sananots ‘Sleop-elated breathing orders in COPO - UpToDate Official reprint from UpToDate” UpToDate’ omarrennemanumonst . @. Wolters Kluwer Sleep-related breathing disorders in COPD ‘Author: Hartmut Schneider, MD, PhD Section Editors: James K Stoller, MD, MS, M Safwan Badr, MD. Deputy Exitors: Helen Hollingsworth, MD, April F Eichler, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Nov 2016. | This topic last updated: Jun 09, 2016. INTRODUCTION — Chronic obstructive pulmonary disease (COPD) is frequently associated with sleep-related breathing disorders (SRBD), including sleep-related hypoxemia, obstructive sleep apnea, central sleep apnea, respiratory effort-related arousals (RERAS), and sleep-related hypoventilation. These SRBDs may be associated with nonrestorative sleep and daytime sleepiness and fatigue [1-10] The various forms of SRBD in COPD wil be reviewed here, with special emphasis on (1) the diagnostic procedures required to detect the COPD-specific SRBD and (2) specific treatment options for SRBD in patients with COPD, A description of SRBD and the evaluation, diagnosis, and treatment of COPD and obstructive and central sleep apnea occurring independently are discussed separately, (See “Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging" and "Management of stable chronic obstructive pulmonary disease" and "Polysomnography in the evaluation of sleep-disordered breathing in adults" and “Overview of obstructive sleep apnea in adults and "Central sleep apnea: Risk factors, clinical presentation, and diagnosis" and "Central sleep apnea: Treatment’) EPIDEMIOLOGY — Sleep-related breathing disorders (SRBD) are common in patients with COPD [1], occurring in approximately 40 percent of patients [11.12]. There are four major domains of sleep-disordered breathing in COPD patients. * Sleep-related hypoxemia — The prevalence of sleep-related hypoxemia (also called nocturnal hypoxemia) increases along with the severity of COPD 2]. Sleep-related hypoxemia is often associated with daytime hypoxemia, but not always. Isolated sleep-related hypoxemia (fallin partial pressure of arterial oxygen [PaQ2] of >10 mmHg or pulse oxygen saturation [SpOz] below 88 percent for more than five minutes) has been reported in up to 70 percent of COPD patients, and can occur in patients with daytime oxygen saturation of 90 to 95 percent [3.13] ‘* Coexisting obstructive sleep apnea — Moderate to severe obstructive sleep apnea (OSA) may be present in 10 to 30 percent of patients with COPD, a prevalence that is similar to that of the general population [1- 314 The coexistence of OSA and COPD has been referred to as the “overlap syndrome" [15], although it is unclear whether itis truly an overlap syndrome or just two common diseases presenting together. ‘* Hypoventilation during sleep — Sleep-related hypoventilation is defined as a greater than normal increase in arterial tension of carbon dioxide (PaCOz) during sleep (PaCO2 of >50 mmHg or rise in PaCOz of >10 mmHg for more than 10 minutes compared to wakefulness). The prevalence of sleep-related hypoventilation is approximately 43 percent in hypercapnic patients with COPD, but is lower (approximately 6 to 10 percent) ipsstwen uptodate. comforters slep-elaod- bathing. disor ders-ir-copaprint?scurce=search resulfsearch= epocdsoletodTile=21~150 9sananots ‘Sleop-elated breathing orders in COPO - UpToDate and often limited to rapid eye movement (REM) sleep in patients with mild COPD and normal daytime arterial blood gases [1.16] «Respiratory effort related arousals — Respiratory effort related arousals [RERAs}, also described as sleep fragmentation due to worsening of breathing mechanics, can be seen in COPD (see ‘Pathoohysioloay’ below). The prevalence, however, remains unclear [1.17.18], and the clinical significance may be limited to patients with advanced stages of COPD with greater degrees of hyperinflation and muscle weakness [19]. RERAs are accounted for in summary measures of OSA severity and are generally considered to be on the pathophysiologic spectrum of OSA. However, COPD-specific alterations in breathing due to lower airway abnormalities may also contribute to RERAS in patients with COPD. (See "Polysomnography in the evaluation of sleep-disordered breathing in adults, section on ‘Respiratory effort-related arousals'.) PATHOPHYSIOLOGY — While the exact pathogenesis of nocturnal hypoxemia in COPD is unclear, normal sleep-related declines in neural drive to upper airway, intercostal, and respiratory pump muscles exacerbate ventilation-perfusion mismatch and hypoventilation in individuals with COPD and can cause a marked deterioration in gas transfer, particularly during rapid eye movement (REM) sleep [16.20.21 Sleep is associated with a depression in the sensitivity and set-point of both hypoxic and hypercapnic ventilatory responses [22]. This sleep-related ventilatory depression leads to modest elevations in arterial tension of carbon dioxide (PaCO,) in normal individuals compared with awake values [22]. In addition, sleep is associated with a loss of drive to upper airway dilator muscles [23.24] that leads to the development of partial upper airway obstruction, also known as inspiratory airflow limitation, in normal non-snoring and snoring individuals without sleep apnea [25]. Reductions in inspiratory airflow can further compromise ventilation and increase PaCO,. (See "Pathophysiology of obstructive sleep apnea in aduks".) COPD can lead to elevations in closing volume, which means that the small airways in the lung are closed during tidal volume breathing and not participating fully in gas exchange. The increase in closing volume in combination with @ reduction in functional residual capacity during sleep can exacerbate ventilation-perfusion mismatch and hypoxemia [26]. COPD is associated with alterations in respiratory mechanics and gas exchange that can lead to dynamic hyperinflation and/or hypoventilation [27]. During wakefulness, patients adopt specific mechanisms to minimize hyperinflation (by prolonging expiratory time) and