Correlates of oxygen desaturation in COPD
Title: Exercise-induced oxygen desaturation determinants including emphysema in patients with chronic obstructive pulmonary disease: results from the ECLIPSE studyShort title: Oxygen desaturation and emphysema in COPDVasileios Andrianopoulos1§ Bartolome R. Celli2Frits M.E. Franssen1 Victor M. Pinto-Plata3Peter M.A Calverley4Lowie E.G.W Vanfleteren1 Ioannis Vogiatzis5J?rgen Vestbo6Alvar Agusti7Per S. Bakke8Stephen I. Rennard9William MacNee10Ruth Tal-Singer11Julie C. Yates12Emiel F.M. Wouters1,13Martijn A. Spruit, PhD1,14Affiliations1Department of Research and Education; CIRO+, Centre of Expertise for Chronic Organ Failure; Horn; the Netherlands2Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA3Department of Respiratory Medicine, School of Clinical Science, University of Liverpool, United Kingdom 4Institute of Ageing and Chronic Disease, University Hospital Aintree, Liverpool, United Kingdom5Department of Physical Education and Sport Sciences, National and Kapodistrian University of Athens, Greece6Centre for Respiratory Medicine and Allergy, University of Manchester, UK7Respiratory Institute, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERES, Barcelona, Spain8Department of Clinical Science, University of Bergen, Bergen, Norway9Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha,Nebraska10University of Edinburgh, Medical Research Council Centre for Inflammation Research,The Queen’s Medical Research Institute, Edinburgh, United Kingdom11GSK Research and Development, King of Prussia, Philadelphia, Pennsylvania, USA12GSK Research Triangle Park, North Carolina, USA13Department of Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands14REVAL – Rehabilitation Research Center, BIOMED – Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, BelgiumEmail addresses of authors: Vasileios Andrianopoulos: vasilisandrianopoulos@ciro-horn.nlBartolome R. Celli: HYPERLINK "mailto:bcelli@" bcelli@Frits M.E. Franssen: HYPERLINK "mailto:fritsfranssen@ciro-horn.nl" fritsfranssen@ciro-horn.nlVictor M. Pinto-Plata: vpinto@Peter M.A Calverley: pmacal@liverpool.ac.ukLowie E.G.W Vanfleteren: HYPERLINK "mailto:lowievanfleteren@ciro-horn.nl" lowievanfleteren@ciro-horn.nlIoannis Vogiatzis: gianvog@phed.uoa.grJ?rgen Vestbo: Jorgen.Vestbo@manchester.ac.ukAlvar Agusti: alvar.agusti@clinic.ub.esPer S. Bakke: HYPERLINK "mailto:per.bakke@med.uib.no" per.bakke@med.uib.noStephen I. Rennard: srennard@unmc.eduWilliam MacNee: w.macnee@ed.ac.ukRuth Tal-Singer: Ruth.M.Tal-Singer@Julie C. Yates: julie.c.yates@Emiel F.M. Wouters: e.wouters@mumc.nlMartijn Spruit: martijnspruit@ciro-horn.nl§Corresponding author informationVasileios AndrianopoulosDepartment of Research and Education; CIRO+, Centre of expertise for chronic organ failure, Hornerheide 1, 6085 NM Horn, the Netherlands. Tel:+31475587600, Fax:+31475587592Email: vasilisandrianopoulos@ciro-horn.nlABSTRACTBackground: Patients with chronic obstructive pulmonary disease (COPD) without resting hypoxemia can exhibit exercise-induced oxygen desaturation (EID). We investigated in the ECLIPSE cohort: (1) the prevalence of EID; (2) the relative weight of several physiological determinants of EID, particularly the severity of airflow limitation and the presence of pulmonary emphysema, and (3) the relationship of EID with certain patients’ clinical characteristics. Methods: Data from 2050 COPD patients (age: 63.3 ±7.1 years; FEV1%: 48.7 ±15.7; 35% women) were analysed. EID was defined as decline of arterial oxygen saturation (SpO2) ≤88% using pulse-oxymetry during six-minute walking test (6MWT). Emphysema was quantified by computed tomography (QCT). Several clinical, functional and imaging characteristics were included in the analysis. Results: 435 patients (21%) exhibited EID, 80% of whom had severe to very severe COPD (GOLD stage III-IV). Subjects with EID generally had also more QCT-emphysema, lower exercise capacity and worse health status (BODE, ADO index) compared to non-EID subjects. Occurrence of EID was increased progressively across emphysema degrees in GOLD II (≤9-fold) but this relative increase was lower in GOLD III-IV. Multivariate logistic model showed that obesity (BMI ≥30kg/m2), low FEV1 (≤44%pred.), moderate to very severe emphysema, and low SpO2 (≤93%) at rest increase the odds for EID. Linear regression indicated that 1-point increase on the ADO score independently elevates odds ratio for EID (≤1.5 fold). Conclusions: About one of five COPD patients in the ECLIPSE cohort presents EID. Emphysema severity determines relatively more the presence of EID in GOLD II compared to GOLD III-IV. Obesity, emphysema, severe airflow obstruction and baseline arterial oxygen saturation are associated to EID. High ADO score is also predictive of EID.Key Words: COPD, 6MWT, SpO2, ADO, CT imagingINTRODUCTIONExercise-induced oxygen desaturation (EID), as defined by fall in saturation to 88% or lower during exercise,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2xsYW5kPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48
