Sleep Disorders

Updated 09.12.2023
Released 10.01.1993
Expires For CME 09.12.2026

Central sleep apnea

Author: Ali Karaki MD

Editor: Antonio Culebras MD FAAN FAHA FAASM

Introduction

Overview

Central sleep apnea is a disease characterized by the absence or decrease of ventilatory effort resulting in the absence or decrease of airflow lasting 10 or more seconds during sleep. A diagnosis of central sleep apnea is made when central apneas or hypopneas constitute 50% or more of the respiratory events, and the central apnea index is five or more per hour of sleep using polysomnography (06).

The International Classification of Sleep Disorders (ICSD 3rd edition) identifies eight forms of central sleep apnea syndrome:

(1) Central sleep apnea with Cheyne-Stokes breathing (Cheyne-Stokes respiration)
(2) Central sleep apnea due to a medical disorder without Cheyne-Stokes respiration
(3) Central sleep apnea due to high altitude periodic breathing
(4) Central sleep apnea due to a medication or substance
(5) Treatment-emergent central sleep apnea
(6) Primary central sleep apnea
(7) Primary sleep apnea of infancy
(8) Primary sleep apnea of prematurity

In this article, the authors present the epidemiology, pathophysiology, diagnostic criteria, and treatment options for central sleep apnea in adults.

Key points

	• Central sleep apnea is caused by a brief failure of the normal ventilatory rhythm.
	• Obstructive and central sleep apnea may coexist within the same individual.
	• Treatment decisions are based on polysomnographic findings and clinical subtypes of central sleep apnea.
	• In patients with heart failure, the presence of Cheyne-Stokes respiration carries a worse prognosis.
	• There is no evidence that treatment of central sleep apnea reduces mortality.
	• The use of adaptive servo-ventilation for central sleep apnea in heart failure with reduced left ventricular ejection fraction (ejection fraction less than 45%) is associated with increased mortality.

Historical note and terminology

Central sleep apnea was first described in 1966. Gastaut and his colleagues reported abnormal breathing patterns observed in an obese man with Pickwickian syndrome (57). He complained of worsening daytime somnolence related to weight gain. Polysomnography showed three abnormal breathing patterns: central, obstructive, and complex apneas. Since then, central sleep apnea in adults has been defined as the absence of airflow and respiratory efforts for at least 10 seconds (57).

John Hunter first reported an abnormal crescendo-decrescendo breathing pattern in the 18th century (05); John Cheyne reported the pattern in 1818 (31). In 1854, William Stokes asserted that this abnormal crescendo-decrescendo breathing pattern is related to a weak heart (149); the breathing pattern was named Cheyne-Stokes respiration.

Clinical manifestations

Presentation and course

Risk factors for the development of central sleep apnea are heart failure, cerebrovascular accident, atrial fibrillation, chronic renal failure, Arnold Chiari malformation, neuromuscular diseases, severe abnormalities in pulmonary hypothyroidism, mechanics (eg, kyphoscoliosis), and use of opioid medications (06).

Prognosis and complications

Several studies have shown that central sleep apnea is associated with higher mortality. In a retrospective analysis of Veterans Health Administration electronic records from 1999 to 2020, including 2961 with central sleep apnea and 1,487,353 with obstructive sleep apnea, central sleep apnea was associated with a higher risk of mortality (adjusted hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.43-4.65) (04). About one-fifth of patients with central sleep apnea had died within approximately 5 years of diagnosis (04). Some have reported that central sleep apnea is associated with higher mortality in patients with heart failure and chronic kidney disease. Although studies have tested different treatments, such as positive airway pressure, noninvasive ventilation, and oxygen therapy to treat central sleep apnea, whether treating central sleep apnea improves mortality or disease progression is yet to be determined.

Patients with heart failure with Cheyne-Stokes respiration and central sleep apnea had higher mortality rates than those without central sleep apnea or Cheyne-Stokes respiration. In a cohort of chronic heart failure patients, Cheyne-Stokes respiration was associated with higher mortality (HR 4.73, 95% CI 1.10-20.28), but not with hospital admission rates after accounting for age and cardiac systolic function (68). In a cohort of patients hospitalized for acute heart failure (LVEF ≤ 45%) without a history of sleep-disordered breathing, both central sleep apnea and obstructive sleep apnea were associated with increased post-discharge mortality (86).

Central sleep apnea was also associated with higher readmission rates in heart failure. In a cohort of hospitalized patients with systolic heart failure (LVEF≤45%), Cheyne-Stokes respiration was an independent predictor of 6-month cardiac readmission (85). In a cohort of heart failure patients who underwent inpatient sleep screening, individuals with central sleep apnea had higher readmission rates and estimated cumulative cost of readmission at both 3 and 6 months after discharge (123). In a single-center cohort of 1547 subjects with heart failure, central sleep apnea was associated with higher readmission and mortality rates at 30 days, 3 months, and 6 months compared to no sleep-disordered breathing (87).

Several studies have shown that central sleep apnea is associated with an increased risk of arrhythmias, which may lead to higher mortality and morbidity. Among 472 congestive heart failure patients with a cardiac resynchronization device and defibrillator, central sleep apnea was associated with a higher incidence of monitored ventricular arrhythmias (21). In subjects with heart failure and implanted cardioverter-defibrillator device, those who were treated for Cheyne-Stokes respiration had a longer period until the first appropriate cardioverter-defibrillator therapies compared those who did not receive treatment (20). Central sleep apnea is associated with an increased risk for atrial fibrillation. Atrial fibrillation is associated with increased mortality and complications, such as strokes (92; 22), which may confound the association between central sleep apnea and mortality.

One study reported that in patients with chronic kidney disease not on dialysis, central sleep apnea was associated with higher all-cause mortality with an adjusted HR of 40.7 (95% CI 4.8-348.1) (163). The model did not account for cardiovascular disease except for hypertension and antihypertensives. Chronic kidney disease was associated with increased mortality and morbidity, mainly through high rates of cardiovascular disease (97), which may explain the observed associations between central sleep apnea and mortality in this population.

Biological basis

Etiology and pathogenesis

Central apnea results from cessation of respiratory output from the pontomedullary respiratory center (74; 134). Respiratory control during sleep is regulated by metabolic control through chemical receptors located centrally (brain) and peripherally (chemoreceptors), whereas, during wakefulness, the brain plays an additional role in suppressing apneas (50). Lesions or functional impairment of the respiratory control system affecting chemoreceptors, autonomic pathways, the medullary respiratory neuronal network, descending motor pathways, anterior horn cells, motor neurons, neuromuscular junction, or respiratory muscles will lead to abnormal breathing patterns during sleep. Some cases of central sleep apnea are idiopathic, with no apparent lesion of neural pathways involved in respiratory control. Here we describe two concepts, CO2 reserve and loop gain, to explain the pathophysiology of central sleep apnea.

