0
Postgraduate Education Corner: CONTEMPORARY REVIEWS IN SLEEP MEDICINE |

Central Sleep Apnea*: Pathophysiology and Treatment FREE TO VIEW

Danny J. Eckert, PhD; Amy S. Jordan, PhD; Pankaj Merchia, MD; Atul Malhotra, MD, FCCP
Author and Funding Information

*From the Division of Sleep Medicine, Sleep Disorders Program and Harvard Medical School (Drs. Eckert, Jordan, and Merchia), and Division of Pulmonary/Critical Care Medicine (Dr. Malhotra), Brigham and Women’s Hospital Boston, MA.

Correspondence to: Danny J. Eckert, PhD, Brigham and Women’s Hospital, Division of Sleep Medicine, Sleep Disorders Program @ BIDMC, 75 Francis St, Boston, MA 02115; e-mail: deckert@rics.bwh.harvard.edu



Chest. 2007;131(2):595-607. doi:10.1378/chest.06.2287
Text Size: A A A
Published online

Central sleep apnea (CSA) is characterized by a lack of drive to breathe during sleep, resulting in repetitive periods of insufficient ventilation and compromised gas exchange. These nighttime breathing disturbances can lead to important comorbidity and increased risk of adverse cardiovascular outcomes. There are several manifestations of CSA, including high altitude-induced periodic breathing, idiopathic CSA, narcotic-induced central apnea, obesity hypoventilation syndrome, and Cheyne-Stokes breathing. While unstable ventilatory control during sleep is the hallmark of CSA, the pathophysiology and the prevalence of the various forms of CSA vary greatly. This brief review summarizes the underlying physiology and modulating components influencing ventilatory control in CSA, describes the etiology of each of the various forms of CSA, and examines the key factors that may exacerbate apnea severity. The clinical implications of improved CSA pathophysiology knowledge and the potential for novel therapeutic treatment approaches are also discussed.

Figures in this Article

Central sleep apnea (CSA) is characterized by a lack of drive to breathe during sleep, resulting in insufficient or absent ventilation and compromised gas exchange. In contrast to obstructive sleep apnea (OSA), in which ongoing respiratory efforts are observed, central apnea is defined by a lack of respiratory effort during cessations of airflow. However, as will be discussed, considerable overlap exists in the pathogenesis and pathophysiology of obstructive and central apnea, making this distinction somewhat difficult at times. CSA, like OSA, is associated with important complications, including frequent nighttime awakenings, excessive daytime sleepiness, and increased risk of adverse cardiovascular outcomes.12 There are several manifestations of CSA. These include high altitude-induced periodic breathing, idiopathic CSA (ICSA), narcotic-induced central apnea, obesity hypoventilation syndrome (OHS), and Cheyne-Stokes breathing (CSB). While the precise precipitating mechanisms involved in the various types of CSA may vary considerably, unstable ventilatory drive during sleep is a principal underlying feature.

The prevalence of CSA varies greatly between the various forms of CSA. Most healthy individuals will have periodic breathing on high-altitude ascent, provided the magnitude of the ascent is sufficient to cause substantial alveolar hypoxia.3Given the global increase in obesity, the prevalence of OHS is likely on the rise.4ICSA is relatively uncommon and may constitute < 5% of patients referred to a sleep clinic.5Conversely, within certain clinical populations the presence of CSA may be extremely high. For example, a recent, prospective prevalence study6 of patients with heart failure and left ventricular ejection fraction < 45% revealed that 37% of patients had CSA. Interestingly, OSA is not uncommon in this population at 12%.6Indeed, instances whereby central respiratory events lead to obstructive respiratory events in patients with vulnerable pharyngeal anatomy, and vice versa, are observed in the majority of sleep apnea patients.7 The overlap between CSA and OSA suggests that common mechanistic traits are likely involved. Typically, CSA is considered to be the primary diagnosis when ≥ 50% of apneas are scored as central in origin (ie, >10 s cessation of breathing in the absence of respiratory effort); however, such thresholds are clearly arbitrary.

Chemoreceptor inputs (medullary neurons responding to CO2 via shifts in H+ concentration and peripherally at the carotid body via Pao2 and Paco2) play a key role in modulating ventilation. The ventilatory output to a given change in Pao2 or Paco2 (“chemosensitivity”) can vary greatly between individuals and with disease status. Highly sensitive chemoresponses can place an individual at risk for unstable breathing patterns because these individuals “overrespond” to small changes in chemical stimuli. The inherent delays in the negative feedback loop controlling ventilation also contribute to the risk for developing instability. For example, for a given increase in Paco2, an individual with high chemosensitivity will respond by increasing ventilation to a greater extent than someone with low chemosensitivity. This increased ventilation will continue until the resultant reduction in Paco2 (caused by the response) is detected at the chemoreceptors. Thus, individuals with high chemoresponsiveness will hyperventilate markedly to a perturbation potentially, lowering Paco2 below the eupnic level and leading to hypoventilation and potential apnea. Similarly, an individual with a long delay in the loop, such as individuals with reduced cardiac output, may have more prolonged hyperventilation, also leading to greater hyperventilation and a subsequent unstable breathing. The details of the control of the respiratory system feedback loop, otherwise known as loop gain, are described in detail elsewhere.810 Just as high chemosensitivity can be destabilizing to the respiratory system, severely blunted chemosensitivity can also be deleterious to cardiorespiratory homeostasis because extremely severe blood gas disturbances occur before a response is mounted.

In addition to chemical control, there are several other important homeostatic feedback mechanisms that regulate ventilation to maintain gas exchange within tightly controlled limits. Afferent information from Golgi tendon organs and muscle spindles from the chest wall and respiratory muscles also play an important role in regulating the rate and depth of breathing. During wakefulness nonrespiratory behavioral influences are also capable of modulating ventilatory activity. Examples include strong emotional expressions involving limbic forebrain structures and performing secondary tasks such as speech and ingestion of food. An independent background augmentation in respiratory drive known as the wakefulness drive to breathe is also present.11

Transition to Sleep

The transition from wakefulness to sleep is an inherently unstable period in terms of cardiorespiratory control.1213 With sleep onset, there is a loss of the wakefulness stimulus and behavioral influences.14In addition, several respiratory control mechanisms are down regulated at sleep onset. Upper airway (UA) dilator and respiratory pump muscle tone is reduced, and there is an accompanying increase in UA resistance leading to a reduction in ventilation for a given level of drive.1516 Chemosensitivity is also likely reduced at sleep onset.17Although of variable magnitude and rate, these normal physiologic responses occur in all individuals. Should the withdrawal of the wakefulness drive be rapid at sleep onset, this in itself may be sufficient to promote hypopnea/apnea due to the delay required to elicit an appropriate compensatory response from the chemoreceptors.18Thus, the dysrhythmic breathing characteristics observed even in healthy individuals at sleep onset likely relates to a combination of state instability and the associated changes in chemoreceptor sensitivity.19

Apnea Threshold

While behavioral influences and neurocompensatory responses strongly appose apnea even in the presence of marked decreases in Paco2 during wakefulness, this is not the case during sleep. Indeed, during sleep all individuals are susceptible to breathing cessation should the Paco2 fall below a critical threshold known as the apnea threshold. The apnea threshold is usually 2 to 6 mm Hg below the eucapnic sleeping Paco2 level. This typically equates to the wakefulness eucapnic Paco2 level or marginally lower2021 (see Dempsey22 for details).

Stable Sleep Changes

In addition to the changes that occur at sleep onset, ventilatory responses to hypoxia and hypercapnia and respiratory load compensation are reduced across sleep stages, particularly during rapid eye movement (REM) sleep.2325 The resultant reduction in ventilation with progressive sleep is coupled with a gradual rise in Paco2 on the order of approximately 3 to 8 mm Hg,26 depending on the prevailing metabolic conditions. Provided stable sleep is achieved, a new sleep-specific CO2 set point is established. Thus, during sleep, chemoreceptor and respiratory reflex feedback become critical components that regulate ventilation, albeit at a reduced homeostatic level compared to wakefulness.

Transition to Wake

Arousal from sleep is an integrated physiologic process that can serve as an important protective response. For example, during periods of compromised ventilation, arousal may be an important mechanism for restoring gas exchange when other compensatory mechanisms fail. However, arousal from sleep can also be deleterious to respiratory control stability. The propensity to develop central apnea is likely influenced by two important components of arousal sensitivity: arousal threshold and the ventilatory response to arousal.

Arousal Threshold

Regardless of the underlying cause of arousal from sleep (ie, spontaneous arousal, periodic leg movements, respiratory load induced arousal), an individual with a low arousal threshold (ie, susceptible to waking up easily) will be vulnerable to sleep state instability. That is, the combination of a predisposition to sleep transition apnea and a low arousal threshold may be sufficient to facilitate a repetitive CSA cycle as the individual oscillates between wakefulness and sleep. The arousal threshold does, however, increase with progressively deeper sleep stage,27 as does breathing stability provided slow wave sleep can be achieved. However, it remains controversial whether slow wave sleep is intrinsically more stable from a respiratory standpoint, or if stable breathing allows sleep to deepen.

Ventilatory Response to Arousal

The rapid switch from sleep to wakefulness that occurs with arousal causes a sudden shift in the underlying homeostatic control of the cardiorespiratory system. The eucapnic set point rapidly shifts from the sleep set point (approximately 45 mm Hg) to the wakefulness level (approximately 40 mm Hg) creating a state of relative hypercapnia. In addition, sleep-induced UA resistance is removed and the wakefulness drive is reintroduced. Accordingly, a ventilatory response is evoked, the magnitude of which is determined by the extent of the shift between the various state-related physiologic changes. In addition, there is evidence to suggest there may be an additional waking reflex that further augments this response.2829 The brisk ventilatory response causes a rapid reduction in Paco2, such that central apnea may ensue during subsequent sleep if the hypocapnia is sufficient to cross the apnea threshold30 (Fig 1 ).

CSA syndromes can be broadly classified into two groups according to the wakefulness CO2 levels (hypercapnic vs nonhypercapnic), although the prevailing abnormalities in these two groups can be quite disparate.31 These underlying physiologic differences contribute to the varying CSA etiologies.

