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Complex Sleep Apnea

  • SLEEP DISORDERS (S CHOKROVERTY, SECTION EDITOR)
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Opinion statement

Complex sleep apnea currently refers to the emergence and persistence of central apneas and hypopneas following the application of positive airway pressure therapy in patients with obstructive sleep apnea. However, this narrow definition is an “outcome” and does not capture the spectrum of pathological activation of the respiratory chemoreflex in sleep apnea. The International Classification of Sleep Disorders – 3rd edition recognizes the phenomenon of Treatment-Related Central Sleep Apnea, but the phenotype is usually evident prior to onset of therapy. The key polysomnographic characteristics of chemoreflex modulated and mediated sleep apnea are nonrapid eye movement (NREM) dominance of respiratory events, short (<30 seconds) or long (>60 seconds) cycle time with a self-similar metronomic timing, and spontaneous improvement during rapid eye movement (REM) sleep. Thus, the majority of chemoreflex effects go unrecognized due to the bias toward obstructive sleep apnea’s current scoring criteria. Any treatment of apparently obstructive sleep apnea, including surgery and oral appliances, can expose chemoreflex-driven instabilities. As both sleep fragmentation and a narrow CO2 reserve or increased loop gain drive the disease, sedatives (to induce longer periods of stable NREM sleep and reduce the destabilizing effects of arousals in NREM sleep) and CO2-based stabilization approaches are logical. Adaptive ventilation reduces mean hyperventilation yet can induce ventilator-patient desynchrony, while enhanced expiratory rebreathing space (EERS, dead space during positive pressure therapy) and CO2 manipulation directly stabilize respiratory control by moving CO2 above the apnea threshold. Carbonic anhydrase inhibition can provide further adjunctive benefits. Novel pharmacological approaches may target mediators of carotid body hypoxic sensitization, such as the balance between gas neurotransmitters. In complex apnea patients, single mode therapy is unlikely to be successful, and the power of multi-modality therapy should be harnessed for optimal outcomes.

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References and Recommended Reading

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  1. Marrone O, Stallone A, Salvaggio A, Milone F, Bellia V, Bonsignore G. Occurrence of breathing disorders during CPAP administration in obstructive sleep apnoea syndrome. Eur Respir J. 1991;4:660–6.

    PubMed  CAS  Google Scholar 

  2. Thomas RJ, Terzano MG, Parrino L, Weiss JW. Obstructive sleep-disordered breathing with a dominant cyclic alternating pattern—a recognizable polysomnographic variant with practical clinical implications. Sleep. 2004;27:229–34.

    PubMed  Google Scholar 

  3. Gilmartin GS, Daly RW, Thomas RJ. Recognition and management of complex sleep-disordered breathing. Curr Opin Pulm Med. 2005;11:485–93.

    Article  PubMed  Google Scholar 

  4. Morgenthaler TI, Kagramanov V, Hanak V, Decker PA. Complex sleep apnea syndrome: is it a unique clinical syndrome? Sleep. 2006;29:1203–9.

    PubMed  Google Scholar 

  5. Goldstein C, Kuzniar TJ. The emergence of central sleep apnea after surgical relief of nasal obstruction in obstructive sleep apnea. J Clin Sleep Med. 2012;8:321–2.

    PubMed  Google Scholar 

  6. Gilmartin G, McGeehan B, Vigneault K, Daly RW, Manento M, Weiss JW, et al. Treatment of positive airway pressure treatment-associated respiratory instability with enhanced expiratory rebreathing space (EERS). J Clin Sleep Med. 2010;6:529–38. A description of adapting the dead space concept to positive airway pressure therapy.

    PubMed  Google Scholar 

  7. Kuzniar TJ, Kovacevic-Ristanovic R, Freedom T. Complex sleep apnea unmasked by the use of a mandibular advancement device. Sleep Breath. 2011;15:249–52.

    Article  PubMed  Google Scholar 

  8. 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;3:462–6.

    PubMed  Google Scholar 

  9. Kuzniar TJ, Pusalavidyasagar S, Gay PC, Morgenthaler T. Natural course of complex sleep apnea—a retrospective study. Sleep Breath. 2008;12:135–9.

