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Original Research: COPD |

Copeptin, C-Reactive Protein, and Procalcitonin as Prognostic Biomarkers in Acute Exacerbation of COPD* FREE TO VIEW

Daiana Stolz, MD; Mirjam Christ-Crain, MD; Nils G. Morgenthaler, MD; Jörg Leuppi, MD; David Miedinger, MD; Roland Bingisser, MD; Christian Müller, MD; Joachim Struck, MD; Beat Müller, MD; Michael Tamm, MD
Author and Funding Information

*From the Clinic of Pneumology and Pulmonary Cell Research (Drs. Stolz, Leuppi, Miedinger, and Tamm), Clinic of Endocrinology, Diabetes and Clinical Nutrition (Drs. Christ-Crain and B. Müller), and Department of Internal Medicine (Drs. Bingisser and C. Müller), University Hospital Basel, Basel, Switzerland; and Research Department (Drs. Morgenthaler and Struck), BRAHMS AG, Biotechnology Centre, Hennigsdorf, Germany.

Correspondence to: Daiana Stolz, MD, Clinic of Pneumology and Pulmonary Cell Research, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland; e-mail: dstolz@uhbs.ch



Chest. 2007;131(4):1058-1067. doi:10.1378/chest.06-2336
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Background: A novel approach to estimate the severity of COPD exacerbation and predict its outcome is the use of biomarkers. We assessed circulating levels of copeptin, the precursor of vasopressin, C-reactive protein (CRP), and procalcitonin as potential prognostic parameters for in-hospital and long-term outcomes in patients with acute exacerbation of COPD (AECOPD) requiring hospitalization.

Methods: Data of 167 patients (mean age, 70 years; mean FEV1, 39.9 ± 16.9 of predicted [± SD]) presenting to the emergency department due to AECOPD were analyzed. Patients were evaluated based on clinical, laboratory, and lung function parameters on hospital admission, at 14 days, and at 6 months.

Results: Plasma levels of all three biomarkers were elevated during the acute exacerbation (p < 0.001), but levels at 14 days and 6 months were similar (p = not significant). CRP was significantly higher in patients presenting with Anthonisen type I exacerbation (p = 0.003). In contrast to CRP and procalcitonin, copeptin on hospital admission was associated with a prolonged hospital stay (p = 0.002) and long-term clinical failure (p < 0.0001). Only copeptin was predictive for long-term clinical failure independent of age, comorbidity, hypoxemia, and lung functional impairment in multivariate analysis (p = 0.005). The combination of copeptin and previous hospitalization for COPD increased the risk of poor outcome (p < 0.0001). Long-term clinical failure was observed in 11% of cases with copeptin < 40 pmol/L and no history of hospitalization, as compared to 73% of patients with copeptin ≥ 40 pmol/L and a history of hospitalization (p < 0.0001).

Conclusions: We suggest copeptin as a prognostic marker for short-term and long-term prognoses in patients with AECOPD requiring hospitalization.

Figures in this Article

Several clinical characteristics have been extensively validated as prognostic factors for mortality in acute exacerbations of COPD (AECOPD).19 Although of epidemiologic interest, the predictive value of clinical parameters vary in the different studies,2,7,9and the majority of them do not allow precise individual risk assessment. Therefore, there has been increasing interest in using pulmonary biomarkers to monitor disease severity in patients with AECOPD.10 However, there is little information about how current biomarkers relate to significant clinical outcomes such as length of hospital stay, need for ICU treatment, and mortality.1014

Arginine vasopressin, also termed antidiuretic hormone, is a nonapeptide produced by the hypothalamus.15Hypotensive, hypoxic, hyperosmolar, or acidotic stimuli, together with infectious conditions, are known to increase circulating vasopressin concentrations.1620 Vasopressin has gained additional interest as a prognostic biomarker and vasopressor agent in septic shock.17,2122 However, its instability makes reliable measurements difficult to achieve and precludes routine use.2324 Copeptin is the more stable C-terminal part of the vasopressin precursor and a 39-amino-acid–long glycosylated peptide. Copeptin remains stable ex vivo for several days at room temperature in serum or plasma and, thus, directly reflects levels of vasopressin.25 Hence, copeptin might be of interest as a biomarker in AECOPD.

C-reactive protein (CRP) is an acute-phase reactant with well-documented sensitivity that is commonly used to diagnose infectious and inflammatory conditions, including exacerbations of COPD.2628 Procalcitonin, a hormokine ubiquitously released during bacterial infection, has been shown to allow antibiotic guidance in AECOPD.29In addition, persistently elevated procalcitonin levels have been shown to have prognostic implications in severe bacterial infections.3032

The aim of our study was threefold: first, to investigated the correlation of copeptin, CRP, and procalcitonin with clinical characteristics thought to define condition severity in patients with AECOPD requiring hospitalization. Second, we analyzed the usefulness of the biomarkers to assess in-hospital prognosis in this population. And finally, we examined whether copeptin, CRP, or procalcitonin were able to predict clinical failure within 6 months after exacerbation.

Setting and Study Population

Data from 167 patients admitted for AECOPD to the emergency department of the University Hospital Basel, Switzerland from November 2003 to March 2005 and included in a randomized study was analyzed. A complete description has been reported elsewhere.29 In brief, the primary end point of the study was to evaluate the prescription and duration of antibiotic use in patients randomly assigned to procalcitonin guidance as compared to usual care. To be eligible for the study, patients had to be admitted on the basis of clinical history, physical examination, and chest radiography, and to meet postbronchodilator spirometric criteria for COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines33 within 48 h after inclusion. Patients were excluded from the study if they were severely immunocompromised, had asthma or cystic fibrosis, or if infiltrates on chest radiography were present at hospital admission.

Baseline assessment included clinical data and routine blood tests. Spontaneously expectorated sputum samples were obtained and examined using standard techniques.34

Spirometry was performed by trained lung function technicians according to American Thoracic Guidelines.35Respiratory symptoms were quantified using a questionnaire for patients with respiratory illnesses (range, 0 to 95, with higher scores indicating greater discomfort).36

This trial was approved by the Basel Ethics Committee and was registered as with the Current Controlled Trials Database.37 All participants gave written informed consent.

Outcome Measurements

The short-term and long-term follow-up visits performed 14 to 18 days and 6 months after hospital admission comprised clinical, laboratory, and lung function assessments. Medical records from hospital admission and family physicians were analyzed. Thereby, patients were classified as clinical success or clinical failure. Clinical failure was defined by the occurrence of an exacerbation of COPD requiring hospitalization or death of any cause up to 6 months after inclusion in the study.