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ADDIN EN.CITE.DATA 3-5 Yet, their physiological determinants and clinical consequences are still subject of debate. In general, patients with EID are characterized by severe airflow limitation, low diffusing carbon monoxide capacity (DLCO), reduced resting arterial oxygenationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZWxsZXk8L0F1dGhvcj48WWVhcj4xOTg2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 10, 11 In addition, EID is also related to numerous variables that include the rate of lung function decline and health status ADDIN EN.CITE <EndNote><Cite><Author>Kim</Author><Year>2013</Year><RecNum>6988</RecNum><DisplayText><style face="superscript">12</style></DisplayText><record><rec-number>6988</rec-number><foreign-keys><key app="EN" db-id="apt9vrdr0vtz0xetxw4xp9rqxrew0f0e0wx0">6988</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kim, C.</author><author>Seo, J. B.</author><author>Lee, S. M.</author><author>Lee, J. S.</author><author>Huh, J. W.</author><author>Lee, J. H.</author><author>Ra, S. W.</author><author>Kim, E. K.</author><author>Kim, T. H.</author><author>Kim, W. J.</author><author>Lee, S. Y.</author><author>Lim, S. Y.</author><author>Shin, T. R.</author><author>Yoon, H. I.</author><author>Sheen, S. S.</author><author>Oh, Y. M.</author><author>Park, Y. B.</author><author>Lee, S. D.</author></authors></contributors><auth-address>Department of Pulmonary and Critical Care Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Republic of Korea.</auth-address><titles><title>Exertional Desaturation as a Predictor of Rapid Lung Function Decline in COPD</title><secondary-title>Respiration</secondary-title></titles><periodical><full-title>Respiration</full-title></periodical><pages>109-16</pages><volume>86</volume><number>2</number><edition>2012/12/14</edition><dates><year>2013</year></dates><isbn>1423-0356 (Electronic)
0025-7931 (Linking)</isbn><accession-num>23235126</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>12, physical activity ADDIN EN.CITE <EndNote><Cite><Author>Vogiatzis</Author><Year>2012</Year><RecNum>5717</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>5717</rec-number><foreign-keys><key app="EN" db-id="apt9vrdr0vtz0xetxw4xp9rqxrew0f0e0wx0" timestamp="1362563639">5717</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vogiatzis, I.</author><author>Zakynthinos, G.</author><author>Andrianopoulos, V.</author></authors></contributors><auth-address>Department of Physical Education and Sport Sciences, National and Kapodistrian University of Athens, 17237 Athens, Greece ; Institute of Clinical Exercise and Health Science, University of West of Scotland, Hamilton ML3 0JB, UK ; 1st Department of Critical Care Medicine, National and Kapodistrian University of Athens, 10675 Athens, Greece ; Thorax Foundation, Research Centre of Intensive and Emergency Thoracic Medicine, 10675 Athens, Greece.</auth-address><titles><title>Mechanisms of physical activity limitation in chronic lung diseases</title><secondary-title>Pulm Med</secondary-title></titles><periodical><full-title>Pulm Med</full-title></periodical><pages>634761</pages><volume>2012</volume><edition>2013/02/01</edition><dates><year>2012</year></dates><isbn>2090-1844 (Electronic)
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ADDIN EN.CITE.DATA 14, 15 The determinants of EID, however, have not been validated in a large cohort of COPD patients followed up prospectively. The design and size of the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study offers a unique opportunity to overcome these limitations.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXN0Ym88L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 16 Herein, we investigated in the ECLIPSE: (1) the prevalence of EID in COPD; (2) the relative weight of several physiological determinants of EID in COPD, particularly the severity of airflow limitation and the presence of emphysema as defined by quantitative computed tomography (QCT) analysisPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdWxsZXI8L0F1dGhvcj48WWVhcj4xOTg4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 17-19; and, (3) the relationship of EID with certain patients’ clinical characteristics. METHODSDesign and participantsThe ECLIPSE study ( identifier NCT00292552; GSK study code SCO104960) was a 3-year non-interventional longitudinal prospective study, as described elsewhere.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXN0Ym88L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 20 We excluded subjects with resting hypoxemia (as defined by SpO2% pre-walk≤88%) from this analysis. The ECLIPSE study was carried out in accordance with the Declaration of Helsinki and good clinical practice guidelines, and was approved by the ethics committees of participating centers. The Institutional Review Boards of all participating institutions approved the study and all participants provided written informed consent. Data from the ECLIPSE study have been published beforePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TcHJ1aXQ8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS
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Tm90ZT4A
ADDIN EN.CITE.DATA 15, 21-23 but the current analysis, which is mostly focus on EID in association with the severity of emphysema, is novel and, therefore, complements previous reports.Patient characterizationDemographic and physiological characteristics, level of dyspnea (using the modified Medical Research Council (mMRC) dyspnea scale), measurements of lung function (post-bronchodilator spirometry and lung volumes), QCT-emphysema degrees, health status (using the St. George’s Respiratory Questionnaire (SGRQ)), and data from 6MWT were used in this analysis. Fat mass and fat free mass were determined using bioelectrical impedance (Bodystat 1500). The fat free mass index (FFMI, kg/m2) was calculated as the mass (kg) divided by the squared height (m2) and the body mass index (BMI, kg/m2) was calculated as weight (kg) divided by squared height (m2). Furthermore, the following multidimensional COPD indices were calculated for the whole cohort; (1) the ADO indexPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QdWhhbjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 25, which incorporates dyspnea by the MRC, BMI, FEV1%, and exercise capacity as measured by 6-minute walking distance (6MWD).CT imagingAll patients underwent a low-dose volumetric computed tomography (CT scan) at full inspiration. Scans were obtained using multi-detector row CT scanners (120 kVp, 40 mAs) and were reconstructed using contiguous 1.00 mm or 1.25 mm slice thickness and an intermediate spatial frequency reconstruction algorithm. The radiation dose was estimated to be 1.67 mSv per CT study or 5 mSv for the entire ECLIPSE protocol. All CT scans were sent for evaluation at the central imaging unit at the University of British Columbia (Vancouver, BC, Canada).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaWV0ZW1hPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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ADDIN EN.CITE.DATA 26 All CT scans were analysed by the use of PulmonaryWorkstation 2.0 software (VIDA Diagnostics, Coralville, IA, USA) and the severity of emphysema was quantified in CT scans (QCT) by radiologists and computers using the % of lung pixels that were low attenuation areas (%LAA) defined as being below 950 Houns?eld Units (density mask technique).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdWxsZXI8L0F1dGhvcj48WWVhcj4xOTg4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 26 Six-minute walk test (6MWT)The 6MWT was performed according to international recommendations. ADDIN EN.CITE <EndNote><Cite><Author>ATS</Author><Year>2002</Year><RecNum>2516</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>2516</rec-number><foreign-keys><key app="EN" db-id="apt9vrdr0vtz0xetxw4xp9rqxrew0f0e0wx0" timestamp="1293566125">2516</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>ATS</author></authors></contributors><titles><title>ATS statement: guidelines for the six-minute walk test</title><secondary-title>Am J Respir Crit Care Med</secondary-title></titles><periodical><full-title>Am J Respir Crit Care Med</full-title></periodical><pages>111-7</pages><volume>166</volume><number>1</number><edition>2002/07/02</edition><keywords><keyword>Data Collection</keyword><keyword>Data Interpretation, Statistical</keyword><keyword>Exercise Test/contraindications/instrumentation/*methods</keyword><keyword>Humans</keyword><keyword>Quality Assurance, Health Care</keyword><keyword>Safety</keyword><keyword>Walking</keyword></keywords><dates><year>2002</year><pub-dates><date>Jul 1</date></pub-dates></dates><isbn>1073-449X (Print)
1073-449X (Linking)</isbn><accession-num>12091180</accession-num><urls><related-urls><url> Briefly, participants were asked to walk indoors in a flat, straight, 30-meter walking course supervised by a well-trained researcher.?A practice 6MWT was not undertaken. Patients were encouraged using standardized encouragement every minute of the 6MWT. ADDIN EN.CITE <EndNote><Cite><Author>Holland</Author><Year>2014</Year><RecNum>6323</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>6323</rec-number><foreign-keys><key app="EN" db-id="apt9vrdr0vtz0xetxw4xp9rqxrew0f0e0wx0" timestamp="1422381200">6323</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Holland, A. E.</author><author>Spruit, M. A.</author><author>Troosters, T.</author><author>Puhan, M. A.</author><author>Pepin, V.</author><author>Saey, D.</author><author>McCormack, M. C.</author><author>Carlin, B. W.</author><author>Sciurba, F. C.</author><author>Pitta, F.</author><author>Wanger, J.</author><author>MacIntyre, N.</author><author>Kaminsky, D. A.</author><author>Culver, B. H.</author><author>Revill, S. M.</author><author>Hernandes, N. A.</author><author>Andrianopoulos, V.</author><author>Camillo, C. A.</author><author>Mitchell, K. E.</author><author>Lee, A. L.</author><author>Hill, C. J.</author><author>Singh, S. J.</author></authors></contributors><auth-address>For a full list of the authors' affiliations please refer to the Acknowledgements a.holland@.au.