    Article  PubMed  Google Scholar 

  10. Kuzniar TJ, Morgenthaler TI. Treatment of complex sleep apnea syndrome. Curr Treat Options Neurol. 2008;10:336–41.

    Article  PubMed  Google Scholar 

  11. Gay PC. Complex sleep apnea: it really is a disease. J Clin Sleep Med. 2008;4:403–5.

    PubMed  Google Scholar 

  12. Endo Y, Suzuki M, Inoue Y, Sato M, Namba K, Hasegawa M, et al. Prevalence of complex sleep apnea among Japanese patients with sleep apnea syndrome. Tohoku J Exp Med. 2008;215:349–54.

    Article  PubMed  CAS  Google Scholar 

  13. Kuzniar TJ, Morgenthaler TI. Treatment of complex sleep apnea syndrome. Chest. 2012;142:1049–57.

    Article  PubMed  Google Scholar 

  14. 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;132:81–7.

    Article  PubMed  Google Scholar 

  15. Cassel W, Canisius S, Becker HF, Leistner S, Ploch T, Jerrentrup A, et al. A prospective polysomnographic study on the evolution of complex sleep apnoea. Eur Respir J. 2011;38:329–37.

    Article  PubMed  CAS  Google Scholar 

  16. Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. J Clin Sleep Med. 2012;8:597–619.

    PubMed  Google Scholar 

  17. Jobin V, Rigau J, Beauregard J, Farre R, Monserrat J, Bradley TD, et al. Evaluation of upper airway patency during Cheyne-Stokes breathing in heart failure patients [published online ahead of print May 17, 2012]. Eur Respir J. 2012;40:1523–30.

    Article  PubMed  Google Scholar 

  18. Thomas RJ, Tamisier R, Boucher J, Kotlar Y, Vigneault K, Weiss JW, et al. Nocturnal hypoxia exposure with simulated altitude for 14 days does not significantly alter working memory or vigilance in humans. Sleep. 2007;30:1195–203.

    PubMed  Google Scholar 

  19. Badr MS, Toiber F, Skatrud JB, Dempsey J. Pharyngeal narrowing/occlusion during central sleep apnea. J Appl Physiol. 1995;78:1806–15.

    PubMed  CAS  Google Scholar 

  20. Sankri-Tarbichi AG, Rowley JA, Badr MS. Expiratory pharyngeal narrowing during central hypocapnic hypopnea. Am J Respir Crit Care Med. 2009;179:313–9.

    Article  PubMed  Google Scholar 

  21. Westhoff M, Arzt M, Litterst P. Prevalence and treatment of central sleep apnoea emerging after initiation of continuous positive airway pressure in patients with obstructive sleep apnoea without evidence of heart failure. Sleep Breath. 2012;16:71–8.

    Article  PubMed  Google Scholar 

  22. Javaheri S, Smith J, Chung E. The prevalence and natural history of complex sleep apnea. J Clin Sleep Med. 2009;5:205–11.

    PubMed  Google Scholar 

  23. Thomas RJ, Mietus JE, Peng CK, Gilmartin G, Daly RW, Goldberger AL, et al. Differentiating obstructive from central and complex sleep apnea using an automated electrocardiogram-based method. Sleep. 2007;30:1756–69.

    PubMed  Google Scholar 

  24. Jordan AS, Wellman A, Edwards JK, Schory K, Dover L, MacDonald M, et al. Respiratory control stability and upper airway collapsibility in men and women with obstructive sleep apnea. J Appl Physiol. 2005;99:2020–7.

    Article  PubMed  Google Scholar 

  25. Badr MS, Skatrud JB, Simon PM, Dempsey JA. Effect of hypercapnia on total pulmonary resistance during wakefulness and during NREM sleep. Am Rev Respir Dis. 1991;144:406–14.

    Article  PubMed  CAS  Google Scholar 

  26. Xie A, Bedekar A, Skatrud JB, Teodorescu M, Gong Y, Dempsey JA. The heterogeneity of obstructive sleep apnea (predominant obstructive vs pure obstructive apnea). Sleep. 2011;34:745–50. The primary physiological difference between virtually pure REM-dominant obstructive sleep apnea and more "mixed" apnea is a reduced CO2 reserve, not differences in airway collapsibility.

    PubMed  Google Scholar 

  27. Dempsey JA, Smith CA, Blain GM, Xie A, Gong Y, Teodorescu M. Role of central/peripheral chemoreceptors and their interdependence in the pathophysiology of sleep apnea. Adv Exp Med Biol. 2012;758:343–9.

