Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Clinical Investigations

Free Access

Effects of Salmeterol on Sleeping Oxygen Saturation in Chronic Obstructive Pulmonary Disease

Ryan S. · Doherty L.S. · Rock C. · Nolan G.M. · McNicholas W.T.

Author affiliations

Sleep Research Laboratory, St. Vincent’s University Hospital, Dublin, Ireland

Corresponding Author

Prof. Walter McNicholas

Department of Respiratory Medicine, St. Vincent’s University Hospital

Elm Park

Dublin 4 (Ireland)

Tel +353 1 277 3702, Fax +353 1 269 7949, E-Mail walter.mcnicholas@ucd.ie

Related Articles for ""

Respiration 2010;79:475–481

Abstract

Background: Sleep is associated with important adverse effects in patients with chronic obstructive pulmonary disease (COPD), such as disturbed sleep quality and gas exchange, including hypoxemia and hypercapnia. The effects of inhaled long-acting β2-agonist therapy (LABA) on these disturbances are unclear. Objectives: The aim of the study was to assess the effect of inhaled salmeterol on nocturnal sleeping arterial oxygen saturation (SaO2) and sleep quality. Methods: In a randomized, double-blind, placebo-controlled, crossover study of moderate/severe stable COPD patients, we compared the effects of 4 weeks of treatment with salmeterol 50 µg b.d. and matching placebo on sleeping SaO2 and sleep quality. Overnight polysomnography (PSG) was performed at baseline, and after 4 and 8 weeks in addition to detailed pulmonary function testing. Of 15 patients included, 12 completed the trial (median age 69 years, forced expiratory volume in 1 s, FEV1: 39%). Results: Both mean SaO2 [salmeterol vs. placebo: 92.9% (91.2, 94.7) vs. 91.0% (88.9, 94.8); p = 0.016] and the percentage of sleep spent below 90% of SaO2 [1.8% (0.0, 10.8) vs. 25.6% (0.5, 53.5); p = 0.005] improved significantly with salmeterol. Sleep quality was similar with both salmeterol and placebo on PSG. Static lung volumes, particularly trapped gas volume, tended to improve with salmeterol. Conclusion: We conclude that inhaled LABA therapy improves sleeping SaO2 without significant change in sleep quality.

© 2009 S. Karger AG, Basel


Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation that is not fully reversible and is a leading cause of morbidity and mortality worldwide [1]. Sleep can be associated with clinically important adverse effects in patients with COPD, such as disordered gas exchange and disturbances in sleep quality [2]. Hypoventilation, a normal feature during sleep, has a disproportionate effect on hypoxemic patients because of their position on the oxyhemoglobin dissociation curve, leading to significant nocturnal desaturation, even in patients with mild awake hypoxemia [3]. In addition, the physiological reductions in accessory muscle contribution to breathing during sleep result in a decreased functional residual capacity (FRC), which leads to worsening ventilation-perfusion relationships and also aggravates hypoxemia [4]. Sleep-related hypoxemia may predispose to pulmonary hypertension, cardiac arrhythmias during sleep and nocturnal death during exacerbations [5,6,7].

Hypoxemia during sleep is easily corrected by supplemental oxygen, although this may not lead to improved sleep quality [8,9,10]. Pharmacological therapies which ameliorate some of the factors contributing to hypoxemia during sleep described above might be an alternative approach, and previous reports from our unit identified an improvement in nocturnal oxygen saturation, but not sleep quality, with the addition of theophylline [11] as well as with the long-acting anticholinergic agent tiotropium [12].

Long-acting β-agonists (LABA) are a recommended part of care in patients with moderate/severe COPD [1], but their effect on nocturnal oxygen saturation and sleep quality is unknown. Previous studies have shown that the addition of the LABA salmeterol results in a decrease in the exacerbation rate, improved health status, an increase in forced expiratory volume in 1 s (FEV1) and in a reduction of lung hyperinflation at rest and during exercise [13,14,15,16,17,18].