For a full list of the authors' affiliations please refer to the Acknowledgements.</auth-address><titles><title>An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease</title><secondary-title>Eur Respir J</secondary-title></titles><periodical><full-title>Eur Respir J</full-title></periodical><pages>1428-46</pages><volume>44</volume><number>6</number><dates><year>2014</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1399-3003 (Electronic)
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ADDIN EN.CITE.DATA 1, 2 Statistical analyses Results are reported as mean (standard deviation) or proportion (%). The statistical significance of differences between groups was assessed by analysis of variance, paired T-tests and Chi-square, as appropriate. Pearson’s correlation coefficients were used to assess the bivariate relationship amongst patients’ characteristics and the variables of SpO2% post-walk, ΔSpO2% and QCT-defined emphysema. Linear regression and univariate and multivariate binary logistical regression models were used to assess individual predictors of EID. Receiver operating characteristics (ROC) curves were used to determine threshold values to predict EID. The Area Under the curve (AUC) was calculated by the trapezoidal rule and the confidence intervals of the AUC was computed by the method of DeLong. ADDIN EN.CITE <EndNote><Cite><Author>DeLong</Author><Year>1988</Year><RecNum>6290</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>6290</rec-number><foreign-keys><key app="EN" db-id="apt9vrdr0vtz0xetxw4xp9rqxrew0f0e0wx0" timestamp="1401881710">6290</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>DeLong, E. R.</author><author>DeLong, D. M.</author><author>Clarke-Pearson, D. L.</author></authors></contributors><auth-address>Quintiles, Inc., Chapel Hill, North Carolina 27514.</auth-address><titles><title>Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach</title><secondary-title>Biometrics</secondary-title><alt-title>Biometrics</alt-title></titles><periodical><full-title>Biometrics</full-title><abbr-1>Biometrics</abbr-1></periodical><alt-periodical><full-title>Biometrics</full-title><abbr-1>Biometrics</abbr-1></alt-periodical><pages>837-45</pages><volume>44</volume><number>3</number><keywords><keyword>Algorithms</keyword><keyword>Analysis of Variance</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Intestinal Obstruction/surgery</keyword><keyword>Models, Statistical</keyword><keyword>Ovarian Neoplasms/complications</keyword><keyword>*Predictive Value of Tests</keyword><keyword>*ROC Curve</keyword></keywords><dates><year>1988</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0006-341X (Print)
0006-341X (Linking)</isbn><accession-num>3203132</accession-num><urls><related-urls><url> Two-sided level of significance was set at P <0.05. Statistical analyses were carried out using MedCalc v.12, Sigmaplot v.12 and SPSS v.19.0.RESULTSSubject characteristics Two thousand and fifty subjects with COPD were included in the study. As shown in Table 1, subjects generally had severe airflow limitation, low oxygen saturation (SpO2 pre), and were normal-weight to overweight. Fifty-five percent (55%) of the subjects were assigned into GOLD III and IV grades while 33% of patients were diagnosed with severe to very severe emphysema. Fifty three percent (53%) of the subjects complained of severe dyspnea (mMRC scale ≥2), and 47% had severely impaired health status (SGRQ Total Score ≥50). Thirty six percent (36%) were current smokers (Table 1).Determinants of EID A total of 435 subjects (21%) exhibited EID while the prevalence of EID was higher across GOLD stages (Figure 1). Subjects with EID were older with more severe airflow limitation, lower FVC, and worse mMRC dyspnea and SGRQ total scores. Also, they were more commonly ex-smokers compared those without EID (non-EID; Table 1). Subjects with EID had a shorter walk distance (6MWD), lower pre-walk SpO2 and higher pre/post-walk heart rate. In addition, EID subjects had greater increase of heart rate from baseline (?HR) and more intense exertional dyspnea compared to non-EID (Table 2). Moreover, those with EID had higher scores of the ADO indexPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QdWhhbjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 25 compared to non-EID subjects (Table 2). The effect of QCT-emphysema on the lowest values of oxygen saturation levels, which defined the EID (SpO2 ≤88%) in the 6MWT, seems to be greater in GOLD stages II compared to GOLD stages III-IV (Figure 2). Occurrence of EID was increased progressively across emphysema degrees in GOLD II by a factor of up to 9 but this relative increase was lower and not distinctively progressive in GOLD III-IV. Both, severity of airflow limitation and emphysema degrees had a negative impact on the SpO2 levels at the end of 6MWT (Online figure 1).Multivariate correlates