CO2 reserve is the difference between PaCO2 and the apneic threshold. The apneic threshold is the level of PaCO2 to which the brain responds by stopping ventilation, resulting in apnea (103). Central apnea results from PaCO2 dropping below the apneic threshold, where breathing stops until PaCO2 level increases above the threshold before breathing resumes (74). Therefore, a narrow CO2 reserve makes individuals more prone to central apnea.

Eupneic PaCO2 level is higher in sleep than awake breathing (45; 46; 47). When awake, CO2 reserve is narrow, 1 to 2 mmHg, whereas CO2 reserve increases to 2 to 5 mmHg in NREM sleep. The CO2 reserve is further increased in REM sleep, resulting in less occurrence of central apnea (162; 42). At sleep onset, breathing ceases for a few seconds until enough CO2 accumulates to stimulate the respiratory drive, at which point breathing resumes. This is a normal phenomenon at sleep onset. Normally, sleep is maintained, and the PaCO2 remains at the higher level required to stimulate respiratory drive during sleep. However, if there are multiple shifts between wakefulness and sleep, central apnea occurs with each new episode of sleep onset.

CO2 reserve is impacted by metabolic status and hypoxemia. In metabolic alkalosis, the CO2 reserve becomes narrow (prone to central apnea), whereas in metabolic acidosis, CO2 reserve is wide (resistance to central apnea) (76; 79). CO2 reserve is reported to alter with hypoxemia. Hypoxemia was reported to narrow CO2 reserve (34; 35; 128).

The ventilatory control (loop system) can be simplified into two factors: controller (ventilator response to CO2 in chemoreceptors) and plant (gas exchange in the lung) (88; 132). Controller chemosensitivity (Δ minute ventilation/ΔPaCO2) is how much change in ventilation the chemoreceptors make in response to changes in PaCO2. Controller requests greater increase in minute ventilation to given PaCO2 changes in subjects with hypoxemia and heart failure compared to normal subjects (161; 132). This state is called high loop gain due to controller gain and overreaction to small PaCO2 changes, resulting in over-correction of PaCO2 levels and causing central apnea (88; 132).

Plant is the efficiency of a lung to change the PaCO2 level with altering ventilation (ΔPaCO2/Δ minute ventilation). Plant gain means small changes in minute ventilation result in large PaCO2 change (42). This is seen in opioid users and hypercapnic conditions. When PaCO2 level is increased, small changes in minute ventilation result in large changes in PaCO2. Large changes in PaCO2 result in crossing the apneic threshold and inducing central sleep apnea.

Compared to awake status, ventilatory responses to both PaCO2 and PaO2 levels are reduced in sleep, especially in REM sleep (45; 46; 47; 42). However, in pathologic states, such as metabolic alkalosis, hypoxemia, heart failure, and opioid use, high loop gain can alter one’s ventilatory control and lead to over-correction of PaCO2 levels below apneic threshold, resulting in central apneas.

Clinically, central sleep apnea can be classified into two main categories: nonhypercapnic and hypercapnic (143; 13). In nonhypercapnic central sleep apnea, PaCO2 is close to the apneic threshold of the ventilatory response to CO2, especially in NREM sleep. PaCO2 tends to be lower in sleeping patients (43). This type of central sleep apnea is seen in patients with heart failure, stroke, high altitude periodic breathing, and chronic kidney disease or end-stage renal disease. Hypercapnic central sleep apnea is seen in conditions affecting ventilation or respiratory drive, such as central nervous system disease (eg, encephalitis), neuromuscular disease (eg, post-polio syndrome, spinal cord injury), medication (respiratory suppressants, most commonly opioids), or abnormalities in respiratory mechanics (eg, kyphoscoliosis) (43).

Table 1. Current Treatment Options for Sleep Hypoventilation and Central Sleep Apnea Syndromes

Categories	Disorders	Pathophysiology
Central sleep apnea syndromes (associated with normal nocturnal carbon dioxide)	Primary central sleep apnea	Idiopathic. Some postulate a failure of expiratory to inspiratory switch influenced by chemoreceptors and mechanoreceptors (chest wall, lung volumes).
	Central sleep apnea due to Cheyne-Stokes	This disorder is primarily seen in patients with heart failure. High loop gain with feedback delays is induced by poor cardiac output. Generally, patients exhibit enhanced ventilatory drive but narrowed apneic thresholds, leading to cyclic over and undershoot of ventilation with sleep state changes.
	Central sleep apnea due to high-altitude periodic breathing	High loop gain induced by hypoxemia due to decreased fractional oxygen concentration at altitude. Patients exhibit enhanced ventilatory drive but narrowed apneic thresholds, leading to cyclic over and undershoot of ventilation with sleep state changes.
	Central sleep apnea due to narcotics	Loop gain is variable, and opioid effects on the pre-Bötzinger complex result in erratic behavior of the ventilatory control center.
Sleep-related hyperventilation disorders (associated with high nocturnal carbon dioxide)	Ventilatory control abnormalities:
	• Congenital central alveolar hypoventilation syndrome (CCAHS)	Loop gain is blunted. For CCAHS, ventilatory control is affected by mutations in the pHOX2B gene.
	• Sleep-related nonobstructive alveolar hypoventilation, idiopathic	For idiopathic sleep-related nonobstructive hypoventilation, the etiology is unknown. It behaves as a low-loop gain system.
	Neuromuscular disorders: • Spinal muscular atrophy • Myotonic dystrophy • Cervical spinal cord injury	Loop gain is reduced. The primary disorder affects the ability to translate ventilatory center output into appropriate action by the neuromuscular apparatus, thus, rendering ventilatory control blunted.
	Chest wall abnormalities: • Kyphoscoliosis • Thoracoplasty • Obesity hypoventilation syndrome	Loop gain is reduced. Increased work of breathing due to thoracic cage abnormalities, such as skeletal rigidity or excessive load from adipose tissue, blunts the intended response to CO2. Over time, the ventilatory control center undergoes adaptation, reducing the responsiveness to CO2.
	Lung disorders: • Chronic obstructive lung disease • Advanced restrictive lung disease	Loop gain is variable. The mechanical effectiveness of ventilation is adversely affected by the underlying respiratory disease. Ultimately, the ventilatory control center undergoes adaptation, reducing the responsiveness to CO2 in COPD. In restrictive disorders, ventilatory drive remains high, but effectiveness is reduced by gas exchange abnormalities secondary to pulmonary parenchymal damage.
From (143; 12)

The mechanism of central sleep apnea differs based on the underlying etiology.

