Overlap Syndrome Obstructive Sleep Apnea in Patients with Chronic Obstructive Pulmonary Disease Emmanuel Weitzenblum1, Ari Chaouat2, Romain Kessler1, and Matthieu Canuet1 1
ˆ pitaux Universitaires de Strasbourg, Strasbourg, France; and 2Service des Maladies Respiratoires et Re´animation De´partement de Pneumologie, Ho Respiratoire, Centre Hospitalier Universitaire de Nancy, Vandoeuvre les Nancy, Nancy, France
Chronic obstructive pulmonary disease (COPD) and sleep apneahypopnea syndrome (SAHS) are both common diseases affecting respectively 10 and 5% of the adult population over 40 years of age, and their coexistence, which is denominated overlap syndrome, can be expected to occur in about 0.5% of this population. A recent epidemiologic study has shown that the prevalence of SAHS is not higher in COPD than in the general population, and that the coexistence of the two conditions is due to chance and not through a pathophysiologic linkage between these two diseases. Patients with overlap have a more important sleep-related O2 desaturation than do patients with COPD with the same degree of bronchial obstruction. They have an increased risk of developing hypercapnic respiratory insufficiency and pulmonary hypertension when compared with patients with SAHS alone and with patients with ‘‘usual’’ COPD. In patients with overlap, hypoxemia, hypercapnia, and pulmonary hypertension can be observed in the presence of mild to moderate bronchial obstruction, which is different from ‘‘usual’’ COPD. Therapy of the overlap syndrome consists of nasal continuous positive airway pressure or nocturnal noninvasive ventilation (NIV), with or without associated nocturnal O2. Patients who are markedly hypoxemic during daytime (PaO2 , 55–60 mm Hg) should be given conventional long-term O2 therapy in addition to nocturnal ventilation. Keywords: chronic obstructive pulmonary disease; sleep apnea-hypopnea syndrome; overlap syndrome; noninvasive ventilation; nasal continuous positive airway pressure
Both chronic obstructive pulmonary disease (COPD) and sleep apnea-hypopnea syndrome (SAHS) are common diseases, and many individuals would be expected to have both conditions by chance alone (1). It has been believed that the presence of COPD could predispose to the development of SAHS (2), since the two conditions share some etiologic factors such as tobacco smoking. In fact, this remained an unresolved question (3) up to very recent years. In 2003 the Sleep Heart Health Study (SHHS) provided us with solid epidemiologic data about the coexistence of COPD and SAHS (4).
DEFINITIONS The combination of chronic obstructive pulmonary disease and sleep apnea-hypopnea syndrome has been denominated ‘‘overlap syndrome’’ by the late David Flenley (5). In his opinion the term ‘‘overlap syndrome’’ could apply as well to the coexistence of SAHS and any chronic respiratory disease such as idiopathic pulmonary fibrosis or cystic fibrosis (5), but the use of
(Received in original form July 27, 2007; accepted in final form September 6, 2007) Correspondence and requests for reprints should be addressed to Emmanuel ˆ pital de Hautepierre, Weitzenblum, Professor of Medicine and Pulmonology, Ho 67098 Strasbourg, France. E-mail:
[email protected] Proc Am Thorac Soc Vol 5. pp 237–241, 2008 DOI: 10.1513/pats.200706-077MG Internet address: www.atsjournals.org
this term is generally limited to the association of SAHS and COPD. COPD is presently defined by the presence of an obstructive ventilatory defect characterized by an FEV1/FVC ratio less than 70% in patients not exhibiting any other chronic respiratory disease (6). There is presently no standardized definition of SAHS. Generally, both a given level of respiratory disturbance index or apnea-hypopnea index (> 10/h, > 15/h, etc.) and the presence of symptoms (daytime sleepiness, poor quality of sleep, etc.) are required (7).
