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Research Priorities in Pathophysiology for -disordered in Patients with Chronic Obstructive Pulmonary Disease An Official American Thoracic Society Research Statement Atul Malhotra, Alan R. Schwartz, Hartmut Schneider, Robert L. Owens, Pamela DeYoung, MeiLan K. Han, Jadwiga A. Wedzicha, Nadia N. Hansel, Michelle R. Zeidler, Kevin C. Wilson, and M. Safwan Badr; on behalf of the ATS Assembly on Sleep and Respiratory Neurobiology

THIS OFFICIAL RESEARCH STATEMENT OF THE AMERICAN THORACIC SOCIETY WAS APPROVED DECEMBER 2017

Background: Obstructive sleep (OSA) and chronic was not a formal systematic review. Evidence was considered and obstructive pulmonary disease (COPD) are common conditions; supplemented with the panelists’ nonsystematic clinical the co-occurrence of these diseases, called the overlap syndrome observations. Important knowledge gaps were identified. (OVS), has been associated with poor health outcomes. Results: Recommendations for research to fill existing knowledge Purpose: The purpose of this Official American Thoracic Society gaps were made. The recommendations were formulated by Research Statement is to describe pathophysiology, epidemiology, discussion and consensus. outcomes, diagnostic metrics, and treatment of OVS, as well as to identify important gaps in knowledge and make recommendations Conclusions: Many important questions about OVS exist. This for future research. American Thoracic Society Research Statement highlights the types of research that leading clinicians and researchers believe will Methods: Clinicians and researchers with expertise in sleep have the greatest impact on better understanding the spectrum of medicine, pulmonary medicine, or both were invited to participate. disease, improving diagnosis, and optimizing therapy. Topics were divided among the participants according to their interest and expertise. A literature search was conducted; the search Keywords: ; sleep; COPD; hypoxia; apnea

Contents Is the AHI Useful in Patients with Should Supplemental Overview COPD? Oxygen Be Withdrawn Key Conclusions Is “” the for Overnight Recommendations Appropriate Term in Patients Polysomnography in Introduction with COPD? Patients with Suspected Methods Is REM-related Oxygen OVS? Significance of SDB in COPD Desaturation Predictive of Poor Revisiting the Sleep Study Pathophysiology Outcomes in Patients with Polysomnographic Features of Diagnosis COPD? SDB in COPD Epidemiology Is Capnometry Valuable in SDB in COPD Outcomes Sleep Studies of Patients with Sample Cases Appraisal of Existing Metrics COPD? Conclusions

Correspondence and requests for reprints should be addressed to Atul Malhotra, M.D., University of California San Diego, Pulmonary, Critical Care, and Sleep Medicine, 9300 Campus Point Drive, #7381, La Jolla, CA 92037. E-mail: [email protected]. This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org. Am J Respir Crit Care Med Vol 197, Iss 3, pp 289–299, Feb 1, 2018 Copyright © 2018 by the American Thoracic Society DOI: 10.1164/rccm.201712-2510ST Internet address: www.atsjournals.org

