In reply: Sleep apnea ABCs

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In reply: Sleep apnea ABCs

In Reply: We thank Dr. Abouda for underscoring the role of arousals in the pathophysiology of obstructive sleep apnea (OSA). Although the focus of the referenced article was to provide a general overview of the epidemiology, diagnostic testing, and cardiovascular ramifications of untreated OSA and not a detailed summary of the underlying pathophysiology, we welcome the comments from Dr. Abouda to highlight the importance of cortical or microarousals in OSA.

Whether cortical arousal during sleep is bad or good is controversial. During the development of the American Academy of Sleep Medicine respiratory event guidelines, the assignment of detriment or benefit to the arousal when considering defining and scoring of a hypopnea event was a topic of much discussion.1,2 Supporters of including arousal in the hypopnea definition cite data that sleep fragmentation without attendant hypoxia is associated with symptoms such as excessive daytime somnolence, which is recognized to be effectively addressed with OSA treatment.3,4 Moreover, experimental data indicate that arousals lead to activation of the sympathetic nervous system.5 On the other hand, those who question the inclusion of cortical arousal in the hypopnea definition cite large-scale epidemiologic studies that have failed to find a significantly increased cardiovascular risk in relation to increasing arousal index, as well as the enhanced potential to introduce measurement variability.1

The effects of cortical arousals as a purported source of sympathetic activation may operate in concert with hypoxic influences, the latter resulting in sustained increases in blood pressure in both animal models and human studies.6,7 Gottlieb et al8 examined the effect of supplemental oxygen vs continuous positive airway pressure (CPAP) on 24-hour mean arterial pressure in a multicenter randomized controlled trial. Although CPAP reduced blood pressure, as expected, the somewhat unanticipated finding that supplemental oxygen did not suggests that other factors such as hypercapnia and cortical arousals with attendant sympathetic activation may represent potential culprits. Along these lines, in patients with OSA and increased loop gain, benefit in response to sedative hypnotics has been shown to reduce ventilatory instability through an increase in arousal threshold.9 A genetic predisposition may influence the intensity of cortical arousals and accompanying cardiovascular influences that appear to be consistent within individuals but that are heterogeneous within populations.10

Few studies have identified increased cortical arousals as a cardiovascular risk factor. In the Cleveland Family Study, an elevated arousal index was associated with hypertension, but respiratory event-specific arousals was not specifically examined.11 Not only have large-scale epidemiologic studies failed to identify an association between arousal index and cardiovascular outcomes, existing data appear to support the contrary. For example, the extent of incident white matter disease identified on brain magnetic resonance imaging was inversely related to the arousal index in a subset of participants of the Sleep Heart Health Study, a large population-based study focused on sleep and cardiovascular outcomes.12 Furthermore, elevated arousal indices in women were associated with reduced incidence of stroke in the Sleep Heart Health Study.13 These data suggest that arousals may represent beneficial, protective biomarkers reflecting truncation of respiratory events translating into reduced duration of hypoxic exposure and decreased work of breathing.

Needed is further investigation dedicated to understanding the impact of cortical arousals on health outcomes in population-based studies and elucidating the mechanistic role of cortical arousals in the autonomic nervous system physiology in various subtypes of sleep-disordered breathing (eg, obstructive vs central sleep apnea) as well as periodic limb movements.

As the upper Airway is central to the pathophysiology of OSA leading to compromise in Breathing and Circulatory or Cardiovascular ramifications, we think it logical that the “A” in ABCs should stand for “airway.” Hopefully, future research will allow us to better understand the associated benefit vs detriment of cortical arousals as they pertain to subgroup susceptibilities and enhance our ability to tailor a personalized medicine approach to the treatment of sleep disorders.