We conducted a randomized, double-blind, placebo-controlled, crossover study to assess the effect of inhaled salmeterol on nocturnal sleeping arterial oxygen saturation (SaO2) and sleep quality. Primary outcome variables were the percentage of total sleep time spent below 90% of SaO2 (TST90) and the mean SaO2 during sleep.

Patients and Methods

Subjects

Subjects included clinically stable patients ≥40 years old with a diagnosis of COPD; a cigarette smoking history ≥10 pack-years; a FEV1 ≤65% of predicted, and a FEV1/forced vital capacity ratio ≤70%, in addition to an awake arterial oxygen tension (PaO2) ≤9.98 kPa (75 mm Hg) prior to study entry. Patients were excluded if they were receiving regular oxygen therapy, had a clinically significant recent or concomitant disease other than COPD, or evidence of sleep apnea on baseline sleep studies (≥10 apneas or hypopneas per hour of sleep). Additional exclusion criteria included: evidence of asthma or atopy; respiratory infection in the preceding 6 weeks; concurrent use of inhaled corticosteroids >1,500 µg daily or oral corticosteroids >10 mg daily. Concurrent treatment with inhaled salbutamol as required and inhaled tiotropium was permitted.

Study Design

This was a randomized, double-blind, placebo-controlled, crossover study, which was approved by the St. Vincent’s University Hospital Ethics Committee. All subjects gave written informed consent. A flow chart of study assessments is given in figure 1. Each subject spent 3 nights in the sleep laboratory: the baseline night (before randomization), the 4-week night after the first study arm and the end-of-study night (8 weeks after randomization). One week before the baseline visit, patients stopped taking regular LABA, if already on this medication. At baseline, each subject underwent detailed clinical assessment, testing for full blood count, liver and kidney function, arterial blood gas measurements (after at least 30 min of rest in the supine position) and a chest X-ray. Polysomnography (PSG) and detailed pulmonary function tests (PFTs; described below) were performed, and the subject’s technique in using a Diskus™ inhaler was assessed by a respiratory specialist nurse. Subjects who met the inclusion criteria were randomized to either salmeterol 50 µg twice daily or placebo via a Diskus inhaler. After each study arm, subjects underwent PSG and PFTs, and were asked to fill out the SF-36 (Short Form-36 quality of life questionnaire) [19] and the Epworth Sleepiness Scale (ESS) [20]. During the whole study period, patients recorded their daytime alertness, perception of sleep quality, respiratory symptoms, number of puffs of rescue salbutamol and compliance with trial medication in a daily diary.

Fig. 1

Flow chart of study assessments. ABG = Arterial blood gas measurement; CXR = chest X-ray

http://www.karger.com/WebMaterial/ShowPic/239834

Procedures

Overnight PSG was performed on an automated system (SleepLab; Viaysis, Wurzburg, Germany) as previously described [21] and manually analyzed according to the criteria of Rechtschaffen and Kales [22].

Spirometry was performed with the patient seated and the best of three efforts recorded, and repeated 20 min after inhalation of 400 µg of salbutamol. Single-breath carbon monoxide diffusing capacity, in addition to static lung volumes by both multi-breath helium dilution and whole-body plethysmography, were also measured using the Jaeger MS Masterscreen Body Box (Jaeger, Hoechberg, Germany).

Both the closed circuit multi-breath helium dilution and body plethysmography techniques permit the assessment of lung hyperinflation. However, the helium dilution method can only measure the volume of gas in the lungs in direct communication with the airways, whereas the body plethysmography technique is not affected by the presence of poorly ventilated air sacs. The difference in FRC obtained during the procedures is therefore used to calculate the trapped gas volume.

Statistical Analysis

The primary endpoints were the mean nocturnal SaO2 and the percentage of TST90 for the comparison of salmeterol and placebo. The expected difference in these variables, which might be clinically important, and the pooled standard deviation were specified on the basis of previously published studies on pharmacological intervention on nocturnal SaO2 on COPD [11,12,23]. The required sample size to detect a difference of 2% in the SaO2 and 10% in TST90 with 90% power at the 5% significance level was 11 subjects.

