Central Sleep Apnea Syndromes

PRIMARY CENTRAL SLEEP APNEA

Primary central sleep apnea (CSA) is of unknown etiology (idiopathic) and is characterized on the polysomnogram by recurrent cessation of respiration during sleep with the apnea having no associated ventilatory effort. Ventilation and ventilatory effort cease simultaneously in a repetitive fashion over the course of the night. This recurrent cessation and resumption of ventilation can lead to sleep fragmentation, yielding excessive daytime sleepiness, frequent nocturnal awakenings, or both. Thus patients may present with symptoms of daytime sleepiness or insomnia. Patients with CSA tend to have low normal arterial PaCO2 during wakefulness (less than 40 mm Hg).

CENTRAL SLEEP APNEA DUE TO CHEYNE STOKES BREATHING PATTERN

Cheyne Stokes breathing pattern is characterized by recurrent apneas, hypopneas, or both apneas and hypopneas alternating with prolonged hyperpneas during which tidal volume gradually waxes and wanes in a crescendo-decrescendo pattern. This prolonged waxing and waning pattern of hyperpnea is the hallmark of Cheyne Stokes breathing pattern and distinguishes it from other forms of CSA in which the hyperpnea is shorter and the rise and decline of ventilation is more abrupt. As in other forms of CSA, apneas and hypopneas are associated with absent or reduced ventilatory effort, respectively, due to diminished central respiratory drive. Thus, ventilation and ventilatory effort decline or cease simultaneously in a repetitive fashion. This recurrent cessation of breathing leads to repetitive hypoxic dips, and this, combined with the effort of breathing upon resumption of respiration, can lead to fragmentation of sleep by arousals and frequent state changes.

CENTRAL SLEEP APNEA DUE TO HIGH-ALTITUDE PERIODIC BREATHING

High-altitude periodic breathing is characterized by cycling periods of apnea and hyperpnea with the apnea being associated with no ventilatory effort (a central apnea). The cycle length of this respiratory pattern is generally 12 to 34 seconds. This periodic breathing occurs on ascent to altitude, with virtually everyone demonstrating this respiratory pattern at elevations higher than 7,600 meters and some at altitude lower than 5,000 meters. This leads to fragmentation of sleep with reduced stages 3 and 4 sleep in favor of stages 1 and 2 sleep; REM sleep may or may not be reduced.

CENTRAL SLEEP APNEA DUE TO MEDICAL CONDITION NOT CHEYNE STOKES

Central sleep apnea that is believed to be secondary to a medical condition and that does not exhibit a characteristic pattern of Cheyne Stokes respirations, are classified here. The majority of these patients are probably individuals with brainstem lesions of vascular, neoplastic, degenerative, demyelinating, or traumatic origin. Other etiologies include cardiac and renal disorders.

CENTRAL SLEEP APNEA DUE TO DRUG OR SUBSTANCE

A small number of studies have documented that users of long-acting opioids may have central apneas during sleep. The most common offending drug is methadone; however, the condition has also been described in patients taking time-release morphine and hydrocodone. Breathing abnormalities associated with these drugs are not restricted to central apneas; obstructive hypoventilation, Biot’s breathing pattern, and periodic breathing may also be seen. The description of these patients is complicated by the fact that many of them are on several other drugs (both prescribed and illicit) that may affect sleep and breathing.

PRIMARY SLEEP APNEA OF INFANCY (Formerly Primary Sleep Apnea of Newborn)

Primary sleep apnea of infancy is characterized by prolonged central, mixed, or obstructive apneas or hypopneas associated with physiological compromise (hypoxemia, bradycardia, or the need for intervention such as stimulation or resuscitation). It is a disorder of respiratory control that can be either a developmental problem associated with immaturity of the brainstem respiratory centers or secondary to other medical conditions that produce apnea by direct depression of central respiratory control, disturbance of oxygen delivery, or ventilation defects. Apnea is remarkably common in small preterm infants (apnea of prematurity), occasionally seen in larger preterm or term newborn infants, and sometimes observed in predisposed young (younger than six-months) infants (apnea of infancy). In the preterm infant, sleep apnea can be anticipated, is primarily related to immaturity, may require supportive respiratory and pharmacologic treatment, and will improve with maturation. Apnea in the newborn or infant may be exacerbated or precipitated by a variety of medical conditions that must be recognized and treated to stabilize the apnea (e.g., anemia, infection, hypoxemia, metabolic disturbances, gastroesophageal reflux, drugs or anesthesia). Despite the heterogeneity of infant risk groups and underlying pathophysiology, most studies report a progressive decrease in frequency of apneas and risk of symptomatic apnea secondary to other medical conditions after the early weeks of life.

