Central Sleep Apnea Syndromes

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 during sleep.^[1] In most cases, central sleep apnea is associated with obstructive sleep apnea syndromes or is caused by an underlying medical condition, recent ascent to high altitude, or narcotic use. Primary central sleep apnea is a rare condition, the etiology of which is not entirely understood.

During polysomnography (PSG), a central apneic event is conventionally defined as cessation of airflow for 10 seconds or longer without an identifiable respiratory effort. In contrast, an obstructive apneic event has a discernible ventilatory effort during the period of airflow cessation.

In general, treatment of central sleep apnea is often more difficult than treatment of obstructive sleep apnea and treatment varies according to the specific syndrome. The International Classification of Sleep Disorders, Third Edition (ICSD-3)^[2] describes several different entities grouped under central sleep apnea with varying signs, symptoms, and clinical and polysomnographic features. Those that affect 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 other than Cheyne-Stokes, and central sleep apnea due to drugs or substances. The primary sleep apnea of infancy primarily affects premature newborns and is excluded from this discussion.

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Pathophysiology

Knowledge of normal ventilatory control mechanisms is important for understanding 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 that involve peripheral and central chemoreceptors, intrapulmonary vagal receptors, the respiratory control centers in the brain stem, and the respiratory muscles.

During wakefulness, signals from cortical areas of the brain influence respiration, a mechanism termed behavioral control. Many nonchemical stimuli, which include pulmonary mechanoreceptors and behavioral or awake stimulation, are known to modulate this phenomenon. During sleep, behavioral control is lost and chemical control is the major mechanism regulating ventilation, PaCO₂ being the major stimulus for ventilation. Central sleep apnea is most often seen during non–rapid eye movement (NREM) sleep, when behavioral influence is least, followed by rapid eye movement (REM) sleep, while a fully awake person is least likely to manifest it. Despite these changes, ventilatory control during sleep remains similar to that during wakefulness.

Sleep is characterized by elevation of arterial carbon dioxide tension (PaCO₂) and a higher PaCO₂ apneic threshold, the PaCO₂ below which apnea occurs. Reduction of PaCO₂ just a few mm Hg below the PaCO₂ set point can result in apneas. Central apneic events commonly occur during the transition between wake and sleep, a period during which the PaCO₂ set point adjusts.

Two types of pathophysiologic phenomena can cause central sleep apnea syndromes: 1) ventilatory instability or 2) depression of the brainstem respiratory centers or chemoreceptors.

Ventilatory instability is the mechanism behind CSB-CSA, high-altitude periodic breathing, and probably primary central sleep apnea.^[3] As with any system that is regulated by feedback loops, the respiratory system is vulnerable to instability. The occurrence and perpetuation of ventilatory instability in the pathogenesis of central sleep apnea can be visualized in the context of loop gain, an engineering term that describes the overall gain of a system controlled by feedback loops.

A system with high loop gain responds rapidly and intensely to a trigger, whereas a low loop gain system responds more gradually and weakly. Loop gain is affected by controller gain and plant gain. Controller gain represents the degree of response to a given disturbance, whereas plant gain reflects the efficiency of the response. In the respiratory system, controller gain is manifested as chemoresponsiveness, whereas plant gain is the effectiveness of a given minute ventilation to eliminate carbon dioxide.

The concept of loop gain can be illustrated by the way a thermostat-controlled air conditioner maintains room temperature within a narrow range. Minor temperature changes trigger a sensitive thermostat to turn the air conditioner on or off. The degree to which a thermostat responds to a change in room temperature represents a controller gain. Plant gain represents the effect of the response on the system, the temperature change in the room as a result of the cooling effect of the air conditioner. A system with high plant gain may have a stronger air conditioner or a smaller room to cool, resulting in a faster response and a greater likelihood of overshooting the limits.

