Central Sleep Apnea (CSA)

Unlike with obstructive sleep apnea, in which airway obstruction restricts airflow, central sleep apnea (CSA) is caused by alterations in respiratory drive (also called ventilatory drive), which during sleep is highly dependent on carbon dioxide levels. Two mechanisms are distinguished:

• Hypoventilation-related CSA: Decreased ventilatory drive causes transient decreases and/or pauses in respiration.

• Hyperventilation-related CSA: Increased ventilatory drive during sleep leads to hypocapnia, which causes a compensatory fall in ventilation that, if abnormally prolonged, leads to recurrent central apnea with arousals.

Hypoventilation-related CSA can result from either an anatomical or functional lesion of the respiratory centers that directly impairs ventilation, resulting in high carbon dioxide (CO₂) levels (hypercapnia). Hypoventilation-related CSA can occur in patients with a central nervous system (eg, primary brain tumor impinging on the brainstem respiratory control center) or neuromuscular disorder (eg, muscular dystrophies). Some medications, particularly opioids, are associated with central sleep apnea.

Paradoxically, in hyperventilation-related CSA, periods of hyperventilation can lead to subsequent apneas. Transient increases in ventilation for any reason may drive the target CO₂ level below the apneic threshold (ie, CO₂ level below which the brainstem ceases respiratory output). The resulting hypocapnia causes periods of subsequent hypoventilation and/or apnea, during which CO₂ increases, eventually triggering a resumption of the breathing cycle. Patients may alternate periodically between hyperventilation and hypoventilation. Cheyne-Stokes breathing is a specific pattern of this ventilatory instability that is characterized by brief periods of apnea followed by progressively faster, deeper breathing (crescendo phase), which then becomes slower and shallower (decrescendo phase) until the patient becomes apneic again and the cycle repeats (see figure Cheyne–Stokes Respiration).

Disturbed ventilation occurs primarily during sleep because during wakefulness there are additional external stimuli for respiration.

Causes of hypoventilation-related CSA with hypercapnia include hypothyroidism, neural lesions (eg, brain stem infarctions, encephalitis, Chiari II type malformation), and certain medications (most commonly opioids, including methadone) (1).

Congenital central hypoventilation syndrome (Ondine curse) is a rare form of idiopathic CSA manifesting in neonates, in some cases associated with Hirschsprung disease (2). A mutation in the PHOX2B gene is responsible for > 90% of cases (3). This mutation produces variable phenotypes, some of which may become recognizable later in life (3). Clinically evident cases are inherited in an autosomal dominant pattern. Sleep hypoventilation can be found in the parents.

An extremely rare condition that can cause CSA is a syndrome of rapid-onset obesity (marked weight gain in < 1 year) with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD); the cause of which is multifactorial. Patients typically present in their second or third decade of life, often after a stress such as infection or surgery (4).

Hyperventilation-related CSA occurs at high altitude in healthy people as a consequence of hypobaric hypoxia. It also occurs in patients with heart failure and Cheyne-Stokes breathing. Sometimes patients treated for OSA with positive airway pressure (PAP) develop central apneas. This phenomenon is referred to as treatment-emergent central sleep apnea (TECSA) (previously known as complex sleep apnea). In most cases, the central apneas resolve over time.

Central sleep apnea may be asymptomatic, detected by caretakers or bed partners who notice long, quiet respiratory pauses and shallow breaths followed by hyperpnea, or restless sleep. Or it may be symptomatic with night time arousals from sleep (sleep maintenance insomnia) or excessive daytime sleepiness (sometimes called wake-time sleepiness), lethargy, or morning headache.

• History and physical examination

• Often polysomnography

• Other studies to identify underlying etiology (eg, arterial blood gas, brainstem imaging, echocardiography)

The diagnosis of CSA is based on careful review of medical history, medication review, and clinical findings, and, when necessary, confirmed by sleep testing at home with portable equipment or in a sleep laboratory using polysomnography (1, 2). However, testing may not be necessary if the cause is evident and reversible (eg, travel to high altitude, heart failure).