to preserve alveolar ventilation (with pursed lip breathing) [28- 30], Sleep is associated with several changes in respiratory control that interfere with the compensatory mechanisms used during wakefulness. In COPD, reductions in ventilation during sleep can produce marked elevations in PaCOz because of concomitant elevations in dead space ventilation [31]. Mechanisms to minimize hypoventilation will exacerbate dynamic hyperinflation, whereas lengthening expiratory time could compromise ventilation during sleep. * Alloss of ventilatory drive leads to significant reductions in tidal volume [32], and compensatory mechanisms to prevent hypoventilation are left to changes in respiratory pattern. An increase in inspiratory time would increase tidal volume but would reduce expiratory time, potentially exacerbating air trapping. Similarly, an increase in respiratory rate would maintain minute ventilation but also reduce expiratory time. In either case, respiratory patterns during sleep in COPD can worsen dynamic hyperinflation by shortening expiratory time {33} ‘Inspiratory flow limitation (IFL) is commonly observed during sleep and even mild degrees of IFL lengthen inspiratory time, further comprising expiratory time [34]. Thus, sleep induces specific alterations in breathing pattern that compromise ventilation and increase ventilatory loads in COPD. It has been shown that hyperinflation is associated with reductions in sleep efficiency [19] ipsshwon uptodate. comcorerts/slep-elaod bathing. disor ders-ir-copaprint?scurce=search resulfsearch= epocSsolectodTile=21~150 29sananots ‘Sleop-elated breathing orders in COPO - UpToDate Moreover, the mechanism by which these changes contribute to sleep fragmentation and morning fatigue in COPD is likely due to increased arousal frequency (RERAs) and is under clinical investigation [35] Obstructive sleep apnea (OSA) is characterized by increased collapsibility of the upper airway leading to inspiratory flow limitation, manifest by snoring, hypopneas, and apneas. The interrelationship of COPD and OSA is complicated, as the manifestations of COPD can vary among individual patients. As an example, some patients have a more emphysematous presentation and others have more airways disease (chronic bronchitis) with less air trapping, Increasing lung volumes due to air trapping are associated with improvements in upper airway collapsibilty [33], which may explain why COPD patients with emphysema (pink puffer) typically do not present with concomitant OSA while obese COPD patients (blue bloater) exhibit significant OSA more often. Regardless, the coexistence of OSA and COPD has been associated with more pronounced hypoxemia and hypercapnia ‘compared with COPD or OSA individually. CONTRIBUTING FACTORS — The majority of patients with COPD have multiple comorbid conditions that are associated with an increased risk of sleep-related breathing disorders, such as metabolic syndrome (approximately 25 to 50 percent), smoking, cardiovascular diseases, and opioid use [36.37] Obesity — The prevalence of obesity (body mass index [BMl] 230 kg/m?) in COPD is increasing, ranging from 25 to 42 percent [37]. In patients with COPD and obesity, respiratory disturbances and blood gas abnormalities (hypoxemia and hypercapnia) first occur during sleep, when ventilation responsiveness to chemical stimuli is, blunted and the wakefulness drive is reduced. In addition, decreases in accessory muscle activity, particularly during rapid eye movement (REM) sleep, place an additional burden on the diaphragm, which is already under mechanical disadvantage. Moreover, obesity is the strongest predictor for having coexisting OSA. A BMI >30 kg/m? increases the probability of having obstructive sleep apnea (OSA) to more than 50 percent in men and approximately 20 to 30 percent in women. (See "Overview of obstructive sleep apnea in adults’, section on ‘Risk factors’) In patients with COPD and obesity, positive airway pressure may not only mitigate OSA but also offset the mechanical disadvantage in obese COPD patients [36]. Smoking — Current smokers have a greater likelihood of snoring and SRBD relative to never smokers [38]. Inhalation of nicotine in cigarette smoke and withdrawal from nicotine during smoking cessation can also cause sleep disruption [39.40 Heart failure — Central sleep apnea is not commonly seen in patients with COPD but can develop in the presence of heart failure or other cardiovascular comorbidities. The primary predisposing condition for central sleep apnea is heart failure with a reduction in cardiac output, leading to Cheyne Stokes type of central apnea. The presence of heart failure with reduced ejection fraction (below 40 percent) increases likelinood of having central sleep apnea to more than 50 percent. (See "Sleep-disordered breathing in heart failure",) Opioid use — Chronic opioid use is an increasingly recognized risk factor for SRBD. Central sleep apnea is the most common form, although obstructive and mixed patterns also occur. Central sleep apnea related to opioid use is often marked by irregular respiratory patterns, including ataxic breathing. (See "Sleep-disordered breathing in patients chronically using opioids” ) CLINICAL FEATURES — The symptoms and signs of SRBD in patients with COPD are essentially the same as for patients without COPD (table 1). However, patients may be asymptomatic or their symptoms may overlap with the features of COPD itself and are thus not reported. A large study demonstrated that nighttime symptoms in COPD patients frequently go unnoticed by physicians and may not be reported by patients themselves [6.41.42]. Thus, a specific sleep history should be sought from both ipsshwor uptodate. coments slep-elaod- bathing. sor ders-ir-copaprint?scurce=search resulfsearch= epocSsoletodTile=21~150 anesananots ‘Sleop-elated breathing orders in COPO - UpToDate the patient and the bed partner because, in many cases, itis only the bed partner who is aware of the abnormal ventilatory patter. ‘The symptoms and signs of SRBD in patients