Loop gain is defined as the response to a disturbance/disturbance itself. In a thermostat-controlled air conditioner system with high loop gain, a small increase in room temperature quickly results in cooling that may overshoot the range for which the thermostat is set, soon causing the air conditioner to be turned off. Such a system would be relatively unstable, with the air conditioner frequently being turned on and off, and the room experiencing swings in temperature.

In the system of ventilatory regulation, controller gain is the degree of ventilatory response to a given change in hypercapnia or hypoxia and is mediated by chemoreceptors. Plant gain is represented by the effect of a ventilatory response on arterial oxygen and carbon dioxide tensions. If a patient has low dead space, a low metabolic rate, a low functional residual capacity, or a high PaCO₂, the effect of ventilatory changes is more marked, resulting in a higher plant gain.

For the ventilatory system, loop gain can be defined as demonstrated in the image below.

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The role of loop gain in determining respiratory instability. A) When loop gain is less than 1, the tendency for an overshoot of the corrective respon....

Loop gain = hyperpnea (response to disturbance)/apnea or hypopnea (disturbance)

If loop gain is less than 1, responses to apneas or hypopneas are more gradual and smaller, allowing ventilation to return to a steady pattern. If loop gain is greater than 1, the large responses to apneas and hypopneas result in swings of hyperventilation and apnea/hypoventilation, causing a state of instability termed periodic breathing. During waking, behavioral control may override periodic breathing patterns, so that the effect of high loop gain on the ventilatory system is most evident during sleep.

In addition to high loop gain, a delay must occur between the detection of a disturbance and the actuation of the response for a system to become unstable. This condition exists for the respiratory system because of the delay between change in PaCO₂ in the pulmonary venous system and detection of the change in the carotid bodies and brainstem. Prolonged circulation time in some patients with congestive heart failure may accentuate the delay, predisposing them to an unstable ventilatory condition, CSB-CSA.

The ventilatory system is at particular risk of instability when the resting PaCO₂ approaches the PaCO₂ apneic threshold. In the situation of either high controller gain or high plant gain in association with a low baseline PaCO₂ close to the apneic threshold, a minor disruption in the system can 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 some 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. In patients with heart failure and central sleep apnea, increased ventilatory response to exercise has been reported that was proportional to the severity of CSB-CSA failure, suggesting augmented peripheral and central chemoreceptor responsiveness.^[4]

Central sleep apnea-hypoventilation syndromes such as those associated with narcotic use or brainstem lesions are due to disturbances of the central respiratory pattern center or peripheral chemoreceptors or both that may become more evident during sleep because of the suppression of wakefulness or behavior drive.

The respiratory "control center" involves several areas of the medulla. During NREM sleep, breathing is controlled by an automatic system that is primarily influenced by chemical stimuli. In REM sleep, both inhibitory and excitatory influences are exerted on the medullary respiratory neurons that are manifested by irregular breathing and occasional "physiologic" central apneas.

Primary disorders of the central nervous system such as meningitis or hemorrhage and tumors or strokes that involve the brainstem can result in an ataxic breathing pattern, referred to as Biot respiration. The Biot pattern may be irregular without any type of periodicity or it can consist of runs of similar-sized breaths alternating with central apneas, as demonstrated in the image below.

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This polysomnogram demonstrates central sleep apnea and Biot respiration in a patient receiving long-term morphine for chronic pain. The Biot pattern ....