PREVALENCE OF THE OVERLAP SYNDROME: IS SAHS MORE PREVALENT IN COPD THAN IN THE GENERAL POPULATION? Previous studies have suggested that the prevalence of SAHS in patients with COPD, and of COPD in patients with SAHS, was high (2, 3, 8, 9)—sometimes unexpectedly high (2). The earliest report suffered from methodologic biases, since the 26 patients with COPD investigated by Guilleminault and coworkers (2) had been in fact referred to a sleep clinic because they complained of excessive daytime somnolence. This probably explains why sleep apneas were found in as many as 22/26 patients. In studies by Bradley and colleagues (8, 9) and by Chaouat and coworkers (3) in which consecutive patients with SAHS were investigated (n 5 50 and 265, respectively) the prevalence of an associated COPD, defined by the presence of bronchial obstruction (either FEV1/FVC , 70% [8, 9] or FEV1/ VC , 60% [3]) was, respectively, of 14% (9) and 11% (3). These figures were considered as high, suggesting that the prevalence of COPD in SAHS exceeded that observed in the general population (3), but it must be underlined that at that time there were very few reliable epidemiologic studies about the prevalence of COPD in the general population (10, 11). We presently know that the prevalence of COPD, defined by an FEV1/FVC ratio less than 70% (GOLD stages I–IV [12]) is over 10% in adults 40 years of age or older, and may exceed 20% (13–16). The 265 patients with SAHS investigated by Chaouat and colleagues (3) had a mean age of 54 6 10 years; 92% were males, and 66% were current smokers or ex-smokers. In such a cohort a prevalence of COPD greater than 10% may be expected. Thirty out of 265 patients had COPD (3). Accordingly, it does not appear that the prevalence of COPD is increased in patients with SAHS, when compared with the general population. A putative association between SAHS and COPD could be explained by the fact that the two conditions are favored by a common etiologic factor, namely smoking. In fact, if the role of smoking is well established in COPD (6, 17), on the contrary smoking is not presently considered as a documented risk factor for SAHS, even if earlier studies (18) have suggested that smoking could favor the occurrence of obstructive sleep apneas. The only way to assess the prevalence of SAHS in COPD, and to confirm whether this prevalence is higher or not than in
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the general population, is to undertake a large epidemiologic study. It should be emphasized that earlier studies on the overlap syndrome (2, 3, 8, 9) have evaluated relatively small samples and have included patients referred to Sleep Laboratories or Respiratory Disease Clinics, which results in a selection bias (4). The Sleep Heart Health Study (SHHS) is a prospective multicenter cohort study that was designed to assess whether SAHS is a risk factor for hypertension and cardiovascular diseases (19). It is the largest study to date but it must be underlined that it focused on a population enriched for cardiovascular risk profiles (including smoking). Participants were recruited from ongoing cohort studies. They were at least 40 years old and had not received positive airway pressure treatment for sleep apnea nor supplemental oxygen. They underwent unattended home polysomnography, and spirometry was performed in all subjects (4). A total of 5,954 participants had complete spirometric data. Obstructive airway disease (OAD), which is synonymous of COPD, was defined by an FEV1/FVC ratio less than 70% (20), which is in agreement with the present consensual definition of COPD (6). The main results of the SHHS are the following (4): the average FEV1/FVC of the cohort was 75.5 6 (SD) 7.9%. Subjects with OAD(n 5 1,138, 19%) had a mean FEV1/FVC of 63.8 6 6.6%, and those without OAD (n 5 4,816, 81%) had a mean FEV1/FVC of 78.3 6 5.3%. Only a small number of participants (n 5 226, 3.8%) had an FEV1/FVC ratio less than 60%. The respiratory disturbance index (RDI), that is, the average number of apneas plus hypopneas per hour of sleep, was not higher in subjects with OAD than in subjects without OAD. On the contrary, participants with OAD had significantly lower mean and median RDI than those without OAD (4) (Table 1). However, after stratification by BMI quartile, RDI values were similar in the participants with and without OAD (4). Thus, the prevalence of SAHS, defined either as an RDI greater than 10 or greater than 15, is not greater in subjects with COPD than in those without COPD among the general population. It ensues that the coexistence of COPD and SAHS is due to chance rather than through a pathophysiologic linkage between the two conditions (4). The very low percentage of subjects with severe COPD may limit the bearing of these results, which cannot be automatically transposed to patients with advanced COPD. Nevertheless, the findings of Sanders and coworkers (4) do not support the hypothesis that the presence of COPD favors the coexistence of SAHS
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and vice versa. If the overlap syndrome is observed in a relatively high number of subjects (or patients), it is simply because COPD and SAHS are both frequent conditions. If COPD is present in about 10% of the adult population 40 years of age or older (13–15), and if the prevalence of SAHS in the same population is in the range of 5 to 10% (21–24), overlap syndrome can be expected to be present in 0.5 to 1% of the population over 40 years of age, which is a far from being negligible.
