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Clinical Investigations: SLEEP AND BREATHING |

Daytime Hypercapnia in Adult Patients With Obstructive Sleep Apnea Syndrome in France, Before Initiating Nocturnal Nasal Continuous Positive Airway Pressure Therapy* FREE TO VIEW

Jean-Pierre Laaban, MD, FCCP; Edmond Chailleux, MD; for the Observatory Group of ANTADIR
Author and Funding Information

*From the Association Nationale pour le Traitement à Domicile de l’Insuffisance Respiratoire Chronique, Paris, France.

Correspondence to: Jean-Pierre Laaban, MD, Department of Pneumology, Hôtel-Dieu, 1 place du Parvis Notre-Dame, 75004 Paris, France; e-mail: j-pierre.laaban@htd.ap-hop-paris.fr



Chest. 2005;127(3):710-715. doi:10.1378/chest.127.3.710
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Published online

Context: Daytime hypercapnia in patients with obstructive sleep apnea syndrome (OSAS) has a highly variable prevalence in the published studies, and is usually thought to be the consequence of an associated disease, COPD, or severe obesity.

Study objectives: To assess the prevalence of daytime hypercapnia in a very large population of adult patients with OSAS, free of associated COPD, and with a wide range of body mass index (BMI), and to evaluate the relationship between daytime hypercapnia and the severity of obesity and obesity-related impairment in lung function.

Design: Retrospective analysis of prospectively collected data.

Methods: The database of the observatory of a national nonprofit network for home treatment of patients with chronic respiratory insufficiency (Association Nationale pour le Traitement à Domicile de l’Insuffisance Respiratoire Chronique) was used. Collected data at treatment initiation were age, apnea-hypopnea index, BMI, FEV1, vital capacity (VC), and arterial blood gases. The study included 1,141 adult patients with OSAS treated in France with nocturnal nasal continuous positive airway pressure (CPAP), FEV1 ≥ 80% predicted, FEV1/VC ≥ 70%, and absence of restrictive respiratory disease other than related to obesity.

Results: The prevalence of daytime hypercapnia (Paco2 ≥ 45 mm Hg) before initiating CPAP therapy was 11% in the whole study population. The prevalence of daytime hypercapnia was 7.2% (27 of 377 patients) with BMI < 30, 9.8% (58 of 590 patients) with BMI from 30 to 40, and 23.6% (41 of 174 patients) with BMI > 40. Patients with daytime hypercapnia had significantly higher BMI values and significantly lower VC, FEV1, and Pao2 values than the normocapnic patients. Stepwise multiple regression showed that Pao2, BMI, and either VC or FEV1 were the best predictors of hypercapnia, but these variables explained only 9% of the variance in Paco2 levels.

Conclusion: Daytime hypercapnia was observed in > 1 of 10 patients with OSAS needing CPAP therapy and free of COPD, and was related to the severity of obesity and obesity-related impairment in lung function. However, other mechanisms than obesity are probably involved in the pathogenesis of daytime hypercapnia in OSAS.

Figures in this Article

Obstructive sleep apnea syndrome (OSAS) can be associated with daytime alveolar hypoventilation and hypercapnia. The prevalence of daytime hypercapnia in patients with OSAS is highly variable, from 12 to 43% in the published studies.14 The prevalence of daytime hypercapnia is raised in particular when OSAS is associated with COPD,34 or when OSAS is associated with severe obesity.5Therefore, some authors6 have concluded that there is no direct link between sleep apneas and daytime hypercapnia, and that daytime hypercapnia observed in patients with OSAS is the complication of an associated abnormality: COPD or severe obesity. However, the results of these studies could be contested, in view of the relatively small number of patients included,12,5 or a biased recruitment with the inclusion of a high number of patients with COPD34 or severe obesity.5 Furthermore, it has been demonstrated that the disappearance of sleep apneas obtained by nasal continuous positive airway pressure therapy (CPAP) can induce a regression in daytime hypercapnia, and is thus a major argument in favor of a direct link between sleep apneas and daytime hypercapnia.7 The aim of this study was firstly to assess the prevalence of daytime hypercapnia before initiating CPAP therapy in a very large population of adult patients with OSAS, free of an associated COPD, and with a wide range of body mass index (BMI), and secondly to evaluate the relationship between daytime hypercapnia and the severity of obesity and obesity-related impairment in lung function.

