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The Appearance of Central Sleep Apnea After Treatment of Obstructive Sleep ApneaCentral Apnea After Obstructive Apnea Treatment FREE TO VIEW

Matthew Hoffman, MD; David A. Schulman, MD, MPH, FCCP
Author and Funding Information

From the Emory University School of Medicine (Drs Hoffman and Schulman), Atlanta, GA.

Correspondence to: David A. Schulman, MD, MPH, FCCP, Emory University School of Medicine, 615 Michael St, Ste 205, Atlanta, GA 30322; e-mail: daschul@emory.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(2):517-522. doi:10.1378/chest.11-2562
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Patients with a primary diagnosis of obstructive sleep apnea frequently demonstrate central sleep apnea that emerges during treatment with CPAP. Although a number of mechanisms for this finding have been hypothesized, the pathophysiology is not definitively known. Controversy exists as to whether the concomitant appearance of the two phenomena represents a distinct meaningful entity. Regardless, the coincidence of these diseases may have important clinical implications. Herein, we review the proposed mechanisms for obstructive sleep apnea complicated by central sleep apnea. Future research is needed to elucidate the relative importance and susceptibility to intervention of the various pathophysiologic mechanisms responsible for this phenomenon, and whether a treatment approach distinct from that of pure obstructive apnea is justified.

Figures in this Article

Isolated central sleep apnea (CSA) is rare in the general population, but occurs more commonly in certain subgroups, such as individuals with systolic heart failure, those living at high altitude, and those who take opioids. Central apneas (CAs) are also often noted to occur in patients with predominantly obstructive sleep apnea (OSA),1,2 but are typically de-emphasized if the obstructive events are more prevalent, perhaps because the observed CAs are thought to be incorrectly scored obstructive events or because they may resolve with CPAP therapy. The application of CPAP is highly effective at reducing or abolishing obstructive apneas in most patients with sleep-disordered breathing. However, a minority of patients will begin to experience CAs during the titration of CPAP to abolish OSA.1-3 In most of these patients who continue to use CPAP, the CAs resolve within a few months,1,4 but a significant minority of these patients will continue to experience frequent CAs that impair sleep, with resultant daytime somnolence. The frequency with which this occurs has not been definitively established.1,4-6

The term “complex sleep apnea syndrome” has been used by a number of authors to describe the phenomenon of CAs that emerge in patients with OSA during therapy with CPAP.1,5,7-10 Noting the multiple, disparate, possible mechanisms for this phenomenon and the likelihood that several of them might occur in the same patient, some have questioned whether these clinical entities should be grouped under a single label.11 Regardless of whether one “lumps” or “splits” these mechanisms, the fact remains that the appearance of CSA after treatment of OSA can lead to uncertainties in management and prognosis.

We describe here the known and proposed mechanisms by which CAs may complicate OSA. Given that many patients with complex sleep apnea demonstrate both pathologies on their diagnostic polysomnography (PSG), we propose the term “obstructive sleep apnea complicated by central sleep apnea” (OSA-CSA) be used for that subset of patients without CSA on initial evaluation in whom CAs develop and then persist despite a period of adherence to therapy for OSA, potentially causing adverse health effects. While this review will focus on the mechanisms by which CPAP therapy could elicit CSA, we will discuss how some of these mechanisms could also be applicable to other treatment modalities. We will then highlight current areas of uncertainty and suggest directions for future inquiry.

During diagnostic PSG, approximately 7% to 8% of patients with OSA will demonstrate a concomitant CA index of ≥5.1,2 During CPAP titration, these central events are attenuated in the majority of patients.2 However, between 5.7% and 20% of patients with OSA develop a significant increase in CAs during CPAP titration, despite successful abolition of obstructive events1,2,4-7,12; these events occur predominantly during nonrapid eye movement sleep.5,7,13 A similar emergence of CAs has also been reported in patients treated for OSA with a mandibular advancement device and after maxillofacial surgery.14-16