Hypercapnic CSA

By definition, patients with impaired ventilatory output during wakefulness will have some degree of daytime hypercapnia. Undoubtedly with the removal of the wakefulness drive and other behavioral influences, hypercapnia will worsen during sleep. Hence, the term sleep hypoventilation is often used to highlight an underlying condition of hypercapnia that worsens with sleep. From a physiologic perspective, patients with hypercapnia can be broadly classified into abnormal central pattern generator output (“won’t breathe”) or impairment of respiratory motor output caudal to the respiratory pattern generator (“can’t breathe”).

Impaired Central Drive (“Won’t Breathe”):

Tumors or trauma-induced lesions to brainstem structures may directly diminish ventilatory output, which on removal of wakefulness/behavioral drive is subject to further decline during sleep resulting in CSA. One form of hypercapnic CSA is congenital central hypoventilation syndrome (CCHS, formerly known as the Ondine curse), which is likely genetic in etiology without clear anatomic pathology. This rare condition is characterized by marked alveolar hypoventilation during sleep often resulting in severe hypercapnia and hypoxemia.32Further complications associated with this condition may include secondary polycythemia, pulmonary hypertension, and cor pulmonale. The breathing pattern during sleep is characterized by near-normal respiratory rate with diminished tidal volume.33Unlike OSA, ventilation in CCHS tends to be more stable during REM compared to non-REM sleep,34 presumably due to the presence of additional respiratory stimulation during REM. Ventilatory responses and sensations of dyspnea to hypercapnia and hypoxia are often absent or greatly diminished in children with CCHS.32 While most cases of CCHS present in the newborn period, a recent report35 has revealed mild cases can present in adulthood.

The respiratory depressant effects of acute use of opioid-based medications are well known3637 but have long been believed to subside with longer-term usage.38However, evidence3940 suggests that long-term use may lead to an increased propensity for CSA in up to 50% of patients. Because of the high prevalence of chronic pain and narcotic use,4142 opioid-induced sleep-disordered breathing (SDB) is likely a major issue although only beginning to be recognized. Reported features of opioid-induced CSA may include prolonged periods of hypoventilation with marked hypoxemia and repetitive central apneas (Fig 2 , top, A). However, again SDB tends to improve during REM sleep.,39 While the precise underlying mechanisms are not clear, opioid-induced impairment of the hypercapnic and hypoxic ventilatory responses likely contribute,43effects that are thought to be dose dependent (Fig 2, bottom, B). However, the consequences of more long-term opioid medication use on the hypoxic ventilatory response and the development of SDB are less clear.44 There is also an emerging literature that disruption of sleep can worsen physical pain, leading to the intriguing hypothesis that narcotic-induced central apnea may worsen narcotic requirements.

Another form of hypercapnic CSA is OHS,45 the prevalence of which is likely on the rise.4 This disorder is typically defined as a combination of obesity (body mass index > 30 kg/m2) and arterial hypercapnia (Paco2 >45 mm Hg) during wakefulness not explained by other known causes of hypoventilation.,46Hypoventilation worsens during non-REM sleep and further during REM sleep, resulting in marked hypercapnia with accompanying hypoxemia. Typical symptoms may be similar to patients with OSA, including morning headaches and daytime hypersomnolence.47 Indeed, some patients with OHS also have OSA, suggesting there is mechanistic overlap between these obesity-related forms of SDB. The underlying mechanisms and the reasons why some obese patients have OHS but not others remains a major unresolved issue within the field. The inability of some patients to compensate for their obesity-related impairment in respiratory mechanics may be related to differences in the anatomic distribution of fat combined with ventilatory control deficits such as blunted chemosensitivity.45,4849 Studies5052 raise the possibility that the hormone leptin, secreted by adipocytes, may also be important in obesity-related hypoventilation in some patients.

Impaired Respiratory Motor Control (“Can’t Breathe”):

Hypercapnic patients with primarily intact central respiratory output from pattern generator neurons who have CSA may have abnormalities from upper motor neurons right down the neuromotor axis to the respiratory muscles. This encompasses a wide range of neuromuscular disorders, including myasthenia gravis (neuromuscular junction), amyotrophic lateral sclerosis (motor neuron disease), post-polio syndrome, and myopathies (eg, acid maltase deficiency). Chest wall syndromes such as kyphoscoliosis can also be associated with hypoventilation and CSA. The etiology and severity of CSA in these types of patient populations varies according to the extent and nature of the underlying abnormality.5

Nonhypercapnic CSA

The factors underlying central apnea in patients who are eucapnic or hypocapnic can be quite different from patients with hypercapnic CSA.

CSB:

CSB is characterized by a waxing and waning pattern of ventilation (Fig 3 ). This disorder is most commonly observed in patients with congestive heart failure (CHF) and left ventricular systolic dysfunction. Apneas or hypopneas occur at the nadir of the characteristic crescendo/decrescendo ventilatory pattern and are most common during lighter sleep (stages 1 and 2). The cycle time of this pattern of unstable ventilation (typically 60 to 90 s) is much longer than other forms of CSA, due to prolonged circulation time in patients with CHF. Arousal typically occurs mid-cycle at the peak of ventilatory effort rather than at the cessation of apnea.53Recent data54suggest that SDB is more severe in the supine vs lateral position in patients with CSB, independent of postural effects on the UA. Characteristic symptoms may include fragmented sleep, paroxysmal nocturnal dyspnea, orthopnea, and daytime fatigue.55 Multiple features likely contribute to the development of the distinctive CSB pattern. These include factors that promote unstable breathing such as high ventilatory drive,5556 minimal difference between the apnea threshold and sleeping eucapnic Paco2,57 long circulation time resulting in a mismatch between arterial blood gas concentration with the respiratory controllers,18,58and impaired cerebrovascular reactivity to CO2.59 Animal data60suggest that pulmonary congestion activates afferent C fibers (J receptors) causing sensory information to relay to the respiratory control centers to elicit a strong inhibitory reflex resulting in apnea followed by a period of hyperventilation that is likely to further destabilize breathing. A strong relationship between pulmonary capillary wedge pressure, hypocapnia, and CSA severity exists in patients with CHF,61 suggesting that similar reflex mechanisms may exist in humans.

ICSA:

While there is clearly mechanistic overlap between ICSA and CSB, patients who have central apneas during sleep that do not display the typical CSB pattern or sleep transition apnea with normocapnia or hypocapnia during wakefulness fall into the category of ICSA. Central apneas in ICSA may occur as distinct features or in a repetitive cyclical manner (Fig 4 ). The duration of the cycle time (typically 20 to 40 s) is much less than CSB, and desaturations associated with events tend to be less severe. Similar to CSB, apneas are most commonly observed during stages 1 and 2 in ICSA. However, arousals typically occur at the termination of central apnea. Insomnia or hypersomnolence are common presenting symptoms. Typically, these patients are thinner and snore less than patents with OSA, although male predominance is likely a common trait.62 As the name implies, the underlying mechanisms for this disorder are not fully understood. Elevated hypercapnic ventilatory responses56,6364 leading to hypocapnia and respiratory control instability are believed to be particularly important. Arousal and the accompanying hyperventilation, which due to the brief reintroduction of the waking stimulus and altered chemosensitivity, likely play an important role in triggering hypocapnia in patients with ICSA, resulting in further destabilization of breathing.30 These destabilizing factors render the patient vulnerable to crossing the apnea threshold, which may be very close to the sleeping eucapnic Paco2, particularly in patients with daytime hypocapnia. An inherently long transition duration between wakefulness and stable sleep, leading to greater exposure for state related breathing instability and high efficiency of CO2 excretion, may also be a causative factor.

According to the Chicago criteria,65the term periodic breathing is generally reserved for altitude-induced breathing instability. Nonetheless, this form of unstable breathing likely shares common mechanistic elements with other forms of nonhypercapnic CSA, such as vulnerability to crossing the apnea threshold due to a relative state of hypocapnia and the propensity for arousal to lead to further ventilatory control instability.66

Hypoxia

While deviations in chemosensitivity from normality may contribute to the pathophysiology of the various forms of CSA, there is evidence to suggest that the depressive effects of hypoxia may further increase disease severity. The different forms of CSA result in varied magnitude and duration of hypoxia, which are likely important determinants for the possible development of hypoxia-induced depressive effects. ICSA and CSB are characterized by intermittent hypoxia during sleep, while OHS is typically characterized by prolonged periods of sustained hypoxia during sleep. Hypoxia-induced central depression has been proposed to be an important contributing mechanism to SDB that occurs at altitude.67Data6869 suggest that acute sustained hypoxia impairs respiratory sensory processing and arousal responses to respiratory stimuli during sleep. These findings raise the possibility that hypoxia may impair respiratory sensory feedback mechanisms and increase disease severity in conditions characterized by sustained hypoxia such as sleep hypoventilation syndrome. Animal data70 demonstrate that the combination of acute hypoxia and pulmonary congestion, which stimulates afferent C fibers (J receptors) to evoke an inhibitory respiratory reflex, may lead to prolonged apnea, which may further perpetuate cyclical breathing in patients with CSB.

UA Anatomy

UA dilator muscles such as the genioglossus muscle receive neural input from central pattern generator neurons. An individual with an anatomically narrow UA is extremely reliant on neural drive to UA muscles for maintaining an open UA, whereas an anatomically larger UA is mechanically less reliant on neural drive. Thus, it is not surprising that in the absence of neural drive (central apnea), depending on the properties of the UA, varying degrees of UA collapse can ensue.7 Correcting an anatomically narrow UA with continuous positive airway pressure (CPAP) in a patient with primarily OSA can also lead to apparent treatment emergent central apnea. Although this phenomenon has been minimally studied,71 CPAP reduces UA resistance thereby improving the efficiency of CO2 excretion, rendering the hypocapnic patient vulnerable to crossing the apnea threshold. Activation of stretch reflexes that may inhibit ventilation secondary to increased lung volume effects of CPAP (especially if overtitrated) may also contribute.,5 While recent data71 have revealed a greater male predominance of treatment-emergent CSA than OSA or other forms of CSA, the clinical presentation of patients with treatment-emergent CSA appears similar. Although there are currently no long-term data available, clinical experience suggests that these treatment emergent central apneas resolve with ongoing treatment, since CSA is relatively uncommon among patients receiving stable CPAP.5

Given the range of pathophysiologic factors contributing to the varied forms of CSA (summarized schematically in Fig 5 ), treatment approaches also vary considerably. Gradual dose reduction of opioid medication may improve high-dose narcotic-induced CSA (Fig 2, bottom, B). Weight loss is likely to lead to improvement of SDB in patients with OHS.46 In practice, both these goals may be difficult to achieve. However, surgical weight loss may be an effective alternative option for morbidly obese patients with OHS.72 Varied strategies to manipulate chemosensitivity and respiratory drive offer promise for stabilizing unstable breathing patterns during sleep for many forms of CSA. However, concerns regarding potential adverse effects given the current lack of long-term randomized controlled trials warrant caution when considering such approaches as therapeutic options. Interventions that improve cardiac status for patients with an underlying heart condition may also attenuate SDB. The current level of evidence, mechanistic action and potential adverse effects for the main treatment options for CSA are discussed in the following section and summarized in Tables 1 and 2 . For a comprehensive approach to the management of CCHS, the reader is referred to the American Thoracic Society guidelines,32 and a recent report35 incorporating investigation for the PHOX2B gene mutation.