Obstructive Sleep Apnea Syndromes

OBSTRUCTIVE SLEEP APNEA, ADULT

Obstructive sleep apnea (OSA) is characterized by repetitive episodes of complete (apnea) or partial (hypopnea) upper airway obstruction occurring during sleep. These events often result in reductions in blood oxygen saturation and are usually terminated by brief arousals from sleep. By definition, apneic and hypopneic events last a minimum of 10 seconds. Most events are 10 to 30 seconds in duration but occasionally persist for one minute or longer. Events can occur in any stage of sleep but more frequently occur in stage 1 and 2 NREM and REM sleep than in stage 3 or 4 NREM sleep. Events are usually longer and associated with more severe decreases in oxygen saturation when they occur in REM sleep. Oxygen saturation usually returns to baseline values following resumption of normal breathing. Snoring between apneas is typically reported by bed partners, as are witnessed episodes of gasping or choking and frequent movements that disrupt sleep. Most patients awaken in the morning feeling tired and unrefreshed regardless of the duration of their time in bed. Apneas, hypopneas, and snoring may be exacerbated following the ingestion of alcohol prior to sleep or following an increase in body weight.

Excessive sleepiness is a major presenting complaint. The sleepiness is most evident when the patient is in a relaxing inactive situation. With extreme sleepiness, the patient may fall asleep while actively conversing, eating, walking, or driving. The patient’s quality of life is adversely affected by unrefreshing sleep, sleepiness, and fatigue and by the disruption of the bed partner’s sleep and his or her resultant irritability. However, the frequency of apneas and hypopneas during sleep correlates poorly with daytime symptom severity and impact on quality of life.

OBSTRUCTIVE SLEEP APNEA, PEDIATRIC

Pediatric OSA is characterized by prolonged partial upper airway obstruction, intermittent complete or partial obstruction (obstructive apnea or hypopnea), or both prolonged and intermittent obstruction that disrupts normal ventilation during sleep, normal sleep patterns, or both. Children with OSA may demonstrate several breathing patterns during sleep. Some children have cyclic episodes of obstructive apnea, similar to that of adults with the syndrome. However, some patients, particularly younger children, have a pattern of obstructive hypoventilation, which consists of long periods of persistent partial upper airway obstruction associated with hypercarbia, arterial oxygen desaturation, or hypercarbia and desaturation. Some children may manifest a pattern of UARS similar to that seen in adults, including snoring without identifiable airflow obstruction and increasingly negative esophageal pressure swings and arousals. In children, upper airway obstruction occurs predominantly during REM sleep. Children often do not have cortical arousals in response to the upper airway obstruction, although they may have movement or autonomic arousals. Perhaps as a result of this higher arousal threshold, sleep architecture is usually normal, with normal amounts of slow-wave sleep. Sleep related breathing events during slow-wave sleep are uncommon. Even short obstructive apneas may be associated with severe hypoxemia because children have a faster respiratory rate and lower functional residual capacity than adults.

Most children with OSA present with a history of snoring and difficulty breathing during sleep. Snoring is usually loud and may be punctuated by pauses and gasps, with associated movements or arousal from sleep. However, some patients, particularly infants and those who are weak, may not snore. Patients with obstructive hypoventilation often have continuous snoring without pauses or arousals. Children have a very compliant rib cage. As a result, paradoxical breathing is a prominent sign in these patients. A pectus excavatum may develop. Thoracic retractions may be present. Children may sleep in unusual positions, such as seated or with their neck hyperextended. Diaphoresis may be present. Morning headaches may occur. Many parents of children with OSA are so concerned about their child’s breathing that they sleep with their child or shake their child to terminate the apneas.

