eMedicine Specialties > Pulmonology > Sleep-Related Disorders
Central Sleep Apnea
Updated: Jul 30, 2009
Introduction
Background
The term central sleep apnea encompasses a heterogeneous group of sleep-related breathing disorders in which respiratory effort is diminished or absent in an intermittent or cyclical fashion due to CNS or cardiac dysfunction. These disorders are further divided into primary forms: those for which the exact etiology is unknown and those due to a known cause.
With polysomnography (PSG), central sleep apnea is conventionally defined as cessation of airflow for 10 seconds or longer without an identifiable respiratory effort. In contrast, an obstructive apnea has a discernible ventilatory effort during the period of airflow cessation. The vast majority of patients with central sleep apnea have concomitant obstructive sleep apnea. Further, treatment of obstructive sleep apnea results in the emergence of central sleep apnea and vice versa, indicating the commonality of pathogenesis between the 2 seemingly distinct, but probably overlapping, disorders of breathing during the sleep state.1,2
In general, treatment of central sleep apnea syndromes is less promising than treatment of obstructive sleep apnea. The International Classification of Sleep Disorders, Second Edition (ICSD-2)3 describes several different entities grouped under central sleep apnea with varying signs, symptoms, and clinical and polysomnographic features. The central sleep apnea syndromes afflicting adults include primary central sleep apnea, Cheyne-Stokes breathing-central sleep apnea (CSB-CSA) pattern, high-altitude periodic breathing, central sleep apnea due to medical conditions not Cheyne-Stokes, and central sleep apnea due to drug or substance. The primary sleep apnea of infancy primarily affects premature newborns and is excluded from this discussion.
Pathophysiology
The pathophysiology of obstructive sleep apnea and central sleep apnea overlap considerably. During normal inspiration, neuronal discharge to the diaphragm and dilator muscles of the pharynx increases. Failure to achieve pharyngeal dilatation in the presence of diaphragmatic contraction results in an obstructive apnea. If the diaphragmatic contractions are diminished, a central sleep apnea occurs. The hypopharynx may or may not be open during a central apnea. Studies have shown considerable narrowing of the hypopharynx during a central apneic event. If the hypopharynx is closed during central apnea and diaphragmatic activity resumes before pharyngeal dilator muscle tone is restored, a mixed apnea results.4
Knowledge of normal ventilatory control mechanisms is imperative in order to understand the pathophysiology of central sleep apnea. Normal ventilation is tightly regulated to maintain levels of arterial oxygen (PaO2) and carbon dioxide (PaCO2) within narrow ranges. This is achieved by feedback loops involving peripheral and central chemoreceptors, intrapulmonary vagal receptors, the respiratory control centers in the brain stem, and efferent motor pathways to the respiratory muscles. A mathematical model of a closed-loop system has been proposed to explain the occurrence and perpetuation of ventilatory instability in the pathogenesis of central sleep apnea. Loop gain is an engineering term and is usually defined by the model and associated equations. In a closed-loop system, loop gain is affected by controller gain and plant gain. Controller gain represents the degree of response to a given disturbance in the closed feedback system.
Take the example of a thermostat mechanism in controlling room temperature. If the room temperature is maintained within narrow ranges, a sensitive thermostat triggers the air conditioner on or off with minor changes in temperature. The degree to which a thermostat responds to a change in room temperature represents a controller gain. In ventilatory control, this represents the degree of response to a given change in hypercapnia or hypoxia and is mediated by chemoreceptors. High controller gain can be seen in metabolic conditions such as acromegaly, in which chemosensitivity is above normal. Plant gain represents the effect of that response on the system. In the thermostat air-conditioning system, this represents the temperature change in the room as a result of the cooling effect of the air conditioner. The stronger the air conditioner or the smaller the room, the faster the response and the higher the likelihood of overshooting the limits, also referred to as plant gain. In case of ventilatory control, this represents the effect of a ventilatory response on arterial oxygen and carbon dioxide tensions. If the patient has low dead space, a low metabolic rate, or functional residual capacity, the effect of ventilatory changes is more marked, resulting in a higher plant gain.