of EID Using receiver operating characteristics (ROC) curves, the threshold values with the best specificity and sensitivity to predict EID were determined for age (≥60 years), sex (female), BMI (≥30 kg/m2), FEV1 (≤44% predicted), QCT-emphysema (moderate to very severe), resting oxygen saturation (SpO2 pre-walk ≤93%) and ADO index (ADO score ≥6 points; Online table 3). Univariate logistical regression analysis revealed that older age and impaired levels of FEV1, visual QCT-emphysema, and SpO2 pre-walk were independent predictors of EID. Multivariate logistical regression model showed that only impaired levels of FEV1, QCT-emphysema, and SpO2 pre-walk remained significant (p ≤0.016). Interestingly, BMI (obesity) reached statistical significance (p <0.003) for contributing EID only within this multivariate-adjusted model and not as independent determinant (Table 3).A combination of certain critical characteristics including obesity, moderate to very severe emphysema, severe airflow limitation (FEV1 ≤44% pred.), and resting SpO2 ≤93% revealed that the 81% of the subjects with all of these characteristics exhibited EID (Figure 3). Relationship of ADO score with EIDThe presence of EID was related to higher ADO indexPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QdWhhbjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 24 scores in EID subjects with GOLD II-III and across all the degrees of emphysema compared to those with non-EID. For each 1-point increase on the ADO score, the odds ratio for EID was independently increased by 1.5 fold while the 40% of patients with ADO ≥6 points had EID (online table 2).DISCUSSIONThis study provides three major observations: (1) about 20% of COPD patients included in the ECLIPSE cohort exhibited EID; (2) emphysema, severity of airflow limitation, arterial oxygen saturation at rest and obesity are associated with EID; and (3) a high ADO index is predictive of EID.It has been previously suggested that the presence of emphysema may determine EID in COPD.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWd1Y2hpPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48
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ADDIN EN.CITE.DATA 10 However, this is the first time that the role of emphysema was investigated in a large well-characterized COPD population (ECLIPSE cohort). In this study, emphysema in association with other determinants, such as obesity (BMI≥30 kg/m2), have a prognostic value in the prediction of EID. Moreover, the relationship of the ADO score with EID was a novel investigation.Interpretation of resultsIn current study, the prevalence of EID was increased across the GOLD stages (Figure 1) while the severity of airflow limitation seems to contribute in the occurrence of EID more than the grades of QCT-emphysema (Figure 2). However, the severity of emphysema was more critical for the presence of EID in patients with GOLD II compared to those with more severe airflow limitation. Specifically, the incidents of EID in GOLD II were progressively increased across to emphysema degrees (≥9-fold) but this was not the case in GOLD III-IV (Figure 2). Ventilation-perfusion inequality (V/Q), which cause EID ADDIN EN.CITE <EndNote><Cite><Author>Vogiatzis</Author><Year>2012</Year><RecNum>5717</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>5717</rec-number><foreign-keys><key app="EN" db-id="apt9vrdr0vtz0xetxw4xp9rqxrew0f0e0wx0" timestamp="1362563639">5717</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vogiatzis, I.</author><author>Zakynthinos, G.</author><author>Andrianopoulos, V.</author></authors></contributors><auth-address>Department of Physical Education and Sport Sciences, National and Kapodistrian University of Athens, 17237 Athens, Greece ; Institute of Clinical Exercise and Health Science, University of West of Scotland, Hamilton ML3 0JB, UK ; 1st Department of Critical Care Medicine, National and Kapodistrian University of Athens, 10675 Athens, Greece ; Thorax Foundation, Research Centre of Intensive and Emergency Thoracic Medicine, 10675 Athens, Greece.</auth-address><titles><title>Mechanisms of physical activity limitation in chronic lung diseases</title><secondary-title>Pulm Med</secondary-title></titles><periodical><full-title>Pulm Med</full-title></periodical><pages>634761</pages><volume>2012</volume><edition>2013/02/01</edition><dates><year>2012</year></dates><isbn>2090-1844 (Electronic)
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ADDIN EN.CITE.DATA 30, 31, and emphysema which is linked to decreased alveolar surface area and loss of elastic recoil of the lungsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaHVybGJlY2s8L0F1dGhvcj48WWVhcj4xOTY3PC9ZZWFy