Narcotics such as heroin, morphine, and methadone cause respiratory depression via stimulation of the opioid Mu receptors on neurons located in the medullary respiratory complex. Although tolerance develops for many central nervous system effects of opioids, studies^[5] have demonstrated abnormal hypercapnic and hypoxic ventilatory responses in chronic narcotic users, and several reports have demonstrated that central sleep apnea is common in individuals on long-term opioids.^{[6, 7]} The possibility that Mu-receptor inhibition of the carotid bodies and other peripheral chemoreceptors plays a role in causing a more subtle form of respiratory depression in long-term narcotic use has been suggested.^[7]

The mechanisms responsible for central sleep apnea and obstructive sleep apnea overlap, and patients with central apneas often have obstructive events. Studies have shown that the hypopharynx may be considerably narrowed during a central apneic event. During normal inspiration, a neuronal discharge occurs to the diaphragm and to the upper airway muscles that stiffens and dilates the pharynx to keep it open. If a decrease in activity occurs in both the diaphragm and upper airway dilators, the result could be a central or obstructive apnea. If, despite a lack of activation of the pharyngeal muscles, the upper airway remains open, the event will be a central apnea. If the upper airway is closed during central apnea and diaphragmatic activity resumes before pharyngeal dilator muscle tone is restored, a mixed apnea results.^[8]

Thus, the susceptibility to upper airway collapse may determine whether central or obstructive apneas occur with cycling due to ventilatory instability. The conversion of obstructive apneas to a Cheyne-Stokes breathing pattern with the introduction of continuous positive airway pressure (CPAP) is an example of this phenomenon. See the images below.

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Obstructive sleep apnea (OSA): This polysomnogram demonstrates typical hypopneas occurring in OSA prior to continuous positive airway pressure titrati....

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Cheyne Stokes: This polysomnogram represents Cheyne Stokes breathing and occurred subsequent to continuous positive airway pressure titration for OSA ....

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Etiology

This discussion includes the differentiation of various central sleep apnea syndromes from one another. Central sleep apnea in various forms can be seen in the following conditions or events:

Cheyne Stokes breathing-central sleep apnea

CSB-CSA is characterized by classic a crescendo-decrescendo pattern that typically occurs with a periodicity of 45 second or greater cycles (see image below). The ICSD-3^[2] specifies that at least 10 central apneas and hypopneas per hour of sleep should occur, accompanied by arousals and derangement of sleep structure. The arousals occur at the peak of the hyperpnea phase. Patients usually have predisposing factors such as heart failure, stroke, or renal failure, as well as a lower resting PaCO₂ than normal. See the following:

• Heart failure
• Stroke
• Renal failure

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  Cheyne Stokes: This polysomnogram represents Cheyne Stokes breathing and occurred subsequent to continuous positive airway pressure titration for OSA ....

   

  

   

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. See the following:

• Stroke
• Diabetes mellitus
• Hypothyroidism
• Parkinson disease
• Multiple system atrophy or Shy-Dragger syndrome
• Familial dysautonomia
• Postpolio syndrome
• Damage to medullary respiratory centers by tumor, infarction, or infection
• Arnold-Chiari malformation types I-III
• Cervical cordotomy
• Muscular dystrophy
• Myasthenia gravis
• Prader-Willi syndrome
• Idiopathic cardiomyopathy
• Acromegaly

High-altitude periodic breathing

The single most important feature is that high-altitude periodic breathing occurs only with recent ascent to 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-CSA, 12-34 seconds.

Use of opiates and other CNS depressants

This is most easily recognized by a history of opiate use. Thirty percent of participants in a stable methadone maintenance program had a central apnea index (CAI) of greater than 5 and 20% had a CAI of greater than 10.^[6] Methadone blood concentration was significantly associated with the severity of central sleep apnea.

Primary central sleep apnea

This is an uncommon condition in which 5 or more central apneas, lasting 10 seconds or more, occur per hour of sleep. Patients have a low-normal PaCO₂. The central apneas terminate abruptly with a large breath and without associated hypoxemia. They do not have a crescendo-decrescendo pattern of breathing.