Determination of Biomarkers Plasma Concentrations

Copeptin was measured using 50 μL of ethylenediamine tetra-acetic acid plasma by a new sandwich immunoluminometric assay employing two polyclonal antibodies to amino acids 132–164 of preprovasopressin (CT-proAVP LIA; BRAHMS AG; Hennigsdorf/Berlin, Germany).25 The lower detection limit of the assay is 1.7 pmol/L, and the functional assay sensitivity is 2.25 pmol/L.25 CRP was measured in ethylenediamine tetra-acetic acid plasma on a Hitachi Instrument 917 (Roche Diagnostics; Rotkreuz, Switzerland). Procalcitonin was measured using 20 to 50 μL of plasma or serum by a time-resolved amplified cryptate emission technology assay (PCT Kryptor; BRAHMS).36 The assay has a functional assay sensitivity of 0.06 μg/L, threefold to tenfold above normal mean values.

Statistical Analysis

Discrete variables are expressed as counts (percentages) and continuous variables as mean ± SD or median (interquartile range [IQR]). Comparability of groups was analyzed by χ2 test, two-sampled t test, Mann-Whitney U test, Kruskal-Wallis analysis of variance, or Wilcoxon matched-pair test, as appropriate. To analyze the relationship among different variables and copeptin levels on hospital admission, a multiple linear regression model including age, cardiopathy, Pao2, leukocyte counts, CRP, procalcitonin, and FEV1 percentage of predicted was used. To analyze the relationship among different clinical parameters and duration of hospital stay, a multiple linear regression model including age, cardiopathy, arterial hypertension, renal failure, diabetes mellitus, Pao2, Paco2, and FEV1 percentage of predicted was used. To assess the influence of age, hospitalization due to AECOPD in the previous year, cardiopathy, Pao2, leukocyte counts, CRP, procalcitonin, and FEV1 percentage of predicted and antimicrobial therapy during the index exacerbation on clinical failure, a Cox regression univariate and multivariate analysis were performed. Correlation analyses were performed using Spearman rank. The time to clinical failure was analyzed by Kaplan-Meier survival curves and compared by the log-rank test. All test were two tailed; p < 0.05 was defined as significant. Data were analyzed using statistical software (Statistical Package for Social Sciences, version 14 for Windows; SPSS; Chicago IL).

Study Population

Detailed baseline characteristics of the study population are presented in Table 1 . Eighty-seven percent of patients were receiving medical treatment for COPD on hospital admission, including inhaled β2-agonists (85%), anticholinergics (52%), inhaled steroids (72%), oral steroids (33%), theophylline (10%), and home oxygen (14%).

Cultures from sputum yielded pathogenic bacteria in 54 patients (32.2%). Gram-negative bacteria accounted for 69%, and Gram-positive organisms for 31% of all microorganisms recovered.

Antibiotic treatment was prescribed for 98 patients (58.7%). Steroids were administered to 147 patients (88%; mean dose, 296 ± 234 mg of prednisone equivalent).

The mean length of hospital stay was 12.1 ± 6.5 days. Sixteen patients (9.6%) required intensive care (3.6 ± 2.3 days). Five patients (3.0%) died within 14 days of hospital admission. Nine patients (5.4%) died between short-term and long-term follow-up at 6 months. Thus, overall mortality rate at 6 months was 8.4% (14 patients). Four patients died of COPD-related respiratory failure, and eight patients died of a medical condition other than COPD. In two cases, the cause of death remained unknown.

Twenty-seven patients (16.2%) required a total of 36 subsequent hospitalizations due to COPD. The mean time to AECOPD leading to hospitalization was 75.4 ± 53.5 days. Long-term clinical failure occurred in 40 patients (24%).

Copeptin, CRP, and Procalcitonin Levels and Patient Characteristics at the Acute Exacerbation

Circulating copeptin, CRP, and procalcitonin levels at the acute exacerbation, after 14 days, and after 6 months are shown in Figure 1 . All three biomarker levels were significantly elevated during the acute exacerbation (p < 0.001). Levels at 14 days and 6 months were similar (p = not significant).

Copeptin, CRP, and procalcitonin levels on hospital admission according to the Anthonisen classification and COPD severity are presented in Table 2 . CRP levels were significantly higher in patients presenting with a type I exacerbation according to Anthonisen and in patients with mild-to-moderate COPD according to the GOLD classification. Plasma levels of copeptin and procalcitonin were similar in all COPD stages (p = not significant).

Spearman correlation coefficients between patient characteristics on hospital admission thought to influence prognosis and copeptin, CRP, and procalcitonin levels are shown in Table 3 . Leukocyte counts correlated weakly with copeptin (p = 0.005), CRP (p = 0.011), and procalcitonin (p = 0.016). We found a negative association between the symptom score and procalcitonin levels on hospital admission (p = 0.012).

Copeptin levels on hospital admission were not affected by long-term oxygen therapy or long-term oral steroid use (p = 0.180 and p = 0.699, respectively). Levels in patients with and without history of AECOPD hospitalization in the previous year were similar (p = 0.057), and the number of hospitalizations due to AECOPD in the previous year did not significantly correlate with copeptin levels (p = 0.058). There was a significant association between copeptin levels on hospital admission and a history of cardiopathy and renal failure (p < 0.0001 and p < 0.0001, respectively); in contrast, patients with diabetes mellitus and systemic arterial hypertension did not show increased copeptin levels (p = 0.345 and p = 0.138). In our multivariate linear regression model, a positive history of cardiopathy (p = 0.001), CRP (p = 0.025), and procalcitonin levels (p < 0.001) were significant predictors of copeptin levels on admission (adjusted R2 = 0.312).

Copeptin, CRP, and Procalcitonin Levels and Short-term Outcome

Copeptin levels correlated significantly with length of hospital stay (r = 0.320, p < 0.001) and length of ICU stay (r = 0.272, p < 0.001). Additionally, patients requiring treatment in the ICU had significantly higher copeptin levels (35.95 pmol/L; IQR, 21.60 to 68.65 pmol/L) than those who were not admitted to the ICU (11.40 pmol/L; IQR, 5.27 to 22.20 pmol/L; p < 0.0001). A comparison of clinical outcomes in patients with copeptin levels < 40 pmol/L and ≥ 40 pmol/L on hospital admission is presented in Table 4 . In patients with copeptin on hospital admission < 40 pmol/L, mean length of hospital stay was 9 days as, compared to 14 days in patients presenting with levels ≥ 40 pmol/L (p = 0.003; Fig 2 ). Considering in-hospital mortality, circulating levels in nonsurvivors (42.00 pmol/L; IQR, 13.50 to 103.20 pmol/L; n = 5) tended to be higher than in survivors (12.60 pmol/L; IQR, 5.49 to 27.05 pmol/L; n = 162; p = 0.06).