CLINICAL AND PULMONARY FUNCTION FEATURES IN THE OVERLAP SYNDROME Quality of Sleep
Many patients with COPD complain of poor-quality sleep, and objective evidence of disturbed sleep in COPD has been demonstrated by adequate EEG studies (25–29): sleep efficiency is reduced, sleep onset is delayed, total sleep time is reduced, and periods of wakefulness are frequent and sometimes prolonged. The causes of this poor-quality sleep are probably multifactorial and include nocturnal cough, nocturnal dyspnea, use of drugs, and the effects of ageing on sleep. In fact, these earlier studies (25–29) have included patients with severe COPD with marked daytime hypoxemia. On the other hand, the SHHS (4) mentioned above, where 1,138 participants with mild COPD were investigated, has shown that in the absence of sleep apnea, sleep was minimally perturbed. No significant differences were observed in sleep architecture in the subjects with the lowest compared with the highest FEV1 quartile (4). Thus, COPD per se does not affect the quality of sleep. Sanders and colleagues (4) have observed that subjects with overlap, compared with subjects who had only obstructive airway disease, had higher Epworth sleepiness scores, lower total sleep time, lower sleep efficiency, and higher arousal index. Only small differences were found between subjects with SAHS alone and those with both disorders (subjects with overlap) (4). Thus, the quality of sleep in COPD is influenced by the presence of SAHS but not by the severity of airway obstruction (4). Severity of Respiratory Events and of Nocturnal Desaturation
Having prospectively investigated a series of 265 patients who were selected on the basis of a confirmed diagnosis of SAHS (apnea-hypopnea index . 20/h), Chaouat and coworkers (3) have found an obstructive spirographic pattern (FEV1/VC ratio < 60%) in 30/265 patients. These patients with overlap did not differ from the remainder by their apnea index or apneahypopnea index (Table 2), but nocturnal hypoxemia was more
TABLE 1. RESPIRATORY DISTURBANCE INDEX ACCORDING TO THE PRESENCE OR NOT OF OBSTRUCTIVE PULMONARY DISEASE
Variables RDI: mean value 6 SD RDI: median value (interquartile range) Participants with RDI . 10/h (%) Participants with RDI . 15/h (%)
Participants without COPD (FEV1/FVC > 70%) (N 5 4,816)
Participants with COPD (FEV1/FVC , 70%) (N 5 1,138)
9.13 6 12.59
7.49 6 11.87*
4.51 (1.36, 11.59) 28.86 18.63
3.51 (1.35, 8.81)† 22.32* 13.97‡
Definition of abbreviations: COPD 5 chronic obstructive pulmonary disease; RDI 5 respiratory disturbance index (events/h) (RDI is equivalent to apneahypopnea index). Results of the Sleep Heart Health Study (SHHS). Adapted by permission from Reference 4. * P , 0.0001. † P , 0.001. ‡ P , 0.0002.
TABLE 2. APNEAS, HYPOPNEAS, AND NOCTURNAL OXYGEN SATURATION IN A SERIES OF 265 CONSECUTIVE PATIENTS WITH SAHS: COMPARISON OF PATIENTS WITH SAHS ALONE (N5235) TO PATIENTS WITH OVERLAP (SAHS 1 COPD)
Variables
Group as a Whole (n 5 265)
AI, events/h RDI, events/h TSA/TST, % M SaO2, %
59 6 38 77 6 33 24 6 17 91 6 4
Patients with overlap (n 5 30) 64 89 22 89
6 6 6 6
41 37 15 4
Patients with SAHS Alone (n 5 235) 59 76 24 91
6 6 6 6
38 32 18 4
t test (overlap vs. SAHS Alone) NS NS NS p , 0.05
Definition of abbreviations: AI 5 apnea index; M SaO2 5 mean nocturnal oxygen transcutaneous saturation; RDI 5 respiratory disturbance index (5 apneahypopnea index); SAHS 5 sleep apnea-hypopnea syndrome; TSA/TST 5 time spent in apnea/total sleep time. Data are expressed as means 6 SD. Adapted by permission from Reference 3.