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ADDIN EN.CITE.DATA 32, 33, can both cause V/Q inequality during exercise contributing to the presence of EID.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZW50PC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 5, 35, might be overlapped with the contribution of severe emphysema on the occurrence of EID. Nevertheless, correlation analysis of this study indicated that emphysema as well as airway obstruction similarly correlated to the post-walk SpO2 (r= -0.35 and r= 0.38, respectively; p <0.001) and this fact demonstrated that severity of emphysema can be also a major determinant of EID, especially in moderate COPD.In this study, important finding is that obesity was associated with the presence of EID in COPD. Previously, the association of lower SpO2 with obesity has been reported for 871 emergency department patients and hospital workers. ADDIN EN.CITE <EndNote><Cite><Author>Witting</Author><Year>2008</Year><RecNum>6579</RecNum><DisplayText><style face="superscript">36</style></DisplayText><record><rec-number>6579</rec-number><foreign-keys><key app="EN" db-id="apt9vrdr0vtz0xetxw4xp9rqxrew0f0e0wx0" timestamp="1445170101">6579</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Witting, M. D.</author><author>Scharf, S. M.</author></authors></contributors><auth-address>Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA. mwitt001@umaryland.edu</auth-address><titles><title>Diagnostic room-air pulse oximetry: effects of smoking, race, and sex</title><secondary-title>Am J Emerg Med</secondary-title><alt-title>The American journal of emergency medicine</alt-title></titles><periodical><full-title>Am J Emerg Med</full-title></periodical><pages>131-6</pages><volume>26</volume><number>2</number><keywords><keyword>Adult</keyword><keyword>Air</keyword><keyword>Continental Population Groups</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Male</keyword><keyword>*Oximetry</keyword><keyword>Prospective Studies</keyword><keyword>Reference Values</keyword><keyword>Sex Factors</keyword><keyword>Smoking/*adverse effects</keyword></keywords><dates><year>2008</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1532-8171 (Electronic)
0735-6757 (Linking)</isbn><accession-num>18272090</accession-num><urls><related-urls><url> Kapur and colleagues have also demonstrated that obesity is associated with a lower resting oxygen saturation examining a large cohort of 2.252 elderly subjects from the Cardiovascular Health Study.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXB1cjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 37 In COPD, one study confirms a correlation between COPD severity with BMI and oxygen saturation but using measurements of SpO2 values at rest. ADDIN EN.CITE <EndNote><Cite><Author>Gupta</Author><Year>2014</Year><RecNum>6570</RecNum><DisplayText><style face="superscript">38</style></DisplayText><record><rec-number>6570</rec-number><foreign-keys><key app="EN" db-id="apt9vrdr0vtz0xetxw4xp9rqxrew0f0e0wx0" timestamp="1444506014">6570</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gupta, S. S.</author><author>Gothi, D.</author><author>Narula, G.</author><author>Sircar, J.</author></authors></contributors><auth-address>Department of Pulmonary Medicine, Era's Lucknow Medical College, Lucknow, India.
Department of Pulmonary Medicine, ESI Hospital, New Delhi, India.</auth-address><titles><title>Correlation of BMI and oxygen saturation in stable COPD in Northern India</title><secondary-title>Lung India</secondary-title><alt-title>Lung India : official organ of Indian Chest Society</alt-title></titles><periodical><full-title>Lung India</full-title></periodical><pages>29-34</pages><volume>31</volume><number>1</number><dates><year>2014</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0970-2113 (Print)
0970-2113 (Linking)</isbn><accession-num>24669078</accession-num><urls><related-urls><url> To the best of our knowledge, our findings revealed for first time a potential relationship between obesity and EID during the 6MWT in subjects with COPD. The direct physiological mechanism underlying the effect of obesity in EID is complex, however, obesity and EID could be related in respect of low baseline SpO2, which can be considered as one of the major determinant of EID.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lbm93ZXI8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 24 and EID. Previously, multidimensional indices for the prognosis of oxygen desaturation have been proposed by Cutaia and colleagues ADDIN EN.CITE <EndNote><Cite><Author>Cutaia</Author><Year>2011</Year><RecNum>6358</RecNum><DisplayText><style face="superscript">39</style></DisplayText><record><rec-number>6358</rec-number><foreign-keys><key app="EN" db-id="apt9vrdr0vtz0xetxw4xp9rqxrew0f0e0wx0" timestamp="1427279575">6358</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cutaia, M.</author><author>Brehm, R.</author><author>Cohen, M.