Evaluating nocturnal oxygen desaturation in COPD e revised

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1 Respiratory Medicine (2011) 105, 1331e1337 available at journal homepage: Evaluating nocturnal oxygen desaturation in COPD e revised Yves Lacasse a, *, Frédéric Sériès a, Nada Vujovic-Zotovic b, Roger Goldstein b, Jean Bourbeau c, Richard Lecours d, Shawn D. Aaron e, François Maltais a a Centre de recherche, Institut universitaire de cardiologie et de pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, Québec G1V 4G5, Canada b West Park Healthcare Centre, Department of Medicine, 82 Buttonwood Avenue, Toronto, Ontario M6M 2J5, Canada c Montreal Chest Institute, McGill University, 3650 St-Urbain, Montreal, Québec H2X 2P4, Canada d Service de pneumologie, Centre hospitalier affilié de l Hôtel-Dieu de Lévis, 143 rue Wolfe, Lévis, Québec G6V 3Z1, Canada e The Ottawa Health Research Institute, University of Ottawa, 725 Parkdale Ave., Ottawa, Ontario K1Y 4E9, Canada Received 12 January 2011; accepted 5 April 2011 Available online 10 May 2011 KEYWORDS COPD; Desaturation; Oxygen; Sleep; Sleep apnea Summary Background: Although in patients with COPD, the approach to daytime hypoxemia using long-term oxygen therapy (LTOT) is established, the best approach to transient nocturnal desaturation varies among clinicians. An understanding of the prevalence of nocturnal desaturation in COPD, in the absence of other respiratory co-morbidities, is an important step towards its standardized management. Methods: We conducted a 5 site cross-sectional study of stable patients with COPD and mild-tomoderate daytime hypoxemia (PaO 2 56e69 mmhg). Nocturnal saturation was monitored using home oximetry on 2 occasions over a 2-week period. Patients were classified in 3 categories: (A) no significant nocturnal desaturation; (B) significant nocturnal desaturation without apnea; (C) significant nocturnal desaturation with apnea. Results: In 128 patients (mean FEV 1 : 37% predicted), we noted an excellent test-retest reliability between the 2 oximetries. Forty-nine patients (38%) were classified as nocturnal desaturators without apnea, and 20 patients (16%) were classified as desaturators with apnea. Nocturnal desaturation without sleep apnea could not be predicted by any patient characteristic or physiological measure. Conclusions: A significant proportion (38%) of patients with moderate-to-severe COPD who do not qualify for home oxygen therapy based on their daytime PaO 2 have nocturnal oxygen desaturation without apnea. Home oximetry is an effective practical method for screening this population. ª 2011 Elsevier Ltd. All rights reserved. * Corresponding author. Tel.: þ ; fax: þ address: Yves.Lacasse@med.ulaval.ca (Y. Lacasse) /$ - see front matter ª 2011 Elsevier Ltd. All rights reserved. doi: /j.rmed

2 1332 Y. Lacasse et al. Introduction Several studies have demonstrated oxygen desaturation during sleep in patients with COPD. 1e8 Two landmark multicentre studies included patients with marked daytime hypoxemia qualifying for long-term oxygen therapy (LTOT). In subsequent studies of patients not qualifying for LTOT, the populations were heterogeneous and the definition of desaturation varied. Moreover, subjects were not evaluated under usual conditions of sleep, but underwent formal respiratory polysomnograms. 3,6e8 There is limited information regarding the extent to which patients with moderate and severe COPD not qualifying for LTOT experience transient nocturnal desaturation. One of the reasons for this situation is that the current definition of significant nocturnal oxygen desaturation is arbitrary and still controversial. Nevertheless many physicians will prescribe nocturnal supplemental oxygen for such patients although the beneficial effects of this therapy have yet to be confirmed. Workshops of the National Heart, Lung, and Blood Institute (NHLBI) on the needs and opportunities for clinical research in COPD identified nocturnal oxygen therapy as a research priority, in order to inform clinical decision making with regard to home oxygen therapy. 