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Original Research: COPD |

Exertional Hypoxemia in Stable COPD Is Common and Predicted by Circulating ProadrenomedullinExertional Desaturation in COPD FREE TO VIEW

Daiana Stolz, MD, MPH; Wim Boersma, MD; Francesco Blasi, MD; Renaud Louis, MD; Branislava Milenkovic, MD; Kostantinos Kostikas, MD, FCCP; Joachim G. Aerts, MD; Gernot Rohde, MD; Alicia Lacoma, PhD; Janko Rakic, MD; Lucas Boeck, MD; Paola Castellotti, MD; Andreas Scherr, MD; Alicia Marin, MD; Sabine Hertel, PhD; Sven Giersdorf, PhD; Antoni Torres, MD, FCCP; Tobias Welte, MD; Michael Tamm, MD, FCCP
Author and Funding Information

From the Department of Pneumology (Drs Stolz, Rakic, Boeck, Scherr, and Tamm), University Hospital, Basel, Switzerland; the Department of Pneumology (Dr Boersma), Medisch Centrum Alkmaar, Alkmaar, The Netherlands; the Department of Pathophysiology and Transplantation (Drs Blasi and Castellotti), University of Milan, IRCCS Fondazione Cà Granda, Milan, Italy; the Department of Pneumology (Dr Louis), University of Liege, Liege, Belgium; the Faculty of Medicine (Dr Milenkovic), University of Belgrade and the Clinic for Pulmonary Diseases (Dr Milenkovic), Clinical Centre of Serbia, Belgrade, Serbia; the University Thessaly Medical School (Dr Kostikas), Larissa, Greece; the Erasmus MC (Dr Aerts), Rotterdam and Amphia Hospital Breda, Breda, The Netherlands; the Department of Respiratory Medicine (Dr Rohde), Maastricht University Medical Center, Maastricht, The Netherlands; the Department of Microbiology (Dr Lacoma), Hospital Universitari Germans Trias i Pujol, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona and CIBER Enfermedades Respiratorias, Badalona, Spain; the Pneumology Department (Dr Marin), Hospital Universitari Germans Trias i Pujol, Badalona, Spain; the Clinical Diagnostics Division (Drs Hertel and Giersdorf), Thermo Scientific Biomarkers, BRAHMS GmbH, Hennigsdorf, Germany; the Pneumology Department (Dr Torres), Hospital Clinic, University of Barcelona, IDIBAPS and CIBERES, Barcelona, Spain; and the Department of Pneumology (Dr Welte), Medizinische Hochschule, Hannover, Germany.

CORRESPONDENCE TO: Daiana Stolz, MD, MPH, Clinic of Pneumology and Pulmonary Cell Research, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland; e-mail: Daiana.Stolz@usb.ch


FUNDING/SUPPORT: PROMISE-COPD was an investigator-initiated study primarily funded by the Clinic of Pulmonary Medicine and Respiratory Cell Research of the University Hospital Basel, Switzerland and by the Swiss National Foundation [Grant PP00-P3_128412/1]. Thermo Scientific Biomarkers (formerly BRAHMS AG), Hennigsdorf, Germany, provided all reagents for those analyses gratis and, through an unrestricted research grant, funded all costs of transporting blood samples to the central biomarker testing facility at University Hospital Basel.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(2):328-338. doi:10.1378/chest.13-1967
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BACKGROUND:  The prevalence of exertional hypoxemia in unselected patients with COPD is unknown. Intermittent hypoxia leads to adrenomedullin (ADM) upregulation through the hypoxia-inducible factor-1 pathway. We aimed to assess the prevalence and the annual probability to develop exertional hypoxemia in stable COPD. We also hypothesized that increased ADM might be associated with exertional hypoxemia and envisioned that adding ADM to clinical variables might improve its prediction in COPD.

METHODS:  A total of 1,233 6-min walk tests and circulating proadrenomedullin (proADM) levels from 574 patients with clinically stable, moderate to very severe COPD enrolled in a multinational cohort study and followed up for 2 years were concomitantly analyzed.

RESULTS:  The prevalence of exertional hypoxemia was 29.1%. In a matrix derived from a fitted-multistate model, the annual probability to develop exertional hypoxemia was 21.6%. Exertional hypoxemia was associated with greater deterioration of specific domains of health-related quality of life, higher severe exacerbation, and death annual rates. In the logistic linear and conditional Cox regression multivariable analyses, both FEV1% predicted and proADM proved independent predictors of exertional hypoxemia (P < .001 for both). Adjustment for comorbidities, including cardiovascular disorders, and exacerbation rate did not influence results. Relative to using FEV1% predicted alone, adding proADM resulted in a significant improvement of the predictive properties (P = .018). Based on the suggested nonlinear nomogram, patients with moderate COPD (FEV1% predicted = 50%) but high proADM levels (> 2 nmol/L) presented increased risk (> 30%) for exertional desaturation.

CONCLUSIONS:  Exertional desaturation is common and associated with poorer clinical outcomes in COPD. ADM improves prediction of exertional desaturation as compared with the use of FEV1% predicted alone.

TRIAL REGISTRY:  ISRCTN Register; No.: ISRCTN99586989; URL: www.controlled-trials.com

Figures in this Article

Exertional hypoxemia portends a poor prognosis for patients with COPD.1,2 Hypoxemia is associated with the development of pulmonary hypertension,3 systemic inflammation,4 and skeletal muscle5 and neurocognitive dysfunction.6 Supplemental oxygen appears to enhance exercise performance,7 decrease the level of dyspnea,8 improve health-related quality of life (QoL),9 and sustain cerebral function10 during activity in individuals with COPD who are normoxemic at rest but who desaturate with exertion. Indeed, because of the great heterogeneity of the population with COPD, ventilation and blood gas parameters vary with time and activity, and, in fact, values obtained during exercise may be most revealing of the need for long-term oxygen therapy.11

The prevalence of exertional hypoxemia in patients with COPD is unknown.12 Differences in the definition of desaturation, mode of exercise, and characteristics of the patient population make it difficult to compare previous studies and apply them to clinical practice. The form of exertion may also affect the detection of exercise-induced desaturation in individuals with COPD.13 These difficulties have driven multiple attempts to correlate various clinical tests with exertional desaturation.1418

Plasma proadrenomedullin (proADM) is the stable, biologically inactive mid-regional fragment of the adrenomedullin (ADM) prohormone and, as such, a surrogate for the mature protein.19,20 Intermittent hypoxia leads to ADM upregulation through the hypoxia-inducible factor-1 pathway, which interacts with nuclear factor-κB to promote the expression of inflammatory genes.2124 There is mounting evidence suggesting that systemic inflammation correlates with clinical outcomes in COPD.25 Accordingly, ADM was associated with all-cause mortality in patients with stable and exacerbated COPD.26,27 This observation led us to hypothesize that proADM might be associated with exertional hypoxemia in COPD. Additionally, we envisioned that adding proADM to clinical variables might improve exertional hypoxemia prediction compared with use of the latter alone.

The primary aim of the present analysis was to evaluate the prevalence and the annual risk to develop exertional hypoxemia during the 6-min walk test (6MWT) among clinically stable patients with COPD in a large, multinational, multicenter, prospective, longitudinal, observational cohort. We also describe the accuracy of a concomitant estimation of the circulating ADM alone or in combination with clinical variables to predict exertional hypoxemia.

