Clinical Neurophysiology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Editorial
Obstructive sleep apnea; is it the anatomy or physiology? See Article, pages xxx–xxx
The pharyngeal collapsibility that is required for normal swallowing and speech imposes a potential risk to respiration during sleep. During normal sleep despite the loss of muscle tone the upper airway remains open and would require a negative pressure ( 5 cm H2O) to collapse. Therefore, as long as the extramural pressure, applied by the soft tissue surrounding the pharyngeal area, is minimal the upper airway would remain patent. However, in patients with obstructive sleep apnea (OSA), because of increased soft tissue and/or narrowing of the pharyngeal opening, the extraluminal pressure would overcome the elasticity and collapse the airway (White, 2005). Obstructive sleep apnea is a common cause of sleep-disordered breathing in adults and children characterized by recurrent episodes of collapse of the upper airway. Its prevalence is estimated at 3–7% in adult population (Punjabi, 2008). The full spectrum of the OSA syndrome goes far beyond its hallmark of excessive daytime sleepiness (EDS). The EDS is presumably related to disruption of normal sleep architecture caused by frequent microarousals at the end of apneic episodes accompanied by hypoxia, hypercapnea, recurrent intrathoracic pressure swings, and sleep disruption. Among the physiological changes recorded during apnea, hypoxia and autonomic dysfunction may be the key risk factors. Overactivation of the sympathetic system during apnea may result in extreme heart rate variability (HRV) and cardiac arrhythmia (Gozal et al., 2013; Palma et al., 2013). The constellation of such physiological changes constitutes the risks for cardio-cerebro-vascular morbidity, and neurocognitive and behavioral, immune, and metabolic dysfunctions. Obstructive sleep apnea is an independent risk factor for stroke and heart attack with higher mortality rates in patients with severe or moderate disease (He et al., 1988; Peppard et al., 2000; Peker et al., 2006; Punjabi and Polotsky, 2005; Gozal et al., 2013; Kim et al., 2013; Sánchez-de-la-Torre et al., 2013). However, these associations may not establish a causal relationship and therefore, the exact pathophysiology of OSA is yet to be explored. The pathogenesis is postulated to include both mechanisms involved in upper airway patency and the physiology of respiratory control system. The current understanding establishes that respiratory activation, and often arousal, that terminates the apneic episode and reopens the airway is controlled by the degree of hypoxia and hypercapnea (White, 2005). On the other hand, other mechanisms have been proposed as the driving force behind this ‘‘breakpoint breath’’ such as stimulation of diaphragm muscle chemoreceptors (Parkes, 2006), increased ventilatory effort acting independently from hypoxia and hypercapnea (Gleeson et al., 1990), and ventilatory control instability (Wellman et al., 2004;
White, 2005). The autonomic system including both sympathetic and parasympathetic nervous systems modulate the heart rate; as a result measuring the HRV has been a target of some investigations in order to study the function of these systems during sleep and apneic episodes. Abnormal HRV, being an independent risk factor for mortality, may help identify high risk patients and has been used to monitor the effects of treatment (Stein and Pu, 2012). Interestingly, there is evidence indicating that HRV might be also a product of hypoxia and not apnea (Gozal et al., 2013; Palma et al., 2013). High rates of cyclic variation of HRV are highly associated with severe OSA (Stein and Pu, 2012). Nevertheless, the presence of a subgroup of patients with OSA who share similar clinical features with other OSA patients (e.g., significant sleep fragmentation and cognitive impairment) but do not experience hypoxia, may provide an opportunity to further explore this controversy. Understanding how these patients maintain normal oxygen saturation during apnea may further our understanding of the pathophysiology of OSA. In this issue of