Sleep Medicine Reviews 22 (2015) 1e2

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GUEST EDITORIAL

The role of high loop gain induced by intermittent hypoxia in the pathophysiology of obstructive sleep apnea

In this issue of Sleep Medicine Reviews, Deacon and Catcheside [1] review in a detailed and comprehensive fashion the role of loop gain in the initiation and perpetuation of cyclic breathing events in individuals with sleep apnea. The authors highlight initially the variables that alter the carbon dioxide reserve; which is the difference in carbon dioxide levels measured during eupneic breathing and the carbon dioxide value that demarcates the apneic threshold (i.e., the point at which breathing ceases during sleep). If the reserve is small, minor decreases in carbon dioxide often result in apnea. As outlined by Deacon and Catcheside [1], factors that alter the reserve include shifts in the eupneic level of breathing along the metabolic hyperbola, changes in the drive to breathe below the chemoreflex threshold (i.e., the drive to breathe which ensures ventilation is maintained during wakefulness when carbon dioxide is below the chemoreflex threshold), shifts in the carbon dioxide level that demarcates the apneic threshold and changes in controller gain (i.e., chemoreflex sensitivity). The review of changes in controller gain was particularly insightful because modification in chemoreflex sensitivity both above and below the point of eupnea was considered in the cyclic perpetuation of apneic events. Based on published work, the review subsequently establishes that increases in controller gain promote apnea by initiating hyperventilation that leads to reductions in carbon dioxide that extend below the apneic threshold. Deacon and Catcheside [1] use this premise as the basis to explore the origins of the increase in controller gain that is evident in individuals with sleep apnea. The review outlines evidence that an increase in controller gain is a consequence of sleep apnea. The authors explore in detail the possibility that increases in controller gain are a consequence of naturally induced exposure to intermittent hypoxia. Many studies from my laboratory [2e5] have established that exposure to experimentally induced intermittent hypoxia enhances controller gain. On the other hand, fewer studies have addressed if the elimination of naturally induced intermittent hypoxia leads to reductions in controller gain. Nonetheless, two studies that measured controller gain during sleep established that treatment with continuous positive airway pressure decreases the sensitivity of the ventilatory response to hypoxia (i.e., decreases controller gain) [6,7]. However, in one study a control group was not employed [6] and in another, a control group was comprised of both healthy individuals and individuals with sleep apnea that were non-compliant with continuous positive airway pressure [7]. As a consequence of this dichotomous control group, comparisons of absolute measures of chemoreflex sensitivity were not possible. Thus, it remains unclear if the reported decreases following treatment reflect a return of controller http://dx.doi.org/10.1016/j.smrv.2015.02.001 1087-0792/© 2015 Published by Elsevier Ltd.

gain to levels seen in healthy individuals or if the reported reduction in controller gain remains elevated above levels in healthy individuals. If this latter scenario is the case it could support the argument that elevations in controller gain are linked to both an inherent trait and natural exposure to intermittent hypoxia, or another perturbation, which is a consequence of sleep apnea. Deacon and Catcheside [1] address the possibility that increases in controller gain may be an inherent trait. However, there is little evidence available in the literature to support this possibility. Despite this paucity of evidence, recent findings from my laboratory indicate that at the very least progressive enhancement of controller gain over a given night is not entirely dependent on exposure to intermittent hypoxia [8]. We showed that despite the elimination of intermittent hypoxia with nasal continuous positive airway pressure, increases in controller gain, coupled to a decrease in the carbon dioxide reserve, during non-rapid eye movement sleep were evident in the early morning compared to the evening and afternoon [8]. In other words, an increase in controller gain was evident despite the elimination of intermittent hypoxia and other associated consequences (e.g., arousal) of sleep apnea. If enhanced controller gain is both a cause and consequence of sleep apnea, further studies are required to determine the manner in which inherent factors interact and are influenced by the consequences of sleep apnea. Future studies that employ patients with sleep apnea treated with “sham” continuous positive airway pressure, combined with the regulation of variables that could potentially influence measures of controller gain (i.e., time of night), will be a factor in determining the contribution of inherited versus acquired enhanced controller gain. Subsequent to addressing the origins of increased controller gain, Deacon and Catcheside examine other forms of plasticity that might be initiated after exposure to intermittent hypoxia. This discussion is presented in the context that instead of promoting breathing instability, via increases in controller gain, exposure to intermittent hypoxia could mitigate breathing instability by initiating long-term facilitation of chest wall or upper airway muscle activity (i.e., respiratory plasticity) [9,10]. Indeed findings from my laboratory have revealed that exposure to intermittent hypoxia initiates long-term facilitation of ventilation in healthy humans [4,11], humans with sleep apnea [2,4,12] and humans with spinal cord injury [13]. Likewise, exposure to intermittent hypoxia initiates long-term facilitation of upper airway muscle activity [11,14]. Sustained increases in upper airway muscle activity following exposure to intermittent hypoxia could potentially improve patency of the upper airway and mitigate breathing events. Prior