Study Design and Ethics

Conducted in 11 centers in eight European countries, the Predicting Outcome Using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study evaluated variables potentially identifying poor outcomes in patients with moderate to very severe COPD. Such disease was defined as postbronchodilator FEV1/FVC < 70% and FEV1 < 80% predicted (ie, GOLD [Global Initiative for Chronic Obstructive Lung Disease] grade II-IV airway obstruction); COPD exacerbation was defined as an acute change from baseline in one or more of dyspnea, cough, and sputum, beyond normal day-to-day variation and possibly warranting medication change.

The study and its analyses were designed and conducted to take an inclusive, exploratory, hypothesis-generating approach. Enrollees had an initial baseline examination and then were followed for at least 2 years in scheduled semiannual visits. Additionally, as necessary, patients made outpatient visits or were hospitalized for treatment of acute exacerbation of COPD, and follow-up visits were specified for 4 weeks after exacerbation onset. Patients were treated as clinically warranted, without restriction, throughout the study period.

PROMISE-COPD, an investigator-initiated and -driven study, complied with the Helsinki Declaration and Good Clinical Practice Guidelines, was approved by the participating centers’ ethics committees (EKBB 295/07), and was registered at www.controlled-trials.com under the identifier ISRCTN99586989. Patients provided prior written informed consent for all study assessments.

Patients

Six hundred thirty-eight patients with COPD were consecutively recruited and followed at pulmonary departments of primary to tertiary care hospitals between November 2008 and October 2011. Patients had to meet the following inclusion criteria: (1) at baseline, clinically stable moderate to very severe COPD based on anamnesis, physical examination, and spirometry performed ≥ 4 weeks after resolution of the latest exacerbation; (2) age ≥ 40 years; (3) smoking history ≥ 10 pack-years. Exclusion criteria were: (1) a non-COPD condition (eg, bronchiectasis, asthma, or pulmonary fibrosis) as the main respiratory disease; (2) rapid fatal disease; (3) immunosuppression, including AIDS, history of organ transplantation, or current chronic steroid use (> 20 mg prednisolone-equivalent/d); (4) musculoskeletal disorder preventing walking.

Baseline and Scheduled Visits Assessment

For each patient, we performed a physical examination, registered vital signs, and obtained a detailed medical history including demographics, smoking status, current treatment, duration of disease, number and severity of exacerbations in the previous year, and comorbidities; using these last data, we calculated the age-adjusted Charlson comorbidity index score. Patients were categorized according to the GOLD 2013 classification in stages (II-IV) and groups (A-D).28 We also obtained plasma samples for biomarker determinations and spontaneous sputum samples for quantitative bacterial culture. Spirometry was administered by trained technicians according to American Thoracic Society guidelines.29 Patients completed the modified Medical Research Council score, the St. George’s Respiratory Questionnaire (SGRQ)-COPD version, and the Short Form-36 (SF-36) health-related quality-of-life questionnaire in validated, or, if this option was not available, unvalidated local language versions. Except for 6MWT, which was performed annually, all other evaluations took place at each scheduled visit (eg, at semiannual basis).

6-Min Walk Test

The 6MWT was performed as described previously by trained technicians according to American Thoracic Society guidelines.30 Exertional hypoxemia was defined as an arterial oxygen saturation < 88% (nadir saturation) measured by continuous transcutaneous, portable, and lightweight pulse oximeter during exercise.31,32 To minimize artifact and optimize signal quality, we verified that the pulse oximeter had an acceptable signal (ie, pulse regularity) and paid special attention to the finger probe placement.

ProADM Determination

Blood samples for biomarker measurement were collected at scheduled and unscheduled visits into Vacutainer tubes through an indwelling venous catheter. Ethylenediaminetetraacetic acid anticoagulant plasma for the proADM estimation was obtained by centrifuging the tubes at 3,000 × g for 10 to 15 min. Serum and plasma specimens were stored at –80°C until analyzed. ProADM was quantified using a fully automated sandwich immunoassay based on time-resolved amplified cryptate emission technology (KRYPTOR; Thermo Fisher Scientific Inc [formerly BRAHMS AG]). The KRYPTOR MR-ProADM assay has a measuring range of 0.05 to 100 nmol/L and a functional sensitivity of 0.25 nmol/L. Biomarker measurements were performed in duplicate within a single run in a central, accredited laboratory by technicians unaware of patients’ clinical data.

Outcome Assessment

Vital status at the 2-year follow-up was confirmed at study visits and, if necessary, by contacting relatives, family physicians, or insurance companies as well as checking medical records, hospital databases, and public registries, which also were used to determine the dates and causes of deaths. Death dates that were otherwise undeterminable were imputed to the halfway point between the last study visit and the date that the investigator learned of the death.

Statistics

Continuous variables are expressed as the mean ± SD or median (interquartile range [25th percentile-75th percentile]) and discrete variables as counts (percentages). Comparisons of proADM concentrations and other clinical characteristics at baseline between patients with and without exertional hypoxemia were made with the Mann-Whitney U test or the t test, as appropriate. Changes over time were analyzed using repeated measurement analyses (mixed-linear models). For the pairwise comparison of instant risk (hazard ratio [HR]) between GOLD stages, the higher stage was used as reference group. We used linear logistic univariable and multivariable analyses to establish the relationship of exertional hypoxemia with established clinical variables including proADM. Circulating proADM values were log-transformed prior to modeling to conform to the normality assumptions of the underlying models. For continuous variables, ORs and HRs were standardized to describe change of one unit range in log(proADM) or 10% changes in FEV1% predicted. To predict exertional hypoxemia over time, a conditional Cox regression allowing for multiple events was performed. It assumes that a subject is not at risk for event k until event k − 1 occurs. Estimated risks could be slightly conservative. Statistical details are described elsewhere.33

The incremental discriminative power offered by adding proADM to FEV1% predicted was analyzed using the net reclassification improvements from combining these predictive modalities.34 The net reclassification improvement relies on reclassification tables generated separately for exertional hypoxemia and nonexertional hypoxemia and quantifies the correct movement in categories—upward for nondesaturators and downward for desaturators. Nomograms provide excellent graphical depictions of the variables in a regression model, in addition to enabling the user to obtain predicted values manually. A linear nomogram based on the conditional Cox model was displayed. Additionally, a multistate model was performed providing 1-year transition probabilities between the clinical states (non-hypoxemia, hypoxemia, death). The model was fitted using the package “msm” in R.35 All analyses used a two-sided P of .05 for significance and were performed using R, version 2.5.1 (http://www.r-project.org) or Statistical Package for the Social Sciences, version 21.0 (IBM).

The study design according to the CONSORT guidelines and patient disposition is summarized in Figure 1. Sixty-four patients were excluded from the analysis because of unavailable lowest oxygen saturation during 6MWT at baseline. The clinical characteristics (sex; race; BMI, airflow obstruction, dyspnea, exercise capacity [BODE] index; and 6-min walk distance [6MWD]) of these patients did not differ from the analysis cohort (P = not significant for all, data not shown). Thus, of 638 patients in the PROMISE-COPD cohort, 574 (90.0%) had complete data and were included in the current analysis.