Cheyne-Stokes respiration is characterized by episodes of central apneas alternating with hyperventilation and exhibiting a crescendo-decrescendo pattern. The periods of hyperventilation cause the PaCO2 to fall below the apnea threshold and central apneas. In these patients, the wake PaCO2 may be slightly low and close to the threshold so that even a slight increase in ventilation, such as occurs with arousals during sleep, drives the CO2 below the threshold and culminates in an apnea. Delayed signaling between controller and plant due to circulatory delay from heart failure results in overcorrection of elevated PaCO2 with hyperventilation, resulting in apnea (42).

In high-altitude central sleep apnea, hypoxemia due to high altitude (low barometric pressure) increases respiratory drive (controller gain), which results in hyperventilation and hypocapnia (84; 161; 119). This is considered an underlying mechanism for high altitude-induced central sleep apnea (84; 161; 119).

Neurologic disease of various etiologies is another frequent cause of central sleep apnea (15). This group includes neuromuscular diseases resulting in respiratory muscle weakness, such as neuropathy, myopathy, myotonic dystrophy, myasthenia gravis, and amyotrophic lateral sclerosis (15; 01). In addition, central nervous system conditions, including encephalitis, cervical cordotomy, and particularly any process involving the medulla (eg, tumor, infarction, hemorrhage, encephalitis), can lead to central apneas. Decompression of the foramen magnum improved central sleep apnea in Arnold Chiari malformation (95).

Myopathies that affect respiratory muscles are likely to decrease tidal volume during sleep, although an increase in respiratory rate may initially allow maintenance of appropriate minute ventilation (01). Hypoventilation during sleep develops with progressive muscle weakness, which leads to frequent sleep disruptions (01). Neuromuscular disorders with effects on respiratory muscle function (eg, encephalitis and poliomyelitis with bulbar involvement, post-polio syndrome, generalized myasthenia gravis, Charcot-Marie-Tooth, Guillain-Barré syndrome, impairment of the phrenic nerve and of nerves involved in the control of respiratory accessory muscles, regardless of the etiology of the neuropathy) can be associated with repetitive central sleep apnea, particularly during REM sleep (02). This is distinct from the more frequent central sleep apnea in NREM sleep seen in other etiologies.

Cardiomyopathy seen in some muscular dystrophies (eg, Duchenne, Becker, limb-girdle, and myotonic dystrophies) (154; 94; 125) and glycogen storage diseases (eg, acid maltase deficiency) (82) may be an additional underlying reason for central sleep apnea and Cheyne-Stokes respiration.

Patients with spinal cord injury have a higher risk of sleep-disordered breathing, especially central sleep apnea (137; 138; 139). High prevalence of central sleep apnea in spinal cord disorders has been reported in traumatic injury (137; 138; 139), spinal muscular atrophy (109; 29), and myelomeningocele (159). The prevalence may vary by level and type of injury and associated comorbid conditions (139). Central sleep apnea is an extremely rare complication of cervical laminectomy for spondylotic myelopathy (156). Studies have shown a higher prevalence of central sleep apnea in cervical compared to thoracic spinal cord injury (137; 138). Patients with tetraplegia are more likely to have central sleep apnea than paraplegia (32).

Spinal cord injury impairs the ability of the ventilatory system to compensate for physiologic challenges, such as neuromuscular weakness, decreased lung volumes, abnormal chest wall mechanics (decreased chest wall compliance) (48; 15), use of respiratory and central nerve system suppressants, and an unopposed parasympathetic system promoting airway narrowing (139). The combination of hypoventilation, increased peripheral chemosensitivity (controller gain), and plant gain (137; 138) is considered in the pathophysiology of central sleep apnea in spinal cord injury (139).

Familial dysautonomia (Riley-Day syndrome), a disorder of the sensory (afferent) autonomic nervous system, is known to have a high prevalence of sleep-disordered breathing: 85% in adults and 95% in children (120). Obstructive sleep apnea is more common in adults, whereas central sleep apnea is more common in children. Abnormal development of chemosensory neurons resulting in abnormal control of ventilator response to hypoxemia and hypercapnia is considered one mechanism for sleep-disordered breathing (118).

Central sleep apnea can occur in patients with congenital and acquired maxillomandibular malformations, enlarged tonsils and adenoids, high and narrow arched hard palate, elongated pharynx, Pierre-Robin syndrome, achondroplasia, and other upper airway changes associated with obstructive sleep apnea and central sleep apnea (93). Treatment of upper airway obstruction often eliminates the central apneas, suggesting that the airway obstruction is the cause of the central apneas; however, mechanisms to explain central sleep apnea are yet to be determined.

Improved upper airway obstruction is associated with the occurrence of central sleep apnea. Treatment-emergent sleep apnea may be seen after initiation of positive airway pressure therapy in obstructive sleep apnea. Conversion of obstructive apneas to central apneas has been reported after surgical correction of nasal or upper airway obstruction (61; 114; 165). High loop gain in obstructive sleep apnea (164; 119), intermittent hypoxemia resulting in increased plant gain and decreased CO2 reserve (34; 35; 119), low arousal threshold (17; 165), prolonged circulation time, and improved CO2 retention with upper airway release (146) are potential mechanisms of central sleep apnea (165).

Epidemiology

	• Central sleep apnea is less prevalent than obstructive sleep apnea (1:10).
	• Central sleep apnea is more prevalent in certain medical conditions (eg, heart failure, atrial fibrillation, stroke, chronic kidney disease, and hypothyroidism).
	• Central sleep apnea can be caused by medications, most commonly opioids.
	• Central sleep apnea can be seen in patients treated for obstructive sleep apnea with positive airway pressure devices.

Prevalence of central sleep apnea is estimated at 5% to 10% of patients with sleep-disordered breathing (103). In a community-based prospective study of adults aged 40 years and older (N = 6441), the prevalence of central sleep apnea and Cheyne-Stokes respiration were 0.9% and 0.4%, respectively (44). Those with central sleep apnea and Cheyne-Stokes respiration were more likely to be older, male gender, and have self-reported cardiovascular disease compared to those with obstructive sleep apnea (44).

Central sleep apnea in medical conditions

Heart failure. A SchlaHF‐XT registry, a cohort of adults with chronic heart failure in Germany, reported the prevalence of central sleep apnea: 15% in reduced LVEF, 12% in mildly reduced LVEF, and 7% in preserved LVEF in 3289 subjects (08). Prevalence of central sleep apnea was higher in men than women (08).

Although heart failure is a risk factor for central sleep apnea and Cheyne-Stokes respiration, studies have failed to consistently show improved central sleep apnea or Cheyne-Stokes respiration with heart transplant or cardiac-assisted device. In a prospective cohort of 13 patients with heart failure and central sleep apnea, central sleep apnea improved in 7 of 13 (54%) and persisted in 3 of 13 (23%), whereas 7 of 13 acquired obstructive sleep apnea more than six months after heart transplant despite normalized cardiac function and sympathetic nerve activity (104). Others also reported similar findings of improved central sleep apnea (36; 155), persistent central apnea (27), and development of obstructive sleep apnea after heart transplant (36; 155).

