Evaluation of mid-regional pro-atrial natriuretic peptide,

procalcitonin, and mid-regional pro-adrenomedullin for the diagnosis and risk stratification of dyspneic ED patients^?,??,?,??

Orhan Cinar MD ^a, Erdem Cevik MD ^a,?, Ayhan Acar MD ^a, Cengiz Kaya MD ^a, Sukru Ardic MD ^a, Bilgin Comert MD ^a, Mehmet Yokusoglu MD ^b, Cumhur Bilgi PhD ^c,

Michael Meisner MD ^d, Troy Madsen MD ^e

^aDepartment of Emergency Medicine, Gulhane Military Medical Academy, GATA Acil Tip Anabilim Dali, Etlik, Ankara, Turkey 06010 ^bDepartment of Cardiology, Gulhane Military Medical Academy, GATA Kardiyoloji Anabilim Dali, Etlik, Ankara, Turkey 06010 ^cDepartment of Medical Biochemistry, Gulhane Military Medical Academy, GATA Biyokimya Anabilim Dali, Etlik,

Ankara, Turkey 06010

^dDresden, Germany, D-01129 Dresden, Industriestr. 40

^eDivision of Emergency Medicine, University of Utah, 30 N. 1900 E. 1C26, Salt Lake City, UT 84132

Received 14 February 2012; revised 3 April 2012; accepted 4 April 2012

Abstract

Objective: The aim of this study was to evaluate the diagnostic and the prognostic value of a laboratory panel consisting of Mid-regional pro-atrial natriuretic peptide , procalcitonin , and Mid-regional pro-adrenomedullin for patients presenting to the emergency department (ED) with acute dyspnea.

Methods: We prospectively enrolled ED patients who presented with a chief complaint of dyspnea and who had an uncertain diagnosis after physician evaluation. Final primary diagnosis of the cause of shortness of breath was confirmed through additional testing per physician discretion. We recorded inpatient admission and 30-day mortality rates.

Results: One hundred fifty-four patients were enrolled in the study. Congestive heart failure exacerbation was the final primary diagnosis in 42.2% of patients, while infectious etiology was diagnosed in 33.1% of patients. For the diagnosis of congestive heart failure exacerbation, MR-proANP

^? Prior Publication: This article is an original work and it has not been published or submitted for publication elsewhere, in whole or in part, before submission to Academic Journal of Emergency Medicine. Abstract of the article has been selected for oral presentation at the 2011 ACEP Research Forum in San Francisco, CA.

^?? Conftict of interest: BRAHMS supplied the reagents needed for the new marker measurements.We declared that we have no commercial, financial, and

other relationships in any way related to the subject of this article all that might create any potential conftict of interest.

^? Funding and support: Nothing to declare.

^?? Statistical Analysis: Statistical analysis was performed by Cengiz Han Acikel, one of the faculty in Department of Public Health, Gulhane Military

Medical Academy.

* Corresponding author. Tel.: + 90 312 304 3080.

E-mail addresses: [email protected] (O. Cinar), [email protected] (E. Cevik), [email protected] (A. Acar), [email protected] (C. Kaya), [email protected] (S. Ardic), [email protected] (B. Comert), [email protected] (M. Yokusoglu), [email protected] (C. Bilgi), [email protected] (M. Meisner), [email protected] (T. Madsen).

0735-6757/$ - see front matter (C) 2012 http://dx.doi.org/10.1016/j.ajem.2012.04.009

had a sensitivity of 92.7% and specificity of 36.8%, with a negative likelihood ratio of 0.16 and a positive likelihood ratio (LR+) of 1.44 (cut-off value: 120 pmol/L). For the diagnosis of an infectious etiology, PCT had a 96.5% specificity and 48.8% sensitivity (LR-: 0.58, LR+: 13.8, cutoff value: 0.25 ng/mL). As a prognostic indicator, MR-proADM demonstrated similar values: odds ratio for 30-day mortality was 8.5 (95% CI, 2.5-28.5, cutoff value: 1.5 nmol/L) and the area under the receiver operating characteristic curve in predicting mortality was 0.81 (95% CI, 0.71-0.91).

Conclusion: The good negative LR- of MR-proANP and the good positive LR+ of PCT may suggest a role for these markers in the early diagnosis of ED patients with dyspnea. Furthermore, MR-proADM may assist in risk stratification and prognosis in these patients..