</author></authors></contributors><auth-address>Pulmonary and Critical Care Section, Department of Medicine, Veteran's Administration Medical Center, SUNY/Downstate Health Sciences Center, 800 Poly Place, Brooklyn, NY 11209, USA. michael.cutaia@</auth-address><titles><title>The relationship of the BODE index to oxygen saturation during daily activities in patients with chronic obstructive pulmonary disease</title><secondary-title>Lung</secondary-title><alt-title>Lung</alt-title></titles><periodical><full-title>Lung</full-title></periodical><alt-periodical><full-title>Lung</full-title></alt-periodical><pages>269-77</pages><volume>189</volume><number>4</number><keywords><keyword>*Activities of Daily Living</keyword><keyword>Aged</keyword><keyword>Cohort Studies</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Oximetry</keyword><keyword>Oxygen/*blood/therapeutic use</keyword><keyword>Pulmonary Disease, Chronic Obstructive/mortality/*physiopathology</keyword><keyword>*Severity of Illness Index</keyword><keyword>Walking/physiology</keyword></keywords><dates><year>2011</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1432-1750 (Electronic)
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ADDIN EN.CITE.DATA 25 (≥7 points) should be evaluated for desaturation during daily activities. ADDIN EN.CITE <EndNote><Cite><Author>Cutaia</Author><Year>2011</Year><RecNum>6358</RecNum><DisplayText><style face="superscript">39</style></DisplayText><record><rec-number>6358</rec-number><foreign-keys><key app="EN" db-id="apt9vrdr0vtz0xetxw4xp9rqxrew0f0e0wx0" timestamp="1427279575">6358</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cutaia, M.</author><author>Brehm, R.</author><author>Cohen, M.</author></authors></contributors><auth-address>Pulmonary and Critical Care Section, Department of Medicine, Veteran's Administration Medical Center, SUNY/Downstate Health Sciences Center, 800 Poly Place, Brooklyn, NY 11209, USA. michael.cutaia@</auth-address><titles><title>The relationship of the BODE index to oxygen saturation during daily activities in patients with chronic obstructive pulmonary disease</title><secondary-title>Lung</secondary-title><alt-title>Lung</alt-title></titles><periodical><full-title>Lung</full-title></periodical><alt-periodical><full-title>Lung</full-title></alt-periodical><pages>269-77</pages><volume>189</volume><number>4</number><keywords><keyword>*Activities of Daily Living</keyword><keyword>Aged</keyword><keyword>Cohort Studies</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Oximetry</keyword><keyword>Oxygen/*blood/therapeutic use</keyword><keyword>Pulmonary Disease, Chronic Obstructive/mortality/*physiopathology</keyword><keyword>*Severity of Illness Index</keyword><keyword>Walking/physiology</keyword></keywords><dates><year>2011</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1432-1750 (Electronic)
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ADDIN EN.CITE.DATA 24 (≥6 points) presented EID in a greater extent (40% vs 19%; p <0.001; online table 2) that can be mostly attributed to severe airflow limitation which was common in those patients with high ADO scores. However, we did not include ADO index in our multivariate logistical model as age and FEV1, which are the main elements of ADO index, were already included as independent determinants in this statistical analysis.In our multivariate logistical regression model, obese subjects with a impaired FEV1 (≤44%), moderate to very severe emphysema, and low pre-walk SpO2 (≤93%) have higher odds for EID. As it was expected, the role of emphysema in EID was critical and therefore emphysematous patients should be screened for EID. Strengths and weaknesses There are certain limitations to our study. First, the 6MWT screening was performed only once at baseline, while the 2014 ERS/ATS technical standard for field walking tests suggests the conduct of two 6MWT. ADDIN EN.CITE <EndNote><Cite><Author>Holland</Author><Year>2014</Year><RecNum>6323</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>6323</rec-number><foreign-keys><key app="EN" db-id="apt9vrdr0vtz0xetxw4xp9rqxrew0f0e0wx0" timestamp="1422381200">6323</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Holland, A. E.</author><author>Spruit, M. A.</author><author>Troosters, T.</author><author>Puhan, M. A.</author><author>Pepin, V.</author><author>Saey, D.</author><author>McCormack, M. C.</author><author>Carlin, B. W.</author><author>Sciurba, F. C.</author><author>Pitta, F.</author><author>Wanger, J.</author><author>MacIntyre, N.</author><author>Kaminsky, D. A.</author><author>Culver, B. H.</author><author>Revill, S. M.</author><author>Hernandes, N. A.</author><author>Andrianopoulos, V.</author><author>Camillo, C. A.</author><author>Mitchell, K. E.</author><author>Lee, A. L.</author><author>Hill, C. J.</author><author>Singh, S. J.</author></authors></contributors><auth-address>For a full list of the authors' affiliations please refer to the Acknowledgements a.holland@.au.
