AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

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.

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)¹ 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.

• Central Sleep Apnea in a Patient Presenting With Daytime Fatigue and Sleepiness
• Patients With Stroke and Obstructive Sleep Apnea at Increased Risk for Early Death
• Management of Excessive Sleepiness in Comorbid Conditions

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.

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.

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.

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 study² 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).

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 study³ 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,⁴ 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.

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. Age distribution in other central sleep apnea syndromes is unknown

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

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 study⁵ 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

This discussion includes the differentiation of various central sleep apnea syndromes from one another, as well as from non–central sleep apnea conditions.

• Obstructive sleep apnea: Patients with obstructive sleep apnea report loud snoring in addition to witnessed apneas and have excessive daytime sleepiness, crowded oropharynx, increased neck and waist circumference, and increased body mass index. Further, PSG shows prominent snoring and obstructive respiratory events. People with obstructive sleep apneas have a normal or occasionally elevated PaCO₂ during wakefulness as opposed to those with primary central sleep apnea and CSB-CSA, who have a low resting PaCO₂.
• Central sleep apnea during sleep-wake transition: Up to 40% of healthy individuals may exhibit central apneas during sleep-wake transition. The central apneas occur during the period that chemoreceptors are resetting and an instability of ventilation control occurs. They are usually brief and not associated with significant oxygen desaturation. The significance of this entity is unknown.
• Postarousal central apnea or postsigh central apnea: During a PSG review, central apneas are commonly seen following an arousal or after a sigh and are usually inconsequential. They are thought to be a result of Herring-Breuer reflex or hypocapnia induced by hyperventilation caused by a sigh or arousal.
• Primary central sleep apnea: Patients have a low-normal PaCO₂. They do not have a crescendo-decrescendo pattern of breathing. The central apneas terminate abruptly with a large breath and without associated hypoxemia. Further, the apnea-hyperpnea cycle time is shorter than in CSB-CSA.
• CSB-CSA: This is characterized by classic a crescendo-decrescendo pattern in the breathing. The arousals occur at the peak of the hyperpnea phase. The patient usually has predisposing factors such as heart failure or stroke. The patients have a lower resting PaCO₂ than normal. Patients with heart failure and CSB-CSA have higher pulmonary capillary wedge pressure than those without CSB-CSA. In patients with heart failure, atrial fibrillation is associated with a higher chance of developing CSB-CSA.
• Sleep-related hypoventilation syndrome: Sleep-related hypoventilation with central sleep apneas can be observed in many conditions such as neuromuscular weakness or chronic obstructive pulmonary disease. These conditions are characterized by a history of a preexisting disorder of hypoventilation, elevated resting PaCO₂, and severe oxygen desaturation during sleep, which is more prominent during REM sleep as opposed to primary central sleep apnea and CSB-CSA, which are most severe during NREM sleep.
• High-altitude periodic breathing: The single most important feature is that high-altitude periodic breathing is seen only at high altitudes. Many patients develop this at an altitude of 5000 meters or greater, while almost everyone develops it at an elevation of 7600 meters. The cycle length is shorter than in CSB.
• Central sleep apnea due to a medical condition: The patient has a history of an underlying disorder other than heart failure or renal failure. Patients with stroke can have either classic CSB-CSA or central apneas without a crescendo-decrescendo pattern.
• Central sleep apnea due to drugs or substance abuse: This is most easily recognized by the history of opiate use.
• Pseudocentral sleep apnea: Patients with diaphragmatic paralysis and other neuromuscular diseases, who are dependent on accessory muscles of breathing to maintain ventilation, may appear to have central apneas during REM sleep. This is due to the REM atonia of skeletal muscles. Many of these patients actually have obstructive sleep apnea but do not have enough diaphragmatic excursions to be recorded with piezoelectric belts used during routine PSG. A history of neuromuscular disease and worsening of central apneas during REM sleep should alert one to the possibility of pseudocentral apnea.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Lab Studies

The laboratory findings in persons with central sleep apnea syndromes are not helpful except for a finding of respiratory alkalosis (PaCO₂ <40 mm Hg while awake) in patients with primary central sleep apnea, high-altitude periodic breathing, and CSB. Patients with heart failure and high-altitude periodic breathing may also have relative or absolute hypoxia shown with arterial blood gas analysis.

In the absence of a history of diabetes, the fasting blood glucose value should be checked because central sleep apnea is more common in patients with diabetes.

