Sleep Medicine 16 (2015) 313–314
Contents lists available at ScienceDirect
Sleep Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p
Editorial
Treatment-emergent central sleep apnea at high altitude
Treatment-emergent central sleep apnea (TE-CSA, formerly complex sleep apnea) describes the appearance of central sleep apneas upon relief of obstruction, typically by positive airway pressure therapy (CPAP), in a patient with obstructive sleep apnea (OSA) [1]. TE-CSA has been described for a decade and it is thought to affect a significant minority of patients with OSA. Several pathophysiological chains of events may lead to the appearance of TE-CSA; mechanisms that have been postulated in its development include elevated chemoreceptor sensitivity [2], decreased arousal threshold [3], prolonged circulation time [4], and use of opioid medications [5]. Through these mechanisms, there is a high “loop gain” of the respiratory system; this term, borrowed from the technology dictionary, describes the system’s instability and its propensity to hypopnea–hyperpnea oscillations in response to stimuli. Living at high altitude increases loop gain as it exposes an individual to several mechanisms that may destabilize breathing. Chronic hypoxemia leads to hyperventilation and hypocapnia, which acutely leads to the development of periodic breathing in most people [6]. With time, a complex process of acclimatization occurs, with a drop of peripheral chemosensitivity, increased cerebral blood flow, and alteration of central chemosensitivity (reviewed in [7]). In long term residents of high altitude, the hypoxic ventilatory response is blunted [8,9] and there may even be anatomical changes in the structure of the carotid bodies [10]. Higher loop gain observed at high altitude may predispose people to TE-CSA. Following that lead, Zapata et al. examined the prevalence of TE-CSA in a group of 988 consecutive patients diagnosed with TE-CSA in Bogota, Columbia, which lies at the altitude of 2,640 m [11]. Among 988 patients with moderate or severe OSA, 115 (11.6%) were found to have TE-CSA in the therapeutic CPAP titration study. In a regression analysis comparing the TE-CSA patients with patients with “pure” OSA, the authors identified the following factors associated with the development of TE-CSA: presence of central sleep apnea on diagnostic study, self-reported history of heart failure, and male sex. According to several studies, TE-CSA affects 2–15% of patients with OSA [12–14]. There was one prior study reporting on the higher prevalence (10.6–38.7%) of TE-CSA in individuals living at high altitude, but the subjects’ long term residence in such altitude was not formally known, raising a possibility of incomplete acclimatization [15]. In addition, subjects had sleep studies with a split night protocol, which may have affected CPAP acclimation [15]. Nevertheless, the prevalence reported by Zapata et al. is lower than expected. The reason for that discrepancy is not clear from the data they presented. However, several polysomnographic variables that were not reported (such as sleep fragmentation, timing of http://dx.doi.org/10.1016/j.sleep.2014.11.001 1389-9457/© 2014 Elsevier B.V. All rights reserved.
arousals, and degree of periodic breathing during diagnostic and therapeutic portions of polysomnography) might have shed light on this discrepancy. Measuring these variables seems to be particularly important in precisely defining the phenotype of a condition that is as heterogeneous as TE-CSA [16]. Another reason for this lower than expected prevalence of TECSA is the variability in tendency towards periodic breathing that has been described in different people living at high altitude. In particular, compared with the Himalayans and Northern Americans living at high altitude, the Andeans display relative hypoventilation in response to hypoxia (reviewed in [17]). This relatively larger difference between the eupneic pCO2 and the apnea threshold may help stabilize breathing. To the extent that the genetic makeup of the population studied by Zapata et al. might be similar to that of the Andean highlanders, it may have protected them from periodic breathing and the development of TE-CSA. Another important finding of Zapata et al. confirming prior research is the higher prevalence of central apnea in men vs women. This lower stability of breathing in men has been observed in subjects living at high altitude [18] and in patients with heart failure [19], and likely results from the higher chemosensitivity to hypoxia of men than of women [20]. Similarly, higher prevalence of TE-CSA in males than in females has also been reported in prior studies on TE-CSA [21,22]. Methodological flaws notwithstanding, this study is an important contribution to the research on TE-CSA. Though the pathophysiology of this entity is thought to involve features typical of obstructive and central sleep apnea, minimal basic studies have been done in this patient population. This paucity of data has been due to relative rarity of TE-CSA and its dynamic character, with features of TE-CSA disappearing or appearing de novo with continued CPAP use [12]. Longitudinal evolution of TE-CSA at high altitude, where breathing might already be less stable, would be an interesting area of future research. Similarly, examining the acclimatization process in OSA patients on CPAP who transfer to high altitude areas may help define mechanisms involved in the disappearance of central apnea activity in OSA.