Subject baseline characteristics and measured variables are expressed as medians (interquartile ranges) and compared using the Wilcoxon signed-rank test for paired samples. p < 0.05 was considered statistically significant.

Results

Subject Characteristics

Consecutive patients with COPD (n = 339) attending our outpatient respiratory clinics were screened for the study; 51 patients met the inclusion criteria and were eligible for enrolment. Fifteen of these patients agreed to participate and proceeded to randomization, and 12 patients completed the study. Two subjects were withdrawn as they experienced an infective exacerbation of COPD during the study period, 1 subject after 2 weeks while on salmeterol and a further subject after 5 weeks currently on placebo. One subject withdrew after the 2nd sleep study night. Baseline characteristics of the entire study population and, separately, the 12 subjects completing the study protocol are given in table 1.

Table 1

Baseline characteristics of the entire study population and separately of all subjects included in the final analysis

http://www.karger.com/WebMaterial/ShowPic/239838

Oxygen Saturation

The principal comparators were the SaO2 levels during sleep between treatment with salmeterol and placebo. There was no difference in awake SaO2 between both treatments (table 2). However, patients on placebo spent significantly more time during sleep below 90% (TST90, p < 0.01) and, furthermore, the mean SaO2 during sleep was significantly lower than on salmeterol (p < 0.02). There was also a trend towards lower minimal SaO2 while on placebo (p = 0.07; table 2).

Table 2

Oxymetry variables before and during total sleep time between salmeterol and placebo (n = 12) groups

http://www.karger.com/WebMaterial/ShowPic/239837

Sleep Quality

PSG data are presented in table 3. In general, there was a wide variation in sleep quality between subjects, however there was no significant difference between studies on salmeterol and placebo. Furthermore, there were no significant differences in subjective daytime sleepiness and placebo, as assessed by the ESS. The ESS in the salmeterol arm was 3.5 [2.0, 5.0] versus 4.0 [2.0, 5.75] in the placebo arm, both values being within the normal range. In addition, there was no difference in quality of life as assessed by the SF-36 questionnaire between salmeterol and placebo.

Table 3

Effect of salmeterol versus placebo on duration of sleep stages, latency to persistent sleep and latency to REM sleep (n = 12)

http://www.karger.com/WebMaterial/ShowPic/239836

Pulmonary Function Testing

Salmeterol had no significant effect on spirometry and diffusing capacity in our cohort (table 4). Lung volumes measured by body plethysmography and helium dilution showed a trend towards a fall with salmeterol. This was particularly evident in the trapped gas volume (p = 0.07), which represents the difference between FRC measured by body plethysmography and helium dilution.

Table 4

Effect of salmeterol versus placebo on pulmonary function testing (n = 12)

http://www.karger.com/WebMaterial/ShowPic/239835

Discussion

The present findings indicate that addition of the inhaled LABA salmeterol improves SaO2 during sleep in patients with advanced COPD. Based on the PFT results we propose a reduction in hyperinflation as one likely underlying mechanism in this improvement. The magnitude of improvement in sleep-related SaO2 as measured by the mean sleep SaO2 is comparable to that previously reported with theophylline [11] and tiotropium [12] therapy. We also measured TST90, which is probably a clinically more relevant variable. Our findings demonstrate a large improvement from about a quarter of TST90 while on placebo to only 2% of sleep on salmeterol, an extent which, given the relatively small study population and the study period, is impressive and clinically relevant, as nocturnal desaturation in COPD has been reported to predispose to cardiac arrhythmias [5], elevated pulmonary arterial pressure levels during sleep [7] and nocturnal death during exacerbations [6].