O2

Nonhypercapnic CSA patients with heightened chemosensitivity may benefit from the stabilizing respiratory control effects associated with O2 therapy. Indeed, several short-term trials have demonstrated that SDB improves with O2 administration in patients with ICSA90 and CSB,9093 and potentially in certain patients with hypoventilation syndrome.78 Although minimally studied, there is some evidence to suggest that sleep efficiency parameters may be more favorable on O2 therapy than CPAP.,93 To date, no large-scale long-term trials have been performed to determine which patients will likely benefit from O2 therapy and its long-term efficacy. There are some concerns that O2 therapy may have cardiodepressant effects mediated via O2 radicals.,109While larger trials are required before O2 therapy can be recommended for the treatment of CSA in patients with heart failure, evidence suggesting favorable cardiovascular function is beginning to emerge.111

CO2

Several studies have demonstrated that mild increases in inspired CO2, delivered directly or via the application of increased dead space, can be highly effective in treating CSA. Overnight trials involving small numbers of subjects have reported marked decreases in the apnea-hypopnea index (AHI) in patients with ICSA100 and CSB,88without apparent acute cardiovascular adverse effects.89 Improvement is likely the result of a widening in the difference between eucapnic sleeping Pco2 and the apnea threshold. However, other reports suggest that despite marked improvement in AHI, increased CO2 does not improve sleep quality,112or reduce the arousal index113and may lead to marked sympathoexcitation.114 Clearly, larger trials are required to determine the long-term efficacy and safety of increased CO2 for the treatment of CSA.

Noninvasive Ventilation

While the need to mechanically ventilate patients with severe hypercapnic CSA may be clear (ie, infants with severe CCHS and end-stage patients), the role of noninvasive ventilation in less severe forms of CSA is somewhat less clear. Nasal CPAP has been shown to be effective in some patients with ICSA.9899 The mechanism for improvement in these patients is not clear but may relate to prevention of inhibitory reflex mechanisms that arise during airway closure and potentially CPAP-induced increases in lung volume/O2 stores.,115CPAP treatment improves hemodynamics and SDB in heart failure patients.116 However, the largest trial83 investigating CPAP in CSA did not reveal improvement in mortality and only partially improved the AHI. The combination of CPAP and increased CO2 may be highly effective in treating ICSA,117and mixed central and obstructive SDB.118However, similar to the effect of increased inhaled CO2 alone, the lack of long-term trials and the potential for sympathoexcitation prevent the use of this approach in routine clinical practice at this time. Bilevel positive airway pressure may be deleterious to certain CSA patients by inducing hypocapnia119 but effective in others.73,76,120 Indeed, when used with a backup rate, bilevel positive airway pressure may lead to significant improvements in ventilation during sleep and a marked reduction in Paco2 in patients with OHS.,77 Other new-generation, adaptive machines may also be effective in treating central apnea.84,87 Evidence8586 suggests that such devices may improve patient adherence that would be predicted to improve symptoms and cardiac function, although data are currently equivocal.

Strategies To Improve Cardiac Function to Treat SDB

Optimization of medications for patients with an underlying heart condition can lead to significant improvement in SDB for patients with CSB.61,8082 Restoration of cardiac function in patients with more severe disease via heart transplantation may also improve CSA, although some patients subsequently acquire OSA.121123 A novel strategy of atrial overdrive pacing to increase heart rate by 15 beats/min significantly improved SDB in patients with symptomatic sinus bradycardia with normal or mildly depressed left ventricular function.101This beneficial effect was attributed to increased cardiac output and decreased pulmonary congestion (decreased loop gain), although the findings remain controversial. The majority of patients with SDB have observed no benefit of overdrive pacing.102107,124 Resynchronization pacemaker therapy has been shown recently to improve CSA and cardiac function in patients with heart failure in two small studies.9495

Respiratory Stimulants

The respiratory stimulants acetazolamide and theophylline have been shown to improve CSA in patients with heart failure.9697 Acetazolamide and has also been shown to improve SDB in ICSA.108 The carbonic anhydrase inhibitor acetazolamide leads to metabolic acidosis that likely shifts the hypercapnic ventilatory response and lowers the Paco2 apnea threshold.,108,125 Theophylline likely improves SDB via increasing central respiratory drive and cardiac contractility. Progesterone increases chemoresponsiveness and may lead to improvement in daytime gas exchange in patients with OHS.79,126However, respiratory stimulants cannot be recommended for routine CSA treatment at this time. Theophylline may increase the risk of cardiac arrhythmias and sudden death in these patients,127128 and long-term trials exploring the efficacy and safety of acetazolamide and progesterone are not yet available.

In summary, CSA encompasses a wide range of distinct yet interrelated forms of unstable breathing that can lead to substantial comorbidity and increased risk of adverse cardiovascular outcomes. The underlying pathophysiology and the prevalence of the various forms of CSA varies greatly. Given the range of pathophysiologic factors contributing to the varied forms of CSA, treatment approaches also vary considerably. NIV remains a major treatment approach for many patients. While short-term studies have highlighted the potential for alternate treatment options, there is currently a lack of long-term randomized trials, an area of investigation that clearly needs to be pursued.

Abbreviations: AHI = apnea-hypopnea index; CCHS = congenital central hypoventilation syndrome; CHF = congestive heart failure; CPAP = constant positive airway pressure; CSA = central sleep apnea; CSB = Cheyne-Stokes breathing; ICSA = idiopathic central sleep apnea; OHS = obesity hypoventilation syndrome; OSA = obstructive sleep apnea; REM = rapid eye movement; SDB = sleep-disordered breathing; UA = upper airway

Dr. Eckert is a recipient of the Thoracic Society of Australia and New Zealand/Allen and Hanbury’s respiratory research fellowship. Dr. Jordan is supported by a grant from the American Heart Association. Dr. Malhotra is funded by National Institute of Aging, Beeson Award (from 2004 to 2008), “Aging Influence on the Development of Sleep Apnea” (AG024837–01), National Institutes of Health (from 2004 to 2008), “Sleep Apnea and Obesity: Cardiovascular Risk Assessment” (RO1-HL73146–01), and National Institutes of Health, Specialized Center of Research Project 1.

Drs. Eckert, Jordan, and Merchia have no conflict of interest to declare in relation to the subject matter contained within this review article. Dr. Malhotra is a consultant for Respironics, Restore Medical, and Inspiration Medication), receiving < $20,000 per year from each of these companies. He has received an unrestricted research grant from Respironics for $100,000 to study the cardiovascular complications of sleep apnea. He has received an industry grant from Restore Medical for $100,000 to develop a computational model of the upper airway.

Figure Jump LinkFigure 1. An example of experimentally induced arousal leading to central apnea. During stable stage 2 sleep, a 55-decibel (db) tone was played to induce an arousal from sleep (shown by solid line under EEG) in a 33-year-old woman (follicular menstrual phase) with severe OSA who was receiving CPAP (14 cm H2O). A brisk ventilatory response ensues driving end-tidal Pco2 (PETCO2) from 44 mm Hg during stable sleep (first arrow, note there is an approximate 3-s sampling delay between ventilation and end-tidal Pco2) to 38 mm Hg by the return to sleep (second arrow) and was accompanied by an approximate 10-s central apnea as documented by no change in epiglottic pressure (Pepi). Vt = tidal volume. Pmask = pressure at the mask.Grahic Jump Location
Figure Jump LinkFigure 2. Top, A: An example of a patient receiving high-dose opioid medication for back pain experiencing repetitive central apneas as demonstrated by a lack of movement of respiratory effort bands (both abdominal and thoracic) with associated oxygen desaturations. Bottom, B: Marked improvement in SDB following gradual dose reduction of opioid medication. Sao2 = arterial oxygen saturationGrahic Jump Location
Figure Jump LinkFigure 3. An example of a patient with CSB. Note the characteristic crescendo/decrescendo pattern of breathing, long circulation time (each oxygen desaturation corresponds to the previous apnea), and arousal occurring at the peak of respiratory effort. See Figure 2 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 4. An example of ICSA. Note the shortened cycle time (approximately 25 s in this example) compared to CSB and that arousal (arrow) occurs at the cessation of apnea. See Figure 2 legend for expansion of abbreviation. Adapted from Malhotra et al5 with permission.Grahic Jump Location
Figure Jump LinkFigure 5. Schematic of the many potential mechanisms contributing to CSA/hypopnea. The gray boxes and largest solid arrows represent the key components contributing to unstable breathing and central apnea/hypopnea during sleep. The smaller solid arrows denote the main factors that lead to or modulate unstable breathing during sleep. Dashed arrows highlight the potential interactive links between obstructive and central apnea/hypopnea and for hypercapnia to cause arousal. Some arrows have been omitted to simplify the Figure. Refer to the text for further detail.Grahic Jump Location
Table Graphic Jump Location
Table 1. Summary of Potential Treatment Strategies and Their Effectiveness for Hypercapnic CSA*
* 

PAP = positive airway pressure; QOL = quality of life; RCT = randomized control trial; ↑ = increase; ↓ = decrease.

Table Graphic Jump Location
Table 2. Summary of Potential Treatment Strategies and Their Effectiveness for Nonhypercapnic CSA*
* 

CRT = cardiac resynchronization therapy; DTS = daytime sleepiness; LVEF = left ventricular ejection fraction; NIV = noninvasive ventilation. See Table 1 for expansion of abbreviation.