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Guest editorial / Sleep Medicine Reviews 22 (2015) 1e2

to examining if this is the case, Deacon and Catcheside [1] provide an updated review of the cellular mechanisms responsible for the initiation of long-term facilitation. Thereafter, the authors review the interaction between enhanced controller gain and long-term facilitation of chest wall and upper airway muscle activity and the outcome of this interaction. Interestingly, the authors highlight evidence obtained from measures of basal breathing that is typically not cited but is indicative of the presence of long-term facilitation in humans exposed to intermittent hypoxia. Subsequently, the authors highlight that long-term facilitation does not dramatically impact on breathing stability during sleep and that enhancement of controller gain, linked to increased breathing instability, is the principle outcome of exposure to intermittent hypoxia [15]. Two primary reasons could explain the diminished or absent role of long-term facilitation in mitigating breathing stability. First, the magnitude of long-term facilitation may be diminished during sleep compared to wakefulness [12]. Second, long-term facilitation does not manifest itself in the presence of hypocapnia [11]. Given the repeated periods of hypocapnia that exist subsequent to arousal from sleep, it is reasonable to suggest that the conditions typically present throughout the night in individuals with sleep apnea is not conducive to the manifestation of long-term facilitation of chest wall or upper airway muscles. Alternatively, periods of stability during slow wave sleep are well-documented in individuals with sleep apnea, and as Deacon and Catcheside [1] point out these periods could be linked to elevated levels of carbon dioxide that allow for the ongoing expression of upper airway muscle activity. Nonetheless, given the degree of breathing instability that is typically evident throughout the night in individuals with sleep apnea it is reasonable to surmise that long-term facilitation does not have a significant role in stabilizing breathing during sleep in individuals naturally exposed to intermittent hypoxia. However, given the potential beneficial impact that long-term facilitation has on breathing stability [16], it is fitting to pursue those conditions that might promote long-term facilitation and diminish controller gain, even if these conditions do not occur naturally on a night to night basis. Presently, my laboratory is investigating if exposure to experimentally induced intermittent hypoxia and sustained hypercapnia leads to reductions in the therapeutic continuous positive airway pressure required to treat sleep apnea. The premise is that administration of continuous positive airway pressure eliminates or reduces the potential destabilizing effect that controller gain has on ventilation. In addition, the concomitant experimentally induced intermittent hypoxia, along with sustained hypercapnia, initiates two beneficial aftereffects. Long-term facilitation of ventilation, which increases the carbon dioxide reserve because of the increase in gain associated with moving leftward along the metabolic hyperbola, and long-term facilitation of upper airway activity which promotes increased upper airway patency. Besides other documented beneficial effects [16], daily exposure to intermittent hypoxia could prove to enhance compliance with continuous positive airway pressure by reducing the pressure required to treat apneic events. Deacon and Catcheside [1] conclude their review by addressing the need for future research to explore other adjunctive therapies that could serve to promote breathing stability by reducing controller gain, increasing the carbon dioxide reserve, or promoting the initiation of other forms of respiratory plasticity. Exploring innovative treatments, which include antioxidant or oxygen therapy, or pharmacological therapies, such as acetazolamide, to

