mortality. 4,5 The primary cardiovascular complication of COPD is the development of pulmonary hyperten-sion following structural changes in the pulmonary vasculature, which are known to occur because of persistent pulmonary vasoconstriction in response to chronic hypoxia. 6
Background: Recently, the use of systemic biomarkers to monitor and assess the clinical evolution of respiratory disease has gained interest. We investigated whether midregional proatrial natri-uretic peptide (MR-proANP) predicts survival in patients with COPD when they are admitted to the hospital for exacerbation. Methods: One hundred sixty-seven patients (mean age 70 years old, 75 men) admitted to the hos-pital for exacerbation were followed up for 2 years. MR-proANP was measured on admission, after 14 days, and at 6 months. The predictive value of clinical, functional, and laboratory param-eters on admission were assessed by Cox regression analyses. The time to death was analyzed by Kaplan-Meier survival curves. Results: MR-proANP level was signifi cantly higher on admission for exacerbation, compared with recovery and stable state ( P 5 .004 for the comparison among all time points). MR-proANP cor-related with the Charlson condition and age-related score ( P , .0001), left ventricular ejection fraction ( P , .0001), C-reactive protein ( P 5 .037), and FEV 1 % predicted ( P 5 .004). MR-proANP levels were similar in patients requiring ICU treatment and in those treated in the medical ward ( P 5 .086). Thirty-seven patients (22%) died within 2 years. MR-proANP levels were higher in nonsurvivors compared with survivors (median [interquartile range] 185 pmol/L [110-286] vs 92 pmol/L [56-158], P , .001). Mortality was higher across MR-proANP quartiles (log rank P , .0001). Charlson condition and age-related score ( P 5 .001), Pa CO 2 ( P , .0001), and MR-proANP ( P 5 .001) predicted mortality in the univariate Cox-regression model. Both MR-proANP and Pa CO 2 were independent predictors of mortality in the multivariate Cox regression model. Conclusions: MR-proANP at exacerbation is associated with 2-year long-term survival in patients with exacerbation of COPD. CHEST 2011; 140(1):91–99
Midregional Proatrial Natriuretic Peptide Predicts Survival in Exacerbations of COPD Maurizio Bernasconi, MD ; Michael Tamm , MD, FCCP ; Roland Bingisser , MD, FCCP ; David Miedinger, MD ; Jörg Leuppi, MD ; Beat Müller, MD ; Mirjam Christ-Crain, MD ; and Daiana Stolz, MD , MPH
COPD is currently the fourth-leading cause of death worldwide and further increases in its prev-
alence and associated mortality are predicted for the coming decades. 1-4 COPD is an increasing health eco-nomic problem, and exacerbations of COPD are the main cause of disease-related costs, morbidity, and
Manuscript received June 8, 2010; revision accepted October 27, 2010. Affi liations: From the Clinic for Pulmonary Medicine and Respi-ratory Cell Research (Drs Bernasconi, Tamm, Miedinger, and Stolz), the Division of Endocrinology, Diabetes and Clinical Nutrition (Dr Christ-Crain), the Department for Emergency Medicine (Dr Bingisser), and the Clinic for Internal Medicine (Dr Leuppi), University Hospital Basel, Basel; and the Clinic for Internal Medi-cine (Dr Müller), Hospital Aarau, Aarau, Switzerland. Funding/Support: Dr Stolz was supported by grants from the Swiss National Foundation [PP00P3_128412/1]. Dr Christ-Crain was supported by grants from the Swiss National Foundation
Obstructive Lung Disease (ProCOLD) study. 24 Data were ana-lyzed from 167 patients admitted to the ED of the University Hospital Basel, Switzerland, for exacerbation of COPD from November 2003 to March 2005. A complete description has been reported elsewhere. 24 In brief, the primary end point of this study was to evaluate the prescription and duration of antibiotic use in patients randomly assigned procalcitonin as compared with usual care. The analysis of prognostic predictors in the study population was a predefi ned secondary end point of the protocol.