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Overview of , nadir of hypoxemia, increasing in epidemic proportions because and area under the oxygen desaturation of the aging population, indoor and The overlap syndrome (OVS) is the curve) as predictors of clinical outcomes outdoor air pollution, historical smoking co-occurrence of chronic obstructive in patients with COPD. trends, and other factors (1). Efforts to pulmonary disease (COPD) and obstructive d We recommend that future research slow the progression of COPD have failed sleep apnea (OSA). This statement evaluate sleep-disordered breathing in the majority of patients, and research summarizes the existing literature, identifies (i.e., central sleep apnea, OSA, increased seeks to identify new therapeutic knowledge gaps, and provides guidance upper , hypoventilation, approaches to improve COPD-related regarding future priorities in research for sleep fragmentation, etc.), rather than outcomes. Like COPD, obstructive sleep sleep-disordered breathing (SDB) in OSA specifically, in patients with COPD. apnea (OSA) has a high prevalence patients with COPD and other lung diseases. d We recommend studies that seek to and is associated with adverse health determine the pathophysiology of consequences (2–4). Patients with both oxygen desaturation during REM OSA and COPD are considered to have Key Conclusions sleep in patients with COPD. the overlap syndrome (OVS), which is d OVS is common because COPD and d fi We recommend trials that compare associated with particularly poor outcomes, OSA are common. There is no de nitive bilevel positive airway pressure to both including high mortality (5, 6). This evidence that patients with COPD are at continuous positive airway pressure and observation has led to an increased focus increased risk for developing OSA. no positive airway pressure therapy in on sleep as an important factor in the care d Mortality associated with OVS is higher patients with COPD who desaturate of the patient with COPD. than mortality associated with either during REM sleep. There exist many important questions COPD alone or OSA alone. Other d We recommend trials that compare about sleep-disordered breathing (SDB) in outcomes are likely worse too but have various methods of measuring gas COPD. Is the pathophysiology of SDB not been adequately measured. exchange in patients with OVS. As unique/special in COPD? How prevalent is d fi The optimal criteria for con rming examples, trials that compare pulse SDB in COPD? Does SDB affect clinical OSA in patients with COPD are unclear. oximetry plus transcutaneous CO2 outcomes in COPD? Should different The usual criteria for OSA rely on measurement to pulse oximetry alone, metrics be used to identify SDB in counting and hypopneas, but the pulse oximetry plus transcutaneous CO2 COPD? Are there polysomnographic predictive values of these respiratory measurement to arterial blood gas characteristics of SDB that are unique in events are unclear in COPD and, measurement, and pulse oximetry plus COPD? How should positive airway therefore, might lead to missed transcutaneous CO2 measurement to pressure therapy be used to treat SDB in diagnoses. fl pulse oximetry plus end-tidal CO2 COPD, given the con icting evidence measurement. (7–10)? How should supplemental oxygen Recommendations d We recommend trials that compare be used in patients with SDB and COPD, d We recommend investigations that supplemental oxygen to both continuous given the uncertain benefits in patients seek to understand mechanisms positive airway pressure therapy and with COPD and either exertional or underlying impaired respiratory bilevel positive airway pressure in nocturnal hypoxemia (11)? mechanics during sleep and how this patients with COPD who exhibit The purpose of this American Thoracic understanding might guide therapy nocturnal oxygen desaturation. Society research statement is to summarize to prevent complications. d We recommend research to develop existing evidence, identify knowledge gaps, d We recommend studies that improve our devices that can identify and characterize and make specific recommendations that understanding of gas exchange sleep without EEG. The goal is to pertain to SDB in patients with COPD. impairment during sleep in COPD. improve the assessment of the severity of d We recommend studies that investigate sleep-disordered breathing in patients whether there is a direct correlation with disruptions in sleep architecture. Methods between the prevalence of OSA and d We recommend studies that compare the severity of COPD. various methods to assess and quantify This research statement was developed d We recommend observational studies ventilation, the severity of inspiratory according to the rules of the American that compare clinical outcomes among and expiratory flow limitation, and the Thoracic Society. Details are provided in the patients with OVS to clinical outcomes presence of hyperinflation during online supplement. among patients with OSA alone or sleep (e.g., pneumotachography, nasal COPD alone. pressure signaling, and flow sensors) in d We recommend randomized trials that patients with COPD. Significance of SDB in COPD compare clinical outcomes among patients with OVS whose OSA is treated Pathophysiology to clinical outcomes among patients Introduction COPD is associated with abnormalities in with OVS whose OSA is untreated. respiratory mechanics and gas exchange d We recommend studies that compare the Chronic obstructive pulmonary disease (12). As a result, sleep is not a period of rest apnea–hypopnea index with other (COPD) is a major source of morbidity, for the , but rather a measures of OSA severity (e.g., duration mortality, and healthcare costs. It is physiological challenge for patients with