CRP levels correlated neither with the length of hospital stay (p = 0.714) nor the length of ICU stay (p = 0.835). Levels in those requiring ICU care were similar to those treated on the ward (p = 0.931). A comparison of clinical outcomes in patients with CRP levels < 50 mg/L and ≥ 50 mg/L on ICU admission is shown in Table 5 . The length of hospital stay did not differ in these two groups of patients (p = 0.417). Levels in survivors and nonsurvivors were similar (p = 0.129).

Procalcitonin levels correlated significantly with the length of hospital stay (r = 0.216, p = 0.002) but not with the length of ICU stay (p = 0.916). Patients requiring ICU stay had significantly higher procalcitonin levels (0.233 ng/mL; IQR, 0.086 to 0.408 ng/mL) than those who did not require ICU admission (0.094 ng/mL; IQR, 0.064 to 0.164; p = 0.005). Clinical outcomes in patients with low procalcitonin levels (< 0.25 ng/mL) and high procalcitonin levels (≥ 0.25 ng/mL) are presented in Table 6 ). There was a trend for a shorter duration of hospitalization in patients with low procalcitonin levels compared to those with high procalcitonin levels (p = 0.056).

In a multivariate linear regression model of clinical and lung functional parameters, 11.8% of the variation in the length of hospital stay could be explained by a combination of age (p = 0.263), FEV1 percentage of predicted (p = 0.353), Pao2 (p = 0.263), Paco2 (p = 0.772), renal failure (p = 0.525), diabetes mellitus (p = 0.084), arterial hypertension (p = 0.723), and cardiopathy (p = 0.041). Thus, among clinical parameters, only cardiopathy was significantly associated with the duration of hospital stay.

Copeptin, CRP, and Procalcitonin Levels and Long-term Outcome

Kaplan-Meier survival curves showing patients with low and high circulating levels of copeptin, CRP, and procalcitonin on hospital admission are shown in Figure 3 . Patients with long-term clinical failure (n = 40) had significantly higher copeptin levels than those with long-term clinical success (n = 127) [23.55 pmol/L; IQR, 10.75 to 43.98 pmol/L; vs 9.62 pmol/L; IQR, 4.97 to 21.00 pmol/L, respectively; p < 0.0001]. Long-term clinical success was documented in 82% of patients with copeptin levels < 40 pmol/L, as compared to 44% of patients with copeptin levels ≥ 40 pmol/L (p < 0.0001). Compared to patients with copeptin levels < 40 pmol/L, the odds ratio for long-term clinical failure in patients presenting with copeptin levels ≥ 40 pmol/L at hospital admission was 3.111 (95% confidence interval, 1.006 to 5.078). Thereby, the absolute risk increase for clinical failure in these patients was 0.3777 (95% confidence interval, 0.179 to 0.575). Conversely, the differences in the time to clinical failure were not significant for patients with high CRP and procalcitonin values (p = 0.157 and p = 0.089, respectively; log-rank test).

Using a multivariate Cox-regression model analysis, we evaluated the prognostic value of copeptin, CRP, and procalcitonin and clinical parameters to predict long-term clinical failure. The copeptin level on hospital admission was the only factor significantly associated with long-term clinical failure (p = 0.005). There was no association for CRP (p = 0.086), procalcitonin (p = 0.171), age (p = 0.128), history of cardiopathy (p = 0.989), Po2 (p = 0.408), leukocyte counts (p = 0.873), FEV1 percentage of predicted (p = 0.358), or antibiotic therapy (p = 0.368). There was a trend for a positive association with a history of hospitalization due to AECOPD in the previous year (p = 0.050). The combination of copeptin levels on hospital admission and a history of AECOPD hospitalization in the previous year increased the risk of long-term clinical failure (p < 0.0001; Fig 4 ). Long-term clinical failure was observed in 11% of the patients with low copeptin levels on hospital admission (< 40 pmol/L) and no history of hospitalization in previous year, as compared to 73% of patients with high copeptin levels on hospital admission (≥ 40 pmol/L) and a history of hospitalization (p < 0.0001). A combination of two or three biomarkers (copeptin, CRP, and procalcitonin) did not improve the prognostic value of the model (p = not significant for all).

The frequency and severity of exacerbation are the most important factors determining overall prognosis in COPD.1,3839 Hence, accurate individual risk assessment at exacerbation is of pivotal importance for clinical management and rational allocation of medical resources in this large and ever-growing population. In comparison to CRP and procalcitonin, copeptin was superior to predict the course of exacerbation in our study population. We observed that elevated copeptin levels at hospital admission predicted in-hospital outcome and length of hospital stay in patients with AECOPD, irrespectively of the clinical presentation. Accordingly, elevated copeptin levels served as a risk factor for long-term clinical failure, including survival, independent of lung functional impairment, comorbidities, or hypoxemia in multivariate analysis. Incorporating the simple information about a history of hospitalization due to AECOPD within the previous year further enhanced the prognostic value of the marker. Procalcitonin in the emergency department may provide some information about the short-term outcome. However, it does not identify patients susceptible to long-term clinical failure as effectively as copeptin does. Finally, although CRP levels are particularly elevated in type I exacerbations according to Anthonisen et al,40 this marker did not prove valuable in predicting exacerbation outcome.

To the best of our knowledge, this is the first study analyzing copeptin plasma levels in exacerbations of COPD. As known for vasopressin, copeptin is significantly increased in bacterial infection and febrile conditions.4142 Critically ill patients as well as those exhibiting postoperative complications generate high circulating vasopressin levels.17,43Vasopressin has been shown to have vasoconstrictive effects, which may correlate to the hypoxia induced-vasoconstriction in severe COPD.4446 Experimental evidence suggests that this response may facilitate cardiovascular adjustments to insufficient tissue oxygenation.47 Increased concentrations of vasopressin may compensate for V1 receptor down-regulation following exposure to sustained hypoxemia.,45,48Conversely, vasopressin appears to exert a negative inotropic effect on the right ventricle in pulmonary hypertension, thereby impairing ventriculoarterial coupling.49Moreover, vasopressin is suggested to further augment the pulmonary vasoconstrictive response in endotoxemia.50 Both responses could potentially link elevated copeptin with a poor clinical outcome in COPD, albeit its pathophysiologic mechanism is not completely understood.