Other laboratory studies are specific to the underlying cause rather than the ventilatory pattern of central sleep apnea. Underlying causes could be elevated serum creatinine levels, decreased glomerular filtration rate in patients with renal failure, and the presence of antibodies to acetylcholine receptors in patients with myasthenia gravis.

Imaging Studies

Imaging studies are also nonspecific and are characteristic of the underlying cause rather than helpful in diagnosing one or more central sleep apnea syndromes. Patients with stroke, CNS tumor, and Arnold-Chiari malformation may have characteristic findings on brain CT scan or MRI examination. However, routine imaging studies are not warranted in the diagnosis of central sleep apnea.

Other Tests

• Echocardiography: Patients with CSB-CSA and heart failure commonly have an ejection fraction of less than 0.40, but it can also be seen in conjunction with diastolic dysfunction. Some cases of CSB-CSA in association with pulmonary artery hypertension have also been reported. Usually, patients have a known history of heart failure and echocardiography is not recommended as a routine test in the absence of risk factors or signs and symptoms of heart failure.
• Polysomnography: Most diagnoses of central sleep apnea are made on the basis of PSG studies.
• • In primary central sleep apnea, more than 5 central apneas occur per hour of sleep, each lasting 10 seconds or longer. They appear to be more common during sleep stages 1 and 2. Severe fragmentation caused by apnea may preclude the patient from going into delta sleep. The events are less common during REM sleep for the reasons explained above. The length of the apneic-ventilatory cycle is less than 45 seconds.
  • The CSB-CSA cycle in heart failure is usually triggered by an arousal resulting in large tidal volume and the consequent lowering of PaCO₂. As the patient falls asleep, the apneic threshold is elevated, and ventilation tends to oscillate around the apneic threshold, propagated by slow circulation time. The cycle length of apnea-hyperpnea is usually greater than 45 seconds and is directly proportional to circulation time and inversely proportional to cardiac output. Shortening of the cycle length has been reported following cardiac transplantation. The arousals typically occur at the peak of the hyperpneic phase. ICSD-2 criteria require the presence of at least 10 central events per hour of sleep in the crescendo-decrescendo pattern to diagnose CSB.
  • For the diagnosis of high-altitude periodic breathing, a central apnea-hypopnea index (AHI) of greater than 5 is required at a high altitude. The usual cycle length is from 12-34 seconds. This condition also gives rise to fragmented sleep, increased stage 1 and 2 sleep, and decreased delta sleep. It is only seen during NREM sleep and improves over the course of a few days.
  • Central sleep apnea due to drugs or substance abuse is also more common during NREM sleep, but it may be seen in sleep stages 3 and 4. Both periodic and nonperiodic breathing patterns can be seen, the cycle length being typically short. An AHI of more than 5 in the absence of periodic breathing and an AHI of more than 10 in the presence of periodic breathing is required to make a diagnosis of central sleep apnea due to drugs or substance abuse. Sometimes, ataxic or a Biot breathing pattern is also seen with narcotics use.
• Esophageal pressure monitoring with a balloon catheter: Sometimes, distinguishing central sleep apnea from obstructive sleep apnea may be difficult, and esophageal pressure monitoring with a balloon catheter is helpful in distinguishing central from obstructive events.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Medical Care

No clear guidelines are available on when or whether to treat central sleep apnea. Clearly, when the symptoms are present, treatment is warranted. In the absence of symptoms, particularly when central sleep apnea is discovered after PSG is performed for another reason, the decision to treat should be made on an individual basis. Several different treatments have been described, which include treatment of the underlying cause, positive airway pressure (PAP), adaptive servo ventilation (ASV), oxygen, acetazolamide, sedative-hypnotics, theophylline, added dead space, and carbon dioxide inhalation.

Up to 20% of central sleep apnea cases have been suggested to resolve spontaneously. If the patient is not symptomatic, observation may be the only appropriate step. This may be the case in patients who have central sleep apnea during sleep-wake transition, patients without significant oxygen desaturation, or in those who experience central sleep apnea during continuous PAP (CPAP) treatment of obstructive sleep apnea.

If a reversible cause is present, treatment improves central sleep apnea. For example, descending to a low altitude is effective in treating high-altitude periodic breathing. Similarly, nocturnal dialysis and optimizing medical treatment for heart failure are often effective against CSB-CSA due to renal failure and heart failure, respectively. Heart transplantation has also been reported either to resolve CSB-CSA or to decrease cycle length of CSB-CSA breathing. Attention should be given to treatment of other predisposing factors such as nasal obstruction.