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AMERICAN THORACIC SOCIETY DOCUMENTS impaired pulmonary mechanics. During hyperinflation and increase the work of Patients with COPD may manifest sleep, the drive to breathe that is normally breathing. Patients with COPD have a subtle oscillations in ventilation, sleep provided by wakefulness is lost (Figure 1). physiological need to lengthen their architecture, and oxygenation that do not This change is associated with impaired expiratory time, but this mechanism meet the 4% detection threshold for load compensation, increased airflow compromises ventilation during sleep, hypopnea (20). The physiological effects resistance, and hypoventilation (13), even particularly in severe COPD (17). of resultant chronic intermittent among healthy persons. Individuals with Marked disturbances of the sleep-wake hypoxia-reoxygenation warrant further COPD have even greater increases in cycle are seen in patients with COPD investigation. Whether these cyclic airflow resistance and elastic loading during analogous to those observed in patients episodes contribute to adverse outcomes sleep because of intrathoracic airway with primary sleep disorders, such as OSA, in patients with COPD is yet to narrowing and hyperinflation, respectively restless legs syndrome, periodic limb be determined. Moreover, there is (16), similar to obese patients with a movements, and psychiatric disorders (18). considerable complexity underlying the narrow upper airway (14, 15). Although A large proportion of the sleep-wake biology of sustained versus intermittent healthy humans are able to preserve stable disturbances exhibited by patients with hypoxemia and the two in combination, sleep and adequate alveolar ventilation COPD are not well described by existing which requires further study. despite such changes, individuals with classification schemes. Sleep disruption RECOMMENDATION: We recommend abnormal respiratory mechanics may be may be related to impaired lung function investigations that seek to understand unable to tolerate the changes and, as a and hyperinflation or, alternatively, to mechanisms underlying impaired result, may deteriorate during sleep (16). changes in sleep-related behaviors respiratory function during sleep and how Patients with COPD may be unable to associated with worsening disease these understandings might guide therapy compensate for added loads. The usual (e.g., increased time in bed or daytime to prevent complications. compensatory physiologic responses to napping). The mechanism for these sustained resistive loading include elevation disturbances remains unclear. Alterations Diagnosis of the respiratory rate or a shortening of the in the sleep-wake cycle are associated with OVS represents the additive or synergistic expiratory time. In patients with COPD, elevations in inflammatory markers, yet the effects of COPD and OSA. The diagnosis however, these responses worsen dynamic long-term effects remain unknown (19). of OVS is made by full, in-laboratory polysomnography performed on a patient with COPD who presents with sleep-related Sleep + Circadian Factors + Supine Position complaints. The typical polysomnographic features are recurrent episodes of hypopnea alternating with hyperpnea, arousals, and a variable degree of oxygen desaturation. fi Decreased Ventilatory ↓ Upper Airway Worsening Airflow These ndings are presumed consequences Motor Output Muscle Activity Obstruction of upper airway narrowing or obstruction. Although this pattern is also seen in patients who have classic sleep apnea/hypopnea Decreased I/E syndrome (i.e., whose risk factors include Airflow unfavorable upper airway anatomy and/or an unstable ventilatory control system), in OVS the cycle of instability may be initiated by triggers such as worsening Expiratory UA Inspiratory Dynamic Alveolar airflow obstruction, hyperinflation, or Narrowing UA Narrowing Hyperinflation Hypoventilation hypoxia (17, 21). The presence and severity of upper airway narrowing during the hypopnea phase is unclear, and methods to identify the underlying pathophysiology Diaphragm Caudal of a hypopnea have not been validated. As ↑PaCO2 ↓PaO2 Dysfunction Traction a result, SDB in patients with COPD has been classified under the rubric “OSA,” owing to the limitation of qualitative diagnostic tools to identify the cause that Increased work of initiated the cycle of instability. Arousal Breathing Stimulation For patients with mild to moderate COPD, the panel has had good clinical experience using home sleep testing in their Ventilatory clinical practices, particularly for patients Overshoot without comorbid insomnia. Although Figure 1. Sleep cycle instability in chronic obstructive pulmonary disease. I/E = inspiratory/expiratory; the detection of apnea is reasonably UA = upper airway. straightforward, hypopneas, as defined by

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AMERICAN THORACIC SOCIETY DOCUMENTS a transient reduction in alveolar ventilation pathophysiological links. An important willingness to pursue CPAP therapy. The of at least two breaths, are more challenging limitation of these studies, however, is that possibility that such factors may be to assess definitively with home sleep most have restricted assessment to cohorts responsible for some of the differences testing, because detection methods rely with only mild COPD. Therefore, it is cannot be excluded (34). Second, patients on the consequences of decreased unknown whether more severe COPD with OVS tend to die from cardiovascular ventilation, namely oxygen desaturation predisposes to OSA. events that are attributed to cardiac disease, and arousals. However, it is unclear if the The prevalence of SDB in COPD may with little acknowledgment that underlying magnitude of oxygen desaturation may be be higher than typically reported if all OSA or COPD may have contributed to the dampened by hyperinflation and/or the severities of COPD are considered, as cardiovascular event (5). Thus, the impact of presence of carboxyhemoglobin (by suggested by a study that demonstrated a OVS, COPD, and OSA on survival may be shifting the oxyhemoglobin dissociation 66% prevalence of OSA among patients with underestimated. The precise mechanisms of curve to the left) (22, 23). moderate to severe COPD (2). Possible increased cardiovascular mortality in OVS RECOMMENDATION:We pathophysiological explanations for a have proven elusive. recommend studies that improve our higher prevalence of OSA among patients Few studies have been performed that understanding of gas exchange with moderate to severe COPD include evaluated the impact of treatment on impairment during sleep in COPD. Such upper airway narrowing due to edema fluid survival. One observational study of more studies could help guide definitions of shifting from the lower extremities to the than 1,000 patients with COPD reported various respiratory events as well as neck in those with cor pulmonale and that the duration of CPAP use directly criteria to judge severity of disease in upper airway myopathy due to either correlated with improved survival (30). patients with COPD and OSA. COPD itself (which can cause a skeletal Such observational data justify randomized muscle myopathy) or inhaled or systemic trials to evaluate the treatment of OSA in Epidemiology steroid use (28). Arguing against a patients with COPD. The epidemiology of SDB in patients with relationship between COPD severity and Myocardial abnormalities. Intermittent respiratory disorders is not well established, OSA is that dynamic hyperinflation may hypoxemia due to OSA with subsequent with inconsistent reports in the literature. reduce upper airway collapsibility due to pulmonary vasoconstriction confers several The inconsistent reports may be due, in tracheal traction (17, 29). undesirable consequences in patients with part, to changes in diagnostic criteria and RECOMMENDATION:We COPD. The increased right ventricular improved testing technology during the past recommend studies that investigate load created by hypoxemia-induced 20 years. For example, the diagnosis of OSA whether there is a direct correlation vasoconstriction can result in hypertrophy, can now be made based on hypoxemia, between the prevalence of OSA and the which is capable of doubling the right which may exaggerate the association of the severity of COPD. ventricular mass, as demonstrated by a study two disorders, because patients with COPD that compared patients with OVS to patients readily desaturate in the presence of mild Outcomes with severity-matched COPD alone (35). flow limitation. Myocardial fibrosis can also be induced by Both OSA and COPD are common Mortality. Patients with OVS have been hypoxemia. A cardiac magnetic resonance disorders. More than 5% of the United long recognized as having a unique and imaging study used a novel, gadolinium- States population (i.e., at least 13.7 million severe phenotype; however, survival data enhancement technique to measure the people) and about 5–10% of the world have only recently become available. One extracellular matrix of the ventricle and population is burdened by COPD (2, 3), study found that individuals with COPD found increased myocardial fibrosis that which is a leading cause of morbidity and plus untreated OSA have decreased survival correlated with worsening hypoxemia (36). mortality. Its high prevalence is attributable compared with individuals with COPD Studies looking at the impact of treatment to high rates of smoking and environmental alone or COPD plus OSA treated with of OSA on right ventricular mass and pollution (41). Among middle-aged continuous positive airway pressure myocardial fibrosis have not been performed (i.e., 50–70 yr) men, the prevalence of (CPAP) (5). These findings have been in patients with COPD. moderate to severe OSA is roughly 17%, confirmed in other cohorts (30) and make Blood gases. Patients with OVS tend whereas among middle-aged women, the intuitive sense; because OSA and COPD to have worse blood gases than those prevalence is approximately 9% (24). These are each known to increase cardiovascular with either COPD alone or OSA alone, prevalences exist throughout most of the risk (31–33), one would expect the as illustrated by the following clinical developed world (25). absence of one (i.e., COPD alone) or the observations of the panel. Patients with OVS The most recent epidemiological studies treatment of one (i.e., COPD plus treated develop daytime hypercapnia at a relatively looking at patients with both OSA and OSA) to be associated with better survival. preserved lung function, whereas patients COPD have estimated that OSA and COPD There are several reasons that the with COPD alone develop daytime coincide at rates predicted by the survival estimates may be incorrect, however. hypercapnia once lung function becomes epidemiology of each disorder alone (26, 27). First, the data do not derive from randomized severely compromised. Patients with OVS About 1 in 10 patients with one disorder will trials and, therefore, it is possible that they also tend to develop daytime hypercapnia have the other disorder by chance alone; are due to unmeasured confounders. As at a lower body mass index and there is no clear evidence that having one examples, individuals who used CPAP in apnea–hypopnea index (AHI) than patients disorder predisposes someone to acquiring the study (2) differed from those who did with OSA alone. Hypoxemia is more the other, despite many theories of potential not in terms of their financial means and prolonged and profound in patients with