The principal mechanisms of hypoxemia during sleep in COPD are a fall in minute ventilation and worsening of preexisting ventilation-perfusion mismatching. Furthermore, loss of accessory muscle activity during REM sleep may contribute to hypoventilation and thereby to a deterioration in pulmonary gas exchange [4]. There is a close relationship between the awake arterial oxygen tension and nocturnal SaO2 levels [24]; however, even patients with mild hypoxemia have been reported to develop significant nocturnal desaturation, which may predispose to pulmonary hypertension [25]. Other studies support an improvement in lung function as an important mechanism of improvements in SaO2 during sleep. Oral theophylline therapy reduces the degree of air trapping in the lungs with consequent improvements in sleep SaO2[11]. Another multicenter study performed in the United Kingdom and Ireland assessed the effect of the long-acting anticholinergic agent tiotropium and reported a similar significant improvement in SaO2 during sleep, which was accompanied by an improvement in spirometry [12]. Furthermore, Postma et al. [23] found that the nocturnal fall in SaO2 occurring in COPD patients was abolished by the β-agonist terbutaline in a slow-release oral form, which was also associated with an improvement in FEV1. β-Agonists in this form are now rarely used and the present study is the first to study the effect of an inhaled LABA, which is widely used in moderate/severe COPD, on SaO2 levels during sleep. Although there was a trend to improved pulmonary function in our study population while on salmeterol, particularly in static lung volumes and in trapped gas volume, our study was not sufficiently powered to detect a statistically significant difference. However, previous studies comparing salmeterol and placebo reported a significant improvement in static lung volumes with salmeterol [15,16,17,26] leading to improved exercise capacity and a reduction in dyspnea perception. It is likely, given the magnitude of improvement in SaO2 during sleep, that reduction in hyperinflation is not the only underlying mechanism of salmeterol in this process and further targeted studies need to be undertaken to specifically address this point.

The present study findings are consistent with previous reports that have failed to show a relationship between correction of hypoxemia and sleep quality in COPD [8,12,27]. Sleep quality is generally poor in patients with COPD and PSG studies demonstrate sleep fragmentation with frequent arousals and diminished slow wave and REM sleep [27]. This is particularly evident in hypoxemic patients and those with severe airflow limitation [9]. In our study, all patients achieved at least 4 h of objectively confirmed sleep assuring good quality studies. However, patients reported frequent awakenings in keeping with previous observations [28]. Salmeterol did not improve variables of sleep quality, but a beneficial effect may require more prolonged treatment or a larger sample size given the high degree of variability in sleep quality in this patient population. While there appeared to be a trend towards less slow-wave sleep with salmeterol, our study was not sufficiently powered to detect a significant difference and further studies would be required to specifically address this point. Notably, there was no deterioration in subjective sleep quality with salmeterol in our patient population as previously reported in another study [29]. Similar to other reports [12,30], patients in our study did not complain of daytime sleepiness, suggesting that their sleep was not disrupted sufficiently to be perceived as nonrestorative, or alternatively, their overall disease perception placed the sleep disturbances into the background.

We excluded patients with obstructive sleep apnea syndrome (OSAS) from the study to avoid a potentially important confounding disorder that might have compromised the ability to assess the direct effects of salmeterol on oxygen levels in COPD patients while asleep. Nonetheless, we recognize the importance of coexisting COPD and OSAS (commonly referred to as the ‘overlap syndrome’), which is likely to be common given the high prevalence of each disorder. The degree of oxygen desaturation during sleep is greater in the overlap syndrome than with either disorder alone [31], but we cannot assess whether salmeterol would have a greater or lesser effect on sleep SaO2 levels in such patients. This question has important practical significance since nocturnal oxygen desaturation has been identified as the most important determinant of systemic inflammation in OSAS patients [32] and in patients with COPD, and systemic inflammation is regarded as an important factor in the development of cardiovascular complications of each disorder [33,34]. Thus, medication that reduces the degree of nocturnal oxygen desaturation in COPD, with or without OSAS, may have an added value in terms of reducing the potential for cardiovascular complications.

A potential limitation of our study is the reliance on subjectively reported compliance. However, the dosage counter on the Diskus device in conjunction with the diary recordings completed by each patient suggests very good compliance. The patient’s technique in using the device was assessed by a respiratory specialist nurse prior to the study and corrective advice was given where necessary. Only subjects who were able to use the Diskus adequately were included in the study.