In the majority (78%-92%) of such patients treated with CPAP, these CAs resolve within months of therapy.1,4 In one of the largest prevalence studies to date,1 1.5% of patients continued to have CSA complicating the previously diagnosed OSA on repeat PSG after 1 to 2 months of CPAP therapy. It should be noted that the follow-up in this article was only 50%, suggesting that the true prevalence of OSA-CSA might be higher (assuming that people with persistent disease might remain symptomatic, grow frustrated, and be more readily lost to follow-up).1 In another small observational series, 8% of patients had OSA-CSA on repeat PSG at 2 to 3 months.4 Almost all reported series to date have been retrospective,1-7 and longitudinal data are mostly limited to patients who underwent repeat PSG for clinical indications (eg, CPAP intolerance, nocturnal hypoxemia, or CAs).1 One prospective study evaluated subjects with repeat PSG 3 months after 12% of these subjects were found to have OSA-CSA at CPAP titration; 74% of this subset showed no persistence of OSA-CSA, although follow-up was limited.12 Interestingly, 4% of the subjects without OSA-CSA during initial CPAP titration demonstrated OSA-CSA at 3-month follow-up, with an overall prevalence at that time point of 7% of the cohort. Considering this body of data together, the small numbers of study patients, inherent selection biases, incomplete follow-up, and significant heterogeneity in findings across studies preclude conclusions as to the association of OSA-CSA with specific demographic features, risk factors, frequency of respiratory events before or after CPAP therapy, or adherence with CPAP.

The long-term risks of OSA-CSA, if any, are unknown. Severe OSA is associated with an increased incidence of cardiovascular events, and CPAP seems to reduce this risk.17,18 People with CSA associated with congestive heart failure (CHF) or opioid therapy have an increased risk of death,19 and treatment with CPAP does not clearly diminish this risk in those with CHF.20 However, potential pathophysiologic differences between these forms of CSA and OSA-CSA make extrapolation to patients with OSA-CSA speculative.

The dorsal respiratory group in the medulla oblongata generates periodic impulses that travel through the cervical spine to the phrenic nerves, generating rhythmic diaphragmatic contraction, resulting in respiration. This medullary drive is influenced by multiple factors (Fig 1):

Figure Jump LinkFigure 1. Inputs to the respiratory control center located in the dorsal respiratory group of the medulla. DRG = dorsal respiratory group; O2 = oxygen.Grahic Jump Location

  • Chemoreceptors in medullary neurons increase respiratory drive in response to decreases in pH and increasing Pco2. Decreases in Pco2 tend to impair respiratory drive via a similar mechanism.

  • Chemoreceptors in the carotid bodies respond to hypoxia and hypercapnea, transmitting a signal back to the medulla via the glossopharyngeal and vagus nerves, generating increased medullary drive in response.

  • The vagus nerve also delivers afferent input from mechanoreceptors and irritant receptors in the lungs and airways to the brainstem; increased activity results in reduced tidal volumes.

  • Inputs from the cerebral cortex (mediating conscious control), the limbic forebrain (mediating the impact of emotional state on breathing), and the hypothalamus (mediating the effect of temperature on respiration) also exist.

At sleep onset, alveolar ventilation declines slightly to keep pace with decreased metabolic demands. This is achieved by several mechanisms, including an increase in upper airway resistance and diminished responsiveness to changes in CO2 concentrations, oxygen concentrations, and pH.21-24 Interestingly, the same neurons that impair wakefulness may also be responsible for some of these changes in respiratory control.25 Despite the blunted response to most respiratory stimuli, the bradypneic response to hypocarbia may actually be enhanced during sleep relative to wake, simply because of the absence of the so-called wakefulness stimulus.26 CAs are manifest by a decrement in neural respiratory drive, and a resultant absence of muscular respiratory effort during sleep, lasting at least 10 s. While a full review of the pathophysiology of CSA is beyond the scope of this article, it has been reviewed by Eckert et al27 in another issue of CHEST.

The mechanism(s) by which CAs develop after the elimination of obstructive events during treatment with CPAP remain unclear and may vary from patient to patient. Several pathophysiologic mechanisms for this phenomenon have been proposed, and are summarized in Table 1.

Table Graphic Jump Location
Table 1 Possible Mechanisms for the Appearance of Central Sleep Apnea During Implementation of CPAP Therapy for Obstructive Sleep Apnea