9,10 It is therefore important to obtain an accurate estimate of the prevalence of nocturnal desaturation in this population prior to initiating clinical trials of nocturnal oxygen therapy. Therefore, the primary objective of this study was to determine the proportion of nocturnal oxygen desaturators in a population of patients with COPD and mild to moderate daytime hypoxemia. Our secondary objectives were (1) to determine, in a pilot study, the accuracy of home nocturnal oximetry to distinguish between sleep apnea and nocturnal oxygen desaturation alone, and (2) to examine the reproducibility (test-retest reliability) of home oximetry and the concordance of its interpretation between respiratory clinicians and a respiratory sleep specialist. Methods Patients This study took place in 5 Canadian outpatient respiratory clinics (Hôpital Laval, Québec; West Park Healthcare Centre, Toronto; Montreal Chest Institute; Hôtel-Dieu de Lévis and Ottawa Hospital), all of which offer a wide range of health care services to patients with moderate-to-severe COPD. We included patients with (1) a diagnosis of COPD supported by a history of past or current smoking and obstructive lung disease with an FEV 1 < 60% predicted and an FEV 1 /FVC < 70%; and (2) mild-to-moderate daytime hypoxemia with a daytime PaO 2 measured in a sitting position in the range of 56e69 mmhg. Patients were excluded if (1) they had experienced an acute exacerbation within 6 weeks, (2) were receiving LTOT, (3) had a prior diagnosis of sleep apnea, (4) had morbid obesity (body mass index > 40 kg/m 2 ), or (5) had any cardio-respiratory comorbidity (such as left heart failure) that might influence the validity of the results. Home nocturnal oximetry and definition of nocturnal oxygen desaturation After obtaining informed consent, each patient underwent two home oximetries over a 2 week period, using a digital recording system (Palmsat 2500, Nonin Medical Inc., Plymouth, MN, USA) for nocturnal saturation (SaO 2 ) monitoring and accepting a minimum recording time of 4 h. Nocturnal desaturation was defined as 30% of the recording time (time in bed) with a transcutaneous SaO 2 < 90%. 8,11 We also noted the mean number of desaturations 3% per hour (desaturation index), the baseline saturation, and the average saturation over the entire tracing. Each patient was classified into categories based on the recording time with an SaO 2 < 90% along with a visual inspection of the printed report. They were classified as having (1) no significant nocturnal desaturation (<30% time with SaO 2 < 90% for both oximetries); (2) significant nocturnal desaturation (>30% time with SaO 2 < 90% on either of the oximetries) without evidence of associated sleep apnea (no periodic variation in saturation) (Fig. 1A); and (3) significant nocturnal desaturation (>30% time with SaO 2 < 90% on either of the oximetries) with evidence of associated sleep apnea (cyclical changes in saturation as well as desaturation on either of the oximetries) (Fig. 1B). 12 All reports were reviewed by a respiratory sleep specialist (FS) with extensive experience in oximetry assessment, who was unaware of the diagnosis submitted by the other investigators. Pilot study: validation of home oximetry in nocturnal desaturators In a subgroup of nocturnal desaturators (i.e., patients with >30% time with SaO 2 < 90% on either of the oximetries, regardless of the suggestion of sleep apnea on oximetry tracing), we conducted a blind comparison of home nocturnal oximetry and laboratory polysomnography obtained within 2 weeks of the second home nocturnal oximetry. This study was conducted in a single centre (Quebec). The polysomnographic recordings included continuous acquisition of electroencephalogram, electroocculogram, submental electromyogram, naso-oral airflow with thermistors, nasal pressure with nasal cannula), chest and abdominal movements with impedance plethysmography (RespitraceÆ, Ambulatory Monitoring Inc, Ardsley, NY), electrocardiogram, and breath sounds by means of two microphones connected to a calibrated sound analyzer. Sleep position was continuously assessed by the attending technician. All variables were digitally recorded (Sandman EliteTM system, Mallinckrotd, Kenilworth, NJ). Sleep apnea was considered to be significant when the apnea/hypopnea index 15/h. Other measures Within 1 month of the first nocturnal oximetry, we extracted baseline clinical information from the medical record (anthropometric measures, current medications, pulmonary function tests) and obtained arterial blood gases while patients were seated and breathing room air. In all sites,