Weitzenblum, Chaouat, Kessler, et al.: Association of COPD and Sleep Apnea
important in patients with overlap than in patients with SAHS alone (P , 0.05). The average FEV1/VC of the 30 overlap patients was 50 6 6% (Table 3) (3), which is lower than the average FEV1/FVC of 63.8 6 6.6% in the SHHS (4), a difference that can be explained by the fact that Chaouat and colleagues (3) have investigated consecutive patients, whereas the SHHS (4) has enrolled participants from the general population. In spite of these differences, the SHHS (4) has also clearly demonstrated that subjects with both SAHS and COPD had greater sleep desaturation than those with only one disorder. After adjusting for age, sex, height, race, smoking status, and awake SpO2, the OR for oxyhemoglobin saturation below levels of 90 and 85% for more than 5% of total sleep time was 20-fold greater in participants with SAHS alone compared with those who had neither disorder and 30-fold greater in participants with both disorders (subjects with overlap) (4). Consequently the risk of significant nocturnal desaturation is clear in patients who exhibit some degree of daytime hypoxemia, which is the case of the patients with overlap investigated by Chaouat and coworkers (3), but is also present in subjects with less severe overlap, as those recruited in the SHHS (4). Pulmonary Function and Arterial Blood Gases
The results of spirography and arterial blood gases in a series of 30 patients with overlap (3) are given in Table 3. They are compared with those of patients with SAHS alone (3) and also to a series of patients with obesity-hypoventilation (30). As mentioned above, ‘‘patients’’ with overlap have lower pulmonary volumes and lower FEV1/VC ratio than do ‘‘subjects’’ with overlap enrolled in cohort studies like the SHHS (4), and these differences might be explained by the different ways of recruitment. On the other hand, the 20 patients with overlap investigated by Alford and colleagues (31) were hospitalized and had an average FEV1/FVC of 63.7 6 10.9%, which is very similar to the average value of the SHHS participants exhibiting an OAD (63.8 6 6.6%). By definition, patients with overlap have an obstructive ventilatory pattern that is most often mild to moderate, with an average FEV1 of 1,580 6 560 ml (52 6 15% of the predicted value) in the series of Chaouat and coworkers (3) (Table 3). Total lung capacity ranges within normal limits (no static hyperinflation). The coexistence of COPD and SAHS favors the presence of hypoxemia, which is rarely observed in patients with SAHS TABLE 3. PULMONARY FUNCTION DATA AND ARTERIAL BLOOD GASES IN PATIENTS WITH OVERLAP COMPARED WITH PATIENTS WITH SAHS ALONE AND WITH PATIENTS WITH THE OBESITY-HYPOVENTILATION SYNDROME
Variables Age, yr BMI, kg/m2 VC, % predicted FEV1, liters FEV1, % predicted FEV1/VC, % TLC, % predicted PaO2, mm Hg PaCO2, mm Hg
OHS (n 5 34) 61 40 79 1.85 70 69 78 59 49
6 6 6 6 6 6 6 6 6
11 8 16 0.64 17 7 11 7 3
SAHS Alone (n 5 235) 53 32 91 2.87 88 75 86 75 38
6 6 6 6 6 6 6 6 6
10 6 15 0.74 17 10 11 10 4
Overlap (n 5 30) 58 31 77 1.58 52 50 88 66 42
6 6 6 6 6 6 6 6 6
9 5 20 0.56 15 6 13 10 6
SAHS Alone versus overlap (P Value) , 0.05 NS , 0.001 , 0.001 , 0.001 , 0.001 NS , 0.001 , 0.001
Definition of abbreviations: BMI 5 body mass index; FEV1 5 forced expiratory volume in one second; OHS 5 obesity-hypoventilation syndrome; SAHS 5 sleep apnea-hypopnea-syndrome; TLC 5 total lung capacity; VC 5 vital capacity. Data are expressed as means 6 SD. Adapted by permission from References 3 and 30.