Despite increased upper airway resistance, people with OSA may have slightly lower end-tidal Pco2, but similar Pco2 apneic thresholds during sleep as compared with healthy control subjects. This results in a lower CO2 reserve (the reduction in Pco2 that will produce a CA).28 Many people with OSA also have heightened ventilatory sensitivity to changes in Pco2, meaning that changes in CO2 concentrations will lead to a greater change in minute ventilation than in healthy counterparts (ie, increased “controller gain”).28,29 Taken together, this reduced CO2 reserve and increased controller gain act as an unstable ventilatory control system vulnerable to self-perpetuating oscillatory loops of hyper- and hypoventilation (similar to Cheyne-Stokes respiration). Applying CPAP improves ventilation, and increases “plant gain” (ventilatory efficiency). The increase in ventilation at a given Pco2 results in hypocapnia and periodic CAs. This increase in ventilatory efficiency could occur by one of several mechanisms. Application of CPAP relieves upper airway obstruction, abruptly improving ventilation during sleep by increasing dynamic compliance. This causes the Pco2 to fall below the apneic set point, resulting in CAs. Additionally, most patients with OSA are obese and, as a result, have a decreased difference between functional residual capacity and closing capacity, particularly while supine; this leaves many open alveoli unable to fully vent their CO2 during exhalation. This leads to significant ventilation-perfusion mismatching, most prominently at the lung bases. When CPAP is applied, it effectively stents open these collapsed airways, abruptly improving air exchange at the lung bases; the improved ventilation and decrease in Pco2 to below the apneic threshold would precipitate CAs.

A similar pathophysiology is believed to underlie the development of CSA after tracheostomy for OSA.30 Salloum et al28 demonstrated that the increased controller gain in patients with OSA can be reduced with regular CPAP use. A gradual recalibration of controller gain could explain the reduction in CAs experienced by the majority of patients after weeks or months of CPAP use. Theoretically, this mechanism could also mediate CSA after initiation of oral appliance therapy for OSA, though this has not been as clearly demonstrated.

The fact that CAs tend to occur more commonly as CPAP is adjusted upward during therapeutic titration suggests the possibility that excessive doses of CPAP induce CAs. This might occur via stimulation of the parenchymal stretch receptors, leading to inhibition of the medullary inspiratory center, as is seen in the Hering-Breuer inflation reflex. Another potential contributor is the existence of increasing air leak as CPAP levels rise, which could lead to the washing out of CO2 from proximal dead-space areas, effectively leading to excessive CO2 clearance, as lower levels of the gas are being rebreathed. It has been suggested that unintentional overtitration of CPAP may occur because of the inappropriate use of pressure transduction as the primary modality for determining optimal pressure during titration, a procedure that has not yet been validated.6

In healthy people, respiratory drive decreases during sleep; waking end-tidal Pco2 levels are 2 to 3 mm Hg lower than those found during sleep.26 The normal transition from wakefulness to sleep is characterized by transient CAs that occur while the waking Pco2 recalibrates to the higher sleeping apneic threshold, demonstrating the inherent instability of ventilation during the transition between wakefulness and sleep. People with OSA often report difficulty adjusting to the CPAP interface, and subjective awakenings during the titration and the first months of therapy are common. During this adjustment period, each CPAP interface-induced arousal would provide an opportunity for repeating the wakefulness-to-sleep recalibration of the apneic Pco2 set point, potentially with recurring CAs.31-35 In one study, OSA-CSA was associated with significantly higher levels of nasal resistance, a physiologic variable that may predict discomfort and intolerance of therapy.36,37 As the patient adjusts to the therapy, these arousals should theoretically attenuate, removing the recurring perturbation that destabilizes the underlying respiratory pattern. This could explain why CAs resolve within weeks in the large majority of people with CPAP-emergent CAs.1,4,5 Because some forms of oral appliance therapy have been associated with jaw discomfort and excessive salivation, most prominently in the first month of treatment, this modality could also potentially elicit CAs via a similar mechanism.38

Mixed apneas, defined in the 2007 revision to the scoring rules by the American Academy of Sleep Medicine,39 are identified by the presence of an initial central component followed by a terminal obstructive component. Though the majority of laboratories diagnose such patients with OSA and treat these events as if they were obstructive, there is evidence that they may be pathophysiologically more similar to CAs.40 In addition, there is a growing body of data identifying components of CSA in patients with predominantly OSA, and vice versa.41-46 Unless a sleep laboratory is monitoring intrapleural pressure, it may be impossible to differentiate obstructive from centrally-mediated hypopneas on standard PSG; accurate methods are available, but are generally infeasible for widespread clinical use.13,47

Based upon the reasonable assumption that many patients labeled with OSA have comorbid (or perhaps predominant) CSA at the time of diagnosis, it follows that CPAP treatment would leave residual, and sometimes significant, CSA. By eliminating the contributing obstructive component, therapy could expose central hypopneas and centrally originating mixed apneas, classified as obstructive on initial PSG, as centrally mediated. Through the mechanisms of improved efficiency of CO2 clearance described previously, CPAP could also aggravate central hypopneas (misclassified as obstructive events) into frank CAs. The net effect of this would be to “unmask” central events, increasing the CA index without actually creating new events. This mechanism could also explain the development of CSA after treatment with oral appliance therapy or upper airway surgery.

