Review
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 07/06/15 For personal use only.
Sleep-related disorders in chronic obstructive pulmonary disease Expert Rev. Respir. Med. 8(1), 79–88 (2014)
Sophie J Crinion and Walter T McNicholas* Department of Respiratory and Sleep Medicine, Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital, Elm Park, Dublin, Ireland Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland *Author for correspondence: Tel.: +35 312 213 702 Fax: +35 312 697 949 [email protected]
Sleep may have several negative consequences in patients with chronic obstructive pulmonary disease (COPD). Sleep is typically fragmented with diminished slow wave and rapid-eye-movement sleep, which likely represents an important contributing factor to daytime symptoms such as fatigue and lethargy. Furthermore, normal physiological adaptations during sleep, which result in mild hypoventilation in normal subjects, are more pronounced in COPD, which can result in clinically important nocturnal oxygen desaturation. The co-existence of obstructive sleep apnea and COPD is also common, principally because of the high prevalence of each disorder, and there is little convincing evidence that one disorder predisposes to the other. Nonetheless, this co-existence, termed the overlap syndrome, typically results in more pronounced nocturnal oxygen desaturation and there is a high prevalence of pulmonary hypertension in such patients. Management of sleep disorders in patients with COPD should address both sleep quality and disordered gas exchange. Non-invasive pressure support is beneficial in selected cases, particularly during acute exacerbations associated with respiratory failure, and is particularly helpful in patients with the overlap syndrome. There is limited evidence of benefit from pressure support in the chronic setting in COPD patients without obstructive sleep apnea. KEYWORDS: cardiovascular co-morbidity • COPD • hypoxemia • inflammation • obstructive sleep apnea • pathophysiology • sleep
“Sleep is the golden chain that ties health and our bodies together.” (Thomas Dekker, 1572–1632). Sleep is an essential part of human life and is needed for optimal health and performance. Sleep deprivation is associated with impaired cognitive and behavioral performance [1], as well as increased levels of anxiety [2]. Sleep has several adverse effects on breathing that include changes in central respiratory control, lung mechanics and muscle contractility, which are not clinically significant in healthy individuals but may result in significant hypoxemia and hypercapnia in patients with chronic obstructive pulmonary disease (COPD), particularly during rapid-eyemovement (REM) sleep [3]. Hypoxemia during sleep in COPD is principally a result of the disorder rather than being a feature of sleep apnea [4]. Normal subjects may experience mild hypoxemia and hypercapnia during sleep, particularly during REM, which is largely a result of mild hypoventilation. Patients with COPD may experience a greater level of hyopoxemia during sleep because of additional factors that contribute to hypoventilation such as airflow obstruction, respiratory www.expert-reviews.com
10.1586/17476348.2014.860357
muscle dysfunction and diminished respiratory drive, in addition to other factors that include ventilation-persusion mismatching. Sleep disturbance is also common in COPD [5], which may be contributed to by the adverse effects of drug therapy, and is likely a contributing factor to daytime symptoms such as fatigue and lethargy [6]. The present review will discuss the mechanisms of sleep and breathing disturbances in COPD and their management, in addition to the clinical syndrome where COPD and sleep apnea co-exist, also referred to as the overlap syndrome. Physiological effects of sleep on respiration & implications for COPD
Normal sleep is associated with several changes in respiratory physiology from a wakeful state, which are illustrated in FIGURE 1. During all stages of sleep, minute ventilation is reduced due to reduced tidal volume with only a small increase in respiratory rate. This decreased minute ventilation leads to hypoxemia and hypercapnia in all stages of sleep. During
2014 Informa UK Ltd
ISSN 1747-6348
79
Review
Crinion & McNicholas
Sleep
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 07/06/15 For personal use only.
Respiratory control • Cortical inputs • Chemoreceptor sensitivity • Respiratory motor neurones
Lung mechanics Respiratory muscle function
• Airflow resistance • FRC • V/Q matching
Hypoventilation hypoxemia, hypercapnia
Figure 1. Physiological impact of sleep on respiration, which is generally negative but does not result in clinically significant changes in ventilation or gas exchange in normal subjects. FRC: Functional residual capacity; V/Q: Ventilation–perfusion.
