+++
Congenital Central
Hypoventilation Syndrome
++
Central hypoventilation syndromes can be primary (congenital central
hypoventilation syndrome and late-onset central hypoventilation
syndrome) or secondary (Table 508-1). Primary
congenital central hypoventilation syndrome (CCHS) is
a relatively rare entity, with less than 1000 cases reported in
the medical literature worldwide. It was originally described in
197072 and is traditionally defined as the idiopathic
failure of automatic control of breathing.72,73 CCHS
is a life-threatening disorder primarily manifesting as sleep-associated
respiratory insufficiency and markedly impaired ventilatory responses
to hypercapnia and hypoxemia.74 Ventilation is
most severely affected during quiet or NREM sleep, a state during
which automatic neural control is predominant. Abnormal respiratory
patterns also occur during active sleep and even during wakefulness,
although to a milder degree. The spectrum of disease in CCHS cases
is far reaching, ranging from relatively mild and often asymptomatic
hypoventilation during quiet sleep with fairly good alveolar ventilation
during wakefulness to recurrent and severe apneic episodes during
sleep also accompanied by severe alveolar hypoventilation during
waking. The increased awareness leading to recognition and earlier
clinical management of CCHS patients has also revealed the presence
of wide-ranging structural and functional impairments of the autonomic
nervous system.75-77 In particular, Hirschsprung
disease75 and tumors of autonomic neural crest
derivatives such as neuroblastoma, ganglioneuroblastoma and ganglioneuroma78,79 are
noted in 20% and in 5% to 10% of CCHS
patients respectively. In addition, abnormal regulation of body
temperature responses or even moment-to-moment heart rate variability
is consistently documented in these patients. In recent years, 3
major advances in our understanding of the pathophysiology and treatment of
CCHS have occurred: (1) paired-like homeobox 2B (PHOX2b)
identification as the putative gene underlying CCHS; (2) functional
imaging of neural structures in patients with CCHS, enabling major
insights into the respiratory and autonomic disturbances of this syndrome;
and (3) implementation of noninvasive mechanical ventilatory support
among many patients leading to improved quality of life without
detriment to survival and other medical outcomes.
++
++
Many years before the discovery of the gene associated with CCHS, substantial
suspicions already supported a genetic cause for this condition.
Early onset during the newborn period in the vast majority of cases,
along with familial recurrence of CCHS as well as parental autosomal
dominant transmission patterns80-85 and the strong
coassociation with Hirschsprung disease, an autosomal recessive
disorder of neural crest origin,92 strongly supported
this assumption. This association of CCHS and Hirschsprung disease
further pointed to the possibility of abnormal development and/or
migration of the neural crest.86-88 Finally, in
2003, a group of investigators from Paris, France, conclusively
identified PHOX2B as the causative gene.89 Not
only were mutations in the PHOX2B, mostly consisting of additional
polyalanine expansions, identified, but the autosomal dominant mode
of inheritance was confirmed, along with evidence of de novo mutation
occurrence in the first generation. The PHOX2B gene plays essential
roles in the embryogenesis of the autonomic nervous system.90-93 Furthermore,
the same team subsequently showed that heterozygous mutations of PHOX2B may
account for several combined or isolated disorders of autonomic nervous
system development, namely, late-onset central hypoventilation syndrome,94,95 Hirschsprung
disease,96 and tumors of the sympathetic nervous
system such as neuroblastoma.97 The identification
of PHOX2b mutations in the vast majority of patients
with CCHS (> 95% of afflicted patients) has enabled genetic
counseling and prenatal diagnosis for this condition. At the same
time, the prevalence of sudden infant death syndrome is high in
CCHS families suggests that the 2 disorders may share common abnormalities
in the embryogenesis of respiratory control.98
++
Functional and advanced structural MRI studies have further revealed
disruptions in the connectivity of brain regions underlying autonomic functions.99-102 As
a corollary to these anatomical findings, decreased heart rate beat-to-beat
variability is consistently found in Holter recordings, and the circadian
patterning of such variability further suggests major imbalances
in sympathetic/parasympathetic regulation in patients with
CCHS.103-106 Furthermore, alterations in blood pressure
regulation during simple daily activities or during sleep further
provide evidence for autonomic nervous system abnormalities.107-109 Neuroocular
findings are also frequently identified in children with CCHS,110 and
marked reduction in the size of arterial chemoreceptors, carotid bodies,
and intrapulmonary neuroepithelial bodies with decreased staining
for tyrosine hydroxylase and serotonin111support
the extensive and diffuse nature of autonomic nervous system involvement.112
+++
Diagnosis and Clinical
Management
++
The clinical presentation of CCHS is extremely variable and therefore requires
a high index of suspicion. For example, some infants will not breathe
at birth and will require assisted ventilation in the newborn nursery.
Such infants may or may not develop adequate breathing during wakefulness
over time, but it will almost universally manifest either apnea
or severe alveolar hypoventilation during sleep that will persist
and become a lifelong problem. The apparent improvement that may
occur over the first few months of life is most likely accounted
for by the normal maturation of the respiratory system and, as such,
does not represent a true change in the severity of the disorder.113 Other
infants may present at a later age with cyanosis, edema, and signs
of right heart failure and may be mistaken for patients with cyanotic
congenital heart disease. However, cardiac catheterization reveals
only pulmonary hypertension. Infants with even less severe CCHS
may present with tachycardia, diaphoresis, and/or cyanosis during
sleep, and others may present with unexplained apnea or an apparent
life-threatening event. Finally, other a priori asymptomatic children
will manifest sleep-associated alveolar hypoventilation following
a respiratory infection or an intercurrent illness at a much later
age, and therefore be assigned to the diagnostic entity of late-onset
CCHS.114-115 The wide spectrum of severity in clinical
manifestations determines the age at which recognition of CCHS takes
place. Increased awareness of this unusual clinical entity and a
comprehensive evaluation of every patient are critical for early
diagnosis and appropriate intervention.