References
  1. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012; 8:597–619.
  2. Ruehland WR, Rochford PD, O’Donoghue FJ, Pierce RJ, Singh P, Thornton AT. The new AASM criteria for scoring hypopneas: impact on the apnea hypopnea index. Sleep 2009; 32:150-157.
  3. Guilleminault C, Stoohs R, Clerk A, Cetel M, Maistros P. A cause of excessive daytime sleepiness. The upper airway resistance syndrome. Chest 1993; 104:781–787.
  4. Bonnet MH, Doghramji K, Roehrs T, et al. The scoring of arousal in sleep: reliability, validity, and alternatives. J Clin Sleep Med 2007; 3:133–145.
  5. Loredo JS, Ziegler MG, Ancoli-Israel S, Clausen JL, Dimsdale JE. Relationship of arousals from sleep to sympathetic nervous system activity and BP in obstructive sleep apnea. Chest J 1999; 116:655–659.
  6. Fletcher EC, Lesske J, Culman J, Miller CC, Unger T. Sympathetic denervation blocks blood pressure elevation in episodic hypoxia. Hypertension 1992; 20:612–619.
  7. Tamisier R, Pépin JL, Rémy J, et al. 14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans. Eur Respir J 2011; 37:119–128.
  8. Gottlieb DJ, Punjabi NM, Mehra R, et al. CPAP versus oxygen in obstructive sleep apnea. N Engl J Med 2014; 370:2276–2285.
  9. Eckert DJ, Owens RL, Kehlmann GB, 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 Lond Engl 1979. 2011; 120:505–514.
  10. Azarbarzin A, Ostrowski M, Hanly P, Younes M. Relationship between arousal intensity and heart rate response to arousal. Sleep 2014; 37:645–653.
  11. Sulit L, Storfer-Isser A, Kirchner HL, Redline S. Differences in polysomnography predictors for hypertension and impaired glucose tolerance. Sleep 2006; 29:777–783.
  12. Ding J, Nieto FJ, Beauchamp NJ, et al. Sleep-disordered breathing and white matter disease in the brainstem in older adults. Sleep 2004; 27:474–479.
  13. Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea-hypopnea and incident stroke: the Sleep Heart Health Study. Am J Respir Crit Care Med 2010; 182:269–277.
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Reena Mehra, MD, MS, FCCP, FAASM
Director, Sleep Disorders Research, Cleveland Clinic

Anna M. May, MD
Division of Pulmonary, Critical Care, and Sleep Medicine, University Hospitals Case Medical Center, Cleveland, OH

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Anna M. May, MD
Division of Pulmonary, Critical Care, and Sleep Medicine, University Hospitals Case Medical Center, Cleveland, OH

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Reena Mehra, MD, MS, FCCP, FAASM
Director, Sleep Disorders Research, Cleveland Clinic

Anna M. May, MD
Division of Pulmonary, Critical Care, and Sleep Medicine, University Hospitals Case Medical Center, Cleveland, OH

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In Reply: We thank Dr. Abouda for underscoring the role of arousals in the pathophysiology of obstructive sleep apnea (OSA). Although the focus of the referenced article was to provide a general overview of the epidemiology, diagnostic testing, and cardiovascular ramifications of untreated OSA and not a detailed summary of the underlying pathophysiology, we welcome the comments from Dr. Abouda to highlight the importance of cortical or microarousals in OSA.

Whether cortical arousal during sleep is bad or good is controversial. During the development of the American Academy of Sleep Medicine respiratory event guidelines, the assignment of detriment or benefit to the arousal when considering defining and scoring of a hypopnea event was a topic of much discussion.1,2 Supporters of including arousal in the hypopnea definition cite data that sleep fragmentation without attendant hypoxia is associated with symptoms such as excessive daytime somnolence, which is recognized to be effectively addressed with OSA treatment.3,4 Moreover, experimental data indicate that arousals lead to activation of the sympathetic nervous system.5 On the other hand, those who question the inclusion of cortical arousal in the hypopnea definition cite large-scale epidemiologic studies that have failed to find a significantly increased cardiovascular risk in relation to increasing arousal index, as well as the enhanced potential to introduce measurement variability.1

The effects of cortical arousals as a purported source of sympathetic activation may operate in concert with hypoxic influences, the latter resulting in sustained increases in blood pressure in both animal models and human studies.6,7 Gottlieb et al8 examined the effect of supplemental oxygen vs continuous positive airway pressure (CPAP) on 24-hour mean arterial pressure in a multicenter randomized controlled trial. Although CPAP reduced blood pressure, as expected, the somewhat unanticipated finding that supplemental oxygen did not suggests that other factors such as hypercapnia and cortical arousals with attendant sympathetic activation may represent potential culprits. Along these lines, in patients with OSA and increased loop gain, benefit in response to sedative hypnotics has been shown to reduce ventilatory instability through an increase in arousal threshold.9 A genetic predisposition may influence the intensity of cortical arousals and accompanying cardiovascular influences that appear to be consistent within individuals but that are heterogeneous within populations.10

Few studies have identified increased cortical arousals as a cardiovascular risk factor. In the Cleveland Family Study, an elevated arousal index was associated with hypertension, but respiratory event-specific arousals was not specifically examined.11 Not only have large-scale epidemiologic studies failed to identify an association between arousal index and cardiovascular outcomes, existing data appear to support the contrary. For example, the extent of incident white matter disease identified on brain magnetic resonance imaging was inversely related to the arousal index in a subset of participants of the Sleep Heart Health Study, a large population-based study focused on sleep and cardiovascular outcomes.12 Furthermore, elevated arousal indices in women were associated with reduced incidence of stroke in the Sleep Heart Health Study.13 These data suggest that arousals may represent beneficial, protective biomarkers reflecting truncation of respiratory events translating into reduced duration of hypoxic exposure and decreased work of breathing.