To be eligible for the study, admitted patients must have received a diagnosis of COPD exacerbation on the basis of clinical history, physical examination, and chest radiograph and had to meet the postbronchodilator spirometric criteria for COPD according to the GOLD (Global Initiative for Chronic Obstruc-tive Lung Disease) guidelines within 48 h after inclusion. 4 Spirom-etry was performed by trained lung function technicians according to American Thoracic Society guidelines within 48 h of inclu-sion. Immunocompromised patients and those with cystic fi bro-sis, active pulmonary TB, or infi ltrates on chest radiographs on presentation were excluded from the evaluation. Spontaneously expectorated sputum samples were obtained and examined using standard techniques. 14 Anthonisen criteria and exacerbation type were recorded for all the included patients. 25 After full recovery, all patients were reevaluated during outpatient visits 14 to 18 days (recovery) and 6 months (stable state) after initial hospital admission. The follow-up assessment included medical history, physical examination, blood tests, and chest radiograph. In addi-tion to the described evaluation, the study cohort included in the present analyses was followed up for another 18 months (ie, for a total of 2 years). Historical echocardiography results obtained during the 6 months prior to hospital admission were acquired from hospital medical records. Relevant pulmonary arterial hyper-tension was defi ned as an estimated systolic pulmonary arterial pressure above 35 mm Hg as measured by echocardiography. 26
The study was carried out according to the principles of the Declaration of Helsinki and was approved by our local ethics committee (Ethics Commission Beider Basel 232/03). Written informed consent was obtained from all participating patients.
Outcome
The recovery phase was defi ned as the time point following exacerbation (14-18 days), in which patients were evaluated based on clinical, laboratory, and lung functional criteria. Stable state was defi ned as the time point of a follow-up visit without any reported worsening of the patient’s condition beyond normal day-to-day variations and with no need for change in regular medication in the preceding 4 weeks, which comprised a clinical, laboratory, and lung function assessment. Exacerbation of COPD was defi ned as “a sustained worsening of the patient’s condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medica-tion in a patient with underlying COPD.” 27 All patients were followed up for a mean ( ! SD) duration of 28.4 ! 5.0 months. Exac-erbation recurrence was defi ned as a new exacerbation occurring after full recovery (14-18 days) from the initial exacerbation and presenting within 2 years of inclusion in the study. Patients who survived until follow-up were categorized as survivors, whereas patients who died within the follow-up period were categorized as nonsurvivors. The cause of death was adjudicated based on the review of medical records (University Hospital Basel, neigh-borhood insti tutions, nursing homes, daycare centers, emergency medical services, and family physicians) and on personal inter-views with attending physicians and/or family physicians. Medical record review was performed by two independent, board-certifi ed pulmonary specialists. Vital status was additionally confi rmed by family physicians and/or health insurance companies.
Age, comorbidities, FEV 1 , loss of fat-free mass, long-term use of oral corticosteroids, respiratory fail-ure, and recurrent need of hospitalization for exacer-bation have been identifi ed as risk factors associated with higher mortality in COPD. 7-10 Recently, interest has been expressed about the use of systemic bio-markers of infl ammatory response and cardiac stress in the risk stratifi cation of patients with exacerbation of COPD. Interest has also been expressed in their role in monitoring and assessing the clinical evolution of the disease. 11-14
Atrial natriuretic peptide (ANP) is a peripheral and pulmonary artery vasodilator, a natriuretic and diuretic hormone, which is released from myocardial cells in the atria, and in some cases in the ventricles, in response to volume expansion and increased cardiac wall stress. 15-19 ANP circulates primarily as a 28-amino-acid polypeptide, consisting of amino acids 99 to 126 from the C-terminal end of its prohormone, pro-ANP. ANP blocks the pulmonary vasopressor response to acute hypoxia via stimulation of cyclic guanosine mono-phosphate accumulation in the pulmonary vascula-ture in rats, 20 reduces pulmonary vascular resistance, and attenuates hypoxia-induced pul monary hyperten-sion. 21 Severe acute hypoxia induced by hypoxic exercise leads to increased ANP levels in healthy subjects. 22 In a mouse model, ANP was shown to play an important antifi brogenic role in the pulmonary vascular adaptation to chronic hypoxia. 21
The high concentration of ANP in the right atrium led to considering its effect on pulmonary circulation and its role in COPD. 11 ANP is expected to correlate with atrial pressure challenges in exacerbation and might, therefore, be a superior prognostic biomarker to brain natriuretic peptide (BNP) in the COPD pop-ulation. 23 The midregional proatrial natriuretic pep-tide (MR-proANP) has a much longer half-life than mature ANP and has, therefore, been suggested as a more reliable analyte for measurement. In this study, we aimed to assess whether circulating serum levels of MR-proANP predict mortality independent of comor-bidities in a well-characterized cohort of patients with COPD admitted to the hospital for exacerbation. The primary end point of this study was all-cause mortality during the 2-year follow-up. Secondary end points were the need for intensive care during the initial hospitalization and the recurrence of exacerbation of COPD requiring hospitalization within 2 years.