Sleep Related Hypoventilation/Hypoxemic Syndromes

SLEEP RELATED NONOBSTRUCTIVE ALVEOLAR HYPOVENTILATION, IDIOPATHIC

Sleep related nonobstructive alveolar hypoventilation is characterized by decreased alveolar ventilation resulting in sleep related arterial oxygen desaturation in patients with normal mechanical properties of the lung. The idiopathic form of alveolar hypoventilation is significantly less common than is hypoventilation associated with medical conditions. In the absence of peripheral impairments, such as severe obesity or abnormalities in pulmonary mechanics such as kyphoscoliosis, the chronic disorder is referred to as idiopathic central alveolar hypoventilation syndrome.

When the patient presents with diurnal, as well as nocturnal, hypoventilation without a readily identifiable pulmonary, endocrine, neurological, ventilatory, muscle, or cardiac cause, the condition should be referred to as idiopathic (primary) alveolar hypoventilation. The defining characteristic is blunted chemoresponsiveness with no other identifiable abnormalities. However, reported cases are few and not studied in enough detail to conclusively establish a well-defined etiology. It is plausible that some patients may have subtle medullary abnormalities not amenable to current imaging modalities. Alternatively, these patients may represent a mixed group of patients with varied underlying conditions erroneously deemed idiopathic as a result of incomplete diagnostic work-up.

A consistent feature of idiopathic diurnal hypoventilation is sleep related hypoventilation. Typically, sleep related hypoventilation develops in the early stages of the condition, as a result of removal of the wakefulness stimulus to breathe. Consequently, ventilatory motor output is severely reduced and therefore insufficient to maintain alveolar ventilation. Nocturnal hypoventilation is often classified as “hypercapnic central apnea,” although it does not meet the strict definition of apnea because ventilatory motor output is reduced but not abolished.

The main feature of the condition is reduced ventilation secondary to decreased tidal volume, with ensuing hypercapnia and hypoxemia. Subsequent sleep fragmentation manifests as an ascent to a lighter sleep stage, transient arousals, or awakening. These sleep effects may lead to insomnia or, if the arousals and awakenings are frequent enough, excessive sleepiness. During REM sleep, hypoventilation is more pronounced, with worsening of the hypoxemia and hypercapnia. Occasionally, patients can have severe oxygen desaturation during sleep, with few arousals and therefore few, if any, sleep complaints. Headaches upon awakening are not infrequent and may be related to the blood-gas abnormalities during sleep.

The presenting clinical picture typically includes both features of the underlying ventilatory insufficiency (e.g., morning headache, cor pulmonale, peripheral edema, polycythemia, and abnormal pulmonary function tests) and features of sleep disturbance (e.g., poor nocturnal sleep and daytime sleepiness). Thus, nocturnal hypoventilation represents either nocturnal ventilatory failure in patients with marginal ventilatory status or worsening of existing chronic ventilatory failure. Arousal from sleep restores alveolar ventilation to a variable degree, only to be decreased again once sleep resumes. Progressive hypoventilation extending into wakefulness frequently occurs. Cardiac arrhythmias, particularly brady-tachycardia, can be associated with the respiratory disturbance. The episodes of oxygen desaturation, which are usually of longer duration than those seen in other forms of sleep related respiratory impairments (e.g., OSA or CSA) can be associated with the development of pulmonary hypertension and heart failure.

CONGENITAL CENTRAL ALVEOLAR HYPOVENTILATION SYNDROME

Congenital central alveolar hypoventilation syndrome (CCHS) is the failure of automatic central control of breathing. CCHS is characterized by the onset of hypoventilation, usually in infancy. The hypoventilation is worse during sleep than wakefulness and is unexplained by primary pulmonary, neurological, or metabolic disease.