Atrial fibrillation. Prevalence and incidence of atrial fibrillation were higher in patients with central sleep apnea than int those with obstructive or no sleep apnea (96; 135). In a large cohort of older men, a trend of higher central apnea index associated with a higher frequency of atrial fibrillation or atrial flutter and Cheyne-Stokes respiration was also associated with a higher risk of atrial fibrillation or atrial flutter (108). These results were replicated in another study in a community cohort of 2912 men and women (151). Central sleep apnea (apnea-hypopnea index [AHI] ≥ 15) was seen in 43% of 267 patients with LVEF 50% or lower, and atrial fibrillation was associated with severe central sleep apnea (AHI > 30) (62). In the Sleep Heart Health Study, both central sleep apnea and Cheyne-Stokes respiration predicted incident atrial fibrillation (CAI ≥ 5, odds ratio [OR], 3.00, 1.40-6.44; CSR OR, 1.83, 0.95-3.54; CSA or CSR OR, 2.00, 1.16-3.44) (151). In another cohort of 843 older men without atrial fibrillation, central sleep apnea (OR 2.58; 95% CI, 1.18-5.66) and central sleep apnea or Cheyne-Stokes respiration (OR 2.27; 95% CI 1.13-4.56), but not obstructive apnea or hypoxemia, predicted incident atrial fibrillation (107). The association between atrial fibrillation and central sleep apnea or Cheyne-Stokes respiration was affected by age, where the association was stronger in older men versus younger men (107).

Cerebrovascular disease. Sleep-related breathing disorders, including central sleep apnea, are associated with cerebrovascular events whereby the incidence was found to increase in the acute phase after stroke and then decrease 3 to 6 months after stroke. The incidence was also associated with the severity of the stroke (130). According to a meta-analysis of 75 studies, the overall prevalence of central sleep apnea was seen in 10% (95%CI 6.5 - 14.9) of patients after stroke (99). The overall prevalence of central sleep apnea (≥ 50% of total apneas scored as central, apnea-hypopnea index > 5/hour) was 12% (95% CI 5.5 - 23.4%) in stroke or transient ischemic attack in another metaanalysis (142).

Central sleep apnea and Cheyne-Stokes respiration are often seen immediately after stroke and improve with time. In a study of first stroke or transient ischemic attack, central sleep apnea and Cheyne-Stokes respiration were observed in 62 (38.2%) and 42 (26.1%), respectively in the acute phase and 25 (29%) and six (7.3%) in a stable phase (mean 3 months after acute event) (121).

In a study of 182 patients with stroke, 35 (19%) exhibited Cheyne-Stokes respiration. Individuals with Cheyne-Stokes respiration were older, had a larger left atrium, and were more likely to have low EF (< 50%) and bilateral hemispheric lesions compared to those without Cheyne-Stokes respiration (89). In another study of stroke patients (N=93), Cheyne-Stokes respiration was found in 19% (116). Those with Cheyne-Stokes respiration tended to have lower nocturnal transcutaneous PaCO2 and lower cardiac dysfunction (LVEF < 40%) (116), suggesting that cardiac dysfunction could be a confounding factor to explain the associations between Cheyne-Stokes respiration and stroke.

Chronic kidney disease. A review of eight studies reported an aggregate point prevalence of 9.6% for central sleep apnea in chronic kidney disease (113). Chronic kidney disease was associated with five times increased risk for central sleep apnea (OR 5.2, 95% CI 2.0 - 13.4) (163). In patients with end-stage renal disease who were on hemodialysis (N=15), central sleep apnea was observed in 33%, and fluid removal by ultrafiltration was associated with improvements in apnea-hypopnea index from 60.4 ± 16.7 to 36.0 ± 19.1 (101). This suggests the role of fluid balance in the pathogenesis of central sleep apnea in end-stage renal disease patients.

Hypothyroidism. A few cases reported the association between hypothyroidism and central sleep apnea (110; 148).

Central apnea due to medication use. The most common class of medications associated with central sleep apnea is opioids. Opioid use is associated with sleep-related hypoventilation, obstructive sleep apnea, and central sleep apnea (133). In a meta-analysis of eight studies (N = 560), the prevalence of central sleep apnea in chronic opioid users was 24% (38). The severity of sleep apnea was associated with a morphine equivalent daily dose, with a threshold of greater than 200 mg (38). A study of 50 methadone program subjects and controls (age and BMI matched) reported a central sleep apnea prevalence of 30% in the methadone group (158). In 140 outpatients who were on a standing dose of opioid therapy, 75% had sleep-disordered breathing (AHI > 5/hour) where 39% had obstructive sleep apnea, 24% had central sleep apnea, and 8% had both obstructive and central sleep apnea (160). In those who used opioids for chronic pain (N=24), 17% had a central apnea index greater than 5/hour, and 45% had PaCO2 greater than 45 mmHg (133).

A study showed that opioid-only users had a nearly 2-fold increase in central sleep apnea odds, whereas those who used a combination of opioids and nonopioid central nerve system active medications had 5-fold higher odds of central sleep apnea relative to the reference group. Non-opioid central nerve system active medication alone had a protective effect on central sleep apnea (59).

Other medications reported to cause central sleep apnea are baclofen (124; 117), sodium oxybate (54; 67), valproic acid (63; 64), and ticagrelor (60; 37; 131; 127).

Although opioid use is associated with a higher prevalence of central sleep apnea, the effects of central sleep apnea on mortality and morbidity in chronic opioid users are yet to be determined.

Treatment-emergent sleep apnea. The reported prevalence of treatment-emergent sleep apnea ranges from 5% to 20.3%, with a higher prevalence in split-night studies compared to full-night titration (114). Resolution of treatment-emergent sleep apnea was seen in two thirds of patients after positive airway pressure treatment (over a few weeks to months), whereas some (0.7% to 4.2%) developed treatment-emergent sleep apnea after more than 1 month of positive airway pressure therapy (115). Risk factors for persistent treatment-emergent sleep apnea are high apnea-hypopnea index and central apnea index at baseline and high residual apnea-hypopnea index at titration (115).

A review reported the prevalence of central sleep apnea after non-positive airway pressure (PAP) therapies, such as mandibular advancement device, hypoglossal nerve stimulation, nasal expiratory positive airway pressure, tongue stabilizing device, tracheostomy, and maxillofacial surgery (16). However, because there have been few studies, further investigation is needed to understand central sleep apnea’s prevalence and natural progress.

