Top

Intensive Care Medicine

Published in:

01-06-2011 | Original

Repeated measurements of endothelin-1 precursor peptides predict the outcome in community-acquired pneumonia

Authors: Philipp Schuetz, Mirjam Christ-Crain, Werner Zimmerli, Beat Mueller

Published in: Intensive Care Medicine | Issue 6/2011

Abstract

Purpose

Excessive activation of the endothelium is associated with adverse outcomes in patients with systemic infections. Endothelium-associated peptides, such as endothelin-1 (ET-1), correlate closely with endothelial activation, and therefore serve as surrogate biomarkers. Our aim was to investigate precursor peptides of endothelin-1 (proET1) on admission and during follow-up on days 3, 5 and 7 in a prospective cohort of 925 patients with community-acquired pneumonia.

Methods

We investigated the association of initial and follow-up proET1 and other prohormone levels with 30-day mortality and ICU admission in proportional Cox regression models with time-varying covariates adjusted for the pneumonia-severity-index (PSI), and calculated reclassification statistics.

Results

The mortality rate and ICU admission rate were 5.4% (95% CI 3.9–6.8%) and 9.0% (95% CI 7.1–10.8%). ProET1 levels on admission and changes from baseline to day 3 were significant mortality predictors with adjusted hazard ratios of 10.5 (95% CI 2.9–38.6) and 28.4 (95% CI 7.0–115.1). Initial proET1 levels improved the PSI in reclassification statistics (net reclassification improvement of 0.29, p < 0.0001) and in c-statistics (from 0.79 to 0.83, p < 0.01). Changes of proET1 on day 3 improved the c-statistic of the combined model of PSI and initial proET1 from 0.80 to 0.85 (p < 0.01) and reclassification tables demonstrated a significant improvement (net reclassification improvement 0.44, p < 0.0001). Similar significant results were found for the risk for ICU admission.

Conclusions

In community-acquired pneumonia, ET-1 precursor peptides on admission and changes from baseline to day 3 were independent predictors for mortality and ICU admission, and significantly improved the PSI. If verified in intervention studies, monitoring of proET1 may be helpful for endothelium targeting therapies and for risk stratification complementary to other prohormones.

Available only for authorised users

Lee WL, Slutsky AS (2010) Sepsis and endothelial permeability. N Engl J Med 363:689–691PubMedCrossRef

Aird WC (2003) The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101:3765–3777PubMedCrossRef

Shah R (2007) Endothelins in health and disease. Eur J Int Med 18:272–282CrossRef

Wanecek M, Weitzberg E, Rudehill A, Oldner A (2000) The endothelin system in septic and endotoxin shock. Eur J Pharmacol 407:1–15PubMedCrossRef

Aird WC (2008) Endothelium in health and disease. Pharmacol Rep 60:139–143PubMed

Hemsen A, Modin A, Weitzberg E (1996) Increased concentrations of endothelin-1 messenger RNA in tissues and endothelin-1 peptide in plasma in septic pigs: modulation by betamethasone. Crit Care Med 24:1530–1536PubMedCrossRef

Brauner JS, Rohde LE, Clausell N (2000) Circulating endothelin-1 and tumor necrosis factor-alpha: early predictors of mortality in patients with septic shock. Intensive Care Med 26:305–313PubMedCrossRef

Tschaikowsky K, Sagner S, Lehnert N, Kaul M, Ritter J (2000) Endothelin in septic patients: effects on cardiovascular and renal function and its relationship to proinflammatory cytokines. Crit Care Med 28:1854–1860PubMedCrossRef

Wanecek M, Oldner A, Sundin P, Alving K, Weitzberg E, Rudehill A (1999) Effects on haemodynamics by selective endothelin ET(B) receptor and combined endothelin ET(A)/ET(B) receptor antagonism during endotoxin shock. Eur J Pharmacol 386:235–245PubMedCrossRef

10.

Krejci V, Hiltebrand LB, Erni D, Sigurdsson GH (2003) Endothelin receptor antagonist bosentan improves microcirculatory blood flow in splanchnic organs in septic shock. Crit Care Med 31:203–210PubMedCrossRef

11.

Oldner A, Wanecek M, Goiny M, Weitzberg E, Rudehill A, Alving K, Sollevi A (1998) The endothelin receptor antagonist bosentan restores gut oxygen delivery and reverses intestinal mucosal acidosis in porcine endotoxin shock. Gut 42:696–702PubMedCrossRef

12.

Iskit AB, Senel I, Sokmensuer C, Guc MO (2004) Endothelin receptor antagonist bosentan improves survival in a murine caecal ligation and puncture model of septic shock. Eur J Pharmacol 506:83–88PubMedCrossRef

13.

Wanecek M, Weitzberg E, Alving K, Rudehill A, Oldner A (2001) Effects of the endothelin receptor antagonist bosentan on cardiac performance during porcine endotoxin shock. Acta Anaesthesiol Scand 45:1262–1270PubMedCrossRef

14.