In conclusion, the present findings provide strong evidence of a clinically significant benefit from the LABA salmeterol on sleeping SaO2 levels in patients with advanced COPD.

Acknowledgments

We would like to thank GlaxoSmithKline, Ireland (Ltd.), for supporting the study. We are grateful to all staff members of the Sleep Laboratory at the St. Vincent’s University Hospital for their help and support and all patients for participating in this study.


References

  1. Celli BR, MacNee W: Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23:932–946.
  2. McNicholas WT: Impact of sleep in COPD. Chest 2000;117(2 suppl):48S–53S.
    External Resources
  3. Catterall JR, Calverley PM, MacNee W, Warren PM, Shapiro CM, Douglas NJ, Flenley DC: Mechanism of transient nocturnal hypoxemia in hypoxic chronic bronchitis and emphysema. J Appl Physiol 1985;59:1698–1703.
  4. Johnson MW, Remmers JE: Accessory muscle activity during sleep in chronic obstructive pulmonary disease. J Appl Physiol 1984;57:1011–1017.
  5. Tirlapur VG, Mir MA: Nocturnal hypoxemia and associated electrocardiographic changes in patients with chronic obstructive airways disease. N Engl J Med 1982;306:125–130.
  6. McNicholas WT, Fitzgerald MX: Nocturnal deaths among patients with chronic bronchitis and emphysema. Br Med J (Clin Res Ed) 1984;289:878.
  7. Fletcher EC, Luckett RA, Miller T, Costarangos C, Kutka N, Fletcher JG: Pulmonary vascular hemodynamics in chronic lung disease patients with and without oxyhemoglobin desaturation during sleep. Chest 1989;95:757–764.
  8. Fleetham J, West P, Mezon B, Conway W, Roth T, Kryger M: Sleep, arousals, and oxygen desaturation in chronic obstructive pulmonary disease. The effect of oxygen therapy. Am Rev Respir Dis 1982;126:429–433.
  9. Calverley PM, 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.
  10. Goldstein RS, Ramcharan V, Bowes G, McNicholas WT, Bradley D, Phillipson EA: Effect of supplemental nocturnal oxygen on gas exchange in patients with severe obstructive lung disease. N Engl J Med 1984;310:425–429.
  11. Mulloy E, McNicholas WT: Theophylline improves gas exchange during rest, exercise, and sleep in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1993;148(4 Pt 1):1030–1036.
  12. McNicholas WT, Calverley PM, Lee A, Edwards JC: Long-acting inhaled anticholinergic therapy improves sleeping oxygen saturation in COPD. Eur Respir J 2004;23:825–831.
  13. Stockley RA, Chopra N, Rice L: Addition of salmeterol to existing treatment in patients with COPD: a 12 month study. Thorax 2006;61:122–128.
  14. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J: Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789.
  15. O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA: Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease. Eur Respir J 2004;24:86–94.
  16. Man WD, Mustfa N, Nikoletou D, Kaul S, Hart N, Rafferty GF, Donaldson N, Polkey MI, Moxham J: Effect of salmeterol on respiratory muscle activity during exercise in poorly reversible COPD. Thorax 2004;59:471–476.
  17. Brouillard C, Pepin V, Milot J, Lacasse Y, Maltais F: Endurance shuttle walking test: responsiveness to salmeterol in COPD. Eur Respir J 2008;31:579–584.
  18. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C: Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361:449–456.
  19. Ware JE, Snow K, Kosinski M, Gandek B: SF-36® Health Survey. Manual and Interpretation Guide. Boston, New England Medical Center, Health Institute, 1993.
  20. Johns MW: A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540–545.
  21. Ryan S, Taylor CT, McNicholas WT: Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 2005;112:2660–2667.
  22. Rechtschaffen A, Kales A: A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Washington, US Government Printing Office, Public Health Service, 1968.
  23. Postma DS, Koeter GH, vd Mark TW, Reig RP, Sluiter HJ: The effects of oral slow-release terbutaline on the circadian variation in spirometry and arterial blood gas levels in patients with chronic airflow obstruction. Chest 1985;87:653–657.
  24. Connaughton JJ, Catterall JR, Elton RA, Stradling JR, Douglas NJ: Do sleep studies contribute to the management of patients with severe chronic obstructive pulmonary disease? Am Rev Respir Dis 1988;138:341–344.
  25. Fletcher EC, Miller J, Divine GW, Fletcher JG, Miller T: Nocturnal oxyhemoglobin desaturation in COPD patients with arterial oxygen tensions above 60 mm Hg. Chest 1987;92:604–608.
  26. O’Donnell DE, Sciurba F, Celli B, Mahler DA, Webb KA, Kalberg CJ, Knobil K: Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise endurance in COPD. Chest 2006;130:647–656.
  27. 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.
  28. Rennard S, Decramer M, Calverley PM, Pride NB, Soriano JB, Vermeire PA, Vestbo J: Impact of COPD in North America and Europe in 2000: subjects’ perspective of Confronting COPD International Survey. Eur Respir J 2002;20:799–805.
  29. Jones PW, Bosh TK: Quality of life changes in COPD patients treated with salmeterol. Am J Respir Crit Care Med 1997;155:1283–1289.
  30. Collard P, Dury M, Delguste P, Aubert G, Rodenstein DO: Movement arousals and sleep-related disordered breathing in adults. Am J Respir Crit Care Med 1996;154(2 Pt 1):454–459.
  31. Chaouat A, Weitzenblum E, Krieger J, Ifoundza T, Oswald M, Kessler R: Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am J Respir Crit Care Med 1995;151:82–86.
  32. Ryan S, Taylor CT, McNicholas WT: Predictors of elevated nuclear factor-ĸB-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2006;174:824–830.
  33. McNicholas WT, Bonsigore MR: Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 2007;29:156–178.
  34. Sin DD, Man SF: Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003;107:1514–1519.