Clinical Neurophysiology, Palma et al. report their findings in two groups of patients with severe OSA withand without hypoxia (OSA+h, and OSA–h, respectively) (Palma et al., 2014). The study was based on the hypothesis that hypoxemia is the trigger for HRV changes: therefore cardiac autonomic tone during sleep should not be affected as much in patients with OSA–h as in those with OSA+h. Both groups had severe OSA with a minimum of 88% oxygen desaturation documented in the OSA+h group. The HRV acquisition was done through standard methods and instead of normalized values, low- to high frequency (LF/HF) ratio was recorded as a measure of sympathetic to vagal balance, i.e., the higher the LF/HF ratio, the more the sympathetic effect. The OSA+h patients were found to have longer apnea durations. (They also had higher BMI, waist circumference, and prior ENT surgery for OSA compared to the OSA–h patients and control, but the subgroup of patients selected for HRV analysis had similar age, BMI, and sleep structure.) The analysis also revealed significantly higher LF/HF ratio in OSA+h patients during N1–N2 and REM sleep compared to OSA-h group and control, indicating sympathetic overactivity in response to hypoxia rather than apnea per se. These findings appear to be in line with the notion that pathogenesis of OSA might not be based only on upper airway patency but may involve decreased sensitivity of respiratory mechanoreceptors (pulmonary or diaphragmatic afferents) (Gleeson et al., 1990; Parkes, 2006). The same authors had previously shown that some patients with OSA–h may not experience complete upper airway collapse during the events although the nasal thermistor
http://dx.doi.org/10.1016/j.clinph.2014.02.004 1388-2457/$36.00 Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
2
Editorial / Clinical Neurophysiology xxx (2014) xxx–xxx
might indicate otherwise (Iriarte et al., 2013). It had been proposed that during apnea central respiratory rhythm would increase and result in a breakpoint breath especially in patients with oversensitive ventilatory control system (Wellman et al., 2004; White, 2005). Individual variability in upper airway anatomy and its dilator muscles’ responsiveness to negative pressure and hypercapnea, variable arousal thresholds in response to ventilatory stimulation, and ventilatory control instability (loop gain), may determine the individual’s risk of developing OSA (White, 2005). The current study provides some support; patients with OSA+h had longer apnea than those with OSA–h i.e., patients with OSA–h might have higher arousal threshold than those with OSA+h hence less chance of developing hypoxemia during the apneic episodes. The above point refers to the fact that patients with OSA have lower threshold for (premature) arousal, and hence frequent awakenings and sleep fragmentation. Buildup of physiological respiratory stimuli, i.e., CO2 and negative pharyngeal pressure during sleep can recruit the dilator muscle and maintain the pharyngeal patency in these patients, but this would happen only if sleep can be maintained long enough. Therefore, premature and frequent arousals, as seen in OSA patients, result in apnea since sleep is not maintained for sufficient accumulation of the endogenous stimuli that could facilitate pharyngeal dilator muscle recruitment. The authors propose that lack of hypoxia in patients with OSA–h might be related to an increased arousal threshold possibly because of an oversensitive ventilatory control system (i.e., high loop gain) (Eckert et al., 2011). The physiopathology of OSA might indeed vary among patients. Further studies are needed to sort out distinct characteristics of the spectrum known as OSA syndrome, their response to therapy, and their risks of developing vascular, neurocognitive, or immune disorders, in regard to the presence or absence of hypoxia and dysautonomia among other potential risk factors. References 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 (Lond) 2011;120:505–14. Gleeson K, Zwillich CW, White DP. The influence of increasing ventilatory effort on arousal from sleep. Am Rev Respir Med 1990;142:295–300.
