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Central sleep apnea: Pathogenesis

Central sleep apnea: Pathogenesis
Literature review current through: Jan 2024.
This topic last updated: Mar 09, 2023.

INTRODUCTION — Central apneas are periods of absent airflow due to lack of respiratory effort. They occur when inhibitory input to the respiratory center of the brain exceeds excitatory input, which may occur during sleep because sleep abolishes wakefulness-related excitatory input. Recurrent central apneas are the hallmark feature of central sleep apnea (CSA).

In this topic review, the pathogenesis of central sleep apnea is discussed. The definition of a central apnea is provided separately. The etiologies, clinical presentation, diagnosis, treatment, and outcome of CSA are also discussed separately. (See "Polysomnography in the evaluation of sleep-disordered breathing in adults" and "Central sleep apnea: Risk factors, clinical presentation, and diagnosis" and "Central sleep apnea: Treatment".)

HYPERVENTILATION-RELATED CENTRAL APNEA — Respiration during non-rapid eye movement (NREM) sleep is critically dependent on chemical influences, especially arterial carbon dioxide tension (PaCO2). Central apnea results if arterial PaCO2 is lowered below a highly sensitive "apneic threshold" (waveform 1) [1].

Cyclic mechanism — Central apnea is best conceptualized as the outcome to a sequence of events:

First, any of a variety of stimuli induce hyperpnea. As an example, hypoxia (eg, due to secretions or decreased lung volumes) is a common trigger of hyperpnea during sleep [2-5].

The hyperpnea causes ventilatory overshoot and hypocapnia, which induces a central apnea.

The central apnea causes the PaCO2 to rise. Mild hypercapnia (4 to 6 mmHg above eucapnia) restores rhythmic respiration, with or without an arousal [6].

Hyperpnea, ventilatory overshoot, hypocapnia, and another central apnea follow [7-10].

Hypocapnia is not an omnipotent mechanism of reduced ventilation during NREM sleep. In fact, transient hyperpnea occurs in most individuals during sleep, but relatively few develop central apneas. In healthy individuals, the hyperpnea elicits a neurologic phenomenon referred to as short-term potentiation (STP). STP delays and mitigates the magnitude of the ventilatory decline that follows the stimulus [3,4,11,12]. In patients who manifest central apneas, prolonged hyperventilation, prolonged hypoxia, or concomitant inhibitory factors offset the effects of STP and allow central apnea to occur when the PaCO2 is reduced below the apneic threshold [13-16].

Influence of upper airway reflexes — The sequence of events that cause a central apnea are cyclic, which explains why central apneas are usually recurrent, rather than isolated events. Upper airway reflexes may accentuate the cycle described above. During a central apnea, the pharyngeal airway narrows and may occlude [17]. Resumption of breathing requires that tissue adhesion forces and cranio-facial gravitational forces be overcome, which requires that greater negative airway pressure be produced [18]. Upper airway deformation caused by negative airway pressure has been shown to induce central apnea in animal models [19]. Whether this mechanism contributes to central apnea in humans is uncertain. Supporting the possibility that it does contribute, central apneas are more common in the supine position (upper airway narrowing and occlusion tend to be greatest in this position), may be reduced or eliminated by moving into the lateral position (upper airway narrowing and occlusion tend to be less in this position), and may be prevented with nasal continuous positive airway pressure (CPAP) [20-23].

HYPOVENTILATION-RELATED CENTRAL APNEA — Hypoventilation is a less common cause of central apnea. It usually occurs in patients who have a marginal ventilatory status due to a central nervous system disease (eg, encephalitis), a neuromuscular disease (eg, post-polio syndrome), or severe abnormalities in pulmonary mechanics (eg, kyphoscoliosis) [24]. Rarely, patients may have primary alveolar hypoventilation, characterized by blunted chemoreceptor responsiveness [1,25-28].

During sleep, the wakefulness stimulus to breathe disappears, resulting in alveolar hypoventilation and central apneas. Ventilation is restored during arousal from sleep, but declines when sleep resumes. In this setting, the central apnea may not meet strict criteria for being "central" or for being an "apnea":

With respect to an event being central, it may be difficult to distinguish absent respiratory effort due to lack of ventilatory output from the brain, from markedly decreased respiratory effort due to respiratory muscle disease or skeletal deformities.

With respect to an event being an apnea, it may be difficult to distinguish an apnea from severe alveolar hypoventilation, making measurement of the duration of the event imprecise. A certain duration of absent airflow is required to define an apnea. (See "Polysomnography in the evaluation of sleep-disordered breathing in adults", section on 'Apneas'.)

SLEEP-ONSET CENTRAL APNEAS — Central apneas may also occur in healthy individuals during transition from wakefulness to non-rapid eye movement (NREM) sleep. This phenomenon is called sleep state oscillation and its mechanism is similar to that of hyperventilation-induced central apneas.

During the transition from wakefulness to NREM sleep, PaCO2 is at or below the apneic threshold [2,29-31]. Once NREM sleep begins, wakefulness-related excitatory input is lost and a central apnea results. The central apnea causes the PaCO2 to rise and stimulate transient wakefulness. Hyperventilation ensues, returning the PaCO2 to a level at or below the apneic threshold. A central apnea can recur when sleep resumes, allowing the above sequence of events to repeat. PaCO2 stabilizes above the apneic threshold once the transition from wakefulness to sleep is complete, thereby terminating the cycle.

In comparison, central apneas are uncommon during rapid eye movement (REM) sleep. This is probably due to increased ventilatory output from the brain, compared to NREM sleep [32,33]. However, a marked reduction of alveolar ventilation due to loss of intercostal and accessory muscle activity can occur during REM sleep, which may be difficult to distinguish from a central apnea. This is particularly true among patients with poor lung function or neuromuscular disease (eg, severe diaphragm dysfunction).

SUMMARY AND RECOMMENDATIONS

Definition – Central apneas are periods of absent airflow due to lack of respiratory effort. Recurrent central apneas are the hallmark feature of central sleep apnea (CSA). They are usually due to hyperventilation, but can be caused by hypoventilation. (See 'Introduction' above.)

Hyperventilation-related apneas – Patients with central apneas due to hyperventilation develop cycles of apnea or hypopnea alternating with hyperpnea during sleep. This triggers a cyclic sequence of events, including ventilatory overshoot, hypocapnia, central apnea, hypercapnia, recurrent hyperpnea, and so on. Central apneas occur when the PaCO2 falls below an "apneic threshold". (See 'Hyperventilation-related central apnea' above.)

Hypoventilation-related apneas – Most patients with hypoventilation-induced central apneas have a marginal ventilatory status due to a central nervous system disease, a neuromuscular disease, or severe abnormalities in pulmonary mechanics. During sleep, the wakefulness stimulus to breathe disappears, resulting in alveolar hypoventilation and central apnea. Ventilation is restored during arousal from sleep, but declines when sleep resumes, resulting in cyclic hypoventilation. (See 'Hypoventilation-related central apnea' above.)

Sleep-onset central apneas – Central apneas may also occur in healthy individuals at sleep onset as sleep state oscillates between wakefulness and non-rapid eye movement (NREM) sleep. The mechanism is similar to that of hyperventilation-induced central apneas. (See 'Sleep-onset central apneas' above.)

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