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01-12-2020 | Septicemia | Research

Circulating bioactive adrenomedullin as a marker of sepsis, septic shock and critical illness

Authors: Oscar H. M. Lundberg, Maria Lengquist, Martin Spångfors, Martin Annborn, Deborah Bergmann, Janin Schulte, Helena Levin, Olle Melander, Attila Frigyesi, Hans Friberg

Published in: Critical Care | Issue 1/2020

Abstract

Background

Biomarkers can be of help to understand critical illness and to identify and stratify sepsis. Adrenomedullin is a vasoactive hormone, with reported prognostic and potentially therapeutic value in sepsis. The primary aim of this study was to investigate the association of circulating bioactive adrenomedullin (bio-ADM) levels at intensive care unit (ICU) admission with mortality in sepsis patients and in a general ICU population. Secondary aims included the association of bio-ADM with organ failure and the ability of bio-ADM to identify sepsis.

Methods

In this retrospective observational study, adult patients admitted to one of four ICUs during 2016 had admission bio-ADM levels analysed. Age-adjusted odds ratios (OR) with 95% CI for log-2 transformed bio-ADM, and Youden’s index derived cut-offs were calculated. The primary outcome was 30-day mortality, and secondary outcomes included the need for organ support and the ability to identify sepsis.

Results

Bio-ADM in 1867 consecutive patients were analysed; 632 patients fulfilled the sepsis-3 criteria of whom 267 had septic shock. The median bio-ADM in the entire ICU population was 40 pg/mL, 74 pg/mL in sepsis patients, 107 pg/mL in septic shock and 29 pg/mL in non-septic patients. The association of elevated bio-ADM and mortality in sepsis patients and the ICU population resulted in ORs of 1.23 (95% CI 1.07–1.41) and 1.22 (95% CI 1.12–1.32), respectively. The association with mortality remained after additional adjustment for lactate in sepsis patients. Elevated bio-ADM was associated with an increased need for dialysis with ORs of 2.28 (95% CI 2.01–2.59) and 1.97 (95% CI 1.64–2.36) for the ICU population and sepsis patients, respectively, and with increased need of vasopressors, OR 1.33 (95% CI 1.23–1.42) (95% CI 1.17–1.50) for both populations. Sepsis was identified with an OR of 1.78 (95% CI 1.64–1.94) for bio-ADM, after additional adjustment for severity of disease. A bio-ADM cut-off of 70 pg/mL differentiated between survivors and non-survivors in sepsis, but a Youden’s index derived threshold of 108 pg/mL performed better.

Conclusions

Admission bio-ADM is associated with 30-day mortality and organ failure in sepsis patients as well as in a general ICU population. Bio-ADM may be a morbidity-independent sepsis biomarker.

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World Health Organization: Improving the prevention, diagnosis and clinical management of sepsis: report by the secretariat, 6 (2017)

Seymour CW, Kennedy JN, Wang S, Chang CH, Elliott CF, Xu Z, Berry S, Clermont G, Cooper G, Gomez H, Huang DT, Kellum JA, Mi Q, Opal SM, Talisa V, van der Poll T, Visweswaran S, Vodovotz Y, Weiss JC, Yealy DM, Yende S, Angus DC. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA. 2019;321(20):2003–17. https://doi.org/10.1001/jama.2019.5791.CrossRef

Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun. 1993;192(2):553–60. https://doi.org/10.1006/bbrc.1993.1451.CrossRef

Hinson JP, Kapas S, Smith DM. Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev. 2000;21(2):138–67. https://doi.org/10.1210/edrv.21.2.0396.CrossRef

Samson WK, Resch ZT, Murphy TC, Vargas TT, Schell DA. Adrenomedullin: is there physiological relevance in the pathology and pharmacology? News Physiol Sci. 1999;14:255–9.

Zudaire E, Portal-Nunez S, Cuttitta F. The central role of adrenomedullin in host defense. J Leukoc Biol. 2006;80(2):237–44. https://doi.org/10.1189/jlb.0206123.CrossRef

Lainchbury JG, Troughton RW, Lewis LK, Yandle TG, Richards AM, Nicholls MG. Hemodynamic, hormonal, and renal effects of short-term adrenomedullin infusion in healthy volunteers. J Clin Endocrinol Metab. 2000;85(3):1016–20.