++
Although other symptoms indicative of brainstem or autonomic
nervous system dysfunction may be present, the criteria for diagnosis
of CCHS usually include (1) persistent evidence of sleep hypoventilation
(PaCO2 greater than 60 mm Hg), particularly during quiet
sleep (best measured by overnight polysomnography); (2) usually,
albeit not exclusively, presentation of symptoms occurring during
the first year of life; and (3) absence of cardiac, pulmonary, or
neuromuscular dysfunction that could explain the alveolar hypoventilation.90,116 Furthermore,
hypercapnic ventilatory challenges are an important component for
the diagnosis of CCHS. Steady-state or rebreathing incremental carbon
dioxide challenges are similarly valid and will usually reveal absent
or near-absent responses. Confounding variables, including asphyxia, infection,
trauma, tumor, and infarction, must be discarded from CCHS by appropriate
assessments. Currently, there are no specific guidelines regarding
the use of genetic testing for CCHS. However, identification of
mutations in genes such as RET, HASH, BDNF, GDNF,
the endothelin gene family, and more particularly the PHOX2b gene,
in the context of clinical manifestations supporting central alveolar
hypoventilation, is highly supportive of the diagnosis of CCHS.117,118
++
Congenital central hypoventilation syndrome is
a lifelong condition, and depending on the severity of clinical
manifestations, patients may require ventilatory support while asleep
or as long as 24 hours a day. As such, a multidisciplinary approach
to provide for comprehensive care and support of every child is
needed. The treatment of CCHS should aim to ensure adequate ventilation when
the patient is unable to achieve adequate gas exchange while breathing
spontaneously. Since CCHS does not resolve spontaneously, chronic
ventilatory support is required, such as positive pressure ventilation
(either via a tracheotomy or nasal mask bilevel positive airway pressure)
or negative pressure ventilation. The majority of children with
CCHS initially require positive pressure ventilation through a permanent tracheotomy,
although successful transition to noninvasive ventilation has been
now extensively reported,75 with a trend toward
earlier transition to noninvasive ventilation.119-124 However,
families may opt for negative pressure ventilation as well. Daytime
diaphragm pacing is usually reserved for children with CCHS who
exhibit 24-hour mechanical ventilation dependency, since this approach
provides greater ability to ambulate during daytime. In recent years,
improved pacer technology has prompted many adolescent and young
adult patients to transition to this modality as well. As a rule,
the diaphragm pacer settings should provide adequate alveolar ventilation
and oxygenation during rest as well as during daily activities such
as exercise, while major disadvantages of diaphragm pacing include
cost, discomfort associated with surgical implantation, and potential
need for repeated surgical revisions due to pacer malfunction.125-128
+++
Secondary Central Hypoventilation Syndromes
++
Patients with myelomeningocele and/or with Arnold-Chiari
type II malformation frequently exhibit sleep-disordered breathing,
and such respiratory control disturbances are frequently suspected
as causative mechanisms in the sudden unexpected deaths that occur
in this population. Moderate or severe breathing disturbances occur
in approximately 20% of cases.132,133 The
largest proportion of cases exhibit central apnea, while others show
obstructed breathing; obstructed cases are seldom resolved with
surgical intervention for tonsillectomy, suggesting that the primary
dysfunction is due to damage to central neural structures. The possible
damage to vermis cerebelli structures from foramen magnum herniation
in Arnold-Chiari type II malformation has the potential to interfere
with both blood pressure and breathing regulation, particularly
under extreme challenges of hypotension or prolonged apnea. Compression
of ventral neural surfaces is also a major concern. The presence
of thoracic or thoracolumbar myelomeningocele or the addition of severe
brainstem malformations has been shown to enhance the potential
for manifesting sleep-disordered breathing. Support for affected
patients with Arnold-Chiari II syndrome must consider the needs
for recovery from pronounced hypotension during sleep, the overall
respiratory disturbances that are present, and the surgical interventions
required for decompression of neural structures. As such, a multidisciplinary
approach is necessary and yields optimal outcomes.134 Of
note, alveolar hypoventilation can also be acquired in a child with previously
normal control of breathing following an event resulting in brainstem
injury, such as severe asphyxia, stroke, brainstem tumors, encephalitis,
and infectious encephalopathies.
+++
Prader-Willi
Syndrome
++
Prader-Willi syndrome (PWS) was first described in 1956 by endocrinologists
Prader, Labhart, and Willi (see Chapter 176).
They reported on several patients with poor feeding in infancy, underdeveloped
sexual characteristics, short stature, hypotonia, small hands and
feet, cognitive impairment, and the onset of gross obesity after
infancy. It was not until 1981 that PWS became the first recognized
microdeletion syndrome identified by high-resolution chromosome
analysis.135 Prader-Willi syndrome is now known
to be one of the most common microdeletion syndromes. It is the
first known human genomic imprinting disorder and is the leading
known genetic cause of obesity. Prader-Willi syndrome is also associated
with growth deficiency, abnormal body composition, hyperghrelinemia,136 hypogonadism,
and specific behavioral and learning issues. PWS syndrome results
when there is an absence of the normally active paternally inherited
genes on the proximal long arm of chromosome 15 and, consequently,
no active copy of this genetic information. In approximately 75% of
cases, the absence is due to a de novo deletion of the paternally
contributed chromosome 15 between bands 15q11 and 15q13.2. Most
of these cases involve the same breakpoints on the chromosome, resulting
in the same 4 megabyte deletion. The remaining patients with PWS
(approximately 20% of the cases), have 2 maternal copies of
chromosomes 15 but no paternal chromosome 15, a phenomenon known
as maternal uniparental disomy.137 Among the genes
located in the PWS deletion region is the human necdin gene,
a maternally imprinted gene thought to be involved in cell cycle control
and apoptosis. The necdin gene is completely absent
in the brain and in fibroblasts of patients with PWS. In the homologous mouse
necdin gene, messenger RNA expression is highest in the hypothalamus,
which is where the main pathology of PWS is thought to occur.138 Consensus
diagnostic criteria for PWS were developed in 1993 to aid in early
recognition and diagnosis and have since been confirmed using molecular
and cytogenetic techniques.139,140 Many of the
clinical features of PWS are believed to be secondary to hypothalamic
insufficiency.