• Acetazolamide (Diamox): Acetazolamide is a carbonic anhydrase inhibitor that causes bicarbaturia and metabolic acidosis, which presumably shifts the apneic threshold of PaCO₂ to a lower level. It has been shown to be effective therapy in primary central sleep apnea and CSB in patients with heart failure and in the treatment of high-altitude periodic breathing. While increased respiratory drive may uncover obstructive sleep apnea, and because most central sleep apnea patients have concomitant obstructive sleep apnea, follow-up PSG is suggested after the initiation of acetazolamide therapy.
• Theophylline: Theophylline has been studied in patients with heart failure and was found to be effective in attenuating CSB.⁶ It is also effective for high-altitude periodic breathing.
• PAP: Both CPAP and bi-level PAP have been used to treat central sleep apnea syndrome. The exact mode of action of CPAP is unclear, but rebreathing and carbon dioxide retention are probably not the underlying mechanisms because most CPAP machines deliver a minimum pressure that is sufficient to wash out carbon dioxide.
• • CPAP increases lung volume, which, in turn, improves oxygenation. Improved oxygenation may decrease the tachypnea and respiratory alkalosis and thus may increase the carbon dioxide reserve above the apneic threshold. Increased lung volumes also provide a “tracheal tug” and indirectly increase the cross-sectional areas and volume of the hypopharyngeal airway. This results in decreased collapsibility of the pharynx, which may have a protective effect against central sleep apnea.
  • Further, stimulation of nasal receptors may play a role in reflex activation of respiratory motor neurons. In patients with heart failure, CPAP increases ejection fraction by decreasing the preload; the effective afterload has been shown to not only improve CSB-CSA but also transplant-free survival in a small study.⁷ 
  • Lastly, CPAP improves obstructive sleep apnea. Untreated obstructive sleep apnea has adverse effects on hemodynamics in patients with heart failure. Large negative swings in intrathoracic pressures can decrease cardiac output and potentially worsen CSB-CSA. Treating the obstructive sleep apnea may mitigate these negative hemodynamic effects of obstructive sleep apnea and improve the CSB-CSA in these patients.
  • Despite all the theoretical benefits mentioned above, a large prospective study, the Canadian Prospective Continuous Positive Airway Pressure (CANPAP) trial for congestive heart failure, failed to show a mortality benefit while attenuating central sleep apnea, improving nocturnal oxygenation, lowering the norepinephrine level, improving the ejection fraction, and improving the distance walked in 6 minutes.⁸
• Bi-level PAP: This is effective for treating patients with hypercapnic central sleep apnea (associated with hypoventilation syndrome). The inspiratory positive airway pressure (IPAP) is higher than the expiratory positive airway pressure (EPAP). The degree of IPAP-to-EPAP differential provides pressure support to augment ventilation. Often, long central apneas may require a back-up rate with bi-level PAP. Patients with high-pressure requirements may benefit by elevation of the head end to 45-60°, which dramatically decreases their pressure requirements.
• • Volume-cycled ventilators are rarely necessary but have their own limitations in terms of inability to adjust for high leaks, humidification, and expense.
• • Patients with nonhypercapnic central sleep apnea, such as CSB-CSA, and primary central sleep apnea have also been shown to benefit from bi-level PAP. Because bi-level PAP can be used with a back-up rate, it is beneficial in patients with long apneas. However, bi-level PAP, especially when used with a high IPAP-to-EPAP differential, has the potential to worsen central sleep apnea by lowering the PaCO₂. Bi-level PAP has been used to treat patients with heart failure and CSB-CSA with variable results, and further studies are needed to better assess the role of bi-level PAP treatment in this group of patients.  
• Added dead space or inhaled carbon dioxide: Added dead space by attaching a plastic cylinder of variable volume (400-800 mL) to a tightly fitting mask can act as a source of increased carbon dioxide concentration in the inspired air and can increase the carbon dioxide reserves above the apneic threshold. Such a treatment in an experimental setting has been shown to be effective against both primary central sleep apnea and CSB-CSA. The increase in PaCO₂ is miniscule (approximately 1.5-2 mm Hg) but effective in stabilizing the breathing pattern. Similar results have been obtained by adding supplemental carbon dioxide (5%), but safety and accuracy of carbon dioxide delivery devices remains a concern. Another potential problem of added dead space or inhaled carbon dioxide is worsening of obstructive sleep apnea by the increased mechanical load. Hypercarbia stimulates sympathetic discharge with potential deleterious effects on the heart.
• ASV: This represents a relatively novel way of approaching treatment of central sleep apnea, especially CSB-CSA.
• • The device provides a fixed CPAP of 5 cm water. Superimposed on this CPAP are pressure swings that vary from a minimum setting of 4-10 cm water. The variation in the pressure swings is controlled by a high-gain integral controller. When the ASV is at its minimum support, a maximum support of 9 cm water and a minimum support of 5 cm water (CPAP) is provided during the pressure swings. If the patient’s breathing decreases, the servo-controlled mechanism increases the pressure swings to achieve a target ventilation of 90% of the patient’s baseline ventilation. A maximum pressure swing of 10 cm water (ie, a maximum pressure of 15 cm water and a minimum of 5 cm water) can be achieved.
• • In preliminary studies, ASV has been shown to be superior to conventional PAP therapy with regard to control of central sleep apnea, microarousals, and daytime hypersomnolence. The efficacy of ASV is limited by the presence of significant obstructive sleep apnea, which may require higher pressures to overcome upper airway obstruction. In addition, pressures greater than 10 cm have a potential to drop the cardiac output by severely reducing preload.
• Oxygen: Supplemental oxygen is thought to work by decreasing the hypoxic drive and thus attenuating the hyperventilatory response to a change in PaCO₂. Oxygen may be effective in some patients with CSB-CSA due to heart failure and has also been shown to decrease catecholamine secretion. Oxygen has not been shown to improve quality of life in patients with CSB-CSA due to heart failure. Oxygen is effective against high-altitude periodic breathing and improves the sleep architecture. Any patient with central sleep apnea and significant hypoxemia is a potential candidate for a trial with supplemental oxygen. Supplemental oxygen can be titrated during PSG until central sleep apnea resolves.
• Other treatments: Sedative hypnotics have been used successfully in treating nonhypercapnic central sleep apnea. Temazepam and zolpidem have been shown to be effective under these circumstances and are believed to work by consolidating the sleep pattern, thus minimizing the instability in ventilation induced by sleep-wake transitions. Overdrive atrial pacing has been shown to be effective in treating CSB associated with some patients with significant bradycardia, and, presumably it works by improving hemodynamics. Cardiac resynchronization with biventricular pacing in patients with severe heart failure has shown promise in attenuating CSB.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Due to the heterogeneity of the central sleep apnea syndromes, different medications have been used under different circumstances. No one medication can be considered as a drug of choice.