Materials and Methods
Setting and Study Population
This prospective cohort study assessed short- and long-term mortality in patients with exacerbations of COPD recruited in the Procalcitonin Guidance of Antibiotic Therapy in Chronic
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carcinoma in fi ve, prostate carcinoma in two, and urogenital carcinoma, peritoneal carcinomatosis, and carcinoma of unknown primary site in one each). In five cases, death was definitively attributed to a cause other than COPD-related respiratory failure
Measurement of MR-proANP
Using a sandwich immunoassay, MR-proANP (epitopes cover-ing amino acids 53-90 of the prohormone N-terminal portion of proANP) was detected in EDTA plasma from all patients on the day of admission to the hospital (exacerbation), at 14 to 18 days (recovery), and at 6 months (stable state) after admission 28 (BRAHMS AG; Hennigsdorf Berlin, Germany). The lower detection limit of the assay was 4.3 pmol/L, and its functional sensitivity of the assay (ie, an interassay coeffi cient of variation , 20%) was 11 pmol/L. The 97.5th percentile in 325 healthy individuals was 163.9 pmol/L, with no difference between women and men. 28
Statistical Analysis
Discrete variables are expressed as counts (percentages) and continuous variables as means ! SD or median (interquartile range). Comparability of groups was analyzed by x 2 test, two-sampled t test, Mann-Whitney U test, Kruskal-Wallis analysis of variance, Wilcoxon matched-pair test, or Friedman test, as appropriate. Cox regression univariate and multivariate analyses were performed to assess the infl uence of Charlson condition and age-related score, BMI, leukocyte counts, C-reactive protein, FEV 1 % predicted, Pa o 2 , Pa co 2 , pulmonary hypertension, and MR-proANP levels on admission on 2 years survival. Correlation analyses were per-formed using Spearman rank. The time to death was analyzed by Kaplan-Meier survival curves and compared by the log-rank tests. Skewed data were logarithmic transformed for regression analy-ses. All tests were two tailed. Statistical analyses were performed using the SPSS/PC, version 17.0, software package (SPSS Inc; Chicago, Illinois). A statistical signifi cance level of , 0.05 was regarded as signifi cant ( P , .05).
Results
Baseline characteristics of the 167 patients, includ-ing classifi cation according to the GOLD stage at the recovery phase of the disease, are presented in Table 1 . Overall, 116 patients (69.5%) had relevant comor-bidities. Sputum cultures grew bacteria in 65 cases (38.9%). Echocardiography results were available for 123 patients (73.7%). A total of 38 patients (22.8%) demonstrated clinically relevant pulmonary arterial hypertension. In 12 cases (7.2%), echocardiogra-phy showed decreased left ventricular ejection frac-tion ( " 40%). Median length of hospital stay was 9 (1-15) days, and 16 patients (9.6%) required inten-sive care. Seventy-three patients (43.7%) required rehospitalization because of exacerbation within 2 years of follow-up. Among patients with recurrence of exacerbation, median time to readmission was 174 (42-395) days.