Conflict of interest The author does not have any conflict of interest. References [1] International classification of sleep disorders – third edition. American Academy of Sleep Medicine; 2014.
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Editorial/Sleep Medicine 16 (2015) 313–314
[2] 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(6):1929–41. [3] Berry RB, Gleeson K. Respiratory arousal from sleep: mechanisms and significance. Sleep 1997;20(8):654–75. [4] Tkacova R, Niroumand M, Lorenzi-Filho G, Bradley TD. Overnight shift from obstructive to central apneas in patients with heart failure: role of PCO2 and circulatory delay. Circulation 2001;103(2):238–43. [5] 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(5):455–61. [6] Latshang TD, Lo Cascio CM, Stowhas AC, Grimm M, Stadelmann K, Tesler N, et al. Are nocturnal breathing, sleep, and cognitive performance impaired at moderate altitude (1,630-2,590 m). Sleep 2013;36(12):1969–76. [7] Ainslie PN, Lucas SJ, Burgess KR. Breathing and sleep at high altitude. Respir Physiol Neurobiol 2013;188(3):233–56. [8] Powell FL, Milsom WK, Mitchell GS. Time domains of the hypoxic ventilatory response. Respir Physiol 1998;112(2):123–34. [9] Lahiri S, Data PG. Chemosensitivity and regulation of ventilation during sleep at high altitudes. Int J Sports Med 1992;13(Suppl. 1):S31–3. [10] Lahiri S, Mokashi A, Di Giulio C, Sherpa A, Huang WX, Data PG. Carotid body adaptation: lessons from chronic stimuli. In: Sutton JR, Coates G, Remmers JE, editors. Hypoxia: the adaptations. Philadelphia: B.C. Decker, Inc.; 1990. p. 127–39. [11] Zapata MA, Martinez W, Vargas L, Herrera K, Gonzalez-Garcia M. Prevalence of central sleep apnea during CPAP titration in patients with obstructive sleep apnea syndrome at an altitude of 2,640 meters. Sleep Med 2014. [12] 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(2):329–37. [13] Javaheri S, Smith J, Chung E. The prevalence and natural history of complex sleep apnea. J Clin Sleep Med 2009;5(3):205–11. [14] Morgenthaler TI, Kagramanov V, Hanak V, Decker PA. Complex sleep apnea syndrome: is it a unique clinical syndrome? Sleep 2006;29(9): 1203–9.
[15] Pagel JF, Kwiatkowski C, Parnes B. The effects of altitude associated central apnea on the diagnosis and treatment of obstructive sleep apnea: comparative data from three different altitude locations in the mountain west. J Clin Sleep Med 2011;7(6):610–5A. [16] Kuzniar TJ, Kasibowska-Kuzniar K, Ray DW, Freedom T. Clinical heterogeneity of patients with complex sleep apnea syndrome. Sleep Breath 2013; 17(4):1209–14. [17] Brutsaert TD. Population genetic aspects and phenotypic plasticity of ventilatory responses in high altitude natives. Respir Physiol Neurobiol 2007;158(2– 3):151–60. [18] Lombardi C, Meriggi P, Agostoni P, Faini A, Bilo G, Revera M, et al. High-altitude hypoxia and periodic breathing during sleep: gender-related differences. J Sleep Res 2013;22(3):322–30. [19] Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999;160(4):1101–6. [20] Caravita S, Faini A, Lombardi C, Valentini M, Gregorini F, Rossi J, et al. Gender and acetazolamide effects on chemoreflex and periodic breathing during sleep at altitude. Chest 2014;doi:10.1378/chest.14-0317. [Epub ahead of print]. [21] Pusalavidyasagar SS, Olson EJ, Gay PC, Morgenthaler TI. Treatment of complex sleep apnea syndrome: a retrospective comparative review. Sleep Med 2006;7(6):474–9. [22] 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):462–6.