The authors are grateful to Dr. Nick Antic and Dr. Rajeev Ratnavadivel of the Adelaide Institute for Sleep Health for providing polysomnography examples of narcotic-induced CSA and CSB, respectively.

Lanfranchi, PA, Somers, VK, Braghiroli, A, et al (2003) Central sleep apnea in left ventricular dysfunction: prevalence and implications for arrhythmic risk.Circulation107,727-732. [PubMed] [CrossRef]
 
Javaheri, S, Parker, TJ, Liming, JD, et al Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences, and presentations.Circulation1998;97,2154-2159. [PubMed]
 
White, DP, Gleeson, K, Pickett, CK, et al Altitude acclimatization: influence on periodic breathing and chemoresponsiveness during sleep.J Appl Physiol1987;63,401-412. [PubMed]
 
Poulain, M, Doucet, M, Major, GC, et al The effect of obesity on chronic respiratory diseases: pathophysiology and therapeutic strategies.Can Med Assoc J2006;174,1293-1299
 
Malhotra, A, Berry, RB, White, DP Central sleep apnea. Carney, PR Berry, RB Geyer, JD eds.Clinical sleep disorders2004,331-346 Lippincott Williams and Wilkins. Philadelphia, PA:
 
Javaheri, S Sleep disorders in systolic heart failure: a prospective study of 100 male patients: the final report.Int J Cardiol2006;106,21-28. [PubMed]
 
Badr, MS, Toiber, F, Skatrud, JB, et al Pharyngeal narrowing/occlusion during central sleep apnea.J Appl Physiol1995;78,1806-1815. [PubMed]
 
Khoo, MC, Kronauer, RE, Strohl, KP, et al Factors inducing periodic breathing in humans: a general model.J Appl Physiol1982;53,644-659. [PubMed]
 
White, DP Pathogenesis of obstructive and central sleep apnea.Am J Respir Crit Care Med2005;172,1363-1370. [PubMed]
 
Wellman, A, Malhotra, A, Fogel, RB, et al Respiratory system loop gain in normal men and women measured with proportional-assist ventilation.J Appl Physiol2003;94,205-212. [PubMed]
 
Orem, J The nature of the wakefulness stimulus for breathing.Prog Clin Biol Res1990;345,23-30discussion 31. [PubMed]
 
Burgess, HJ, Kleiman, J, Trinder, J Cardiac activity during sleep onset.Psychophysiology1999;36,298-306. [PubMed]
 
Trinder, J, Whitworth, F, Kay, A, et al Respiratory instability during sleep onset.J Appl Physiol1992;73,2462-2469. [PubMed]
 
Skatrud, JB, Berssenbrugge, AD Effect of sleep state and chemical stimuli on breathing.Prog Clin Biol Res1983;136,87-95. [PubMed]
 
Kay, A, Trinder, J, Bowes, G, et al Changes in airway resistance during sleep onset.J Appl Physiol1994;76,1600-1607. [PubMed]
 
Worsnop, C, Kay, A, Pierce, R, et al Activity of respiratory pump and upper airway muscles during sleep onset.J Appl Physiol1998;85,908-920. [PubMed]
 
Dunai, J, Wilkinson, M, Trinder, J Interaction of chemical and state effects on ventilation during sleep onset.J Appl Physiol1996;81,2235-2243. [PubMed]
 
Khoo, MC, Gottschalk, A, Pack, AI Sleep-induced periodic breathing and apnea: a theoretical study.J Appl Physiol1991;70,2014-2024. [PubMed]
 
Dunai, J, Kleiman, J, Trinder, J Ventilatory instability during sleep onset in individuals with high peripheral chemosensitivity.J Appl Physiol1999;87,661-672. [PubMed]
 
Meza, S, Mendez, M, Ostrowski, M, et al Susceptibility to periodic breathing with assisted ventilation during sleep in normal subjects.J Appl Physiol1998;85,1929-1940. [PubMed]
 
Skatrud, JB, Dempsey, JA Interaction of sleep state and chemical stimuli in sustaining rhythmic ventilation.J Appl Physiol1983;55,813-822. [PubMed]
 
Dempsey, JA Crossing the apnoeic threshold: causes and consequences.Exp Physiol2005;90,13-24. [PubMed]
 
White, DP, Douglas, NJ, Pickett, CK, et al Hypoxic ventilatory response during sleep in normal premenopausal women.Am Rev Respir Dis1982;126,530-533. [PubMed]
 
Douglas, NJ, White, DP, Weil, JV, et al Hypoxic ventilatory response decreases during sleep in normal men.Am Rev Respir Dis1982;125,286-289. [PubMed]
 
Wiegand, L, Zwillich, CW, White, DP Sleep and the ventilatory response to resistive loading in normal men.J Appl Physiol1988;64,1186-1195. [PubMed]
 
Skatrud, JB, Dempsey, JA, Badr, S, et al Effect of airway impedance on CO2retention and respiratory muscle activity during NREM sleep.J Appl Physiol1988;65,1676-1685. [PubMed]
 
Gugger, M, Bogershausen, S, Schaffler, L Arousal responses to added inspiratory resistance during REM and non-REM sleep in normal subjects.Thorax1993;48,125-129. [PubMed]
 
Horner, RL, Rivera, MP, Kozar, LF, et al The ventilatory response to arousal from sleep is not fully explained by differences in CO(2) levels between sleep and wakefulness.J Physiol2001;534,881-890. [PubMed]
 
Trinder, J, Padula, M, Berlowitz, D, et al Cardiac and respiratory activity at arousal from sleep under controlled ventilation conditions.J Appl Physiol2001;90,1455-1463. [PubMed]
 
Xie, A, Wong, B, Phillipson, EA, et al Interaction of hyperventilation and arousal in the pathogenesis of idiopathic central sleep apnea.Am J Respir Crit Care Med1994;150,489-495. [PubMed]
 
Bradley, TD, McNicholas, WT, Rutherford, R, et al Clinical and physiologic heterogeneity of the central sleep apnea syndrome.Am Rev Respir Dis1986;134,217-221. [PubMed]
 
American Thoracic Society.. Idiopathic congenital central hypoventilation syndrome: diagnosis and management.Am J Respir Crit Care Med1999;160,368-373. [PubMed]
 
Weese-Mayer, DE, Silvestri, JM, Menzies, LJ, et al Congenital central hypoventilation syndrome: diagnosis, management, and long-term outcome in thirty-two children.J Pediatr1992;120,381-387. [PubMed]
 
Fleming, PJ, Cade, D, Bryan, MH, et al Congenital central hypoventilation and sleep state.Pediatrics1980;66,425-428. [PubMed]
 
Antic, NA, Malow, BA, Lange, N, et al PHOX2B mutation-confirmed congenital central hypoventilation syndrome: presentation in adulthood.Am J Respir Crit Care Med2006;174,923-927. [PubMed]
 
Santiago, TV, Edelman, NH Opioids and breathing.J Appl Physiol1985;59,1675-1685. [PubMed]
 
Shook, JE, Watkins, WD, Camporesi, EM Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depression.Am Rev Respir Dis1990;142,895-909. [PubMed]
 
The use of opioids for the treatment of chronic pain: a consensus statement from the American Academy of Pain Medicine and the American Pain Society.Clin J Pain1997;13,6-8. [PubMed]
 
Farney, RJ, Walker, JM, Cloward, TV, et al Sleep-disordered breathing associated with long-term opioid therapy.Chest2003;123,632-639. [PubMed]
 
Wang, D, Teichtahl, H, Drummer, O, et al Central sleep apnea in stable methadone maintenance treatment patients.Chest2005;128,1348-1356. [PubMed]
 
Elliott, AM, Smith, BH, Penny, KI, et al The epidemiology of chronic pain in the community.Lancet1999;354,1248-1252. [PubMed]
 
Luo, X, Pietrobon, R, Hey, L Patterns and trends in opioid use among individuals with back pain in the United States.Spine2004;29,884-890discussion 891. [PubMed]
 
Weil, JV, McCullough, RE, Kline, JS, et al Diminished ventilatory response to hypoxia and hypercapnia after morphine in normal man.N Engl J Med1975;292,1103-1106. [PubMed]
 
Teichtahl, H, Wang, D, Cunnington, D, et al Ventilatory responses to hypoxia and hypercapnia in stable methadone maintenance treatment patients.Chest2005;128,1339-1347. [PubMed]
 
Zwillich, CW, Sutton, FD, Pierson, DJ, et al Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome.Am J Med1975;59,343-348. [PubMed]
 
Olson, AL, Zwillich, C The obesity hypoventilation syndrome.Am J Med2005;118,948-956. [PubMed]
 
Strumpf, DA, Millman, RP, Hill, NS The management of chronic hypoventilation.Chest1990;98,474-480. [PubMed]
 
Sampson, MG, Grassino, K Neuromechanical properties in obese patients during carbon dioxide rebreathing.Am J Med1983;75,81-90
 
Sharp, JT, Henry, JP, Sweany, SK, et al Effects of mass loading the respiratory system in man.J Appl Physiol1964;19,959-966. [PubMed]
 
Shimura, R, Tatsumi, K, Nakamura, A, et al Fat accumulation, leptin, and hypercapnia in obstructive sleep apnea-hypopnea syndrome.Chest2005;127,543-549. [PubMed]
 
O’Donnell, CP, Schaub, CD, Haines, AS, et al Leptin prevents respiratory depression in obesity.Am J Respir Crit Care Med1999;159,1477-1484. [PubMed]
 
Phipps, PR, Starritt, E, Caterson, I, et al Association of serum leptin with hypoventilation in human obesity.Thorax2002;57,75-76. [PubMed]
 
Trinder, J, Merson, R, Rosenberg, JI, et al Pathophysiological interactions of ventilation, arousals, and blood pressure oscillations during Cheyne-Stokes respiration in patients with heart failure.Am J Respir Crit Care Med2000;162,808-813. [PubMed]
 
Szollosi, I, Roebuck, T, Thompson, B, et al Lateral sleeping position reduces severity of central sleep apnea/Cheyne-Stokes respiration.Sleep2006;29,1045-1051. [PubMed]
 
Naughton, M, Benard, D, Tam, A, et al Role of hyperventilation in the pathogenesis of central sleep apneas in patients with congestive heart failure.Am Rev Respir Dis1993;148,330-338. [PubMed]
 