Figure Jump LinkFigure 1 –  Patient disposition for the present analysis according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. 6MWT = 6-min walk test; GOLD = Global Initiative for Chronic Obstructive Lung Disease; PROMISE-COPD = Predicting Outcome Using Systemic Markers in Severe Exacerbations of COPD.Grahic Jump Location
Prevalence of Exertional Desaturation

A total of 1,233 6MWTs were performed during the study. Overall, the prevalence of hypoxemia during exercise was 29.1% at baseline. In the stratified analysis, exertional hypoxemia was significantly more prevalent in GOLD stage IV (54.7%) but also frequent in GOLD stage III (38.8%) and stage II (15.1%), P < .001. The HRs differed significantly between GOLD III and II (HR, 2.90; 95% CI, [1.95-4.31]; P < .001) and GOLD IV and II (HR, 3.76; 95% CI, [2.40-5.88]; P < .001) and differed not significantly between GOLD IV and III (HR, 1.30; 95% CI, [0.91-1.84]; P = .145) (Fig 2). According to the combined assessment as suggested by GOLD 2013 classification, exertional hypoxemia was more common among patients classified in group D (42.7%) and C (31.3%), followed by group B (17.1%) and A (11.5%) (P < .001).

Figure Jump LinkFigure 2 –  Probability of freedom from event (exertional hypoxemia) after the first visit in patients stratified by GOLD stage. The hazard ratios (HRs) differed significantly between GOLD III and II (HR, 2.90; 95% CI, [1.95-4.31]; P < .001) and GOLD IV and II (HR, 3.76; 95% CI, [2.40-5.88]; P < .001) and nonsignificantly between GOLD IV and IIII (HR, 1.30; 95% CI, [0.91-1.84]; P = .145). See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Characteristics of Patients With Exertional Hypoxemia

Table 1 presents the baseline characteristics of the 574 patients according to the presence or absence of hypoxemia during 6MWT at baseline. Patients presenting exertional hypoxemia had a longer duration of the disease, more dyspnea, poorer health-related QoL, shorter 6MWD, higher heart rates at rest and exercise, lower resting oxygen saturation, reduced FEV1 and FEV1/FVC, and increased circulating proADM levels. Patients developing hypoxemia during exercise had more frequently a diagnosis of pulmonary hypertension.

Table Graphic Jump Location
TABLE 1 ]  Baseline Characteristics of 574 Patients With COPD for the Entire Cohort and According to Exertional Desaturation (No Desaturation vs Desaturation) at Baseline

Continuous data are shown as mean ± SD or median [IQR], and categorical variables are shown as No. (%). 6MWD = 6-min walk distance; bpm = beats/min; brd = bronchodilator; GOLD = Global Initiative for Chronic Obstructive Lung Disease; IQR = interquartile range; mMRC = modified Medical Research Council; proADM = proadrenomedullin; Sao2 = peripheral oxygen saturation; SF-36 = Short Form-36; SGRQ = St. George’s Respiratory Questionnaire.

a 

GOLD grades are based on FEV1 % predicted: II, ≥ 50% < 80%; III, ≥ 30% < 50%; IV, ≤ 30%. There were no patients with GOLD grade I COPD because of study inclusion criteria.

Outcomes in Patients With Exertional Hypoxemia

As depicted in Table 2, exertional hypoxemia was associated with greater deterioration of the health-related QoL as assessed by the activity score of the SGRQ (P = .038) and the physical function domain of the SF-36 (P = .034). Furthermore, these patients presented higher severe exacerbation (P = .006) and death (P = .020) annual rates. Noteworthy, changes in both 6MWD and lung function parameters (FEV1, FEV1/FVC) did not differ over time between those with and without exertional hypoxemia at baseline.

Table Graphic Jump Location
TABLE 2 ]  Functional Parameters Change per Year in 574 Patients With COPD for the Entire Cohort and According to Exertional Desaturation (No Desaturation vs Desaturation) at Baseline

Continuous data are shown as means ± SD or median [IQR] and categorical variables are shown as No. (%). See Table 1 legend for expansion of abbreviations.

Predicting Exertional Hypoxemia

Table 3 presents results of the univariable and multivariable linear logistic regression analysis involving exertional hypoxemia at baseline. In the multivariable analysis, FEV1% predicted and proADM remained independent predictors of hypoxemia during exercise. Variables independently associated with exertional desaturation at baseline were included in univariable and multivariable conditional Cox regression analyses for all 6MWTs (n = 1,233) performed during the 2-year follow-up (Table 4). Both FEV1% predicted and proADM portrayed a persistent association with exertional hypoxemia. A further multivariable Cox regression model including both annual exacerbation rate (HR, 1.13; 95% CI, [1.01-1.26]) and Charlson adjusted score (HR, 1.17; 95% CI, [1.04-1.31]) confirmed an independent association between FEV1% predicted (HR, 0.78; 95% CI, [0.71-0.85]) and proADM (HR, 4.07; 95% CI, [1.59-10.44]) with exertional hypoxemia. An additional model focusing on cardiovascular disease substantiated the independent association of FEV1% predicted and proADM with exertional hypoxemia after multivariable adjustment for coronary artery disease, history of myocardial infarction, and congestive heart failure, each separately and all three in combination (P = not significant for all). Adding proADM to FEV1% predicted resulted in a net reclassification improvement (95% CI) of 7.4% of patients (1.3%-13.6%, P = .0184) relative to using FEV1% predicted alone.

Table Graphic Jump Location
TABLE 3 ]  Univariable and Multivariable Linear Logistic Models for Exertional Desaturation Prediction in 6MWT of 574 Patients With Stable COPD at Baseline

6MWT = 6-min walk test. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 4 ]  Univariable and Multivariable Conditional Cox Regression Models for Exertional Desaturation Prediction in 1,233 6MWTs of 574 Patients With Stable COPD Over 2-Y Follow-up

Hazard ratio per unit increase (Log10 proADM) or 10% change (FEV1% predicted). See Table 1 and 3 legends for expansion of abbreviations.

To refine risk estimation in a clinically feasible fashion, we designed a two-dimensional diagram for risk stratification in COPD (Fig 3). In this linear nomogram, FEV1% predicted and proADM, assessed at baseline, predicted the risk of exertional hypoxemia. For instance, a patient with FEV1 40% and proADM 2 nmol/L would have a predicted risk of 37% for exertional hypoxemia, whereas the predicted risk would be < 8% if proADM = 0.25 nmol/l.

Figure Jump LinkFigure 3 –  Nonlinear nomogram to predict exercise hypoxemia after the first visit based on the FEV1% predicted (x-axis) and proadrenomedullin values (y-axis).Grahic Jump Location

The overall transition probability among the states (no exertional hypoxemia, exertional hypoxemia, and death) is depicted in a matrix derived from a fitted multistate model for the time interval of 1 year (Table 5). For instance, the probability to develop exertional hypoxemia after 1 year in patients without hypoxemia at baseline was 21.6%. In contrast, in those with hypoxemia at baseline, the probability for persistent exertional hypoxemia after 1 year was 37.3%. Interestingly, in patients presenting with exertional hypoxemia, there was a 48.5% probability to recover (ie, no exercise-related hypoxemia) after 1 year. Neither FEV1% predicted (HR, 0.98; 95% CI, [0.97-1.00]) nor proADM (HR, 1.38; 95% CI, [0.57-3.32]) significantly influenced the risk for development of hypoxemia. Conversely, only FEV1% predicted was significantly associated with improvement from hypoxemia to non-hypoxemia (HR, 1.04; 95% CI, [1.02-1.06]). The mortality risk for patients with exertional hypoxemia was 14.3% as compared with 3.1% in patients without exertional hypoxemia. ProADM was significantly associated with evolution from hypoxemia to death (HR, 11.22; 95% CI, [3.42-36.80]).