The distinction between OSA and CSA may conceal the complexity and interdependence of these two diseases; this has been best demonstrated in patients with CHF,48,49 but is probably also present in those without CHF.40 Investigations suggest the possibility that OSA itself may cause ventilatory instability and predisposition to CAs,28,50 which may explain why as many as 20% of people develop “new” CAs in excess of five events/h during CPAP titration.

Only a small fraction of people with OSA will develop persistent OSA-CSA on CPAP therapy. Given the prevalence of OSA, however, this would potentially represent hundreds of thousands of people in the United States. Better understanding of the subjective symptoms and health outcomes of people with OSA-CSA over time are needed to guide management decisions and further research efforts. For the time being, available technology does not enable further characterization of OSA-CSA into subtypes that would permit providers to determine whether the finding is benign, in which case it could be ignored, or representative of something more concerning, which would benefit from further evaluation and therapy. Longitudinal observational studies with well defined entry criteria and clinical outcomes as endpoints would be the best next step. Limited studies have suggested a reduction in sleep disturbance with the use of more sophisticated home ventilatory systems51,52 or with rebreathing of CO253; if OSA-CSA improves over time with usual care or results in no adverse outcomes, it is conceivable that these more expensive therapies may not be necessary. The main limitation to such research is the need for serial PSG, and current technologies for use outside of a monitored setting (eg, home PSG) may not be sufficiently accurate at distinguishing OSA from CSA. Improved devices with monitoring and reporting capabilities, whose output could generate large research data sets, could help solve this problem.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Javaheri S, Smith J, Chung E. The prevalence and natural history of complex sleep apnea. J Clin Sleep Med. 2009;5(3):205-211.
 
Lehman S, Antic NA, Thompson C, Catcheside PG, Mercer J, McEvoy RD. Central sleep apnea on commencement of continuous positive airway pressure in patients with a primary diagnosis of obstructive sleep apnea-hypopnea. J Clin Sleep Med. 2007;3(5):462-466.
 
Pusalavidyasagar SS, Olson EJ, Gay PC, Morgenthaler TI. Treatment of complex sleep apnea syndrome: a retrospective comparative review. Sleep Med. 2006;7(6):474-479.
 
Dernaika T, Tawk M, Nazir S, Younis W, Kinasewitz GT. The significance and outcome of continuous positive airway pressure-related central sleep apnea during split-night sleep studies. Chest. 2007;132(1):81-87.
 
Kuzniar TJ, Pusalavidyasagar S, Gay PC, Morgenthaler TI. Natural course of complex sleep apnea—a retrospective study. Sleep Breath. 2008;12(2):135-139.
 
Yaegashi H, Fujimoto K, Abe H, Orii K, Eda S, Kubo K. Characteristics of Japanese patients with complex sleep apnea syndrome: a retrospective comparison with obstructive sleep apnea syndrome. Intern Med. 2009;48(6):427-432.
 
Morgenthaler TI, Kagramanov V, Hanak V, Decker PA. Complex sleep apnea syndrome: is it a unique clinical syndrome? Sleep. 2006;29(9):1203-1209.
 
Gilmartin GS, Daly RW, Thomas RJ. Recognition and management of complex sleep-disordered breathing. Curr Opin Pulm Med. 2005;11(6):485-493.
 
Gay PC. Complex sleep apnea: it really is a disease. J Clin Sleep Med. 2008;4(5):403-405.
 
Bitter T, Westerheide N, Hossain MS, et al. Complex sleep apnoea in congestive heart failure. Thorax. 2011;66(5):402-407.
 
Malhotra A, Bertisch S, Wellman A. Complex sleep apnea: it isn’t really a disease. J Clin Sleep Med. 2008;4(5):406-408.
 
Cassel W, Canisius S, Becker HF, et al. A prospective polysomnographic study on the evolution of complex sleep apnoea. Eur Respir J. 2011;38(2):329-337.
 
Thomas RJ, Mietus JE, Peng CK, et al. Differentiating obstructive from central and complex sleep apnea using an automated electrocardiogram-based method. Sleep. 2007;30(12):1756-1769.
 
Kuźniar TJ, Kovačević-Ristanović R, Freedom T. Complex sleep apnea unmasked by the use of a mandibular advancement device. Sleep Breath. 2011;15(2):249-252.
 
Avidan AY. The development of central sleep apnea with an oral appliance. Sleep Med. 2006;7(1):85-86.
 