(C) 2012

Introduction

Dyspnea is one of the most common presenting symptoms in the emergency department (ED) [1]. Although early diagnosis and treatment are critical to patient care to prevent increased risk of mortality and morbidity [2], the differential diagnosis of dyspnea is usually challenging, often requiring further evaluation such as echocardiography and computed tomography (CT) scan [3]. These diagnostic tools are usually time consuming, expensive and may not always be available in the ED setting. In addition to the diagnosis, early prognostic evaluation of the acute dyspnea patients is another major interest for ED physicians. Identifying patients at high-risk for complication and mortality can instigate earlier admission to the intensive care unit.

Several newly described pro-hormones may aid in diagnosis and prognosis in ED patients with dyspnea: mid- regional pro-atrial natriuretic peptide (MR-proANP) as a marker of Acute heart failure ; procalcitonin as a marker of an infectious etiology such as pneumonia or chronic obstructive pulmonary disease (COPD) exacerba- tion; and mid-regional pro-adrenomedullin (MR-proADM) for risk stratification and prognosis.

MR-proANP is a mid-regional sequence of ANP, a peptide hormone mainly released by atrial myocytes in response to chamber distension [4]. Previous studies have shown that MR-proANP is as useful as B-type Natriuretic Peptide and closely correlated with NT-proBNP for diagnosis of AHF in dyspneic patients [5,6] and may provide additional clinical utility when BNP is difficult to interpret [6]. PCT is a well- documented marker for diagnosis of respiratory tract in- fections and antibiotic guidance [7,8]. MR-proADM is the stable fragment of adrenomedullin which was originally isolated from human pheochromocytoma cells and has later been detected in other tissues, including heart, adrenal medulla, lungs, and kidneys [9,10] MR-proADM has been shown as a good prognostic marker for mortality in various conditions such as AHF [6], pneumonia [11], and dyspnea [10]. It is not known, however, whether these three biomarkers, as a panel, can assist ED physicians with diagnosis and risk stratification of acute dyspnea patients.

We aimed to evaluate the diagnostic and the prognostic

value of this marker panel by determining, first, the

diagnostic accuracy of MR-proANP and PCT in patients presenting to the ED with acute dyspnea. Second, we planned to evaluate whether the use of this marker panel improves the diagnostic accuracy over standard clinical judgment of ED physicians in the assessment of acute dyspnea patients. Finally, we planned to determine whether a single MR-proADM measurement at presentation predicts the 30-day mortality in ED patients with acute dyspnea.

Methods

Study design and setting

We conducted a prospective observational cohort study in an academic emergency department with an annual patient census of 120000 patient visits between January 2010 and December 2010. The study was approved by the Institutional Review Board, and informed consent was obtained from all participants.

Selection of participants

We enrolled ED adult patients who presented with a chief complaint of acute dyspnea and who had an uncertain diagnosis after physician evaluation. If the treating emer- gency physician (EP) was certain about the diagnosis after initial evaluation without further testing such as echocardi- ography and CT scan, those patients were excluded from the study. Patients under the age of 18 and trauma patients were excluded from the study.

Data collection and processing

After the treating EP’s initial evaluation, a patient who fulfilled the inclusion and exclusion criteria underwent a laboratory panel consisting of MR-proANP, PCT, and MR- proADM. The EP recorded patient data, including de- mographics, medical history, physical examination, electro- cardiogram, and chest X-ray findings. We collected the EPs’ initial diagnoses, and requested a self-rating of EP’s Diagnostic certainty on a 5-point Likert scale (1 = 0%-20%

Fig. 1 Flow diagram for diagnostic evaluation.

certain, 2 = 20%-40% certain, 3 = 40%-60% certain, 4 = 60%-80% certain, 5 = 80%-100% certain). Physician’s Initial diagnosis was obtained after the history and physical exam, EKG, chest x-ray evaluation. BNP was not used in any enrolled patients. Results of the laboratory panel were available to the treating physician in about 30-60 minutes and were used as part of the diagnostic process.