In-hospital mortality was 3.0% (fi ve patients). There were another 32 deaths during the follow-up period. Hence, a total of 37 patients (22.2%) died within 2 years of the initial hospitalization. The main causes of mortality were respiratory conditions (COPD-related respiratory failure including pneumonia) in 19 patients and cardiovascular disorders in 12 patients. For one patient, the cause of death is unknown. Of the 37 patients who died during the 2-year follow-up, 10 (27%) had concomitant malignancy (bronchial
Table 1— Baseline Characteristics of 167 Patients Requiring Hospitalization for Exacerbation of COPD
Characteristics Values (N 5 167)
Male gender 75 (44.9)Age, y, mean (range) 70 (42-91)BMI 24.6 ! 4.8Smoking, pack-years 45 (30-60)Mean duration of COPD, mo 127 ! 86Hospitalization for COPD in previous year 0.98 ! 1.3Duration of exacerbation, d 4 (3-7)Cough 142 (85)Increased sputum production 113 (67.7)Discolored sputum 95 (56.9)Dyspnea 155 (92.8)Fever 68 (40.7)Comorbidities, % Cardiopathy 76 (45.5) Arterial hypertension 42 (25.1) Malignancy 24 (14.4) Diabetes mellitus 19 (11.4) Renal failure 15 (9.0)Respiratory medication, % b 2 -Agonists 142 (85) Anticholinergics 86 (52) Inhaled steroids 120 (72) Oral steroids 55 (33) Theophylline 16 (10) Antibiotics 37 (22)Long-term home oxygen therapy 23 (14)Type of exacerbation, Anthonisen criteria, % 1. Dyspnea, sputum purulence, sputum volume 80 (47.9) 2. Two of the above 36 (21.6) 3. One of the above and one minor fi nding a 51 (30.5)Severity of COPD, GOLD Stage, % I, FEV 1 % . 80% predicted 14 (8.4) II, 50% predicted . FEV 1 % , 80% predicted 37 (22.2) III, 30% predicted . FEV 1 % , 50% predicted 76 (45.5) IV, FEV 1 % , 30% predicted 40 (24.0)Charlson weighted index of comorbidities 2 (1-4)Charlson condition and age-related score b 5 (4-7)Estimated 10-y survival, % 21 (0-53)FEV 1 , L 0.89 ! 0.40FEV 1 % predicted 39.9 ! 16.9Pa o 2 , mm Hg 62.9 ! 15.7Pa co 2 , mm Hg 43.8 ! 11.0Leukocyte counts, 3 10 9 /L 11.27 ! 4.7C-reactive protein, mg/L 26.5 (7.4-60.1)Ejection fraction, c % 53.1 ! 17.5Pulmonary arterial pressure, c mm Hg 19.1 ! 18
Data are presented as No. (%), mean ! SD, or median (interquartile range), unless indicated otherwise. GOLD 5 Global Initiative for Chronic Obstructive Lung Disease. a Lung function values represent postbronchodilator spirometric results obtained during the recovery phase; all other characteristics were assessed on admission. b Charlson condition and age-related score 5 Charlson comorbidity score. c Echocardiography results available for 123 patients.
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tion and those remaining recurrence free within 2 years of the initial exacerbation had similar median MR-proANP values on admission (102 pmol/L [52.3-147] vs 101 pmol/L [55.3-197], P 5 .603).
MR-proANP Plasma Levels on Admission and Probability of 2-Year Survival
MR-proANP levels on hospital admission for exac-erbation were signifi cantly higher in long-term non-survivors compared with long-term survivors (median [interquartile range] 185 pmol/L [110-286] vs 92 pmol/L [56-158], P , .001) ( Fig 2 ). This difference was also signifi cant for patients who died within 6 months of exacerbation (189.5 pmol/L [125.8-169.8] vs 101 pmol/L [52.4-172], P 5 .001). The probability of survival across MR-proANP quartiles on admission was estimated with the Kaplan-Meier method. Mortality differed signifi cantly across MR-proANP quartiles (log rank P , .0001) ( Fig 3 ). Using a univariate Cox regres-sion model, we evaluated the prognostic value of MR-proANP and clinical and laboratory parameters on hospital admission to predict 2-year survival fol-lowing hospitalization for exacerbation ( Table 3 ). Charlson condition and age-related score, Pa co 2 , and MR-proANP levels on admission were associ-ated with 2-year survival, whereas no association was found for BMI, Pa o 2 , leukocyte counts, C-reactive protein, FEV 1 % predicted, and presence of pulmo-nary hypertension. In the multivariate Cox regres-sion model analysis, both MR-proANP and Pa co 2 remained independent predictors of 2-year survival ( Table 4 ).
Discussion
In this study, we report three major fi ndings: First, MR-proANP plasma levels are elevated in patients hospitalized for exacerbation of COPD compared with during the recovery and the stable phase of the disease. Second, MR-proANP levels at exacerbation are increased in long-term nonsurvivors compared with survivors, and the probability of survival mark-edly differs across MR-proANP quartiles. Third, MR-proANP and Pa co 2 are independent predictors of 2-year survival in patients with COPD.