REM sleep, both hypoxemia and hypercapnia are further exaggerated, mean inspiratory flow rate is reduced and breathing is shallow and irregular [7]. Respiratory control mechanisms are diminished during sleep, including the respiratory centre, and particularly during REM sleep [8]. Also, the responses of respiratory muscles, particularly the accessory muscles, are diminished during REM. These changes result in a reduced minute ventilation, particularly during REM sleep, predominantly because of a reduction in tidal volume [7]. These physiologic changes are not associated with any clinically significant deterioration in gas exchange among normal subjects, but may produce significant nocturnal oxygen desaturation in patients with COPD. The ribcage contribution to breathing is reduced during REM sleep compared with wakefulness and non-REM sleep because of a marked reduction in accessory muscle activity, whereas diaphragmatic contraction is less affected [8]. Since COPD patients are more dependent on the accessory muscles to maintain adequate ventilation because of the effects of lung hyperinflation, these physiological changes during REM may produce more profound adverse effects [9]. There are physiological diurnal changes in airway caliber, which may result in mild nocturnal airway narrowing and can be more pronounced in asthma [10]. Furthermore, the functional residual capacity is reduced during sleep, which could contribute in COPD to ventilation-perfusion mismatching as a result of combined factors that include cephalad displacement of the diaphragm and diminished lung compliance [11]. Sleep-related changes in COPD Sleep quality & architecture
Sleep quality is often impaired in patients with COPD, which is likely an important factor in the chronic fatigue, sleepiness 80
and overall impairment in quality of life reported by these patients [12,13]. There is an increased prevalence of insomnia, use of hypnotic medications, and an increase in daytime sleepiness in subjects with COPD than in the general population [14]. Klink et al. reported that 39% of patients with nocturnal cough or wheezing reported difficulty initiating or maintaining sleep. If cough and wheeze were both present, 53% reported difficulty initiating or maintaining sleep, and 23% reported excessive daytime sleepiness [15]. It seems that in patients with mild obstructive airways disease, there is little impact on sleep quality [16]. However, as COPD becomes more severe, there are increasing sleep complaints with possibly more deleterious physiologic effects [5,13]. In COPD, sleep tends to be fragmented, with frequent arousals and a diminished amount of REM sleep [5,17]. Recently, McSharry et al. published retrospective data on objective sleep quality measurements on patients with COPD who underwent overnight attended polysomnography. In the 106 patients with mean forced expiratory volume in 1 second (FEV1) of 33% and mean FEV1/forced vital capacity (FVC) ratio of 44%, there was generally poor sleep quality indicated by low sleep efficiency, high arousal index and diminished length of REM sleep [5]. Soler et al. while investigating the effect of pulmonary rehabilitation programs, assessed the sleep quality of patients enrolled in the program using the Pittsburgh Sleep Quality Index [18]. Of the 46 patients with obstructive lung disease, the average Pittsburgh Sleep Quality Index global index before pulmonary rehabilitation was 6.6. A score of >5 suggests significant sleep disturbance [19]. The cause of this poor sleep quality in COPD is not entirely clear. Kwon et al. reported a strong relationship between hyperinflation and lower sleep efficiency in patients with the overlap syndrome, but the effect was independent of obstructive sleep apnea (OSA) after correction for the apnea–hypopnoea index (AHI) [20]. The role of hypoxemia as a respiratory stimulant is rather weak, since quality of sleep does not improve by adding oxygen, and thus, hypercapnia is considered as a much stronger stimulant provoking arousals [21]. Also, increased inspiratory loads due to hyperinflation and intrinsic positive end-expiratory pressure can substantially add to the work of breathing, and hence elicit arousals contributing to poorer sleep efficiency [20]. The arousal response is lowest for hypercapnia and hypoxia during REM sleep, but the arousal response to inspiratory loading is relatively preserved [13]. They common symptom of nocturnal cough may also disturb sleep in these patients. Last but not least, cigarette smokers manifest disturbances in the sleep EEG that are not evident in conventional measures of sleep architecture. Nicotine in cigarette smoke and withdrawal from it during sleep may contribute to a higher alpha power and the subjective experience of non-restorative sleep [4]. Unfortunately, sleep impairment is an aspect of COPD that is frequently neglected by many physicians, and also in trials designed to assess the impact of COPD on quality of life [4]. Phillips et al. showed in a small number of patient with COPD that enforced sleep deprivation is associated with a mild decrease in Expert Rev. Respir. Med. 8(1), (2014)
Sleep-related disorders in chronic obstructive pulmonary disease
FVC (-5%) and FEV1 (-6%) [22]. When extrapolating these data toward the general COPD population, it could be speculated that persistent disturbed sleep quality in COPD patients could lead to worse outcome.
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 07/06/15 For personal use only.
Ventilation & gas exchange
As discussed earlier, in normal subjects the minute ventilation decreases during sleep but there is minimal physiological effect. In COPD, however, minute ventilation decreases by up to 32% during REM sleep [23]. The combined effects of reliance on accessory muscles during sleep, and the associated physiological muscle hypotonia during REM sleep likely explain much of these negative ventilatory effects together with the consequential hypoxemia/hypercapnia. Lewis et al. have shown a prevalence of 49% of nocturnal desaturation (defined as spending at least 30% of the night with SaO2
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 07/06/15 For personal use only.