++
Patients with PWS present a unique combination of sleep- and
breathing-related manifestations.141-143 Excessive
daytime sleepiness and increased frequency of REM sleep periods
occurs in a subset of PWS patients, while others show disturbances
in circadian rhythmicity with a tendency for multiple microsleep
periods. In addition, the combination of obesity and hypotonia favors
the occurrence of OSA. Patients with PWS also display significant
alterations in central and peripheral elements of respiratory control
that, although not immediately related to the obesity, can be severely
modified and exacerbated by the mechanical consequences of increased
adiposity, ultimately leading to ventilatory failure. A unique and
almost universal feature of these patients is the absence of ventilatory
responses to peripheral chemoreceptor stimulation; this deficiency leads
to abnormal arousal patterns during sleep.144-147 When
untreated, obesity progressively reduces central chemosensitivity
as well, with the latter being ameliorated by growth hormone therapy
and increased muscle mass.148,149 However, growth
hormone therapy has also been associated with reports of sudden
unexpected death, the mechanisms of which remain to be elucidated.150,151
++
Rett syndrome is a severe neurodevelopmental disorder primarily
affecting females and has an incidence of 1:10,000 female births
by the age of 12 years, making it one of the most common genetic causes
of severe mental retardation in females (see Chapter 575).152 The postnatal neurodevelopmental
disorder Rett syndrome is caused by mutations in the gene encoding
methyl-CpG-binding protein 2 (MeCP2), a transcriptional repressor
involved in chromatin remodeling and the modulation of RNA splicing.153,154eTable 508.1 depicts the diagnostic criteria
for Rett syndrome as proposed in 2002.155,156
++
++
The autonomic features of Rett syndrome include abnormalities
in cardiorespiratory patterns and the presence of abnormal blood
pressure responses. Some of the more prominent features of respiratory
pattern abnormalities have been replicated in the murine model of
this disease and should permit a better understanding on the role
of MeCP2 in this respiratory phenotype.157-159 The
typical respiratory abnormalities include hyperventilation, apnea,
breath-holding, and rapid shallow-breathing during wakefulness and
occasionally during sleep.160-162 During wakefulness,
breathing abnormalities are associated with behavioral agitation
as well as with other stereotypic motor functions. During sleep,
an increased frequency of desaturation events and periodic breathing
has been reported. Girls with Rett syndrome who demonstrate hypoxemia
without hypercarbia, awake or asleep, need to be treated with supplemental
oxygen, while those patients who demonstrate evidence for OSA, usually
without a treatable cause, need to be treated with mask bilevel
positive airway pressure during sleep, such as to prevent some of
the morbidities associated with repeated desaturation episodes.
Of note, recent reports using desipramine in mice suggest a potentially
promising role for this pharmacological approach in patients with
Rett syndrome.163,164
+++
Familial Dysautonomia
(Riley-Day Syndrome)
++
Familial dysautonomia (FD) is one of the multiple hereditary
diseases associated with insensitivity to pain. It is an autosomal
recessive disorder with extensive central and peripheral autonomic
abnormalities associated with abnormal development and survival
of unmyelinated sensory and autonomic neurons, with the sympathetic
system being more extensively affected.168 Patients
with FD display inappropriate cardiovascular or catecholamine responses
to physical stress, position changes, or exercise. The gene encoding
for this disorder has been identified as IKBKAP (IκB
kinase–associated protein gene), and more than 99% of
individuals with FD are homozygous for a mutation in intron 20,
which leads to marked reductions in the correctly spliced messenger
RNA in neuronal tissues and consequently to absent expression of
the normal protein.169,170 It should be noted that
although central autonomic symptoms are present, no consistent central neuropathology has been described.
Many of the respiratory disturbances have been attributed to dysfunction
of both chemoreceptors and baroreceptors.171,172 Typically,
patients develop severe and prolonged breath-holding episodes, usually
following emotional outbursts, that can result in decerebrate posturing.
In addition, periodic breathing and central apnea during sleep,
lack of appropriate reflexive tachypnea with respiratory infections,
and inability to adapt to low-oxygen environments are all frequently
reported. When sustained hyperventilation occurs, it is usually
followed by prolonged apnea or even respiratory arrest, further
emphasizing the abnormal chemoreceptor functions in these patients.
Therefore, sleep studies and more extended cardiorespiratory recordings
appear to be necessary in the evaluation and potential treatment
of the respiratory disturbances frequently encountered in patients
with familial dysautonomia.173
++
Apnea in infants has been traditionally defined as a pause in
breathing of greater than 20 seconds or an apneic event of less
than 20 seconds associated with bradycardia and/or cyanosis. Recurrent
episodes of apnea are common in preterm infants, and the incidence
and severity increases as gestational age decreases. Reduced respiratory
drive and impaired pulmonary function due to lung immaturity as
well as a variety of mechanical factors adversely affecting respiratory mechanics
will predispose the premature infant to apnea and hypoventilation,
which, in turn, may precipitate oxyhemoglobin desaturations and/or bradycardia.