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OVS than in those with COPD alone or mild degrees of chronic intermittent breathing) —was designed to assess the OSA alone and, perhaps as a result, patients hypoxia may predispose individuals to severity of sleep apnea, generally in obese with OVS more frequently have pulmonary adverse metabolic outcomes. Such mild men without underlying lung disease hypertension than those with OSA alone intermittent hypoxia is common in patients (40–42). However, the AHI has many (35, 37, 38). with OVS and can be undetected in limitations, some of which are particularly Inflammation and . conventional polysomnographic analyses. relevant to patients with COPD and may Patients with OVS have increased chronic affect the detection of OSA. inflammation and, possibly, impaired RECOMMENDATIONS: The definition of hypopnea has varied metabolism. In patients with OSA, sleep 1. We recommend observational studies over time and across organizations, but fragmentation and chronic intermittent that compare clinical outcomes among most definitions include oxyhemoglobin hypoxia facilitate oxidative injury and patients with OVS to clinical outcomes oxygen desaturation as a criterion. There chronic inflammation. In patients with among patients with OSA alone or have been calls for reductions in airflow with COPD, impaired gas exchange similarly COPD alone. electrocortical arousal to be considered facilitates oxidative injury and chronic 2. We recommend randomized trials that hypopneas even without major oxygen inflammation, which may contribute to compare clinical outcomes among desaturation. However, EEG is usually extrapulmonary complications of COPD patients with OVS whose OSA is treated not performed during home sleep studies (i.e., loss of skeletal muscle mass, decreased to clinical outcomes among patients and, therefore, the presence or absence of bone mineral density, atherosclerosis, and with OVS whose OSA is untreated. oxygen desaturation remains a key criterion 3. Clinical outcomes in the preceding insulin resistance). The pathways mediating for evaluating hypopneas, as recommended recommendations include mortality, oxidative injury and inflammation are by the United States’ major healthcare cardiovascular-specific mortality, probably similar in COPD and OSA, payer, Medicare (43). Existing definitions nonfatal cardiovascular events, quality because the profiles of elevated markers of of hypopnea have important flaws. One of life, and excessive daytime sleepiness. these processes are similar among patients problem is that the degree and duration with these conditions. of oxygen desaturation are not considered. Data from the Sleep Heart Health Study Appraisal of Existing Metrics Thus, an individual with 20 minutes of (39) demonstrated that sleep-related sustained hypoxemia to the 70–80% range respiratory events accompanied by Is the AHI Useful in Patients with due to hypoventilation would only be oxyhemoglobin oxygen desaturation greater COPD? counted as having had a single hypopnea than or equal to 2% are associated with The AHI—the sum of apneas (cessations in (Figure 2). A second problem is that fasting hyperglycemia. This suggests that breathing) plus hypopneas (reductions in recurrent arousals for any reason (i.e., poor