Loop gain = Response to disturbance/disturbance itself
A loop gain of less than 1 results in an oscillatory response, which quickly dampens to regain stability. A loop gain of more than 1 in association with a delay in system response sets the tone for instability of the system, which then starts to oscillate in the self-perpetuating factor. This is because each response to the disruption in the system overshoots the upper or lower limits and generates an opposite response, which is somewhat delayed, but also overshoots the desired limit. In the ventilatory control system, an inherent delay between chemoreceptor response and ventilatory output occurs. This can be exaggerated by a slow circulation time, as in heart failure, and sets the tone for a self-perpetuating oscillatory response.
As shown in Media File 1, the higher the baseline PaCO2, the lower the change in ventilation required to produce an apneic threshold; small changes in ventilation produce relatively large changes in PaCO2 (increased plant gain). This implies that patients with baseline hypoventilation are at an increased risk of central sleep apnea, while hyperventilation, per se, is protective against central sleep apnea. (This is not be confused with the hyperventilatory response to chemoreceptor stimulation, which would, in fact, predispose to ventilatory instability.) Many nonchemical stimuli, which include pulmonary mechanoreceptors and behavioral or awake stimulation, are known to modulate this response. A patient in non–rapid eye movement (NREM) sleep, when the behavioral influence is the least, is more likely to demonstrate central sleep apnea than during rapid eye movement (REM) sleep. A fully awake person is least likely to manifest central sleep apnea.
Relationship between alveolar ventilation (VA) and alveolar PCO2 (PACO2). Changing the background drive without changing the slope of ∆ VA vs ∆ PACO2 relationship below eupnea. For example, background hyperventilation raises VA and lowers PACO2 along the isometabolic ∆ VA- ∆ PACO2 hyperbola. This means that a greater transient increase in VA and reduction in PACO2 is required to reach the apneic threshold than it would be under controlled, normocapnic conditions. The reverse is true for the conditions that cause hypoventilation. Courtesy of Exp Physiol. 2004; 90(1):13-24.
As shown in Media File 2, the steeper the response of ventilation is to a given change in PaCO2, the more likely it is to produce large changes in ventilation with small changes in PaCO2 (high controller gain). This puts the system at a risk of instability, especially when the resting PaCO2 approaches the apneic threshold. Occurrence of either of the above 2 conditions in association with a low baseline PaCO2 close to the apneic threshold provides a potentially unstable condition. A minor disruption in the system can destabilize the ventilatory control and give rise to a cyclic appearance of central apneas and hyperpneas. Patients with hypocapnia and heart failure and those ascending to high altitudes often develop these conditions, predisposing them to a periodic breathing pattern. The credibility to this concept is supported by the observations that increasing the dead space, increasing the inhaled concentration of PaCO2, or providing increased baseline ventilation by acetazolamide are, under many circumstances, protective against periodic breathing.
Relationship between alveolar ventilation (VA) and alveolar PCO2 (PACO2). At any given level of background PACO2, changing the slope (or responsiveness) of ∆ VA- ∆ PACO2 relationship below eupnea would change the carbon dioxide reserve for the reduction in PACO2 required to cause apnea. This response slope increases in hypoxia and in some patients with chronic heart failure. Courtesy of Exp Physiol. 2004; 90(1):13-24.