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alone (Table 3). In the study by Chaouat and colleagues (3), 17/30 (57%) patients with overlap had a PaO2 less than or equal to 65 mm Hg versus 54/235 (23%) of patients with SAHS alone (P , 0.001); 8/30 (27%) patients with overlap were hypercapnic (PaCO2 > 45 mm Hg) versus 19/235 (8%) patients with SAHS alone (P , 0.05) (3). Of interest, these arterial blood gases results are very similar to those of Alford and coworkers (PaO2 5 65 6 6.8 mm Hg, PaCO2 5 45.2 6 6.6 mm Hg) in their 20 patients with overlap whose bronchial obstruction was less pronounced) (31). Hypoxemia and hypercapnia are more severe in patients with obesity-hypoventilation than in patients with overlap (Table 3), all patients having been investigated in a stable state of the disease, several weeks after any exacerbation (30). Pulmonary Hypertension
Patients with overlap are at risk of developing pulmonary hypertension (PH) even though their obstructive defect is not severe. Chaouat and colleagues (3) have observed that among the 26 patients with overlap who underwent right heart catheterization, 11 had PH defined by a mean pulmonary artery pressure (Ppa) greater than 20 mm Hg (Table 4). The prevalence of PH was of 36% in patients with overlap, much higher than in ‘‘usual’’ SAHS (19/181 5 9%), but somewhat lower than in the obesity-hypoventilation syndrome (Table 4) (30). Patients with overlap can develop PH even if they do not exhibit a marked degree of bronchial obstruction. In ‘‘usual’’ COPD, PH is generally observed in the case of severe bronchial obstruction (FEV1 , 50% of the predicted value, and generally < 1,000 ml) leading to significant hypoxemia. This discordance has been emphasized by several authors (2, 3, 8, 9, 31–35). The hypoxemic–hypercapnic SAHS investigated by Bradley and colleagues (8, 9) exhibited cor pulmonale. The subjects from that study were patients with overlap, but their average FEV1 (2.0 6 0.31 l) and FEV1/FVC (59 6 5%) did not indicate severe bronchial obstruction. Similarly, the FEV1/FVC of the patients with overlap investigated by Fletcher and coworkers (34) was close to 60%, which contrasted with marked hypoxemia and PH. This can be explained by the synergistic effects of the diseases on gas exchange and pulmonary hemodynamics (3, 32, 34, 35). In patients with COPD, PH is generally observed when daytime PaO2 is less than 55 to 60 mm Hg (36). The average daytime PaO2 of the patients with overlap in the study by Chaouat and colleagues (3) was higher (66 6 10 mm Hg) (Table 3) and only 8/30 had a PaO2 less than 60 mm Hg. It must be kept in mind that if the daytime PaO2 of these patients is about 65 mm Hg, the mean PaO2 during sleep is certainly lower because of TABLE 4. PULMONARY HEMODYNAMICS IN PATIENTS WITH OVERLAP COMPARED WITH PATIENTS WITH SAHS ALONE AND WITH PATIENTS WITH THE OBESITY-HYPOVENTILATION SYNDROME Variables
OHS (n 5 27)
Ppa, mm Hg 23 6 10 PVR, mm Hg/L/min 4.0 6 1.5 Cardiac output, L/min 6.2 6 18 PH, n (%) 17 (58)
SAHS Alone (n 5 180)
Overlap (n 5 26)
SAHS Alone versus overlap (P Value)
15 6 5 2.7 6 1.2 5.9 6 1.6 19 (9)
20 6 6 3.6 6 1.8 5.9 6 1.6 11 (36)
, 0.001 , 0.002 NS , 0.001
Definition of abbreviations: OHS 5 obesity-hypoventilation syndrome; Ppa 5 pulmonary artery mean pressure; PVR 5 pulmonary vascular resistance; PH 5 pulmonary hypertension (defined by a Ppa . 20 mm Hg); SAHS 5 sleep apneahypopnea syndrome. Data are expressed as means 6 SD. Adapted by permission from References 3 and 30.
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the repetition of apneas and hypopneas (the time spent in apnea represented 22 6 15% of the total sleep time in the overlap group [3]). Thus, the combination of marked nocturnal hypoxemia with a mild to moderate diurnal hypoxemia could explain the occurrence of pulmonary hypertension.