In this study, we did not find a direct correlation of copeptin with Pao2. This observation is in line with some data5152 but not all previous data.47,5354 We cannot rule out that more sophisticated methods, ie, mixed venous saturation or oxygen delivery index measurements, would have allowed us to detect insufficient oxygen tissue supply even if the Po2 was in the normal range.55 In our population, copeptin levels on hospital admission were higher in presence of cardiopathy and chronic renal failure. Neither of them, however, correlated independently to clinical failure. Thus, high copeptin levels seem to provide additional information regarding poor outcome, irrespective of comorbidities.

Although copeptin was the only covariate significantly associated with long-term clinical failure, there was a trend for a correlation with a history of hospitalization due to AECOPD in the previous year. The later finding is in accordance with earlier reports.3,9,56 The combination of high copeptin levels on hospital admission and a positive history of hospitalization further increased the risk of long-term clinical failure. Interestingly enough, copeptin levels did not correlate with a history of hospitalization due to exacerbation, supporting that copeptin is an independent marker for clinical failure following a particular exacerbation.

In agreement to previous studies,14,5758 CRP levels were significantly elevated at the exacerbation and decreased substantially thereafter, with comparable levels after 14 days and 6 months. Elevated CRP is known to be a predictor of adverse events in cardiovascular disease and to be associated with decline in lung function and worsening of chronic COPD.5960 However, a further novel finding of the current study is that CRP levels on hospital admission are not correlated to short-term or long-term outcome of the exacerbation. This could be explained by the fact that CRP levels rise rapidly during infection or after injury, to just decline after the initial stimulus has vanished. Due to its high sensitivity but low specificity, CRP fails to provide any further information about prognosis in the acute event. Nevertheless, CRP levels were significantly elevated in Anthonisen type I exacerbations as compared to type II and type III, and a cutoff of 50 mg/dL is suggested to be associated with bacterial infection requiring antibiotic therapy.6162

We are the first to report the prognostic value of procalcitonin in AECOPD. In analogy to other infectious conditions, such as sepsis, elevated procalcitonin levels were associated with a poorer in-hospital prognosis, including a longer hospital stay and need for ICU care. In contrast, long-term prognosis was not influenced by procalcitonin levels at presentation. It could be hypothesized that elevated procalcitonin reflects clinically relevant bacterial infection, perhaps invasive parenchymal disease, which was not yet evident in the conventional chest radiography.62 This might explain the early discrimination of severe and mild cases.

In contrast to previous reports, we did not find age,2,46 Pao2,,4,69 and Pco234,9 to be significantly associated with 6-month prognosis. It is possible that the influence of these factors would become noticeable if the follow-up up period of the study were longer. Another possible limitation of this study is that inferences about mortality are bounded due to the overall low death rate. However, they apply uniformly to all prognostic parameters, thereby not affecting relative comparisons within results.

In conclusion, our results suggest that copeptin has a better prognostic value than clinical parameters, CRP, and procalcitonin in AECOPD. Thus, if future studies happen to confirm these findings, copeptin levels might be used as a prognostic marker for poor short-term and long-term prognoses in AECOPD patients requiring hospitalization.

Abbreviations: AECOPD = acute exacerbations of COPD; CRP = C-reactive protein; GOLD = Global Initiative for Chronic Obstructive Lung Disease; IQR = interquartile range

Dr. B. Müller has served as consultant and received payments from BRAHMS (the manufacturer of procalcitonin and copeptin assays) to attend advisory board meetings and speaker engagements, or research. Dr. Morgenthaler and Dr. Struck are employees of BRAHMS. The other authors have no conflicts of interest to disclose.

Table Graphic Jump Location
Table 1. Baseline Characteristics of 167 Patients Presenting With AECOPD (n = 167)*
* 

Data are presented as No. (%), median (IQR), or mean ± SD.

 

Minor findings include fever (> 38°C) without other cause; increased wheezing; increased cough; or increased respiratory rate as compared with stable baseline condition.

 

Classification of severity of COPD based on lung function tests performed at 6 months (stable phase).

Figure Jump LinkFigure 1. Top, A: copeptin levels at hospital admission, at 14 days, and at 6 months. On hospital admission, copeptin levels were significantly elevated (12.45 pmol/L; IQR, 4.97 to 25.05 pmol/L) as compared to after 14 days (6.10 pmol/L; IQR, 4.02 to 14.20 pmol/L) and 6 months (6.38 pmol/L; IQR, 3.95 to 12.25 pmol/L). *p<0.001 comparing levels on hospital admission vs 14 days and 6 months. Levels at 14 days and 6 months were similar (p = 0.783). Center, B: CRP on admission, at 14 days, and at 6 months. On hospital admission, CRP levels were significantly elevated (26.5 mg/L; IQR, 7.4 to 60.1 mg/L) as compared to after 14 days (7.5 mg/L; IQR, 2 to 19.5) and 6 months (4 mg/L; IQR, 2 to 11 mg/L). *p<0.001 comparing levels at admission vs 14 days and 6 months. Levels at 14 days and 6 months were similar (p = 0.127). Bottom, C: procalcitonin levels at admission, at 14 days, and at 6 months. *On hospital admission, procalcitonin levels were significantly elevated (0.088 ng/mL; IQR, 0.053 to 0.161 ng/mL) as compared to after 14 days (0.020 ng/mL; IQR, 0.014 to 0.051 ng/mL) and 6 months (0.021 ng/mL; IQR, 0.010 to 0.040 ng/mL). *p<0.001 comparing levels on hospital admission vs 14 days and 6 months. Levels at 14 days and 6 months were similar (p = 0.554).Grahic Jump Location
Table Graphic Jump Location
Table 2. Copeptin, CRP, and Procalcitonin Levels at Hospital Admission According to Anthonisen Classification and COPD GOLD Stage*
* 

Data are presented as median (IQR).

 

According to Anthonisen classification.

Table Graphic Jump Location
Table 3. Spearman Correlation Coefficients for Copeptin, CRP, and Procalcitonin and Patient Characteristics at Hospital Admission
* 

Denotes statistical significance.