    Article  PubMed  Google Scholar 

  28. Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea. Physiol Rev. 2010;90:47–112.

    Article  PubMed  CAS  Google Scholar 

  29. Javaheri S, Dempsey JA. Central sleep apnea. Compr Physiol. 2013;3:141–63.

    PubMed  CAS  Google Scholar 

  30. Miller YE, Karoor V, Dempsey EC, Fagan KA. Sleep-disordered breathing, hypoxemia, and cancer mortality. Am J Respir Crit Care Med. 2013;187:330–1.

    Article  PubMed  Google Scholar 

  31. White DP, Douglas NJ, Pickett CK, Weil JV, Zwillich CW. Sexual influence on the control of breathing. J Appl Physiol. 1983;54:874–9.

    PubMed  CAS  Google Scholar 

  32. Jordan AS, Eckert DJ, Catcheside PG, McEvoy RD. Ventilatory response to brief arousal from nonrapid eye movement sleep is greater in men than in women. Am J Respir Crit Care Med. 2003;168:1512–9.

    Article  PubMed  Google Scholar 

  33. Hume KI, Van F, Watson A. A field study of age and gender differences in habitual adult sleep. J Sleep Res. 1998;7:85–94.

    Article  PubMed  CAS  Google Scholar 

  34. Xie A, Rutherford R, Rankin F, Wong B, Bradley TD. Hypocapnia and increased ventilatory responsiveness in patients with idiopathic central sleep apnea. Am J Respir Crit Care Med. 1995;152:1950–5.

    Google Scholar 

  35. Malhotra A, Bertisch S, Wellman A. Complex sleep apnea: it isn't really a disease. J Clin Sleep Med. 2008;4:406–8.

    PubMed  Google Scholar 

  36. Loewen A, Ostrowski M, Laprairie J, Atkar R, Gnitecki J, Hanly P, et al. Determinants of ventilatory instability in obstructive sleep apnea: inherent or acquired? Sleep. 2009;32:1355–65.

    PubMed  Google Scholar 

  37. Meza S, Mendez M, Ostrowski M, Younes M. Susceptibility to periodic breathing with assisted ventilation during sleep in normal subjects. J Appl Physiol. 1998;85:1929–40.

    PubMed  CAS  Google Scholar 

  38. Younes M. Role of respiratory control mechanisms in the pathogenesis of obstructive sleep disorders. J Appl Physiol. 2008;105:1389–405.

    Article  PubMed  CAS  Google Scholar 

  39. Younes M, Ostrowski M, Atkar R, Laprairie J, Siemens A, Hanly P. Mechanisms of breathing instability in patients with obstructive sleep apnea. J Appl Physiol. 2007;103:1929–41.

    Article  PubMed  Google Scholar 

  40. Younes M, Ostrowski M, Thompson W, Leslie C, Shewchuk W. Chemical control stability in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2001;163:1181–90.

    Article  PubMed  CAS  Google Scholar 

  41. Thomas RJ. Strong chemoreflex modulation of sleep-breathing: some answers but even more questions. J Clin Sleep Med. 2009;5:212–4.

    PubMed  Google Scholar 

  42. Wellman A, Edwards BA, Sands SA, Owens RL, Nemati S, Butler J, et al. A simplified method for determining phenotypic traits in patients with obstructive sleep apnea. J Appl Physiol. 2013;114:911–22.

    Article  PubMed  CAS  Google Scholar 

  43. Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A. Defining phenotypic causes of obstructive sleep apnea: identification of novel therapeutic targets. Am J Respir Crit Care Med. 2013. doi:10.1164/rccm.201303-0448OC.

  44. Dellweg D, Kerl J, Hoehn E, Wenzel M, Koehler D. Randomized controlled trial of noninvasive positive pressure ventilation (NPPV) versus servoventilation in patients with CPAP-induced central sleep. Apnea (Complex Sleep Apnea). Sleep. 2013;36:1163–71.

    PubMed  Google Scholar 

  45. Teschler H, Dohring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med. 2001;164:614–9.

    Article  PubMed  CAS  Google Scholar 

  46. Koyama T, Watanabe H, Tamura Y, Oguma Y, Kosaka T, Ito H. Adaptive servo-ventilation therapy improves cardiac sympathetic nerve activity in patients with heart failure. Eur J Heart Fail. 2013;15:902–9 [published online ahead of print March 15, 2013].