Tomasz J. Kuz´niar Division of Pulmonary and Critical Care Medicine, NorthShore University HealthSystem, Evanston, IL, USA Tel.: +1 847 570 2714; fax: +1 847 733 5109. E-mail address: [email protected] Available online 11 November 2014
Contents lists available at ScienceDirect
Sleep Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p
Editorial
Treatment-emergent central sleep apnea at high altitude
Treatment-emergent central sleep apnea (TE-CSA, formerly complex sleep apnea) describes the appearance of central sleep apneas upon relief of obstruction, typically by positive airway pressure therapy (CPAP), in a patient with obstructive sleep apnea (OSA) [1]. TE-CSA has been described for a decade and it is thought to affect a significant minority of patients with OSA. Several pathophysiological chains of events may lead to the appearance of TE-CSA; mechanisms that have been postulated in its development include elevated chemoreceptor sensitivity [2], decreased arousal threshold [3], prolonged circulation time [4], and use of opioid medications [5]. Through these mechanisms, there is a high “loop gain” of the respiratory system; this term, borrowed from the technology dictionary, describes the system’s instability and its propensity to hypopnea–hyperpnea oscillations in response to stimuli. Living at high altitude increases loop gain as it exposes an individual to several mechanisms that may destabilize breathing. Chronic hypoxemia leads to hyperventilation and hypocapnia, which acutely leads to the development of periodic breathing in most people [6]. With time, a complex process of acclimatization occurs, with a drop of peripheral chemosensitivity, increased cerebral blood flow, and alteration of central chemosensitivity (reviewed in [7]). In long term residents of high altitude, the hypoxic ventilatory response is blunted [8,9] and there may even be anatomical changes in the structure of the carotid bodies [10]. Higher loop gain observed at high altitude may predispose people to TE-CSA. Following that lead, Zapata et al. examined the prevalence of TE-CSA in a group of 988 consecutive patients diagnosed with TE-CSA in Bogota, Columbia, which lies at the altitude of 2,640 m [11]. Among 988 patients with moderate or severe OSA, 115 (11.6%) were found to have TE-CSA in the therapeutic CPAP titration study. In a regression analysis comparing the TE-CSA patients with patients with “pure” OSA, the authors identified the following factors associated with the development of TE-CSA: presence of central sleep apnea on diagnostic study, self-reported history of heart failure, and male sex. According to several studies, TE-CSA affects 2–15% of patients with OSA [12–14]. There was one prior study reporting on the higher prevalence (10.6–38.7%) of TE-CSA in individuals living at high altitude, but the subjects’ long term residence in such altitude was not formally known, raising a possibility of incomplete acclimatization [15]. In addition, subjects had sleep studies with a split night protocol, which may have affected CPAP acclimation [15]. Nevertheless, the prevalence reported by Zapata et al. is lower than expected. The reason for that discrepancy is not clear from the data they presented. However, several polysomnographic variables that were not reported (such as sleep fragmentation, timing of http://dx.doi.org/10.1016/j.sleep.2014.11.001 1389-9457/© 2014 Elsevier B.V. All rights reserved.
arousals, and degree of periodic breathing during diagnostic and therapeutic portions of polysomnography) might have shed light on this discrepancy. Measuring these variables seems to be particularly important in precisely defining the phenotype of a condition that is as heterogeneous as TE-CSA [16]. Another reason for this lower than expected prevalence of TECSA is the variability in tendency towards periodic breathing that has been described in different people living at high altitude. In particular, compared with the Himalayans and Northern Americans living at high altitude, the Andeans display relative hypoventilation in response to hypoxia (reviewed in [17]). This relatively larger difference between the eupneic pCO2 and the apnea threshold may help stabilize breathing. To the extent that the genetic makeup of the population studied by Zapata et al. might be similar to that of the Andean highlanders, it may have protected them from periodic breathing and the development of TE-CSA. Another important finding of Zapata et al. confirming prior research is the higher prevalence of central apnea in men vs women. This lower stability of breathing in men has been observed in subjects living at high altitude [18] and in patients with heart failure [19], and likely results from the higher chemosensitivity to hypoxia of men than of women [20]. Similarly, higher prevalence of TE-CSA in males than in females has also been reported in prior studies on TE-CSA [21,22]. Methodological flaws notwithstanding, this study is an important contribution to the research on TE-CSA. Though the pathophysiology of this entity is thought to involve features typical of obstructive and central sleep apnea, minimal basic studies have been done in this patient population. This paucity of data has been due to relative rarity of TE-CSA and its dynamic character, with features of TE-CSA disappearing or appearing de novo with continued CPAP use [12]. Longitudinal evolution of TE-CSA at high altitude, where breathing might already be less stable, would be an interesting area of future research. Similarly, examining the acclimatization process in OSA patients on CPAP who transfer to high altitude areas may help define mechanisms involved in the disappearance of central apnea activity in OSA.