Table Graphic Jump Location
Table 4. Comparison of Clinical Outcome in Patients With Copeptin Levels < 40 pmol/L and ≥ 40 pmol/L on Hospital Admission*
* 

Data are presented as % (No.), median (IQR), or mean ± SD.

Figure Jump LinkFigure 2. Length of hospital stay in the group of patients with low copeptin levels (< 40 pmol/L) and in those with high copeptin levels (≥ 40 pmol/L) on hospital admission.Grahic Jump Location
Table Graphic Jump Location
Table 5. Comparison of Clinical Outcome in Patients With CRP Levels < 50 mg/L and ≥ 50 mg/L at Hospital Admission*
* 

Data are presented as % (No.), median (IQR), or mean ± SD.

Table Graphic Jump Location
Table 6. Comparison of Clinical Outcome in Patients With Procalcitonin Levels < 0.25 ng/mL and ≥ 0.25 ng/mL at Hospital Admission*
* 

Data are presented as % (No.), median (IQR), or mean ± SD.

Figure Jump LinkFigure 3. Top, A: Kaplan-Meier curves showing the incidence of clinical failure (death or rehospitalization for AECOPD) in patients with low copeptin levels (< 40 pmol/L) and high copeptin levels (≥ 40 pmol/L) at hospital admission; p = log-rank test. Center, B: Kaplan-Meier curves showing the incidence of clinical failure (death or rehospitalization for AECOPD) in patients with low CRP levels (< 50 mg/L) and in those with high CRP levels (≥ 50 mg/L) at hospital admission; p = log-rank test. Bottom, C: Kaplan-Meier curves showing the incidence of clinical failure (death or rehospitalization for AECOPD) in patients with low procalcitonin levels (< 0.25 ng/mL) and in those with high procalcitonin levels (≥ 0.25 ng/mL) at hospital admission; p = log-rank test.Grahic Jump Location
Figure Jump LinkFigure 4. Kaplan-Meier curves showing the incidence of clinical failure (death or re-hospitalization for AECOPD) in patients with low copeptin levels on hospital admission (< 40 pmol/L) and no history of hospitalization (HOSP) due to AECOPD in previous year (n = 73) [(A)]; low copeptin levels (< 40 pmol/L) and history of hospitalization (n = 67) [(B)]; high copeptin levels (≥ 40 pmol/L) and no history of hospitalization (n = 12) [(C)]; and high copeptin levels (≥ 40 pmol/L) and history of hospitalization (n = 15) [(D)]. p = log-rank test (overall p < 0.0001; (A) vs (B), p = 0.005; (A) vs (C), p = 0.023; (A) vs (D), p < 0.0001; (B) vs (C), p = 0.478; (B) vs (D), p < 0.0001; (C) vs (D), p = 0.062)Grahic Jump Location
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Schrier, RW, Berl, T, Anderson, RJ Osmotic and nonosmotic control of vasopressin release.Am J Physiol1979;236,F321-332. [PubMed]
 
Schrier, RW, Abraham, WT Hormones and hemodynamics in heart failure.N Engl J Med1999;341,577-585. [PubMed]
 
Wood, CE, Chen, HG Acidemia stimulates ACTH, vasopressin, and heart rate responses in fetal sheep.Am J Physiol1989;257,R344-349. [PubMed]
 
Landry, DW, Levin, HR, Gallant, EM, et al Vasopressin deficiency contributes to the vasodilation of septic shock.Circulation1997;95,1122-1125. [PubMed]
 
Dunser, MW, Mayr, AJ, Ulmer, H, et al Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study.Circulation2003;107,2313-2319. [PubMed]
 
Preibisz, JJ, Sealey, JE, Laragh, JH, et al Plasma and platelet vasopressin in essential hypertension and congestive heart failure.Hypertension1983;5,I129-138. [PubMed]
 
Robertson, GL, Mahr, EA, Athar, S, et al Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma.J Clin Invest1973;52,2340-2352. [PubMed]
 
Morgenthaler, NG, Struck, J, Alonso, C, et al Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin.Clin Chem2006;52,112-119. [PubMed]
 
Malo, O, Sauleda, J, Busquets, X, et al Systemic inflammation during exacerbations of chronic obstructive pulmonary disease [in Spanish].Arch Bronconeumol2002;38,172-176. [PubMed]
 
Hurst, JR, Donaldson, GC, Perera, WR, et al Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease.Am J Respir Crit Care Med2006;174,867-874. [PubMed]
 
Muller, B, Tamm, M Biomarkers in acute exacerbation of chronic obstructive pulmonary disease: among the blind, the one-eyed is king.Am J Respir Crit Care Med2006;174,848-849. [PubMed]
 
Stolz, D, Christ-Crain, M, Bingisser, R, et al Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy.Chest2007;131,9-19. [PubMed]
 
Boussekey, N, Leroy, O, Alfandari, S, et al Procalcitonin kinetics in the prognosis of severe community-acquired pneumonia.Intensive Care Med2006;32,469-472. [PubMed]
 
Christ-Crain, M, Stolz, D, Bingisser, R, et al Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial.Am J Respir Crit Care Med2006;174,84-93. [PubMed]
 
Masia, M, Gutierrez, F, Shum, C, et al Usefulness of procalcitonin levels in community-acquired pneumonia according to the patients outcome research team pneumonia severity index.Chest2005;128,2223-2229. [PubMed]
 
Global Initiative for Chronic Obstructive Lung Disease. Available at: www.goldcopd.com. Accessed January 13, 2007.
 
Isenberg, H. Clinical microbiology procedures handbook. 1992; Blackwell. Washington, DC:.
 
Society, AT Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma.Am Rev Respir Dis1987;136,225-244. [PubMed]
 
Christ-Crain, M, Jaccard-Stolz, D, Bingisser, R, et al Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial.Lancet2004;363,600-607. [PubMed]
 
ISRCTN Register. Procalcitonin-guided antibiotic therapy in acute exacerbations of COPD (AECOPD); a randomised trial; the ProCOLD study. Available at: http://controlled-trials.com/ISRCTN77261143/procalcitonin-guided+antibiotic+therapy.html. Accessed October 30, 2006.
 
Kanner, RE, Anthonisen, NR, Connett, JE Lower respiratory illnesses promote FEV(1) decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study.Am J Respir Crit Care Med2001;164,358-364. [PubMed]
 
Donaldson, GC, Wedzicha, JA COPD exacerbations: 1; epidemiology.Thorax2006;61,164-168. [PubMed]
 
Anthonisen, NR, Manfreda, J, Warren, CP, et al Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease.Ann Intern Med1987;106,196-204. [PubMed]
 
Morgenthaler NG, Struck J, Alonso C, et al. Measurement of the very stable vasopressin precursor copeptin as alternative to vasopressin in the clinical routine. Exp Clin Endocrinol Diabet 2007 (in press).
 