Table Graphic Jump Location
TABLE 5 ]  Overall Transition Probability Matrix Among States of No Exertional Hypoxemia, Exertional Hypoxemia, and Death for the Time Interval of 1 Y in 574 Patients and 1,233 6MWTs With Stable COPD

See Table 3 legend for expansion of abbreviation.

We used data of a multinational, longitudinal cohort study to assess the prevalence and the annual probability to develop exertional hypoxemia among unselected, stable patients with moderate to very severe COPD followed up during a median time of 2 years. We found that exertional hypoxemia is present in almost one-third of the patients, with a prevalence ranging from one out of six patients in GOLD stage II to one out of two patients in GOLD stage IV. The cumulative HR of exertional hypoxemia significantly increased during the observation time, and, as expected, this increase was more pronounced in patients with severe and very severe disease.

Up to now, the prevalence of exertional hypoxemia was not exactly known. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial reported, for instance, that only 2% of the 5,993 participants were being prescribed supplemental oxygen.36 In contrast, 21% to 80% of selected patients with advanced disease (ie, those admitted for pulmonary rehabilitation or enrolled in the National Emphysema Treatment Trial) fulfill criteria to receive some form of oxygen therapy.3740 Data on unselected patients, particularly including GOLD II stage, are much scarcer.41 To our knowledge, this is the largest prospective study to our knowledge examining the prevalence of exertional hypoxemia in an ambulatory population with moderate to very severe COPD. Therefore, the high prevalence of exertional hypoxemia in GOLD stage III and IV is remarkable and substantiates previous results of some smaller studies.4144 Interestingly, exercise-induced hypoxemia was also observed in patients with moderate disease, thus,c refuting the notion that patients with preserved lung function (FEV1% > 50%) rarely desaturate during exercise.45

We confirmed that exertional hypoxemia is associated with more severe systemic repercussions of COPD (ie, more dyspnea, poorer health-related QoL, shorter exercise capacity and impaired lung function).2 Similarly, our longitudinal data sustained a connection with disease progression (ie, greater deterioration of the health-related QoL and physical function). This study also corroborated the link between exertional hypoxemia, severe exacerbations of COPD, and death.2

Given the evident clinical relevance of exertional hypoxemia, we have strived to refine risk estimation in a clinically feasible fashion. Herein, we identify anew FEV1% as an important predictor for exercised-induced desaturation.2,41,46 Additionally, proADM emerged as an independent factor associated with exertional hypoxemia. High proADM levels were particularly informative in patients with relatively preserved lung function in whom the probability of exercise-induced hypoxemia would be otherwise neglected.

There are two clear pathophysiologic links between hypoxia and ADM in COPD. First, intermittent hypoxia leads to ADM upregulation through the hypoxia-inducible factor-1 pathway, which interacts with nuclear factor κ-light-chain-enhancer of activated B-cells (NF-βB) to promote the expression of inflammatory genes.2124 Systemic inflammation promotes cardiovascular disease, drives atherosclerosis, and contributes to the development of skeletal muscle dysfunction, osteopenia, and depression in COPD.4 Additionally, it has been consistently correlated with clinical outcomes.47 We have previously suggested that proADM predicted death and rehospitalization in patients with exacerbated COPD.26 Recently, we reported that proADM refines the BODE index (“BODE-A” index) and replaces the more cumbersome 6MWD (“BODA” index) without sacrificing the predictive properties of the original composite score.27 Second, both hypoxia and ADM are associated with vascular remodeling and contribute to the development of pulmonary hypertension.48,49 Accordingly, we found significantly higher proADM values and more commonly a diagnosis of pulmonary hypertension among patients developing exertional hypoxemia. Despite our partial understanding of the interactions between ADM, hypoxia, and COPD, it remains so far controversial whether ADM actually contributes as an effective pathophysiologic mediator or merely acts as an informative bystander. Further studies examining the impact of therapeutic measures on circulating proADM are, therefore, needed.

The annual probability to develop exertional hypoxemia for the overall COPD population stage GOLD II to IV averaged 20%. Neither FEV1% predicted nor proADM individually influenced this risk. In contrast and even more intriguingly, patients developing exercise-induced hypoxemia had a 50% probability to sustain peripheral oxygen saturation (Sao2) during exercise at a later time point (ie, 1 year later). Only FEV1% predicted significantly affected this risk. This study seems to be by far the largest one longitudinally assessing the reproducibility of oxygen desaturation during the 6MWT in patients with COPD.13,50 The 6MWT is a standardized test commonly used to assess the need for ambulatory oxygen prescription in patients with COPD.32 To be reimbursed for home oxygen therapy, the Centers for Medicare & Medicaid Services has strict criteria.32 Although the timed walks are remarkably consistent in term of the distance walked, the reproducibility of exercise-induced oxygen desaturation in 6MWT in COPD is modest. A previous study including 88 patients with COPD undergoing pulmonary rehabilitation reported a poor reproducibility of exercised-induced hypoxemia during the 6MWT (paired-observation agreement between the tests, 51%; κ-value, 0.62).50 Accordingly, only 30% of the patients showed consistent reductions of Sao2 ≤ 88% in all three tests performed within 12 days. This phenomenon has been also described regarding nocturnal desaturation in COPD.51 Our study confirms the fact that exertional hypoxemia is found intermittently in patients with COPD. However, despite its low reproducibility, we could still demonstrate a robust association between desaturation in the 6MWT and important clinical outcomes, such as deterioration of QoL, exacerbation rate, and survival. Therefore, one could assume that the prognosis in patients depicting exercise-induced desaturation at any time is already compromised in comparison with patient sustaining oxygen saturation at all times. Moreover, considering the numerous potential sources of nondifferential misclassification bias (ie, variability of the observers, medication posology, climatic variation) as well as technical issues related to the 6MWT itself (adequacy of the perfusion signal, cooperation of the patient, and so forth), we believe it is fair to assume an even stronger association between exercise-related hypoxemia and outcome under strict experimental conditions. Nevertheless, the paramount question of why patients with explicitly stable COPD develop intermittent desaturation during exercise remains unanswered. The use of sedatives, hypnotics, and alcohol might explain the fluctuation in oxygen saturation, because of its suppressive effect on the central ventilatory drive, in only a minority of cases.52 Hence, we hypothesize that the subclinical instability of the disease (“subclinical exacerbations”) leading to variable deterioration of ventilation/perfusion mismatch53 and/or dynamic hyperinflation52 might explain the short-term variations in gas exchange. Another assessment of ventilation/perfusion mismatch and dynamic hyperinflation during these events would be necessary to provide insights in this regard.