Sleep-related disorders in chronic obstructive pulmonary disease Expert Rev. Respir. Med. 8(1), 79–88 (2014)
Sophie J Crinion and Walter T McNicholas* Department of Respiratory and Sleep Medicine, Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital, Elm Park, Dublin, Ireland Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland *Author for correspondence: Tel.: +35 312 213 702 Fax: +35 312 697 949 [email protected]
Sleep may have several negative consequences in patients with chronic obstructive pulmonary disease (COPD). Sleep is typically fragmented with diminished slow wave and rapid-eye-movement sleep, which likely represents an important contributing factor to daytime symptoms such as fatigue and lethargy. Furthermore, normal physiological adaptations during sleep, which result in mild hypoventilation in normal subjects, are more pronounced in COPD, which can result in clinically important nocturnal oxygen desaturation. The co-existence of obstructive sleep apnea and COPD is also common, principally because of the high prevalence of each disorder, and there is little convincing evidence that one disorder predisposes to the other. Nonetheless, this co-existence, termed the overlap syndrome, typically results in more pronounced nocturnal oxygen desaturation and there is a high prevalence of pulmonary hypertension in such patients. Management of sleep disorders in patients with COPD should address both sleep quality and disordered gas exchange. Non-invasive pressure support is beneficial in selected cases, particularly during acute exacerbations associated with respiratory failure, and is particularly helpful in patients with the overlap syndrome. There is limited evidence of benefit from pressure support in the chronic setting in COPD patients without obstructive sleep apnea. KEYWORDS: cardiovascular co-morbidity • COPD • hypoxemia • inflammation • obstructive sleep apnea • pathophysiology • sleep
“Sleep is the golden chain that ties health and our bodies together.” (Thomas Dekker, 1572–1632). Sleep is an essential part of human life and is needed for optimal health and performance. Sleep deprivation is associated with impaired cognitive and behavioral performance [1], as well as increased levels of anxiety [2]. Sleep has several adverse effects on breathing that include changes in central respiratory control, lung mechanics and muscle contractility, which are not clinically significant in healthy individuals but may result in significant hypoxemia and hypercapnia in patients with chronic obstructive pulmonary disease (COPD), particularly during rapid-eyemovement (REM) sleep [3]. Hypoxemia during sleep in COPD is principally a result of the disorder rather than being a feature of sleep apnea [4]. Normal subjects may experience mild hypoxemia and hypercapnia during sleep, particularly during REM, which is largely a result of mild hypoventilation. Patients with COPD may experience a greater level of hyopoxemia during sleep because of additional factors that contribute to hypoventilation such as airflow obstruction, respiratory www.expert-reviews.com
10.1586/17476348.2014.860357
muscle dysfunction and diminished respiratory drive, in addition to other factors that include ventilation-persusion mismatching. Sleep disturbance is also common in COPD [5], which may be contributed to by the adverse effects of drug therapy, and is likely a contributing factor to daytime symptoms such as fatigue and lethargy [6]. The present review will discuss the mechanisms of sleep and breathing disturbances in COPD and their management, in addition to the clinical syndrome where COPD and sleep apnea co-exist, also referred to as the overlap syndrome. Physiological effects of sleep on respiration & implications for COPD
Normal sleep is associated with several changes in respiratory physiology from a wakeful state, which are illustrated in FIGURE 1. During all stages of sleep, minute ventilation is reduced due to reduced tidal volume with only a small increase in respiratory rate. This decreased minute ventilation leads to hypoxemia and hypercapnia in all stages of sleep. During
2014 Informa UK Ltd
ISSN 1747-6348
79
Review
Crinion & McNicholas
Sleep
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 07/06/15 For personal use only.
Respiratory control • Cortical inputs • Chemoreceptor sensitivity • Respiratory motor neurones
Lung mechanics Respiratory muscle function
• Airflow resistance • FRC • V/Q matching
Hypoventilation hypoxemia, hypercapnia
Figure 1. Physiological impact of sleep on respiration, which is generally negative but does not result in clinically significant changes in ventilation or gas exchange in normal subjects. FRC: Functional residual capacity; V/Q: Ventilation–perfusion.
