OBSTRUCTIVE SLEEP APNEA IN CHILDREN
From a Midsummer Night’s Wheeze, sponsored by the California Society of Allergy, Asthma, and Immunology and
University of Southern California Keck School of Medicine
David Gozal, MD, Professor and Children’s Foundation Chair for Pediatric Research, Vice Chair for Research, and
Director, Kosair Children’s Hospital Research Institute, Department of Pediatrics, University of Louisville School of
Medicine, Louisville, KY
| Features: cessation of airflow despite ongoing respiratory effort; oxygen desaturation; apneic event may terminate with
arousal; sleep cycle—in children, respiratory events and arousals occur during rapid eye movement (REM) sleep; reduced
tone in skeletal muscles leaves airway vulnerable to obstruction; desaturation events become more severe as night
progresses (not identified in abbreviated sleep studies); common features in children—increased upper airway resistance
with paradoxical breathing; obstructive alveolar hypoventilation (airflow and saturation appear normal, but CO2 elevated)
|
| Prevalence: 7% to 13% of children 1 to 8 yr of age exhibit habitual snoring (≥3 times/wk); prevalence decreases to 4% to
5% in older children, then increases in mid-to-late adulthood; 20% to 25% of habitually snoring children meet criteria for
obstructive sleep apnea (OSA)
|
| Diagnosis: detailed history and physical examination often insufficient for diagnosing OSA (60%-65% accuracy); risk
factors—adenotonsillar hypertrophy; obesity; allergic rhinitis; asthma; black ethnicity; craniofacial abnormalities (eg,
micrognathia); neuromuscular disorders (eg, Down syndrome); daytime findings—mouth breathing and limited nasal
airflow; chronic rhinorrhea; adenoid facies; recurrent ear infections; difficulty swallowing; pectus excavatum (in children
with long history of breathing difficulties); retrognathia; enlarged neck circumference and obesity; frequent visits to primary
care provider for respiratory-related symptoms (3-4 times as often as children without habitual snoring); nighttime
findings—snoring; difficulty breathing, with snorting episodes; restless sleep with frequent awakening; excessive sweating;
night terrors; enuresis; breathing pauses reported by parents; overnight polysomnography—diagnostic gold standard
|
| Clinical consequences: attention-deficit/hyperactivity disorder (ADHD); neurobehavioral problems; depression and
low self-esteem; sleepiness; hypertension; left ventricular (LV) hypertrophy; pulmonary hypertension; failure to thrive
(FTT); reduced quality of life (QOL)
|
| Anatomic factors: previously thought that, in young children, adenoid and tonsillar tissues grow faster than underlying
structures of upper airway; view disproved by quanitative imaging studies (magnetic resonance imaging [MRI]); children
with OSA have smaller airways than normal controls; not all children with large tonsils snore or have OSA; size of airway
does not correlate with apnea-hypopnea index; adenotonsillar volume accounts for 25% to 30% of variation (other
factors involved); cross-sectional area of airway—reduced where adenoids and tonsils overlap; children with OSA
have longer segment of narrowed airway, compared to controls
|
| Airway collapse: Starling resistor model—collapsibility of system depends on pressure in segment upstream to collapsible
segment (ie, flow and negative pressure generated in nasal segment drive collapsibility of airway); pressure in
downstream segment (ie, lungs) relatively unimportant; airway patency—difficult to collapse airway in children who
do not snore; upper airway collapsibility of snoring child without OSA higher than in children who do not snore; in child
with OSA, airway collapses easily, even without negative pressure; study data show that after critical pressure, airway
collapse and OSA much more likely; contributory factors—neuromechanical problems; inflammation
|
| Neuromechanical problems: during wakefulness, mechanoreceptors and proprioceptors in airway initiate dilatory reflex
in upper airway dilator muscles (primarily genioglossus) when airway begins to collapse; reflex attenuated during
sleep; study—topical anesthesia applied to upper airway to inactivate dilatory reflex; no change in cross-sectional area
observed in controls (these children normally do not rely on reflex to maintain patency of airway), but area decreased by
≈30% in children with OSA (reflex normally important while awake); when added to history and physical examination,
test increases diagnostic accuracy to 93% to 97% (may eliminate need for sleep study in many cases; validation of
method by other centers needed)
|
| Other issues: small study found ≈33% of children with OSA had persistent symptoms after treatment, possibly attributed
to inflammation in upper airway; respiratory control mechanisms (eg, sensing CO2 or hypoxia) normal in children with
OSA
|
| SLEEP ANALYSIS AND SLEEPINESS
|
| Sleepiness: only 7% of children with OSA have complaint of daytime sleepiness; parents’ perception of child’s sleepiness