Solin, P, Roebuck, T, Johns, DP, et al Peripheral and central ventilatory responses in central sleep apnea with and without congestive heart failure.Am J Respir Crit Care Med2000;162,2194-2200. [PubMed]
 
Xie, A, Skatrud, JB, Puleo, DS, et al Apnea-hypopnea threshold for CO2in patients with congestive heart failure.Am J Respir Crit Care Med2002;165,1245-1250. [PubMed]
 
Hall, MJ, Xie, A, Rutherford, R, et al Cycle length of periodic breathing in patients with and without heart failure.Am J Respir Crit Care Med1996;154,376-381. [PubMed]
 
Xie, A, Skatrud, JB, Khayat, R, et al Cerebrovascular response to carbon dioxide in patients with congestive heart failure.Am J Respir Crit Care Med2005;172,371-378. [PubMed]
 
Paintal, AS Vagal sensory receptors and their reflex effects.Physiol Rev1973;53,159-227. [PubMed]
 
Solin, P, Bergin, P, Richardson, M, et al Influence of pulmonary capillary wedge pressure on central apnea in heart failure.Circulation1999;99,1574-1579. [PubMed]
 
Bradley, TD, Phillipson, EA Central sleep apnea.Clin Chest Med1992;13,493-505. [PubMed]
 
Solin, P, Jackson, DM, Roebuck, T, et al Cardiac diastolic function and hypercapnic ventilatory responses in central sleep apnoea.Eur Respir J2002;20,717-723. [PubMed]
 
Xie, A, Rutherford, R, Rankin, F, et al Hypocapnia and increased ventilatory responsiveness in patients with idiopathic central sleep apnea.Am J Respir Crit Care Med1995;152,1950-1955. [PubMed]
 
Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research: the report of an American Academy of Sleep Medicine Task Force.Sleep1999;22,667-689. [PubMed]
 
Khoo, MC, Anholm, JD, Ko, SW, et al Dynamics of periodic breathing and arousal during sleep at extreme altitude.Respir Physiol1996;103,33-43. [PubMed]
 
Dempsey, JA, Smith, CA, Harms, CA, et al Sleep-induced breathing instability: University of Wisconsin-Madison Sleep and Respiration Research Group.Sleep1996;19,236-247. [PubMed]
 
Hlavac, MC, Catcheside, PG, McDonald, R, et al Hypoxia impairs the arousal response to external resistive loading and airway occlusion during sleep.Sleep2006;29,624-631. [PubMed]
 
Eckert, DJ, Catcheside, PG, McDonald, R, et al Sustained hypoxia depresses sensory processing of respiratory resistive loads.Am J Respir Crit Care Med2005;172,1047-1054. [PubMed]
 
Xu, F, Gu, QH, Zhou, T, et al Acute hypoxia prolongs the apnea induced by right atrial injection of capsaicin.J Appl Physiol2003;94,1446-1454. [PubMed]
 
Morgenthaler, TI, Kagramanov, V, Hanak, V, et al Complex sleep apnea syndrome: is it a unique clinical syndrome.Sleep2006;29,1203-1209. [PubMed]
 
Gastrointestinal surgery for severe obesity: National Institutes of Health Consensus Development Conference statement.Am J Clin Nutr1992;55,615S-619S. [PubMed]
 
Perez de Llano, LA, Golpe, R, Ortiz Piquer, M, et al Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome.Chest2005;128,587-594. [PubMed]
 
Berger, KI, Ayappa, I, Chatr-Amontri, B, et al Obesity hypoventilation syndrome as a spectrum of respiratory disturbances during sleep.Chest2001;120,1231-1238. [PubMed]
 
Hida, W, Okabe, S, Tatsumi, K, et al Nasal continuous positive airway pressure improves quality of life in obesity hypoventilation syndrome.Sleep Breath2003;7,3-12. [PubMed]
 
Shneerson, JM, Simonds, AK Noninvasive ventilation for chest wall and neuromuscular disorders.Eur Respir J2002;20,480-487. [PubMed]
 
Storre, JH, Seuthe, B, Fiechter, R, et al Average volume-assured pressure support in obesity hypoventilation: a randomized crossover trial.Chest2006;130,815-821. [PubMed]
 
McNicholas, WT, Carter, JL, Rutherford, R, et al Beneficial effect of oxygen in primary alveolar hypoventilation with central sleep apnea.Am Rev Respir Dis1982;125,773-775. [PubMed]
 
Sutton, FD, Jr, Zwillich, CW, Creagh, CE, et al Progesterone for outpatient treatment of Pickwickian syndrome.Ann Intern Med1975;83,476-479. [PubMed]
 
Baylor, P, Tayloe, D, Owen, D, et al Cardiac failure presenting as sleep apnea: elimination of apnea following medical management of cardiac failure.Chest1988;94,1298-1300. [PubMed]
 
Dark, DS, Pingleton, SK, Kerby, GR, et al Breathing pattern abnormalities and arterial oxygen desaturation during sleep in the congestive heart failure syndrome: improvement following medical therapy.Chest1987;91,833-836. [PubMed]
 
Walsh, JT, Andrews, R, Starling, R, et al Effects of captopril and oxygen on sleep apnoea in patients with mild to moderate congestive cardiac failure.Br Heart J1995;73,237-241. [PubMed]
 
Bradley, TD, Logan, AG, Kimoff, RJ, et al Continuous positive airway pressure for central sleep apnea and heart failure.N Engl J Med2005;353,2025-2033. [PubMed]
 
Teschler, H, Dohring, J, Wang, YM, et al Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure.Am J Respir Crit Care Med2001;164,614-619. [PubMed]
 
Philippe, C, Stoica-Herman, M, Drouot, X, et al Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six month period.Heart2006;92,337-342. [PubMed]
 
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 Med2003;168,1109-1114. [PubMed]
 
Pittman, S, Hill, P, Malhotra, A, et al Stabilizing Cheyne Stokes respiration associated with congestive heart failure using computer assisted positive airway pressure.Comput Cardiol2000;,201-204
 
Lorenzi-Filho, G, Rankin, F, Bies, I, et al Effects of inhaled carbon dioxide and oxygen on Cheyne-Stokes respiration in patients with heart failure.Am J Respir Crit Care Med1999;159,1490-1498. [PubMed]
 
Khayat, RN, Xie, A, Patel, AK, et al Cardiorespiratory effects of added dead space in patients with heart failure and central sleep apnea.Chest2003;123,1551-1560. [PubMed]
 
Franklin, KA, Eriksson, P, Sahlin, C, et al Reversal of central sleep apnea with oxygen.Chest1997;111,163-169. [PubMed]
 
Javaheri, S, Ahmed, M, Parker, TJ, et al Effects of nasal O2on sleep-related disordered breathing in ambulatory patients with stable heart failure.Sleep1999;22,1101-1106. [PubMed]
 
Hanly, PJ, Millar, TW, Steljes, DG, et al The effect of oxygen on respiration and sleep in patients with congestive heart failure.Ann Intern Med1989;111,777-782. [PubMed]
 
Krachman, SL, D’Alonzo, GE, Berger, TJ, et al Comparison of oxygen therapy with nasal continuous positive airway pressure on Cheyne-Stokes respiration during sleep in congestive heart failure.Chest1999;116,1550-1557. [PubMed]
 
Sinha, AM, Skobel, EC, Breithardt, OA, et al Cardiac resynchronization therapy improves central sleep apnea and Cheyne-Stokes respiration in patients with chronic heart failure.J Am Coll Cardiol2004;44,68-71. [PubMed]
 
Gabor, JY, Newman, DA, Barnard-Roberts, V, et al Improvement in Cheyne-Stokes respiration following cardiac resynchronisation therapy.Eur Respir J2005;26,95-100. [PubMed]
 
Javaheri, S, Parker, TJ, Wexler, L, et al Effect of theophylline on sleep-disordered breathing in heart failure.N Engl J Med1996;335,562-567. [PubMed]
 
Javaheri, S Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study.Am J Respir Crit Care Med2006;173,234-237. [PubMed]
 
Hoffstein, V, Slutsky, AS Central sleep apnea reversed by continuous positive airway pressure.Am Rev Respir Dis1987;135,1210-1212. [PubMed]
 
Issa, FG, Sullivan, CE Reversal of central sleep apnea using nasal CPAP.Chest1986;90,165-171. [PubMed]
 
Xie, A, Rankin, F, Rutherford, R, et al Effects of inhaled CO2and added dead space on idiopathic central sleep apnea.J Appl Physiol1997;82,918-926. [PubMed]
 
Garrigue, S, Bordier, P, Jais, P, et al Benefit of atrial pacing in sleep apnea syndrome.N Engl J Med2002;346,404-412. [PubMed]
 
Melzer, C, Fietze, I, Duru, F, et al Nocturnal overdrive pacing for the treatment of sleep apnea syndrome.Sleep2006;29,1197-1202. [PubMed]
 
Luthje, L, Unterberg-Buchwald, C, Dajani, D, et al Atrial overdrive pacing in patients with sleep apnea with implanted pacemaker.Am J Respir Crit Care Med2005;172,118-122. [PubMed]
 
Unterberg, C, Luthje, L, Szych, J, et al Atrial overdrive pacing compared to CPAP in patients with obstructive sleep apnoea syndrome.Eur Heart J2005;26,2568-2575. [PubMed]
 
Pepin, JL, Defaye, P, Garrigue, S, et al Overdrive atrial pacing does not improve obstructive sleep apnoea syndrome.Eur Respir J2005;25,343-347. [PubMed]
 
Krahn, AD, Yee, R, Erickson, MK, et al Physiologic pacing in patients with obstructive sleep apnea: a prospective, randomized crossover trial.J Am Coll Cardiol2006;47,379-383. [PubMed]
 
Simantirakis, EN, Schiza, SE, Chrysostomakis, SI, et al Atrial overdrive pacing for the obstructive sleep apnea-hypopnea syndrome.N Engl J Med2005;353,2568-2577. [PubMed]
 
White, DP, Zwillich, CW, Pickett, CK, et al Central sleep apnea: improvement with acetazolamide therapy.Arch Intern Med1982;142,1816-1819. [PubMed]
 
Mak, S, Azevedo, ER, Liu, PP, et al Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure.Chest2001;120,467-473. [PubMed]
 
Shigemitsu, M, Nishio, K, Kusuyama, T, et al Nocturnal oxygen therapy prevents progress of congestive heart failure with central sleep apnea.Int J Cardiol2007;(in press)
 