PRINCIPLES OF TREATMENT OF THE OVERLAP SYNDROME Long-term nasal continuous positive airway pressure (nCPAP) is the first line treatment of SAHS (37). This treatment is efficient in suppressing apneas and hypopneas and sleep-related hypoxemia in patients with SAHS. However, adherence to therapy is poor in some patients and this will negatively influence the long-term results of this treatment. To our knowledge, there are no data about the adherence to treatment in a population with COPD compared with a population without COPD. In our experience, the follow-up of patients with COPD when given nCPAP does not differ from that of ‘‘usual’’ COPD, and we are not aware of outcome studies in this subpopulation. nCPAP may be inefficient for correcting nighttime hypoxemia in patients with an associated COPD (38, 39). In these patients some degree of sleep-related hypoxemia may persist, particularly during REM sleep. Consequently, it is necessary to add supplementary O2 (1.5–3 L/min) to nCPAP when the mean nocturnal SaO2 under nCPAP alone is less than 90%. It is also possible in these cases to shift to another mode of nocturnal ventilation, such as bilevel positive airway pressure, which is also called nocturnal noninvasive ventilation (NIV) or nocturnal noninvasive positive pressure ventilation. In patients with severe hypercapnic COPD without associated SAHS, the longterm effects of NIV have not been so far convincingly demonstrated (40–42), whereas the results of NIV are excellent in the obesity-hypoventilation syndrome (43–46). To our knowledge there has been no controlled study on the effects of NIV in patients with overlap. The efficiency of NIV (abolition of apneas and correction of hypoxemia) must be assessed by nocturnal oximetry and, whenever possible, by polysomnography. Finally, in the most severe overlap patients, a marked daytime hypoxemia may persist in spite of the efficient treatment of nocturnal apneas-hypopneas. These patients require conventional long-term oxygen therapy (LTOT) (> 16–18 h/d) in addition to nCPAP or NIV, when the standard criteria for oxygen therapy are fulfilled (47)—namely, a daytime PaO2 regularly less than 55 to 60 mm Hg. These patients are the most likely to develop PH (34), and LTOT may help to decrease or at least stabilize PAP (48).
CONCLUSIONS Overlap syndrome is not a rare condition, due to the high prevalence of both COPD and SAHS. A recent epidemiologic study has clearly shown that the presence of COPD does not favor the occurrence of SAHS and vice versa. Patients with overlap have a more important sleep-related O2 desaturation than patients with COPD with the same degree of bronchial obstruction. They have an increased risk of developing hypercapnic respiratory insufficiency and pulmonary hypertension when compared with patients with SAHS alone. In patients with overlap, hypoxemia, hypercapnia, and pulmonary hypertension can be observed in the presence of mild to moderate bronchial obstruction, which is quite different from ‘‘usual’’ COPD. Therapy of the overlap syndrome consists of nCPAP or nocturnal NIV with or without associated nocturnal O2. Patients
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who are markedly hypoxemic during daytime (PaO2 , 55– 60 mm Hg) should receive conventional LTOT in addition to nocturnal ventilation. Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