Patients with heart failure and central sleep apnea have been shown to have an augmented ventilatory response to change in PaCO2 compared with patients with heart failure and obstructive sleep apnea. Hypoxia augments the ventilatory response to changes in PaCO2 (increases the slope of response) and predisposes to instability in ventilation. A change in PaCO2 may be more important than the low PaCO2 because patients with chronic liver disease also have low PaCO2 but do not develop central sleep apnea. A 2003 study5 has confirmed increased peripheral and central chemoreceptor responsiveness in patients with heart failure undergoing exercise testing. These patients had an increased ventilatory response to exercise (minute ventilation vs carbon dioxide production [VE/VCO2] slope).6
During wakefulness, the input from cortical areas of the brain influences the respiration by so-called behavioral control. Many nonchemical stimuli, which include pulmonary mechanoreceptors and behavioral or awake stimulation, are known to modulate this response. During sleep, this behavioral control is lost and chemical control is the major mechanism regulating ventilation. Sleep is also characterized by elevation of arterial carbon dioxide tension (PaCO2), elevation of apneic threshold of PaCO2 (PaCO2 below which no stimulation of the ventilatory drive by carbon dioxide occurs and apnea ensues), and increased upper-airway resistance. Despite these changes, ventilatory control during sleep remains similar in nature to that in the state of wakefulness. A patient in NREM sleep, when the behavioral influence is least, is more likely to demonstrate central sleep apnea than during REM sleep, while a fully awake person is least likely to manifest it. Thus, sleep provides another potentially unstable condition for the generation of central sleep apnea.
Stimulation medullary Mu receptors by narcotics depresses the central ventilatory drive in patients on methadone or other narcotics and is thought to be responsible for the generation of central sleep apneas in these patients. Patients who use opiates have decreased REM sleep and high baseline PaCO2. However, other factors, which include microscopic strokes from the use of other substances (especially cocaine) or from vasculitis, may also contribute to the development of central sleep apnea.
Intrinsic factors (inadequate development) or extraneous factors (inflammation, degenerative diseases, ischemia, drugs) that alter the brain stem control mechanism may also predispose a person to central sleep apnea. Primary sleep apnea of infancy resolves as gestational age progresses. Further, excitation of certain receptors in the nose is known to have a stimulatory effect on ventilation, and pharyngeal collapse is supposed to have an inhibitory effect on the ventilation. This may explain the occurrence of central sleep apnea in association with nasal obstruction and reports of positional dependence of central sleep apnea. Hormonal factors are also known to modulate the ventilatory pattern. The apneic threshold is lower in premenopausal women, as is the incidence of central sleep apnea. Administration of testosterone to healthy premenopausal women elevates their apneic threshold.
Frequency
United States
No epidemiologic studies have been performed to determine the prevalence of central sleep apnea in the general population. Predominant central apnea is uncommon and is seen in less than 10% of patients presenting for PSG. In the general population, the prevalence of primary central apnea, high-altitude periodic breathing, and central sleep apnea due to medical conditions is unknown. Cheyne-Stokes breathing pattern (CSB) has been reported in 25-40% of patients with heart failure and in 10% of patients who have had a stroke. One study7 has reported the prevalence rate of central sleep apnea at 30% in a population of patients in a stable methadone maintenance program.