We used the database of the observatory of a national nonprofit network for home treatment of patients with chronic respiratory insufficiency (Association Nationale pour le Traitement A Domicile de l’Insuffisance Respiratoire chronique [ANTADIR]). ANTADIR was set up in France in the 1970s as a nonprofit network for the home treatment of patients with chronic respiratory insufficiency. Home treatment of patients with OSAS was started in 1985. ANTADIR has collected clinical data on treated patients in an observatory since 1984. At treatment initiation, data are collected from the social security form that is filled in by the prescriber concerning the patient’s age, sex, height, weight, and etiology of chronic respiratory disease needing home treatment. In the patients with OSAS, the apnea-hypopnea index (AHI) is collected. FEV1, vital capacity (VC), and arterial blood gases in room air are required in patients with chronic respiratory insufficiency, but not in patients with OSAS. However, a certain number of pulmonologists that prescribe home treatment for patients with OSAS in the ANTADIR network usually perform pulmonary function tests and arterial blood gas analysis in these patients. The anonymous registration of patients was approved by the “Commission Nationale de l’Informatique et des Libertés.”

Patients

The inclusion criteria were as follows: (1) patients with OSAS needing home treatment with nasal CPAP, in whom FEV1,VC, and arterial blood gas values were performed before starting CPAP therapy; (2) patient data collected in the ANTADIR observatory from January 1, 1985, until January 1, 2000; (3) AHI ≥ 10/h8; (4) age ≥ 18 years; (5) absence of restrictive respiratory disease, other than that related to obesity, namely pulmonary fibrosis, sequels of pulmonary tuberculosis, chest wall diseases, and neuromuscular disorders; (6) FEV1/VC ratio ≥ 70%; therefore, patients with an associated COPD defined by a FEV1/VC ratio < 70% were excluded9; and (7) FEV1 ≥ 80% of normal European values predicted; therefore, we excluded patients with severe restriction which could account in itself for hypercapnia.

Statistical Analysis

Daytime hypercapnia was defined by Paco2 ≥ 45 mm Hg. This cut-off was chosen because daytime chronic alveolar hypoventilation is usually defined by a Paco2 ≥ 45 mm Hg.6,10 The anthropometric, polysomnographic, and functional characteristics of the patients with daytime hypercapnia (Paco2 ≥ 45 mm Hg) and of those with Paco2 < 45 mm Hg were compared using the χ2 test and the Student t test. The correlations between Paco2 and anthropometric, polysomnographic, and functional data were studied by linear correlation and displayed graphically by dividing BMI, Pao2, VC, and FEV1 values into classes of 5 mm Hg, 10 mm Hg, 10% predicted, and 5% predicted, respectively. Multivariate analysis was performed using multiple linear regression and logistic regression, in order to find the best association of predictive factors for hypercapnia. Significance was recognized at p < 0.05.

During the study period, 88,548 patients with chronic respiratory insufficiency and 30,131 patients with OSAS needing CPAP therapy were included in the ANTADIR observatory. The values of FEV1, VC, and arterial blood gases were available in 2,217 adult patients with OSAS, defined by an AHI ≥ 10 events/h, and free of a restrictive respiratory disease other than that related to obesity. Age, sex ratio, BMI, and AHI did not significantly differ between the patients with OSAS in whom pulmonary function tests and arterial blood gas analyses were available, and those in whom they were not. After the exclusion of 614 patients with FEV1/VC ratio < 70% and the exclusion of 462 patients with FEV1 < 80% predicted, the study population included 1,141 patients (943 men and 198 women). The demographic, functional, polysomnographic, and anthropometric data for the study population according to sex are shown on Table 1 .

The prevalence of daytime hypercapnia (Paco2 ≥ 45 mm Hg) was 11% (126 of 1,141 patients) in the study population. The prevalence of daytime hypercapnia was 10.3% in men and 14.6% in women (not significant [NS] difference). The prevalence of daytime hypercapnia according to BMI is shown on Table 2 . The prevalence of daytime hypercapnia was 7.2% (27 of 377 patients) in the nonobese (BMI < 30), 9.8% (58 of 590 patients) in moderate or severe obesity (BMI 30 to 40), and 23.6% (41 of 174 patients) with massive obesity (BMI > 40). The prevalence of daytime hypercapnia associated with daytime hypoxemia (Pao2 < 70 mm Hg) was 5.6% (63 of 1,141 patients).