3 Nocturnal oxygen in COPD 1333 Figure 1 Nocturnal oximetry tracings in patients with COPD not qualifying for LTOT. (A) oxygen desaturation (>30% of the recording time with a saturation < 90%) with non-periodic variation in saturation throughout sleep. This tracing is not suggestive of sleep apnea. (B) oxygen desaturation with cyclical changes in saturation suggesting sleep apnea. lung function measurements were made in keeping with the American Thoracic Society and European Respiratory Society guidelines. 13e15 Statistics Descriptive statistics (proportions or means and standard deviations, and associated 95% confidence intervals [CI]) were used to describe the study population. We examined the reproducibility (test-retest reliability) of the oximetry by correlating parameters obtained on the two recordings (Time 1 vs. Time 2) using intra-class coefficients of correlation. In the pilot sudy, we computed the proportion of true positives and true negatives from home nocturnal oximetry for the diagnosis of sleep apnea, with the result of the laboratory polysomnography considered as the gold standard. The concordance between the patient classification by the investigators in each site and the respiratory sleep specialist was measured using the weighted Kappa statistic. 16 Final classification was according to the specialist s opinion. Clinical characteristics of the desaturators, both with and without apnea and the nondesaturators, were compared using 2-tailed Fischer s exact tests for the categorical variables and analyses of variance for the continuous variables. Finally, we conducted logistic regression analyses using the patients baseline characteristics as possible predictors of the dependent variable, nocturnal oxygen desaturation without apnea. In these analyses, given the multitude of comparisons involved, statistical significance was set at the 0.01 level. Preliminary data obtained from a small and independent convenience sample of patients (n Z 12) indicated that about 25% of the patients with moderate-to-severe COPD meeting the inclusion criteria of our study would meet our definition of nocturnal desaturation without evidence of sleep apnea (unpublished data). We determined that a sample size of 128 patients was needed to ensure a 95% confidence interval of 7.5% around the final estimate of the proportion of desaturators. 17 Results Patients Of 245 patients screened, 128 completed the study. Excluded patients were as follows: daytime PaO 2 > 69 mmhg (n Z 51), refused to participate (n Z 41), recent acute exacerbation (n Z 6), FEV 1 /FVC or FEV 1 > 70% predicted (n Z 5), use of oxygen (n Z 3), previous diagnosis of sleep apnea (n Z 3), diffuse bronchiectasis as the main cause of obstructive lung disease (n Z 2), BMI > 40 kg/m 2 (n Z 2), and other reasons (n Z 3). Only 1 eligible patient withdrew before obtaining the second oximetry. The baseline characteristics of the 128 patients who completed the study are summarized in Table 1. On average, they had severe COPD (FEV % predicted, GOLD stage IV 18 ) and moderate hypoxemia (PaO mmHg). Validation of home oxymetry in nocurnal desaturators Ten consecutive patients with nocturnal oxygen desaturation underwent laboratory polysomnography. Sleep apnea was diagnosed by polysomnography in 3 of the 5 patients who were classified by the sleep specialist as nocturnal desaturators with apnea on home oximetry. Five were classified as desaturators without evidence of associated sleep apnea on home oximetry; in all 5 patients, sleep apnea was ruled out by polysomnography.

4 1334 Y. Lacasse et al. Table 1 Baseline characteristics (n Z 128). Age, years (SD) 70 (8) Gender, number of men (%) 49 (38%) Body mass index, kg/m 2 (SD) 25 (6) Current smokers, number (%) 21 (16%) Pack-years, mean (SD) 50 (25) Medication, number (%) Theophyline 21 (16%) Tiotropium 104 (81%) Long acting beta-agonists (LABA) alone 35 (27%) Inhaled steroids (ICS) alone 5 (4%) Combinations (LABA þ ICS) 58 (45%) Prednisone 7 (5%) ph, (SD) 7.42 (0.03) PaCO 2, mmhg (SD) 43 (5) PaO 2, mmhg (SD) 65 (4) Hemoglobin, g/l (SD) 145 (14) Hematocrit, % (SD) 0.44 (0.04) FEV 1, % predicted (SD) 36 (11) FVC, % predicted (SD) 78 (20) FEV 1 /FVC, % (SD) 36 (11) FRC, % predicted (SD) 164 (34) TLC, % predicted (SD) 126 (21) RV, % predicted (SD) 192 (51) DLCO, % predicted (SD) 45 (16) KCO, % predicted (SD) 63 (19) Test-retest reliability and agreement studies The oximetry measurements between the first and second recording showed high correlations with intra-class coefficients of 0.74e0.88. This high reproducibility in patterns of desaturation (p < ) was noted in all 4 comparison indices, on consecutive recordings within 2 weeks of each another (Table 2). Also, we found very close agreement between the respiratory clinician investigators and the respiratory sleep specialist in their assessment of the oximeter tracings (Kappa: 0.86; 95% CI: 0.78e0.94). When evaluating only those with significant nocturnal desaturation, with or without apnea, agreement remained very close (Kappa: 0.65; 95% CI: 0.45e0.86). Prevalence of nocturnal oxygen desaturation A total of 49 patients (38%; 95% CI: 30%e47%) met our criterion for nocturnal desaturators without evidence of sleep apnea. Among these 49 patients, 5 would have been Table 2 COPD. Test-retest reliability of nocturnal oximetry in Intra-class coefficients of correlation p value Desaturation