Corcoran S, Mysliwiec V, Niven AS, Fallah D. Development of central sleep apnea after maxillofacial surgery for obstructive sleep apnea. J Clin Sleep Med. 2009;5(2):151-153.
 
Peker Y, Carlson J, Hedner J. Increased incidence of coronary artery disease in sleep apnoea: a long-term follow-up. Eur Respir J. 2006;28(3):596-602.
 
Milleron O, Pillière R, Foucher A, et al. Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study. Eur Heart J. 2004;25(9):728-734.
 
Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation. 1999;99(11):1435-1440.
 
Bradley TD, Logan AG, Kimoff RJ, et al; CANPAP Investigators Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med. 2005;353(19):2025-2033.
 
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Figures

Figure Jump LinkFigure 1. Inputs to the respiratory control center located in the dorsal respiratory group of the medulla. DRG = dorsal respiratory group; O2 = oxygen.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Possible Mechanisms for the Appearance of Central Sleep Apnea During Implementation of CPAP Therapy for Obstructive Sleep Apnea

References

Javaheri S, Smith J, Chung E. The prevalence and natural history of complex sleep apnea. J Clin Sleep Med. 2009;5(3):205-211.
 
Lehman S, Antic NA, Thompson C, Catcheside PG, Mercer J, McEvoy RD. Central sleep apnea on commencement of continuous positive airway pressure in patients with a primary diagnosis of obstructive sleep apnea-hypopnea. J Clin Sleep Med. 2007;3(5):462-466.
 
Pusalavidyasagar SS, Olson EJ, Gay PC, Morgenthaler TI. Treatment of complex sleep apnea syndrome: a retrospective comparative review. Sleep Med. 2006;7(6):474-479.
 
Dernaika T, Tawk M, Nazir S, Younis W, Kinasewitz GT. The significance and outcome of continuous positive airway pressure-related central sleep apnea during split-night sleep studies. Chest. 2007;132(1):81-87.
 
Kuzniar TJ, Pusalavidyasagar S, Gay PC, Morgenthaler TI. Natural course of complex sleep apnea—a retrospective study. Sleep Breath. 2008;12(2):135-139.
 
Yaegashi H, Fujimoto K, Abe H, Orii K, Eda S, Kubo K. Characteristics of Japanese patients with complex sleep apnea syndrome: a retrospective comparison with obstructive sleep apnea syndrome. Intern Med. 2009;48(6):427-432.
 
Morgenthaler TI, Kagramanov V, Hanak V, Decker PA. Complex sleep apnea syndrome: is it a unique clinical syndrome? Sleep. 2006;29(9):1203-1209.
 
Gilmartin GS, Daly RW, Thomas RJ. Recognition and management of complex sleep-disordered breathing. Curr Opin Pulm Med. 2005;11(6):485-493.
 
Gay PC. Complex sleep apnea: it really is a disease. J Clin Sleep Med. 2008;4(5):403-405.
 
Bitter T, Westerheide N, Hossain MS, et al. Complex sleep apnoea in congestive heart failure. Thorax. 2011;66(5):402-407.
 
Malhotra A, Bertisch S, Wellman A. Complex sleep apnea: it isn’t really a disease. J Clin Sleep Med. 2008;4(5):406-408.
 
Cassel W, Canisius S, Becker HF, et al. A prospective polysomnographic study on the evolution of complex sleep apnoea. Eur Respir J. 2011;38(2):329-337.
 
Thomas RJ, Mietus JE, Peng CK, et al. Differentiating obstructive from central and complex sleep apnea using an automated electrocardiogram-based method. Sleep. 2007;30(12):1756-1769.
 
Kuźniar TJ, Kovačević-Ristanović R, Freedom T. Complex sleep apnea unmasked by the use of a mandibular advancement device. Sleep Breath. 2011;15(2):249-252.
 
Avidan AY. The development of central sleep apnea with an oral appliance. Sleep Med. 2006;7(1):85-86.
 
Corcoran S, Mysliwiec V, Niven AS, Fallah D. Development of central sleep apnea after maxillofacial surgery for obstructive sleep apnea. J Clin Sleep Med. 2009;5(2):151-153.
 
Peker Y, Carlson J, Hedner J. Increased incidence of coronary artery disease in sleep apnoea: a long-term follow-up. Eur Respir J. 2006;28(3):596-602.
 
Milleron O, Pillière R, Foucher A, et al. Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study. Eur Heart J. 2004;25(9):728-734.
 
Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation. 1999;99(11):1435-1440.
 
Bradley TD, Logan AG, Kimoff RJ, et al; CANPAP Investigators Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med. 2005;353(19):2025-2033.
 
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