    Article  PubMed  Google Scholar 

  47. Koyama T, Watanabe H, Igarashi G, Terada S, Makabe S, Ito H. Short-term prognosis of adaptive servo-ventilation therapy in patients with heart failure. Circ J. 2011;75:710–2.

    Article  PubMed  Google Scholar 

  48. Iwaya S, Yoshihisa A, Nodera M, Owada T, Yamada S, Sato T, et al. Suppressive effects of adaptive servo-ventilation on ventricular premature complexes with attenuation of sympathetic nervous activity in heart failure patients with sleep-disordered breathing. Heart Vessels. 2013. doi:10.1007/s00380-013-0394-2.

  49. D'Elia E, Vanoli E, La Rovere MT, Fanfulla F, Maggioni A, Casali V, et al. Adaptive servo ventilation reduces central sleep apnea in chronic heart failure patients: beneficial effects on autonomic modulation of heart rate. J Cardiovasc Med. 2013;14:296–300.

    Article  Google Scholar 

  50. Randerath WJ, Nothofer G, Priegnitz C, Anduleit N, Treml M, Kehl V, et al. Long-term auto-servoventilation or constant positive pressure in heart failure and coexisting central with obstructive sleep apnea. Chest. 2012;142:440–7.

    Article  PubMed  CAS  Google Scholar 

  51. Javaheri S, Goetting MG, Khayat R, Wylie PE, Goodwin JL, Parthasarathy S. The performance of two automatic servo-ventilation devices in the treatment of central sleep apnea. Sleep. 2011;34:1693–8.

    PubMed  Google Scholar 

  52. Arzt M, Schroll S, Series F, Lewis K, Benjamin A, Escourrou P, et al. Auto-servo ventilation in heart failure with sleep apnea - a randomized controlled trial. Eur Respir J. 2012. doi:10.1183/09031936.00083312.

  53. Oldenburg O, Bitter T, Wellmann B, Fischbach T, Efken C, Schmidt A, et al. Trilevel adaptive servoventilation for the treatment of central and mixed sleep apnea in chronic heart failure patients. Sleep Med. 2013;14:422–7.

    Article  PubMed  Google Scholar 

  54. Bitter T, Westerheide N, Hossain MS, Lehmann R, Prinz C, Kleemeyer A, et al. Complex sleep apnoea in congestive heart failure. Thorax. 2011;66:402–7.

    Article  PubMed  Google Scholar 

  55. Cowie MR, Woehrle H, Wegscheider K, Angermann C, d’Ortho MP, Erdmann E, et al. Rationale and design of the SERVE-HF study: treatment of sleep-disordered breathing with predominant central sleep apnoea with adaptive servo-ventilation in patients with chronic heart failure. Eur J Heart Fail. 2013;15:937–43.

    Article  PubMed  Google Scholar 

  56. Morgenthaler TI, Gay PC, Gordon N, Brown LK. Adaptive servoventilation versus noninvasive positive pressure ventilation for central, mixed, and complex sleep apnea syndromes. Sleep. 2007;30:468–75.

    PubMed  Google Scholar 

  57. Xie A, Teodorescu M, Pegelow DF, Teodorescu MC, Gong Y, Fedie JE, et al. Effects of stabilizing or increasing respiratory motor outputs on obstructive sleep apnea. J Appl Physiol. 2013;115:22–33. The best recent demonstration of phenotypic spectrum of responsiveness to CO2 in sleep apnea patients. Safe use of CO2 will, however, need to make low concentrations effective, such as with concomitant use of positive pressure therapy or even an oral appliance.

    Article  PubMed  Google Scholar 

  58. 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. Sleep. 2005;28:69–77.

    PubMed  Google Scholar 

  59. Mebrate Y, Willson K, Manisty CH, Baruah R, Mayet J, Hughes AD, Parker KH, Francis DP. Dynamic CO2 therapy in periodic breathing: a modeling study to determine optimal timing and dosage regimes. J Appl Physiol. 2009;107:696–706.

    Google Scholar 

  60. Sakakibara M, Sakata Y, Usui K, Hayama Y, Kanda S, Wada N, et al. Effectiveness of short-term treatment with nocturnal oxygen therapy for central sleep apnea in patients with congestive heart failure. J Cardiol. 2005;46:53–61.