Needed is further investigation dedicated to understanding the impact of cortical arousals on health outcomes in population-based studies and elucidating the mechanistic role of cortical arousals in the autonomic nervous system physiology in various subtypes of sleep-disordered breathing (eg, obstructive vs central sleep apnea) as well as periodic limb movements.

As the upper Airway is central to the pathophysiology of OSA leading to compromise in Breathing and Circulatory or Cardiovascular ramifications, we think it logical that the “A” in ABCs should stand for “airway.” Hopefully, future research will allow us to better understand the associated benefit vs detriment of cortical arousals as they pertain to subgroup susceptibilities and enhance our ability to tailor a personalized medicine approach to the treatment of sleep disorders.

In Reply: We thank Dr. Abouda for underscoring the role of arousals in the pathophysiology of obstructive sleep apnea (OSA). Although the focus of the referenced article was to provide a general overview of the epidemiology, diagnostic testing, and cardiovascular ramifications of untreated OSA and not a detailed summary of the underlying pathophysiology, we welcome the comments from Dr. Abouda to highlight the importance of cortical or microarousals in OSA.

Whether cortical arousal during sleep is bad or good is controversial. During the development of the American Academy of Sleep Medicine respiratory event guidelines, the assignment of detriment or benefit to the arousal when considering defining and scoring of a hypopnea event was a topic of much discussion.1,2 Supporters of including arousal in the hypopnea definition cite data that sleep fragmentation without attendant hypoxia is associated with symptoms such as excessive daytime somnolence, which is recognized to be effectively addressed with OSA treatment.3,4 Moreover, experimental data indicate that arousals lead to activation of the sympathetic nervous system.5 On the other hand, those who question the inclusion of cortical arousal in the hypopnea definition cite large-scale epidemiologic studies that have failed to find a significantly increased cardiovascular risk in relation to increasing arousal index, as well as the enhanced potential to introduce measurement variability.1

The effects of cortical arousals as a purported source of sympathetic activation may operate in concert with hypoxic influences, the latter resulting in sustained increases in blood pressure in both animal models and human studies.6,7 Gottlieb et al8 examined the effect of supplemental oxygen vs continuous positive airway pressure (CPAP) on 24-hour mean arterial pressure in a multicenter randomized controlled trial. Although CPAP reduced blood pressure, as expected, the somewhat unanticipated finding that supplemental oxygen did not suggests that other factors such as hypercapnia and cortical arousals with attendant sympathetic activation may represent potential culprits. Along these lines, in patients with OSA and increased loop gain, benefit in response to sedative hypnotics has been shown to reduce ventilatory instability through an increase in arousal threshold.9 A genetic predisposition may influence the intensity of cortical arousals and accompanying cardiovascular influences that appear to be consistent within individuals but that are heterogeneous within populations.10

Few studies have identified increased cortical arousals as a cardiovascular risk factor. In the Cleveland Family Study, an elevated arousal index was associated with hypertension, but respiratory event-specific arousals was not specifically examined.11 Not only have large-scale epidemiologic studies failed to identify an association between arousal index and cardiovascular outcomes, existing data appear to support the contrary. For example, the extent of incident white matter disease identified on brain magnetic resonance imaging was inversely related to the arousal index in a subset of participants of the Sleep Heart Health Study, a large population-based study focused on sleep and cardiovascular outcomes.12 Furthermore, elevated arousal indices in women were associated with reduced incidence of stroke in the Sleep Heart Health Study.13 These data suggest that arousals may represent beneficial, protective biomarkers reflecting truncation of respiratory events translating into reduced duration of hypoxic exposure and decreased work of breathing.

Needed is further investigation dedicated to understanding the impact of cortical arousals on health outcomes in population-based studies and elucidating the mechanistic role of cortical arousals in the autonomic nervous system physiology in various subtypes of sleep-disordered breathing (eg, obstructive vs central sleep apnea) as well as periodic limb movements.

As the upper Airway is central to the pathophysiology of OSA leading to compromise in Breathing and Circulatory or Cardiovascular ramifications, we think it logical that the “A” in ABCs should stand for “airway.” Hopefully, future research will allow us to better understand the associated benefit vs detriment of cortical arousals as they pertain to subgroup susceptibilities and enhance our ability to tailor a personalized medicine approach to the treatment of sleep disorders.