Author Contacts

Prof. Walter McNicholas

Department of Respiratory Medicine, St. Vincent’s University Hospital

Elm Park

Dublin 4 (Ireland)

Tel +353 1 277 3702, Fax +353 1 269 7949, E-Mail walter.mcnicholas@ucd.ie


Article / Publication Details

First-Page Preview
Abstract of Clinical Investigations

Received: January 21, 2009
Accepted: June 11, 2009
Published online: August 14, 2009
Issue release date: May 2010

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 4

ISSN: 0025-7931 (Print)
eISSN: 1423-0356 (Online)

For additional information: https://www.karger.com/RES


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Celli BR, MacNee W: Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23:932–946.
  2. McNicholas WT: Impact of sleep in COPD. Chest 2000;117(2 suppl):48S–53S.
    External Resources
  3. Catterall JR, Calverley PM, MacNee W, Warren PM, Shapiro CM, Douglas NJ, Flenley DC: Mechanism of transient nocturnal hypoxemia in hypoxic chronic bronchitis and emphysema. J Appl Physiol 1985;59:1698–1703.
  4. Johnson MW, Remmers JE: Accessory muscle activity during sleep in chronic obstructive pulmonary disease. J Appl Physiol 1984;57:1011–1017.
  5. Tirlapur VG, Mir MA: Nocturnal hypoxemia and associated electrocardiographic changes in patients with chronic obstructive airways disease. N Engl J Med 1982;306:125–130.
  6. McNicholas WT, Fitzgerald MX: Nocturnal deaths among patients with chronic bronchitis and emphysema. Br Med J (Clin Res Ed) 1984;289:878.
  7. Fletcher EC, Luckett RA, Miller T, Costarangos C, Kutka N, Fletcher JG: Pulmonary vascular hemodynamics in chronic lung disease patients with and without oxyhemoglobin desaturation during sleep. Chest 1989;95:757–764.
  8. Fleetham J, West P, Mezon B, Conway W, Roth T, Kryger M: Sleep, arousals, and oxygen desaturation in chronic obstructive pulmonary disease. The effect of oxygen therapy. Am Rev Respir Dis 1982;126:429–433.
  9. Calverley PM, 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.
  10. Goldstein RS, Ramcharan V, Bowes G, McNicholas WT, Bradley D, Phillipson EA: Effect of supplemental nocturnal oxygen on gas exchange in patients with severe obstructive lung disease. N Engl J Med 1984;310:425–429.
  11. Mulloy E, McNicholas WT: Theophylline improves gas exchange during rest, exercise, and sleep in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1993;148(4 Pt 1):1030–1036.
  12. McNicholas WT, Calverley PM, Lee A, Edwards JC: Long-acting inhaled anticholinergic therapy improves sleeping oxygen saturation in COPD. Eur Respir J 2004;23:825–831.
  13. Stockley RA, Chopra N, Rice L: Addition of salmeterol to existing treatment in patients with COPD: a 12 month study. Thorax 2006;61:122–128.
  14. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J: Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789.
  15. O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA: Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease. Eur Respir J 2004;24:86–94.