Gozal D, Hakim F, Kheirandish-Gozal L. Chemoreceptors, baroreceptors, and autonomic deregulation in children with obstructive sleep apnea. Respir Physiol Neurobiol 2013;185:177–85. He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea: experience in 385 male patients. Chest 1988;94:9–14. Iriarte J, Palma JA, Fernandez S, Urrestarazu E, Alegre M, Artieda J, et al. Aryngolaryngoscopic video-recording in obstructive sleep apnea during natural N2 sleep. A case report of a non-complete obstructive mechanism. Sleep Med 2013;14:217–9. Kim H, Yun CH, Thomas RJ, Lee SH, Seo HS, Cho ER. Obstructive sleep apnea as a risk factor for cerebral white matter change in a middle-aged and older general population. Sleep 2013;1:709B–15B. Palma JA, Urrestarazu E, Lopez-Azcarate J, Alegre M, Fernandez S, Artieda J, et al. Increased sympathetic and decreased parasympathetic cardiac tone in patients with sleep related alveolar hypoventilation. Sleep 2013;36:933–40. Palma JA, Iriarte J, Fernandez S, Valencia M, Alegre M, Artieda J, et al. Characterizing the phenotypes of obstructive sleep apnea: clinical, sleep, and autonomic features of obstructive sleep apnea with and without hypoxia. Clin Neurophysiol 2014 [this issue]. Parkes MJ. Breath-holding and its breakpoint. Exp Physiol 2006;91:1–15. Peker Y, Carlson J, Hedner J. Increased incidence of coronary artery disease in sleep apnoea: a long-term follow-up. Eur Respir J 2006;28:596–602. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–84. Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008;15:136–43. Punjabi NM, Polotsky VY. Disorders of glucose metabolism in sleep apnea. J Appl Physiol 2005;99:1998–2007. Sánchez-de-la-Torre M, Campos-Rodriguez F, Barbé F. Obstructive sleep apnea and cardiovascular disease. Lancet Respir Med 2013;1:61–72. Stein PK, Pu Y. Heart rate variability, sleep and sleep disorders. Sleep Med Rev 2012;16:47–66. Wellman A, Jordan A, Malhotra A, Fogel R, Katz E, Schory K, et al. Ventilatory control and airway anatomy in obstructive sleep apnea. Am J Respir Crit Care Med 2004;170:1225–32. White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med 2005;172:1363–70.
⇑
Gholam K. Motamedi Department of Neurology, Georgetown University Hospital, USA ⇑ Address: Department of Neurology, PHC 7, Georgetown University Hospital, 3800 Reservoir Rd., NW, Washington, DC 20007, USA. Tel.: +1 202 444 4564; fax: +1 202 444 4115. E-mail address: [email protected] Available online xxxx
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Editorial
Obstructive sleep apnea; is it the anatomy or physiology? See Article, pages xxx–xxx
The pharyngeal collapsibility that is required for normal swallowing and speech imposes a potential risk to respiration during sleep. During normal sleep despite the loss of muscle tone the upper airway remains open and would require a negative pressure ( 5 cm H2O) to collapse. Therefore, as long as the extramural pressure, applied by the soft tissue surrounding the pharyngeal area, is minimal the upper airway would remain patent. However, in patients with obstructive sleep apnea (OSA), because of increased soft tissue and/or narrowing of the pharyngeal opening, the extraluminal pressure would overcome the elasticity and collapse the airway (White, 2005). Obstructive sleep apnea is a common cause of sleep-disordered breathing in adults and children characterized by recurrent episodes of collapse of the upper airway. Its prevalence is estimated at 3–7% in adult population (Punjabi, 2008). The full spectrum of the OSA syndrome goes far beyond its hallmark of excessive daytime sleepiness (EDS). The EDS is presumably related to disruption of normal sleep architecture caused by frequent microarousals at the end of apneic episodes accompanied by hypoxia, hypercapnea, recurrent intrathoracic pressure swings, and sleep disruption. Among the physiological changes recorded during apnea, hypoxia and autonomic dysfunction may be the key risk factors. Overactivation of the sympathetic system during apnea may result in extreme heart rate variability (HRV) and cardiac arrhythmia (Gozal et al., 2013; Palma et al., 2013). The constellation of such physiological changes constitutes the risks for cardio-cerebro-vascular morbidity, and neurocognitive and behavioral, immune, and metabolic dysfunctions. Obstructive sleep apnea is an independent risk factor for stroke and heart attack with