Diagnostic workup

In contrast to assessments for obstructive sleep apnea (eg, STOPBANG questionnaire), there are no validated questionnaires to assess the risk of central sleep apnea. Central sleep apnea can be suspected from symptoms, clinical course, medical history, and medication and substance use.

There are four different types of sleep studies. Type 1 studies (attended polysomnography) are in-facility polysomnography conducted by sleep technicians. This study is widely used at sleep centers. Type 2 studies (unattended polysomnography) use the same number of channels to monitor sleep but are performed outside the sleep facility without a sleep technician. There is limited evidence that type 2 studies can detect central sleep apnea. Type 3 studies (home sleep testing) are widely used to diagnose obstructive sleep apnea. One study showed a good correlation of detecting central sleep apnea and central hypopneas between type 2 and type 3 sleep studies in heart failure patients (11). Central apnea index detected with WatchPAT, a home sleep test that utilizes seven channels, was also shown to have an excellent correlation of 0.9 with polysomnography-detected central apnea index (126). Nocturnal pulse oximetry is not recommended to diagnose sleep-disordered breathing (91). However, studies have been reinvestigating this diagnostic method, with one study using pulse oximetry to diagnose sleep apnea and another investigating pulse oximetry in combination with questionnaires. The diagnosis of obstructive sleep apnea with this method is potentially promising, but the results must be further tested and studied before the method can be recommended (81; 106). Thus, although some studies have shown that central sleep apnea can be detected in non-type 1 studies, type 1 is the only recommended sleep study for diagnosing central sleep apnea (91).

With standard polysomnography (type 1 study), central and obstructive apneas can be differentiated, the degree of hypoxemia and sleep disturbance can be assessed, and associated cardiac arrhythmias can be identified. End-tidal CO2 monitoring can also be used during the polysomnography, which could help differentiate central sleep apnea versus expiratory apneas and detect hypoventilation. In Duchenne muscular dystrophy, evaluation with polysomnography with continuous end-tidal CO2 monitoring is recommended for any symptomatic subjects, asymptomatic subjects with significant weight gain or adenotonsillar hypertrophy, and nonambulatory subjects not already using nocturnal ventilation and preoperatively (19; 102). Additional evaluation for respiratory function includes spirometry, maximal mid-expiratory flow rate, maximum inspiratory and expiratory pressure, peak cough flow, SpO2 and CO2 using capnography or transcutaneous monitor, venous or capillary blood sample, or arterial blood gas (19).

In some neuromuscular disorders, simultaneous monitoring of intrathoracic pressure with an esophageal balloon catheter will help to distinguish partial airway obstruction from inadequate respiratory effort. Accessory muscle montage, which includes EMG of sternocleidomastoid, nasal alae, and intercostal muscles, can be added for further evaluation in neuromuscular patients. Additional studies that may be helpful in selected cases include arterial blood gases, ambulatory cardiac monitor, supine and sitting spirometry, and assessment of ventilator response to hypercapnia.

Scoring rules for central apnea and central hypopnea. Rules for scoring respiratory events are described in the American Association of Sleep Medicine (AASM) scoring manual (18). Central apnea is scored when:

	(1) The peak signal excursion drops by 90% or greater from baseline on thermal sensor,
	(2) The duration is 10 or more seconds, and
	(3) There is absent inspiratory effort throughout the entire period of absent airflow (18).

Central hypopnea is scored when hypopneas (ie, peak signal excursion drops by 30% or more from baseline in nasal pressure, duration lasts two or more breaths, and the event is associated with a 3% or greater drop in oxygen saturation or arousal) do not meet any of the following criteria:

	(1) Snoring during the event
	(2) Increased inspiratory flattening of the nasal pressure
	(3) Thoraco-abdominal paradox during the event

Cheyne-Stokes breathing is scored when:

	(1) Three or more consecutive central apneas or central hypopneas are separated by a crescendo and decrescendo change in breathing amplitude with a cycle length of 40 or more seconds (typically 45 to 60 seconds) (06), and
	(2) Five or more central apneas or central hypopneas per hour of sleep associated with the crescendo and decrescendo breathing pattern are recorded over 2 or more hours of monitoring.

Diagnostic criteria. The diagnostic criteria for central sleep apnea include subjective excessive daytime sleepiness, witnessed apneas, snoring, or insomnia, and the disorder is not explained by another current sleep disorder, medical disorder, or neurologic disorder; medication use; or substance use disorder. In addition to those criteria, each type of central sleep apnea requires the following specific findings (06; 103).

Central sleep apnea with Cheyne-Stokes breathing (ICD-10: R06.3). Diagnostic criteria: (A or B) + C + D:
	(A) Presence of symptoms (ie, sleepiness, difficulty initiating or maintaining sleep, frequent awakening or nonrestorative sleep, awakening short of breath, snoring, and witnessed apnea). (B) Presence of atrial fibrillation or flutter, congestive heart failure, or a neurologic disorder. (C) Polysomnography (need to meet all 3):
		(1) Five or more central apneas or central hypopneas per hour of sleep.
		(2) The total number of apneas or central hypopneas is greater than 50% of the total numbers of apnea or hypopneas.
		(3) The pattern of ventilation meets criteria for Cheyne-Stokes breathing.
	(D) The disorder is not better explained by another current sleep disorder, medical or neurologic disorder, medication use, or substance use disorder.
Central sleep apnea due to a medical disorder without Cheyne Stokes breathing (ICD-10: G47.37). Criteria A to C must be met:
	(A) Presence of symptoms (ie, sleepiness, difficulty initiating or maintaining sleep, frequent awakening or nonrestorative sleep, awakening short of breath, snoring, and witnessed apnea). (B) Polysomnography (need to meet all 3):
		(1) Five or more central apneas or central hypopneas per hour of sleep.
		(2) The total number of apneas or central hypopneas is greater than 50% of the total number of apnea or hypopneas.
		(3) Absence of Cheyne-Stokes breathing.
	(C) The disorder occurs as a consequence of a medical or neurologic disorder but is not due to medication use or substance use.
NOTE: The majority of patients have brainstem lesions.
Central sleep apnea due to high-altitude periodic breathing (ICD-10: G47.22). Criteria A to D must be met:
	(A) Recent ascent to high altitude (typically at least 2500 meters [8202 feet], although some individuals may exhibit the disorder at as low as 1500 meters). (B) Presence of symptoms (ie, sleepiness, difficulty initiating or maintaining sleep, frequent awakening, or nonrestorative sleep, awakening short of breath, snoring, and witnessed apnea). (C) The symptoms are clinically attributable to high-altitude periodic breathing; polysomnography, if performed, demonstrates recurrent central apneas or hypopneas primarily during NREM sleep at a frequency of five or more per hour. (D) The disorder is not better explained by another current sleep disorder, medical or neurologic disorder, medication use, or substance use disorder.
*Cycle length in central sleep apnea due to high altitude should be 12 to 34 seconds.
Central sleep apnea due to a medication or substance (ICD-10: G47.39). Criteria A to E must be met:
	(A) Taking an opioid or other respiratory depressant. (B) Presence of symptoms (ie, sleepiness, difficulty initiating or maintaining sleep, frequent awakening or nonrestorative sleep, awakening short of breath, snoring, and witnessed apnea). (C) Polysomnography (need to meet all 3):
		(1) Five or more central apneas or central hypopneas per hour of sleep.
		(2) The total number of apneas or central hypopneas is greater than 50% of the total number of apnea or hypopneas.
		(3) Absence of Cheyne-Stokes breathing.
	(D) The disorder occurs as a consequence of an opioid or other respiratory depressant. (E) The disorder is not better explained by another current sleep disorder.
Primary central sleep apnea (ICD-10: G47.31). Criteria A to D must be met:
	(A) Presence of symptoms (ie, sleepiness, difficulty initiating or maintaining sleep, frequent awakening or nonrestorative sleep, awakening short of breath, snoring, and witnessed apnea) (B) Polysomnography (need to meet all 3):
		(1) Five or more central apneas or central hypopneas per hour of sleep.
		(2) The total number of apneas or central hypopneas is greater than 50% of the total number of apnea or hypopneas.
		(3) Absence of Cheyne-Stokes breathing.
	(C) There is no evidence of daytime or nocturnal hypoventilation. (D) The disorder is not better explained by another current sleep disorder, medical or neurologic disorder, medication use, or substance use disorder.
Treatment-emergent central sleep apnea (ICD-10: G47.39). Criteria A to C must be met:
	(A) Diagnostic polysomnography shows five or more predominantly obstructive respiratory events. (B) Polysomnography during the use of positive airway pressure without a backup rate shows significant resolution of obstructive events and emergence or persistence of central apnea or central hypopnea with all of the following:
		(1) Central apnea index five or more per hour.
		(2) The total number of apneas or central hypopneas is greater than 50% of the total number of apnea or hypopneas.
		(3) Absence of Cheyne-Stokes breathing.
	(C) The central sleep apnea is not better explained by another central sleep apnea disorder.