  16. Man WD, Mustfa N, Nikoletou D, Kaul S, Hart N, Rafferty GF, Donaldson N, Polkey MI, Moxham J: Effect of salmeterol on respiratory muscle activity during exercise in poorly reversible COPD. Thorax 2004;59:471–476.
  17. Brouillard C, Pepin V, Milot J, Lacasse Y, Maltais F: Endurance shuttle walking test: responsiveness to salmeterol in COPD. Eur Respir J 2008;31:579–584.
  18. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C: Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361:449–456.
  19. Ware JE, Snow K, Kosinski M, Gandek B: SF-36® Health Survey. Manual and Interpretation Guide. Boston, New England Medical Center, Health Institute, 1993.
  20. Johns MW: A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540–545.
  21. Ryan S, Taylor CT, McNicholas WT: Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 2005;112:2660–2667.
  22. Rechtschaffen A, Kales A: A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Washington, US Government Printing Office, Public Health Service, 1968.
  23. Postma DS, Koeter GH, vd Mark TW, Reig RP, Sluiter HJ: The effects of oral slow-release terbutaline on the circadian variation in spirometry and arterial blood gas levels in patients with chronic airflow obstruction. Chest 1985;87:653–657.
  24. Connaughton JJ, Catterall JR, Elton RA, Stradling JR, Douglas NJ: Do sleep studies contribute to the management of patients with severe chronic obstructive pulmonary disease? Am Rev Respir Dis 1988;138:341–344.
  25. Fletcher EC, Miller J, Divine GW, Fletcher JG, Miller T: Nocturnal oxyhemoglobin desaturation in COPD patients with arterial oxygen tensions above 60 mm Hg. Chest 1987;92:604–608.
  26. O’Donnell DE, Sciurba F, Celli B, Mahler DA, Webb KA, Kalberg CJ, Knobil K: Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise endurance in COPD. Chest 2006;130:647–656.
  27. 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.
  28. Rennard S, Decramer M, Calverley PM, Pride NB, Soriano JB, Vermeire PA, Vestbo J: Impact of COPD in North America and Europe in 2000: subjects’ perspective of Confronting COPD International Survey. Eur Respir J 2002;20:799–805.
  29. Jones PW, Bosh TK: Quality of life changes in COPD patients treated with salmeterol. Am J Respir Crit Care Med 1997;155:1283–1289.
  30. Collard P, Dury M, Delguste P, Aubert G, Rodenstein DO: Movement arousals and sleep-related disordered breathing in adults. Am J Respir Crit Care Med 1996;154(2 Pt 1):454–459.
  31. Chaouat A, Weitzenblum E, Krieger J, Ifoundza T, Oswald M, Kessler R: Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am J Respir Crit Care Med 1995;151:82–86.
  32. Ryan S, Taylor CT, McNicholas WT: Predictors of elevated nuclear factor-ĸB-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2006;174:824–830.
  33. McNicholas WT, Bonsigore MR: Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 2007;29:156–178.
  34. Sin DD, Man SF: Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003;107:1514–1519.
ppt logo Download Images (.pptx)


Figures
Thumbnail

Tables
Thumbnail
Thumbnail
Thumbnail
Thumbnail