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s Figure 2. Prolonged respiratory events. A representative polysomnograph recording in a patient with sleep-disordered breathing and obstructive lung disease demonstrates how sustained desaturation due to prolonged hypoventilation would be counted as a single respiratory event.

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AMERICAN THORACIC SOCIETY DOCUMENTS sleep quality, hyperinflation, and patients suggests that different treatment fragmentation, and other abnormalities nocturnal cough) may result in an irregular strategies be deployed. that are not necessarily implied by breathing pattern that could be interpreted It is unknown whether the AHI traditional terminology. as recurrent hypopneas. Conversely, predicts clinical outcomes in patients with RECOMMENDATION: We recommend that frequent arousals due to repetitive COPD, including symptoms, cardiovascular future research evaluate SDB (i.e., central respiratory events may not exhibit oxygen consequences, and metabolic complications. sleep apnea, OSA, increased upper airway desaturations and, therefore, would not be In theory, the area under the oxygen resistance, hypoventilation, sleep scored as hypopneas. Such patients may desaturation curve or the total hypoxemic fragmentation, etc.), rather than OSA benefit from therapy, even though they may load may have better predictive value than specifically, in patients with COPD. not meet traditional criteria on the basis of the AHI in patients with COPD, as may the Mechanistic research could help identify AHI. Finally, smokers may have nadir oxygen saturation, but this has not endotypes amenable to targeted considerable carbon monoxide circulating been evaluated. intervention rather than simply describing in their blood, which can shift the RECOMMENDATION:Werecommend different airflow patterns. oxyhemoglobin curve to the left, leading to studies that compare the AHI with other Is REM-related Oxygen Desaturation higher saturations for any given PaO2 (22), measures of severity potentially masking clinically important (e.g., duration of hypoxemia, nadir of Predictive of Poor Outcomes in hypoxemia. Each of these limitations may hypoxemia, arterial tonometry, and area Patients with COPD? affect the detection of OSA among patients under the oxygen desaturation curve) as REM sleep is defined by skeletal muscle with COPD. predictors of clinical outcomes in patients atonia that affects most muscles of the body, The issue of sustained oxygen with COPD. Various definitions of severity with some notable exceptions, including the desaturation leading to underestimation of OVS could be assessed for their predictive diaphragm (46). It is characterized by of the AHI (and, therefore, underestimation value using hard clinical outcomes. variability in the EEG and other of the severity of the condition) is physiological signals. Phasic eye particularly pertinent to patients with Is “Sleep Apnea” the Appropriate movements during REM sleep have been COPD, because one of the major findings on Term in Patients with COPD? associated with suppressed upper airway polysomnography in patients with COPD is A large proportion of patients with COPD motor tone and reductions in ventilation. nocturnal oxygen desaturation with experience some deterioration in gas Patients with sleep apnea often have more sustained hypoxemia, without frequent exchange and respiratory mechanics respiratory events during REM sleep. apneas and hypopneas. There are a during sleep. Non-REM sleep is Therefore, oxygen desaturation tends to variety of reasons for the oxygen characterized by increased upper airway worsen during REM in patients with OVS. desaturation other than upper airway resistance, impaired load compensation, and Controversy exists regarding the obstruction, including a drop in ventilation blunted chemosensitivity, all of which may clinical importance of respiratory events that occurs during sleep (especially REM disturb gas exchange. REM sleep may and gas exchange alterations during REM sleep) and ventilation–perfusion further compromise respiratory function sleep (47), with most believing that the mismatch that worsens during sleep. The because of a propensity for upper airway importance likely depends on the magnitude of oxygen desaturation may be collapse and skeletal muscle atonia in underlying cause of the hypoxemia. particularly severe in patients with COPD accessory muscles of Fluctuations in tidal volume during REM because of the sigmoidal shape of the (e.g., intercostal muscles) (44). sleep are expected, and hypoxemia due to oxyhemoglobin oxygen desaturation curve. These sleep-related changes probably such fluctuations is unlikely to be indicative Those with mild baseline hypoxemia all contribute to the observation that a large of major pathology or require therapy (48). (e.g., oxygen saturation of 90–93%) are proportion of patients with COPD This is supported by a study that showed uniquely positioned near the steep portion desaturate during sleep, even those who are no major symptoms associated with of the oxyhemoglobin dissociation curve, not hypoxemic during wakefulness. This respiratory events occurring during REM where small changes in PaO2 lead to large was illustrated by a study that found that sleep (49). However, occasional patients changes in oxygen saturation. Thus, even 38% of patients with moderate to severe exhibit profound oxygen desaturations with mild perturbations, sustained and COPD who do not qualify for home oxygen during REM sleep that are likely a result of intermittent oxygen desaturations therapy on the basis of their daytime PaO2 atonia in the accessory muscles of commonly occur. have nocturnal oxygen desaturation respiration (48). Such derangements in gas Taking these observations together, it is without evidence of sleep apnea. Therefore, exchange are unlikely to be physiologic and, clear that the quantification of hypopneas the assessment of gas exchange during sleep thus, provide rationale for therapy. This and apneas alone may be insufficient to is critical in patients with COPD (45). view is supported by a study that found identify and characterize OSA in patients SDB and OSA are sometimes conflated. important consequences, such as arterial with COPD. As an example, a patient with However, we believe that SDB better hypertension, associated with REM-related partial upper airway obstruction describes the pathophysiology that occurs in respiratory events (47). (hypopneas) plus severe COPD and a patients with COPD. SDB encompasses all In patients with COPD, data during patient with complete upper airway respiratory dysfunction during sleep, REM sleep remain sparse, but the panel’s obstruction (apneas) plus mild COPD will including central and obstructive sleep clinical experience suggests that some both be diagnosed as having OVS. However, apnea, worsening airflow obstruction, patients with severe COPD will experience the different pathogenesis of OSA in the hypoventilation, oxygen desaturation, sleep major oxygen desaturations during REM