As shown in Table 3 , patients with daytime hypercapnia had significantly lower VC, FEV1, and Pao2 values than the normocapnic patients. Weight and BMI were significantly higher in patients with daytime hypercapnia than in the normocapnic patients. There was no significant difference between the hypercapnic and the normocapnic patients with regard to age, FEV1/VC ratio, and AHI.

In univariate analysis, Paco2 was significantly correlated with Pao2 (r = − 0.277, p < 0.001), BMI (r = 0.163, p < 0.001), FEV1 percentage of predicted (r = − 0.126, p < 0.001), and VC percentage of predicted (r = − 0.119, p < 0.001). These correlations were significant in men as well as in women. Figure 1 shows the variations in the prevalence of daytime hypercapnia in relation to BMI, Pao2, VC percentage of predicted, and FEV1 percentage of predicted.

After stepwise multiple regression, two final models were retained, including Pao2, BMI, and either VC percentage of predicted or FEV1 percentage of predicted. These two equivalent models explained only 9% of the Paco2 variance. Similarly, the stepwise logistic regression that was performed by dividing the numeric variables by a cut-off value chosen from receiving operating characteristic curves indicated that the same associations of variables were the best predictors of hypercapnia (Table 4 ).

This study shows that the prevalence of daytime hypercapnia for OSAS is 11% in the absence of associated COPD, in a very large group of adult patients with OSAS, before initiating CPAP therapy. The prevalence of daytime hypercapnia is particularly high (24%) for OSAS associated with massive obesity. Apart from the Pao2, the predictive variables of Paco2 are the BMI, and the VC or the FEV1. However, these variables can only explain < 10% of the Paco2 variance, and daytime hypercapnia has been observed in 7% of patients with an OSAS not associated with obesity. The total number of studied patients (n = 1,141) is far higher than that of other studies,15 which included between 50 patients and 265 patients.

The presence of associated COPD is a major element of confusion in the study of daytime alveolar hypoventilation in OSAS. The prevalence of daytime hypercapnia in OSAS is higher when associated with COPD. In the study of Chaouat et al,4 including 265 patients with OSAS, the prevalence of daytime hypercapnia was 27% in the 30 patients with an associated COPD and only 8% in the 235 patients without COPD. Similar results were reported by Resta et al.3 In studies12 that did not exclude patients with COPD, apneic and hypercapnic patients had a lower FEV1 and FEV1/VC ratio than apneic and normocapnic patients. More often than not, this denotes a moderate obstructive ventilatory abnormality. In multivariate analyses, Paco2 is inversely correlated in a significant fashion with FEV1 and the FEV1/VC ratio, independent of BMI.,12 In our study, we excluded patients with an FEV1/VC ratio < 70%, and the mean value of the FEV1/VC ratio was 80% in hypercapnic and normocapnic patients. Hypercapnia observed in 11% of the patients with OSAS included in our study cannot be blamed on an obstructive ventilatory disorder, even when moderate in nature.

In our study, the AHI did not significantly differ between the hypercapnic and the normocapnic patients. Studies2,5,1113 published on hypercapnia in OSAS have shown no relation between the severity of the OSAS and the presence of daytime hypercapnia: the apnea index, the AHI, and the duration of apneas do not differ between hypercapnic and normocapnic patients. Nighttime hypoxemia in apneic and hypercapnic patients is usually more serious than in apneic and normocapnic patients since they have a lower daytime Pao2 and therefore a lower preapneic arterial oxygen saturation.