Mortality/Morbidity
The mortality and morbidity associated with primary central apnea remains unknown; however, these individuals are unlikely to develop significant hypercarbia or hypoxia to the detriment of pulmonary circulation or cor pulmonale. Patients with heart failure and CSB-CSA have a higher mortality rate than those without it. In one study by Hanly and colleagues,8 the 2-year survival rate for patients in heart failure without concomitant CSB-CSA was 86%, versus 56% in those with CSB-CSA. The central apneic events in CSB-CSA are associated with increased sympathetic drive as manifested by muscle sympathetic nerve activity and catecholamine excretion. Even though the central events do not cause a decrease in afterload, as the obstructive apneas do, the increased sympathetic drive is thought to be detrimental to the heart and vasculature and may contribute to increased mortality in these patients.9
In a study of sleep-disordered breathing and nocturnal cardiac arrhythmias in older men, Mehra et al found that the likelihood of atrial fibrillation or complex ventricular ectopy increased along with the severity of sleep-disordered breathing. In addition, different forms of sleep-disordered breathing were associated with the different types of arrhythmias. Polysomnography in 2911 participants showed that the odds of atrial fibrillation (P = .01) and of complex ventricular ectopy (P <.001) increased with increasing quartiles of the respiratory disturbance index (a major index including all apneas and hypopneas).10
Central sleep apnea was more strongly associated with atrial fibrillation (odds ratio [OR], 2.69; 95% confidence interval [CI], 1.61-4.47) than with complex ventricular ectopy (OR, 1.27; 95% CI, 0.97-1.66). In contrast, obstructive sleep apnea and hypoxia was associated with complex ventricular ectopy; participants in the highest hypoxia category had an increased odds of complex ventricular ectopy (OR, 1.62; 95% CI, 1.23-2.14) compared with the lowest quartile. The results suggest that different sleep-related stresses may contribute to atrial and ventricular arrhythmogenesis in older men.10
Race
No data are available on racial distribution of central sleep apnea syndromes. Periodic breathing has been noted to be more prevalent in persons with diabetes than in those without diabetes. Because the prevalence of diabetes differs in persons of various races, certain types of central apneas may be more prevalent in certain races; however, this remains to be elucidated.
Sex
CSB-CSA shows a striking male preponderance. Although some studies indicate a preponderance of primary central sleep apnea in males, the agreement is not unanimous. Sex distribution in other types of central sleep apnea syndromes has not been studied. Central sleep apnea is uncommon in premenopausal women. One explanation for this discrepancy is the presence of a lower apneic threshold of PaCO2 in women compared with men. Thus, women require a greater reduction in their PaCO2 to initiate apnea than do men.
Age
Primary central sleep apnea mostly affects middle-aged or elderly individuals. CSB-CSA increases in prevalence among individuals older than 60 years.11 Age distribution in other central sleep apnea syndromes is unknown
Clinical
History
Many patients with central sleep apnea syndromes may be symptomatic. The most common reported symptoms are insomnia and excessive daytime sleepiness or fatigue. In general, the degree of daytime hypersomnolence is less than that observed with obstructive sleep apnea and insomnia is more prominent. The presence of insomnia may actually put these patients at increased risk of central apneas because a greater number of sleep-wake transitions means more opportunities for an unstable breathing pattern to set in.
Sometimes, bed partners report witnessed apneas and mild snoring. Patients report frequent awakenings, a nonrestorative sleep, choking, and shortness of breath. Paroxysmal nocturnal dyspnea can be seen with CSB-CSA.
History may reveal symptoms pertaining to the underlying cause (eg, symptoms of heart failure, stroke, renal failure, Parkinson disease, or multiple system atrophy). Dyspnea, orthopnea, lower extremity edema, exercise intolerance, cough, dysphagia, dysarthria, diplopia, weakness, rigidity, gait disturbance, postural hypotension, lack of sweating, and bowel disturbance may indicate an underlying secondary cause. A history of diabetes may be present in a higher proportion of patients with central sleep apnea than those without it. A history of poliomyelitis may be present in patients with postpolio syndrome.
Physical
In contrast to obstructive sleep apnea, no physical findings predict the presence or absence of central sleep apnea. The patients usually have a normal body habitus. Patients with central sleep apnea may develop hypertension due to the increased adrenergic response to hypoxia and arousals, but robust data on the prevalence of hypertension in patients with central sleep apnea is lacking. One study12 has implicated central sleep apnea in the development of atrial fibrillation, but the methods used to differentiate central and obstructive events were not satisfactory. Patients with CSB-CSA may exhibit a periodic breathing pattern even while awake. Most other patients have nonspecific findings, which may include signs of heart failure, neurologic signs, or previous needle-track marks.