After marker results were available, we asked the treating physician if their initial diagnosis changed and asked them to rate their diagnostic certainty again. Final diagnosis as the primary cause of shortness of breath was confirmed through further evaluation such as echocardiography, chest CT, cardiology and pulmonology consultation per physician discretion. Final primary diagnosis was documented based on the physician diagnosis either at the time of discharge from the ED or, in admitted patients, at the time of discharge from the Inpatient unit (Fig. 1). We evaluated the inftuence of the marker profile on the physician’s diagnosis by comparing the physician’s initial and marker related diagnosis to the final primary diagnosis. Thirty-day mortality was evaluated via hospital records and telephone contact with patients.

Methods of measurement

Blood samples for determination of MR-proADM, MR- proANP, and PCT were collected at presentation into tubes containing potassium EDTA. Samples were analyzed in the ED laboratory by previously trainED technicians directly after the blood sampling. MR-proADM and MR-proANP were detected with an automated sandwich chemiluminescence immunoassay. PCT was measured with a time-resolved, amplified cryptate emission assay on the KRYPTOR System (BRAHMS AG, Hennigsdorf/Berlin, Germany).

Outcome measures

Primary outcome measures were the final diagnosis of congestive heart failure (CHF) exacerbation for MR-proANP and final diagnosis of infectious causes for PCT. Primary outcome measure for MR-proADM was 30-day mortality rates and inpatient admissions. A cut-off value of 120 pmol/L was used for MR-proANP, 0.25 ng/mL for PCT, 1.5 nmol/L

for MR-proADM as suggested by the producer (BRAHMS AG, Hennigsdorf/Berlin, Germany).

Primary data analysis

Descriptive statistics are presented as frequency (percent- age) for categorical variables, whereas continuous data is presented as mean +- SD for normally distributed data and median (interquartile range (IQR) for non-normally distrib- uted data. Decision statistics (accuracy, sensitivity, specific- ity and positive and negative predictive values) were calculated with 2 x 2 tables to evaluate the diagnostic utility of the marker panel. Patients who had the final primary diagnosis of CHF exacerbation were compared with the non- CHF group. Patients given the final primary diagnosis of infectious etiology were compared with the non-infectious group. The effect of markers on physician decision was evaluated by comparing the initial and marker-related diagnosis with final primary diagnosis. Comparison of decision statistics for initial and marker-related diagnosis was made with ?2 testing, and t test was used for comparing the probability of the diagnosis. Receiver operating characteristic curve analysis was performed to evaluate the prognostic utility of MR-proADM on mortality and inpatient admission. SPSS 17.0 (SPSS Inc, Chicago, IL) and MedCalc 11.3 (MedCalc Software, Mariakerke, Bel- gium) were used for statistical analyses with P b .05 considered as statistically significant.

Results

We enrolled 154 patients with a chief complaint of shortness of breath and uncertain diagnosis in the study. Median age was 74 (IQR: 67-79) years and 50.6% (n = 78) of patients were women. 50.6% (n = 78) of patients were admitted to an inpatient unit; 15.6% (n = 24) of patients died during the 30-day follow-up period. CHF exacerbation was the final primary diagnosis in 42.2% (n = 65) of patients while infectious etiology, such as pneumonia or COPD exacerbation, was diagnosed in 33.1% (n = 51) of patients, with 24.6% (n = 38) classified as “other” (Table 1).

.001 respectively). Concerning the diagnosis of infectious etiology, physician initial diagnosis without marker results had a sensitivity of 80.7%, a specificity of 77.3% and an accuracy of 78.5%. After marker results were made available, marker-related diagnosis had increased to a sensitivity of 89.2%, a specificity of 91.8% and an accuracy of 90.9% (P b .042, P = .001, P = .006 respectively). The Diagnostic probability also increased from 3.7 to 4.3 (P b

Table 1 Study cohort demographics and clinical characteristics (n = 154)

Variable

Median age in years (IQR) Female

Admission to inpatient unit Mortality

SOFA score (median, IQR) History and clinical features History of COPD

History of CHF Infiltration on CXR Diagnosis

CHF exacerbation Infectious cause Other

Value

74 (67-79)

50.6 % (n = 78)

50.6 % (n = 78)

15.6% (n = 24)

2 (1-3)

27.2 % (n = 42)

35 % (n = 54)

14.9 % (n = 23)

42% (n = 65)

33% (n = 51)

25% (n = 38)

.001) in CHF exacerbation patients and from 3.4 to 3.8 (P b

.001) in infectious etiology patients (Table 3).