Complex sleep apnea

Central sleep apnea may emerge during titration of CPAP in patients previously diagnosed with obstructive sleep apnea. This syndrome, termed complex sleep apnea, has become a controversial topic in the sleep literature^[9] and has been raised as a possible type of difficult-to-treat obstructive sleep apnea. As many as 6.5% of patients with obstructive sleep apnea may develop emergent or persistent central sleep apnea with CPAP treatment. CPAP emergent central sleep apnea is generally transitory and is eliminated after eight weeks of CPAP therapy. Persistent CPAP-related central sleep apnea has been observed in approximately 1.5% of treated patients.^[10] Similarly, complex sleep apnea can occur following a tracheostomy for obstructive sleep apnea. Central apneas have been found initially after a tracheostomy, but after an extended period, central sleep apnea decreased on repeat PSG.^[11]

Physiologically normal apneic events

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 instability of ventilation control occurs. They are usually brief and not associated with significant oxygen desaturation. The clinical significance of this entity is unknown. Once stable sleep is reached, normal individuals should not have more than 5 central apneas per hour of sleep.

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.

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Epidemiology

US frequency

Predominant central apnea is uncommon and is seen in less than 10% of patients presenting for PSG. In the general population, the prevalence of central sleep apnea is less than 1%.^[12] CSB-CSA has been reported in 25-40% of patients with heart failure and in 10% of patients who have had a stroke. One study^[6] has reported the prevalence rate of central sleep apnea at 30% in a population of patients in a stable methadone maintenance program.

Race

No data are available on the racial distribution of central sleep apnea syndromes.

Sex

CSB-CSA shows a striking male preponderance. 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.^[13] Age distribution in other central sleep apnea syndromes is unknown

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Prognosis

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, the 2-year survival rate for patients in heart failure with concomitant CSB-CSA higher than in those without CSB-CSA.^[14] A more recent study demonstrated a higher mortality rate in congestive heart failure patients with central sleep apnea than those with no sleep apnea. However, the observed difference was no longer significant after adjusting for age and New York Heart Association functional class.^[15]

A study of sleep-disordered breathing and nocturnal cardiac arrhythmias in older men documented that the likelihood of atrial fibrillation or complex ventricular ectopy increased along with the severity of sleep-disordered breathing, which included obstructive sleep apnea and CSB-CSA.^[16] Different forms of sleep-disordered breathing were associated with different types of arrhythmias, and central sleep apnea was strongly associated with atrial fibrillation/flutter. 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).

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History

Like obstructive sleep apnea, central sleep apnea frequently presents with nighttime awakenings, nocturnal hypoxia, and excessive daytime sleepiness.^[17] Sometimes, bed partners report witnessed apneas and mild snoring. Patients also report nonrestorative sleep, choking, and shortness of breath.

The most common reported symptoms are insomnia, excessive daytime sleepiness and 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 provide more opportunities for an unstable breathing pattern.

Patients also may have symptoms pertaining to the underlying cause (eg, symptoms of heart failure, stroke, renal failure, Parkinson disease, or multiple system atrophy). Dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and other heart failure symptoms can be seen with CSB-CSA.

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Physical Examination

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. Because CSB-CSA is highly prevalent in patients with congestive heart failure, signs of heart failure may be sought.^[18] Sleep-disordered breathing is associated with nocturnal cardiac arrhythmias.^[16] One study^[19] 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.

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Laboratory 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.

Underlying causes should be sought if clinically relevant. For example, fasting blood glucose levels should be checked because central sleep apnea is more common in patients with diabetes mellitus, serum creatinine levels can be measured to assess for renal failure, or antibodies to acetylcholine receptors can be evaluated in patients with suspected myasthenia gravis.

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Imaging Studies

Imaging study finding are also nonspecific and are characteristic of the underlying cause rather than helpful in diagnosing a specific central sleep apnea syndrome. 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.

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Other Tests

The American College of Physicians has provided new guidelines on the diagnosis of sleep apnea, as follows^{[20, 21]} :

• Patients with unexplained daytime sleepiness should undergo a sleep study, preferably polysomnography (PSG).
• When polysomnography is not available for diagnostic testing, portable sleep monitors should be used in patients without serious comorbidities.
• Indirect evidence exists that type III monitors performed better than type IV monitors in predicting apnea-hypopnea index scores suggestive of obstructive sleep apnea. Type IV monitors have an important limitation in that they are unable to distinguish obstructive from central sleep apnea.

