiratory resistance loading (74) and by applying nega- activation was observed subsequent to obstructive apneas,
tive pressure through a nose mask (61). These studies have hypopneas, and respiratory effort–related arousals 91, 83, and
demonstrated a variety of strategies to compensate for in- 80% of the time, respectively (15). In addition, several studies
creased upper airway resistance. Using inspiratory resistance indicate that subtle abnormalities of sleep architecture occur in
loading, Marcus and coworkers reported that patients with OSA children with OSA, including decreased spontaneous arousals
developed intermittent obstructive cycling associated with (18), increased slow wave sleep (18), respiratory cycle–related
arousals (74). Thus, children with OSA must rely on arousal EEG changes (20), and alteration in the amount of the cyclic
mechanisms to sustain minute ventilation, which disrupt sleep alternating pattern (21).
Katz and D’Ambrosio: Pathophysiology of Pediatric OSA 259

Figure 4. Raw data from three normal children during stage 4 sleep, demonstrating the range of genioglossus EMG (EMGgg) responsiveness and
nasal airflow (Flow) during six negative pressure challenges. Each tracing represents approximately 4 minutes. (A) No increase in the EMGgg or flow
is evident during the negative pressure challenges. (B) A small increase in the EMGgg occurs during challenges 2–6. An increase in inspiratory flow is
evident on breaths 4 and 5 during challenges 2–4. (C ) A brisk EMGgg response accompanies challenges 2–6 and is associated with flow at or above
baseline without arousal. Reproduced by permission from Reference 61.

VENTILATORY CONTROL CO2 levels may drop below an apneic threshold that is a unique
property of non-REM sleep. As a result, there is a decrease in
Oxygen and carbon dioxide tensions are regulated within the central respiratory drive and innervation of the pharyngeal
narrow limits during wakefulness in children with and without musculature producing narrowing of the airway, and thus
OSA. However, during sleep, regular oscillations in ventilation initiating an obstructive event in a predisposed airway. A
are observed during non-REM sleep, and irregular variations greater reduction in CO2 levels may result in complete loss of
occur in REM sleep. The principal determinant of central phasic central respiratory output, resulting in a central apnea.
respiratory drive is the carbon dioxide level. During non- This apnea threshold during non-REM sleep may be close (1
REM sleep, the ventilatory response to CO2 is robust, and mm Hg) to eupneic CO2 levels, producing a potentially unstable
hyperpnea may lead to a ventilatory overshoot. Consequently, situation (79). Central, mixed, and obstructive apneas in infants

Figure 5. A series of apneic–

hypopneic events associated
with reductions in the tonic
and phasic genioglossal elec-
tromyogram (EMGgg). GG 5
genioglossus; MTA 5 moving
time average. Reproduced by
permission from Reference 70.
260 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 5 2008

and children all occur at the nadir of oscillations in ventilation robust activation of pharyngeal dilator muscles and a stable
(80) and genioglossal activity (70). Breathing exogenous carbon ventilatory pattern. At sleep onset, there is a marked reduction
dioxide has been shown to decrease obstructive apneas and flow in the activation of airway muscles, an increased ventilatory
limitation in children with OSA, presumably by augmenting variability particularly in REM sleep, and the appearance of an
pharyngeal dilator activity (66), and to decrease central apneas apneic threshold close to eupneic levels in non-REM sleep.
in infants (81). Arousal from sleep contributes to ventilatory instability and
Arousal from sleep increases the gain of the central chemo- therefore exacerbates obstructive cycling. During non-REM
receptors and augments neuromuscular activation of the upper sleep, reduction in ventilatory drive during ventilatory over-
airway, thereby decreasing airway resistance. Ventilatory cy- shoot results in sudden reductions in airway muscle activation,
cling in patients with OSA is facilitated by large changes in tidal producing obstructive events (Figures 1–5). During REM sleep,
volume occurring as the airway opens and closes. If the obstruc- paroxysmal reductions in pharyngeal dilator activity related to
tive event is associated with an arousal, the ventilatory over- central REM sleep processes likely account for the predisposi-
shoot is magnified (61). The airways most vulnerable are those tion toward obstructive events.
with a Pcrit near atmospheric pressure (82). Thus, arousal has
Conflict of Interest Statement: Neither author has a financial relationship with
a destabilizing effect on ventilation during sleep. In children, a commercial entity that has an interest in the subject of this manuscript.
robust neuromuscular compensation mechanisms can augment
minute ventilation without an EEG arousal or ventilatory over-
shoot. The cycling frequency and magnitude will also be depen-
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