For a full list of the authors' affiliations please refer to the Acknowledgements.</auth-address><titles><title>An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease</title><secondary-title>Eur Respir J</secondary-title></titles><periodical><full-title>Eur Respir J</full-title></periodical><pages>1428-46</pages><volume>44</volume><number>6</number><dates><year>2014</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1399-3003 (Electronic)
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ADDIN EN.CITE.DATA 24 as an additional clinical tool for screening EID in patients with COPD. Our findings may help clinicians to better understand the relationship of emphysema with EID and predict more accurately the EID in patients with COPD.Conclusions In summary, EID occurs in about 20% of COPD patients. The severity of emphysema in moderate COPD increases EID in progressive manner. Several physiological determinants including presence of emphysema, severity of airflow limitation, impaired arterial oxygenation at rest and obesity, contribute to EID which seems to be captured by high ADO index values.AcknowledgementsThe authors like to thank all patients who volunteered to participate in the present study. VA obtained an ERS Long Term Research Fellowship (LTRF 63-2012).TablesTable 1. Baseline characteristics of COPD patients categorized by the prevalence of EIDCharacteristicsAll Subjects(n=2050)Non-EID(n=1615, 79%)EID(n=435, 21%)PValueWomen, #, (%)710(35)544(34)166(38)Age, years63.3±7.163.1± 7.264.1± 6.80.012BMI, kg/m226.5±5.626.5± 5.526.7± 5.8NSUnderweight98(5)81(5)17(4)Normal range751(37)591(36)160(37)Overweight743(36)594(37)149(34)Obese458(22)349(22)109(25)NS#FFMI, kg/m217.8±3.417.8± 3.517.6± 3.4NSFEV1, % predicted48.7±15.751.2± 15.239.5± 13.9<0.001FVC, % predicted80.0±19.881.2± 19.2 75.4± 21.0<0.001FEV1/FVC, %44.7±11.446.2± 11.039.1± 11.1<0.001GOLD Classification§Stage II925(45)836(52)89(20)Stage III861(42)639(39)222(51)Stage IV263(13)139(9)124(29)<0.001#Emphysema extent §§ <5% [absent-trivial]478(26)431(30)47(11) 5-25% [Mild]406(22)356(24)50(12) 25-50% [Moderate]361(19)293(20)68(17)>50% [Severe-very severe]622(33)375(26)247(60)<0.001#mMRC, Dyspnea.grade 1.7± 1.01.6± 1.02.0± 1.0<0.001 ≥2 1062(53)775(48)287(66)<0.001#SGRQ-C Total Score47.8± 18.146.5± 18.552.6± 15.6<0.001≥50 points, n (%)934(47)700(43)234(54)Current Smokers, n (%)742(36)639(40)103(24)<0.001#Values expressed as mean ± SD; § One patients had a confirmed diagnosis for COPD but could not be assigned to a GOLD stage; §§ in total 183 patient had undefined extent of emphysema (% valid percent); #Pearson Chi-SquareTable 2. Six-Minute Walk Test characteristics and multi-dimensional indices categorized by the prevalence of EID CharacteristicsAll Patients(n=2050)Non-EID(n=1615, 79%)EID(n=435, 21%)PValue6MWD, m, ±SD372±121382±119334±12<0.0016MWD, % predicted64±2166±2058±21<0.001SpO2, % pre94.7±2.295.1±2.093.1±2.3<0.001SpO2, % post91.8±5.093.9±2.684.1±4.3<0.001?SpO2, % -2.9±4.3-1.2±2.4-9.0±4.8<0.001HR pre, b/m 82±1481±1485±14<0.001HR post, b/m100±1898±17108±19<0.001?HR, b/m ?18±1417±1323±16<0.001Borg ScaleDyspnea, pre1.6±1.81.5±1.81.7±1.9NSDyspnea , post3.9±2.43.6±2.34.7±2.3<0.001?Dyspnea2.3±2.02.1±1.93.0±2.2<0.001Fatigue , pre1.3±1.81.3±1.81.3±1.8NSFatigue, post2.7±2.52.6±2.52.7±2.5NS?Fatigue1.4±1.91.4±1.81.4±1.9NSADO index, score3.7±1.53.5±1.54.4±1.4<0.001BODE index, score3.1±2.12.8±2.04.2±2.1<0.001Values expressed as mean ± SDTable 3. Logistic regression: Determinants of EID in COPD patients Determinants Subjects nEID n, (% ) Crude OR (95%CI) PvalueAdjust OR(95%CI)PvalueAge<60 years 594106 (18)11≥60 years 1456329 (23)1.34 (1.05-1.71)0.0171.21 (0.91-1.61)NSSexMale1340269 (20)11Female710166 (23)1.22 (0.98-1.51)NS1.30 (1.00-1.68)NSBMI<30 kg/m21592326 (20)11≥30 kg/m2458109 (24)1.21 (0.95-1.55)NS1.57 (1.15-2.14)0.005FEV1>44% 1198141 (12)1<0.0011<0.001≤44% 851294 (35)3.96 (3.16-4.96)3.14 (2.42-4.07) EmphysemaAbsent to mild 88497 (11)11Moderate to very severe 983315 (32)3.83 (2.98-4.91)<0.0013.37 (2.52-4.51)<0.001SpO2% pre-walk>93%1506194 (13)11≤93%544241 (44)5.38 (4.29-6.75)<0.0014.75 (3.69-6.13)<0.001A multivariate-adjusted regression analysis; all the determinants (age, sex, BMI, FEV1, emphysema, and SpO2 pre-walk) were included in the multivariate model.FiguresFigure 1Figure 1. EID progressively increased across the GOLD stages in COPD. 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