References
  1. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012; 8:597–619.
  2. Ruehland WR, Rochford PD, O’Donoghue FJ, Pierce RJ, Singh P, Thornton AT. The new AASM criteria for scoring hypopneas: impact on the apnea hypopnea index. Sleep 2009; 32:150-157.
  3. Guilleminault C, Stoohs R, Clerk A, Cetel M, Maistros P. A cause of excessive daytime sleepiness. The upper airway resistance syndrome. Chest 1993; 104:781–787.
  4. Bonnet MH, Doghramji K, Roehrs T, et al. The scoring of arousal in sleep: reliability, validity, and alternatives. J Clin Sleep Med 2007; 3:133–145.
  5. Loredo JS, Ziegler MG, Ancoli-Israel S, Clausen JL, Dimsdale JE. Relationship of arousals from sleep to sympathetic nervous system activity and BP in obstructive sleep apnea. Chest J 1999; 116:655–659.
  6. Fletcher EC, Lesske J, Culman J, Miller CC, Unger T. Sympathetic denervation blocks blood pressure elevation in episodic hypoxia. Hypertension 1992; 20:612–619.
  7. Tamisier R, Pépin JL, Rémy J, et al. 14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans. Eur Respir J 2011; 37:119–128.
  8. Gottlieb DJ, Punjabi NM, Mehra R, et al. CPAP versus oxygen in obstructive sleep apnea. N Engl J Med 2014; 370:2276–2285.
  9. Eckert DJ, Owens RL, Kehlmann GB, 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 Lond Engl 1979. 2011; 120:505–514.
  10. Azarbarzin A, Ostrowski M, Hanly P, Younes M. Relationship between arousal intensity and heart rate response to arousal. Sleep 2014; 37:645–653.
  11. Sulit L, Storfer-Isser A, Kirchner HL, Redline S. Differences in polysomnography predictors for hypertension and impaired glucose tolerance. Sleep 2006; 29:777–783.
  12. Ding J, Nieto FJ, Beauchamp NJ, et al. Sleep-disordered breathing and white matter disease in the brainstem in older adults. Sleep 2004; 27:474–479.
  13. Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea-hypopnea and incident stroke: the Sleep Heart Health Study. Am J Respir Crit Care Med 2010; 182:269–277.
References
  1. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012; 8:597–619.
  2. Ruehland WR, Rochford PD, O’Donoghue FJ, Pierce RJ, Singh P, Thornton AT. The new AASM criteria for scoring hypopneas: impact on the apnea hypopnea index. Sleep 2009; 32:150-157.
  3. Guilleminault C, Stoohs R, Clerk A, Cetel M, Maistros P. A cause of excessive daytime sleepiness. The upper airway resistance syndrome. Chest 1993; 104:781–787.
  4. Bonnet MH, Doghramji K, Roehrs T, et al. The scoring of arousal in sleep: reliability, validity, and alternatives. J Clin Sleep Med 2007; 3:133–145.
  5. Loredo JS, Ziegler MG, Ancoli-Israel S, Clausen JL, Dimsdale JE. Relationship of arousals from sleep to sympathetic nervous system activity and BP in obstructive sleep apnea. Chest J 1999; 116:655–659.
  6. Fletcher EC, Lesske J, Culman J, Miller CC, Unger T. Sympathetic denervation blocks blood pressure elevation in episodic hypoxia. Hypertension 1992; 20:612–619.
  7. Tamisier R, Pépin JL, Rémy J, et al. 14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans. Eur Respir J 2011; 37:119–128.
  8. Gottlieb DJ, Punjabi NM, Mehra R, et al. CPAP versus oxygen in obstructive sleep apnea. N Engl J Med 2014; 370:2276–2285.
  9. Eckert DJ, Owens RL, Kehlmann GB, 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 Lond Engl 1979. 2011; 120:505–514.
  10. Azarbarzin A, Ostrowski M, Hanly P, Younes M. Relationship between arousal intensity and heart rate response to arousal. Sleep 2014; 37:645–653.
  11. Sulit L, Storfer-Isser A, Kirchner HL, Redline S. Differences in polysomnography predictors for hypertension and impaired glucose tolerance. Sleep 2006; 29:777–783.
  12. Ding J, Nieto FJ, Beauchamp NJ, et al. Sleep-disordered breathing and white matter disease in the brainstem in older adults. Sleep 2004; 27:474–479.
  13. Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea-hypopnea and incident stroke: the Sleep Heart Health Study. Am J Respir Crit Care Med 2010; 182:269–277.
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Cleveland Clinic Journal of Medicine - 82(9)
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Cleveland Clinic Journal of Medicine - 82(9)
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555-556, 562
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555-556, 562
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In reply: Sleep apnea ABCs
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