CCHS presents in an otherwise normal-appearing infant who does not breathe spontaneously or breathes only shallowly or erratically. In most infants, a problem is evident at birth. The infant requires intubation and then cannot be weaned from mechanically assisted ventilation, despite appearing vigorous and having a normal chest radiogram. Some infants may appear to breathe adequately on clinical examination but experience episodes of hypoventilation (not necessarily apnea) characterized by hypoxemia and hypercapnia. These patients may occasionally present later in life with cyanosis, an apparent life-threatening event, cor pulmonale, or hypoxic neurological damage.

Most patients with CCHS have severe hypoventilation during sleep, to the point that they require mechanically assisted ventilation, although this state-dependent difference may not be apparent during early infancy. Some patients hypoventilate during wakefulness as well as during sleep and require continuous ventilatory support. Most patients with CCHS do not require ventilatory support during wakefulness but may have subtle abnormalities in gas exchange when physically inactive.

Sleep Related Hypoventilation/Hypoxemia Due to Medical Condition

SLEEP RELATED HYPOVENTILATION/HYPOXEMIA DUE TO PULMONARY PARENCHYMAL OR VASCULAR PATHOLOGY

Significant sleep related hypoxemia and the presence of lung parenchymal disease (as documented by pulmonary function testing or radiographic imaging) or pulmonary vascular pathology (as documented by echocardiography, pulmonary artery catheter measurements, or laboratory studies [e.g., in the case of hemoglobinopathies]) are essential features. The observed hypoxemia is not entirely a function of other sleep related breathing disorders such as OSA, CSA or Cheyne Stokes breathing pattern. Diseases known to cause sleep related hypoventilation/hypoxemia due to pulmonary parenchymal or vascular pathology include, but are not limited to, interstitial lung diseases such as desquamative interstitial pneumonitis, usual interstitial pneumonitis, and hypersensitivity pneumonitis; idiopathic and secondary forms of pulmonary hypertension; and sickle cell anemia and other hemoglobinopathies.

The gold standard for identifying sleep related hypoventilation/hypoxemia due to underlying pulmonary parenchymal disease or vascular pathology is sustained (i.e., without saw tooth pattern fluctuations) oxyhemoglobin desaturation in the absence of obstructive, mixed or central apneas or hypopneas, inspiratory airflow limitation (consistent with partial upper airway obstruction), or snoring. Although the PaCO2 during sleep may reflect absolute alveolar hypoventilation with a PaCO2 greater than 45 mm Hg, blood gases may reflect a PaCO2 that is not greater than 45 mm Hg but is abnormally increased relative to awake levels, thereby reflecting a permissive environment for sleep related hypoxemia. In the absence of arterial blood-gas data, sleep related hypoxemia associated with alveolar hypoventilation may be inferred from prolonged and sustained (e.g., without saw-tooth pattern fluctuations) oxyhemoglobin desaturation in the absence of evidence of upper airway obstruction.

SLEEP RELATED HYPOVENTILATION/HYPOXEMIA DUE TO LOWER AIRWAYS OBSTRUCTION

Obstruction or increased airflow resistance in airways below the laryngeal apparatus characterizes these disorders. This results in a heterogeneous distribution of ventilation throughout the gas-exchange units of the lung with consequent underventilation of some regions and normal or over-ventilation of other regions. Chronic obstructive pulmonary disease (COPD) reflects an umbrella term for chronic bronchitis and emphysema. These disorders are associated with incompletely reversible (e.g., by bronchodilator agents) lower airways obstruction. Chronic bronchitis is a clinical entity characterized by a chronic productive cough for at least three months of the year, for at least two consecutive years, in the absence of other identifiable etiologies. It is pathologically characterized by airways inflammation. Emphysema is further characterized by destruction of lung tissue without evident fibrosis. Although a parenchymal disease, emphysema is included in this section due to its association with increased lower airways resistance. Emphysema and chronic bronchitis often coexist in patients. Alpha-1 antitrypsin deficiency is a genetic cause of COPD with an incidence of three in 3,000 live births. Unlike asthma, the airway obstruction characterizing these disorders is generally fixed and not reversed following administration of an inhaled bronchodilator. Bronchiectasis and cystic fibrosis are conditions in which there is obstruction to normal flow of gas. Bronchiectasis is characterized by lower airway inflammation and increased airflow resistance. Increased sputum production is often present as well. Cystic fibrosis was discussed in the section on sleep related hypoventilation/hypoxemia due to pulmonary parenchymal pathology.