with COPD include snoring, insomnia, awakening with a sensation of gasping or choking, morning headaches, daytime sleepiness or fatigue, and poor concentration or memory impairment (table 1). Additional features that may suggest SRBD include a large neck circumference, shallow or “crowded airway,” and obesity Patients with severe COPD typically have disrupted sleep and often have desaturations during non-rapid eye movement (NREM) sleep that are more pronounced during rapid eye movement (REM) sleep [43]. Ina population-based study, nocturnal oxygen desaturation was more common among those whose forced expiratory volume in one second/forced vital capacity (FEV;/FVC) ratio was <0.65 [2]. While patients with acute hypercapnia may develop symptoms of hypercapnia (eg, anxiety, dyspnea, daytime sluggishness, morning headaches, hypersomnolence, confusion) when the PaCO, is above 75 mmHg, patients with chronic hypercapnia may not develop symptoms until the PaCO, rises above 90 mmHg. (See "Mechanisms, causes, and effects of hypercapnia’. section on ‘Effects of hypercapnia.) DIAGNOSIS — The diagnosis of SRBD in patients with COPD requires a high index of suspicion and formal sleep testing with polysomnography, since clinical features and questionnaires lack sensitivity and often overlap with symptoms of COPD. Detecting SRBD is challenging in patients with COPD due to the following: ‘* The primary sleep problems reported by patients are difficulties initiating and maintaining sleep and reduced sleep time, and these often supersede other symptoms of SRBD such as unrefreshed sleep, waking up gasping and choking, morning headaches, and increased daytime sleepiness [1] ‘* Nocturnal hypoxemia, while commonly observed in COPD patients with borderline daytime oxygen levels of, 90 to 95 percent, does not produce specific symptoms [3] and often remains undetected. ‘* Standardized questionnaires for screening and determining probability of obstructive sleep apnea (OSA), such as the Epworth Sleepiness Scale and the Sleep Apnea Clinical Score, have limited utility and are not validated for use in COPD patients [44] When should SRBD be suspected in COPD? The following criteria have been recommended as disorders in COPD [45] ications for evaluation for possible sleep-related breathing ‘* Patients with COPD who report typical symptoms suggestive of OSA such as snoring (especially expiratory), gasping and choking, morning headaches, or increased daytime sleepiness [46] ‘© Obesity (body mass index [BMI] >35) with or without specific symptoms of OSA ‘* Reduced daytime pulse oxygen saturation (below 93 percent) at rest or during exercise Daytime hypercapnia Neck circumference >43 om (17 inches) in men and >41 cm (16 inches) in women. Signs of pulmonary hypertension or right heart failure Polycyther Morning headaches, especially in response to oxygen therapy Patients who use drugs that are known to affect breathing such as opioids and hypnotic medications ipsshwen uptodate. comforters slep-elaod bathing. sor ders-ir-copaprint?scurce=search resulfsearch=epocdsolectodTile=21~150 angsan22016 ‘Slop relate breathing sordrs in COPO - UpTeDate Overnight pulse oximetry — For asymptomatic patients with a resting awake pulse oxygen saturation (SpO;) of 90 to 95 percent, overnight oximetry at home may be an appropriate initial step as a screening device for certain types of SRBD [3.47.48]. Among patients with sleep-related desaturation detected by overnight oximetry, approximately half have OSA, and a polysomnogram (PSG) is needed to identify these patients. However, overnight oximetry when measured alone is not recommended as a screening test for OSA. (See “Home sleep apnea testing for obstructive sleep apnea in adults", section on ‘Pulse oximetry’) The reliability of overnight pulse oximetry in COPD was found to be consistent in identifying nocturnal hypoxemia in one study [48], but less reliable in another [49]. More than one night of observation may be appropriate to adequately evaluate nocturnal hypoxemia In-laboratory polysomnography — In-laboratory PSG is required to diagnose sleep-related breathing disorders in patients with COPD. (See "Polysomnography in the evaluation of sleep-disordered breathin adults".) Home sleep apnea testing (HSAT), which is widely used for the diagnosis of OSA in otherwise healthy individuals, is not adequate in patients with COPD and should not be substituted for in-laboratory PSG [50]. HSAT has not been validated in patients with COPD and, unlike in-laboratory PSG, does not include sufficient monitoring to detect the full range of COPD-specific SRBD, such as hypoventilation without severe hypoxemia using CO, monitoring devices or periods of inspiratory and expiratory airflow limitation leading to frequent arousal [45]. (See ‘Clinical presentation and diagnosis of obstructive sleep apnea in adults", section on ‘Home sleep apnea testing’ and "Hom nea testing for obstructiv. nea in adults",) Full-night study (preferred) — For patients with symptoms or signs of a SRBD, the preferred test is a standard in-laboratory PSG with continuous monitoring of carbon dioxide via an end-tidal (etCO,) or transcutaneous (teCO,) system, particularly in those patients with daytime hypercapnia or daytime hypoxemia. Full-night PSG is preferred over a split-night study for patients with COPD, even if severe sleep apnea is apparent in the first third of the night in a range that would qualify for continuous positive airway pressure (CPAP), because patients with COPD may have more than one type of SRBD. Patients with severe emphysema often use accessory intercostals muscles to support ventilation. These patients are more vulnerable to decompensation during rapid eye movement (REM) sleep due to muscle atonia/hypotonia, and REM sleep usually predominates in the second half of the night. A full-night PSG will allow determination of whether REM sleep-related hypotonia/atonia worsens OSA, gas transfer, and breathing mechanics. (See 'Solit-niaht protocol’ below.) Additional considerations relevant to patients