For the diagnosis of CHF exacerbation, MR-proANP had a sensitivity of 92.7% and specificity of 36.8%, with a negative likelihood ratio (LR-) of 0.16 and a positive likelihood ratio (LR+) of 1.44 (cut-off value: 120 pmol/L). For the diagnosis of an infectious etiology, PCT had a 48.8% sensitivity and a 96.5% specificity (LR-: 0.58, LR+: 13.8, cut-off value: 0.25 ng/mL) (Table 2). MR-proADM levels were elevated in non-survivors compared to survivors (median (IQR) 2.4 (1.5 to 3.7) nmol/L vs. 1.0 (0.6 to 1.5) nmol/L; P b .001). As a prognostic indicator, MR-proADM demonstrated similar value: odds ratio for 30-day mortality was 8.5 (95% CI: 2.5-28.5, cut-off value: 1.5 nmol/L) and the area under the ROC curve (AUC) in predicting mortality was 0.81 (95% CI 0.71 to 0.91). AUC in predicting inpatient admission was 0.67 (95% CI 0.53 to 0.72) (Fig. 2).

For the diagnosis of CHF exacerbation, physician initial diagnosis without marker results had a sensitivity of 72.3%, a specificity of 83.1 % and an accuracy of 78.5%. After marker results were made available, their marker-related diagnosis had increased to a sensitivity of 93.8%, a specificity of 94.3% and an accuracy of 94.1% (P b .001, P = .004, P b

Table 2 Biomarker results

Discussion

In this study, we found that the biomarker panel consisting of MR-proANP, PCT, and MR-proADM may be helpful for ED physicians in the diagnosis and risk stratification of patients presenting with acute dyspnea. Use of this marker panel may improve the diagnostic accuracy over standard clinical judgment of ED physicians. The accuracy of the diagnosis was significantly increased in both CHF exacerbation and infectious etiology groups. ED physicians also reported more confidence in their marker related diagnosis.

These findings are consistent with previous studies evaluating the utility of diagnostic markers, which compared BNP results with clinician diagnostic gestalt [12-14]. In one of the studies, investigators found that adding BNP to clinical judgment would have enhanced diagnostic accuracy from 74% to 81% [13]. A current American College of Emergency Physicians clinical policy states that the addition of a single BNP or NT-proBNP measurement can improve the diagnostic accuracy compared to standard clinical judgment alone in the diagnosis of acute heart failure syndrome among patients presenting to the ED with acute dyspnea (level B recommendation) [15]. Our results suggest that the use of MR-proANP and PCT had an additive effect on diagnostic accuracy.

MR-proANP (cut-off: 120 pmol/L)		PCT (cut-off: 0.25 ng/mL)	MR-proADM/L (cut-off: 1.5 nmol/L)
Median (IQR)	243 (101-417)	0.08 (0.05-0.17 )	1.122 (0.721-1.950 )
Min-Max	14-1879	0-6.24	0.001-7.990
Sensitivity ?	92.7% (82.4%-97.3%)	48.8 (%30.3%-57.6%)	82.3% (56.5%-95.9%)
Specificity ?	36.8% (30.6%-52.1%)	96.5% (91.0%-99.3%)	72.4% (62.5%-80.9%)
Negative predictive value ?	87.5 % (74.9%-96.0%)	79.4% (66.1%-82.1%)	95.9% (88.5%-99.1%)
Positive predictive value ?	51.5% (43.8%-63.3%)	87.5% (70.8%-97.5%)	34.1% (20.1%-50.5%)
Accuracy ?	60.5 % (53.2%-69.1%)	77.8% (63.1%-81.1%)	73.9 % (65.1%-79.1%)
Positive likelihood ratio ?	1.44 (1.33-1.97)	13.8 (24.3-43.7)	2.99 (2.03-4.41)
Negative likelihood ratio ?	0.16 (0.08-0.44)	0.58 (0.46-0.74)	0.24 (0.09-0.69)
Odds ratio ?	-	-	8.5 (7.4-8.9)
* 95% confidence interval.

Fig. 2 ROC curve for MR-proADM and mortality.