Causes
Central sleep apnea in various forms can be seen in the following conditions or events:
- Heart failure
- Stroke
- High altitude
- Renal failure
- Use of opiates and other CNS depressants
- Parkinson disease
- Multiple system atrophy or Shy-Dragger syndrome
- Familial dysautonomia
- Diabetes mellitus
- Hypothyroidism
- Acromegaly
- Postpolio syndrome
- Damage to medullary respiratory centers by tumor, infarction, or infection
- Arnold-Chiari malformation types I-III
- Cervical cordotomy
- Following tracheostomy for obstructive sleep apnea
- Muscular dystrophy
- Myasthenia gravis
- Idiopathic cardiomyopathy
- Prader-Willi syndrome
- Nasal obstruction
Central sleep apnea due to drugs or other substances occurs mostly after 2 months of opiate, especially methadone, use and improves after approximately 5-7 months of continuous usage. Other opiates, such as morphine, can also cause central sleep apnea.
Virtually anyone ascending to an altitude of 7600 meters develops high-altitude periodic breathing.
More on Central Sleep Apnea |
 Overview: Central Sleep Apnea |
| Differential Diagnoses & Workup: Central Sleep Apnea |
| Treatment & Medication: Central Sleep Apnea |
| Follow-up: Central Sleep Apnea |
| Multimedia: Central Sleep Apnea |
| References |
| Further Reading |
| Next Page » |
References
Panossian LA, Avidan AY. Review of sleep disorders. Med Clin North Am. Mar 2009;93(2):407-25, ix. [Medline].
Schafer T, Schlafke ME, Westhoff M, et al. [Central sleep apnea]. Pneumologie. Mar 2009;63(3):144-58; quiz 159-62. [Medline].
American Academy of Sleep Medicine. International Classification of Sleep Disorders. 2nd ed. Westchester, Ill: American Academy of Sleep Medicine; 2005.
Verbraecken JA, De Backer WA. Upper Airway Mechanics. Respiration. May 29 2009;[Medline].
Arzt M, Harth M, Luchner A, Muders F, Holmer SR, Blumberg FC, et al. Enhanced ventilatory response to exercise in patients with chronic heart failure and central sleep apnea. Circulation. Apr 22 2003;107(15):1998-2003. [Medline].
Ueno LM, Drager LF, Rodrigues AC, et al. Effects of exercise training in patients with chronic heart failure and sleep apnea. Sleep. May 1 2009;32(5):637-47. [Medline].
Wang D, Teichtahl H, Drummer O, et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest. Sep 2005;128(3):1348-56. [Medline].
Hanly PJ, Zuberi-Khokhar NS. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med. Jan 1996;153(1):272-6. [Medline].
Luo Q, Zhang HL, Tao XC, Zhao ZH, Yang YJ, Liu ZH. Impact of untreated sleep apnea on prognosis of patients with congestive heart failure. Int J Cardiol. Apr 2 2009;[Medline].
[Best Evidence] Mehra R, Stone KL, Varosy PD, et al. Nocturnal Arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med. Jun 22 2009;169(12):1147-55. [Medline].
Johansson P, Alehagen U, Svanborg E, Dahlström U, Broström A. Sleep disordered breathing in an elderly community-living population: Relationship to cardiac function, insomnia symptoms and daytime sleepiness. Sleep Med. May 21 2009;[Medline].
Leung RS, Huber MA, Rogge T, Maimon N, Chiu KL, Bradley TD. Association between atrial fibrillation and central sleep apnea. Sleep. Dec 1 2005;28(12):1543-6. [Medline].
[Best Evidence] Tonelli de Oliveira AC, Martinez D, Vasconcelos LF, et al. Diagnosis of obstructive sleep apnea syndrome and its outcomes with home portable monitoring. Chest. Feb 2009;135(2):330-6. [Medline].
[Best Evidence] Antic NA, Buchan C, Esterman A, et al. A randomized controlled trial of nurse-led care for symptomatic moderate-severe obstructive sleep apnea. Am J Respir Crit Care Med. Mar 15 2009;179(6):501-8. [Medline].