Sharples, PM, Seckl, JR, Human, D, et al Plasma and cerebrospinal fluid arginine vasopressin in patients with and without fever.Arch Dis Child1992;67,998-1002. [PubMed]
 
Luckner, G, Dunser, MW, Jochberger, S, et al Arginine vasopressin in 316 patients with advanced vasodilatory shock.Crit Care Med2005;33,2659-2666. [PubMed]
 
Westphal, M, Sielenkamper, AW, Van Aken, H, et al Dopexamine reverses the vasopressin-associated impairment in tissue oxygen supply but decreases systemic blood pressure in ovine endotoxemia.Anesth Analg2004;99,878-885. [PubMed]
 
Herrera, EA, Riquelme, RA, Sanhueza, EM, et al Cardiovascular responses to arginine vasopressin blockade during acute hypoxemia in the llama fetus.High Alt Med Biol2000;1,175-184. [PubMed]
 
Perez, R, Espinoza, M, Riquelme, R, et al Arginine vasopressin mediates cardiovascular responses to hypoxemia in fetal sheep.Am J Physiol1989;256,R1011-R1018. [PubMed]
 
Akagi, K, Berdusco, ET, Challis, JR Cortisol inhibits ACTH but not the AVP response to hypoxaemia in fetal lambs at days 123–128 of gestation.J Dev Physiol1990;14,319-324. [PubMed]
 
Jin, HK, Yang, RH, Chen, YF, et al Hemodynamic effects of arginine vasopressin in rats adapted to chronic hypoxia.J Appl Physiol1989;66,151-160. [PubMed]
 
Leather, HA, Segers, P, Berends, N, et al Effects of vasopressin on right ventricular function in an experimental model of acute pulmonary hypertension.Crit Care Med2002;30,2548-2552. [PubMed]
 
Westphal, M, Stubbe, H, Sielenkamper, AW, et al Effects of titrated arginine vasopressin on hemodynamic variables and oxygen transport in healthy and endotoxemic sheep.Crit Care Med2003;31,1502-1508. [PubMed]
 
du Souich, P, Saunier, C, Hartemann, D, et al Effect of moderate hypoxemia on atrial natriuretic factor and arginine vasopressin in normal man.Biochem Biophys Res Commun1987;148,906-912. [PubMed]
 
Sameshima, H, Ikenoue, T, Kamitomo, M, et al Vasopressin and catecholamine responses to 24-hour, steady-state hypoxemia in fetal goats.J Matern Fetal Med1996;5,262-267. [PubMed]
 
Akagi, K, Challis, JR Relationship between blood gas values and hormonal response to acute hypoxemia in fetal sheep.Gynecol Obstet Invest1990;30,65-70. [PubMed]
 
Colice, GL, Ramirez, G The effect of furosemide during normoxemia and hypoxemia.Am Rev Respir Dis1986;133,279-285. [PubMed]
 
Mohring, J, Glanzer, K, Maciel, JA, Jr, et al Greatly enhanced pressor response to antidiuretic hormone in patients with impaired cardiovascular reflexes due to idiopathic orthostatic hypotension.J Cardiovasc Pharmacol1980;2,367-376. [PubMed]
 
Garcia-Aymerich, J, Monso, E, Marrades, RM, et al Risk factors for hospitalization for a chronic obstructive pulmonary disease exacerbation: eFRAM study.Am J Respir Crit Care Med2001;164,1002-1007. [PubMed]
 
Hurst, JR, Donaldson, GC, Perera, WR, et al Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease.Am J Respir Crit Care Med2006;174,867-874. [PubMed]
 
Weis, N, Almdal, T C-reactive protein: can it be used as a marker of infection in patients with exacerbation of chronic obstructive pulmonary disease?Eur J Intern Med2006;17,88-91. [PubMed]
 
Sin, DD, Man, SF Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease.Circulation2003;107,1514-1519. [PubMed]
 
Gan, WQ, Man, SF, Sin, DD The interactions between cigarette smoking and reduced lung function on systemic inflammation.Chest2005;127,558-564. [PubMed]
 
Woodhead, M, Blasi, F, Ewig, S, et al Guidelines for the management of adult lower respiratory tract infections.Eur Respir J2005;26,1138-1180. [PubMed]
 
Stolz, D, Christ-Crain, M, Gencay, MM, et al Diagnostic value of signs, symptoms and laboratory values in lower respiratory tract infection.Swiss Med Wkly2006;136,434-440. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Top, A: copeptin levels at hospital admission, at 14 days, and at 6 months. On hospital admission, copeptin levels were significantly elevated (12.45 pmol/L; IQR, 4.97 to 25.05 pmol/L) as compared to after 14 days (6.10 pmol/L; IQR, 4.02 to 14.20 pmol/L) and 6 months (6.38 pmol/L; IQR, 3.95 to 12.25 pmol/L). *p<0.001 comparing levels on hospital admission vs 14 days and 6 months. Levels at 14 days and 6 months were similar (p = 0.783). Center, B: CRP on admission, at 14 days, and at 6 months. On hospital admission, CRP levels were significantly elevated (26.5 mg/L; IQR, 7.4 to 60.1 mg/L) as compared to after 14 days (7.5 mg/L; IQR, 2 to 19.5) and 6 months (4 mg/L; IQR, 2 to 11 mg/L). *p<0.001 comparing levels at admission vs 14 days and 6 months. Levels at 14 days and 6 months were similar (p = 0.127). Bottom, C: procalcitonin levels at admission, at 14 days, and at 6 months. *On hospital admission, procalcitonin levels were significantly elevated (0.088 ng/mL; IQR, 0.053 to 0.161 ng/mL) as compared to after 14 days (0.020 ng/mL; IQR, 0.014 to 0.051 ng/mL) and 6 months (0.021 ng/mL; IQR, 0.010 to 0.040 ng/mL). *p<0.001 comparing levels on hospital admission vs 14 days and 6 months. Levels at 14 days and 6 months were similar (p = 0.554).Grahic Jump Location
Figure Jump LinkFigure 2. Length of hospital stay in the group of patients with low copeptin levels (< 40 pmol/L) and in those with high copeptin levels (≥ 40 pmol/L) on hospital admission.Grahic Jump Location
Figure Jump LinkFigure 3. Top, A: Kaplan-Meier curves showing the incidence of clinical failure (death or rehospitalization for AECOPD) in patients with low copeptin levels (< 40 pmol/L) and high copeptin levels (≥ 40 pmol/L) at hospital admission; p = log-rank test. Center, B: Kaplan-Meier curves showing the incidence of clinical failure (death or rehospitalization for AECOPD) in patients with low CRP levels (< 50 mg/L) and in those with high CRP levels (≥ 50 mg/L) at hospital admission; p = log-rank test. Bottom, C: Kaplan-Meier curves showing the incidence of clinical failure (death or rehospitalization for AECOPD) in patients with low procalcitonin levels (< 0.25 ng/mL) and in those with high procalcitonin levels (≥ 0.25 ng/mL) at hospital admission; p = log-rank test.Grahic Jump Location
Figure Jump LinkFigure 4. Kaplan-Meier curves showing the incidence of clinical failure (death or re-hospitalization for AECOPD) in patients with low copeptin levels on hospital admission (< 40 pmol/L) and no history of hospitalization (HOSP) due to AECOPD in previous year (n = 73) [(A)]; low copeptin levels (< 40 pmol/L) and history of hospitalization (n = 67) [(B)]; high copeptin levels (≥ 40 pmol/L) and no history of hospitalization (n = 12) [(C)]; and high copeptin levels (≥ 40 pmol/L) and history of hospitalization (n = 15) [(D)]. p = log-rank test (overall p < 0.0001; (A) vs (B), p = 0.005; (A) vs (C), p = 0.023; (A) vs (D), p < 0.0001; (B) vs (C), p = 0.478; (B) vs (D), p < 0.0001; (C) vs (D), p = 0.062)Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Baseline Characteristics of 167 Patients Presenting With AECOPD (n = 167)*
* 