In this study, we have shown that the patients with OSAS associated with daytime hypercapnia have a significantly higher BMI than the patients with an OSAS free of associated daytime hypercapnia. Similar results have been reported by various authors.2,5,14 Furthermore, our study has formally demonstrated, by stepwise logistic regression, that the increase in BMI is an independent predictive factor of daytime hypercapnia in a very large group of patients in various degrees of obesity. This relationship between hypercapnia and obesity was observed, although the exclusion of patients with FEV1 < 80% predicted presumably excluded patients with severe restriction due to massive obesity. Some studies have found no link between the importance of the obesity and daytime hypercapnia in OSAS, but there are methodologic biases in these studies: either a predominant number of patients were moderately obese,1 or a too small group of patients was included in the study.1112

In our study, the stepwise logistic regression showed that the decrease in VC is an independent predictive factor of daytime hypercapnia. The total lung capacity, functional residual capacity, and expiratory reserve volume were not systematically measured in our study, but the decrease in VC observed in the hypercapnic patients is very likely the consequence of more severe obesity, since the patients had neither chronic airflow obstruction nor any restrictive pulmonary problem other than obesity. Various studies5,1415 have shown that the daytime hypercapnia of OSAS is associated with a more serious restrictive pattern associated with more severe obesity.

One could even make the assumption that daytime hypercapnia in patients with OSAS is not secondary to sleep apneas, but is directly related to the consequences of obesity on lung function. Obesity is associated with a restrictive ventilatory deficit and a decrease in forced expiratory flow rates at low lung volumes.1619 In fact, a certain number of arguments plead in favor of a direct link between sleep apneas and daytime hypercapnia. Most patients with an “obesity hypoventilation syndrome” have associated OSAS, in 88% of cases (23 of 26 patients) in the series by Kessler et al.14 Conversely, in our study, daytime hypercapnia was observed in 7.2% (27 of 377 patients) with OSAS and without obesity (BMI < 30), whereas these patients were free of COPD and restrictive pulmonary abnormalities, suggesting a relationship between sleep apneas and daytime hypercapnia. The major argument in favor of a cause and effect between sleep apneas and daytime hypercapnia is the fact that the disappearance of sleep apneas obtained with nasal CPAP can lead to a regression in daytime hypercapnia, even in the absence of weight loss or improved ventilatory function.7,20

Various hypotheses have been suggested to explain the relation between obstructive apneas and daytime hypercapnia, and more particularly, a dysfunction of the respiratory centers induced by the apneas.8,21 It has been demonstrated that the ventilatory responses to hypoxia and hypercapnia are lower in apneic and hypercapnic patients than in apneic and normocapnic patients, matched for BMI, ventilatory function, and age, and that they increase after suppression of sleep apneas with CPAP, along with a regression in daytime hypercapnia.20 These data therefore suggest that the daytime alveolar hypoventilation of the OSAS can result from an alteration of the ventilatory drive, which could be secondary to repeated episodes of nighttime hypoxemia and hypercapnia and sleep fragmentation. Nevertheless, some authors2223 have not observed a decreased ventilatory response to hypercapnia in patients with OSAS, and others7 have reported that the suppression of sleep apneas can bring about a normalization in daytime Paco2, in absence of any variation in ventilatory response to hypercapnia. Other hypotheses have been proposed to explain daytime hypercapnia of OSAS: diaphragmatic fatigue secondary to repeated inspiratory efforts associated with obstructive apneas,,10 decrease in the postapneic ventilatory response,8,24marked decrease in the upper airway size,25and leptin resistance.2627

The prevalence of daytime hypercapnia was 11% in a very large group of patients with OSAS needing CPAP therapy and free of COPD. The prevalence of daytime hypercapnia was related to the severity of obesity and obesity-related impairment in lung function, and was especially high (> 20%) in patients with massive obesity. However, daytime hypercapnia was also demonstrated in patients without obesity, with a prevalence of 7%. Further studies should be performed to estimate the prevalence of daytime hypercapnia in patients with less severe OSAS, and to determine whether the leptin-related abnormalities in ventilatory control and respiratory muscle fatigue play a role in the pathogenesis of daytime alveolar hypoventilation in patients with OSAS.

Abbreviations: AHI = apnea-hypopnea index; ANTADIR = Association Nationale pour le Traitement à Domicile de l’Insuffisance Respiratoire Chronique; BMI = body mass index; CPAP = continuous positive airway pressure; NS = not significant; OSAS = obstructive sleep apnea syndrome; VC = vital capacity

Table Graphic Jump Location
Table 1. Demographic, Functional, Polysomnographic, and Anthropometric Data in the Study Population With OSAS According to Sex*
* 

Data are presented as mean ± SD or % of patients.