Our study has some limitations. First, although we defined exertional hypoxemia by a widely used clinical threshold, there is no uniform definition of exertional desaturation or standardized exercise protocol to elicit decreases in oxygen in individuals with COPD.12 Consequently, we cannot extrapolate our findings to other definitions or exercise protocols. Second, information on this patient population cannot be generalized to asymptomatic or untreated patients and to those with mild COPD (FEV1 > 80% predicted). Third, we have not assessed histopathology (emphysema severity or bronchiolar score), chest CT imaging (emphysema severity), and other pulmonary function tests (diffusion lung capacity) in their ability to predict exertional hypoxemia. Thus, we do not know whether proADM would remain an independent prognosticator if those variables would have been taken into account. Finally, although we have shown an association between proADM and desaturation, we cannot infer its causality.

In conclusion, exertional hypoxemia is common and associated with poorer clinical outcomes in stable COPD. According to the current guidelines, one-third of all patients GOLD II to IV should be considered for oxygen therapy. The annual probability to develop exertional hypoxemia for the overall COPD population stage GOLD II to IV averages 20%. Circulating proADM improves prediction of exertional desaturation as compared with the use of FEV1% predicted alone.

Author contributions: All authors take responsibility for the integrity of the work as a whole, from inception to published article.

D. S. and M. T. contributed to conceiving and designing the study and collected and analyzed study data; D. S. and S. H. contributed to conducting statistical analyses; W. B., F. B., R. L., B. M., K. K., J. G. A., G. R., J. R., L. B., A. S., A. M., A. T., T. W., and M. T. contributed to collecting study data; and D. S., W. B., F. B., R. L., B. M., K. K., J. G. A., G. R., A. L., J. R., L. B., P. C., A. S., A. M., S. H., S. G., A. T., T. W., and M. T. contributed to and approved the final manuscript draft.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Stolz received payment for lectures from Thermo Fisher Scientific Biomarkers. Dr Milenkovic received payment for lectures from GlaxoSmithKline; Merck & Co, Inc; and Boehringer Ingelheim GmbH. Dr Rohde received payment for lectures from Pfizer Inc; Boehringer Ingelheim GmbH; Solvay; GlaxoSmithKline; Essex Pharma GmbH; Merck & Co, Inc; Novartis Corp; and AstraZeneca. Drs Hertel and Giersdorf are full-time employees of Thermo Scientific Biomarkers, BRAHMS GmbH. Drs Boersma, Blasi, Louis, Kostikas, Aerts, Lacoma, Rakic, Boeck, Castellotti, Scherr, Marin, Torres, Welte, and Tamm have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors of this investigator-initiated project were not involved in the study design or conduct, statistical analysis, or approval of the manuscript.

Other contributions: The principal investigators of all study centers had full and final control of the study design and conduct, database, statistical analysis plan and analyses, manuscript content, and publication decisions. Andy Schötzau (Eudox Statistische Beratungen AG) conducted statistical analyses.

6MWD

6-min walk distance

6MWT

6-min walk test

ADM

adrenomedullin

BODE

BMI, airway obstruction, dyspnea, and exercise capacity

GOLD

Global Initiative for Chronic Obstructive Lung Disease

HR

hazard ratio

proADM

proadrenomedullin

PROMISE-COPD

Predicting Outcome Using Systemic Markers in Severe Exacerbations of COPD

QoL

quality of life

Sao2

peripheral oxygen saturation

SF-36

Short-Form 36

SGRQ

St. George’s Respiratory Questionnaire

Tojo N, Ichioka M, Chida M, Miyazato I, Yoshizawa Y, Miyasaka N. Pulmonary exercise testing predicts prognosis in patients with chronic obstructive pulmonary disease. Intern Med. 2005;44(1):20-25. [CrossRef] [PubMed]
 
Casanova C, Cote C, Marin JM, et al. Distance and oxygen desaturation during the 6-min walk test as predictors of long-term mortality in patients with COPD. Chest. 2008;134(4):746-752. [CrossRef] [PubMed]
 
Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J. 2008;32(5):1371-1385. [CrossRef] [PubMed]
 
Agusti AG. Systemic effects of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2(4):367-370. [CrossRef] [PubMed]
 
Davidson AC, Leach R, George RJ, Geddes DM. Supplemental oxygen and exercise ability in chronic obstructive airways disease. Thorax. 1988;43(12):965-971. [CrossRef] [PubMed]
 
Dodd JW, Getov SV, Jones PW. Cognitive function in COPD. Eur Respir J. 2010;35(4):913-922. [CrossRef] [PubMed]
 
Emtner M, Porszasz J, Burns M, Somfay A, Casaburi R. Benefits of supplemental oxygen in exercise training in nonhypoxemic chronic obstructive pulmonary disease patients. Am J Respir Crit Care Med. 2003;168(9):1034-1042. [CrossRef] [PubMed]
 
Jolly EC, Di Boscio V, Aguirre L, Luna CM, Berensztein S, Gené RJ. Effects of supplemental oxygen during activity in patients with advanced COPD without severe resting hypoxemia. Chest. 2001;120(2):437-443. [CrossRef] [PubMed]
 
Eaton T, Garrett JE, Young P, et al. Ambulatory oxygen improves quality of life of COPD patients: a randomised controlled study. Eur Respir J. 2002;20(2):306-312. [CrossRef] [PubMed]
 
Jensen G, Nielsen HB, Ide K, et al. Cerebral oxygenation during exercise in patients with terminal lung disease. Chest. 2002;122(2):445-450. [CrossRef] [PubMed]
 
Croxton TL, Bailey WC. Long-term oxygen treatment in chronic obstructive pulmonary disease: recommendations for future research: an NHLBI workshop report. Am J Respir Crit Care Med. 2006;174(4):373-378. [CrossRef] [PubMed]
 
Panos RJ, Eschenbacher W. Exertional desaturation in patients with chronic obstructive pulmonary disease. COPD. 2009;6(6):478-487. [CrossRef] [PubMed]
 
Poulain M, Durand F, Palomba B, et al. 6-minute walk testing is more sensitive than maximal incremental cycle testing for detecting oxygen desaturation in patients with COPD. Chest. 2003;123(5):1401-1407. [CrossRef] [PubMed]
 
Barbera JA, Roca J, Ramirez J, Wagner PD, Ussetti P, Rodriguez-Roisin R. Gas exchange during exercise in mild chronic obstructive pulmonary disease. Correlation with lung structure. Am Rev Respir Dis. 1991;144(3 pt 1):520-525. [CrossRef] [PubMed]
 
Mohsenifar Z, Collier J, Belman MJ, Koerner SK. Isolated reduction in single-breath diffusing capacity in the evaluation of exertional dyspnea. Chest. 1992;101(4):965-969. [CrossRef] [PubMed]
 
Hadeli KO, Siegel EM, Sherrill DL, Beck KC, Enright PL. Predictors of oxygen desaturation during submaximal exercise in 8,000 patients. Chest. 2001;120(1):88-92. [CrossRef] [PubMed]
 
Mohsenifar Z, Lee SM, Diaz P, et al. Single-breath diffusing capacity of the lung for carbon monoxide: a predictor of PaO2, maximum work rate, and walking distance in patients with emphysema. Chest. 2003;123(5):1394-1400. [CrossRef] [PubMed]
 