index 0.88 < Baseline saturation 0.76 < Average saturation 0.74 < % recording time with saturation < 90% 0.84 < classified as non-desaturators if only the first oximetry had been considered. Twenty 20 patients (16%) were desaturators with suspected sleep apnea. Of the remaining 59 patients (46%) who did not have significant nocturnal desaturation, 12 had at least one tracing suggestive of sleep apnea. Therefore, 32 patients (20 þ 12; 25%; 95% CI: 18%e33%) had at least one oximetry tracing suggestive of sleep apnea. Predictors of nocturnal oxygen desaturation The baseline clinical characteristics among the three groups were similar with the exception of smoking history, body mass index (Table 3). In the physiological measures they differed only in baseline PaCO 2 (Table 4). These differences were only apparent in the desaturators suspected of having sleep apnea. The non-desaturators and the desaturators without apnea were similar in all characteristics. The comparisons of nocturnal oximetry results are summarized in Table 5. The observed differences are from our classification of patients that we defined apriori. In the logistic regression analyses, baseline saturation at night was one of the only 2 significant predictors of nocturnal oxygen desaturation in patients without evidence of sleep apnea (odds ratio, by 1% decrement in baseline saturation: 1.48; 95% CI: 1.22e1.80). The other significant predictor (PaCO 2 ) was unlikely to be of value as the absolute differences (42 versus 43 mmhg) fell within the precision range of the test. 19 Discussion In this cross-sectional study across 5 clinical sites, almost 40% of patients with moderate-to-severe COPD who would not qualify for LTOT exhibited meaningful nocturnal oxygen desaturation without apnea. Given that this desaturation could not be predicted from simple anthropometric or lung function measures, nocturnal saturation should be measured directly in this population. The study that best compares to ours in terms of inclusion and exclusion criteria was that of Lewis et al. 20 In this small study, nocturnal oximetry was performed in 59 patients with COPD who did not qualify for LTOT. Their study protocol was different from ours in that patients suspected of having obstructive sleep apnea on the basis of typical symptoms and an Epworth Sleepiness score 10 were excluded. Twenty-nine (49%) were desaturators. Our results are therefore very consistent with theirs and confirms the high prevalence of nocturnal desaturators among patients with COPD not qualifying for LTOT. Our study adds to the precision of the prevalence estimate by our evaluating a larger sample size (59 patients in Lewis vs. 128 in ours). Although the definition of nocturnal oxygen desaturation (i.e., 30% of the recording time with an oxygen saturation < 90%) adopted in this study is arbitrary, it is nevertheless widely used, with some variation, in Canada 21 and Europe. 11 Given the absence of recommendations regarding the number of recordings and the night-to-nigh variability in nocturnal desaturation in COPD reported by Lewis et al. 22, we elected to obtain 2 nocturnal recordings on each patient. This variability may be of importance when the

5 Nocturnal oxygen in COPD 1335 Table 3 Comparisons of baseline clinical characteristics. No significant nocturnal desaturation (n Z 59) desaturation without apnea (n Z 49) desaturation with apnea (n Z 20) P value Age, years (SD) 71 (8) 68 (7) 69 (9) 0.21 Gender (% male) 39 (66%) 24 (49%) 16 (80%) 0.04 Body mass index, kg/m 2 (SD) 24 (5) 25 (5) 29 (7) Current smokers (%) 8 (13%) 10 (20%) 3 (15%) 0.62 Pack-years (SD) 49 (24) 49 (19) 67 (34) Theophyline 14 (24%) 5 (10%) 2 (10%) 0.12 Tiotropium 49 (83%) 41 (84%) 14 (70%) 0.37 Long acting beta-agonists 14 (23%) 15 (31%) 6 (30%) 0.70 (LABA) alone Inhaled steroids (ICS) alone 3 (5%) 2 (4%) 0 (0%) 0.60 Combinations (LABA þ ICS) 28 (47%) 23 (47%) 7 (35%) 0.60 Prednisone 3 (5%) 3 (6%) 1 (5%) 0.97 time spent below a saturation < 90% approaches the diagnostic threshold. For instance, an individual could spend 28% and 32% of the recording time with an oxygen saturation < 90% during a first and second night respectively. Such an individual would be classified as a non-desaturator after the former and a desaturator following the latter. The rationale of assessing for nocturnal desaturation in COPD is that it may decrease survival. 