Alternatively, excessive peripheral chemoreceptor sensitivity can
lead to destabilization of the respiratory system by creating exaggerated
ventilatory responses to small fluctuations in oxyhemoglobin saturation,
which then may lead to hypocapnia below the apneic threshold and
reduced respiratory drive, thereby promoting apnea. Although apneic
episodes can occur spontaneously and be attributable to the interactions
of prematurity and sleep state alone, such apneic events can also
be provoked or worsened if there is some additional insult, such
as infection, underlying hypoxemia, hyperthermia, or any evolving
intracranial pathology. Although most of the apneic events are self-resolving
and seldom prompt medical recognition or intervention, apneic events
associated with hypoxemia and reflex bradycardia may require active
resuscitative efforts to reverse this condition.
++
Idiopathic apnea of prematurity (AOP) is a common, albeit often
unsuspected, problem in the clinical setting174 and
seems to be primarily related to the immaturity of the infant neurological
and respiratory systems. Premature infants breathe irregularly during
sleep, with markedly greater breath-to-breath variability during
all sleep and waking states, and this enhanced irregularity in their
pattern of breathing renders them susceptible to apnea. Both central
and obstructive apneas are frequently reported in preterm infants,
although the most common form of apnea is mixed apnea (ie, the occurrence
of an initial central apnea that then develops an obstructive pattern
as respiratory effort begins in the context of a collapsed airway).
Mixed apnea typically accounts for more than half of all clinically
relevant apneic episodes, followed in decreasing frequency by central
and obstructive apnea. By definition, there is no airway obstruction
in central apnea, although some studies suggest that the central
airways frequently will progressively reduce their cross-sectional
area and even collapse during the course of a central apnea, with
a rule of thumb proposing that such airway occlusion will be more
likely as the duration of the event is prolonged.175-178 Such
apneic events have also been termed silent obstruction due
to the lack of respiratory effort. Apnea of prematurity generally
resolves by about 36 to 40 weeks postconceptional age. However,
in the most premature infants (born at 24–28 weeks of gestation),
apnea may frequently persist beyond 40 weeks postconceptional age,
finally resolving by 43 to 44 weeks postconceptional age.179,180 Beyond
this developmental stage, the incidence and severity of cardiorespiratory
events does not appear to differ between babies born at term and
those born prematurely.
++
Immaturity of central respiratory control and of the various
ventilatory muscles and ribcage is the key element in the pathogenesis
of AOP.181,182 Since breathing patterns are more disorganized
during REM sleep, the predominant mode of sleep in preterm infants,
it is not surprising that apneic events will be more common, longer,
and more frequently associated with profound bradycardia during
active or REM sleep than during quiet or NREM sleep.183,184 Premature
infants have altered responses to increased CO2 and decreased
O2 and will, for example, reduce rather than mount an increased
respiratory effort response when exposed to elevated CO2.185,186 This
remarkably different response of respiratory timing during hypercapnia
is associated with prolongation of expiratory duration,187,188 which
appears to be centrally mediated within the brainstem,189 especially
via the inhibitory neurotransmitter γ-aminobutyric
acid (GABA).190,191 It is also well established
that premature infants exhibit a biphasic ventilatory response to
decreases in inspired oxygen concentration: a rapid increase in
minute ventilation associated with peripheral chemoreceptor stimulation
is subsequently followed by a decline in ventilation to levels that
fall below those in normoxia. The decrease in ventilation, also
termed hypoxic ventilatory depression,192,193 may
persist for several weeks and even months postnatally and is probably
the result of interactions between the decrease in partial pressure
of carbon dioxide (PaCO2) in arterial blood secondary to
the initial hyperventilation, the accompanying decrease in cerebral blood
flow, a decrease in metabolic rate with hypoxia, the direct inhibitory
of effect of hypoxia on central respiratory centers and neural transmission,
and the activation of inhibitory receptors such as GABAergic, adenosinergic, and/or
platelet-derived growth factor β receptors.194-196 In
this context, administration of adenosine receptor antagonists such
as theophylline or caffeine is routinely used for the treatment
of AOP.
++
There has been speculation that when hypoxic ventilatory depression
develops, additional episodes of apnea are more likely to develop.
In other words, infants experiencing more apneic episodes would
have reduced initial increases in ventilation and subsequent greater
depression of ventilation in response to hypoxia. However, Nock
and colleagues197 has challenged this concept and documented
increased initial ventilation but attenuated ventilatory depression
during the hypoxic challenge in premature infants who developed
more frequent and severe apnea. As indicated earlier, infants with
more severe and/or prolonged apnea may have greater peripheral
chemoreceptor sensitivity and possibly increased central respiratory
drive due to the repetitive periods of intermittent hypoxia, which
are known to induce a condition called long-term facilitation of
ventilation,198 and that therefore, these changes will
promote respiratory instability and thus facilitate the occurrence
of further apneic episodes.197
++
The site of obstruction during either mixed or obstructive apneic events
in the upper airways of premature infants suffering from AOP is
mostly within the pharynx; however, it may also occur at the level
of the larynx, and possibly at both locations.199-201 Integrated
pharyngeal muscle dilator functions are reduced during sleep and
will result in airway collapse and subsequent apnea in susceptible
infants. In addition, the airway may be compromised by postural
changes, such as flexing of the neck, such that spontaneous obstructive
apnea in the absence of a positional issue is uncommon. Reflexes
originating in the upper airway may alter the pattern of respiration
and play a role in the initiation and termination of apneas.202 Stimulation
of the laryngeal mucosa, either by chemical (ie, milk water, saliva)
or mechanical (eg, swallowing) stimuli, may induce reflex inhibition
of breathing and apnea. There appears to be a maturational change
in this type of reflex-induced apnea.203 since
chemical stimulation of the larynx in newborn piglets will elicit
respiratory arrest, which does not develop in older piglets. Preterm
infants have an exaggerated laryngeal inhibitory reflex, which may
elicit prolonged apnea in response to instilling saline in the oropharynx,
gastroesophageal reflux, or during the course of respiratory syncytial
virus infection.204-207
++
Although AOP typically results from immaturity of the respiratory control
system, it also may be the presenting sign of other unrelated diseases
or pathophysiologic states frequently affecting preterm infants.208 AOP
can be diagnosed only after a thorough evaluation has been completed
and all other potential causes of apnea have been ruled out (eTable 508.2).