Knower MT, Dunagan DP, Adair NE, Chin R Jr. Baseline oxygen saturation predicts exercise desaturation below prescription threshold in patients with chronic obstructive pulmonary disease. Arch Intern Med. 2001;161(5):732-736. [CrossRef] [PubMed]
 
Struck J, Tao C, Morgenthaler NG, Bergmann A. Identification of an Adrenomedullin precursor fragment in plasma of sepsis patients. Peptides. 2004;25(8):1369-1372. [CrossRef] [PubMed]
 
Morgenthaler NG, Struck J, Alonso C, Bergmann A. Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clin Chem. 2005;51(10):1823-1829. [CrossRef] [PubMed]
 
MacManus CF, Campbell EL, Keely S, Burgess A, Kominsky DJ, Colgan SP. Anti-inflammatory actions of adrenomedullin through fine tuning of HIF stabilization. FASEB J. 2011;25(6):1856-1864. [CrossRef] [PubMed]
 
Pfeil U, Aslam M, Paddenberg R, et al. Intermedin/adrenomedullin-2 is a hypoxia-induced endothelial peptide that stabilizes pulmonary microvascular permeability. Am J Physiol Lung Cell Mol Physiol. 2009;297(5):L837-L845. [CrossRef] [PubMed]
 
Fitzpatrick SF, Tambuwala MM, Bruning U, et al. An intact canonical NF-κB pathway is required for inflammatory gene expression in response to hypoxia. J Immunol. 2011;186(2):1091-1096. [CrossRef] [PubMed]
 
Marinoni E, Pacioni K, Sambuchini A, Moscarini M, Letizia C, DI Iorio R. Regulation by hypoxia of adrenomedullin output and expression in human trophoblast cells. Eur J Obstet Gynecol Reprod Biol. 2011;154(2):146-150. [CrossRef] [PubMed]
 
Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(3):250-255. [CrossRef] [PubMed]
 
Stolz D, Christ-Crain M, Morgenthaler NG, et al. Plasma pro-adrenomedullin but not plasma pro-endothelin predicts survival in exacerbations of COPD. Chest. 2008;134(2):263-272. [CrossRef] [PubMed]
 
Stolz D, Kostikas K, Blasi F, et al. Adrenomedullin refines mortality prediction by the BODE index in COPD - The “BODE-A” index. Eur Respir J. 2014;43(2):397-408. [CrossRef] [PubMed]
 
Global strategy for diagnosis, management, and prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease website. http://www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html. Accessed December 13, 2013.
 
Brusasco V, Crapo R, Viegi G; American Thoracic Society; European Respiratory Society. Coming together: the ATS/ERS consensus on clinical pulmonary function testing. Eur Respir J. 2005;26(1):1-2. [CrossRef] [PubMed]
 
ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111-117. [CrossRef] [PubMed]
 
Medicare National coverage determinations (NCD) manual. Centers for Medicare & Medicaid Services website. http://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Internet-Only-Manuals-IOMs-Items/CMS014961.html. Accessed December 13, 2013.
 
National coverage determination (NCD) for home use of oxygen (240.2). Centers for Medicare & Medicaid Services website. http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=169&ncdver=1&NCAId=169&NcaName=Home+Use+of+Oxygen&IsPopup=y&bc=AAAAAAAAIAAA&. Accessed December 13, 2013.
 
Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. New York, NY: Springer-Verlag; 2000.
 
Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med. 2008;27(2):157-172. [CrossRef] [PubMed]
 
Jackson CH. Multi-state models for panel data: the msm package for R. J Stat Softw. 2011;38(8):1-29.
 
Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-1554. [CrossRef] [PubMed]
 
Crisafulli E, Iattoni A, Venturelli E, et al. Predicting walking-induced oxygen desaturations in COPD patients: a statistical model. Respir Care. 2013;58(9):1495-1503. [CrossRef] [PubMed]
 
Martinez FJ, Foster G, Curtis JL, et al; NETT Research Group. Predictors of mortality in patients with emphysema and severe airflow obstruction. Am J Respir Crit Care Med. 2006;173(12):1326-1334. [CrossRef] [PubMed]
 
Scott AS, Baltzman MA, Chan R, Wolkove N. Oxygen desaturation during a 6 min walk test is a sign of nocturnal hypoxemia. Can Respir J. 2011;18(6):333-337. [PubMed]
 
Jenkins S, Čečins N. Six-minute walk test: observed adverse events and oxygen desaturation in a large cohort of patients with chronic lung disease. Intern Med J. 2011;41(5):416-422. [CrossRef] [PubMed]
 
van Gestel AJ, Clarenbach CF, Stöwhas AC, et al. Prevalence and prediction of exercise-induced oxygen desaturation in patients with chronic obstructive pulmonary disease. Respiration. 2012;84(5):353-359. [CrossRef] [PubMed]
 
Pilling J, Cutaia M. Ambulatory oximetry monitoring in patients with severe COPD: a preliminary study. Chest. 1999;116(2):314-321. [CrossRef] [PubMed]
 
Soguel Schenkel N, Burdet L, de Muralt B, Fitting JW. Oxygen saturation during daily activities in chronic obstructive pulmonary disease. Eur Respir J. 1996;9(12):2584-2589. [CrossRef] [PubMed]
 
Casanova C, Hernández MC, Sánchez A, et al. Twenty-four-hour ambulatory oximetry monitoring in COPD patients with moderate hypoxemia. Respir Care. 2006;51(12):1416-1423. [PubMed]
 
Owens GR, Rogers RM, Pennock BE, Levin D. The diffusing capacity as a predictor of arterial oxygen desaturation during exercise in patients with chronic obstructive pulmonary disease. N Engl J Med. 1984;310(19):1218-1221. [CrossRef] [PubMed]
 
Jehn M, Schindler C, Meyer A, et al. Associations of daily walking activity with biomarkers related to cardiac distress in patients with chronic obstructive pulmonary disease. Respiration. 2013;85(3):195-202. [CrossRef] [PubMed]
 
Sin DD, Man SF. Systemic inflammation and mortality in chronic obstructive pulmonary disease. Can J Physiol Pharmacol. 2007;85(1):141-147. [CrossRef] [PubMed]
 
Matsui H, Shimosawa T, Itakura K, Guanqun X, Ando K, Fujita T. Adrenomedullin can protect against pulmonary vascular remodeling induced by hypoxia. Circulation. 2004;109(18):2246-2251. [CrossRef] [PubMed]
 
Qi JG, Ding YG, Tang CS, Du JB. Chronic administration of adrenomedullin attenuates hypoxic pulmonary vascular structural remodeling and inhibits proadrenomedullin N-terminal 20-peptide production in rats. Peptides. 2007;28(4):910-919. [CrossRef] [PubMed]
 
Chatterjee AB, Rissmiller RW, Meade K, et al. Reproducibility of the 6-minute walk test for ambulatory oxygen prescription. Respiration. 2010;79(2):121-127. [CrossRef] [PubMed]
 
Lewis CA, Eaton TE, Fergusson W, Whyte KF, Garrett JE, Kolbe J. Home overnight pulse oximetry in patients with COPD: more than one recording may be needed. Chest. 2003;123(4):1127-1133. [CrossRef] [PubMed]
 