with COPD include the following: * Sleep-related hypercapnia — In patients with COPD, tcCO2 monitoring is the preferred method to detect, sleep-related hypercapnia or worsening of hypercapnia because e{COr underestimates COr due to abnormalities in breathing mechanics and shortened expiratory time during inspiratory flow limitation. In addition, etCOz cannot be performed during titration of PAP. However, etCO2 monitoring is more widely available than toCO2 monitoring, (See "Polysomnography in the evaluation of sleep-disordered breathing in adults’, section on 'Ventilation’.) * Periodic leg movements — Special emphasis should also be placed on monitoring periodic leg movements, as periodic leg movements of sleep (PLMS) are common during non-REM (NREM) sleep in COPD patients and they can be mistaken for respiratory events, when associated with either arousal or inspiratory flow limitation [Z]. (See “Polysomnography in the evaluation of abnormal movements during sleep") ‘* Supplemental oxygen — In patients with daytime hypoxemia who desaturate readily during sleep, supplemental oxygen will markedly alter the frequency and severity of nocturnal oxyhemoglobin tpsihwm.uploate com eortrssleop oats breathing csordrsin-coperint2source=search resussearch=epockselectedTile=21~150 59san22016 ‘Slop relate breathing sordrs in COPO - UpTeDate desaturations, Most COPD sleep centers initiate a sleep study omitting supplemental oxygen in patients who have pulse oxygen saturation (SpOz) levels >88 percent and then add oxygen if SpOz decreases to below 88 percent in NREM sleep for more than 10 minutes. Split-night protocol — For patients with a high likelihood of OSA and without baseline hypercapnia, it may be practical to order a split-night study with initial documentation of OSA and then initiation of CPAP, following the usual acceptability criteria that are described separately, (See "Overview of polysomnography in adults", section ‘on Split-night protocol’) Although split-night studies are now well established for sleep apnea patients, their value in COPD patients remains unclear for the following reasons: (1) REM sleep represents a particular vulnerability for patients with COPD and documentation of the REM effect often cannot be obtained from the first two to three hours of sleep; (2) Initiation of CPAP can worsen hyperinflation and may cause patients to reject CPAP in the latter part of the night. A careful adaptation to CPAP and its modalities are warranted in these cases. A split-night study must document an apnea hypopnea index (AHI) 240 during a minimum of two hours and then titrate CPAP for more than three hours, as respiratory events can worsen during the latter part of the night. CPAP must eliminate respiratory events during REM and NREM sleep, including REM sleep when supine. Diagnostic criteria — Diagnostic criteria for the various forms of SRBD have been established by the American Academy of Sleep Medicine [51] * Sleep-related hypoxemia — Significant sleep-related hypoxemia is defined as a SpO2 of <88 percent (<90 percent in children) for 25 minutes and the absence of sleep-related hypoventilation. In addition, the sleep- related hypoxemia is not better explained by another disorder (eg, OSA). ‘* Obstructive sleep apnea — OSA is defined by the presence of 25 predominantly obstructive respiratory events (ie, obstructive and mixed apneas, hypopneas, or respiratory effort-related arousals [RERAs]) per hour of sleep (for in-laboratory PSG) or recording time (for out-of-center sleep testing) AND symptoms (eg, sleepiness, nonrestorative sleep, awakening with gasping or choking, snoring) or signs (eg, hypertension, cognitive dysfunction, heart failure) consistent with OSA [51]. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults’, section on ‘Diagnosis'.) ‘© Central sleep apnea — Central sleep apnea (CSA) is defined by the presence of 25 central apneas and/or hypopneas per hour of sleep (or recording time if a home study) plus a requirement that more than 50 percent of the total number of apneas and hypopneas are central [51]. In addition, patients must have one or more symptoms related to the disorder (eg, sleepiness, nonrestorative sleep, snoring, witnessed apneas). (See "Central sleep apnea: Risk factors, clinical presentation, and diagnosis", section on ‘Diagnostic criteria’) ‘* Sleep-related hypoventilation — Sleep-related hypoventilation is defined as an arterial tension of carbon dioxide (PaCOp) >45 mmHg or an increase in PaCOz 210 mm Hg during sleep compared to PaCOz levels in wakefulness or in a supine position, The primary cause of hypoventilation is related to COPD (or another pulmonary disorder), but not obesity hypoventilation. Sleep-related hypoventilation is generally most severe during REM sleep. Hypoxemia may or may not be present. (See "Polysomnography in the evaluation of sleep-disordered breathing in adults’, section on ‘Hypoventilation’.) For patients with COPD, hypercapnia can be due to dead space ventilation and ventilation-perfusion mismatching from COPD or concomitant obesity hypoventilation syndrome, OSA, or neuromuscular weakness (eg, diaphragmatic paralysis). (See "Mechanism ‘Mechanisms and etiologies of hypercapnia’ ) ipsshwen uptodate. comforters slep-elaod bathing. sor ders-ir-copaprint?scurce=search resulfsearch=epocdsolectodTile=21~150 arssananots ‘Sleop-elated breathing orders in COPO - UpToDate DIFFERENTIAL DIAGNOSIS — The differential diagnosis of SRBD includes a variety of non-respiratory causes of sleep disturbances and daytime sleepiness. Sleep fragmentation may be due to coughing or shortness of breath and other processes that can cause SRBD that are unassociated with COPD (eg, heart failure) [37]. Depression and anxiety are common among patients with COPD and can contribute to poor sleep quality and excessive daytime sleepiness [52.53]. Polysomnography (PSG) is often necessary to exclude SRBD in patients with depression or anxiety. (See “Clinical presentation and diagnosis of obstructive sleep apnea in adults’, section on Differential