These include prematurity, infection, impaired oxygenation, central
nervous system problems such as intracranial hemorrhage or brain
malformation, metabolic disorders such as hypoglycemia, electrolyte
imbalance, fatty acid disorders and metabolic acidosis, temperature
instability, and drugs such as narcotics or anticonvulsants. Often,
apnea is attributed to the occurrence of coexisting gastroesophageal
reflux (GER),209,210 but studies assessing the
timing of reflux in relation to apneic events do not support this
association.211-213 Furthermore, there is no clear
evidence that treatment of GER will affect the frequency or severity
of apnea in most preterm infants. Thus, even the presence of GER, as
shown by esophageal pH monitoring in an infant with proven apnea
in a sleep study, should not necessarily assign the cause of the respiratory
disturbance during sleep to GER. When a high level of suspicion
is present, simultaneous assessment of sleep measures and of esophageal
pH and, if possible, impedance esophageal recordings are necessary
to establish that GER and apnea are present and enable formulation
of a more effective management plan in these infants.
++
++
As a reminder, alveolar hypoventilation, oxygen desaturation,
and even frank apnea and bradycardia may occur in premature infants
during nutritive sucking as the result of immaturity. In the normal
healthy infant, as fluid enters the pharynx or larynx, breathing
will be discontinued to protect the airway and prevent aspiration. However,
this protective reflex is excessive in some premature or even full-term
infants and may promote prolonged apnea. With advancing maturation,
feeding-associated apneic events become less frequent and eventually
disappear.214
++
Treatment is usually with either pharmacologic therapy or continuous
positive airway pressure (CPAP) ventilation, although other supportive measures,
such as placing the infant with the head in the midline and the
neck in the neutral position to minimize upper airway obstruction are
clearly recommended. Methylxanthines have been the mainstay of pharmacologic
treatment of apnea of prematurity.215 Both theophylline
and caffeine citrate can be used and are effective possibly through
multiple physiologic and pharmacologic mechanisms of action. A likely
major mechanism of action for xanthine therapy is through competitive
antagonism of adenosine receptors, because adenosine acts as an
inhibitory neuroregulator in the central nervous system.
++
It is important to rule out systemic conditions (sepsis), seizure
disorders, and severe GER before initiation of methylxanthine therapy,
since these compounds will lower the seizure threshold and decrease
muscle tone of the esophageal sphincter.216 Methylxanthines
stimulate the central nervous system and rapidly decrease the frequency
of all types of apnea. Xanthine therapy has been shown to increase
minute ventilation, improve carbon dioxide sensitivity, decrease
hypoxic depression of breathing, enhance diaphragmatic activity,
and decrease periodic breathing. REM sleep may also be acutely decreased,
although this effect will slowly fade over time with ongoing treatment.217 Caffeine
has clear advantages over other methylxanthines because it more
effectively stimulates the central nervous and respiratory systems
and has a higher therapeutic index; as such, central nervous system
toxicity is less of a concern. A recent meta-analysis on the use
of methylxanthines in AOP concluded that both theophylline and caffeine
are effective in reducing the frequency and severity of apneic episodes and
are also of value in reducing the need for mechanical ventilation.218 Elimination
of methylxanthines is prolonged in infants when compared to children
and adults and is especially prolonged in preterm infants. Thus,
serum measurement of theophylline should be monitored whenever aminophylline
or theophylline are used. Caffeine levels are less critical but
should also be followed at least during the initial phases of treatment.
++
The decision to discontinue xanthine therapy is largely empirical,
although it is to be encouraged at least 1 to 2 weeks prior to discharge
from the nursery. Toxic levels of xanthines may cause tachycardia,
cardiac dysrhythmias, feeding intolerance, diuresis, and seizures,
although these side effects are less commonly seen with caffeine
at commonly prescribed therapeutic doses. Although recent concerns
about potential long-term side effects of methylxanthines on the
neurodevelopmental outcomes of low-birth-weight infants have been
recently dispelled, discontinuation of treatment as soon as possible
should be pursued.219,220
+++
Role of Continuous
Positive Airway Pressure
++
Among the nonpharmacologic strategies widely used in the treatment
of AOP, CPAP is relatively safe and effective and usually requires
relatively low pressures to achieve the desired effect (3–6
cm H2O).221,222 CPAP appears to be effective
by splinting the upper airway with positive pressure and decreasing
the risk of pharyngeal or laryngeal obstruction, and also by increasing functional
residual capacity and improving oxygenation. Studies have also compared
nasal CPAP to nasal intermittent positive pressure ventilation (NIPPV)
in the treatment of AOP and found that NIPPV reduces the frequency
of apneas more effectively than nasal CPAP, particularly when apnea
is frequent or severe.223,224 In addition, high-flow
nasal cannula therapy seems to be equivalently efficacious to nasal
CPAP but allows for greater mobility of the infant by parents and
caretakers.225,226 Of course, endotracheal intubation
and artificial ventilation may be needed as a last resort when extremely
severe or refractory episodes are present.