Sasayama, S, Izumi, T, Seino, Y, et al Effects of nocturnal oxygen therapy on outcome measures in patients with chronic heart failure and Cheyne-Stokes respiration.Circ J2006;70,1-7. [PubMed]
 
Steens, RD, Millar, TW, Su, X, et al Effect of inhaled 3% CO2on Cheyne-Stokes respiration in congestive heart failure.Sleep1994;17,61-68. [PubMed]
 
Szollosi, I, Jones, M, Morrell, MJ, et al Effect of CO2inhalation on central sleep apnea and arousals from sleep.Respiration2004;71,493-498. [PubMed]
 
Andreas, S, Weidel, K, Hagenah, G, et al Treatment of Cheyne-Stokes respiration with nasal oxygen and carbon dioxide.Eur Respir J1998;12,414-419. [PubMed]
 
Krachman, SL, Crocetti, J, Berger, TJ, et al Effects of nasal continuous positive airway pressure on oxygen body stores in patients with Cheyne-Stokes respiration and congestive heart failure.Chest2003;123,59-66. [PubMed]
 
Arzt, M, Bradley, TD Treatment of sleep apnea in heart failure.Am J Respir Crit Care Med2006;173,1300-1308. [PubMed]
 
Hommura, F, Nishimura, M, Oguri, M, et al Continuous versus bilevel positive airway pressure in a patient with idiopathic central sleep apnea.Am J Respir Crit Care Med1997;155,1482-1485. [PubMed]
 
Thomas, RJ, Daly, RW, Weiss, JW Low-concentration carbon dioxide is an effective adjunct to positive airway pressure in the treatment of refractory mixed central and obstructive sleep-disordered breathing.Sleep2005;28,69-77. [PubMed]
 
Johnson, KG, Johnson, DC Bilevel positive airway pressure worsens central apneas during sleep.Chest2005;128,2141-2150. [PubMed]
 
Masa, JF, Celli, BR, Riesco, JA, et al The obesity hypoventilation syndrome can be treated with noninvasive mechanical ventilation.Chest2001;119,1102-1107. [PubMed]
 
Collop, NA Cheyne-stokes ventilation converting to obstructive sleep apnea following heart transplantation.Chest1993;104,1288-1289. [PubMed]
 
Mansfield, DR, Solin, P, Roebuck, T, et al The effect of successful heart transplant treatment of heart failure on central sleep apnea.Chest2003;124,1675-1681. [PubMed]
 
Javaheri, S, Abraham, WT, Brown, C, et al Prevalence of obstructive sleep apnoea and periodic limb movement in 45 subjects with heart transplantation.Eur Heart J2004;25,260-266. [PubMed]
 
Himmrich, E, Przibille, O, Zellerhoff, C, et al Proarrhythmic effect of pacemaker stimulation in patients with implanted cardioverter-defibrillators.Circulation2003;108,192-197. [PubMed]
 
Nakayama, H, Smith, CA, Rodman, JR, et al Effect of ventilatory drive on carbon dioxide sensitivity below eupnea during sleep.Am J Respir Crit Care Med2002;165,1251-1260. [PubMed]
 
Zwillich, CW, Natalino, MR, Sutton, FD, et al Effects of progesterone on chemosensitivity in normal men.J Lab Clin Med1978;92,262-269. [PubMed]
 
Bittar, G, Friedman, HS The arrhythmogenicity of theophylline: a multivariate analysis of clinical determinants.Chest1991;99,1415-1420. [PubMed]
 
Suissa, S, Hemmelgarn, B, Blais, L, et al Bronchodilators and acute cardiac death.Am J Respir Crit Care Med1996;154,1598-1602. [PubMed]
 

Figures

Figure Jump LinkFigure 1. An example of experimentally induced arousal leading to central apnea. During stable stage 2 sleep, a 55-decibel (db) tone was played to induce an arousal from sleep (shown by solid line under EEG) in a 33-year-old woman (follicular menstrual phase) with severe OSA who was receiving CPAP (14 cm H2O). A brisk ventilatory response ensues driving end-tidal Pco2 (PETCO2) from 44 mm Hg during stable sleep (first arrow, note there is an approximate 3-s sampling delay between ventilation and end-tidal Pco2) to 38 mm Hg by the return to sleep (second arrow) and was accompanied by an approximate 10-s central apnea as documented by no change in epiglottic pressure (Pepi). Vt = tidal volume. Pmask = pressure at the mask.Grahic Jump Location
Figure Jump LinkFigure 2. Top, A: An example of a patient receiving high-dose opioid medication for back pain experiencing repetitive central apneas as demonstrated by a lack of movement of respiratory effort bands (both abdominal and thoracic) with associated oxygen desaturations. Bottom, B: Marked improvement in SDB following gradual dose reduction of opioid medication. Sao2 = arterial oxygen saturationGrahic Jump Location
Figure Jump LinkFigure 3. An example of a patient with CSB. Note the characteristic crescendo/decrescendo pattern of breathing, long circulation time (each oxygen desaturation corresponds to the previous apnea), and arousal occurring at the peak of respiratory effort. See Figure 2 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 4. An example of ICSA. Note the shortened cycle time (approximately 25 s in this example) compared to CSB and that arousal (arrow) occurs at the cessation of apnea. See Figure 2 legend for expansion of abbreviation. Adapted from Malhotra et al5 with permission.Grahic Jump Location
Figure Jump LinkFigure 5. Schematic of the many potential mechanisms contributing to CSA/hypopnea. The gray boxes and largest solid arrows represent the key components contributing to unstable breathing and central apnea/hypopnea during sleep. The smaller solid arrows denote the main factors that lead to or modulate unstable breathing during sleep. Dashed arrows highlight the potential interactive links between obstructive and central apnea/hypopnea and for hypercapnia to cause arousal. Some arrows have been omitted to simplify the Figure. Refer to the text for further detail.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Summary of Potential Treatment Strategies and Their Effectiveness for Hypercapnic CSA*
* 

PAP = positive airway pressure; QOL = quality of life; RCT = randomized control trial; ↑ = increase; ↓ = decrease.

Table Graphic Jump Location
Table 2. Summary of Potential Treatment Strategies and Their Effectiveness for Nonhypercapnic CSA*
* 

CRT = cardiac resynchronization therapy; DTS = daytime sleepiness; LVEF = left ventricular ejection fraction; NIV = noninvasive ventilation. See Table 1 for expansion of abbreviation.

References

Lanfranchi, PA, Somers, VK, Braghiroli, A, et al (2003) Central sleep apnea in left ventricular dysfunction: prevalence and implications for arrhythmic risk.Circulation107,727-732. [PubMed] [CrossRef]
 
Javaheri, S, Parker, TJ, Liming, JD, et al Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences, and presentations.Circulation1998;97,2154-2159. [PubMed]
 
White, DP, Gleeson, K, Pickett, CK, et al Altitude acclimatization: influence on periodic breathing and chemoresponsiveness during sleep.J Appl Physiol1987;63,401-412. [PubMed]
 
Poulain, M, Doucet, M, Major, GC, et al The effect of obesity on chronic respiratory diseases: pathophysiology and therapeutic strategies.Can Med Assoc J2006;174,1293-1299
 
Malhotra, A, Berry, RB, White, DP Central sleep apnea. Carney, PR Berry, RB Geyer, JD eds.Clinical sleep disorders2004,331-346 Lippincott Williams and Wilkins. Philadelphia, PA:
 
Javaheri, S Sleep disorders in systolic heart failure: a prospective study of 100 male patients: the final report.Int J Cardiol2006;106,21-28. [PubMed]
 
Badr, MS, Toiber, F, Skatrud, JB, et al Pharyngeal narrowing/occlusion during central sleep apnea.J Appl Physiol1995;78,1806-1815. [PubMed]
 
Khoo, MC, Kronauer, RE, Strohl, KP, et al Factors inducing periodic breathing in humans: a general model.J Appl Physiol1982;53,644-659. [PubMed]
 
White, DP Pathogenesis of obstructive and central sleep apnea.Am J Respir Crit Care Med2005;172,1363-1370. [PubMed]
 
Wellman, A, Malhotra, A, Fogel, RB, et al Respiratory system loop gain in normal men and women measured with proportional-assist ventilation.J Appl Physiol2003;94,205-212. [PubMed]
 
Orem, J The nature of the wakefulness stimulus for breathing.Prog Clin Biol Res1990;345,23-30discussion 31. [PubMed]
 
Burgess, HJ, Kleiman, J, Trinder, J Cardiac activity during sleep onset.Psychophysiology1999;36,298-306. [PubMed]
 
Trinder, J, Whitworth, F, Kay, A, et al Respiratory instability during sleep onset.J Appl Physiol1992;73,2462-2469. [PubMed]
 
Skatrud, JB, Berssenbrugge, AD Effect of sleep state and chemical stimuli on breathing.Prog Clin Biol Res1983;136,87-95. [PubMed]
 
Kay, A, Trinder, J, Bowes, G, et al Changes in airway resistance during sleep onset.J Appl Physiol1994;76,1600-1607. [PubMed]
 
Worsnop, C, Kay, A, Pierce, R, et al Activity of respiratory pump and upper airway muscles during sleep onset.J Appl Physiol1998;85,908-920. [PubMed]
 
Dunai, J, Wilkinson, M, Trinder, J Interaction of chemical and state effects on ventilation during sleep onset.J Appl Physiol1996;81,2235-2243. [PubMed]
 
Khoo, MC, Gottschalk, A, Pack, AI Sleep-induced periodic breathing and apnea: a theoretical study.J Appl Physiol1991;70,2014-2024. [PubMed]
 
Dunai, J, Kleiman, J, Trinder, J Ventilatory instability during sleep onset in individuals with high peripheral chemosensitivity.J Appl Physiol1999;87,661-672. [PubMed]
 
Meza, S, Mendez, M, Ostrowski, M, et al Susceptibility to periodic breathing with assisted ventilation during sleep in normal subjects.J Appl Physiol1998;85,1929-1940. [PubMed]
 
Skatrud, JB, Dempsey, JA Interaction of sleep state and chemical stimuli in sustaining rhythmic ventilation.J Appl Physiol1983;55,813-822. [PubMed]
 
Dempsey, JA Crossing the apnoeic threshold: causes and consequences.Exp Physiol2005;90,13-24. [PubMed]
 