Management

Management of central sleep apnea depends on the underlying etiology (10). The urgency of initiation of therapy also depends on the severity of symptoms and the severity of physiological sequelae (eg, oxyhemoglobin desaturation during sleep). If the symptoms are mild, emphasis is given to the management of the underlying disorder.

Below, we include available therapies for central sleep apnea. The basic rule for treating central sleep apnea is to treat the underlying etiology. Improving heart failure control is the priority in treating central sleep apnea in patients with heart failure and central sleep apnea (136). Reduction in pulmonary capillary wedge pressure was associated with decreased central sleep apnea in patients with stable heart failure (147). Cases were reported on cardiac resynchronizing therapy (145; 83; 14), left ventricular-assisted device (155; 153), and heart transplant (36; 104) improving central sleep apnea. However, the effects of these interventions on central sleep apnea have not been consistent. In end-stage renal disease, bicarbonate buffer use during hemodialysis and nocturnal dialysis improved central sleep apnea (10).

Continuous positive airway pressure (CPAP), adaptive servo-ventilation (ASV), bilevel positive airway pressure (BPAP), oxygen, phrenic nerve stimulation, and pharmacologic therapies are studied and available in treating hyperventilation-related central sleep apnea. In hypercapnic central sleep apnea, BPAP-S, S/T, or nocturnal ventilatory support to improve ventilation is recommended to improve ventilation. Evidence for the modalities in treating the centrally triggered respiratory events remains circumstantial. Adequately powered randomized controlled trials with hard endpoints, such as mortality, are needed to determine which treatment modality provides the largest clinical benefit in individuals with central sleep apnea.

Continuous positive airway pressure (CPAP) is considered the first-line therapy for central sleep apnea with or without Cheyne-Stokes respiration in heart failure patients (STANDARD recommendation) (10; 09). In-facility CPAP titration is recommended for heart failure patients with central sleep apnea. Use of automatic positive airway pressure is not recommended.

The CANPAP trial is the largest randomized clinical trial to date, involving 258 heart failure patients with central sleep apnea treated with CPAP (26). This trial did not demonstrate an effect of CPAP on heart transplant-free survival; however, posthoc analysis demonstrated a reduction in the apnea-hypopnea index of less than 15, with CPAP therapy associated with improved transplant-free survival compared to control subjects (07). In a retrospective cohort of patients with newly diagnosed heart failure (N = 30,719), those who were tested, diagnosed, and treated had better survival compared to those “not tested” (HR 0.33, 95% CI 0.21-0.51) and those “tested, diagnosed, but not treated” (HR 0.49, 95% CI 0.29-0.84), accounting for age, gender, and Charlson Comorbidity Index (73). CPAP and oxygen were two treatments used in this cohort, where most subjects used CPAP (512 of 545) (73).

Physiological benefits have been reported for CPAP therapy. CPAP has been shown to reduce apnea-hypopnea index and improve left ventricular ejection fraction in meta-analyses (10). The rationale for CPAP therapy comes from animal models in which upper airway narrowing and generation of increased negative intrathoracic pressures leading to ventilator overshoot and hypocapnia is thought to play a role (66). Care must be taken in CPAP titration; if the pressure necessary to alleviate the problem is exceeded, central sleep apnea may appear again due to the excessive pressure, presumably related to an increased expiratory load with excessive nasal positive pressures. However, recognition of CPAP-induced central sleep apnea can be problematic because patients titrated with CPAP for obstructive sleep apnea may also have central sleep apnea if excessive pressures are used.

Adaptive servo-ventilation is an advanced BPAP with a unique internal algorithm that tracks the patient's breathing pattern and adjusts the inspiratory pressure support breath-by-breath to maintain slightly reduced minute ventilation to prevent periodic hyperventilation and episodic hypocapnia. Adaptive pressure support maintains lung insufflation during apneic episodes, but unlike BPAP, this support is rapidly withdrawn at the end of apnea and with the commencement of respiration. This prevents hyperventilation and, thereby, provocation of the next apneic event (72).

SERVE-HF was an international, multicenter, randomized, parallel-group study that enrolled 1325 patients with congestive heart failure and central sleep apnea. Patients were randomized to receive medical treatment with adaptive servo-ventilation or medical treatment alone (control). The primary endpoint was either death from any cause, lifesaving cardiovascular intervention (eg, resuscitation for cardiac arrest, cardiac transplantation), or worsening heart failure necessitating hospitalization. The secondary endpoint included cardiovascular death. The addition of adaptive servo-ventilation to medical treatment did not improve the quality of life or symptoms of heart failure, but a surprising finding from the study was that the risk of cardiovascular death was increased. All-cause mortality and cardiovascular mortality were significantly higher in the adaptive servo-ventilation group than in the control group (HR for death from any cause, 1.28; 95% CI 1.06-1.55; and HR for cardiovascular death, 1.34; 95% CI 1.09-1.65) (41; 49). This study used an older version of adaptive servo-ventilation in which the EPAP was fixed and may have been the reason for the results, but further trials need to be done to evaluate this theory. At this time, adaptive servoventilation is not recommended for patients with moderate or severe central sleep apnea with an ejection fraction of 45% or less (09).