diagnosis’ and "Clinical manifestations and diagnosis of obesity hypoventilation syndrome" and "Sleep-disordered breathing in heart failure".) Medications used to treat COPD can contribute to sleep disturbance. Medications such as theophylline and glucocorticoids are known to produce insomnia, but can also cause breathing abnormalities in sleep by stimulating ventilation (theophylline) or affecting upper airway resistance (glucocorticoids) [54.55]. However, the use of these medications does not necessarily explain sleep disturbances and should not preclude in-laboratory evaluation for possible sleep apnea. TREATMENT — Management of SRBD in patients with COPD should be individualized according to the type and severity of SRBD. Treatment options range from nocturnal oxygen in patients with isolated sleep-related hypoxemia to positive airway pressure therapy in patients with obstructive or central sleep apnea. The goals of therapy are to alleviate hypoxemia during sleep, improve sleep quality, and reduce COPD-related morbidity and possibly mortality [37.41.56] Pharmacotherapy including anticholinergic and beta-agonist drugs and theophvline are well-established treatments to improve bronchial airway properties and ventilation; thus they can also improve SRBD in COPD and poor sleep quality [41]. The use of these treatments in COPD is discussed separately. Similarly, although lung volume reduction therapy has been shown to improve breathing mechanics and sleep, the primary indication for this intervention is not sleep-disordered breathing, and thus, it is also discussed separately. (See ‘Management of stable chronic obstructive pulmonary disease" and "Lung volume reduction surgery in COPD") Sleep-related hypoxemia Indications for treatment — The treatment of sleep-related hypoxemia in the absence of other SRBDs is based on the severity and duration of hypoxemia. Importantly, nocturnal oxygen therapy alone is not recommended for patients with comorbid COPD and obstructive sleep apnea (OSA). (See ‘Obstructive sleep apnea’ below.) Medicare criteria for nocturnal oxygen supplementation include: ‘* A decrease in pulse oxygen saturation (SpOz) more than 5 percent for at least five minutes during sleep. ‘* Associated symptoms or signs reasonably attributed to hypoxemia (eg, impaired cognition, nocturnal restlessness, pulmonary hypertension, erythrocytosis) [57] ‘* Absence of another cause of sleep-related hypoxemia (eg, OSA). If determination of nocturnal desaturation is made by overnight oximetry, concomitant OSA should be excluded by careful history and/or polysomnography. (See ‘Diagnostic criteria’ above.) When indicated, supplemental oxygen is generally supplied by nasal cannula at a flow rate sufficient to maintain the SpO> in the range of 90 to 92 percent [41]. (See “Long-term supplemental oxygen therapy".) Efficacy — The strength of the evidence in favor of administering supplemental oxygen to prevent long-term consequences of sleep-related hypoxemia depends on the degree of daytime hypoxemia Severe daytime hypoxemia — Continuous home oxygen therapy is recommended in patients with severe resting awake hypoxemia (partial pressure of arterial oxygen [PaOz] less than 55 mmHg [8 kPa]) due to ipstwor uptodate. comcorerts/slep-elaod bathing. disor ders-ir-copaprint?source=search resulfsearch= epocSsoletodTile=21~150 m9sananots ‘Sleop-elated breathing orders in COPO - UpToDate COPD because it improves survival and quality of lfe [58.59]. The use of long-term oxygen therapy (LTOT) in COPD is described separately. (See ‘Long-term supplemental oxygen therapy", section on 'Benefits'.) The exact flow rate of supplemental oxygen needed to prevent sleep-related hypoxemia may be higher than the amount needed when the patient is awake. In the Nocturnal Oxygen Therapy Trial, the oxygen flow was routinely increased by 1 Lminute during sleep [58]. We typically obtain an overnight oximetry study to guide ‘oxygen supplementation in patients with pulmonary hypertension or significant hyperinflation due to COPD. ‘These patients often have significant perfusion/ventilation mismatch or a right-left shunt with severe hypoxemia that is unresponsive to supplemental oxygen. ‘* Mild to moderate daytime hypoxemia — While long-term home oxygen therapy improves survival in COPD patients with severe hypoxemia, home oxygen therapy does not appear to improve survival in patients with mild to moderate hypoxemia or in those with arterial desaturation only at night [60]. However, one study demonstrated an improvement in cycle ergometry time and end-exercise dyspnea in patients on LTOT (2 Limin for >15 hours/day) for one year [64]. Nevertheless, sleep-related oxygen desaturation is considered by many physicians (including us) as an indication for providing nocturnal oxygen therapy in patients who would not otherwise qualify for LTOT, and a number of patients are currently treated with nocturnal oxygen (62). The forthcoming results from the Long- term Oxygen Treatment Trial (LOTT) should help clarify the role of nocturnal oxygen in these patients. * Nocturnal hypoxemia without daytime hypoxemia — The rationale behind treatment of nocturnal hypoxemia in patients without daytime hypoxemia is based on the observation that pulmonary hypertension in COPD is related to the severity of desaturation occurring during sleep [63]. However, data on long-term ‘outcomes of nocturnal oxygen therapy (including sleep quality) in such patients are not available. In the absence of clinical trials, justification for nocturnal oxygen therapy in these patients is based on comorbidities in which hypoxemia is known to be a risk factor such as pulmonary hypertension, right heart failure, cardiac arrhythmia, and coronary artery disease. In these patients we recommend correction of nocturnal hypoxia with nocturnal supplemental oxygen. Risk of hypoventilation with supplemental oxygen — In approximately 20 percent of COPD patients requiring oxygen, oxygen therapy at night can worsen hypoventilation during sleep, but this rise in CO2 rarely worsens