    PubMed  Google Scholar 

  61. Gold AR, Bleecker ER, Smith PL. A shift from central and mixed sleep apnea to obstructive sleep apnea resulting from low-flow oxygen. Am Rev Respir Dis. 1985;132:220–3.

    PubMed  CAS  Google Scholar 

  62. Allam JS, Olson EJ, Gay PC, Morgenthaler TI. Efficacy of adaptive servoventilation in treatment of complex and central sleep apnea syndromes. Chest. 2007;132:1839–46.

    Article  PubMed  Google Scholar 

  63. Chowdhuri S, Ghabsha A, Sinha P, Kadri M, Narula S, Badr MS. Treatment of central sleep apnea in U.S. veterans. J Clin Sleep Med. 2012;8:555–63.

    PubMed  Google Scholar 

  64. Thomas RJ, Mietus JE, Peng CK, Goldberger AL. An electrocardiogram-based technique to assess cardiopulmonary coupling during sleep. Sleep. 2005;28:1151–61.

    PubMed  Google Scholar 

  65. Edwards BA, Connolly JG, Campana LM, Sands SA, Trinder JA, White DP, et al. Acetazolamide attenuates the ventilatory response to arousal in patients with obstructive sleep apnea. Sleep. 2013;36:281–5. This report demonstrates that acetazolamide has potentially beneficial effects beyond reduction of loop gain in sleep apnea patients.

    PubMed  Google Scholar 

  66. Jordan AS, Eckert DJ, Wellman A, Trinder JA, Malhotra A, White DP. Termination of respiratory events with and without cortical arousal in obstructive sleep apnea. Am J Respir Crit Care Med. 2011;184:1183–91.

    Article  PubMed  Google Scholar 

  67. Quadri S, Drake C, Hudgel DW. Improvement of idiopathic central sleep apnea with zolpidem. J Clin Sleep Med. 2009;5:122–9.

    PubMed  Google Scholar 

  68. Bonnet MH, Dexter JR, Arand DL. The effect of triazolam on arousal and respiration in central sleep apnea patients. Sleep. 1990;13:31–41.

    PubMed  CAS  Google Scholar 

  69. Guilleminault C, Crowe C, Quera-Salva MA, Miles L, Partinen M. Periodic leg movement, sleep fragmentation and central sleep apnoea in two cases: reduction with Clonazepam. Eur Respir J. 1988;1:762–5.

    PubMed  CAS  Google Scholar 

  70. Nickol AH, Leverment J, Richards P, Seal P, Harris GA, Cleland J, et al. Temazepam at high altitude reduces periodic breathing without impairing next-day performance: a randomized cross-over double-blind study. J Sleep Res. 2006;15:445–54.

    Article  PubMed  Google Scholar 

  71. Eckert DJ, Owens RL, Kehlmann GB, Wellman A, Rahangdale S, Yim-Yeh S, et al. Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold. Clin Sci. 2011;120:505–14.

    Article  PubMed  Google Scholar 

  72. Eckert DJ, Kehlmann G, Wellman A, White D, Malhotra A. Effects of trazodone on the respiratory arousal threshold and upper airway dilator muscle responsiveness during sleep in obstructive sleep apnea. Sleep. 2011;34:A156–7.

    Google Scholar 

  73. Wang D, Teichtahl H, Drummer O, Goodman C, Cherry G, Cunnington D, et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest. 2005;128:1348–56.

    Article  PubMed  Google Scholar 

  74. Sharkey KM, Kurth ME, Anderson BJ, Corso RP, Millman RP, Stein MD. Obstructive sleep apnea is more common than central sleep apnea in methadone maintenance patients with subjective sleep complaints. Drug Alcohol Depend. 2010;108:77–83.

    Article  PubMed  Google Scholar 

  75. Charpentier A, Bisac S, Poirot I, Vignau J, Cottencin O. Sleep quality and apnea in stable methadone maintenance treatment. Subst Use Misuse. 2010;45:1431–4.

    Article  PubMed  Google Scholar 

  76. Walker JM, Farney RJ, Rhondeau SM, Boyle KM, Valentine K, Cloward TV, et al. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med. 2007;3:455–61.