References 1. Fleetham JA. Is chronic obstructive pulmonary disease related to sleep apnea-hyponea syndrome? Am J Respir Crit Care Med 2003;167:3–4. 2. Guilleminault C, Cummiskey J, Motta J. Chronic obstructive airflow disease and sleep studies. Am Rev Respir Dis 1980;122:397–406. 3. Chaouat A, Weitzenblum E, Krieger J, Ifoundza T, Oswald M, Kessler R. Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am Rev Respir Dis 1995;151:82–86. 4. Sanders MH, Newman AB, Haggerty CL, Redline S, Lebowitz M, Samet J, O’Connor GT, Punjabi NM, Shahar E for the Sleep Heart Health Study. Sleep and sleep-disordered breathing in adults with predominantly mild obstructive airway disease. Am J Respir Crit Care Med 2003;167:7–14. 5. Flenley DC. Sleep in chronic obstructive lung disease. Clin Chest Med 1985;6:51–61. 6. Pauwels RA, Buist AS, Calverley PMA, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163: 1256–1276. 7. American Academy of Sleep Medicine. Sleep related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 1999;22:667–689. 8. Bradley TD, Rutherford A, Grossmann RF, Lue F, Zamel N, Moldofsky H, Phillipson EA. Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1985;131:835–839. 9. Bradley TD, Butherford A, Lue F, Moldofsky H, Grossmann RF, Zamel N, Phillipson EA. Role of diffuse airway obstruction in the hypercapnia of obstructive apnea. Am Rev Respir Dis 1986;134:920–924. 10. Petty TL, Pierson DJ, Dick NP, Hudson LD, Walker SH. Follow-up evaluation of a prevalence for chronic bronchitis and chronic airway obstruction. Am Rev Respir Dis 1976;114:881–890. 11. Lebowitz MD. The trends in airway obstructive disease morbidity in the Tucson epidemiologic study. Am Rev Respir Dis 1989;140:S35–S41. 12. Fabbri L, Pauwels RA, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary updated 2003. COPD 2004;1:105–141. 13. Lopez AD, Shibuya K, Rao C, Hansell AL, Held LS, Schmid V, Buist S. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J 2006;27:397–412. 14. Menezes AM, Perez-Padilla R, Jardim JR, Muino A, Lopez MV, Valdivia G, Montes de Oca M, Talamo C, Hallal PC, Victora CG. PLATINO Team. Chronic obstructive pulmonary disease in five Latin American cities (the PLATINO study): a prevalence study. Lancet 2005;366:1875–1881. 15. Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thun MJ, Connel C, Jemai A, Lee TA, Miravitlles M, et al. Epidemiology and costs of chronic obstructive pulmnary disease. Eur Respir J 2006; 27:188–207. 16. Buist AS, Wollmer WM, Sullivan SD, Weiss KB, Lee TA, Menezes AM, Crapo RO, Jensen RL, Burney PG. The burden of obstructive lung disease initiative (BOLD): rationale and design. COPD 2005;2:277– 283. 17. Davis RM, Novotny TE. The epidemiology of cigarette smoking and its impact on chronic obstructive pulmonary disease. Am Rev Respir Dis 1989;140:S82–S84. 18. Wetter DW, Young TB, Bidwell TR, Badr MS, Palta M. Smoking as a risk factor for sleep-disordered breathing. Arch Intern Med 1994;154: 2219–2224. 19. Quan SF, Howard BV, Iber C, Kiley JP, Nieto FJ, O’Connor GT, Rapoport DM, Redline S, Robbins J, Samet JM, et al. The Sleep Heart Health Study: design, rationale, and methods. Sleep 1997;20: 1077–1085. 20. Enright PL, Johnson LR, Connett JE, Voelker H, Buist AS. Spirometry and the lung health study. Am Rev Respir Dis 1991;143:1215–1223. 21. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;323:1230–1235.
Weitzenblum, Chaouat, Kessler, et al.: Association of COPD and Sleep Apnea 22. Bixler E, Vgontzas A, Ten Have T, Tyson K, Kales A. Effects of age on sleep apnea in men. Am J Respir Crit Care Med 1998;157:144–148. 23. Bixler E, Vgontzas A, Lin H, Ten Have T, Rein J, Vela-Buen A, Kales A. Prevalence of sleep-disordered breathing in women. Am J Respir Crit Care Med 2001;163:608–613. 24. Duran J, Esnaola S, Rubio R, Iztueta A. Obstructive sleep apneahypopnea and related clinical features in a population-based sample of subjects aged 30 to 70 yr. Am J Respir Crit Care Med 2001;163:685– 689. 25. Leitch AG, Clancy LI, Leggett RJE, Tweeddate P, Dawson P, Evans JJ. Arterial blood gas tensions, hydrogen ion, and electroencephalogram during sleep in patients with chronic ventilatory failure. Thorax 1976;31: 730–735. 26. Arand DL, Mc Ginty DJ, Littner MR. Respiratory patterns associated with hemoglobin desaturation during sleep in chronic obstructive pulmonary disease. Chest 1981;80:183–190. 