may explain low prevalence; in children, signs include restlessness, emotional lability, and attentional problems;
multiple sleep latency test—child given nap opportunities at 2-hr intervals during day; mean sleep latency (time to fall
asleep; average from 5 naps) measures degree of sleepiness; latency period decreases with increasing sleepiness; sleepiness
increases with severity of OSA; normal children take ≈38 min to fall asleep, while normal adults take ≈20 min;
based on current criteria, few children have excessive daytime sleepiness; test has good specificity but low sensitivity, ie,
does not allow differentiation between sleepy and nonsleepy children
|
| Arousal indices: number of spontaneous arousals per hour genetically determined (typically 5-10/hr); total number of
arousals increases with disease severity, but spontaneous arousals decrease and respiratory arousals increase; sleep pressure
score—numerical factor that indicates how much pressure to sleep develops as respiratory arousals increase; score
increases, then levels off; increase quicker in children than in adults
|
| Polysomnography: children typically have to wait 6 mo for appointment; other diagnostic tests needed
|
| Vascular endothelial growth factor (VEGF): induced by hypoxia; released into serum; level correlates with disease
severity (especially in children), but not predictive on its own
|
| Rationale: upper airway obstruction results in intermittent hypoxia, sleep fragmentation, and alveolar hypoventilation, all
of which should affect gene expression and protein production
|
| Genomic methods: study participants divided into snorers, snorers with OSA, and controls; blood drawn morning after
sleep study; RNA extracted from white blood cells (WBCs); mRNA purified; computer analysis identifies differences in
gene expression among study groups; results—children with OSA have distinct gene expressions in peripheral blood in
groups of genes related to adaptation and injury; application—low cost; research ongoing; results have led to insights
on pathophysiology of disease; may help identify children at risk for morbidities
|
| Proteomic methods: urine and blood collected in morning after sleep study; surface enhanced laser desorption ionization
(SELDI) and mass spectrometry used to identify differences in protein production between children with OSA and
habitual snorers without OSA; predictive accuracy—high sensitivity and specificity (especially when based on urine
samples); screening—12 proteins identified as potential biomarkers; one of them, urocortin 2, stress protein involved in
feeding, anxiety, depresson, and blood pressure regulation; monoclonal antibodies to urocortin 2 developed; goal of ongoing
research to assess whether urocortin 2 can be used to distinguish children with OSA from habitual snorers
|
| IMPACT ON QUALITY OF LIFE
|
| Sleep apnea in children: substantially reduces QOL, even in children with mild disease; habitual snoring also reduces
QOL; obesity-associated decreases in QOL seen only in absence of snoring (ie, obesity does not independently affect
QOL in children who snore); quantifying QOL—on scale of 0 to 100, average child has score of 97 to 98; children with
habitual snoring have average score of 78 (intermediate between scores of children with cancer and those with severe
asthma); depression—≈33% of habitually snoring children have increased depression scores (prevalence likely underestimated);
treatment—leads to substantial improvement in QOL
|
| Growth: FTT not as frequent as previously thought (occurs in ≈5% of children with OSA); somatic growth increases
slightly after treatment for OSA, even in obese children; OSA may affect growth hormone-insulin-like growth factor axis
|
| CARDIOVASCULAR CONSEQUENCES
|
| Adults: OSA associated with increased prevalence of ischemic heart disease, myocardial infarction (MI), sudden death
following MI, arrhythmias, ischemic stroke, and hypertension
|
| Children: daytime and nighttime systemic diastolic hypertension; increased sympathetic activity during sleep and wakefulness
(increased sympathetic vasomotor tone associated with poor prognosis and increased risk for metabolic syndrome
and related disorders); decreased LV contractility, increased LV mass, and increased pressure in pulmonary artery (long-
term consequences unknown)
|
| Vascular reactivity: sigh maneuver—large vital-capacity breaths induce increased sympathetic activity, resulting in
vasoconstriction in peripheral cutaneous blood vessels, eg, in fingers; in children with OSA, sigh results not only in increased
sympathetic tone but also in exaggerated sympathetic responsiveness
|
| Disease interaction: OSA likely exacerbates preexisting cardiovascular risk; ≈33% of children with OSA have significant
family history of cardiovascular disease; OSA affects sympathetic vasomotor system, blood pressure, and LV function;
animal models suggest OSA impairs endothelial function and accelerates atherogenesis
|
| Systemic inflammation: evidence that OSA systemic inflammatory disease; intermittent hypoxia induces expression