Relevant tests are further described below.

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 with more than 50% of the events determined to be central rather than obstructive. They appear to be more common during sleep stages 1 and 2. Severe fragmentation caused by apnea may preclude the patient from going into deep sleep (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, is directly proportional to circulation time, and is 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-3^[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 non–rapid eye movement (NREM) sleep and improves over the course of a few days.

Central sleep apnea due to drugs or substance abuse is more common during NREM sleep than REM sleep.^[6] Both periodic and nonperiodic breathing patterns can be seen, the cycle length typically being short. An AHI of greater than 5 in the absence of periodic breathing and an AHI of greater 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. Esophageal pressure monitoring with a balloon catheter is helpful in distinguishing central from obstructive events by revealing the substantial reduction in intrapleural pressure that occurs with the obstructive events.

Home monitoring

No studies have evaluated the accuracy of portable monitoring devices for the detection of central apneas,^[22] but CSA can be suspected from review of tracings on many portable monitoring platforms. Data, however, demonstrate portable monitoring can be an effective diagnostic tool to diagnose obstructive sleep apnea syndrome in suspected moderate-to-severe obstructive sleep apnea.^{[23, 24]}

Echocardiography

Patients with CSB-CSA and heart failure commonly have an ejection fraction of less than 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 for the evaluation of central sleep apnea in the absence of risk factors or signs and symptoms of heart failure.

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Medical Care

No clear guidelines are available on when or whether to treat central sleep apnea in the absence of symptoms, particularly when central sleep apnea is discovered after polysomnography (PSG) is performed for another reason. Clearly, when the symptoms are present, treatment is warranted. The decision to treat should be made on an individual basis.

Up to 20% of central sleep apnea cases 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 positive airway pressure (CPAP) treatment of obstructive sleep apnea.

If present, treatment of the underlying disorder often improves central sleep apnea. For example, descending to a low altitude is effective in treating high-altitude periodic breathing. Similarly, instituting nocturnal dialysis and optimizing medical treatment are often effective for Cheyne-Stokes breathing-central sleep apnea (CSB-CSA) due to renal failure and heart failure, respectively. Heart transplantation has also been reported either to resolve CSB-CSA or to decrease the cycle length of CSB-CSA breathing. Interestingly, a small study indicates that exercise training lessens the severity of obstructive sleep apnea but does not affect central sleep apnea in patients with heart failure and sleep disordered breathing.^[25] These findings provide compelling evidence for prescribing exercise training in the treatment of patients with heart failure with sleep apnea, particularly in those with obstructive sleep apnea, but larger studies are needed to verify this finding.

Several different treatments aimed at central sleep apnea include positive airway pressure, adaptive servo ventilation (ASV), oxygen, added dead space, carbon dioxide inhalation, and overdrive atrial pacing.

Continuous positive airway pressure

CPAP improves cardiac function in patients with congestive heart failure and CSB-CSA.

A study published in 2000 suggesting that CPAP may reduce the combined rate of mortality and cardiac transplantation in heart failure patients with CSB-CSA.^[26] This observation raised substantial interest and resulted in the institution of a large prospective study, the Canadian Prospective Continuous Positive Airway Pressure (CANPAP) trial for congestive heart failure trial. While this latter study failed to confirm a mortality benefit, CPAP was associated with attenuation of central sleep apnea, improvement of nocturnal oxygenation, lowering of norepinephrine levels, improvement in ejection fraction, and the increased distance walked in six minutes.^[27]

Another study demonstrated that despite lowering of the AHI, CPAP had no significant effect on the frequency of arousals, sleep efficiency, or the amounts of total, slow wave, or rapid eye movement (REM) sleep in heart failure patients with central sleep apnea.^[28]