Table Graphic Jump Location
Table 2. Prevalence of Daytime Hypercapnia in Patients With OSAS According to BMI
Table Graphic Jump Location
Table 3. Demographic, Functional, Polysomnographic, and Anthropometric Data in Normocapnic and Hypercapnic Patients With OSAS*
* 

Data are presented as mean ± SD or No.

Figure Jump LinkFigure 1. Prevalence of daytime hypercapnia according to BMI, Pao2, VC percentage of predicted, and FEV1 percentage of predicted.Grahic Jump Location
Table Graphic Jump Location
Table 4. Stepwise Logistic Regression: Final Models for Prediction of Daytime Hypercapnia
Krieger, J, Sforza, E, Apprill, M, et al (1989) Pulmonary hypertension, hypoxemia, and hypercapnia in obstructive sleep apnea patients.Chest96,729-737. [CrossRef] [PubMed]
 
Bradley, TD, Rutherford, R, Lue, F, et al Role of diffuse airway obstruction in the hypercapnia of obstructive sleep apnea.Am Rev Respir Dis1986;134,920-924. [PubMed]
 
Resta, O, Barbaro, MPF, Brindicci, C, et al Hypercapnia in overlap syndrome: possible determinant factors.Sleep Breath2002;6,11-17. [CrossRef] [PubMed]
 
Chaouat, A, Weitzenblum, E, Krieger, J, et al Association of chronic obstructive pulmonary disease and sleep apnea syndrome.Am J Respir Crit Care Med1995;151,82-86. [PubMed]
 
Leech, JA, Onal, E, Baer, P, et al Determinants of hypercapnia in occlusive sleep apnea syndrome.Chest1987;92,807-813. [CrossRef] [PubMed]
 
Weitzenblum, E, Chaouat, A, Kessler, R, et al Daytime hypoventilation in obstructive sleep apnoea syndrome.Sleep Med Rev1999;3,79-93. [CrossRef] [PubMed]
 
Rapoport, DM, Garay, SM, Epstein, H, et al Hypercapnia in the obstructive sleep apnea syndrome: a reevaluation of the Pickwickian syndrome.Chest1986;89,627-635. [CrossRef] [PubMed]
 
Strohl, KP, Redline, S Recognition of obstructive sleep apnea.Am J Respir Crit Care Med1996;154,279-289. [PubMed]
 
Pauwels, RA, Buist, AS, Calverley, PMA, et al Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO global initiative for chronic obstructive lung disease (GOLD) workshop summary.Am J Respir Crit Care Med2001;163,1256-1276. [PubMed]
 
Martin, TJ, Sanders, MH Chronic alveolar hypoventilation: a review for the clinician.Sleep1995;18,617-634. [PubMed]
 
Garay, SM, Rapoport, D, Sorkin, B, et al Regulation of ventilation in the obstructive sleep apnea syndrome.Am Rev Respir Dis1981;124,451-457. [PubMed]
 
Javaheri, S, Colangelo, G, Corser, B, et al Familial respiratory chemosensitivity does not predict hypercapnia of patients with sleep apnea-hypopnea syndrome.Am Rev Respir Dis1992;145,837-840. [PubMed]
 
Laaban, JP, Orvoen-Frija, E, Cassuto, D, et al Mechanisms of diurnal hypercapnia in sleep apnea syndrome in morbidly obese subjects.Presse Med1996;25,12-16. [PubMed]
 
Kessler, R, Chaouat, A, Schinkewitch, P, et al The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive cases.Chest2001;120,369-376. [CrossRef] [PubMed]
 
Jones, JB, Wilhoit, SC, Findley, LJ, et al Oxyhemoglobin saturation during sleep in subjects with and without the obesity-hypoventilation syndrome.Chest1985;88,9-15. [CrossRef] [PubMed]
 
Rubinstein, I, Zamel, N, DuBarry, L, et al Airflow limitation in morbidly obese, nonsmoking men.Ann Intern Med1990;112,828-832. [PubMed]
 
Zerah, F, Harf, A, Perlemuter, L, et al Effects of obesity on respiratory resistance.Chest1993;103,1470-1476. [CrossRef] [PubMed]
 