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AMERICAN THORACIC SOCIETY DOCUMENTS sleep, likely as a result of hypoventilation. hypoventilation, upper airway collapse, whether bilevel positive airway pressure or Such patients may benefit from bilevel ventilation–perfusion mismatch, shunting, CPAP therapy is more appropriate. positive airway pressure therapy, although and other factors. In our clinical practices, we prefer outcome data are lacking. Similarly, volume- The addition of capnometry could be transcutaneous CO2 monitoring over end- assured devices are becoming available but helpful for several reasons. First, tidal CO2 in patients with COPD, have been minimally studied in this context. capnometry plus pulse oximetry is more particularly if supplemental oxygen is being sensitive than pulse oximetry alone. Because provided. In patients with unstable breathing RECOMMENDATIONS: of the shape of the oxyhemoglobin patterns, particularly if tidal volume is low, 1. We recommend studies that seek to dissociation curve, important end-tidal PCO2 can be unreliable because of determine the pathophysiology of hypoventilation may occur with only minor the absence of an alveolar plateau. oxygen desaturation during REM sleep – changes in SaO . For example, a 10 mm Hg Transcutaneous CO2 is particularly helpful in patients with COPD. 2 increase in PaCO2 may drop PaO2 from semiquantitatively, because it is directionally 2. We recommend trials that compare 80 mm Hg to roughly 70 mm Hg, which accurate regarding disturbances in gas bilevel positive airway pressure to both would not lead to any major change in the exchange. Depending on the device being CPAP and no positive airway pressure saturation. Moreover, patients who are used, however, transcutaneous CO2 changes therapy in patients with COPD who receiving supplemental oxygen may can be delayed because of slow time desaturate during REM sleep. experience marked hypoventilation that constants, making abrupt dynamic changes could be overlooked because of lack of difficult to assess. Other methods of Is Capnometry Valuable in Sleep oxygen desaturation. Capnometry has the measuring gas exchange, such as arterial Studies of Patients with COPD? potential to detect hypoventilation that blood gases, have been scarcely studied. Monitoring gas exchange is critical to a pulse oximetry may miss in these situations. RECOMMENDATION: We recommend thorough evaluation of sleep and breathing. Second, pulse oximetry does not provide trials that compare various methods of Traditionally, oxygen saturation has been information about the mechanism measuring gas exchange in patients with used as a surrogate for gas exchange under underlying oxygen desaturation, but OVS, for example, trials that compare the assumption that most important capnometry may in some circumstances. pulse oximetry plus transcutaneous CO2 disturbances would lead to oxygen For example, a decrease in oxygen measurement to pulse oximetry desaturation, and because of high cost and saturation accompanied by an increase in alone, pulse oximetry plus transcutaneous poor availability of reliable transcutaneous PaCO2 is suggestive of hypoventilation as the CO2 measurement to arterial blood gas systems. However, oxygen saturation is an underlying mechanism rather than measurement, and pulse oximetry plus imperfect measure, as an occurrence of ventilation–perfusion mismatch or other transcutaneous CO2 measurement to oxygen desaturation could in theory be factors. Mechanistic information might pulse oximetry plus end-tidal CO2 related to multiple mechanisms, including help to guide the choice of therapy, such as measurement.

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.672 21674 21676 21678 21680 21682 21684 21686 21688 21690 21692 21694 21696 21698 21700 21 Figure 3. Alpha intrusion. A representative polysomnograph recording in a patient with sleep-disordered breathing and obstructive lung disease demonstrates an increase in alpha intrusion and illustrates how it can be difficult to detect hypopneas terminating in arousals from sleep.