Kent BD, Mitchell PD, McNicholas WT. Hypoxemia in patients with COPD: cause, effects, and disease progression. Int J Chron Obstruct Pulmon Dis. 2011;6:199-208. [PubMed]
 
Barberà JA, Roca J, Ferrer A, et al. Mechanisms of worsening gas exchange during acute exacerbations of chronic obstructive pulmonary disease. Eur Respir J. 1997;10(6):1285-1291. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Patient disposition for the present analysis according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. 6MWT = 6-min walk test; GOLD = Global Initiative for Chronic Obstructive Lung Disease; PROMISE-COPD = Predicting Outcome Using Systemic Markers in Severe Exacerbations of COPD.Grahic Jump Location
Figure Jump LinkFigure 2 –  Probability of freedom from event (exertional hypoxemia) after the first visit in patients stratified by GOLD stage. The hazard ratios (HRs) differed significantly between GOLD III and II (HR, 2.90; 95% CI, [1.95-4.31]; P < .001) and GOLD IV and II (HR, 3.76; 95% CI, [2.40-5.88]; P < .001) and nonsignificantly between GOLD IV and IIII (HR, 1.30; 95% CI, [0.91-1.84]; P = .145). See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 3 –  Nonlinear nomogram to predict exercise hypoxemia after the first visit based on the FEV1% predicted (x-axis) and proadrenomedullin values (y-axis).Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Baseline Characteristics of 574 Patients With COPD for the Entire Cohort and According to Exertional Desaturation (No Desaturation vs Desaturation) at Baseline

Continuous data are shown as mean ± SD or median [IQR], and categorical variables are shown as No. (%). 6MWD = 6-min walk distance; bpm = beats/min; brd = bronchodilator; GOLD = Global Initiative for Chronic Obstructive Lung Disease; IQR = interquartile range; mMRC = modified Medical Research Council; proADM = proadrenomedullin; Sao2 = peripheral oxygen saturation; SF-36 = Short Form-36; SGRQ = St. George’s Respiratory Questionnaire.

a 

GOLD grades are based on FEV1 % predicted: II, ≥ 50% < 80%; III, ≥ 30% < 50%; IV, ≤ 30%. There were no patients with GOLD grade I COPD because of study inclusion criteria.

Table Graphic Jump Location
TABLE 2 ]  Functional Parameters Change per Year in 574 Patients With COPD for the Entire Cohort and According to Exertional Desaturation (No Desaturation vs Desaturation) at Baseline

Continuous data are shown as means ± SD or median [IQR] and categorical variables are shown as No. (%). See Table 1 legend for expansion of abbreviations.

Table Graphic Jump Location
TABLE 3 ]  Univariable and Multivariable Linear Logistic Models for Exertional Desaturation Prediction in 6MWT of 574 Patients With Stable COPD at Baseline

6MWT = 6-min walk test. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 4 ]  Univariable and Multivariable Conditional Cox Regression Models for Exertional Desaturation Prediction in 1,233 6MWTs of 574 Patients With Stable COPD Over 2-Y Follow-up

Hazard ratio per unit increase (Log10 proADM) or 10% change (FEV1% predicted). See Table 1 and 3 legends for expansion of abbreviations.

Table Graphic Jump Location
TABLE 5 ]  Overall Transition Probability Matrix Among States of No Exertional Hypoxemia, Exertional Hypoxemia, and Death for the Time Interval of 1 Y in 574 Patients and 1,233 6MWTs With Stable COPD

See Table 3 legend for expansion of abbreviation.

References

Tojo N, Ichioka M, Chida M, Miyazato I, Yoshizawa Y, Miyasaka N. Pulmonary exercise testing predicts prognosis in patients with chronic obstructive pulmonary disease. Intern Med. 2005;44(1):20-25. [CrossRef] [PubMed]
 
Casanova C, Cote C, Marin JM, et al. Distance and oxygen desaturation during the 6-min walk test as predictors of long-term mortality in patients with COPD. Chest. 2008;134(4):746-752. [CrossRef] [PubMed]
 
Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J. 2008;32(5):1371-1385. [CrossRef] [PubMed]
 
Agusti AG. Systemic effects of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2(4):367-370. [CrossRef] [PubMed]
 
Davidson AC, Leach R, George RJ, Geddes DM. Supplemental oxygen and exercise ability in chronic obstructive airways disease. Thorax. 1988;43(12):965-971. [CrossRef] [PubMed]
 
Dodd JW, Getov SV, Jones PW. Cognitive function in COPD. Eur Respir J. 2010;35(4):913-922. [CrossRef] [PubMed]
 
Emtner M, Porszasz J, Burns M, Somfay A, Casaburi R. Benefits of supplemental oxygen in exercise training in nonhypoxemic chronic obstructive pulmonary disease patients. Am J Respir Crit Care Med. 2003;168(9):1034-1042. [CrossRef] [PubMed]
 
Jolly EC, Di Boscio V, Aguirre L, Luna CM, Berensztein S, Gené RJ. Effects of supplemental oxygen during activity in patients with advanced COPD without severe resting hypoxemia. Chest. 2001;120(2):437-443. [CrossRef] [PubMed]
 
Eaton T, Garrett JE, Young P, et al. Ambulatory oxygen improves quality of life of COPD patients: a randomised controlled study. Eur Respir J. 2002;20(2):306-312. [CrossRef] [PubMed]
 
Jensen G, Nielsen HB, Ide K, et al. Cerebral oxygenation during exercise in patients with terminal lung disease. Chest. 2002;122(2):445-450. [CrossRef] [PubMed]
 
Croxton TL, Bailey WC. Long-term oxygen treatment in chronic obstructive pulmonary disease: recommendations for future research: an NHLBI workshop report. Am J Respir Crit Care Med. 2006;174(4):373-378. [CrossRef] [PubMed]
 
Panos RJ, Eschenbacher W. Exertional desaturation in patients with chronic obstructive pulmonary disease. COPD. 2009;6(6):478-487. [CrossRef] [PubMed]
 
Poulain M, Durand F, Palomba B, et al. 6-minute walk testing is more sensitive than maximal incremental cycle testing for detecting oxygen desaturation in patients with COPD. Chest. 2003;123(5):1401-1407. [CrossRef] [PubMed]
 
Barbera JA, Roca J, Ramirez J, Wagner PD, Ussetti P, Rodriguez-Roisin R. Gas exchange during exercise in mild chronic obstructive pulmonary disease. Correlation with lung structure. Am Rev Respir Dis. 1991;144(3 pt 1):520-525. [CrossRef] [PubMed]
 
Mohsenifar Z, Collier J, Belman MJ, Koerner SK. Isolated reduction in single-breath diffusing capacity in the evaluation of exertional dyspnea. Chest. 1992;101(4):965-969. [CrossRef] [PubMed]
 
Hadeli KO, Siegel EM, Sherrill DL, Beck KC, Enright PL. Predictors of oxygen desaturation during submaximal exercise in 8,000 patients. Chest. 2001;120(1):88-92. [CrossRef] [PubMed]
 