Weitzberg E, Hemsen A, Rudehill A, Modin A, Wanecek M, Lundberg JM (1996) Bosentan-improved cardiopulmonary vascular performance and increased plasma levels of endothelin-1 in porcine endotoxin shock. Br J Pharmacol 118:617–626PubMed

15.

Struck J, Morgenthaler NG, Bergmann A (2005) Proteolytic processing pattern of the endothelin-1 precursor in vivo. Peptides 26:2482–2486PubMedCrossRef

16.

Papassotiriou J, Morgenthaler NG, Struck J, Alonso C, Bergmann A (2006) Immunoluminometric assay for measurement of the C-terminal endothelin-1 precursor fragment in human plasma. Clin Chem 52:1144–1151PubMedCrossRef

17.

Schuetz P, Christ-Crain M, Morgenthaler N, Struck J, Bergmann A, Müller B (2007) Circulating precursor levels of endothelin-1 and adrenomedullin, two endothelium-derived, counteracting substances, in sepsis. Endothelium 14:345–351PubMedCrossRef

18.

Schuetz P, Stolz D, Mueller B, Morgenthaler NG, Struck J, Mueller C, Bingisser R, Tamm M, Christ-Crain M (2008) Endothelin-1 precursor peptides correlate with severity of disease and outcome in patients with community acquired pneumonia. BMC Infect Dis 8:22PubMedCrossRef

19.

Kruger S, Ewig S, Giersdorf S, Hartmann O, Suttorp N, Welte T (2010) Cardiovascular and inflammatory biomarkers to predict short- and long-term survival in community-acquired pneumonia. Am J Respir Crit Care Med 182:1426–1434PubMedCrossRef

20.

Samransamruajkit R, Moonviriyakit K, Vanapongtipagorn P, Prapphal N, Deerojanawong J, Poovorawan Y (2002) Plasma endothelin-1 in infants and young children with acute bronchiolitis and viral pneumonia. Asian Pac J Allergy Immunol 20:229–234PubMed

21.

Ando T, Ogawa K, Yamaki K, Hara M, Takagi K (1996) Plasma concentrations of atrial, brain, and C-type natriuretic peptides and endothelin-1 in patients with chronic respiratory diseases. Chest 110:462–468PubMedCrossRef

22.

Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, Neidert S, Fricker T, Blum C, Schild U, Regez K, Schoenenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Mueller B (2009) Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 302:1059–1066PubMedCrossRef

23.

Schuetz P, Wolbers M, Christ-Crain M, Thomann R, Falconnier C, Widmer I, Neidert S, Fricker T, Blum C, Schild U, Morgenthaler NG, Schoenenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Mueller B (2010) Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections. Crit Care (London, England) 14:R106CrossRef

24.

Vazquez M, Jockers K, Christ-Crain M, Zimmerli W, Muller B, Schuetz P (2010) MR-pro-atrial natriuretic peptide (MR-proANP) predicts short- and long-term outcomes in respiratory tract infections: a prospective validation study. Int J Cardiol [Epub ahead of print]

25.

Schuetz P, Widmer I, Chaudri A, Christ-Crain M, Zimmerli W, Mueller B (2010) Prognostic value of procalcitonin in community-acquired pneumonia. Eur Respir J 37:384–392PubMedCrossRef

26.

Schuetz P, Christ-Crain M, Wolbers M, Schild U, Thomann R, Falconnier C, Widmer I, Neidert S, Blum CA, Schonenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Muller B (2007) Procalcitonin guided antibiotic therapy and hospitalization in patients with lower respiratory tract infections: a prospective, multicenter, randomized controlled trial. BMC Health Serv Res 7:102PubMedCrossRef

27.

Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG (2007) Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44(Suppl 2):S27–S72PubMedCrossRef

28.

Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, Dean N, File T, Fine MJ, Gross PA, Martinez F, Marrie TJ, Plouffe JF, Ramirez J, Sarosi GA, Torres A, Wilson R, Yu VL (2001) Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 163:1730–1754PubMed

29.

Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, Coley CM, Marrie TJ, Kapoor WN (1997) A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 336:243–250PubMedCrossRef

30.

Struck J, Morgenthaler NG, Bergmann A (2005) Copeptin, a stable peptide derived from the vasopressin precursor, is elevated in serum of sepsis patients. Peptides 26:2500–2504PubMedCrossRef

31.

Morgenthaler NG, Struck J, Alonso C, Bergmann A (2005) Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clin Chem 51:1823–1829PubMedCrossRef

32.

Struck J, Tao C, Morgenthaler NG, Bergmann A (2004) Identification of an adrenomedullin precursor fragment in plasma of sepsis patients. Peptides 25:1369–1372PubMedCrossRef

33.

Morgenthaler NG, Struck J, Thomas B, Bergmann A (2004) Immunoluminometric assay for the midregion of pro-atrial natriuretic peptide in human plasma. Clin Chem 50:234–236PubMedCrossRef

34.

Cook NR (2008) Statistical evaluation of prognostic versus diagnostic models: beyond the ROC curve. Clin Chem 54:17–23PubMedCrossRef

35.