higher mortality rates in patients with severe or moderate disease (He et al., 1988; Peppard et al., 2000; Peker et al., 2006; Punjabi and Polotsky, 2005; Gozal et al., 2013; Kim et al., 2013; Sánchez-de-la-Torre et al., 2013). However, these associations may not establish a causal relationship and therefore, the exact pathophysiology of OSA is yet to be explored. The pathogenesis is postulated to include both mechanisms involved in upper airway patency and the physiology of respiratory control system. The current understanding establishes that respiratory activation, and often arousal, that terminates the apneic episode and reopens the airway is controlled by the degree of hypoxia and hypercapnea (White, 2005). On the other hand, other mechanisms have been proposed as the driving force behind this ‘‘breakpoint breath’’ such as stimulation of diaphragm muscle chemoreceptors (Parkes, 2006), increased ventilatory effort acting independently from hypoxia and hypercapnea (Gleeson et al., 1990), and ventilatory control instability (Wellman et al., 2004;
White, 2005). The autonomic system including both sympathetic and parasympathetic nervous systems modulate the heart rate; as a result measuring the HRV has been a target of some investigations in order to study the function of these systems during sleep and apneic episodes. Abnormal HRV, being an independent risk factor for mortality, may help identify high risk patients and has been used to monitor the effects of treatment (Stein and Pu, 2012). Interestingly, there is evidence indicating that HRV might be also a product of hypoxia and not apnea (Gozal et al., 2013; Palma et al., 2013). High rates of cyclic variation of HRV are highly associated with severe OSA (Stein and Pu, 2012). Nevertheless, the presence of a subgroup of patients with OSA who share similar clinical features with other OSA patients (e.g., significant sleep fragmentation and cognitive impairment) but do not experience hypoxia, may provide an opportunity to further explore this controversy. Understanding how these patients maintain normal oxygen saturation during apnea may further our understanding of the pathophysiology of OSA. In this issue of Clinical Neurophysiology, Palma et al. report their findings in two groups of patients with severe OSA withand without hypoxia (OSA+h, and OSA–h, respectively) (Palma et al., 2014). The study was based on the hypothesis that hypoxemia is the trigger for HRV changes: therefore cardiac autonomic tone during sleep should not be affected as much in patients with OSA–h as in those with OSA+h. Both groups had severe OSA with a minimum of 88% oxygen desaturation documented in the OSA+h group. The HRV acquisition was done through standard methods and instead of normalized values, low- to high frequency (LF/HF) ratio was recorded as a measure of sympathetic to vagal balance, i.e., the higher the LF/HF ratio, the more the sympathetic effect. The OSA+h patients were found to have longer apnea durations. (They also had higher BMI, waist circumference, and prior ENT surgery for OSA compared to the OSA–h patients and control, but the subgroup of patients selected for HRV analysis had similar age, BMI, and sleep structure.) The analysis also revealed significantly higher LF/HF ratio in OSA+h patients during N1–N2 and REM sleep compared to OSA-h group and control, indicating sympathetic overactivity in response to hypoxia rather than apnea per se. These findings appear to be in line with the notion that pathogenesis of OSA might not be based only on upper airway patency but may involve decreased sensitivity of respiratory mechanoreceptors (pulmonary or diaphragmatic afferents) (Gleeson et al., 1990; Parkes, 2006). The same authors had previously shown that some patients with OSA–h may not experience complete upper airway collapse during the events although the nasal thermistor
http://dx.doi.org/10.1016/j.clinph.2014.02.004 1388-2457/$36.00 Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
2
Editorial / Clinical Neurophysiology xxx (2014) xxx–xxx