hypercapnia and acidosis in the morning (64. Even in patients with severe COPD (mean arterial carbon dioxide tension [PaCO,] 53 mmHg), the administration of supplemental oxygen at night was associated with only small (<6 mmHg) increases in PaCOz throughout sleep [65]. Nevertheless, if the rise in PaCOp offsets the beneficial effect of oxygenation, institution of positive airway pressure (PAP) therapy can mitigate the worsening of hypoventilation. The possibility that nocturnal oxygen therapy may worsen SRBD in patients with COPD is being examined in an National institutes of Health (NIH)-sponsored trial [66] Obstructive sleep apnea — Treatment of OSA includes a combination of patient education, lifestyle modifications (eg, weight loss for patients who are overweight or obese, alcohol avoidance), and PAP. An overview of OSA management is provided separately along with guidance regarding the initiation and titration of PAP. (See “Management of obstructive sleep apnea in adults” and “Initiation of positive airway pressure therapy for obstructive sleep apnea in adults" and "Mode selection for positive airway pressure titration in adults with obstructive sleep apnea") Initiating positive airway pressure — PAP is the mainstay of therapy for OSA, almost always starting with continuous positive airway pressure (CPAP). Patients with COPD and OSA are considered to have complicated OSA and generally require initiation and manual titration of PAP in a sleep laboratory; moderate to severe COPD and oxygen-dependent COPD are considered contraindications to initiating CPAP with auto-titrating devices at ipstwor uptodate. comcorerts/slep-elaod bathing. disor ders-ir-copaprint?source=search resulfsearch= epocSsoletodTile=21~150 aresananots ‘Sleop-elated breathing orders in COPO - UpToDate home, (See “Initiation of positive airway pressure therapy for obstructive sleep apnea in adults", section on 'Modes of positive airway pressure’.) Initiation of PAP - The initiation of PAP in patients with COPD and OSA, generally follows the protocol outlined for routine treatment of OSA and starts with CPAP at 4 cm H,O. Heated humidification is generally recommended for patients receiving CPAP. However, some patients with COPD are sensitive to changes in humidity and may report increased cough or dyspnea when the level of humidity is too high (or too low) for them. (See “Initiation of positive airway pressure therapy for obstructive si nea in adults", ‘Determining the amount of positive airway pressure’ and “Initiation of positive airway pressure therapy for obstructive sleep apnea in adults’, section on ‘Humidification’.) * Efficacy — For patients with coexisting obstructive sleep apnea and COPD, PAP has been shown to reduce mortality, morbidity, and exacerbation rates [57]. In a prospective study, 651 COPD patients, 228 with OSA and treated with CPAP, 213 with OSA but not treated with CPAP, and 210 patients without OSA, were followed for a median duration of 9.4 years [67]. Patients with OSA not treated with CPAP had a higher mortality (relative risk 1.79, 95% Cl 1.16-2.77) and were more likely to experience a severe COPD exacerbation leading to hospitalization compared with the COPD-only group. In addition, patients with OSA treated with CPAP had no increased risk for mortality or exacerbations compared with patients with COPD alone. The latter finding was extended in a post hoc analysis of 10,272 COPD patients showing that greater time on CPAP was associated with reduced mortality [68] CPAP is also effective in mitigating the excess risk of mortality in hypercapnic patients [69] and in hypoxemic COPD patients {70} CPAP failure or intolerance — While CPAP is sufficient in most patients with concomitant OSA and COPD, ‘some patients require high levels of PAP to achieve control of OSA. The American Academy of Sleep Medicine (AASM) suggests changing to bilevel positive airway pressure (BPAP) in the spontaneous mode, if residual obstructive events or snoring are observed on CPAP therapy at a pressure of 215 om H,0 [74]. The application of PAP in patients with severe emphysema can also worsen dynamic hyperinflation and increase work of breathing, particularly at pressures exceeding 10 cm HzO [16]. In these patients, newer PAP devices that allow reduction in expiratory pressures or even the application of bilevel PAP may help to get patients adjusted to PAP and lower the side effects Other modalities of inspiratory pressure support (adaptive server ventilation [ASV] or auto-adapting bi-positive pressure ventilation [AVAP]) may further improve nocturnal and diurnal blood gases, although it remains unclear whether these modalities provide additional clinical benefit in these patients compared to CPAP alone [72]. (See ‘Modes of mechanical ventilation’, section on ‘Adaptive support ventilation’) Central sleep apnea — Data regarding the consequences of central sleep-disordered breathing events in patients with COPD are lacking. Nevertheless, as for central sleep apnea (CSA) in the absence of COPD, treatment should be considered if CSA and the underlying cause (ie, heart failure) impose additional health risks to the patient [1,73]. (See "Central sleep apnea: Treatment’. ‘Some patients develop central apneas during the initiation of CPAP for OSA, a phenomenon known as treatment ‘emergent CSA. The management of treatment-emergent CSA generally involves continuing CPAP, as many patients will spontaneously improve, Patients who do not improve (and do not have heart failure) can be switched to ASV; bilevel PAP (BPAP) with a backup rate is a reasonable alternative, Treatment-emergent OSA is described separately. (See "Mode selection for positive airway pressure titration in adult patients with central sleep apnea syndromes" and "Treatment-emergent central sleep apnea") ipsshwor uptodate. coments slep-elaod- bathing. sor ders-ir-copaprint?scurce=search resulfsearch= epocSsoletodTile=21~150 a9san22016 ‘Slop relate breathing sordrs in COPO - UpTeDate Sleep-related hypoventilation — Patients with severe COPD and