Mohsenifar Z, Lee SM, Diaz P, et al. Single-breath diffusing capacity of the lung for carbon monoxide: a predictor of PaO2, maximum work rate, and walking distance in patients with emphysema. Chest. 2003;123(5):1394-1400. [CrossRef] [PubMed]
 
Knower MT, Dunagan DP, Adair NE, Chin R Jr. Baseline oxygen saturation predicts exercise desaturation below prescription threshold in patients with chronic obstructive pulmonary disease. Arch Intern Med. 2001;161(5):732-736. [CrossRef] [PubMed]
 
Struck J, Tao C, Morgenthaler NG, Bergmann A. Identification of an Adrenomedullin precursor fragment in plasma of sepsis patients. Peptides. 2004;25(8):1369-1372. [CrossRef] [PubMed]
 
Morgenthaler NG, Struck J, Alonso C, Bergmann A. Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clin Chem. 2005;51(10):1823-1829. [CrossRef] [PubMed]
 
MacManus CF, Campbell EL, Keely S, Burgess A, Kominsky DJ, Colgan SP. Anti-inflammatory actions of adrenomedullin through fine tuning of HIF stabilization. FASEB J. 2011;25(6):1856-1864. [CrossRef] [PubMed]
 
Pfeil U, Aslam M, Paddenberg R, et al. Intermedin/adrenomedullin-2 is a hypoxia-induced endothelial peptide that stabilizes pulmonary microvascular permeability. Am J Physiol Lung Cell Mol Physiol. 2009;297(5):L837-L845. [CrossRef] [PubMed]
 
Fitzpatrick SF, Tambuwala MM, Bruning U, et al. An intact canonical NF-κB pathway is required for inflammatory gene expression in response to hypoxia. J Immunol. 2011;186(2):1091-1096. [CrossRef] [PubMed]
 
Marinoni E, Pacioni K, Sambuchini A, Moscarini M, Letizia C, DI Iorio R. Regulation by hypoxia of adrenomedullin output and expression in human trophoblast cells. Eur J Obstet Gynecol Reprod Biol. 2011;154(2):146-150. [CrossRef] [PubMed]
 
Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(3):250-255. [CrossRef] [PubMed]
 
Stolz D, Christ-Crain M, Morgenthaler NG, et al. Plasma pro-adrenomedullin but not plasma pro-endothelin predicts survival in exacerbations of COPD. Chest. 2008;134(2):263-272. [CrossRef] [PubMed]
 
Stolz D, Kostikas K, Blasi F, et al. Adrenomedullin refines mortality prediction by the BODE index in COPD - The “BODE-A” index. Eur Respir J. 2014;43(2):397-408. [CrossRef] [PubMed]
 
Global strategy for diagnosis, management, and prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease website. http://www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html. Accessed December 13, 2013.
 
Brusasco V, Crapo R, Viegi G; American Thoracic Society; European Respiratory Society. Coming together: the ATS/ERS consensus on clinical pulmonary function testing. Eur Respir J. 2005;26(1):1-2. [CrossRef] [PubMed]
 
ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111-117. [CrossRef] [PubMed]
 
Medicare National coverage determinations (NCD) manual. Centers for Medicare & Medicaid Services website. http://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Internet-Only-Manuals-IOMs-Items/CMS014961.html. Accessed December 13, 2013.
 
National coverage determination (NCD) for home use of oxygen (240.2). Centers for Medicare & Medicaid Services website. http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=169&ncdver=1&NCAId=169&NcaName=Home+Use+of+Oxygen&IsPopup=y&bc=AAAAAAAAIAAA&. Accessed December 13, 2013.
 
Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. New York, NY: Springer-Verlag; 2000.
 
Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med. 2008;27(2):157-172. [CrossRef] [PubMed]
 
Jackson CH. Multi-state models for panel data: the msm package for R. J Stat Softw. 2011;38(8):1-29.
 
Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-1554. [CrossRef] [PubMed]
 
Crisafulli E, Iattoni A, Venturelli E, et al. Predicting walking-induced oxygen desaturations in COPD patients: a statistical model. Respir Care. 2013;58(9):1495-1503. [CrossRef] [PubMed]
 
Martinez FJ, Foster G, Curtis JL, et al; NETT Research Group. Predictors of mortality in patients with emphysema and severe airflow obstruction. Am J Respir Crit Care Med. 2006;173(12):1326-1334. [CrossRef] [PubMed]
 
Scott AS, Baltzman MA, Chan R, Wolkove N. Oxygen desaturation during a 6 min walk test is a sign of nocturnal hypoxemia. Can Respir J. 2011;18(6):333-337. [PubMed]
 
Jenkins S, Čečins N. Six-minute walk test: observed adverse events and oxygen desaturation in a large cohort of patients with chronic lung disease. Intern Med J. 2011;41(5):416-422. [CrossRef] [PubMed]
 
van Gestel AJ, Clarenbach CF, Stöwhas AC, et al. Prevalence and prediction of exercise-induced oxygen desaturation in patients with chronic obstructive pulmonary disease. Respiration. 2012;84(5):353-359. [CrossRef] [PubMed]
 
Pilling J, Cutaia M. Ambulatory oximetry monitoring in patients with severe COPD: a preliminary study. Chest. 1999;116(2):314-321. [CrossRef] [PubMed]
 
Soguel Schenkel N, Burdet L, de Muralt B, Fitting JW. Oxygen saturation during daily activities in chronic obstructive pulmonary disease. Eur Respir J. 1996;9(12):2584-2589. [CrossRef] [PubMed]
 
Casanova C, Hernández MC, Sánchez A, et al. Twenty-four-hour ambulatory oximetry monitoring in COPD patients with moderate hypoxemia. Respir Care. 2006;51(12):1416-1423. [PubMed]
 
Owens GR, Rogers RM, Pennock BE, Levin D. The diffusing capacity as a predictor of arterial oxygen desaturation during exercise in patients with chronic obstructive pulmonary disease. N Engl J Med. 1984;310(19):1218-1221. [CrossRef] [PubMed]
 
Jehn M, Schindler C, Meyer A, et al. Associations of daily walking activity with biomarkers related to cardiac distress in patients with chronic obstructive pulmonary disease. Respiration. 2013;85(3):195-202. [CrossRef] [PubMed]
 
Sin DD, Man SF. Systemic inflammation and mortality in chronic obstructive pulmonary disease. Can J Physiol Pharmacol. 2007;85(1):141-147. [CrossRef] [PubMed]
 
Matsui H, Shimosawa T, Itakura K, Guanqun X, Ando K, Fujita T. Adrenomedullin can protect against pulmonary vascular remodeling induced by hypoxia. Circulation. 2004;109(18):2246-2251. [CrossRef] [PubMed]
 
Qi JG, Ding YG, Tang CS, Du JB. Chronic administration of adrenomedullin attenuates hypoxic pulmonary vascular structural remodeling and inhibits proadrenomedullin N-terminal 20-peptide production in rats. Peptides. 2007;28(4):910-919. [CrossRef] [PubMed]
 
Chatterjee AB, Rissmiller RW, Meade K, et al. Reproducibility of the 6-minute walk test for ambulatory oxygen prescription. Respiration. 2010;79(2):121-127. [CrossRef] [PubMed]
 
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NOTE:
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    Print ISSN: 0012-3692
    Online ISSN: 1931-3543