The diagnostic utility of MR-proANP in AHF has been evaluated previously. Maisel et al, in the BACH (Biomarkers in Acute Heart Failure) trial, found that MR- proANP had a sensitivity of 97.0% and a specificity of 59.9% for the diagnosis of CHF exacerbation [6]. However, we noted lower values than the BACH trial (sensitivity of 92.7% and a specificity of 36.8%), a finding which may be explained by differences in methodology. Induction of

NT-proBNP and ANP in patients with diagnosis other than CHF like PE or COPD has been reported as well This induction may be explained by increased cardiac stress or inftammatory activation.

The diagnostic value of PCT in respiratory infection, such as pneumonia [16] and COPD exacerbation [17], is well documented. The diagnostic utility of PCT in acute dyspnea patients in the ED, however, has not received significant attention. Our study showed that, although PCT had an excellent specificity and positive predictive value, it had a very low sensitivity. These findings suggest that an elevated PCT concentration (higher than 0.25 ng/mL) may indicate an infectious etiology of dyspnea, while normal PCT values do not exclude the possibility of an infectious etiology.

For prognostic evaluation, our study suggested that MR- proADM is a good prognostic indicator of mortality and may assist in the risk stratification of acute dyspnea patients. Potocki et al, in their study of the prognostic values of Natriuretic peptides in acute dyspnea patients, reported a similar AUC value (0.81) to that which we noted for prediction of 30-day mortality [10]. They concluded that MR-proADM alone or combined with NT-proBNP has the potential to assist clinicians in risk stratifying patients presenting with acute dyspnea, regardless of the underlying disease. In the BACH trial, the investigators reported an AUC value of 0.73 for 30-day mortality in CHF exacerbation patients and found that MR-proADM was superior to BNP and NT-proBNP for predicting mortality [6]. The prognostic value of MR-proADM has also been reported in cases of dyspnea such as pneumonia [11,18], COPD [19], sepsis [20], and CHF [21] in various studies. These various studies, in combination with our results, support the potential for risk stratification of patients with acute dyspnea using MR-proADM.

Table 3 Marker effect on physician diagnosis Initial diagnosis Markers-assisted diagnosis P
		Value	95% CI		Value	95% CI
Diagnosis of CHF	Sensitivity	72.3%	59.8%-82.6%		93.8%	84.9%-98.2%	P b .001
	Specificity	83.1%	73.7%-90.2%		94.3%	87.3%-98.1%	P = .004
	Positive likelihood ratio	4.29	2.64-6.97		16.7	7.1-39.2
	Negative likelihood ratio	0.33	0.22-0.50		0.07	0.03-0.17
	Positive predictive value	75.8%	63.2%-85.7%		92.4%	83.1%-97.4%	P b .001
	Negative predictive value	80.4%	70.8%-87.9%		95.4%	88.7%-98.7%	P b .001
	Accuracy	78.5%	72.1%-83.3%		94.1%	86.4%-97.4%	P b .001
	Diagnostic probability	3.7	3.5-3.8		4.3	4.0-4.4	P b .001
Diagnosis of infectious etiology	Sensitivity	80.7%	68.0%-89.9%		89.2%	78.1%-95.9%	P = .042
	Specificity	77.3%	67.7%-85.2%		91.8%	84.5%-96.4%	P = .001
	Positive likelihood ratio	3.56	2.41-5.25		10.9	5.60-21.38
	Negative likelihood ratio	0.25	0.15-0.43		0.12	0.05-0.25
	Positive predictive value	67.6%	55.2%-78.4%		86.2%	74.6%-93.8%	P b .001
	Negative predictive value	87.2%	78.2%-93.4%		93.7%	86.8%-97.6%	P = .117
	Accuracy	78.5%	70.2%-86.4%		90.9%	82.2%-93.4%	P = .006
	Diagnostic probability	3.4	3.1-3.6		3.8	3.5-4.2	P b .001

Limitations

Several limitations exist in our study. Primarily, this was a single center study, which needs to be replicated in a larger multicenter study design. Study results may be unique to our institution and to practices at this site, and may not translate to other institutions.

Additionally, our study was limited to the physician’s diagnostic performance, while the effects of marker use on patient outcomes such as mortality, inpatient admission and cost were not evaluated in our study. Before routine use of this marker panel in dyspneic patients in the ED, it should be determined whether using this marker panel reduces the mortality, morbidity, cost and duration of ED stay. Further randomized studies evaluating these patient outcome param- eters are required.