The gold standard for identifying sleep related hypoventilation/hypoxemia due to lower airways obstruction is a PaCO2 greater than 45 mm Hg measured during sleep. Alternatively, although PaCO2 during sleep may reflect absolute alveolar hypoventilation with a PaCO2 greater than 45 mm Hg, blood gases during sleep may reflect a PaCO2 that is not greater than 45 mm Hg but is abnormally increased relative to awake levels, thereby reflecting a permissive environment for sleep related hypoxemia. In the absence of arterial blood-gas data, sleep related hypoxemia associated with alveolar hypoventilation may be inferred from prolonged and sustained (e.g., without saw-tooth pattern fluctuations) oxyhemoglobin desaturation in the absence of obstructive, mixed, or central apnea or hypopneas; inspiratory airflow limitation (consistent with partial upper airway obstruction); or snoring.

Patients with chronic lower airways obstruction are increasingly predisposed to developing hypoventilation/hypoxemia as the severity of the underlying lower airways obstruction (as reflected by pulmonary function testing) increases. The odds ratio (adjusted for age, sex, height, weight, smoking, and awake oxyhemoglobin) for spending more than 5% of the sleep time with an oxyhemoglobin saturation less than 90% is 3.36-fold greater when the ratio of forced expiratory volume exhaled in one-second/forced vital capacity is less than 60%.

SLEEP RELATED HYPOVENTILATION/HYPOXEMIA DUE TO NEUROMUSCULAR AND CHEST WALL DISORDERS

Those neuromuscular and chest wall disorders that are relevant to sleep related alveolar hypoventilation share the common feature of an abnormal “ventilatory pump.” Under the conditions imposed by normal sleep physiology, the abnormal pump is unable to meet the ventilatory requirements for maintaining the PaCO2 at or below 45 mm Hg. Impairment of the ventilatory pump in these disorders is related to reduced ventilatory muscle (intercostals, diaphragm, and accessory muscle) contractility or anatomic distortion of the chest wall structures that alters the mechanics and configuration of the ventilatory muscles such that their efficiency is reduced.

OSA may coexist with neuromuscular and chest wall disorders. Sleep related hypoventilation/hypoxemia due to neuromuscular and chest wall disorders may be accentuated in the presence of OSA. In addition, some of these patients have reduced central neural chemoresponsiveness. These factors accentuate the impact of abnormal ventilatory muscles on sleep related hypoventilation/hypoxemia due to neuromuscular and chest wall disorders. The presence of OSA in patients with neuromuscular and chest wall disorders increases the magnitude of daytime sleepiness. Obesity predisposes individuals to developing this condition by increasing the burden on disadvantaged ventilatory muscles. Patients with neuromuscular and chest wall disorders are predisposed to developing atelectasis. Atelectasis reduces oxygen stores and predisposes the individual to having oxyhemoglobin desaturation during sleep. In addition, some patients experience abnormal deglutition and increased risk for aspiration of oral contents into the lungs, which also will promote desaturation during sleep. Some neuromuscular diseases are associated with a cardiomyopathy, which superimposes the comorbidities of congestive heart failure and arrhythmias or dysrhythmias on the ventilatory muscle dysfunction. In this regard, patients with neuromuscular disorders may have orthopnea on the basis of diaphragm weakness, congestive heart failure, or both.

Other Sleep Related Breathing Disorders

SLEEP APNEA/SLEEP RELATED BREATHING DISORDER, UNSPECIFIED

This diagnosis is used for forms of SRBD that cannot be classified elsewhere or may not neatly fit into one category but are believed to be a function of respiratory disturbance in sleep. In some cases, this diagnosis may be assigned on a temporary basis when a SRBD diagnosis seems appropriate but further evaluation is required to determine the specific type of breathing abnormality in sleep.

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Source: American Academy of Sleep Medicine, International Classification of Sleep Disorders, 2nd ed.: Diagnostic and Coding Manual, Westchester, Illinois: American Academy of Sleep Medicine, 2005.