Polysomnography

Image

This photo shows an adolescent with narcolepsy being prepared for polysomnography. The electrodes measure brain activity and eye and facial movement when awake and when asleep.

ELISABETH SCHNEIDER CHARPENTIER/SCIENCE PHOTO LIBRARY

The breathing pattern on polysomnography may help distinguish between different causes of central sleep apnea. For example, Cheyne-Stokes breathing, characterized by a regular crescendo-decrescendo breathing pattern between apneas with a cycle length of approximately 60 to 90 seconds suggests heart failure, stroke, or kidney failure. Periodic breathing without a crescendo-decrescendo breathing pattern and a shorter cycle length suggests idiopathic (primary) or high-altitude CSA. Ataxic (also called irregular) breathing may indicate opioid or other drug-induced CSA.

Cheyne–Stokes Respiration

This figure shows graphs that plot respiratory amplitude measured over time in seconds. The graph on the left shows a normal breathing pattern. The graph on the right shows Cheyne-Stokes respiration, a type of abnormal breathing pattern characterized by alternating periods of a regular crescendo-decrescendo (hyperpnea-hypopnea) breathing pattern and cycles of apnea. Cheyne-Stokes respiration can occur in some patients with central sleep apnea (CSA).

Arterial blood gases and bicarbonate levels during wakefulness are helpful in distinguishing hypercapnic from hypocapnic pathophysiology. To diagnose central nervous system causes of apnea with hypercapnia, brain or brain stem imaging may be indicated. If a Cheyne-Stokes pattern is observed, cardiac evaluation, including echocardiography, may also be warranted.

See also Approach to the Patient With a Sleep or Wakefulness Disorder.

• Treatment of underlying disorders

• Supportive care

• Sometimes medications (eg, acetazolamide) and devices (eg, phrenic nerve stimulation)

The treatment of symptomatic central sleep apnea primarily involves optimizing the management of any underlying disorders (eg, heart failure) and avoidance or reduction of exposure to opioids, alcohol, and other sedatives (1, 2). Treatment of patients with symptomatic CSA may additionally involve a trial of supplemental oxygen or respiratory stimulants. Other patients may use positive airway pressure or other devices, depending on the underlying disorder. Patients with minimal symptoms may not require specific therapy.

For patients who have CSA and Cheyne-Stokes breathing despite optimization of cardiac function, supplemental oxygen may decrease apneic and hypopneic episodes. Similarly, continuous positive airway pressure (CPAP) can sometimes be effective in reducing the severity of central sleep apnea caused by heart failure and/or presenting as Cheyne-Stokes breathing (3, 4). The potential benefit of CPAP may in part be due to improvements in hypoxemia and reductions in cardiac preload and afterload.

More advanced PAP ventilation strategies such as adaptive servo-ventilation (ASV) have also been used (5). These ventilation algorithms provide respiratory support or breaths during periods of apnea, then diminish support when patients breathe on their own. The overall clinical impact is regularization of minute ventilation. ASV, when administered with best supportive care, can effectively reduce the severity of central sleep apnea in patients with heart failure (2, 4). However, one clinical trial showed harm in patients with a reduced ejection fraction (6, 7). Thus, the role of ASV in patients with central sleep apnea due to heart failure remains to be clarified. It continues to be used in those with preserved ejection fraction, and guidelines recommend its use with caution in patients with reduced ejection fraction.

Acetazolamide, which causes increased bicarbonate excretion and metabolic acidosis and stimulates respiration, is effective for CSA caused by high altitude and is useful in some patients with heart failure (2).

Electrical pacing of the diaphragm, typically done by transvenous phrenic nerve stimulation, is an option, such as for children > 2 years with congenital central hypoventilation syndrome, or for adults with symptomatic recurrent CSA. Programmable phrenic nerve or diaphragm stimulation systems can produce a rhythmic breathing pattern that stabilizes tidal volume, airflow, and oxygenation, entrains breathing during sleep, and potentially alters disease progression (8).