of proinflammatory genes; interleukin-6 (IL-6)—study of 111 children with habitual snoring found increased levels of
IL-6, correlating with apnea-hypopnea index; C-reactive protein (CRP)—marker for cardiovascular disease; inflammatory
protein induced by IL-6 and increased in children with OSA; increase correlates with severity of disease, even after
controlling for variations in body mass index (BMI); effect of treatment—small study found significant improvement in
levels of CRP in 80% of children treated with tonsillectomy and adenoidectomy
|
| Endothelial function: soluble P-selectin—marker of endothelial dysfunction; when platelets and activated WBCs interact
with endothelium, P-selectin expressed on endothelial surface and shed; this soluble fraction measured in circulation;
elevations seen in children with mild and severe sleep disordered breathing (SDB); biochemical evidence of
endothelial dysfunction (beginning of atherogenesis)
|
| COGNITIVE AND BEHAVIORAL CONSEQUENCES
|
| School performance study: poorly-performing first-graders recruited for sleep studies; OSA 6 to 9 times more common
than in general population; those children with OSA who underwent surgical treatment had significant academic improvement
in second grade
|
| Cognition and attention: other studies have confirmed increased prevalence of cognitive and behavioral problems in
children with OSA; multivariate analysis identified respiratory disturbance as best predictor for cognitive dysfunction,
and sleep pressure score (measure of sleep fragmentation) as best predictor for attentional dysfunction; some children
with habitual snoring but without OSA also exhibit slight cognitive and behavioral problems
|
| Risk for morbidity: severity of disease accounts for ≈40% of variance in morbidity; other contributory factors include
individual susceptibility and lifestyle; factors that increase risk—activity of proinflammatory genes; atherogenic diet;
increased oxidative stress or decreased ability to counteract oxidative stress; presence of apolipoprotein E (ApoE) ┖
(also associated with cardiovascular disease, hypercholesterolemia, and Alzheimer’s disease); factors that decrease
risk—intellectually challenging home environment or other intellectual activity; physical activity
|
| LOCALIZED INFLAMMATION OF UPPER AIRWAY
|
| Local inflammation and snoring: passive smoking, asthma, and allergic rhinitis increase risk for habitual snoring;
evidence for increased upper airway inflammation—morning measurements of exhaled air show that patients with
SDB have increased levels of nitric oxide and pentane in air exhaled from upper airway (but not lower airway); biopsies
of upper airway in adults with OSA showed increased presence of inflammatory cells (eg, T helper cells) in smooth muscle;
exhaled condensate collected from upper airways of children with OSA had higher levels of prostaglandin E2 and
leukotrienes, compared to controls; levels increased with severity of disease
|
| Leukotriene receptors (LTRs): immunohistochemistry performed on tonsillar and adenoid tissues collected from
children with OSA or recurrent tonsillitis; evidence of upregulation of LTR1 and LTR2 in children with OSA; LTR1 and
LTR2 expressed on inflammatory cells (myeloperoxidase-positive) from germinal centers of tonsils of children with
OSA but not of children with recurrent tonsillitis; findings unrelated to infection, allergy, or asthma
|
| Options: surgery standard for children with OSA; no evidence-based treatment recommendations for children with upper
airway resistance syndrome (habitual snoring with some degree of sleep disturbance but does not meet diagnostic criteria
for OSA); leukotriene modifiers—small open-label study found significant improvement in several clinical parameters
(eg, respiratory disturbance, snoring, volume of adenoid tissue) with montelukast therapy; some progression seen in untreated
group; corticosteroids—small study found little improvement with 5-day treatment with systemic corticosteroids;
2 randomized double-blind studies showed improvement of OSA and upper airway resistance syndrome in children
treated with intranasal fluticasone
|
| Efficacy of surgery: OSA resolved (normal sleep studies) in ≈25% of children (N=110) after undergoing tonsillectomy
and adenoidectomy; ≈35% of children considered “not cured”; remainder had some residual symptoms; obesity increases
risk for treatment failure
|
| Adjuvant anti-inflammatory therapy: children with mild residual SDB after tonsillectomy and adenectomy randomized
to 12 wk of treatment with intranasal budesonide and oral montelukast or control (no treatment); treatment
group and control group similar in age, sex, ethnicity, BMI, and severity of disease (before and after surgery); some deterioration
in respiratory resistance seen in control group; respiratory resistance and arousal index almost normalized, and
O2 saturation improved in treatment group
|
Suggested Reading
Arens R et al: Changes in upper airway size during tidal breathing in children with obstructive sleep apnea syndrome.