might indicate otherwise (Iriarte et al., 2013). It had been proposed that during apnea central respiratory rhythm would increase and result in a breakpoint breath especially in patients with oversensitive ventilatory control system (Wellman et al., 2004; White, 2005). Individual variability in upper airway anatomy and its dilator muscles’ responsiveness to negative pressure and hypercapnea, variable arousal thresholds in response to ventilatory stimulation, and ventilatory control instability (loop gain), may determine the individual’s risk of developing OSA (White, 2005). The current study provides some support; patients with OSA+h had longer apnea than those with OSA–h i.e., patients with OSA–h might have higher arousal threshold than those with OSA+h hence less chance of developing hypoxemia during the apneic episodes. The above point refers to the fact that patients with OSA have lower threshold for (premature) arousal, and hence frequent awakenings and sleep fragmentation. Buildup of physiological respiratory stimuli, i.e., CO2 and negative pharyngeal pressure during sleep can recruit the dilator muscle and maintain the pharyngeal patency in these patients, but this would happen only if sleep can be maintained long enough. Therefore, premature and frequent arousals, as seen in OSA patients, result in apnea since sleep is not maintained for sufficient accumulation of the endogenous stimuli that could facilitate pharyngeal dilator muscle recruitment. The authors propose that lack of hypoxia in patients with OSA–h might be related to an increased arousal threshold possibly because of an oversensitive ventilatory control system (i.e., high loop gain) (Eckert et al., 2011). The physiopathology of OSA might indeed vary among patients. Further studies are needed to sort out distinct characteristics of the spectrum known as OSA syndrome, their response to therapy, and their risks of developing vascular, neurocognitive, or immune disorders, in regard to the presence or absence of hypoxia and dysautonomia among other potential risk factors. References 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 (Lond) 2011;120:505–14. Gleeson K, Zwillich CW, White DP. The influence of increasing ventilatory effort on arousal from sleep. Am Rev Respir Med 1990;142:295–300.
Gozal D, Hakim F, Kheirandish-Gozal L. Chemoreceptors, baroreceptors, and autonomic deregulation in children with obstructive sleep apnea. Respir Physiol Neurobiol 2013;185:177–85. He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea: experience in 385 male patients. Chest 1988;94:9–14. Iriarte J, Palma JA, Fernandez S, Urrestarazu E, Alegre M, Artieda J, et al. Aryngolaryngoscopic video-recording in obstructive sleep apnea during natural N2 sleep. A case report of a non-complete obstructive mechanism. Sleep Med 2013;14:217–9. Kim H, Yun CH, Thomas RJ, Lee SH, Seo HS, Cho ER. Obstructive sleep apnea as a risk factor for cerebral white matter change in a middle-aged and older general population. Sleep 2013;1:709B–15B. Palma JA, Urrestarazu E, Lopez-Azcarate J, Alegre M, Fernandez S, Artieda J, et al. Increased sympathetic and decreased parasympathetic cardiac tone in patients with sleep related alveolar hypoventilation. Sleep 2013;36:933–40. Palma JA, Iriarte J, Fernandez S, Valencia M, Alegre M, Artieda J, et al. Characterizing the phenotypes of obstructive sleep apnea: clinical, sleep, and autonomic features of obstructive sleep apnea with and without hypoxia. Clin Neurophysiol 2014 [this issue]. Parkes MJ. Breath-holding and its breakpoint. Exp Physiol 2006;91:1–15. Peker Y, Carlson J, Hedner J. Increased incidence of coronary artery disease in sleep apnoea: a long-term follow-up. Eur Respir J 2006;28:596–602. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–84. Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008;15:136–43. Punjabi NM, Polotsky VY. Disorders of glucose metabolism in sleep apnea. J Appl Physiol 2005;99:1998–2007. Sánchez-de-la-Torre M, Campos-Rodriguez F, Barbé F. Obstructive sleep apnea and cardiovascular disease. Lancet Respir Med 2013;1:61–72. Stein PK, Pu Y. Heart rate variability, sleep and sleep disorders. Sleep Med Rev 2012;16:47–66. Wellman A, Jordan A, Malhotra A, Fogel R, Katz E, Schory K, et al. Ventilatory control and airway anatomy in obstructive sleep apnea. Am J Respir Crit Care Med 2004;170:1225–32. White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med 2005;172:1363–70.
⇑
Gholam K. Motamedi Department of Neurology, Georgetown University Hospital, USA ⇑ Address: Department of Neurology, PHC 7, Georgetown University Hospital, 3800 Reservoir Rd., NW, Washington, DC 20007, USA. Tel.: +1 202 444 4564; fax: +1 202 444 4115. E-mail address: [email protected] Available online xxxx