intermittent or persistent daytime hypercapnia often experience worsening hypoventilation during sleep even in the absence of OSA. Noninvasive ventilation — The optimal role for noninvasive ventilation (NIV; eg, CPAP or BPAP) in these patients is unclear and data are limited [74]. Patients with poor sleep quality and/or daytime sleepiness may be more likely to derive benefit. Nocturnal NIV has been used in combination with supplemental oxygen in patients with daytime hypercapnia and may improve survival, but not necessarily quality of life [74], Nocturnal NIV with supplemental oxygen improved sleep quality and daytime blood gases better than oxygen alone in some studies [75.76], but not in others [ZZ]. The benefits on sleep and daytime blood gases have been attributed to improvements in breathing mechanics such as reductions in micro-atelectasis with positive pressure, prevention of collapse in the intrapulmonary airways, and reduction in work of breathing all of which contribute to resting of chronically fatigued respiratory muscles [41]. The rationale for nocturnal NIV in COPD, its implementation, and effects on survival and quality of life in patients with COPD are discussed separately, (See "Nocturnal ventilator in COPD") For patients with sleep-related hypoventilation due to COPD, PAP is typically initiated in a sleep laboratory, if it has not already been titrated during a hospitalization. The details of initiation of noctumal NIV in patients with COPD are discussed separately. (See "Nocturnal ventilatory support in COPD", section on ‘Practical aspects’) Pharmacotherapy — Respiratory stimulants such as progestational agent, theophylline, acetazolamide, and protriptyline were once used to treat hypercapnia, but the benefits were modest and not maintained. They are rarely utilized for this indication. (See "Central sleep apnea: Treatment", section on ‘Pharmacologic therapy’ and "Disorders of venti trol", section on ‘Drugs affecting ventilatory drive’) Future directions — Ongoing research is aimed at determining whether nocturnal oxygen therapy is beneficial in mild hypoxemia (see ‘Sleep-related hypoxemia! above), whether ASV or AVAP have a role in the treatment for CSA, and whether more comfortable and effective interfaces and modes for treating SRBD in patients with COPD will improve sleep quality and adherence. As an example, nasal high flow therapy with oxygen or room air may have a role in SRBD. Positive airway pressure (CPAP, BPAP), noninvasive ventilation (NIV), and long-term oxygen therapy are the mainstream treatments for sleep-disordered breathing in COPD, but adherence rates are low [78-80]. For these patients, nasal high flow of warm and humidified air (NHF) may represent an alternative means to improve sleep- disordered breathing. NHF of oxygen or room air through an open nasal cannula was first introduced to improve ‘oxygenation in infants and children with hypoxic respiratory failure [81]. It has then been extended to adult pulmonary care [82-84]. Moreover, several studies also demonstrate that it may improve arterial blood gases and exacerbation rate in COPD patients with hypercapnic respiratory failure [85.86]. The mechanisms have been attributed to reductions in dead space ventilation [87], slight increases in positive expiratory pressure (88), and reductions in work of breathing [87]. Although several nasal high flow medical devices exist for use in various hospital settings using pressurized air outlets (eg, TNI Soft Flow, Optifiow, Precision Flow) there are only a few devices that provide adequate comfort and minimal noise required for use during sleep. Whether nocturnal use of NHF air can prevent nocturnal hypercapnia and improve daytime outcomes similar to CPAP or long-term oxygen therapy is being examined in several clinical trials [89.90]. PROGNOSTIC IMPLICATIONS — SRBD may adversely affect quality of life, morbidity, and mortality in patients with COPD. * Sleep-related hypoxemia — Several ines of evidence suggest that sleep-related hypoxemia may increase morbidity and mortality in COPD. First, in the Nocturnal Oxygen Treatment Trial [13.58], a post hoc analysis, ps:vn upladoe.com/corertssleep-telaod- breathing disorders copaprint@source= search resulBsearch=epocSselecodTile=21~150 1019san22016 ‘Slop relate breathing sordrs in COPO - UpTeDate revealed increased mortality in patients with noctumal hypoxemia. Second, sleep-related oxygen desaturation has been associated with worsening pulmonary hypertension and cor pulmonale [21,92]. Third, sleep-related hypoxemia is associated with neurocognitive dysfunction [93,94], which can improve with treatment for sleep-disordered breathing [25]. Nevertheless, studies examining the effects of nocturnal ‘oxygen administration on outcomes in COPD have been inconclusive due to small sample sizes and high attrition rates [13.17.96] ‘* Obstructive sleep apnea — Several large studies now show that the coexistence of obstructive sleep apnea (OSA) is a negative prognostic predictor for both cardiovascular disease and mortality in COPD patients [67] In a retrospective case control study consisting of 10,981 men with OSA, comorbid COPD was associated with a seven-fold increased risk for all-cause mortality [97]. Decreased survival has been attributed to a greater frequency of exacerbations, more severe hypoxemia and hypercapnia, pulmonary hypertension, and cor pulmonale with potentially lethal arrhythmias. ‘¢ Pulmonary hypertension — While pulmonary hypertension (PH) is not common in patients with even severe OSA, the risk for having pulmonary arterial hypertension with OSA is increased in patients with coexisting COPD, chronic hypoventilation, and obesity [60]. The prevalence of pulmonary hypertension in patients with COPD GOLD stage 2 to 3 is approximately 25 percent (22 to 27 percent) and increases to 33 to 53 percent in patients with GOLD stage 4 COPD [98,99]. The combination of OSA and COPD increased right ventricular remodeling compared to COPD alone and may explain the increased mortality compared to COPD or OSA