Bilevel positive airway pressure

Bilevel positive airway pressure (BIPAP) is effective for treating patients with hypercapnic central sleep apnea (associated with hypoventilation). The inspiratory positive airway pressure (IPAP) is higher than the expiratory positive airway pressure (EPAP). A high IPAP-to-EPAP differential provides breath-by-breath pressure support to augment ventilation. In addition to reinforcing the spontaneous breaths, patients with central sleep apnea may require additional breaths set as a back-up rate, especially when the central apneas are long. Patients with high-pressure requirements may benefit by elevation of the head end to 45-60°, which often dramatically decreases their pressure requirements.

Pressure-cycled BIPAP is usually adequate. Volume-cycled ventilators are rarely necessary and have their own limitations in terms of inability to adjust for high leaks, humidification, and expense.

Some patients with nonhypercapnic central sleep apnea, such as CSB-CSA, and primary central sleep apnea have been shown to benefit from BIPAP. Because BIPAP can be used with a back-up rate, it is beneficial in patients with long apneas. However, BIPAP, especially when used with a high IPAP-to-EPAP differential, has the potential to worsen central sleep apnea by lowering the PaCO₂. BIPAP 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 BIPAP 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 was effective against both primary central sleep apnea and CSB-CSA. The increase in PaCO₂ is miniscule (approximately 1.5-2 mm Hg) but can be effective in stabilizing the breathing pattern.

Minimizing hypocapnia, by adding 100-150 mL enhanced expiratory rebreathing space (EERS), was documented to improve CSA and is a potentially useful adjunctive therapy for positive pressure–associated respiratory instability and salvage of some CPAP treatment failures.^[29]

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.

Adaptive servo ventilation

ASV is used for treatment for CSA, especially CSB-CSA.

ASV provides positive expiratory airway pressure (EPAP) and inspiratory pressure support (IPAP), which is servocontrolled based on the detection of CSA. The device provides a fixed EPAP determined to eliminate obstructive sleep apnea. The ASV device changes the inspiratory pressure above the expiratory pressure as required to normalize patients’ ventilation. Pressure support may be set to a minimum of 0 and maximum pressure minus the EPAP (the MaxPS should equal MaxPressure – MinEPAP). With normal breathing, the device acts like fixed CPAP by providing minimal pressure support. When the device detects CSA, the device increases the pressure support above the expiratory pressure up to a maximum pressure, which can be set by the user. Additionally, an automatic, timed backup up rate is available.

Studies demonstrate that ASV is superior to conventional positive airway pressure therapy for controlling the number of central sleep apneas,^{[30, 31]} improving sleep architecture and daytime hypersomnolence, particularly for CSB-CSA, central sleep apnea syndrome, and complex sleep apnea. In one study, both ASV and CPAP decreased the AHI, but, noticeably, only ASV completely corrected CSA-CSA by attaining a AHI below 10/h.^[30] ASV may also effectively reduced central apneas and the overall AHI in patients on long-term opiates.^[32]

The acute use of ASV is effective on CSA by increasing oxygen saturation and reducing heart rate and heart rate variability.^[33] In a long-term 12-month study, ASV improved CSA-CSR and brain natriuretic peptide more effectively than CPAP in patients with heart failure.^[34]

The benefit of ASV in treating patients with heart failure and CSB-CSA is dependent on the suppression of the periodic breathing.^[35] Therefore, ASV should be prescribed with the guidance of PSG that documents suppression of CSB-CSA.

Oxygen

Supplemental oxygen may be effective in some patients with CSB-CSA due to heart failure and has also been shown to improve ejection fraction.^[36] It is thought to work by decreasing the hypoxic drive and thus attenuating the hyperventilatory response to a change in PaCO₂. When comparing oxygen therapy to ASV, CSA-CSR is reduced to a greater extent by ASV than oxygen therapy over 8 weeks but oxygen therapy is better accepted.^[37] 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. The optimal flow rate can be titrated during PSG until central sleep apnea resolves.