Am J Resp Crit Care Med 171:1298, 2005; Cherniack EP: Vascular endothelial growth factor and sleep apnea: clutching
at straws in the night. Respiration 74:17, 2007; Constantin E et al: Adenotonsillectomy improves sleep, breathing,
and quality of life but not behavior. J Pediatr 150:540, 2007; Flint J et al: Association between inadequate sleep and insulin
resistance in obese children. J Pediatr 150:364, 2007; Goldbart AD et al: Inflammatory mediators in exhaled
breath condensate of children with obstructive sleep apnea syndrome. Chest 130:143, 2006; Kheirandish-Gozal L et
al: Plasma C-reactive protein in nonobese children with obstructive sleep apnea before and after adenotonsillectomy. J
Clin Sleep Med 2:301, 2006; Mehra R et al: Soluble interleukin 6 receptor: A novel marker of moderate to severe sleep-
related breathing disorder. Arch Intern Med 166:1725, 2006; Minoguchi K et al: Silent brain infarction and platelet activation
in obstructive sleep apnea. Am J Respir Crit Care Med 175:612, 2007; Mitchell RB, Kelly J: Behavior, neurocognition,
and quality-of-life in children with sleep-disordered breathing. Int J Pediatr Otorhinolaryngol 70:395, 2006;
Nacher M et al: Recurrent obstructive apneas trigger early systemic inflammation in a rat model of sleep apnea. Respir
Physiol Neurobiol 155:93, 2007; Punjabi NM, Beamer BA: C-reactive protein is associated with sleep disordered
breathing independent of adiposity. Sleep 30:29, 2007; Tauman R et al: Persistence of obstructive sleep apnea syndrome
in children after adenotonsillectomy. J Pediatr 149:803, 2006.
Educational Objectives
| The goal of this program is to improve quality of life and decrease comorbidity associated with obstructive sleep apnea
(OSA) in children. After hearing and assimilating this program, the clinician will be better able to:
|
 | 1. Diagnose and treat children with OSA.
|
| 2. Describe the anatomic and pathophysiologic mechanisms involved in OSA in children.
|
| 3. Recognize the impact of OSA on quality of life in children
|
| 4. List the cardiovascular abnormalities associated with OSA in children and discuss the implications on morbidity
later in life.
|
| 5. Discuss the role of anti-inflammatory therapy in the management of OSA.
|
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified
conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business
or commercial interest. For this program, the following has been disclosed: Dr. Gozal is on the Speakers’ Bureau for Merck,
Inc.
Acknowledgements
Dr. Gozal was recorded at A Midsummer Night’s Wheeze, sponsored by the California Society of Allergy, Asthma,
and Immunology and Office of Continuing Medical Education, University of Southern California Keck School of
Medicine, and held July 21-23, 2006, in Huntington Beach, CA. The Audio-Digest Foundation thanks Dr. Gozal and
the sponsors for their cooperation in the production of this program.
|