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Should Supplemental Oxygen Be these studies differed from our patients of of events with and without arousal). This Withdrawn for Overnight interest (i.e., rather than COPD with approach allows the detection of SDB in Polysomnography in Patients with confirmed nocturnal oxygen desaturation, the most cases. However, the severity of the Suspected OVS? studies enrolled patients with COPD with SDB may be underestimated by Many patients with COPD are given exercise-induced oxygen desaturation or polysomnography in patients with COPD, supplemental oxygen on a long-term basis patients with OSA with or without COPD). particularly those who require supplemental because of demonstrable abnormal gas RECOMMENDATION: We recommend oxygen or who have disturbances in sleep exchange or for comfort. However, trials that compare supplemental oxygen architecture due to depression or insomnia supplemental oxygen may mask hypopneas to both CPAP therapy and bilevel positive (both increase alpha intrusion and make it during overnight polysomnography by airway pressure in patients with COPD difficult to detect hypopneas terminating in blunting oxygen desaturation due to who exhibit nocturnal oxygen arousals from sleep) (Figure 3). hypoventilation. For this reason, we routinely desaturation. Polysomnography is not intended to remove supplemental oxygen before detect COPD-specific respiratory polysomnography, unless the oxygen saturation disturbances, such as expiratory during relaxed wakefulness is less than 88%. Revisiting the Sleep Study with associated flow limitation (52, 53) It is important that oxygen desaturation (Figure 4) or dynamic hyperinflation (see be detected and the response to positive Polysomnographic Features of SDB in Figures E2–E4 in the online supplement). airway pressure titration be assessed during COPD In one study, expiratory snoring had polysomnography, because positive airway Polysomnography in patients with COPD is 11-times higher odds of being associated fl , pressure alone may eliminate oxygen adequate to categorize sleep apnea and with air ow obstruction (FEV1/FVC 70%) desaturation, eliminating the need for sleep-related respiratory events (e.g., central than the absence of expiratory snoring. nocturnal supplemental oxygen with its versus obstructive sleep apnea, hypopneas Additional measurements that quantify expense and risks. Supplemental oxygen alone versus apneas), as well as to quantify the ventilation and/or respiratory effort are is generally considered ineffective for the severity of sleep apnea (e.g., number of required to detect SDB in COPD. For treatment of OSA and can worsen hypercapnia events per hour, duration of events, degree example, a pneumotachograph affixed to a (11, 50, 51), although the patients enrolled in of hypoxia with each event, and percentage mask would best serve to quantify

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Figure 4. Expiratory flow limitation and expiratory snoring in chronic obstructive pulmonary disease. A representative polysomnograph recording during non-REM sleep in a patient with sleep-disordered breathing and obstructive lung disease. Arrows point to the expiratory flow limitation and expiratory snoring. Chin = chin electromyogram; EOG = electrooculogram; P-Flow = pressure flow; P-Snoring = snoring tracing obtained by pressure flow sensor; snoring = snoring tracing obtained by chin microphone (53).

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AMERICAN THORACIC SOCIETY DOCUMENTS ventilation, the severity of inspiratory and 2. We recommend studies that compare inspiratory time reduces expiratory time, expiratory flow limitation, and the presence various methods to quantify which may lead to dynamic hyperinflation of hyperinflation during sleep. However, ventilation, the severity of inspiratory in patients with COPD. Similarly, an conventional pneumotachographs are of and expiratory flow limitation, and increase in the respiratory rate would limited use in patients with COPD during the presence of hyperinflation during seemingly be another compensatory sleep, because they are too cumbersome sleep (e.g., pneumotachograph, nasal mechanism, but this also reduces expiratory and impose excessive dead space and pressure signaling, and flow sensors) in time. In either case, respiratory patterns resistive loads on the respiratory system patients with COPD. during sleep in COPD may worsen (54). Alternative flow surrogates include an dynamic hyperinflation by shortening the unfiltered nasal pressure signal at a high expiratory time. In addition, an inspiratory SDB in COPD sampling rate (preferably .200 Hz) or flow limitation is commonly observed COPD is associated with alterations in flow sensors with negligible resistance during sleep, and even mild degrees of respiratory mechanics and gas exchange, and dead space, both of which can be inspiratory flow limitation lengthen leading to dynamic hyperinflation and/or readily integrated into conventional inspiration and further compromise hypoventilation (55). During wakefulness, polysomnographic units. Similarly, expiratory time. Thus, normal sleep- patients compensate for expiratory flow esophageal catheters would be best suited to induced alterations in breathing pattern can obstruction by adopting specific quantify respiratory loads but are rarely be detrimental in patients with COPD. compensatory mechanisms to minimize used in clinical sleep studies. Inductive hyperinflation (e.g., by prolonging plethysmography or intercostal EMG expiratory time or pursed lip breathing) Sample Cases activity might be good surrogates for and preserve alveolar ventilation. Sleep is We use a series of cases to illustrate the detecting changes in inspiratory or associated with changes in respiratory spectrum of novel COPD-specific events for expiratory effort. control that interfere with these which both pneumotachograph and RECOMMENDATIONS: compensatory mechanisms (Figure 5) and esophageal pressure signals are required to 1. We recommend research to develop lead to a cascade of events (Figure 1). Most detect SDB events. Although these methods and/or validate devices that can notably, loss of the ventilatory drive leads to have not been widely adopted for diagnostic identify and characterize sleep without significant reductions in tidal volume. An purposes in most sleep centers, these signals EEG. The goal is to improve the increase in inspiratory time would can illuminate breathing disturbances assessment of the severity of SDB in seemingly be an effective compensatory during sleep that can be easily detected by patients with disruptions in sleep mechanism to mitigate the reduction in currently used surrogate signals. The cases architecture. tidal volume. However, increased are provided in the online supplement.

