5 - SLEEP DISORDERS
breathing (SDB) describes a group of disorders characterized
by abnormalities of respiratory pattern (pauses in breathing)
or the quantity of ventilation during sleep. Obstructive sleep
apnea (OSA), the most common such disorder, is characterized
by the repetitive collapse or partial collapse of the pharyngeal
airway during sleep and the need to arouse to resume ventilation.
Sleep is thus disrupted, yielding waking somnolence and diminished
neurocognitive performance. The recurrent sleep arousal in association
with intermittent hypoxia and hypercapnia has been implicated
in the occurrence of adverse cardiovascular outcomes. In addition,
there is evolving evidence that SDB may contribute to insulin
resistance and other components of the metabolic syndrome. Despite
considerable progress, most patients remain undiagnosed and
the principal therapeutic approach, continuous positive airway
pressure (CPAP), remains somewhat cumbersome and hence not associated
with optimal compliance rates.
SDB is exacerbated
by alcohol intake. We continue to have a very incomplete understanding
of the neurobiologic mechanisms responsible for the sleep-induced
changes in upper airway motor control that lead to pharyngeal
collapse. The reversibility with therapy of apnea-induced hypertension
and other presumed adverse cardiovascular outcomes is largely
untested. The explanation for reduced prevalence of SDB in women
compared to men and why women present for therapy even less
often than the prevalence numbers would suggest remain unresolved.
It is unclear to what extent SDB in the elderly represents the
same disorder as is encountered in younger populations and thus
deserves similar therapy.
another type of SDB, is characterized by a crescendo - decrescendo
pattern of respiration and is commonly seen during sleep in
patients with congestive heart failure. The presence of this
respiratory pattern appears to be an important risk factor for
the progression of heart failure. More data are needed, however,
to clarify the mechanisms leading to Cheyne-Stokes respiration,
the impact of this abnormal ventilatory pattern on cardiac function,
and the effect of treatment on survival.
In The Last 5 Years
- Reversibility with
CPAP therapy of many of the neurocognitive and quality of life
detriments associated with SDB is suggested by relatively small,
- The strength of
the association between SDB and systemic hypertension in animal
models and large, prospective epidemiologic studies is becoming
more evident. Cross-sectional data also suggest an important
association between SDB and stroke, myocardial infarction, and
congestive heart failure.
- Studies addressing
control of the pharyngeal musculature awake and asleep have
demonstrated the ability of these muscles to respond to local
stimuli awake, thereby compensating for deficient anatomy/collapsibility
and maintaining airway patency. The loss of these reflex mechanisms
during sleep is an important factor in the pathogenesis of SDB.
- Increasing evidence
suggests a familial/genetic influence on predisposition to SDB
independent of obesity. This genetic influence may be mediated
differently in different racial and ethnic groups (Section IV).
- The efficacy of
oral appliances (primarily mandibular advancing devices) in
patients with mild to moderate SDB and of upper airway surgical
procedures over a range of apnea severity has been evaluated.
However, more information is needed before their roles can be
- Data suggest that
positive airway pressure therapy can, over several weeks, eliminate
Cheyne-Stokes respiration in heart failure patients and lead
to improved transplant-free survival.
- Investigate and
advance our understanding of the genetic, neurobiologic and
physiologic mechanisms that are pathophysiologically important
in the development, potentiation, and maintenance of SDB. Studies
are also needed to access the interaction between cardiac dysfunction
and the ventilatory control system in the pathogenesis of Cheyne-Stokes
- Conduct adequately
powered clinical trails, particularly in high risk populations,
to assess the impact of therapy of SDB on functional status,
psychiatric disorders, neurocognitive function, and other disease
processes (hypertension, cardiovascular disease, metabolic syndromes,
etc). Studies assessing the impact of successful therapy of
Cheyne-Stokes respiration on cardiac dysfunction, quality of
life and survival are needed as well.
- Design new and
improved modalities for the treatment of SDB, including pharmacologic,
surgical, oral appliance, behavioral, muscle stimulation, positive
airway pressure (including CPAP compliance), and other novel
approaches. Methods to individualize these therapies to the
different SDB phenotypes are also needed, for example improved
upper airway imaging approaches to define site of collapse.