Several clinical and laboratory parameters have been proposed as prognostic markers of morbidity and mortality at exacerbation but their predictive value has varied across studies. A growing number of reports have shown that ANP levels are elevated in patients hospitalized with infl ammatory and infec-tious conditions 29-32 and lower respiratory tract infec-tions. 16,29,33-35 To the best of our knowledge, the current study is the fi rst to report on the prognostic value of MR-proANP in the exacerbation of COPD.
or cardiovascular disease (bronchial carcinoma in one, colon diverticulitis in two, ischemic colitis in one, and Staphylococcus aureus endocarditis in one).
MR-proANP Plasma Levels at Exacerbation, Recovery, and Stable Phase and Correlation to Patient’s Characteristics
MR-proANP plasma levels at exacerbation, recov-ery, and stable phase were 95.9 pmol/L (52.5-166.3), 80.0 pmol/L (53.7-130.5), and 81.5 pmol/L (58.5-116.8), respectively ( Fig 1 ). Compared with the recovery and stable phase, MR-proANP was signifi cantly elevated on admission ( P 5 .004 for the comparison among all time points). MR-proANP levels in the recovery phase and in the stable phase were similar ( P 5 .539). Spearman correlation coeffi cients for patients’ characteristics and MR-proANP levels on hospital admission are shown in Table 2 . MR-proANP on admission correlated signifi -cantly with Charlson comorbidity score, C-reactive pro-tein, FEV 1 % predicted, and left ventricular ejection fraction. Moreover, the presence of cardiopathy and renal failure was signifi cantly associated with higher MR-proANP values at admission ( P , .0001 for both).
MR-proANP Plasma Levels and the Need for ICU on Admission and Recurrence of Exacerbation Requiring Hospital Admission Within 2 Years
Median MR-proANP values in patients requiring intensive care did not differ signifi cantly from those in patients treated in the medical ward (146.5 pmol/L [88-296.5] vs 101 pmol/L [59.4-180 pmol/L], P 5 .086). Patients presenting a recurrence of severe exacerba-
Figure 1. Log MR-proANP at exacerbation, recovery, and stable state of the disease. At exacerbation, MR-proANP plasma levels were signifi cantly elevated (95.9 pmol/L [52.5-166.3]) compared with the recovery (80.0 pmol/L [53.7-130.5]) and stable phase (81.5 pmol/L [58.5-116.8], P 5 .004 for the comparison among all time points). Levels in the recovery phase and in the stable phase were similar ( P 5 .539). ! 5 outliners, *␣ 5 extreme values. MR-proANP 5 midregional proatrial natriuretic peptide.
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vasorelaxant activity. 39 IV ANP application has led to acute, partial reversibility of increased pulmonary vas-cular resistance and a reduction in pulmonary arterial pressures in patients with COPD. 15 Thus, we postu-late that ANP secretion could be stimulated by IL-6 release from the human pulmonary artery smooth muscle cells to counteract the pulmonary artery vaso-constriction related to the exacerbation of COPD.