Data are presented as No. (%), median (IQR), or mean ± SD.

 

Minor findings include fever (> 38°C) without other cause; increased wheezing; increased cough; or increased respiratory rate as compared with stable baseline condition.

 

Classification of severity of COPD based on lung function tests performed at 6 months (stable phase).

Table Graphic Jump Location
Table 2. Copeptin, CRP, and Procalcitonin Levels at Hospital Admission According to Anthonisen Classification and COPD GOLD Stage*
* 

Data are presented as median (IQR).

 

According to Anthonisen classification.

Table Graphic Jump Location
Table 3. Spearman Correlation Coefficients for Copeptin, CRP, and Procalcitonin and Patient Characteristics at Hospital Admission
* 

Denotes statistical significance.

Table Graphic Jump Location
Table 4. Comparison of Clinical Outcome in Patients With Copeptin Levels < 40 pmol/L and ≥ 40 pmol/L on Hospital Admission*
* 

Data are presented as % (No.), median (IQR), or mean ± SD.

Table Graphic Jump Location
Table 5. Comparison of Clinical Outcome in Patients With CRP Levels < 50 mg/L and ≥ 50 mg/L at Hospital Admission*
* 

Data are presented as % (No.), median (IQR), or mean ± SD.

Table Graphic Jump Location
Table 6. Comparison of Clinical Outcome in Patients With Procalcitonin Levels < 0.25 ng/mL and ≥ 0.25 ng/mL at Hospital Admission*
* 

Data are presented as % (No.), median (IQR), or mean ± SD.

References

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Barnes, PJ, Chowdhury, B, Kharitonov, SA, et al Pulmonary biomarkers in chronic obstructive pulmonary disease.Am J Respir Crit Care Med2006;174,6-14. [PubMed]
 
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Wedzicha, JA, Seemungal, TA, MacCallum, PK, et al Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels.Thromb Haemost2000;84,210-215. [PubMed]
 
Dev, D, Wallace, E, Sankaran, R, et al Value of C-reactive protein measurements in exacerbations of chronic obstructive pulmonary disease.Respir Med1998;92,664-667. [PubMed]
 
Robertson, GL Antidiuretic hormone. Normal and disordered function.Endocrinol Metab Clin North Am2001;30,671-694,vii. [PubMed]
 
Kovacs, L, Robertson, GL Syndrome of inappropriate antidiuresis.Endocrinol Metab Clin North Am1992;21,859-875. [PubMed]
 
Jochberger, S, Mayr, VD, Luckner, G, et al Serum vasopressin concentrations in critically ill patients.Crit Care Med2006;34,293-299. [PubMed]
 
Schrier, RW, Berl, T, Anderson, RJ Osmotic and nonosmotic control of vasopressin release.Am J Physiol1979;236,F321-332. [PubMed]
 
Schrier, RW, Abraham, WT Hormones and hemodynamics in heart failure.N Engl J Med1999;341,577-585. [PubMed]
 
Wood, CE, Chen, HG Acidemia stimulates ACTH, vasopressin, and heart rate responses in fetal sheep.Am J Physiol1989;257,R344-349. [PubMed]
 
Landry, DW, Levin, HR, Gallant, EM, et al Vasopressin deficiency contributes to the vasodilation of septic shock.Circulation1997;95,1122-1125. [PubMed]
 
Dunser, MW, Mayr, AJ, Ulmer, H, et al Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study.Circulation2003;107,2313-2319. [PubMed]
 
Preibisz, JJ, Sealey, JE, Laragh, JH, et al Plasma and platelet vasopressin in essential hypertension and congestive heart failure.Hypertension1983;5,I129-138. [PubMed]
 
Robertson, GL, Mahr, EA, Athar, S, et al Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma.J Clin Invest1973;52,2340-2352. [PubMed]
 
Morgenthaler, NG, Struck, J, Alonso, C, et al Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin.Clin Chem2006;52,112-119. [PubMed]
 
Malo, O, Sauleda, J, Busquets, X, et al Systemic inflammation during exacerbations of chronic obstructive pulmonary disease [in Spanish].Arch Bronconeumol2002;38,172-176. [PubMed]
 
Hurst, JR, Donaldson, GC, Perera, WR, et al Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease.Am J Respir Crit Care Med2006;174,867-874. [PubMed]
 
Muller, B, Tamm, M Biomarkers in acute exacerbation of chronic obstructive pulmonary disease: among the blind, the one-eyed is king.Am J Respir Crit Care Med2006;174,848-849. [PubMed]
 
Stolz, D, Christ-Crain, M, Bingisser, R, et al Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy.Chest2007;131,9-19. [PubMed]
 
Boussekey, N, Leroy, O, Alfandari, S, et al Procalcitonin kinetics in the prognosis of severe community-acquired pneumonia.Intensive Care Med2006;32,469-472. [PubMed]
 
Christ-Crain, M, Stolz, D, Bingisser, R, et al Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial.Am J Respir Crit Care Med2006;174,84-93. [PubMed]
 
Masia, M, Gutierrez, F, Shum, C, et al Usefulness of procalcitonin levels in community-acquired pneumonia according to the patients outcome research team pneumonia severity index.Chest2005;128,2223-2229. [PubMed]
 
Global Initiative for Chronic Obstructive Lung Disease. Available at: www.goldcopd.com. Accessed January 13, 2007.
 