23 In addition, its treatment with supplemental oxygen may prolong life. This suggestion comes from an indirect comparison of the British Medical Research Council Study 24 and the National Heart Lung and Blood Institute s trial 25 suggesting that patients receiving 12 h of oxygen/day (most of which was provided at night) was associated with better survival than those receiving no oxygen therapy. However, these were severely hypoxemic patients with a daytime PaO 2 55 mmhg who would qualify for LTOT. To date, only two randomized trials directly addressed the issue of nocturnal oxygen therapy in patients with COPD with significant nocturnal oxygen desaturation who would not qualify for LTOT 26,27 and a meta-analysis of these two studies concluded that nocturnal oxygen therapy had no effect on survival (pooled odds ratio: 0.97; 95% CI: 0.41e2.31). 28 However, the number of patients randomized in these 2 trials was small and the issue remains unresolved. Also, determination of nocturnal desaturation may be important because it may impact on sleep quality and/or health-related quality of life. However, this hypothesis is not supported by Lewis findings who could not demonstrate any association between nocturnal desaturation and impairment of health-related quality of life, sleep quality or daytime function. 20 The effect of nocturnal oxygen therapy on quality of life and sleep quality was directly addressed in a single randomized, placebo-controlled cross-over trial involving 19 daytime normoxemic COPD patients with nocturnal oxygen desaturation. 29 The authors observed significant differences only in the sleep dimension of the Nottingham Health Profile. All the other dimensions of the Nottingham Health Profile, SF-36 and St-George s Respiratory Questionnaire showed no difference between nocturnal oxygen and placebo. Unfortunately, the interpretation of Table 4 Comparisons of arterial blood gases and pulmonary function tests results. No significant nocturnal desaturation (n Z 59) desaturation without evidence of sleep apnea (n Z 49) desaturation with evidence of sleep apnea (n Z 20) ph 7.43 (0.02) 7.42 (0.03) 7.41 (0.03) 0.06 PaCO 2 42 (4) 42 (5) 46 (6) PaO 2 66 (3) 64 (4) 64 (4) 0.07 Hemoglobin 146 (14) 145 (13) 142 (15) 0.69 Hematocrit 0.44 (0.04) 0.44 (0.04) 0.45 (0.05) 0.56 FEV 1 % 35 (10) 36 (12) 36 (11) 0.37 FVC % 79 (23) 81 (19) 69 (15) 0.08 FEV 1 /FVC 35% (9) 35% (12) 40% (13) 0.17 FRC % 167 (36) 163 (31) 159 (35) 0.68 TLC % 128 (23) 126 (18) 121 (20) 0.42 RV % 194 (57) 192 (44) 185 (51) 0.84 DLCO % 45 (14) 42 (17) 55 (18) 0.02 KCO, % predicted (SD) 63 (18) 59 (20) 74 (19) 0.02 P value

6 1336 Y. Lacasse et al. Table 5 Comparisons of nocturnal oximetry results. a No significant nocturnal desaturation (n Z 59) desaturation without apnea (n Z 49) desaturation with apnea (n Z 20) P value Recording time (hours) 7.4 (1.4) 7.4 (1.3) 7.7 (1.3) 0.63 Desaturation index 5 (6) 5 (3) 21 (16) < Baseline saturation 92 (1) 89 (2) 88 (4) < Average saturation 89 (2) 86 (3) 85 (3) < % recording time with saturation 90% 9 (8) 57 (27) 69 (24) < a Only the results of the second oximetry are shown. results of both Lewis and Orth s studies are limited by their small sample size. We did not study all our patients with respiratory polysomnography, an obvious study limitation. Nevertheless, the results of our validation study suggested that home oximetry has high negative predictive value for the diagnosis of sleep apnea. This property is of particular interest in clinical practice if the purpose of home oximetry is only to identify those patients with nocturnal desaturation who could benefit from nocturnal oxygen therapy. Given the shape of the oxyhemoglobin dissociation curve, cyclical changes in saturation in addition to the desaturations would be expected if sleep apnea existed. Nocturnal oximetry demonstrating a steady tracing with non-periodic variation in saturation throughout sleep may exclude sleep apnea. Further validation is needed however. It is noteworthy that in a recent survey of prescribing practices most respirologists indicated that they would accept a diagnosis of nocturnal oxygen desaturation on the basis of oximetry tracings. 21 Our finding of a high prevalence of nocturnal oxygen desaturation in patients with moderate-to-severe COPD not qualifying for LTOT may be an indication of the need for regular screening of this patient population using home oximetry, especially as the benefits of administering nocturnal oxygen to this population remains to be established. Acknowledgements The authors would like to thank Hélène Villeneuve BSc RN (study coordinator), Rommel Mangaser (Montreal Chest Institute), Kathy Vandemheen (Ottawa Hospital), Sylvie Martin MSc (data management), and Serge Simard MSc (statistical analysis) for their expert assistance. Conflict of interest statement Supported by the Respiratory Health Network of the Fonds de recherche en santé du Québec (FRSQ) and Altana Canada (now Nycomed Canada). 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