A retrospective analysis of patients with heart failure (LVEF ≤ 45%) and apnea-hypopnea index greater than 15/hour with positive airway pressure therapy (N = 231, ASV 62%, BPAP 1%, CPAP 36.8%) showed no negative or positive impact on lung function, including respiratory muscle strength (53). Therefore, positive airway pressure therapy is safe from a respiratory perspective. It is important to note that this study included both obstructive sleep apnea and central sleep apnea patients.

In meta-analyses, adaptive servo-ventilation was considered superior in reducing the apnea-hypopnea index compared to CPAP, oxygen, or control therapy in heart failure (30). A meta-analysis comparing treatments for central sleep apnea and heart failure (EF ≤ 50%) reported that CPAP showed positive impacts on quality of life and cardiovascular outcomes at 3 months, whereas the benefits were not seen at 6 months (157). However, at this time, it is unclear what outcomes we should target for the treatment. Because the apnea-hypopnea index is not associated with mortality, the importance of this finding is yet to be determined.

Bilevel positive airway pressure (BPAP) may be used if the patients require high positive airway pressure levels or ventilator support for alveolar hypoventilation. In patients with hypoventilation, BPAP-S, BPAP-ST, and average volume-assured pressure support can be considered (143). Careful assessment is recommended because BPAP could precipitate central apneas by augmenting ventilation (10). In heart failure, BPAP-ST has been studied in nonrandomized studies (10). BPAP-ST can be considered only when adequate response is not achieved with other therapies, CPAP, adaptive servo-ventilation, or oxygen therapies (10).

Opioid-related central sleep apnea can be treated with BPAP-S/T and adaptive servo-ventilation rather than CPAP, though the evidence behind this management is not very robust (28). Adaptive servo-ventilation is effective for both central and obstructive apnea associated with opioid use (77; 75). In five chronic opioid users, CPAP therapy decreased obstructive apnea events but increased central apnea events, whereas adaptive servo-ventilation improved both obstructive and central events. In a prospective intervention study of chronic pain patients (100 or more morphine equivalents for longer than 4 months) treated with adaptive servo-ventilation, overall apnea-hypopnea index, central apnea index, and obstructive apnea index decreased at three months (144).

Oxygen therapy has been shown to reduce central sleep apnea. Supplemental oxygen is hypothesized to improve central sleep apnea by (1) decreasing apneic threshold (increase in CO2 reserve) and (2) decreasing hypocapnic ventilator response and lowering resting eupneic pCO2, leading to decreased plant gain (34; 35; 119). However, oxygen must be used cautiously because it can prolong apneas by abolishing the hypoxic drive.

A randomized controlled study of 56 patients with Cheyne-Stokes respiration and heart failure (LVEF ≤ 45%) found a decrease in apnea-hypopnea index and oxygen desaturation index and an increase in left ventricular ejection fraction in the nocturnal oxygen group (as compared with usual care) at 12 weeks (140). A randomized trial of 25 stable heart failure patients (mean LVEF 17 ± 0.8%) with 14 patients with Cheyne-Stokes respiration showed both oxygen therapy and nasal CPAP therapy decreased the apnea-hypopnea index (baseline 44 ± 9 to 18 ± 5 and 15 ± 8 events per hour, respectively) without significant difference between the two groups (90). Another randomized, open trial of 51 adults with LVEF less than or equal to 45% with at least moderate sleep apnea (mean AHI 36.8 with central index 23.3) reported decreased apnea-hypopnea index with nocturnal oxygen therapy at first night and 6 months (24).

Adding supplemental oxygen to CPAP may be an alternative when the central sleep apnea persists with positive airway pressure therapy. In a retrospective chart review of 162 United States veterans with central sleep apnea, CPAP was effective in eliminating central sleep apnea (CAI ≤ 5/hour) in 48%, CPAP + O2 combination was effective in an additional 25%, and BPAP + O2 in 11% (33).

Phrenic nerve stimulation may be considered for symptomatic central sleep apnea patients who cannot tolerate or fail to respond to positive airway pressure or other therapies. It is an implantable device that causes unilateral transvenous phrenic nerve stimulation(03; 56; 55).

A meta-analysis of five trials (one RCT and four intervention studies) showed an overall reduction of apnea-hypopnea index by 26.7/hour with phrenic nerve stimulation (100). In a pooled cohort analysis (N = 208), the use of a phrenic nerve stimulation device (Remedi) decreased the apnea-hypopnea index by a median of 22.6/hour and central apnea index by a median of 19.6 at 6 months, resulting in a central apnea index of median 1.5/hour (range 0.2-5.9) (56). These effects persisted at the 12-month follow-up. There were significant improvements in Epworth Sleepiness Scale score, Patient Global Assessment, NYHA classification, Minnesota Living with Heart Failure Questionnaire, and left ventricular ejection fraction at 12 months (56). Studies have shown that phrenic nerve stimulation improved apnea-hypopnea index, sleep symptoms, and patient-reported outcomes such as quality of life, persisting up to 36 months (39; 70; 69; 40; 52). Transvenous phrenic nerve stimulation reduced heart failure hospitalization at 6 months (157). However, no trial compared phrenic nerve stimulation with CPAP or other therapies. Although this device has been approved by the United States Food and Drug Administration since 2017, optimal candidates for this therapy are yet to be determined (152).

Patients with treatment-emergent central sleep apnea are at higher risk of discontinuing the therapy (98). Using data from a United States telemonitoring device (N=133,006), Liu and colleagues reported a central sleep apnea prevalence of 3.5% at 1 or 13 weeks; 55% were transient, 25% persistent, and 20% emergent. Those with treatment-emergent central sleep apnea were older and had a high residual apnea-hypopnea index and central apnea index at week 13 and more leaks (compared to those without treatment-emergent central sleep apnea) (98).

The conservative approach is watchful waiting on CPAP therapy, as treatment-emergent central sleep apnea may spontaneously resolve (80; 115). The other approach is to initiate adaptive servo-ventilation or BPAP-S/T if the left ventricular ejection fraction is greater than 45% and CPAP with oxygen if the left ventricular ejection fraction 45% or less (111).