alone. Nevertheless, compared with daytime hypoxia, hypercapnia and reduced forced expiratory volume in one second (FEV;), indices that reflect OSA severity (such as apnea hypopnea index [AHI] or oxygen desaturation index [OD!]), play a minor role for developing pulmonary hypertension and right heart failure [41,56]. Moreover, while daytime hypoxemia is the strongest predictor for the development of PH, there is no evidence that nocturnal hypoxia alone increases the risk for PH. SUMMARY AND RECOMMENDATIONS * Chronic obstructive pulmonary disease (COPD) is associated with a spectrum of sleep-related breathing disorders (SRBD; formerly called sleep disordered breathing) that include sleep-related hypoxemia, obstructive sleep apnea (OSA), central sleep apnea, respiratory effort-related arousals, and sleep-related hypoventilation. (See ‘Introduction’ above.) ‘The majority of patients with COPD have at least one comorbid condition and more than half have at least four coexisting conditions (eg, obesity, heart failure, smoking, opioid use) that are associated with a higher prevalence of sleep-related breathing disorders. (See ‘Contributing factors’ above.) ‘© The symptoms and signs of SRBD in patients with COPD are essentially the same as for those without COPD (eg, snoring, insomnia, awakening with gasping or choking, morning headaches, daytime sleepiness or fatigue, and poor concentration or memory impairment). However, patients may be asymptomatic or may have symptoms that overlap with the features of COPD itself and thus not report them. (See ‘Clinical features’ above.) ‘* The diagnosis of SRBD in patients with COPD requires a high index of suspicion and formal sleep testing with polysomnography. Indications include symptoms of SRBD, obesity (body mass index [BMI] >35), neck circumference >43 cm (17 inches) in men or >41 cm (16 inches) in women, pulse oxygen saturation [SpO2] <93 percent, daytime hypercapnia, pulmonary hypertension, or cor pulmonale. (See ‘When should SRBD be suspected in COPD?’ above.) ‘* For patients with a high likelihood of OSA and without baseline hypercapnia, it may be practical to obtain a split-night study due to issues with accessibility; otherwise a full night polysomnogram is preferred. When ipstwor uptodate. comcorerts/slep-elaod bathing. disor ders-ir-copaprint?source=search resulfsearch= epocSsoletodTile=21~150 9sananoe ‘Sleep-lated breathing disorders in COPD - UpTeDate possible, continuous monitoring of carbon dioxide via an end-tidal (etCOz) or transcutaneous (teCO2) system, is helpful, particularly in patients with daytime hypercapnia or daytime hypoxemia. (See ‘in- laboratory polysomnography’ above.) ‘* Diagnostic criteria for the various SRBD have been established by the American Academy of Sleep Medicine, (See ‘Diagnostic criteria’ above.) ‘* For patients with COPD and sleep-related hypoxemia, but without other SRBD, supplemental oxygen via nasal cannula is the mainstay of therapy for desaturation that does not improve after optimizing COPD therapy. (See ‘Sleep-related hypoxemia’ above.) ‘* Treatment of OSA in patients with COPD includes a combination of patient education, lifestyle modifications, and positive airway pressure (PAP). Initiation and titration of PAP should be performed manually in a sleep laboratory. (See 'Obstructive sleep apnea! above.) ‘* For patients with hypercapnia due to a combination of COPD and OSA, bilevel PAP (BPAP) may be preferred over continuous PAP (CPAP) in order to improve alveolar ventilation and reduce hypercapnia. (See ‘Noninvasive ventilation’ above.) 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Topic 7680 Version 19.0 ipsshwen uptodate. comforters slep-elaod bathing. sor ders-ir-copaprint?scurce=search resulfsearch=epocdsolectodTile=21~150 amgsan016 ‘Sleop-elated breathing orders in COPO - UpToDate GRAPHICS Clinical features of obstructive sleep apnea (OSA) Symptoms Examination findings = Daytime sleepiness = Narrow or "crowded" airway 1» Nonrestorative slees = Obesity = Loud snoring 1 Large neck circumference 1» Witnessed apneas by bed partner = Systemic hypertension = Awakening with choking = Hypercapnia 1 Nocturnal restlessness = Cardiovascular disease 1 Insomnia with frequent awakenings 1 Cerebrovascular disease 1 Lack of concentration 1 Cardiac dysrhythmias Cognitive deficits = Pulmonary hypertension Changes in mood = Cor pulmonale 1 Morning headaches = Polycythemia 1 Vivie, strange, or threatening dreams = Floppy eyelid syndrome ‘= Gastroesophageal reflux = Nocturia Graphic $5633 Version 7.0, ipsshwor uptodate. coments slep-elaod- bathing. sor ders-ir-copaprint?scurce=search resulfsearch= epocSsoletodTile=21~150 swi9sananots ‘Sleop-elated breathing orders in COPO - UpToDate Contributor Disclosures Hartmut Schneider, MD, PhD Grant/Research/Clinical Trial Support: CF Foundation [COPD (High nasal airflow)]. Consultant/Advisory Boards: Fisher & Paykel Healthcare [COPD, CF (High nasal airflow)]; Itamar, Inc {OSA (Home sleep testing)]. Patent Holder: Johns Hopkins University [Respiratory Measurement (Disposable low resistance flow sensor)]. Equity Ownership/Stock Options: Resp(EQ) [Inhaled medication monitor]. Other Financial Interest: Ad hoc lectures (invited): H&L [COPD (Weaning and high flow therapy)]; GmbH [COPD (Weaning and high flow therapy)]; TNI Medical [COPD (High nasal airflow)]. James K Stoller, MD, MS Grant/Research/Ciinical Trial Support: CSL Behring [Alpha-1 antitrypsin detection (Pooled human alpha-1 antiprotease)]. Consultant/Advisory Boards: CSL Behring; Grifols; Baxalta [Alpha-1 antitrypsin detection (Pooled human alpha-1 antiprotease)|; Arrowhead Pharmaceuticals [Alpha-1 antitrypsin deficiency]. M Safwan Badr, MD Nothing to disclose Helen Hollingsworth, MD Nothing to disclose April F Eichler, MD, MPH Equity ‘Ownership/Stock Options: Johnson & Johnson [Dementia (galantamine), Epilepsy (topiramate)] Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy ipsshwor uptodate. coments slep-elaod- bathing. sor ders-ir-copaprint?scurce=search resulfsearch= epocSsoletodTile=21~150 199