++
The effect of supplemental oxygen on cardiorespiratory events
and sleep architecture in premature infants has also been examined,
and low-flow supplemental oxygen via a nasal cannula will lead to
resolution of AOP and periodic breathing.227-229 The
modest increase in inspired oxygen concentration required to reduce
AOP is probably best explained by a decrease in breath-to-breath
variability.230 Of particular note, unsuspected cardiorespiratory
events, such as apnea and bradycardia, occur very frequently in
otherwise healthy premature infants, and supplemental oxygen will
not only prevent these events but also improve sleep architecture.231 As
mentioned earlier, AOP generally resolves by 36 to 40 weeks postconceptional
age, and beyond 43 to 44 weeks, the risk appears to be similar to
that of term infants, such that the majority of premature infants
should be AOP-free by the time they are discharged home.232 In
this context, the safe minimum apnea-free observation period before
discharge has been suggested as 8 apnea-free days.233 However,
accurate and thorough monitoring in the neonatal intensive care
unit is critical because clinically significant apneas with either
bradycardia and/or desaturation will likely go unnoticed.234-236
++
The clinical significance and long-term consequences of persistent
apnea, bradycardia, or desaturation are still under considerable
debate, particularly because idiopathic apnea is most often seen
in high-risk preterm infants, such that separation of the consequences
of premature birth from the specific effects of AOP is difficult.237,238 Premature
infants who were followed until early school age showed that AOP
was one of the predictors of poor neurodevelopmental outcomes, but
this issue requires more extensive and comprehensive studies before
a definitive conclusion can be reached.
+++
Obstructive
Sleep Apnea
++
The spectrum of sleep-disordered breathing (SDB), which includes obstructive
sleep apnea (OSA), upper airway resistance syndrome, and primary
snoring, occurs in children across the complete age spectrum. OSA
is characterized by repeated events of either partial or complete
upper airway obstruction during sleep, resulting in disruption of
normal gas exchange and sleep patterns.239 OSA
was initially described over a century ago240 and
was rediscovered in children by Guilleminault in 1976241;
the clinical characterization of this syndrome is therefore still evolving,
particularly since this complex and prevalent disorder became recognized
as a major public health problem.
++
Common nighttime symptoms and signs of SDB include snoring, paradoxical
chest and abdomen motion, retractions, witnessed apnea, snorting
episodes, enuresis, frequent nightmares and night terrors, difficulty
breathing, cyanosis, sweating, and restless sleep. Daytime symptoms can
include morning headaches, mouth breathing, difficulty in waking
up, moodiness, nasal obstruction, daytime sleepiness and tiredness, hyperactivity,
and cognitive problems, with severe cases of OSA associated with
cor pulmonale, failure to thrive, developmental delay, or even death.
++
It is clear that the classic clinical syndrome of OSA in children
is a distinct disorder from the condition that occurs in adults,
particularly with respect to gender distribution, clinical manifestations,
polysomnographic findings, and treatment approaches.242,243 OSA
in children is frequently diagnosed in association with adenotonsillar
hypertrophy and is also common in children with obesity, craniofacial
abnormalities, and neurological disorders affecting upper airway
patency.
++
OSA occurs in all pediatric age groups. Although accurate prevalence
information is missing in infants, OSA is particularly common in young
children (preschool and early school years) with a peak prevalence
around 2 to 8 years of age and subsequent declines in frequency,244 the
latter probably related to age-related reductions in viral loads that
contribute to adenotonsillar lymphoid tissue proliferation.245,246 Habitual
snoring, the hallmark indicator of increased upper airway resistance
during sleep, is an extremely frequent occurrence and affects up
to 27% of children, with median frequencies revolving around
10% to 12%.247-254 While specific
clinical and sleep study–based criteria that link polysomnographically
defined thresholds with OSA-associated morbidity are only now being
developed, the current diagnosis of OSA relies on several consensus guidelines255 and
is currently estimated to affect approximately 2% to 3% of
children.256 Thus, the odds for identifying OSA
vary between 1 of every 4 to 6 snoring children. Unfortunately, reliable
identification of habitually snoring children who have OSA, on the
basis of medical history and physical examination, is particularly
arduous and error prone.257,258 Therefore, at this
time, overnight sleep studies remain the only objective and validated
diagnostic approach for establishing the diagnosis of OSA in children.
++
OSA occurs when the upper airway collapses during inspiration,
a dynamic process that involves interactions between sleep state,
pressure-flow airway mechanics, and respiratory drive. When resistance
to inspiratory flow increases or when activation of the pharyngeal
dilator muscle decreases, negative inspiratory pressure may collapse
the airway.47 Both functional and anatomic factors
may tilt the balance toward airway collapse. For example, the site
of upper airway closure in children with OSA is at the site where
the tonsils and adenoids overlap in the upper airway, whereas in
children with OSA in the absence of hypertrophied adenoids and tonsils,
collapse is more likely to occur at the level of the soft palate.43 The
size of the tonsils and adenoids increases from birth to approximately
12 years of age, with the greatest increase occurring in the first
few years of life, albeit proportionately to the growth of other
upper airway structures.43 However, the mass of
upper airway lymphadenoid tissue will particularly proliferate in
children exposed to cigarette smoking,249,259 children
with allergic rhinitis,260,261 asthmatic children,262 and
obviously in children exposed to a variety of upper airway respiratory
infections, particularly viruses.263
++
It is important to remember that although childhood OSA is associated
with adenotonsillar hypertrophy, the presence of the latter does
not mandatorily imply that OSA will be present. OSA is clearly the
combined result of structural, anatomical, and neuromuscular factors
within the upper airway, since patients with OSA do not obstruct
their upper airway during wakefulness, and the correlation between
upper airway adenotonsillar size and OSA is only modest at best. In
addition, a small percentage of children with adenotonsillar hypertrophy
but no other known risk factors for OSA will not be cured by surgical removal
of tonsils and adenoids, while in others, postsurgical improvements
may be only temporary,264,265 Therefore, childhood
OSA is a dynamic process resulting from the combination of structural
and neuromotor abnormalities rather than from structural abnormalities alone.
These predisposing factors occur as part of a spectrum: In some
children (eg, those with craniofacial anomalies), structural abnormalities
predominate, whereas in others (eg, those with cerebral palsy),
neuromuscular factors predominate. In otherwise healthy children
with adenotonsillar hypertrophy and OSA, neuromuscular abnormalities
are subtle.