- Develop novel non-invasive
screening / diagnostic methodologies that are less expensive
and more widely applicable than standard full polysomnography.
This might include biomarkers as indicators of the presence
of SDB, of its severity or of its consequences.
Snoring, a symptom
of increased upper airway resistance during sleep, is extremely
frequent in children, and affects 18-20% of infants, 7-13% of
2-8 year-old children, and 3-5% of older children. The pathophysiology
of SDB in children is still poorly understood. Indeed, while
adenotonsillar hypertrophy is certainly a major contributor
to SDB, other factors such as obesity, craniofacial genetics,
and neural control mechanisms of upper airway patency also appear
to be important. It is clear that the spectrum of disease and
morbidity associated with SDB in children is expanding. As such,
degrees of severity that might have once been considered clinically
irrelevant are now recognized as having substantial neurobehavioral
and cardiovascular consequences.
In The Last 5 Years
- In recent years,
it has become apparent that SDB and snoring are not as innocuous
as previously thought. Indeed, epidemiological and pre-post
treatment analyses have identified substantial morbidities that
primarily affect cardiovascular and neurobehavioral systems.
These morbidities include pulmonary hypertension, arterial hypertension,
nocturnal enuresis, reduced somatic growth, learning and cognitive
deficits, and behavioral problems that resemble attention deficit-hyperactivity
- Failure to timely
diagnosis and treat may prevent some of these morbid complications
from being completely reversible, leading to long-lasting residual
consequences. However, the point of transition between what
constitutes pathology and what is normal remains to be defined.
- Improved phenotypic
characterization of SDB and its manifestations are facilitating
extrapolation of basic science concepts to the pediatric population.
Extended population studies are needed which incorporate gene
databases and also include multi-organ multi-functional categorization
of SDB-related morbidity and response to therapy. Such studies
would allow for development of databases permitting correlation
analyses of large datasets and exploration of multiple hypotheses
generated from basic research findings.
- As part of such
phenotype delineation, development of more sensitive and accurate
tools for definition of disease and morbidity are needed. Currently
available tools are insensitive to morbidity and do not provide
accurate determinations of the degree of homeostatic disturbance
that occurs during sleep and during daytime.
- Develop longitudinal
normative data on sleep and cardiorespiratory patterning in
- Identify genes
and gene products that may contribute to the pathophysiology
of SDB. Conducting these studies in pediatric populations may
have distinct advantages because they are less likely to be
"contaminated" by age-associated co-morbidities present
in adult populations. Some of the "at-risk genes"
may be operative only during infancy and childhood, e.g., genes
responsible for immune modulation and lymphatic tissue growth,
while other genes such as those underlying obesity or craniofacial
phenotype, appear applicable to both children and adults. In
addition, environmental factors or gene-gene interactions during
childhood may modify the phenotypic expression of the disease
- There is considerable
variation in the magnitude of SDB associated morbidities in
both children and adults, and this heterogeneity in end-organ
injury could be due to differences in gene and protein responses
to the various components of SDB. Identification of such genes/proteins,
their functions and interactions, and their post-translational
modifications using currently available genomic and proteomic
approaches may provide opportunities for development of promising
targets for intervention and for reducing morbidity.
- Longitudinal studies
are needed to assess the long-term impact of SDB during childhood
and into adulthood. Particular attention to outcomes among obese
children is important considering the increasing prevalence
of obesity in children.
- One of the major
limitations in diagnosing SDB is the need for relatively complex,
burdensome, and costly procedures such as overnight polysomnography.
Research efforts need to focus on development of reliable screening
methods that are applicable to children and to provide accurate
indicators of either the presence/absence of the disease or
the occurrence of end-organ morbidity. Such developments include,
for example, application of new biomedical sensor technologies,
multi-modality imaging strategies, development of disease-related
artificial intelligence networks, and systematic exploration
of gene and protein markers in biological fluids.
- First-line treatment
of pediatric SDB routinely relies on surgical removal of the
tonsils and adenoids. However, this treatment does have measurable
morbidity, mortality, and financial cost. Thus, novel interventional
approaches need to be developed.