Randerath WJ, Galetke W, Kenter M, Richter K, Schafer T. Combined adaptive servo-ventilation and automatic positive airway pressure (anticyclic modulated ventilation) in co-existing obstructive and central sleep apnea syndrome and periodic breathing. Sleep Med. Mar 19 2009;[Medline].
Javaheri S, Parker TJ, Wexler L, Liming JD, Lindower P, Roselle GA. Effect of theophylline on sleep-disordered breathing in heart failure. N Engl J Med. Aug 22 1996;335(8):562-7. [Medline].
Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation. Jul 4 2000;102(1):61-6. [Medline].
Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med. Nov 10 2005;353(19):2025-33. [Medline].
Sasayama S, Izumi T, Matsuzaki M, et al. Improvement of Quality of Life With Nocturnal Oxygen Therapy in Heart Failure Patients With Central Sleep Apnea. Circ J. May 18 2009;[Medline].
Dempsey JA. Crossing the apnoeic threshold: causes and consequences. Exp Physiol. Jan 2005;90(1):13-24. [Medline].
Javaheri S. Central sleep apnea in congestive heart failure: prevalence, mechanisms, impact, and therapeutic options. Semin Respir Crit Care Med. Feb 2005;26(1):44-55. [Medline].
Pepperell JC, Maskell NA, Jones DR, et al. A randomized controlled trial of adaptive ventilation for Cheyne-Stokes breathing in heart failure. Am J Respir Crit Care Med. Nov 1 2003;168(9):1109-14. [Medline].
Roehrs T, Conway W, Wittig R, Zorick F, Sicklesteel J, Roth T. Sleep-wake complaints in patients with sleep-related respiratory disturbances. Am Rev Respir Dis. Sep 1985;132(3):520-3. [Medline].
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Further Reading
Clinical guidelines
Management of obstructive sleep apnoea/hypopnoea syndrome in adults. A national clinical guideline.
Scottish Intercollegiate Guidelines Network - National Government Agency [Non-U.S.]. 2003 Jun. 35 pages. NGC:003
Screening for obstructive sleep apnea in the primary care setting.
University of Texas at Austin School of Nursing, Family Nurse Practitioner Program - Academic Institution. 2006 May. 13 pages. NGC:005057
Diagnosis and treatment of obstructive sleep apnea in adults.
Institute for Clinical Systems Improvement - Private Nonprofit Organization. 2003 Apr (revised 2008 Jun). 55 pages. NGC:006582
Clinical trials
Treatment of Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients With Heart Failure
Buspirone as a Potential Treatment for Recurrent Central Apnea
Role of Obstructive Sleep Apnea in Stroke Appearance
Effect of Oxygen on Core Temperature
Related eMedicine topics
Obstructive Sleep Apnea
Obstructive Sleep Apnea-Hypopnea Syndrome
Snoring and Obstructive Sleep Apnea, CPAP
Snoring and Obstructive Sleep Apnea, Upper Airway Evaluation
Polysomnography
Keywords
sleep apnea, sleep-related breathing disorders, Cheyne-Stokes breathing, periodic breathing, high-altitude periodic breathing, high-altitude sleep apnea, central sleep apnea due to medical conditions, primary central sleep apnea, polysomnogram, PSG, obstructive sleep apnea, loop gain, ventilatory control mechanism, controller gain, plant gain, heart failure, stroke, high altitude, renal failure, opiate use, Parkinson disease, multiple system atrophy, Shy-Dragger syndrome, familial dysautonomia, diabetes mellitus, hypothyroidism, acromegaly, postpolio syndrome, medullary respiratory center damage, Arnold-Chiari malformation, cervical cordotomy, tracheostomy, muscular dystrophy, myasthenia gravis, idiopathic cardiomyopathy, Prader-Willi syndrome, nasal obstruction