Distension of the right atrium, a typical feature of pulmonary hypertension, is aggravated by hypoxia and leads to an increase in plasma ANP levels. 22 In contrast, in patients with chronic lung disease but normal pulmonary hemodynamics, plasma ANP con-centrations remain low despite chronic hypoxia. 22 This suggests that hypoxia itself does not infl uence ANP release. Accordingly, we did not fi nd a signifi cant cor-relation between MR-proANP and Pa o 2 in exacerba-tion of COPD. It is worth noting that hypoxia induced by exercise leads to increased ANP levels in healthy subjects, suggesting different links among hypoxia, pulmonary artery vasoconstriction, and an increase in ANP between healthy subjects and patients with COPD. 22 Interestingly, hypoxemia did not remain an independent predictor of hospitalization in the Cox proportional-hazards model in a study assessing pre-dictors of hospitalization for exacerbation in patients with COPD. 40
According to recent data from the Towards a Revolution in COPD Health (TORCH) study, which investigated cause-specifi c mortality in a large cohort of patients with COPD, 30% of deaths were attrib-utable to cardiac causes and 40% of deaths were related to COPD. 41 Similarly, in our study, 84% of the patients who died during the follow-up of 2 years died from a respiratory (51%) or cardiovascular dis-order (32%). These data underline the signifi cance of cardiovascular disease in patients with COPD and suggest well-recognized prognostic biomarkers of heart disease (eg, BNP) as potential prognostic bio-markers in a COPD population. We demonstrated that BNP plasma levels were signifi cantly elevated during exacerbation compared with recovery, and accurately predicted the need for ICU care, but failed to predict short- and long-term mortality in patients with exacerbation of COPD. 42 Although BNP summarizes the extent of left ventricular systolic and diastolic impairment, ANP seems to be more spe-cifi c for assessing right-sided heart, and particularly atrial, dysfunction. The results of our study sug-gest that MR-proANP plasma levels correlate better with the pulmonary vascular changes that charac-terize COPD. Interestingly, and in contrast to BNP, MR-proANP values in patients requiring ICU care for exacerbation were similar to those in patients treated in the medical ward. It is possible to hypothesize that patients with manifested left-sided heart failure in
The stimuli leading to increased MR-proANP levels in exacerbation of COPD might be manifold. IL-6 is suggested as representing an important link between ANP release and COPD-related conditions, such as infection and aggravation of pulmonary hyper-tension. 35 In bacterial infection, IL-6 correlated strongly with plasma ANP, and IL-6 infusion increased ANP gene expression in cardiac myocytes. 32,36,37 Patients with pulmonary hypertension related to COPD have increased plasma IL-6 values. 38 In this context, exper-imental data demonstrated that ANP has pulmonary
Table 2— Spearman’s r Correlation Between Clinical and Laboratory Markers and Plasma MR-proANP on
Hospital Admission
Parameter r Coeffi cient P Value
Charlson condition and age-related score
0.641 , .0001
Pack-years 2 0.061 .435Duration of COPD, mo 0.084 .283Body temperature, °C 0.055 .478Heart rate, beats/min 0.001 .987Respiratory rate, breaths/min 0.07 .368Pa o 2 , mm Hg 0.091 .306Pa co 2 , mm Hg 0.12 .177Leukocytes, 3 10 9 0.087 .267C-reactive protein, 3 10 9 /L 0.162 .037FEV 1 , % predicted 0.248 .004LVEF, % 2 0.313 , .0001Pulmonary artery pressure, mm Hg 0.125 .168
Figure 2. MR-proANP values at exacerbation of COPD in 2-year survivors and nonsurvivors. MR-proANP levels at exacerbation were signifi cantly higher in long-term nonsurvivors compared with long-term survivors (median [interquartile range] 185 pmol/L [110-286] vs 92 pmol/L [56-158], P , .001). See Figure 1 legend for expansion of abbreviation.
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In the multivariate Cox regression analysis, Pa co 2 and MR-proANP were independent predictors of 2-year mortality in patients with exacerbation of COPD. Short- and long-term respiratory failure with rise of Pa co 2 was shown previously to be an important prognostic factor following severe exacerbation of COPD. 8,40,43,44 Kessler et al 40 reported Pa co 2 and pul-monary arterial pressure to be independent predictors of short-term hospitalization in a cohort of 64 patients with moderate to severe COPD at exacerbation. Of note, even moderate hypercapnia appeared to be asso-ciated with a higher reexacerbation risk. In line with these fi ndings, short- and long-term mortality was sig-nifi cantly higher in patients with Pa co 2 . 50 mm Hg ( P 5 .025 and P , .0001, respectively) in the present cohort, in which hypercapnia was moderate in most patients (range, 28-96 mm Hg). Moderate hypercap-nia at exacerbation, suggestive of ventilation-perfusion mismatch with or without alveolar hypoventilation, might identify patients who easily downplay their respiratory conditions and therefore develop acute respiratory failure. 40 Unfortunately, we cannot infer whether the prognosis differs between patients who remain hypercapnic after resolution of the short-term episode and those with reversible hypercapnic respira-tory failure, because blood gas analyses were obtained at exacerbation only. 45 In contrast to previous studies evaluating patients with severe COPD, our study did
addition to COPD have been admitted to the ICU more often; however, this discrepancy should be ana-lyzed in further studies.
Figure 3. Kaplan-Meier probability of survival over 720 days after admission across MR-proANP quartiles. ProANP 5 proatrial natriuretic peptide. See Figure 1 legend for expansion of the other abbreviation.