Wakefulness

Respiratory loads Compensatory Mechanisms

Pathophysiology Sleep Impaired Compensatory Mechanisms

Sleep Abnormal Breathing Disturbances Patterns Polysomnographic Sleep Disturbances • Atypical obstructive apnea/hypopnea Features in COPD • Disturbance in sleep architecture • Expiratory flow limitation • Frequent arousals • Inspiratory flow limitation with dynamic hyperinflation • Sympathetic/parasympathetic imbalance • REM-related hypoxia/hypercapnia • Alpha intrusion • Tachypnea (rapid shallow breathing) • Sustained hypoxia and hypercapnia (CO2 retention)

Daytime symptoms Cardiopulmonary findings • Morning fatigue • Endothelial dysfunction • Daytime sleepiness • Arterial and Clinical Outcomes • Decline in executive functions • Hypercapnia and hypoxia • Depression • Increase in mortality • Chronic fatigue syndrome • PTSD/pain management problems Figure 5. Sleep-disordered breathing in chronic obstructive pulmonary disease (COPD). PTSD = post-traumatic stress disorder.

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Conclusions with or without severe alterations in gas outcomes, ranging from insomnia to exchange. The same principles described hypersomnia with and without Polysomnographic features in COPD are a in this statement for COPD may also apply cardiopulmonary complications. We consequence of sleep-induced respiratory to other respiratory diseases characterized strongly advocate for further research into loads. Patients with COPD may respond to by lower airway obstruction, such as SDB in patients with COPD, to increased respiratory loads with marked asthma and cystic fibrosis. Depending on understand better the spectrum of disease, sleep disturbances or, alternatively, which polysomnographic features optimize the definitions and equipment they may have minimal sleep disturbance predominate, patients may present with a used to assess patients, and determine the but a highly abnormal breathing pattern variety of daytime symptoms and clinical optimal mode of therapy. n

This official research statement was prepared by an ad hoc subcommittee of the ATS Assembly on Sleep and Respiratory Neurobiology.

Members of the subcommittee are as follows: received a philanthropic donation from support from ImThera Medical, inSleep ATUL MALHOTRA, M.D. (Chair) ResMed in support of their sleep center. Health, and Maxis; and holds stock, stock M. SAFWAN BADR, M.D. M.K.H. served as a consultant for options, or other ownership interests in AstraZeneca, Boehringer Ingelheim, Discover Medical and RespEQ. J.A.W. PAMELA DEYOUNG, R.P.S.C.-T. GlaxoSmithKline, Novartis, and Sunovion; and served as a speaker and on an advisory MEILAN K. HAN, M.D. received research support and served as a committee for AstraZeneca, Boehringer NADIA N. HANSEL, M.D., M.P.H. speaker for Novartis. N.N.H. received research Ingelheim, GlaxoSmithKline, and Novartis; ROBERT L. OWENS, M.D. support and served on an advisory committee received research support from HARTMUT SCHNEIDER, M.D. for AstraZeneca and GlaxoSmithKline; and GlaxoSmithKline, Johnson and Johnson, ALAN R. SCHWARTZ, M.D. received research support from Boehringer Novartis, OM Pharma, Takeda, and Vifor Ingelheim. R.L.O. received honorarium and Pharma; served on an advisory committee JADWIGA A. WEDZICHA, M.D. travel reimbursement from ResMed and for Johnson and Johnson; served as a KEVIN C. WILSON, M.D. Itamar; and served on a scientific advisory speaker for Chiesi; and had meeting MICHELLE R. ZEIDLER, M.D. board for Novartis. H.S. holds a patent (U.S. expenses covered by AstraZeneca, Boehringer 200800922898) issued to RespEQ for a Ingelheim, GlaxoSmithKline, Novartis, Pfizer, disposable sleep and breathing monitor. and Teva. M.S.B., P.D., K.C.W., and M.R.Z. Author Disclosures: A.M. practices at A.R.S. served as a consultant for inSleep reported no relationships with relevant University of California San Diego, which Health and Respicardia; received research commercial interests.

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