Overdrive atrial pacing

Overdrive atrial pacing has been shown to reduce both obstructive and central apneas in patients with sleep-disordered breathing who have dual-chamber pacemakers. One study demonstrated a reduction in AHI of approximately 60% in patients who received pacemakers for symptomatic sinus bradycardia.^[38] Obstructive apneas fell from 6 to 3 per hour, central apneas from 13 to 6 per hour, and the overall AHI from 28 to 11 events per hour. The mechanism behind this phenomenon has not been definitively characterized, although stabilization of autonomic tone has been suggested to play a role. Other researchers, however, failed to reproduce these results.^[39]

Implantable device

In October 2017, the US Food and Drug Administration (FDA) approved an implantable device for the treatment of central sleep apnea.^[40] Called the remedē System, it is a battery pack that is implanted under the skin on the upper chest, and it sends electrical current to the phrenic nerve to innervate the diaphragm. Clinical trial results showed that 51% of the patients with the active implant had at least a 50% reduction in their AHI. The control group (subjects with an inactive implant) had an 11% decrease in their AHI. The most common adverse effects in the trial were implant site infection, concomitant device interaction, local tissue damage or pocket erosion, and swelling.

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Medication Summary

Due to the heterogeneity of the central sleep apnea syndromes, different medications have been used under different circumstances. No single medication can be considered a drug of choice.^[1] Several different medications aimed at improving central sleep apnea include acetazolamide, theophylline, and sedative-hypnotic agents.

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.

This agent has been studied in patients with heart failure and was found to be effective in attenuating CSB.^[41] It may also be effective for high-altitude periodic breathing.

These agents 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. A case series showed zolpidem reduced central apneas, and the overall apnea-hypopnea index, without worsening obstructive events.^[42]

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Acetazolamide (Diamox)

• Dosing, Interactions, etc.

Clinical Context:  Acetazolamide is a carbonic anhydrase inhibitor for acclimatization to altitude in high-altitude cerebral edema (HACE) and acute mountain sickness (AMS). It helps prevent AMS in forced rapid ascent or in patients with a history of repeated AMS. It improves symptomatic periodic breathing and hypoxia experienced at high altitudes. Acetazolamide is not indicated for general prophylaxis of AMS. Treatment of AMS may be discontinued when the patient is asymptomatic.

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Class Summary

These agents are used to induce metabolic acidosis and increase baseline ventilation.

• References

Temazepam (Restoril)

• Dosing, Interactions, etc.

Clinical Context:  The intermediate rate of absorption and duration of action make this drug useful for treating initial and middle insomnia. Temazepam has no active metabolites, which reduces cognitive impairment and grogginess the following day.

• References

Class Summary

These agents are used to promote deeper stages of sleep.

• References

Zolpidem (Ambien)

• Dosing, Interactions, etc.

Clinical Context:  Zolpidem is rapidly absorbed, with a fast onset of action (20-30 min), which makes this a good drug for sleep induction. The ER product (Ambien CR) consists of a coated 2-layer tablet and is useful for insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The first layer releases drug content immediately to induce sleep, whereas second layer gradually releases additional drug to provide continuous sleep.

• References

Class Summary

These agents are used to consolidate sleep.

• References

Theophylline (Theo-dur)

• Dosing, Interactions, etc.

Clinical Context:  Theophylline has a number of physiological effects, including increases in collateral ventilation, respiratory muscle function, mucociliary clearance, and central respiratory drive. It partially acts by inhibiting phosphodiesterase, elevating cellular cyclic AMP levels, or antagonizing adenosine receptors in the bronchi, resulting in relaxation of smooth muscle. However, clinical efficacy is controversial, especially in acute settings.

• References

Class Summary

These agents are respiratory stimulants.

• References