    PubMed  Google Scholar 

  77. Teichtahl H, Wang D, Cunnington D, Quinnell T, Tran H, Kronborg I, et al. Ventilatory responses to hypoxia and hypercapnia in stable methadone maintenance treatment patients. Chest. 2005;128:1339–47.

    Article  PubMed  Google Scholar 

  78. Shore ET, Millman RP. Central sleep apnea and acetazolamide therapy. Arch Intern Med. 1983;143:1278–80.

    Article  PubMed  CAS  Google Scholar 

  79. Inoue Y, Takata K, Sakamoto I, Hazama H, Kawahara R. Clinical efficacy and indication of acetazolamide treatment on sleep apnea syndrome. Psychiatry Clin Neurosci. 1999;53:321–2.

    Article  PubMed  CAS  Google Scholar 

  80. Edwards BA, Sands SA, Eckert DJ, White DP, Butler JP, Owens RL, et al. Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep apnoea. J Physiol. 2012;590:1199–211. Support for use of acetazolamide in appropriate phentyped sleep apnea patients. The challenge in accurate clinical phenotyping.

    PubMed  Google Scholar 

  81. Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey JA. Effect of ventilatory drive on carbon dioxide sensitivity below eupnea during sleep. Am J Respir Crit Care Med. 2002;165:1251–60.

    Article  PubMed  Google Scholar 

  82. Javaheri S. Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study. Am J Respir Crit Care Med. 2006;173:234–7.

    Article  PubMed  CAS  Google Scholar 

  83. Latshang TD, Nussbaumer-Ochsner Y, Henn RM, Ulrich S, Lo Cascio CM, Ledergerber B, et al. Effect of acetazolamide and autoCPAP therapy on breathing disturbances among patients with obstructive sleep apnea syndrome who travel to altitude: a randomized controlled trial. JAMA. 2012;308:2390–8. A clear demonstration of the role of "multimodality" therapy targeting combined pathophysiologies. The paper makes a case for the routine use of acetazolamide when sleep apnea patients are exposed to high altitiude.

    Article  PubMed  CAS  Google Scholar 

  84. Glidewell RN, Orr WC, Imes N. Acetazolamide as an adjunct to CPAP treatment: a case of complex sleep apnea in a patient on long-acting opioid therapy. J Clin Sleep Med. 2009;5:63–4.

    PubMed  Google Scholar 

  85. De Simone G, Di Fiore A, Menchise V, Pedone C, Antel J, Casini A, et al. Carbonic anhydrase inhibitors. Zonisamide is an effective inhibitor of the cytosolic isozyme II and mitochondrial isozyme V: solution and X-ray crystallographic studies. Bioorg Med Chem Lett. 2005;15:2315–20.

    Article  PubMed  Google Scholar 

  86. Westwood AJ, Vendrame M, Montouris G, Auerbach SH. Pearls & oysters: treatment of central sleep apnea with topiramate. Neurology. 2012;78:e97–9.

    Article  PubMed  Google Scholar 

  87. Nussbaumer-Ochsner Y, Latshang TD, Ulrich S, Kohler M, Thurnheer R, Bloch KE. Patients with obstructive sleep apnea syndrome benefit from acetazolamide during an altitude sojourn: a randomized, placebo-controlled, double-blind trial. Chest. 2012;141:131–8.

    Article  PubMed  CAS  Google Scholar 

  88. Sankri-Tarbichi AG, Grullon K, Badr MS. Effects of clonidine on breathing during sleep and susceptibility to central apnoea. Respir Physiol Neurobiol. 2013;185:356–61.

    Article  PubMed  CAS  Google Scholar 

  89. Braga CW, Chen Q, Burschtin OE, Rapoport DM, Ayappa I. Changes in lung volume and upper airway using MRI during application of nasal expiratory positive airway pressure in patients with sleep-disordered breathing. J Appl Physiol. 2011;111:1400–9. Potential mechanisms are demonstrated for efficacy of nasal expiratory pressure using imaging techniques.

    Article  PubMed  CAS  Google Scholar 

  90. Patel AV, Hwang D, Masdeu MJ, Chen GM, Rapoport DM, Ayappa I. Predictors of response to a nasal expiratory resistor device and its potential mechanisms of action for treatment of obstructive sleep apnea. J Clin Sleep Med. 2011;7:13–22.