Sahebjami, H, Gartside, P Pulmonary function in obese subjects with a normal FEV1/FVC ratio.Chest1996;110,1425-1429. [CrossRef] [PubMed]
 
Lazarus, R, Sparrow, D, Weiss, ST Effects of obesity and fat distribution on ventilatory function: the normative aging study.Chest1997;111,891-898. [CrossRef] [PubMed]
 
Han, F, Chen, E, Wei, H, et al Treatment effects on carbon dioxide retention in patients with obstructive sleep apnea-hypopnea syndrome.Chest2001;119,1814-1819. [CrossRef] [PubMed]
 
Lopata, M, Onal, E Mass loading, sleep apnea, and the pathogenesis of obesity hypoventilation.Am Rev Respir Dis1982;126,640-645. [PubMed]
 
Appelberg, J, Sundström, G Ventilatory response to CO2in patients with snoring, obstructive hypopnoea and obstructive apnoea.Clin Physiol1997;17,497-507. [CrossRef] [PubMed]
 
Sin, DD, Jones, RL, Man, GC Hypercapnic ventilatory response in patients with and without obstructive sleep apnea: do age, gender, obesity, and daytime Paco2matter?Chest2000;117,454-459. [CrossRef] [PubMed]
 
Satoh, M, Hida, W, Chonan, T, et al Role of hypoxic drive in regulation of postapneic ventilation during sleep in patients with obstructive sleep apnea.Am Rev Respir Dis1991;143,481-485. [PubMed]
 
Chan, CS, Grunstein, RR, Bye, PTP, et al Obstructive sleep apnea with severe chronic airflow limitation: comparison of hypercapnic and eucapnic patients.Am Rev Respir Dis1989;140,1274-1278. [CrossRef] [PubMed]
 
Phipps, PR, Starrit, E, Caterson, I, et al Association of serum leptin with hypoventilation in human obesity.Thorax2002;57,75-76. [CrossRef] [PubMed]
 
O’Donnell, CP, Schaub, CD, Haines, AS, et al Leptin prevents respiratory depression in obesity.Am J Respir Crit Care Med1999;159,1477-1484. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Prevalence of daytime hypercapnia according to BMI, Pao2, VC percentage of predicted, and FEV1 percentage of predicted.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Demographic, Functional, Polysomnographic, and Anthropometric Data in the Study Population With OSAS According to Sex*
* 

Data are presented as mean ± SD or % of patients.

Table Graphic Jump Location
Table 2. Prevalence of Daytime Hypercapnia in Patients With OSAS According to BMI
Table Graphic Jump Location
Table 3. Demographic, Functional, Polysomnographic, and Anthropometric Data in Normocapnic and Hypercapnic Patients With OSAS*
* 

Data are presented as mean ± SD or No.

Table Graphic Jump Location
Table 4. Stepwise Logistic Regression: Final Models for Prediction of Daytime Hypercapnia

References

Krieger, J, Sforza, E, Apprill, M, et al (1989) Pulmonary hypertension, hypoxemia, and hypercapnia in obstructive sleep apnea patients.Chest96,729-737. [CrossRef] [PubMed]
 
Bradley, TD, Rutherford, R, Lue, F, et al Role of diffuse airway obstruction in the hypercapnia of obstructive sleep apnea.Am Rev Respir Dis1986;134,920-924. [PubMed]
 
Resta, O, Barbaro, MPF, Brindicci, C, et al Hypercapnia in overlap syndrome: possible determinant factors.Sleep Breath2002;6,11-17. [CrossRef] [PubMed]
 
Chaouat, A, Weitzenblum, E, Krieger, J, et al Association of chronic obstructive pulmonary disease and sleep apnea syndrome.Am J Respir Crit Care Med1995;151,82-86. [PubMed]
 
Leech, JA, Onal, E, Baer, P, et al Determinants of hypercapnia in occlusive sleep apnea syndrome.Chest1987;92,807-813. [CrossRef] [PubMed]
 
Weitzenblum, E, Chaouat, A, Kessler, R, et al Daytime hypoventilation in obstructive sleep apnoea syndrome.Sleep Med Rev1999;3,79-93. [CrossRef] [PubMed]
 