Drug Category: Carbonic Anhydrase Inhibitor

To induce metabolic acidosis and increase baseline ventilation.

Drug Category: Benzodiazepines

To promote deeper stages of sleep.

Drug Category: Nonbenzodiazepine sedative hypnotic

To consolidate sleep.

Drug Category: Phosphodiesterase inhibitor

Respiratory stimulant.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Summary

Central sleep apnea is a relatively uncommon group of heterogeneous disorders characterized by intermittent or cyclical cessation of ventilatory effort. Instability of respiratory control feedback mechanisms is usually responsible. Symptoms and physical findings are nonspecific. PSG is required to make the diagnosis. Different treatment modalities are available. For asymptomatic patients with mild disease, observation is usually sufficient. If central sleep apnea is secondary to pathology, treating the underlying cause may attenuate the ventilatory disturbance. If no cause is found, acetazolamide or sedative hypnotics may be tried with caution. If significant hypoxia is associated, supplemental oxygen may also be tried. CPAP and bi-level PAP, especially with back-up rate, are other options, although adherence remains a problem. ASV holds promise but has its own limitations.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Media file 1:  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.
	View Full Size Image
Media type:  Graph

Media file 2:  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.
	View Full Size Image
Media type:  Chart

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

1. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 2^nd ed. Westchester, Ill: American Academy of Sleep Medicine; 2005.
2. 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].
3. Wang D, Teichtahl H, Drummer O, Goodman C, Cherry G, Cunnington D, et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest. Sep 2005;128(3):1348-56. [Medline].
4. 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].
5. 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].
6. 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].
7. 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].
8. Bradley TD, Logan AG, Kimoff RJ, Sériès F, Morrison D, Ferguson K, 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].
9. Dempsey JA. Crossing the apnoeic threshold: causes and consequences. Exp Physiol. Jan 2005;90(1):13-24. [Medline].
10. 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].
11. Pepperell JC, Maskell NA, Jones DR, Langford-Wiley BA, Crosthwaite N, Stradling JR, 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].
12. 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].
13. White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med. Dec 1 2005;172(11):1363-70. [Medline].

Article Last Updated: Apr 4, 2008