Conflict of interest The author does not have any conflict of interest. References [1] International classification of sleep disorders – third edition. American Academy of Sleep Medicine; 2014.
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Editorial/Sleep Medicine 16 (2015) 313–314
[2] 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(6):1929–41. [3] Berry RB, Gleeson K. Respiratory arousal from sleep: mechanisms and significance. Sleep 1997;20(8):654–75. [4] Tkacova R, Niroumand M, Lorenzi-Filho G, Bradley TD. Overnight shift from obstructive to central apneas in patients with heart failure: role of PCO2 and circulatory delay. Circulation 2001;103(2):238–43. [5] 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(5):455–61. [6] Latshang TD, Lo Cascio CM, Stowhas AC, Grimm M, Stadelmann K, Tesler N, et al. Are nocturnal breathing, sleep, and cognitive performance impaired at moderate altitude (1,630-2,590 m). Sleep 2013;36(12):1969–76. [7] Ainslie PN, Lucas SJ, Burgess KR. Breathing and sleep at high altitude. Respir Physiol Neurobiol 2013;188(3):233–56. [8] Powell FL, Milsom WK, Mitchell GS. Time domains of the hypoxic ventilatory response. Respir Physiol 1998;112(2):123–34. [9] Lahiri S, Data PG. Chemosensitivity and regulation of ventilation during sleep at high altitudes. Int J Sports Med 1992;13(Suppl. 1):S31–3. [10] Lahiri S, Mokashi A, Di Giulio C, Sherpa A, Huang WX, Data PG. Carotid body adaptation: lessons from chronic stimuli. In: Sutton JR, Coates G, Remmers JE, editors. Hypoxia: the adaptations. Philadelphia: B.C. Decker, Inc.; 1990. p. 127–39. [11] Zapata MA, Martinez W, Vargas L, Herrera K, Gonzalez-Garcia M. Prevalence of central sleep apnea during CPAP titration in patients with obstructive sleep apnea syndrome at an altitude of 2,640 meters. Sleep Med 2014. [12] 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(2):329–37. [13] Javaheri S, Smith J, Chung E. The prevalence and natural history of complex sleep apnea. J Clin Sleep Med 2009;5(3):205–11. [14] Morgenthaler TI, Kagramanov V, Hanak V, Decker PA. Complex sleep apnea syndrome: is it a unique clinical syndrome? Sleep 2006;29(9): 1203–9.
[15] Pagel JF, Kwiatkowski C, Parnes B. The effects of altitude associated central apnea on the diagnosis and treatment of obstructive sleep apnea: comparative data from three different altitude locations in the mountain west. J Clin Sleep Med 2011;7(6):610–5A. [16] Kuzniar TJ, Kasibowska-Kuzniar K, Ray DW, Freedom T. Clinical heterogeneity of patients with complex sleep apnea syndrome. Sleep Breath 2013; 17(4):1209–14. [17] Brutsaert TD. Population genetic aspects and phenotypic plasticity of ventilatory responses in high altitude natives. Respir Physiol Neurobiol 2007;158(2– 3):151–60. [18] Lombardi C, Meriggi P, Agostoni P, Faini A, Bilo G, Revera M, et al. High-altitude hypoxia and periodic breathing during sleep: gender-related differences. J Sleep Res 2013;22(3):322–30. [19] Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999;160(4):1101–6. [20] Caravita S, Faini A, Lombardi C, Valentini M, Gregorini F, Rossi J, et al. Gender and acetazolamide effects on chemoreflex and periodic breathing during sleep at altitude. Chest 2014;doi:10.1378/chest.14-0317. [Epub ahead of print]. [21] Pusalavidyasagar SS, Olson EJ, Gay PC, Morgenthaler TI. Treatment of complex sleep apnea syndrome: a retrospective comparative review. Sleep Med 2006;7(6):474–9. [22] 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):462–6.
Tomasz J. Kuz´niar Division of Pulmonary and Critical Care Medicine, NorthShore University HealthSystem, Evanston, IL, USA Tel.: +1 847 570 2714; fax: +1 847 733 5109. E-mail address: [email protected] Available online 11 November 2014