Table 3— Univariate Cox Regression Analysis for the Association Between Clinical and Laboratory
Parameters on Hospital Admission and 2-y Mortality in Patients Hospitalized for Exacerbation of COPD
Characteristics Hazard Ratio 95% CI P Value
Charlson condition and age-related score
1.289 1.175-1.414 .001
Male gender 0.824 0.428-1.519 .564BMI 0.998 0.932-1.068 .944Pack-years 1.006 0.995-1.117 .277Exacerbation in previous
year, No.1.155 0.988-1.351 .071
History of cardiopathy 1.605 0.837-3.076 .154Antibiotics use current
exacerbation1.806 0.892-3.656 .100
Anthonisen criteria 1.089 0.754-1.074 .649Leukocytes, 3 10 9 0.96 0.885-1.043 .336C-reactive protein 3 10 9 /L 0.998 0.001-1.005 .547FEV 1 % predicted 0.985 0.966-1.005 .141LVEF , 40% 0.261 0.036-1.917 .187PAP . 35 mm Hg 0.907 0.371-2.219 .831Log Pa o 2 , mm Hg 0.276 0.049-1.564 .146Log Pa co 2 , mm Hg 22.591 5.296-96.360 , .0001 Log MR-proANP, pmol/L 2.385 1.642-3.464 .001
PAP 5 pulmonary arterial pressure. See Tables 1 and 2 for expansion of other abbreviations.
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Dr Bingisser: contributed to patient recruitment and drafting the manuscript for important intellectual content. Dr Miedinger: contributed to patient recruitment and drafting the manuscript for important intellectual content. Dr Leuppi: contributed to patient recruitment and drafting the manuscript for important intellectual content. Dr Müller: contributed to data collection and drafting the manu-script for important intellectual content. Dr Christ-Crain: contributed to data collection drafting the manu-script for important intellectual content. Dr Stolz: contributed to the study concept, study design, data analysis, and drafting the manuscript for important intellectual content. Financial/nonfi nancial disclosures: The authors have reported to CHEST that no potential confl icts of interest exist with any companies/organizations whose products or services may be dis-cussed in this article. Role of sponsors: The sponsors of this investigator-initiated project had no involvement in design and conduct of the study, collection, management, analysis, and interpretation of the data, nor in the preparation, review, and approval of the manuscript or decision to submit the manuscript.
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not demonstrate that pulmonary hypertension is associated with mortality following severe exacerba-tion. 40,46,47 However, in the current study, pulmonary arterial pressures were assessed solely by echocar-diography, whereas in the series by Kessler et al, 40 all patients underwent right-sided heart catheteriza-tion both at rest and during a steady-state exercise at exacerbation. It may be hypothesized that an invasive evaluation could have produced similar results in the present cohort.
Some limitations should be considered in inter-preting our results. First, this is an observational study and, therefore, hypothesis generating. The data were collected in a single center and only in patients who were hospitalized consecutively. The demographics of our COPD cohort are comparable to those of previ-ously published studies analyzing patients with severe exacerbation of COPD. 8,43,48 The mortality rate reported in this study fi ts well in the lower range of the one described previously. 49-51 However, the results might not be applicable to patients with exacerbation treated as outpatients. The representative study population and the long observational period lasting until 2 years after the initial hospitalization are advantages of our study.
Conclusions
In conclusion, our results support the long-term prognostic value of MR-proANP plasma level on hospital admission in patients with exacerbation of COPD. Studies are needed to evaluate whether an MR-proANP guided-approach is able to infl uence survival in the COPD population.
Acknowledgments Author contributions: All authors reviewed and approved the fi nal manuscript. Dr Bernasconi: contributed to data analysis and writing of the manuscript. Dr Tamm: contributed to the study concept, study design, data analysis, and drafting the manuscript for important intellectual content.
Table 4— Multivariate Cox Regression Analysis for the Association Between Clinical and Laboratory
Parameters on Hospital Admission and 2-y Mortality in Patients Hospitalized for Exacerbation of COPD
Characteristics Hazard Ratio 95% CI P Value
Charlson condition and age-related score
1.122 0.994-1.266 .063
Log Pa co 2 11.537 2.434-54.694 .002Log MR-proANP 1.681 1.037-2.726 .035
See Table 2 for expansion of abbreviations.
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