Nicholls MG, Lainchbury JG, Lewis LK, McGregor DO, Richards AM, Troughton RW, Yandle TG. Bioactivity of adrenomedullin and proadrenomedullin n-terminal 20 peptide in man. Peptides. 2001;22(11):1745–52.CrossRef

Geven C, Bergmann A, Kox M, Pickkers P. Vascular effects of adrenomedullin and the anti-adrenomedullin antibody adrecizumab in sepsis. Shock. 2018;50(2):132–40. https://doi.org/10.1097/SHK.0000000000001103.CrossRef

10.

Christ-Crain M, Morgenthaler NG, Struck J, Harbarth S, Bergmann A, Muller B. Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care. 2005;9(6):816–24. https://doi.org/10.1186/cc3885.CrossRef

11.

Guignant C, Voirin N, Venet F, Poitevin F, Malcus C, Bohe J, Lepape A, Monneret G. Assessment of pro-vasopressin and pro-adrenomedullin as predictors of 28-day mortality in septic shock patients. Intensive Care Med. 2009;35(11):1859–67. https://doi.org/10.1007/s00134-009-1610-5.CrossRef

12.

Marino R, Struck J, Maisel AS, Magrini L, Bergmann A, Di Somma S. Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis. Crit Care. 2014;18(1):34. https://doi.org/10.1186/cc13731.CrossRef

13.

Lundberg OH, Bergenzaun L, Ryden J, Rosenqvist M, Melander O, Chew MS. Adrenomedullin and endothelin-1 are associated with myocardial injury and death in septic shock patients. Crit Care. 2016;20(1):178. https://doi.org/10.1186/s13054-016-1361-y.CrossRef

14.

Caironi P, Latini R, Struck J, Hartmann O, Bergmann A, Maggio G, Cavana M, Tognoni G, Pesenti A, Gattinoni L, Masson S, Investigators AS. Circulating biologically active adrenomedullin (bio-adm) predicts hemodynamic support requirement and mortality during sepsis. Chest. 2017;152(2):312–20. https://doi.org/10.1016/j.chest.2017.03.035.CrossRef

15.

Mebazaa A, Geven C, Hollinger A, Wittebole X, Chousterman BG, Blet A, Gayat E, Hartmann O, Scigalla P, Struck J, Bergmann A, Antonelli M, Beishuizen A, Constantin JM, Damoisel C, Deye N, Di Somma S, Dugernier T, Francois B, Gaudry S, Huberlant V, Lascarrou JB, Marx G, Mercier E, Oueslati H, Pickkers P, Sonneville R, Legrand M, Laterre PF, Adren OSSsi. Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational adrenomedullin and outcome in sepsis and septic shock-1 (adrenoss-1) study. Crit Care 2018;22(1):354. https://doi.org/10.1186/s13054-018-2243-2

16.

Kim H, Hur M, Struck J, Bergmann A, Di Somma S. Circulating biologically active adrenomedullin predicts organ failure and mortality in sepsis. Ann Lab Med. 2019;39(5):454–63. https://doi.org/10.3343/alm.2019.39.5.454.CrossRef

17.

Khan SQ, O’Brien RJ, Struck J, Quinn P, Morgenthaler N, Squire I, Davies J, Bergmann A, Ng LL. Prognostic value of midregional pro-adrenomedullin in patients with acute myocardial infarction: the lamp (leicester acute myocardial infarction peptide) study. J Am Coll Cardiol. 2007;49(14):1525–32. https://doi.org/10.1016/j.jacc.2006.12.038.CrossRef

18.

Maisel A, Mueller C, Nowak RM, Peacock WF, Ponikowski P, Mockel M, Hogan C, Wu AH, Richards M, Clopton P, Filippatos GS, Di Somma S, Anand I, Ng LL, Daniels LB, Neath SX, Christenson R, Potocki M, McCord J, Hartmann O, Morgenthaler NG, Anker SD. Midregion prohormone adrenomedullin and prognosis in patients presenting with acute dyspnea: results from the bach (biomarkers in acute heart failure) trial. J Am Coll Cardiol. 2011;58(10):1057–67. https://doi.org/10.1016/j.jacc.2011.06.006.CrossRef

19.