REM sleep, both hypoxemia and hypercapnia are further exaggerated, mean inspiratory flow rate is reduced and breathing is shallow and irregular [7]. Respiratory control mechanisms are diminished during sleep, including the respiratory centre, and particularly during REM sleep [8]. Also, the responses of respiratory muscles, particularly the accessory muscles, are diminished during REM. These changes result in a reduced minute ventilation, particularly during REM sleep, predominantly because of a reduction in tidal volume [7]. These physiologic changes are not associated with any clinically significant deterioration in gas exchange among normal subjects, but may produce significant nocturnal oxygen desaturation in patients with COPD. The ribcage contribution to breathing is reduced during REM sleep compared with wakefulness and non-REM sleep because of a marked reduction in accessory muscle activity, whereas diaphragmatic contraction is less affected [8]. Since COPD patients are more dependent on the accessory muscles to maintain adequate ventilation because of the effects of lung hyperinflation, these physiological changes during REM may produce more profound adverse effects [9]. There are physiological diurnal changes in airway caliber, which may result in mild nocturnal airway narrowing and can be more pronounced in asthma [10]. Furthermore, the functional residual capacity is reduced during sleep, which could contribute in COPD to ventilation-perfusion mismatching as a result of combined factors that include cephalad displacement of the diaphragm and diminished lung compliance [11]. Sleep-related changes in COPD Sleep quality & architecture
Sleep quality is often impaired in patients with COPD, which is likely an important factor in the chronic fatigue, sleepiness 80
and overall impairment in quality of life reported by these patients [12,13]. There is an increased prevalence of insomnia, use of hypnotic medications, and an increase in daytime sleepiness in subjects with COPD than in the general population [14]. Klink et al. reported that 39% of patients with nocturnal cough or wheezing reported difficulty initiating or maintaining sleep. If cough and wheeze were both present, 53% reported difficulty initiating or maintaining sleep, and 23% reported excessive daytime sleepiness [15]. It seems that in patients with mild obstructive airways disease, there is little impact on sleep quality [16]. However, as COPD becomes more severe, there are increasing sleep complaints with possibly more deleterious physiologic effects [5,13]. In COPD, sleep tends to be fragmented, with frequent arousals and a diminished amount of REM sleep [5,17]. Recently, McSharry et al. published retrospective data on objective sleep quality measurements on patients with COPD who underwent overnight attended polysomnography. In the 106 patients with mean forced expiratory volume in 1 second (FEV1) of 33% and mean FEV1/forced vital capacity (FVC) ratio of 44%, there was generally poor sleep quality indicated by low sleep efficiency, high arousal index and diminished length of REM sleep [5]. Soler et al. while investigating the effect of pulmonary rehabilitation programs, assessed the sleep quality of patients enrolled in the program using the Pittsburgh Sleep Quality Index [18]. Of the 46 patients with obstructive lung disease, the average Pittsburgh Sleep Quality Index global index before pulmonary rehabilitation was 6.6. A score of >5 suggests significant sleep disturbance [19]. The cause of this poor sleep quality in COPD is not entirely clear. Kwon et al. reported a strong relationship between hyperinflation and lower sleep efficiency in patients with the overlap syndrome, but the effect was independent of obstructive sleep apnea (OSA) after correction for the apnea–hypopnoea index (AHI) [20]. The role of hypoxemia as a respiratory stimulant is rather weak, since quality of sleep does not improve by adding oxygen, and thus, hypercapnia is considered as a much stronger stimulant provoking arousals [21]. Also, increased inspiratory loads due to hyperinflation and intrinsic positive end-expiratory pressure can substantially add to the work of breathing, and hence elicit arousals contributing to poorer sleep efficiency [20]. The arousal response is lowest for hypercapnia and hypoxia during REM sleep, but the arousal response to inspiratory loading is relatively preserved [13]. They common symptom of nocturnal cough may also disturb sleep in these patients. Last but not least, cigarette smokers manifest disturbances in the sleep EEG that are not evident in conventional measures of sleep architecture. Nicotine in cigarette smoke and withdrawal from it during sleep may contribute to a higher alpha power and the subjective experience of non-restorative sleep [4]. Unfortunately, sleep impairment is an aspect of COPD that is frequently neglected by many physicians, and also in trials designed to assess the impact of COPD on quality of life [4]. Phillips et al. showed in a small number of patient with COPD that enforced sleep deprivation is associated with a mild decrease in Expert Rev. Respir. Med. 8(1), (2014)
Sleep-related disorders in chronic obstructive pulmonary disease
FVC (-5%) and FEV1 (-6%) [22]. When extrapolating these data toward the general COPD population, it could be speculated that persistent disturbed sleep quality in COPD patients could lead to worse outcome.
Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 07/06/15 For personal use only.
Ventilation & gas exchange
As discussed earlier, in normal subjects the minute ventilation decreases during sleep but there is minimal physiological effect. In COPD, however, minute ventilation decreases by up to 32% during REM sleep [23]. The combined effects of reliance on accessory muscles during sleep, and the associated physiological muscle hypotonia during REM sleep likely explain much of these negative ventilatory effects together with the consequential hypoxemia/hypercapnia. Lewis et al. have shown a prevalence of 49% of nocturnal desaturation (defined as spending at least 30% of the night with SaO2