White, DP, Douglas, NJ, Pickett, CK, et al Hypoxic ventilatory response during sleep in normal premenopausal women.Am Rev Respir Dis1982;126,530-533. [PubMed]
 
Douglas, NJ, White, DP, Weil, JV, et al Hypoxic ventilatory response decreases during sleep in normal men.Am Rev Respir Dis1982;125,286-289. [PubMed]
 
Wiegand, L, Zwillich, CW, White, DP Sleep and the ventilatory response to resistive loading in normal men.J Appl Physiol1988;64,1186-1195. [PubMed]
 
Skatrud, JB, Dempsey, JA, Badr, S, et al Effect of airway impedance on CO2retention and respiratory muscle activity during NREM sleep.J Appl Physiol1988;65,1676-1685. [PubMed]
 
Gugger, M, Bogershausen, S, Schaffler, L Arousal responses to added inspiratory resistance during REM and non-REM sleep in normal subjects.Thorax1993;48,125-129. [PubMed]
 
Horner, RL, Rivera, MP, Kozar, LF, et al The ventilatory response to arousal from sleep is not fully explained by differences in CO(2) levels between sleep and wakefulness.J Physiol2001;534,881-890. [PubMed]
 
Trinder, J, Padula, M, Berlowitz, D, et al Cardiac and respiratory activity at arousal from sleep under controlled ventilation conditions.J Appl Physiol2001;90,1455-1463. [PubMed]
 
Xie, A, Wong, B, Phillipson, EA, et al Interaction of hyperventilation and arousal in the pathogenesis of idiopathic central sleep apnea.Am J Respir Crit Care Med1994;150,489-495. [PubMed]
 
Bradley, TD, McNicholas, WT, Rutherford, R, et al Clinical and physiologic heterogeneity of the central sleep apnea syndrome.Am Rev Respir Dis1986;134,217-221. [PubMed]
 
American Thoracic Society.. Idiopathic congenital central hypoventilation syndrome: diagnosis and management.Am J Respir Crit Care Med1999;160,368-373. [PubMed]
 
Weese-Mayer, DE, Silvestri, JM, Menzies, LJ, et al Congenital central hypoventilation syndrome: diagnosis, management, and long-term outcome in thirty-two children.J Pediatr1992;120,381-387. [PubMed]
 
Fleming, PJ, Cade, D, Bryan, MH, et al Congenital central hypoventilation and sleep state.Pediatrics1980;66,425-428. [PubMed]
 
Antic, NA, Malow, BA, Lange, N, et al PHOX2B mutation-confirmed congenital central hypoventilation syndrome: presentation in adulthood.Am J Respir Crit Care Med2006;174,923-927. [PubMed]
 
Santiago, TV, Edelman, NH Opioids and breathing.J Appl Physiol1985;59,1675-1685. [PubMed]
 
Shook, JE, Watkins, WD, Camporesi, EM Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depression.Am Rev Respir Dis1990;142,895-909. [PubMed]
 
The use of opioids for the treatment of chronic pain: a consensus statement from the American Academy of Pain Medicine and the American Pain Society.Clin J Pain1997;13,6-8. [PubMed]
 
Farney, RJ, Walker, JM, Cloward, TV, et al Sleep-disordered breathing associated with long-term opioid therapy.Chest2003;123,632-639. [PubMed]
 
Wang, D, Teichtahl, H, Drummer, O, et al Central sleep apnea in stable methadone maintenance treatment patients.Chest2005;128,1348-1356. [PubMed]
 
Elliott, AM, Smith, BH, Penny, KI, et al The epidemiology of chronic pain in the community.Lancet1999;354,1248-1252. [PubMed]
 
Luo, X, Pietrobon, R, Hey, L Patterns and trends in opioid use among individuals with back pain in the United States.Spine2004;29,884-890discussion 891. [PubMed]
 
Weil, JV, McCullough, RE, Kline, JS, et al Diminished ventilatory response to hypoxia and hypercapnia after morphine in normal man.N Engl J Med1975;292,1103-1106. [PubMed]
 
Teichtahl, H, Wang, D, Cunnington, D, et al Ventilatory responses to hypoxia and hypercapnia in stable methadone maintenance treatment patients.Chest2005;128,1339-1347. [PubMed]
 
Zwillich, CW, Sutton, FD, Pierson, DJ, et al Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome.Am J Med1975;59,343-348. [PubMed]
 
Olson, AL, Zwillich, C The obesity hypoventilation syndrome.Am J Med2005;118,948-956. [PubMed]
 
Strumpf, DA, Millman, RP, Hill, NS The management of chronic hypoventilation.Chest1990;98,474-480. [PubMed]
 
Sampson, MG, Grassino, K Neuromechanical properties in obese patients during carbon dioxide rebreathing.Am J Med1983;75,81-90
 
Sharp, JT, Henry, JP, Sweany, SK, et al Effects of mass loading the respiratory system in man.J Appl Physiol1964;19,959-966. [PubMed]
 
Shimura, R, Tatsumi, K, Nakamura, A, et al Fat accumulation, leptin, and hypercapnia in obstructive sleep apnea-hypopnea syndrome.Chest2005;127,543-549. [PubMed]
 
O’Donnell, CP, Schaub, CD, Haines, AS, et al Leptin prevents respiratory depression in obesity.Am J Respir Crit Care Med1999;159,1477-1484. [PubMed]
 
Phipps, PR, Starritt, E, Caterson, I, et al Association of serum leptin with hypoventilation in human obesity.Thorax2002;57,75-76. [PubMed]
 
Trinder, J, Merson, R, Rosenberg, JI, et al Pathophysiological interactions of ventilation, arousals, and blood pressure oscillations during Cheyne-Stokes respiration in patients with heart failure.Am J Respir Crit Care Med2000;162,808-813. [PubMed]
 
Szollosi, I, Roebuck, T, Thompson, B, et al Lateral sleeping position reduces severity of central sleep apnea/Cheyne-Stokes respiration.Sleep2006;29,1045-1051. [PubMed]
 
Naughton, M, Benard, D, Tam, A, et al Role of hyperventilation in the pathogenesis of central sleep apneas in patients with congestive heart failure.Am Rev Respir Dis1993;148,330-338. [PubMed]
 
Solin, P, Roebuck, T, Johns, DP, et al Peripheral and central ventilatory responses in central sleep apnea with and without congestive heart failure.Am J Respir Crit Care Med2000;162,2194-2200. [PubMed]
 
Xie, A, Skatrud, JB, Puleo, DS, et al Apnea-hypopnea threshold for CO2in patients with congestive heart failure.Am J Respir Crit Care Med2002;165,1245-1250. [PubMed]
 
Hall, MJ, Xie, A, Rutherford, R, et al Cycle length of periodic breathing in patients with and without heart failure.Am J Respir Crit Care Med1996;154,376-381. [PubMed]
 
Xie, A, Skatrud, JB, Khayat, R, et al Cerebrovascular response to carbon dioxide in patients with congestive heart failure.Am J Respir Crit Care Med2005;172,371-378. [PubMed]
 
Paintal, AS Vagal sensory receptors and their reflex effects.Physiol Rev1973;53,159-227. [PubMed]
 
Solin, P, Bergin, P, Richardson, M, et al Influence of pulmonary capillary wedge pressure on central apnea in heart failure.Circulation1999;99,1574-1579. [PubMed]
 
Bradley, TD, Phillipson, EA Central sleep apnea.Clin Chest Med1992;13,493-505. [PubMed]
 
Solin, P, Jackson, DM, Roebuck, T, et al Cardiac diastolic function and hypercapnic ventilatory responses in central sleep apnoea.Eur Respir J2002;20,717-723. [PubMed]
 
Xie, A, Rutherford, R, Rankin, F, et al Hypocapnia and increased ventilatory responsiveness in patients with idiopathic central sleep apnea.Am J Respir Crit Care Med1995;152,1950-1955. [PubMed]
 
Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research: the report of an American Academy of Sleep Medicine Task Force.Sleep1999;22,667-689. [PubMed]
 
Khoo, MC, Anholm, JD, Ko, SW, et al Dynamics of periodic breathing and arousal during sleep at extreme altitude.Respir Physiol1996;103,33-43. [PubMed]
 
Dempsey, JA, Smith, CA, Harms, CA, et al Sleep-induced breathing instability: University of Wisconsin-Madison Sleep and Respiration Research Group.Sleep1996;19,236-247. [PubMed]
 
Hlavac, MC, Catcheside, PG, McDonald, R, et al Hypoxia impairs the arousal response to external resistive loading and airway occlusion during sleep.Sleep2006;29,624-631. [PubMed]
 
Eckert, DJ, Catcheside, PG, McDonald, R, et al Sustained hypoxia depresses sensory processing of respiratory resistive loads.Am J Respir Crit Care Med2005;172,1047-1054. [PubMed]
 
Xu, F, Gu, QH, Zhou, T, et al Acute hypoxia prolongs the apnea induced by right atrial injection of capsaicin.J Appl Physiol2003;94,1446-1454. [PubMed]
 
Morgenthaler, TI, Kagramanov, V, Hanak, V, et al Complex sleep apnea syndrome: is it a unique clinical syndrome.Sleep2006;29,1203-1209. [PubMed]
 
Gastrointestinal surgery for severe obesity: National Institutes of Health Consensus Development Conference statement.Am J Clin Nutr1992;55,615S-619S. [PubMed]
 
Perez de Llano, LA, Golpe, R, Ortiz Piquer, M, et al Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome.Chest2005;128,587-594. [PubMed]
 
Berger, KI, Ayappa, I, Chatr-Amontri, B, et al Obesity hypoventilation syndrome as a spectrum of respiratory disturbances during sleep.Chest2001;120,1231-1238. [PubMed]
 
Hida, W, Okabe, S, Tatsumi, K, et al Nasal continuous positive airway pressure improves quality of life in obesity hypoventilation syndrome.Sleep Breath2003;7,3-12. [PubMed]
 
Shneerson, JM, Simonds, AK Noninvasive ventilation for chest wall and neuromuscular disorders.Eur Respir J2002;20,480-487. [PubMed]
 
Storre, JH, Seuthe, B, Fiechter, R, et al Average volume-assured pressure support in obesity hypoventilation: a randomized crossover trial.Chest2006;130,815-821. [PubMed]
 