+++
Associated Conditions
++
OSA also occurs in children with upper airway narrowing due to craniofacial
anomalies and in those with neuromuscular abnormalities such as
hypotonia (eg, muscular dystrophy) or muscular discoordination (eg,
myelomeningocele). In addition to craniofacial anomalies and abnormalities
of the central nervous system, altered soft tissue size may result
from obesity, infection of the airways, allergy, supraglottic edema,
adenotonsillar hypertrophy, mucopolysaccharide storage disease, laryngomalacia,
subglottic stenosis, neck tumors, or enlarged thyroid gland in the
context of hypothyroidism. Of particular emphasis, the global epidemic
increase in obesity around the world is leading to marked increases
in the proportion of obese symptomatic children referred for evaluation
of habitual snoring. Genetic factors clearly also play a role in the
pathophysiology of OSA, as demonstrated by studies of family cohorts,266,267 but
it remains unclear whether this is due to the modulating influence of
genetic factors on ventilatory drive, anatomic features, or both. Ethnicity
is also important, with OSA occurring more commonly in African American
and Hispanic children.253,268,269eTable
508.3 lists the major conditions associated with OSA in children.
++
+++
Clinical Evaluation
and Diagnosis
++
The clinical presentation of a child with suspected OSA syndrome
is usually very nonspecific and therefore requires not only increased
awareness but also consistent and periodic assessments using specific
questions on sleep during physician visits. If symptoms are present,
a thorough history should be obtained and should include detailed
information pertaining to the sleep environment (Table
508-2). In the otherwise normal child, the principal parental
complaint will be snoring during sleep, such that even when the
clinical consultation is conducted by a sleep specialist, the predictive
accuracy of OSA based on history alone is poor, and an overnight
polysomnographic assessment is required. The routine physical examination of
a snoring child is usually not likely to demonstrate significant and
obvious findings. Attention to the size of the tonsils270,271 with
careful documentation of their position and relative intrusion into
the retropalatal space should be conducted. In addition, the presence
of allergic rhinitis, nasal polyps, nasal septum deviation, or any
other factor likely to increase nasal airflow resistance should
be sought. The relative size (ie, micrognathia) and positioning of
the mandible (ie, retrognathia) should also be documented. Finally,
attention should be paid to systemic blood pressure values and to the
presence of auscultatory findings suggestive of increased pulmonary
artery pressures.
++
++
An overnight sleep study remains the only definitive diagnostic
approach for OSA.239,272,273 The American Academy
of Pediatrics has published a consensus statement outlining the
requirements for pediatric polysomnography.255eTable 508.4 shows the currently recommended channels
usually used in the laboratory evaluation of snoring children. Normative
reference values in children are now available, and specific guidelines
for event definitions have also been recently defined.274-284 Of
note, one of the differences between children and adults consists in
the relative resistance of the pediatric upper airway to collapse, and
as such, complete obstructive events are less likely to develop and
are replaced instead by prolonged periods of increased upper airway
resistance leading to alveolar hypoventilation (also termed obstructive
hypoventilation).285 Also worthy of mention,
children with OSA may not manifest electroencephalographic arousals
following obstructive apneas,286,287 and therefore,
sleep architecture is usually relatively preserved even in children
with relatively severe OSA.288 Notwithstanding, although
initial parental surveys suggested that excessive sleepiness is
present among only 7% of children with OSA,257 more
recent studies that included more specific questions on behaviors
associated with excessive daytime sleepiness indicated 40% to 50% have
such symptoms.289 When sleepiness was measured objectively
using the multiple sleep latency test, approximately 13% to
20% of children with OSA displayed increased sleepiness, with
obese children being much more severely affected.290-292
++
++
Of note, the use of ambulatory sleep studies using restricted
number of channels or assessing only specific issues during sleep
(home video or sound recordings or nocturnal oximetry) is now being
intensively evaluated.293-299
+++
Short-Term and
Long-Term Morbidity
++
The consequences of untreated OSA in young children can be serious.
Early reports of children with severe OSA were often associated
with the presence of failure to thrive, although currently only
a minority of children with OSA will present with this problem.
A combination of increased energy expenditure during sleep300,301 and
disruption of the growth hormone and insulin growth factor and binding
proteins302,303 most likely accounts for the reductions
in growth velocity. Adenotonsillectomy and complete resolution of
OSA in children will result in catch-up growth and will also increase
the height and weight velocities even in obese children.304
++
Frequent oxygen desaturations during sleep are common in children with
OSA. Elevation of pulmonary artery pressure due to hypoxia-induced
pulmonary vasoconstriction is a serious consequence of OSA in children
and can lead to cor pulmonale. While pulmonary hypertension is probably more
frequent than predicted from clinical assessment, the exact prevalence
of this complication is unknown. In addition, while treatment of
OSA will result in normalization of pulmonary artery pressures, some
remodeling of the pulmonary circulation may have occurred.305-307 Furthermore,
intermittent hypoxia may also affect left ventricular function through
both direct and indirect effects on myocardial contractility308 and
will lead to increased sympathetic neural activity, and the latter will
be sustained and induce changes in baroreceptor function, leading to
systemic hypertension.309 Increased tonic and reactive
sympathetic activity is present in children with OSA,310-312 and
elevation of arterial blood pressure will occur.313-318 Furthermore,
preliminary evidence suggests that OSA-induced disruption of baroreceptor
function may not resolve after treatment and in fact may be lifelong
in susceptible individuals.319 This concept in
which childhood perturbations may lead to lifelong consequences
deserves further exploration, particularly when considering the
endothelial functional abnormalities and alterations in lipid profiles
among both obese and nonobese children with OSA.320,321 The
long-term implications of the cardiovascular morbidity identified in
pediatric OSA patients has yet to be evaluated.