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. Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections. Crit Care. 2010;14(3):106. https://doi.org/10.1186/cc9055.CrossRef

20.

Stolz D, Christ-Crain M, Morgenthaler NG, Miedinger D, Leuppi J, Muller C, Bingisser R, Struck J, Muller B, Tamm M. Plasma pro-adrenomedullin but not plasma pro-endothelin predicts survival in exacerbations of copd. Chest. 2008;134(2):263–72. https://doi.org/10.1378/chest.08-0047.CrossRef

21.

Self WH, Storrow AB, Hartmann O, Barrett TW, Fermann GJ, Maisel AS, Struck J, Bergmann A, Collins SP. Plasma bioactive adrenomedullin as a prognostic biomarker in acute heart failure. Am J Emerg Med. 2016;34(2):257–62. https://doi.org/10.1016/j.ajem.2015.10.033.CrossRef

22.

Yuyun MF, Narayan HK, Quinn PA, Struck J, Bergmann A, Hartmann O, Ng LL. Prognostic value of human mature adrenomedullin in patients with acute myocardial infarction. J Cardiovasc Med (Hagerstown). 2017;18(1):42–50. https://doi.org/10.2459/JCM.0000000000000299.CrossRef

23.

Kremer D, Ter Maaten JM, Voors AA. Bio-adrenomedullin as a potential quick, reliable, and objective marker of congestion in heart failure. Eur J Heart Fail. 2018;20(9):1363–5. https://doi.org/10.1002/ejhf.1245.CrossRef

24.

Ter Maaten JM, Kremer D, Demissei BG, Struck J, Bergmann A, Anker SD, Ng LL, Dickstein K, Metra M, Samani NJ, Romaine SPR, Cleland J, Girerd N, Lang CC, van Veldhuisen DJ, Voors AA. Bio-adrenomedullin as a marker of congestion in patients with new-onset and worsening heart failure. Eur J Heart Fail. 2019;21(6):732–43. https://doi.org/10.1002/ejhf.1437.CrossRef

25.

Morgenthaler NG, Struck J, Alonso C, Bergmann A. Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clin Chem. 2005;51(10):1823–9. https://doi.org/10.1373/clinchem.2005.051110.CrossRef

26.

Hippenstiel S, Witzenrath M, Schmeck B, Hocke A, Krisp M, Krull M, Seybold J, Seeger W, Rascher W, Schutte H, Suttorp N. Adrenomedullin reduces endothelial hyperpermeability. Circ Res. 2002;91(7):618–25.CrossRef

27.

Ertmer C, Morelli A, Rehberg S, Lange M, Hucklenbruch C, Van Aken H, Booke M, Westphal M. Exogenous adrenomedullin prevents and reverses hypodynamic circulation and pulmonary hypertension in ovine endotoxaemia. Br J Anaesth. 2007;99(6):830–6. https://doi.org/10.1093/bja/aem295.CrossRef

28.

Temmesfeld-Wollbruck B, Brell B, David I, Dorenberg M, Adolphs J, Schmeck B, Suttorp N, Hippenstiel S. Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock. Intensive Care Med. 2007;33(4):703–10. https://doi.org/10.1007/s00134-007-0561-y.CrossRef

29.

Kox M, Pickkers P. Adrenomedullin: its double-edged sword during sepsis slices yet again. Intensive Care Med Exp. 2014;2(1):1. https://doi.org/10.1186/2197-425X-2-1.CrossRef

30.

Struck J, Hein F, Karasch S, Bergmann A. Epitope specificity of anti-adrenomedullin antibodies determines efficacy of mortality reduction in a cecal ligation and puncture mouse model. Intensive Care Med Exp. 2013;1(1):22. https://doi.org/10.1186/2197-425X-1-3.CrossRef

31.

Geven C, Blet A, Kox M, Hartmann O, Scigalla P, Zimmermann J, Marx G, Laterre PF, Mebazaa A, Pickkers P. A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase ii clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentration (adrenoss-2). BMJ Open. 2019;9(2):024475. https://doi.org/10.1136/bmjopen-2018-024475.CrossRef

32.

Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The strengthening the reporting of observational studies in epidemiology (strobe) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147(8):573–7.CrossRef

33.