Rapoport, DM, Garay, SM, Epstein, H, et al Hypercapnia in the obstructive sleep apnea syndrome: a reevaluation of the Pickwickian syndrome.Chest1986;89,627-635. [CrossRef] [PubMed]
 
Strohl, KP, Redline, S Recognition of obstructive sleep apnea.Am J Respir Crit Care Med1996;154,279-289. [PubMed]
 
Pauwels, RA, Buist, AS, Calverley, PMA, et al Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO global initiative for chronic obstructive lung disease (GOLD) workshop summary.Am J Respir Crit Care Med2001;163,1256-1276. [PubMed]
 
Martin, TJ, Sanders, MH Chronic alveolar hypoventilation: a review for the clinician.Sleep1995;18,617-634. [PubMed]
 
Garay, SM, Rapoport, D, Sorkin, B, et al Regulation of ventilation in the obstructive sleep apnea syndrome.Am Rev Respir Dis1981;124,451-457. [PubMed]
 
Javaheri, S, Colangelo, G, Corser, B, et al Familial respiratory chemosensitivity does not predict hypercapnia of patients with sleep apnea-hypopnea syndrome.Am Rev Respir Dis1992;145,837-840. [PubMed]
 
Laaban, JP, Orvoen-Frija, E, Cassuto, D, et al Mechanisms of diurnal hypercapnia in sleep apnea syndrome in morbidly obese subjects.Presse Med1996;25,12-16. [PubMed]
 
Kessler, R, Chaouat, A, Schinkewitch, P, et al The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive cases.Chest2001;120,369-376. [CrossRef] [PubMed]
 
Jones, JB, Wilhoit, SC, Findley, LJ, et al Oxyhemoglobin saturation during sleep in subjects with and without the obesity-hypoventilation syndrome.Chest1985;88,9-15. [CrossRef] [PubMed]
 
Rubinstein, I, Zamel, N, DuBarry, L, et al Airflow limitation in morbidly obese, nonsmoking men.Ann Intern Med1990;112,828-832. [PubMed]
 
Zerah, F, Harf, A, Perlemuter, L, et al Effects of obesity on respiratory resistance.Chest1993;103,1470-1476. [CrossRef] [PubMed]
 
Sahebjami, H, Gartside, P Pulmonary function in obese subjects with a normal FEV1/FVC ratio.Chest1996;110,1425-1429. [CrossRef] [PubMed]
 
Lazarus, R, Sparrow, D, Weiss, ST Effects of obesity and fat distribution on ventilatory function: the normative aging study.Chest1997;111,891-898. [CrossRef] [PubMed]
 
Han, F, Chen, E, Wei, H, et al Treatment effects on carbon dioxide retention in patients with obstructive sleep apnea-hypopnea syndrome.Chest2001;119,1814-1819. [CrossRef] [PubMed]
 
Lopata, M, Onal, E Mass loading, sleep apnea, and the pathogenesis of obesity hypoventilation.Am Rev Respir Dis1982;126,640-645. [PubMed]
 
Appelberg, J, Sundström, G Ventilatory response to CO2in patients with snoring, obstructive hypopnoea and obstructive apnoea.Clin Physiol1997;17,497-507. [CrossRef] [PubMed]
 
Sin, DD, Jones, RL, Man, GC Hypercapnic ventilatory response in patients with and without obstructive sleep apnea: do age, gender, obesity, and daytime Paco2matter?Chest2000;117,454-459. [CrossRef] [PubMed]
 
Satoh, M, Hida, W, Chonan, T, et al Role of hypoxic drive in regulation of postapneic ventilation during sleep in patients with obstructive sleep apnea.Am Rev Respir Dis1991;143,481-485. [PubMed]
 
Chan, CS, Grunstein, RR, Bye, PTP, et al Obstructive sleep apnea with severe chronic airflow limitation: comparison of hypercapnic and eucapnic patients.Am Rev Respir Dis1989;140,1274-1278. [CrossRef] [PubMed]
 
Phipps, PR, Starrit, E, Caterson, I, et al Association of serum leptin with hypoventilation in human obesity.Thorax2002;57,75-76. [CrossRef] [PubMed]
 
O’Donnell, CP, Schaub, CD, Haines, AS, et al Leptin prevents respiratory depression in obesity.Am J Respir Crit Care Med1999;159,1477-1484. [PubMed]
 
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