++
Another potentially
very sobering consequence of OSA in children involves its short-term
and long-term deleterious effects on neuronal and intellectual functions. Although
reports of decreased intellectual function in children with tonsillar
and adenoidal hypertrophy date back to 1889, when Hill reported
on “some causes of backwardness and stupidity in children,”322 only
more recently has this topic been investigated in a more systematic
fashion. Schooling problems have been repeatedly reported in case
series of children with OSA, and OSA may in fact underlie more extensive
behavioral disturbances such as restlessness, aggressive behavior, excessive
daytime sleepiness and poor test performances.323-335 Moreover,
habitual snoring in the absence of OSA has also been demonstrated
to be associated with neurocognitive deficits.336
++
There is increasing evidence to support an association between OSA
and attention deficit hyperactivity disorder (ADHD) in children,
particularly with the hyperactive/impulsive subtype.331 Several
subjective studies have documented that children with habitual snoring
and with OSA often have problems with attention and behavior similar
to those observed in children with ADHD. In addition, multiple survey
studies encompassing almost large cohorts of children have documented
daytime sleepiness, hyperactivity, and aggressive behavior in children who
snored.
++
The mechanism(s) by which OSA may contribute to hyperactivity
remain unknown. It is possible that both the sleep fragmentation
(ie, recurrent arousals) and episodic hypoxia that characterize
OSA will lead to alterations within the neurochemical substrate
of the prefrontal cortex with resultant executive dysfunction.337,338
++
Inverse relationships between memory, learning, and OSA have
also been documented. In addition, improvements in learning and
behavior have been reported following treatment for OSA in children,324,338-344 suggesting
the neurocognitive deficits are at least partially reversible. However,
children who snored frequently and loudly during their early childhood
were at greater risk for poor academic performance in later years,
well after snoring had resolved, suggesting that long-term sequelae
may occur.345
++
In rodent models, intermittent hypoxia during sleep is associated with
significant increases in neuronal cell loss and adverse effects on
spatial memory tasks in the absence of significant sleep fragmentation
or deprivation, and these consequences are magnified during development.346-348
++
Incremental evidence suggestive of adverse effects of sleep-disordered breathing
on quality of life,349-351 depressive mood,351 enuresis,352-354 fatty
liver disease in obese children,355 and increased
health-related costs and morbidity356-358 further
reinforce the extensive and multifactorial implications of this condition.
++
Tonsillectomy and adenoidectomy is usually the first line of
treatment for pediatric OSA, and a recent meta-analysis on the efficacy
of tonsillectomy and adenoidectomy suggested a relatively high immediate
efficacy for this surgical procedure.359 Since
OSA is the conglomerate result of the relative size and structure
of the upper airway components rather than the absolute size of
the adenotonsillar tissue, both tonsils and adenoids should be removed
even when one or the other appears to be the primary culprit. It
should be emphasized that children with OSA are at risk for respiratory
compromise postoperatively due to upper airway edema, increased
secretions, respiratory depression secondary to analgesic and anesthetic
agents, and postobstructive pulmonary edema. A high risk for such
complications is particularly encountered among children younger
than 3 years old, those with severe OSA, and those with additional medical
conditions such as craniofacial syndromes; these patients should
not undergo outpatient surgery, and cardiorespiratory monitoring
should be performed for at least 24 hours postoperatively to ensure
their stability.360-363 Supplemental oxygen results
in improved arterial oxygen saturation in children with OSA without worsening
of the degree of obstruction. However, since oxygen does not address
many of the pathophysiologic features associated with the symptoms
of OSA, it should be reserved as a temporary palliative measure
prior to surgery and clearly should not be used as the first-line
treatment. Furthermore, supplemental oxygen should never be used
without monitoring the potential resultant changes in PCO2 because
some patients with OSA can develop unpredictable and potentially
life-threatening hypercapnia when breathing supplemental oxygen.364,365
++
It has become apparent over the last few years that the outcomes
of tonsillectomy and adenoidectomy may not be as favorable as previously
anticipated,366-369 particularly when OSA is severe preoperatively
or when obesity is present. The frequency of residual mild OSA after
surgical removal of adenoids and tonsils is estimated at 45% to
50% with an additional 20% to 25% displaying moderate
to severe OSA after surgery. These findings have prompted a heated
debate as to whether overnight sleep studies should routinely be
conducted after tonsillectomy and adenoidectomy.370,371 Additional
unresolved issues include the choice of the surgical technique (eg,
cold surgery, coblation, and harmonic laser), the need for tonsillectomy
and adenoidectomy versus nonsurgical approaches, the use of 1 of
these 2 surgical procedures alone, or whether tonsillotomy is preferable to
tonsillectomy.372-376
++
Additional treatment options are available for the management
of OSA in children before tonsillectomy and adenoidectomy, for those
children who do not respond to tonsillectomy and adenoidectomy,
or for the small minority in whom tonsillectomy and adenoidectomy
is contraindicated. When residual OSA after tonsillectomy and adenoidectomy
is moderate to severe, administration of nasal CPAP is usually preferred
and is overall effective and associated with minimal complications.377-385 However,
the cost-benefit ratio of CPAP in milder cases of residual OSA probably
does not justify its use; other approaches are now being advocated.
For example, anti-inflammatory therapy is increasingly being recognized
as a potential alternative to surgery or as an effective intervention
in residual mild OSA after adenotonsillectomy.386-390 In
addition, favorable initial experience with oral appliances and orthodontic
approaches for treatment of OSA in children are now being reported.391-393
++
Selected surgical procedures have been used for complicated cases
of OSA in children. Uvulopharyngopalatoplasty has been found to
be useful in patients with upper airway hypotonia (ie, those with
Down syndrome or cerebral palsy). Craniofacial reconstructive procedures
are usually reserved for some children with craniofacial anomalies.
Other procedures, such as tongue wedge resection, epiglottoplasty,
and mandibular advancement or distraction, may occasionally be indicated.
With the advent of CPAP, tracheostomy is now rarely if ever required.