    PubMed  Google Scholar 

  91. Avidan AY. The development of central sleep apnea with an oral appliance. Sleep Med. 2006;7:85–6.

    Article  PubMed  Google Scholar 

  92. Denbar MA. A case study involving the combination treatment of an oral appliance and auto-titrating CPAP unit. Sleep Breath. 2002;6:125–8.

    Article  PubMed  Google Scholar 

  93. El-Solh AA, Moitheennazima B, Akinnusi ME, Churder PM, Lafornara AM. Combined oral appliance and positive airway pressure therapy for obstructive sleep apnea: a pilot study. Sleep Breath. 2011;15:203–8.

    Article  PubMed  Google Scholar 

  94. Colrain IM, Black J, Siegel LC, Bogan RK, Becker PM, Farid-Moayer M, Goldberg R, Lankford DA, Goldberg AN, Malhotra A. A multicenter evaluation of oral pressure therapy for the treatment of obstructive sleep apnea. Sleep Med. 2013;14:830–7.

    Google Scholar 

  95. Szollosi I, Roebuck T, Thompson B, Naughton MT. Lateral sleeping position reduces severity of central sleep apnea / Cheyne-Stokes respiration. Sleep. 2006;29:1045–51.

    PubMed  Google Scholar 

  96. Joho S, Oda Y, Hirai T, Inoue H. Impact of sleeping position on central sleep apnea/Cheyne-Stokes respiration in patients with heart failure. Sleep Med. 2010;11:143–8.

    Article  PubMed  Google Scholar 

  97. White LH, Bradley TD. Role of nocturnal rostral fluid shift in the pathogenesis of obstructive and central sleep apnoea. J Physiol. 2013;591:1179–93.

    Article  PubMed  Google Scholar 

  98. Redolfi S, Yumino D, Ruttanaumpawan P, Yau B, Su MC, Lam J, et al. Relationship between overnight rostral fluid shift and obstructive sleep apnea in nonobese men. Am J Respir Crit Care Med. 2009;179:241–6.

    Article  PubMed  Google Scholar 

  99. Kasai T, Motwani SS, Yumino D, Mak S, Newton GE, Bradley TD. Differing relationship of nocturnal fluid shifts to sleep apnea in men and women with heart failure. Circ Heart Fail. 2012;5:467–74.

    Article  PubMed  Google Scholar 

  100. Friedman O, Bradley TD, Chan CT, Parkes R, Logan AG. Relationship between overnight rostral fluid shift and obstructive sleep apnea in drug-resistant hypertension. Hypertension. 2010;56:1077–82.

    Article  PubMed  CAS  Google Scholar 

  101. Elias RM, Bradley TD, Kasai T, Motwani SS, Chan CT. Rostral overnight fluid shift in end-stage renal disease: relationship with obstructive sleep apnea. Nephrol Dial Transplant. 2012;27:1569–73.

    Article  PubMed  Google Scholar 

  102. Prabhakar NR. Carbon monoxide (CO) and hydrogen sulfide (H(2)S) in hypoxic sensing by the carotid body. Respir Physiol Neurobiol. 2012;184:165–9.

    Article  PubMed  CAS  Google Scholar 

  103. Del Rio R, Marcus NJ, Schultz HD. Inhibition of hydrogen sulfide restores normal breathing stability and improves autonomic control during experimental heart failure. J Appl Physiol. 2013;114:1141–50.

    Article  PubMed  Google Scholar 

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Conflicts of Interest

Robert Joseph Thomas has served as a consultant for DeVilbiss HealthCare and GLG Consulting; has received grant support from the NHLBI; holds patents with MyCardio, LLC and PAPGAM; and has received royalties from MyCardio, LLC.

Harish Rao declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with animal subjects performed by any of the authors. With regard to the authors’ research cited in this paper, all procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 and 2008.

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Authors and Affiliations

  1. Boston Children’s Hospital & Harvard Medical School, 300 Longwood Avenue, Boston, MA, USA

    Harish Rao MD, MRCPCH & Robert Joseph Thomas MD, MMSc

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  1. Harish Rao MD, MRCPCH
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  2. Robert Joseph Thomas MD, MMSc
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Correspondence to Robert Joseph Thomas MD, MMSc.

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Rao, H., Thomas, R.J. Complex Sleep Apnea. Curr Treat Options Neurol 15, 677–691 (2013). https://doi.org/10.1007/s11940-013-0260-7

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