replace or enhance the effectiveness of continuous positive airway pressure is required in future studies given the limited compliance that often accompanies treatment with continuous positive airway pressure. Conflict of interest The author does not have any conflicts of interest to disclose. References [1] Deacon NL, Catcheside PG. The role of high loop gain induced by intermittent hypoxia in the pathophysiology of obstructive sleep apnoea. Sleep Med Rev 2015;22:3e14. http://dx.doi.org/10.1016/j.smrv.2014.10.003. [2] Gerst III DG, Yokhana SS, Carney LM, et al. The hypoxic ventilatory response and ventilatory long-term facilitation are altered by time of day and repeated daily exposure to intermittent hypoxia. J Appl Physiol 2011;110:15e28. [3] Khodadadeh B, Badr MS, Mateika JH. The ventilatory response to carbon dioxide and sustained hypoxia is enhanced after episodic hypoxia in OSA patients. Respir Physiol Neurobiol 2006;150:122e34. [4] Lee DS, Badr MS, Mateika JH. Progressive augmentation and ventilatory longterm facilitation are enhanced in sleep apnoea patients and are mitigated by antioxidant administration. J Physiol 2009;15:5451e67. [5] Mateika JH, Mendello C, Obeid D, Badr MS. Peripheral chemoreflex responsiveness is increased at elevated levels of carbon dioxide after episodic hypoxia in awake humans. J Appl Physiol 2004;96:1197e205. [6] Loewen A, Ostrowski M, Laprairie J, et al. Determinants of ventilatory instability in obstructive sleep apnea: inherent or acquired? Sleep 2009;32: 1355e65. [7] Salloum A, Rowley JA, Mateika JH, Chowdhuri S, Omran Q, Badr MS. Increased propensity for central apnea in patients with obstructive sleep apnea: effect of nasal continuous positive airway pressure. Am J Respir Crit Care Med 2010;181:189e93. [8] El-Chami M, Shaheen D, Ivers B, et al. Time of day affects chemoreflex sensitivity and the carbon dioxide reserve during NREM sleep in participants with sleep apnea. J Appl Physiol 2014;117:1149e56. [9] Mateika JH, Narwani G. Intermittent hypoxia and respiratory plasticity in humans and other animals: does exposure to intermittent hypoxia promote or mitigate sleep apnoea? Exp Physiol 2009;94:279e96. [10] Mateika JH, Syed Z. Intermittent hypoxia, respiratory plasticity and sleep apnea in humans: present knowledge and future investigations. Respir Physiol Neurobiol 2013;188:289e300. [11] Harris DP, Balasubramaniam A, Badr MS, Mateika JH. Long-term facilitation of ventilation and genioglossus muscle activity is evident in the presence of elevated levels of carbon dioxide in awake humans. Am J Physiol Regul Integr Comp Physiol 2006;291:R1111e9. [12] Syed Z, Lin HS, Mateika JH. The impact of arousal state, sex, and sleep apnea on the magnitude of progressive augmentation and ventilatory long-term facilitation. J Appl Physiol 2013;114:52e65. [13] Tester NJ, Fuller DD, Fromm JS, Spiess MR, Behrman AL, Mateika JH. Long-term facilitation of ventilation in humans with chronic spinal cord injury. Am J Respir Crit Care Med 2014;189:57e65. [14] Chowdhuri S, Pierchala L, Aboubakr SE, Shkoukani M, Badr MS. Long-term facilitation of genioglossus activity is present in normal humans during NREM sleep. Respir Physiol Neurobiol 2008;160:65e75. [15] Yokhana SS, Gerst III DG, Lee DS, Badr MS, Qureshi T, Mateika JH. Impact of repeated daily exposure to intermittent hypoxia and mild sustained hypercapnia on apnea severity. J Appl Physiol 2012;112:367e77. [16] Mateika JH, El-Chami M, Shaheen D, Ivers B. Intermittent hypoxia: a low risk research tool with therapeutic value in humans. J Appl Physiol 2014. http:// dx.doi.org/10.1152/japplphysiol.00564.2014 [Epub].

Jason H. Mateika, PhD* John D. Dingell VA Medical Center, 4646 John R (11R), Room 4332, Detroit, MI 48201, USA *

Tel.: þ1 313 576 4481; fax: þ1 313 576 1112. E-mail address: [email protected]. 30 January 2015 Available online 10 February 2015

The role of high loop gain induced by intermittent hypoxia in the pathophysiology of obstructive sleep apnea.

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