Pharmacologic therapy. There is insufficient evidence to recommend medication therapy for central sleep apnea (09). It can be considered in patients who do not tolerate or benefit from positive airway pressure therapy. Treatment with respiratory stimulants, such as theophylline, acetazolamide, and medroxyprogesterone, may decrease central sleep apnea. However, it is important to note that benzodiazepines and other sedative medications are contraindicated in patients with central sleep apnea associated with significant hypoxemia or those secondary to hypoventilation syndromes.

Acetazolamide may be considered for primary central sleep apnea (OPTION) (10). A meta-analysis showed favorable effects of acetazolamide on both central and obstructive sleep apnea (141). Overall reduction in the apnea-hypopnea index was 37.7%, corresponding to 13.8/hour, and dose-dependent effects were seen up to 500 mg/day. In subgroup analyses, acetazolamide decreased the apnea-hypopnea index in those with central sleep apnea due to high altitude, heart failure, and idiopathic causes.

Zolpidem and triazolam may be considered for primary central sleep apnea (OPTION) when the patient does not have a risk factor for respiration depression (10; 09). In an open-label study of 20 patients with newly diagnosed idiopathic central sleep apnea without systolic or diastolic cardiac dysfunction, zolpidem for an average of nine weeks decreased central apnea-hypopnea index from 26 ± 17.2 to 7.1 ± 11.8/hour and overall arousals (129). In a small placebo-controlled, crossover trial, triazolam decreased central apnea index from 16.3 to 9.4 (0.125 mg group) and 8.0 (0.25 mg), consolidated sleep, and reduced arousals that may lead to central apnea during the wake-sleep transition period (23). In a randomized, placebo-controlled trial of 15 subjects with ischemic heart failure with LVEF less than or equal to 45%, no changes were shown in overall, central, or obstructive apnea-hypopnea index with zolpidem CR 12.5 mg (58).

In central sleep apnea due to high altitude, acetazolamide and temazepam improved sleep disturbances and central sleep apnea. In a randomized 3-way crossover study, acetazolamide was noted to be superior to almitrine at ameliorating periodic breathing (65). Almitrine and acetazolamide both increased saturations during sleep, but only acetazolamide decreased periodic breathing. An earlier randomized, double-blind placebo-controlled study by Fischer and colleagues demonstrated that both theophylline and acetazolamide improved sleep-disordered breathing and reduced oxyhemoglobin desaturation during sleep, with acetazolamide significantly improving basal oxyhemoglobin saturation during sleep (51). A double-blind, randomized, crossover trial in 33 healthy volunteers showed temazepam is effective in reducing periodic breathing and is safe to use without adverse effects on next-day performance at high altitude (112).

A randomized, double-blind trial compared temazepam and acetazolamide at an altitude of 3,540 meters on 34 healthy trekkers with self-reports of high-altitude sleep disturbance (150). Temazepam was associated with increased subjective sleep quality compared to acetazolamide without differences in mean nocturnal oxygen saturation, proportion of the night spent in periodic breathing, relative desaturations, sleep onset latency, awakenings, wakening after sleep onset, sleep efficiency, Stanford Sleepiness Scale scores, daytime drowsiness, or change in self-reported Lake Louise Acute Mountain Sickness scores.

Acetazolamide and theophylline are listed as an OPTION to treat central sleep apnea related to heart failure only after optimization of standard medical therapy if positive airway pressure is not tolerated and able to have a close clinical follow-up (09). A short-term, randomized, double-blind, cross-over study of 12 males with stable congestive heart failure found that acetazolamide significantly reduced central apneas (49 ± 28 vs. 23 ± 21) (71). This study also found a reduction in the frequency of oxyhemoglobin saturations below 90% and improved subjective overall sleep quality. A 5-day course of theophylline reduced central apnea index and SpO2<90% in men with compensated heart failure with a left ventricular ejection fraction 45% or less (78).

Another drug emerging as a possible treatment for central sleep apnea associated with heart failure is sacubitril-valsartan. Two studies have shown it reduces the apnea burden among patients with heart failure and reduced ejection fraction. Both studies demonstrated a decrease in apnea events, whereas only one of the studies showed an improvement in the apnea-hypopnea index (122; 105).

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Central sleep apnea

Associated Disorders

Achondroplasia
Acid maltase deficiency
Central alveolar hypoventilation
Cervical spinal cord injury
Charcot-Marie-Tooth disease
- Chronic renal failure
- Chronic sleep fragmentation
- Congenital myopathies
- Congestive heart failure
- Encephalitis
- Familial dysautonomia
- Guillain-Barré syndrome
- Hypothyroidism
- Myasthenia gravis
- Myotonic dystrophy
- Obstructive sleep apnea
- Pierre-Robin syndrome
- Poliomyelitis
- Riley-Day syndrome

Differential Diagnosis

obstructive sleep apnea
periodic limb movement disorder

Also Relevant

Central alveolar hypoventilation
Central sleep apnea due to high-altitude periodic breathing
Chiari malformation
Drug-induced parasomnias, sleep apnea, and restless legs syndrome
Hypersomnolence
- Hypothyroidism
- Insomnia
- Neurologic disorders associated with obesity
- Neurostimulation in sleep medicine
- Obstructive sleep apnea
- Posttraumatic sleep disturbance
- Sleep and cardiac disorders
- Sleep and cerebral degenerative disorders
- Sleep and chronic pulmonary disorders
- Sleep and medical disorders
- Sleep disorders
- Sleep, stroke, and vascular dementia

Clinical Categories

Sleep Disorders

Patient Handouts

Web References

Clinical Trials

NIH: Sleep Apnea

Central sleep apnea …

Central sleep apnea

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Table 1. Current Treatment Options for Sleep Hypoventilation and Central Sleep Apnea Syndromes

Epidemiology

Central sleep apnea in medical conditions

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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to access the full version.

Questions or Comment?

Also in This Category

Sleep-related bruxism

Epileptic encephalopathy with spike-wave activation during sleep

Autonomic dysfunction in sleep disorders

Irregular sleep-wake rhythm disorder

Delayed sleep-wake phase disorder

Sleep-related rhythmic movement disorder

Drug-induced parasomnias, sleep apnea, and restless legs syndrome

Non-24-hour sleep-wake disorder

Central sleep apnea

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Table 1. Current Treatment Options for Sleep Hypoventilation and Central Sleep Apnea Syndromes

Epidemiology

Central sleep apnea in medical conditions

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Sleep-related bruxism

Epileptic encephalopathy with spike-wave activation during sleep

Autonomic dysfunction in sleep disorders

Irregular sleep-wake rhythm disorder

Delayed sleep-wake phase disorder

Sleep-related rhythmic movement disorder

Drug-induced parasomnias, sleep apnea, and restless legs syndrome

Non-24-hour sleep-wake disorder

This is an article preview.
Start a Free Account
to access the full version.