Isenberg, H. Clinical microbiology procedures handbook. 1992; Blackwell. Washington, DC:.
 
Society, AT Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma.Am Rev Respir Dis1987;136,225-244. [PubMed]
 
Christ-Crain, M, Jaccard-Stolz, D, Bingisser, R, et al Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial.Lancet2004;363,600-607. [PubMed]
 
ISRCTN Register. Procalcitonin-guided antibiotic therapy in acute exacerbations of COPD (AECOPD); a randomised trial; the ProCOLD study. Available at: http://controlled-trials.com/ISRCTN77261143/procalcitonin-guided+antibiotic+therapy.html. Accessed October 30, 2006.
 
Kanner, RE, Anthonisen, NR, Connett, JE Lower respiratory illnesses promote FEV(1) decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study.Am J Respir Crit Care Med2001;164,358-364. [PubMed]
 
Donaldson, GC, Wedzicha, JA COPD exacerbations: 1; epidemiology.Thorax2006;61,164-168. [PubMed]
 
Anthonisen, NR, Manfreda, J, Warren, CP, et al Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease.Ann Intern Med1987;106,196-204. [PubMed]
 
Morgenthaler NG, Struck J, Alonso C, et al. Measurement of the very stable vasopressin precursor copeptin as alternative to vasopressin in the clinical routine. Exp Clin Endocrinol Diabet 2007 (in press).
 
Sharples, PM, Seckl, JR, Human, D, et al Plasma and cerebrospinal fluid arginine vasopressin in patients with and without fever.Arch Dis Child1992;67,998-1002. [PubMed]
 
Luckner, G, Dunser, MW, Jochberger, S, et al Arginine vasopressin in 316 patients with advanced vasodilatory shock.Crit Care Med2005;33,2659-2666. [PubMed]
 
Westphal, M, Sielenkamper, AW, Van Aken, H, et al Dopexamine reverses the vasopressin-associated impairment in tissue oxygen supply but decreases systemic blood pressure in ovine endotoxemia.Anesth Analg2004;99,878-885. [PubMed]
 
Herrera, EA, Riquelme, RA, Sanhueza, EM, et al Cardiovascular responses to arginine vasopressin blockade during acute hypoxemia in the llama fetus.High Alt Med Biol2000;1,175-184. [PubMed]
 
Perez, R, Espinoza, M, Riquelme, R, et al Arginine vasopressin mediates cardiovascular responses to hypoxemia in fetal sheep.Am J Physiol1989;256,R1011-R1018. [PubMed]
 
Akagi, K, Berdusco, ET, Challis, JR Cortisol inhibits ACTH but not the AVP response to hypoxaemia in fetal lambs at days 123–128 of gestation.J Dev Physiol1990;14,319-324. [PubMed]
 
Jin, HK, Yang, RH, Chen, YF, et al Hemodynamic effects of arginine vasopressin in rats adapted to chronic hypoxia.J Appl Physiol1989;66,151-160. [PubMed]
 
Leather, HA, Segers, P, Berends, N, et al Effects of vasopressin on right ventricular function in an experimental model of acute pulmonary hypertension.Crit Care Med2002;30,2548-2552. [PubMed]
 
Westphal, M, Stubbe, H, Sielenkamper, AW, et al Effects of titrated arginine vasopressin on hemodynamic variables and oxygen transport in healthy and endotoxemic sheep.Crit Care Med2003;31,1502-1508. [PubMed]
 
du Souich, P, Saunier, C, Hartemann, D, et al Effect of moderate hypoxemia on atrial natriuretic factor and arginine vasopressin in normal man.Biochem Biophys Res Commun1987;148,906-912. [PubMed]
 
Sameshima, H, Ikenoue, T, Kamitomo, M, et al Vasopressin and catecholamine responses to 24-hour, steady-state hypoxemia in fetal goats.J Matern Fetal Med1996;5,262-267. [PubMed]
 
Akagi, K, Challis, JR Relationship between blood gas values and hormonal response to acute hypoxemia in fetal sheep.Gynecol Obstet Invest1990;30,65-70. [PubMed]
 
Colice, GL, Ramirez, G The effect of furosemide during normoxemia and hypoxemia.Am Rev Respir Dis1986;133,279-285. [PubMed]
 
Mohring, J, Glanzer, K, Maciel, JA, Jr, et al Greatly enhanced pressor response to antidiuretic hormone in patients with impaired cardiovascular reflexes due to idiopathic orthostatic hypotension.J Cardiovasc Pharmacol1980;2,367-376. [PubMed]
 
Garcia-Aymerich, J, Monso, E, Marrades, RM, et al Risk factors for hospitalization for a chronic obstructive pulmonary disease exacerbation: eFRAM study.Am J Respir Crit Care Med2001;164,1002-1007. [PubMed]
 
Hurst, JR, Donaldson, GC, Perera, WR, et al Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease.Am J Respir Crit Care Med2006;174,867-874. [PubMed]
 
Weis, N, Almdal, T C-reactive protein: can it be used as a marker of infection in patients with exacerbation of chronic obstructive pulmonary disease?Eur J Intern Med2006;17,88-91. [PubMed]
 
Sin, DD, Man, SF Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease.Circulation2003;107,1514-1519. [PubMed]
 
Gan, WQ, Man, SF, Sin, DD The interactions between cigarette smoking and reduced lung function on systemic inflammation.Chest2005;127,558-564. [PubMed]
 
Woodhead, M, Blasi, F, Ewig, S, et al Guidelines for the management of adult lower respiratory tract infections.Eur Respir J2005;26,1138-1180. [PubMed]
 
Stolz, D, Christ-Crain, M, Gencay, MM, et al Diagnostic value of signs, symptoms and laboratory values in lower respiratory tract infection.Swiss Med Wkly2006;136,434-440. [PubMed]
 
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