McNicholas, WT, Carter, JL, Rutherford, R, et al Beneficial effect of oxygen in primary alveolar hypoventilation with central sleep apnea.Am Rev Respir Dis1982;125,773-775. [PubMed]
 
Sutton, FD, Jr, Zwillich, CW, Creagh, CE, et al Progesterone for outpatient treatment of Pickwickian syndrome.Ann Intern Med1975;83,476-479. [PubMed]
 
Baylor, P, Tayloe, D, Owen, D, et al Cardiac failure presenting as sleep apnea: elimination of apnea following medical management of cardiac failure.Chest1988;94,1298-1300. [PubMed]
 
Dark, DS, Pingleton, SK, Kerby, GR, et al Breathing pattern abnormalities and arterial oxygen desaturation during sleep in the congestive heart failure syndrome: improvement following medical therapy.Chest1987;91,833-836. [PubMed]
 
Walsh, JT, Andrews, R, Starling, R, et al Effects of captopril and oxygen on sleep apnoea in patients with mild to moderate congestive cardiac failure.Br Heart J1995;73,237-241. [PubMed]
 
Bradley, TD, Logan, AG, Kimoff, RJ, et al Continuous positive airway pressure for central sleep apnea and heart failure.N Engl J Med2005;353,2025-2033. [PubMed]
 
Teschler, H, Dohring, J, Wang, YM, et al Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure.Am J Respir Crit Care Med2001;164,614-619. [PubMed]
 
Philippe, C, Stoica-Herman, M, Drouot, X, et al Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six month period.Heart2006;92,337-342. [PubMed]
 
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 Med2003;168,1109-1114. [PubMed]
 
Pittman, S, Hill, P, Malhotra, A, et al Stabilizing Cheyne Stokes respiration associated with congestive heart failure using computer assisted positive airway pressure.Comput Cardiol2000;,201-204
 
Lorenzi-Filho, G, Rankin, F, Bies, I, et al Effects of inhaled carbon dioxide and oxygen on Cheyne-Stokes respiration in patients with heart failure.Am J Respir Crit Care Med1999;159,1490-1498. [PubMed]
 
Khayat, RN, Xie, A, Patel, AK, et al Cardiorespiratory effects of added dead space in patients with heart failure and central sleep apnea.Chest2003;123,1551-1560. [PubMed]
 
Franklin, KA, Eriksson, P, Sahlin, C, et al Reversal of central sleep apnea with oxygen.Chest1997;111,163-169. [PubMed]
 
Javaheri, S, Ahmed, M, Parker, TJ, et al Effects of nasal O2on sleep-related disordered breathing in ambulatory patients with stable heart failure.Sleep1999;22,1101-1106. [PubMed]
 
Hanly, PJ, Millar, TW, Steljes, DG, et al The effect of oxygen on respiration and sleep in patients with congestive heart failure.Ann Intern Med1989;111,777-782. [PubMed]
 
Krachman, SL, D’Alonzo, GE, Berger, TJ, et al Comparison of oxygen therapy with nasal continuous positive airway pressure on Cheyne-Stokes respiration during sleep in congestive heart failure.Chest1999;116,1550-1557. [PubMed]
 
Sinha, AM, Skobel, EC, Breithardt, OA, et al Cardiac resynchronization therapy improves central sleep apnea and Cheyne-Stokes respiration in patients with chronic heart failure.J Am Coll Cardiol2004;44,68-71. [PubMed]
 
Gabor, JY, Newman, DA, Barnard-Roberts, V, et al Improvement in Cheyne-Stokes respiration following cardiac resynchronisation therapy.Eur Respir J2005;26,95-100. [PubMed]
 
Javaheri, S, Parker, TJ, Wexler, L, et al Effect of theophylline on sleep-disordered breathing in heart failure.N Engl J Med1996;335,562-567. [PubMed]
 
Javaheri, S Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study.Am J Respir Crit Care Med2006;173,234-237. [PubMed]
 
Hoffstein, V, Slutsky, AS Central sleep apnea reversed by continuous positive airway pressure.Am Rev Respir Dis1987;135,1210-1212. [PubMed]
 
Issa, FG, Sullivan, CE Reversal of central sleep apnea using nasal CPAP.Chest1986;90,165-171. [PubMed]
 
Xie, A, Rankin, F, Rutherford, R, et al Effects of inhaled CO2and added dead space on idiopathic central sleep apnea.J Appl Physiol1997;82,918-926. [PubMed]
 
Garrigue, S, Bordier, P, Jais, P, et al Benefit of atrial pacing in sleep apnea syndrome.N Engl J Med2002;346,404-412. [PubMed]
 
Melzer, C, Fietze, I, Duru, F, et al Nocturnal overdrive pacing for the treatment of sleep apnea syndrome.Sleep2006;29,1197-1202. [PubMed]
 
Luthje, L, Unterberg-Buchwald, C, Dajani, D, et al Atrial overdrive pacing in patients with sleep apnea with implanted pacemaker.Am J Respir Crit Care Med2005;172,118-122. [PubMed]
 
Unterberg, C, Luthje, L, Szych, J, et al Atrial overdrive pacing compared to CPAP in patients with obstructive sleep apnoea syndrome.Eur Heart J2005;26,2568-2575. [PubMed]
 
Pepin, JL, Defaye, P, Garrigue, S, et al Overdrive atrial pacing does not improve obstructive sleep apnoea syndrome.Eur Respir J2005;25,343-347. [PubMed]
 
Krahn, AD, Yee, R, Erickson, MK, et al Physiologic pacing in patients with obstructive sleep apnea: a prospective, randomized crossover trial.J Am Coll Cardiol2006;47,379-383. [PubMed]
 
Simantirakis, EN, Schiza, SE, Chrysostomakis, SI, et al Atrial overdrive pacing for the obstructive sleep apnea-hypopnea syndrome.N Engl J Med2005;353,2568-2577. [PubMed]
 
White, DP, Zwillich, CW, Pickett, CK, et al Central sleep apnea: improvement with acetazolamide therapy.Arch Intern Med1982;142,1816-1819. [PubMed]
 
Mak, S, Azevedo, ER, Liu, PP, et al Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure.Chest2001;120,467-473. [PubMed]
 
Shigemitsu, M, Nishio, K, Kusuyama, T, et al Nocturnal oxygen therapy prevents progress of congestive heart failure with central sleep apnea.Int J Cardiol2007;(in press)
 
Sasayama, S, Izumi, T, Seino, Y, et al Effects of nocturnal oxygen therapy on outcome measures in patients with chronic heart failure and Cheyne-Stokes respiration.Circ J2006;70,1-7. [PubMed]
 
Steens, RD, Millar, TW, Su, X, et al Effect of inhaled 3% CO2on Cheyne-Stokes respiration in congestive heart failure.Sleep1994;17,61-68. [PubMed]
 
Szollosi, I, Jones, M, Morrell, MJ, et al Effect of CO2inhalation on central sleep apnea and arousals from sleep.Respiration2004;71,493-498. [PubMed]
 
Andreas, S, Weidel, K, Hagenah, G, et al Treatment of Cheyne-Stokes respiration with nasal oxygen and carbon dioxide.Eur Respir J1998;12,414-419. [PubMed]
 
Krachman, SL, Crocetti, J, Berger, TJ, et al Effects of nasal continuous positive airway pressure on oxygen body stores in patients with Cheyne-Stokes respiration and congestive heart failure.Chest2003;123,59-66. [PubMed]
 
Arzt, M, Bradley, TD Treatment of sleep apnea in heart failure.Am J Respir Crit Care Med2006;173,1300-1308. [PubMed]
 
Hommura, F, Nishimura, M, Oguri, M, et al Continuous versus bilevel positive airway pressure in a patient with idiopathic central sleep apnea.Am J Respir Crit Care Med1997;155,1482-1485. [PubMed]
 
Thomas, RJ, Daly, RW, Weiss, JW Low-concentration carbon dioxide is an effective adjunct to positive airway pressure in the treatment of refractory mixed central and obstructive sleep-disordered breathing.Sleep2005;28,69-77. [PubMed]
 
Johnson, KG, Johnson, DC Bilevel positive airway pressure worsens central apneas during sleep.Chest2005;128,2141-2150. [PubMed]
 
Masa, JF, Celli, BR, Riesco, JA, et al The obesity hypoventilation syndrome can be treated with noninvasive mechanical ventilation.Chest2001;119,1102-1107. [PubMed]
 
Collop, NA Cheyne-stokes ventilation converting to obstructive sleep apnea following heart transplantation.Chest1993;104,1288-1289. [PubMed]
 
Mansfield, DR, Solin, P, Roebuck, T, et al The effect of successful heart transplant treatment of heart failure on central sleep apnea.Chest2003;124,1675-1681. [PubMed]
 
Javaheri, S, Abraham, WT, Brown, C, et al Prevalence of obstructive sleep apnoea and periodic limb movement in 45 subjects with heart transplantation.Eur Heart J2004;25,260-266. [PubMed]
 
Himmrich, E, Przibille, O, Zellerhoff, C, et al Proarrhythmic effect of pacemaker stimulation in patients with implanted cardioverter-defibrillators.Circulation2003;108,192-197. [PubMed]
 
Nakayama, H, Smith, CA, Rodman, JR, et al Effect of ventilatory drive on carbon dioxide sensitivity below eupnea during sleep.Am J Respir Crit Care Med2002;165,1251-1260. [PubMed]
 
Zwillich, CW, Natalino, MR, Sutton, FD, et al Effects of progesterone on chemosensitivity in normal men.J Lab Clin Med1978;92,262-269. [PubMed]
 
Bittar, G, Friedman, HS The arrhythmogenicity of theophylline: a multivariate analysis of clinical determinants.Chest1991;99,1415-1420. [PubMed]
 
Suissa, S, Hemmelgarn, B, Blais, L, et al Bronchodilators and acute cardiac death.Am J Respir Crit Care Med1996;154,1598-1602. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

CHEST Journal Articles
Adult Obstructive Sleep Apnea*: Pathophysiology and Diagnosis
Rapid Eye Movement-Related Disordered Breathing*: Clinical and Polysomnographic Features
CHEST Collections
PubMed Articles
Sleep in heart failure. Prog Cardiovasc Dis 2009 Jan-Feb;51(4):339-49.
Central serotonin neurons are required for arousal to CO2. Proc Natl Acad Sci U S A 2010;107(37):16354-9.
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543