27. Fleetham J, West P, Mezon B, Conway W, Roth T, Kryger MH. Sleep, arousals and oxygen desaturation in chronic obstructive pulmonary disease: the effect of oxygen therapy. Am Rev Respir Dis 1982;126:429–433. 28. Calverley PMA, Brezinova V, Douglas NJ, Catterall JR, Flenley DC. The effect of oxygenation on sleep quality in chronic bronchitis and emphysema. Am Rev Respir Dis 1982;126:206–210. 29. Cormick W, Olson LG, Hensley MJ, Saunders NA. Nocturnal hypoxaemia and quality of sleep in patients with chronic obstructive lung disease. Thorax 1986;41:846–854. 30. Kessler R, Chaouat A, Schinkewitch Ph, Faller M, Casel S, Krieger J, Weitzenblum E. The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive cases. Chest 2001;120:369–376. 31. Alford NJ, Fletcher EC, Nickeson D. Acute oxygen in patients with sleep apnea and COPD. Chest 1986;89:30–38. 32. Fletcher EC. Interaction of sleep apnea and chronic lung disease. In: Peter JH, Podszus T, Von Wichert P, editors. Sleep related disorders and internal diseases. Berlin, Heidelberg: Springer-Verlag; 1987. pp. 279–298. 33. Fletcher EC. Chronic lung disease in the sleep apnea syndrome. Lung 1990;168:751–761. 34. Fletcher EC, Schaal JM, Miller J, Fletcher JG. Long-term cardiopulmonary sequelae in patients with sleep apnea and chronic lung disease. Am Rev Respir Dis 1987;135:525–533. 35. Weitzenblum E, Krieger J, Apprill M, Valle´e E, Ehrhart M, Ratomaharo J, Oswald M, Kurtz D. Daytime pulmonary hypertension in patients with obstructive sleep apnea syndrome. Am Rev Respir Dis 1988;138: 345–349.
241
36. Ashutosh K, Mead G, Dunsky M. Early effects of oxygen administration and prognosis in chronic obstructive pulmonary disease and cor pulmonale. Am Rev Respir Dis 1983;127:399–404. 37. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981;1:862–865. 38. Rapoport DM, Garay SM, Epstein H, Goldring HA. Hypercapnia in the obstructive sleep apnoea syndrome: a re-evaluation of the Pickwickian syndrome. Chest 1986;89:627–635. 39. Kessler R, Chaouat A, Weitzenblum E, Oswald M, Ehrhart M, Apprill M, Krieger J. Pulmonary hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences. Eur Respir J 1996;9:787–794. 40. Strumpf DA, Millman RP, Carlisle CC, Grattan LM, Ryan SM, Erickson AD, Hill NS. Nocturnal positive-pressure ventilation via nasal mask in patients with severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1991;144:1234–1239. 41. Meecham-Jones DJ, Paul EA, Jones PW. Nasal pressure support ventilation plus oxygen compared with oxygen therapy alone in hypercapnic COPD. Am J Respir Crit Care Med 1995;152:538–544. 42. Gay PC, Hubmayr RD, Stroetz RW. Efficacy of nocturnal nasal ventilation in stable, severe chronic obstructive pulmonary disease during a 3-month controlled trial. Mayo Clin Proc 1996;71:533–542. 43. Subramanian S, Strohl KP. A management guideline for obesityhypoventilation syndromes. Sleep Breath 1999;3:131–138. 44. Perez de Liano LA, Golpe R, Piquer MO, Racamonde AV, Caruncho MV, Muinelos OC, Carro CA. Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Chest 2005;128:587–594. 45. Masa JF, Celli BR, Riesco JA, Hernandez M, Sanchez de Cos J, Disdier C. The obesity hypoventilation syndrome can be treated with noninvasive mechanical ventilation. Chest 2001;119:1102–1107. 46. Chouri-Pontarollo N, Borel JC, Tamisier R, Wuyam B, Levy P, Pe´pin JL. Impaired objective daytime vigilance in obesity-hypoventilation syndrome: impact of non-invasive ventilation. Chest 2007;131:148– 155. 47. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152(Suppl 5):S77–S120. 48. Weitzenblum E, Sautegeau A, Ehrhart M, Mammosser M, Pelletier A. Long-term oxygen therapy can reverse the progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1985;131:493–498.