Grambsch PM, Therneau TM, Fleming TR (1995) Diagnostic plots to reveal functional form for covariates in multiplicative intensity models. Biometrics 51:1469–1482PubMedCrossRef

36.

Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS (2008) Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 27:157–172 discussion 207–112PubMedCrossRef

37.

Grandel U, Grimminger F (2003) Endothelial responses to bacterial toxins in sepsis. Crit Rev Immunol 23:267–299PubMedCrossRef

38.

Kedzierski RM, Yanagisawa M (2001) Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol 41:851–876PubMedCrossRef

39.

Sanai L, Haynes WG, MacKenzie A, Grant IS, Webb DJ (1996) Endothelin production in sepsis and the adult respiratory distress syndrome. Intensive Care Med 22:52–56PubMedCrossRef

40.

Voerman HJ, Stehouwer CD, van Kamp GJ, Strack van Schijndel RJ, Groeneveld AB, Thijs LG (1992) Plasma endothelin levels are increased during septic shock. Crit Care Med 20:1097–1101PubMedCrossRef

41.

File TM Jr, Marrie TJ (2010) Burden of community-acquired pneumonia in North American adults. Postgrad Med 122:130–141PubMedCrossRef

42.

Fine MJ, Hough LJ, Medsger AR, Li YH, Ricci EM, Singer DE, Marrie TJ, Coley CM, Walsh MB, Karpf M, Lahive KC, Kapoor WN (1997) The hospital admission decision for patients with community-acquired pneumonia. Results from the pneumonia Patient Outcomes Research Team cohort study. Arch Intern Med 157:36–44PubMedCrossRef

43.

Schuetz P, Koller M, Christ-Crain M, Steyerberg E, Stolz D, Muller C, Bucher HC, Bingisser R, Tamm M, Muller B (2008) Predicting mortality with pneumonia severity scores: importance of model recalibration to local settings. Epidemiol Infect 136:1628–1637PubMedCrossRef

44.

Schuetz P, Christ-Crain M, Muller B (2009) Procalcitonin and other biomarkers to improve assessment and antibiotic stewardship in infections—hope for hype? Swiss Med Wkly 139:318–326PubMed

45.

Albertini M, Clement MG, Hussain SN (2003) Role of endothelin ETA receptors in sepsis-induced mortality, vascular leakage, and tissue injury in rats. Eur J Pharmacol 474:129–135PubMedCrossRef

46.

Antonelli M, Azoulay E, Bonten M, Chastre J, Citerio G, Conti G, De Backer D, Lemaire F, Gerlach H, Hedenstierna G, Joannidis M, Macrae D, Mancebo J, Maggiore SM, Mebazaa A, Preiser JC, Pugin J, Wernerman J, Zhang H (2010) Year in review in Intensive Care Medicine 2009: I. Pneumonia and infections, sepsis, outcome, acute renal failure and acid base, nutrition and glycaemic control. Intensive Care Med 36:196–209PubMedCrossRef

47.

Andrews P, Azoulay E, Antonelli M, Brochard L, Brun-Buisson C, De Backer D, Dobb G, Fagon JY, Gerlach H, Groeneveld J, Macrae D, Mancebo J, Metnitz P, Nava S, Pugin J, Pinsky M, Radermacher P, Richard C (2007) Year in review in Intensive Care Medicine, 2006. II. Infections and sepsis, haemodynamics, elderly, invasive and noninvasive mechanical ventilation, weaning, ARDS. Intensive Care Med 33:214–229PubMedCrossRef

48.

Sligl WI, Majumdar SR, Marrie TJ (2009) Triaging severe pneumonia: what is the “score” on prediction rules? Crit Care Med 37:3166–3168PubMedCrossRef

49.

Leone M, Boutiere B, Camoin-Jau L, Albanese J, Horschowsky N, Mege JL, Martin C, Dignat-George F (2002) Systemic endothelial activation is greater in septic than in traumatic-hemorrhagic shock but does not correlate with endothelial activation in skin biopsies. Crit Care Med 30:808–814PubMedCrossRef

Title: Repeated measurements of endothelin-1 precursor peptides predict the outcome in community-acquired pneumonia
Authors: Philipp Schuetz
Mirjam Christ-Crain
Werner Zimmerli
Beat Mueller
Publication date: 01-06-2011
Publisher: Springer-Verlag
Published in: Intensive Care Medicine / Issue 6/2011
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-011-2208-2

2024 ASCO Annual Meeting

Springer Medicine

Repeated measurements of endothelin-1 precursor peptides predict the outcome in community-acquired pneumonia

Abstract

Purpose

Methods

Results

Conclusions

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 6/2011

Emergence of autoantibodies to HMGB1 is associated with survival in patients with septic shock

Optimisation of positive end-expiratory pressure by forced oscillation technique in a lavage model of acute lung injury

Long-term sedation in intensive care unit: a randomized comparison between inhaled sevoflurane and intravenous propofol or midazolam

The deteriorating ward patient: a Swedish–Australian comparison

Acute intestinal failure in critically ill patients: is plasma citrulline the right marker?

Dose-related effect of smoking on mortality in critically ill patients: a multicentre cohort study