Lengquist M, Lundberg OHM, Spangfors M, Annborn M, Levin H, Friberg H, Frigyesi A. Sepsis is underreported in swedish intensive care units: a retrospective observational multicentre study. Acta Anaesthesiol Scand. 2020;64(8):1167–76. https://doi.org/10.1111/aas.13647.CrossRef

34.

Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche J-D, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent J-L, Angus DC. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–10.CrossRef

35.

Weber J, Sachse J, Bergmann S, Sparwaßer A, Struck J, Bergmann A. Sandwich immunoassay for bioactive plasma adrenomedullin. J Appl Lab Med. 2019;2(2):222–33. https://doi.org/10.1373/jalm.2017.023655.CrossRef

36.

Nordlund P, Walther S. Riskjusteringsmodeller inom svensk intensivvård. 2019. https://www.icuregswe.org/globalassets/publikationer/fokusrapporter/fokusrapport_riskjustering_i_sir.pdf. Accessed 01 Oct 2019

37.

Moreno RP, Metnitz PG, Almeida E, Jordan B, Bauer P, Campos RA, Iapichino G, Edbrooke D, Capuzzo M, Le Gall J-R. SAPS 3–from evaluation of the patient to evaluation of the intensive care unit. Part 2: development of a prognostic model for hospital mortality at ICU admission. Intensive Care Med. 2005;31(10):1345–55.CrossRef

38.

Hosmer DW, Lemeshow S. Assessing the fit of the model, Chap 5. Hoboken: Wiley; 2005. p. 143–202. https://doi.org/10.1002/0471722146.ch5.CrossRef

39.

Harrington DP, Fleming TR. A class of rank test procedures for censored survival data. Biometrika. 1982;69(3):553.CrossRef

40.

Fawcett T. An introduction to ROC analysis. Pattern Recogn Lett. 2006;27(8):861–74. https://doi.org/10.1016/j.patrec.2005.10.010.CrossRef

41.

DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44(3):837.CrossRef

42.

Ranganathan S, Nakai K, Schönbach C. Encyclopedia of bioinformatics and computational biology: ABC of bioinformatics, vol 1–3. 1st ed. Amsterdam: Elsevier; 2019.

43.

Wilhelms S, Huss F, Granath G, Sjöberg F. Assessment of incidence of severe sepsis in Sweden using different ways of abstracting international classification of diseases codes: difficulties with methods and interpretation of results. Crit Care Med. 2010;38(6):1442.CrossRef

44.

Fleischmann-Struzek C, Thomas-Ruddel DO, Schettler A, Schwarzkopf D, Stacke A, Seymour CW, Haas C, Dennler U, Reinhart K. Comparing the validity of different ICD coding abstraction strategies for sepsis case identification in German claims data. PLoS ONE. 2018;13(7):0198847.CrossRef

45.

Blet A, de Roquetaillade C, Hartmann O, Struck J, Mebazaa A, Chousterman BG, Adrenoss-1 study i. Added value of serial bio-adrenomedullin measurement in addition to lactate for the prognosis of septic patients admitted to ICU. Crit Care. 2020;24(1):69. https://doi.org/10.1186/s13054-020-2794-x

46.

Lemasle L, Blet A, Geven C, Cherifa M, Deniau B, Hollinger A, Fournier MC, Monnet X, Rennuit I, Darmon M, Laterre PF, Struck J, Hartmann O, Bergmann A, Mebazaa A, Gayat E. Bioactive adrenomedullin, organ support therapies, and survival in the critically ill: results from the French and European outcome registry in ICU study. Crit Care Med. 2020;48(1):49–55. https://doi.org/10.1097/CCM.0000000000004044.CrossRef

47.

Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304–77.CrossRef

Title: Circulating bioactive adrenomedullin as a marker of sepsis, septic shock and critical illness
Authors: Oscar H. M. Lundberg
Maria Lengquist
Martin Spångfors
Martin Annborn
Deborah Bergmann
Janin Schulte
Helena Levin
Olle Melander
Attila Frigyesi
Hans Friberg
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Septicemia
Septicemia
Septic Shock
Biomarkers
Published in: Critical Care / Issue 1/2020
Electronic ISSN: 1364-8535
DOI: https://doi.org/10.1186/s13054-020-03351-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Circulating bioactive adrenomedullin as a marker of sepsis, septic shock and critical illness

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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