Another limitation of our study related to the evaluation of mortality outcomes. We utilized a relatively short 30-day time period for follow-up mortality data. Longer term mortality results may be particularly helpful in evaluating the prognostic value of MR-proADM. Also, our assessment was limited to all-cause mortality without any classification of mortality. Given this limitation, we are unsure whether the cause of mortality related to the patient’s reason for initial ED presentation.

Conclusions

In conclusion, the good negative LR- of MR-proANP and the good positive LR+ of PCT may suggest a role for these markers in the early diagnosis of ED patients with dyspnea. Use of this marker panel may improve the diagnostic accuracy in the ED. Furthermore, MR-proADM, may assist in risk stratification and prognosis in these patients. Additional studies may assist in determining the utility of these markers on patient outcome parameters such as mortality, Time to discharge and cost in the ED setting.

References

1. Nawar EW, Niska RW, Xu J. National Hospital Ambulatory Medical Care Survey: 2005 emergency department summary. Adv Data 2007; 386:1-32.
2. Green SM, Martinez-Rumayor A, Gregory SA, et al. Clinical uncertainty, diagnostic accuracy, and outcomes in emergency depart- ment patients presenting with dyspnea. Arch Intern Med 2008;168: 741-8.
3. Wills CP, Young M, White DW. Pitfalls in the evaluation of shortness of breath. Emerg Med Clin North Am 2010;28:163-81.
4. Lainscak M, Von Haehling S, Anker SD. Natriuretic peptides and other biomarkers in chronic heart failure: from BNP, NT-proBNP, and

MR-proANP to routine biochemical markers. Int J Cardiol 2009;132: 303-11.

1. Gegenhuber A, Struck J, Poelz W, et al. Midregional pro-A-type natriuretic peptide measurements for diagnosis of acute destabilized heart failure in short-of-breath patients: comparison with B-type natriuretic peptide and amino-terminal proBNP. Clin Chem 2006;52:827-31.
2. Maisel A, Mueller C, Nowak R, et al. Mid-region pro-hormone markers for diagnosis and prognosis in acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial. J Am Coll Cardiol 2010;55:2062-76.
3. 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. Chest 2007;131:9-19.
4. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin- based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009;302:1059-66.
5. Kitamura K, Kangawa K, Kawamoto M, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 1993;192:553-60.
6. Potocki M, Breidthardt T, Reichlin T, et al. Midregional pro- adrenomedullin in addition to B-type natriuretic peptides in the risk stratification of patients with acute dyspnea: an observational study. Crit Care 2009;13:R122.
7. Huang DT, Angus DC, Kellum JA, et al. Midregional proadrenome- dullin as a Prognostic tool in community-acquired pneumonia. Chest 2009;136:823-31.
8. Collins SP, Ronan-Bentle S, Storrow AB. Diagnostic and prognostic usefulness of natriuretic peptides in emergency department patients with dyspnea. Ann Emerg Med 2003;41:532-45.
9. McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002;106:416-22.
10. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161-7.
11. Silvers SM, Howell JM, Kosowsky JM, et al. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes. Ann Emerg Med 2007;49:627-69.
12. Muller B, Harbarth S, Stolz D, et al. Diagnostic and Prognostic accuracy of clinical and laboratory parameters in community-acquired pneumonia. BMC Infect Dis 2007;7:10.
13. Stolz D, Christ-Crain M, Morgenthaler NG, et al. Copeptin, C-reactive protein, and procalcitonin as Prognostic biomarkers in acute exacerbation of COPD. Chest 2007;131:1058-67.
14. Christ-Crain M, Morgenthaler NG, Stolz D, et al. Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia [ISRCTN04176397]. Crit Care 2006;10:R96.
15. 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;134:263-72.
16. Christ-Crain M, Morgenthaler NG, Struck J, et al. Mid-regional pro- adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care 2005;9:R816-24.
17. Gegenhuber A, Struck J, Dieplinger B, et al. Comparative evaluation of B-type natriuretic peptide, mid-regional pro-A-type natriuretic peptide, mid-regional pro-adrenomedullin, and Copeptin to predict 1- year mortality in patients with acute destabilized heart failure. J Card Fail 2007;13:42-9.