Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter August 29, 2018

Mid-regional pro-adrenomedullin predicts poor outcome in non-selected patients admitted to an intensive care unit

  • Chiara Bellia , Luisa Agnello , Bruna Lo Sasso , Giulia Bivona , Maurizio Santi Raineri , Antonino Giarratano and Marcello Ciaccio EMAIL logo



Mortality risk and outcome in critically ill patients can be predicted by scoring systems, such as APACHE and SAPS. The identification of prognostic biomarkers, simple to measure upon admission to an intensive care unit (ICU) is an open issue. The aim of this observational study was to assess the prognostic value of plasma mid-regional pro-adrenomedullin (MR-proADM) at ICU admission in non-selected patients in comparison to Acute Physiology and Chronic Health Evaluation II (APACHEII) and Simplified Acute Physiology Score II (SAPSII) scores.


APACHEII and SAPSII scores were calculated after 24 h from ICU admission. Plasma MR-proADM levels were measured by TRACE-Kryptor on admission (T0) and after 24 h (T24). The primary endpoint was intra-hospital mortality; secondary endpoint was length of stay (LOS).


One hundred and twenty-six consecutive non-selected patients admitted to an ICU were enrolled. Plasma MR-proADM levels were correlated with LOS (r=0.28; p=0.0014 at T0; r=0.26; p=0.005 at T24). Multivariate analysis showed that T0 MR-proADM was a significant predictor of mortality (odds ratio [OR]: 1.27; 95% confidence interval [95%CI]: 1.03–1.55; p=0.022). Receiver operating characteristic curves analysis revealed that MR-proADM on ICU admission identified non-survivors with high accuracy, not inferior to the one of APACHEII and SAPSII scores (area under the curve [AUC]: 0.71; 95%CI: 0.62–0.78; p=0.0002 for MR-proADM; AUC: 0.71; 95%CI: 0.62–0.79; p<0.0001 for APACHEII; AUC: 0.8; 95%CI: 0.71–0.87; p<0.0001 for SAPSII).


Our findings point out a role of MR-proADM as a prognostic tool in non-selected patients in ICUs being a reliable predictor of mortality and LOS and support its use on admission to an ICU to help the management of critically ill patients.

Corresponding author: Professor Marcello Ciaccio, MD, PhD, Department of Biopathology and Medical Biotechnologies, Section of Clinical Biochemistry and Clinical Molecular Medicine, Policlinico P. Giaccone, University of Palermo, Via del Vespro, 129, CAP 90127, Palermo, Italy, Phone: +39 091 23865701, Fax: +39 091 655 3275
aChiara Bellia and Luisa Agnello contributed equally to this work.


Thermo Fisher Scientific provided the reagents for MR-proADM measurement and provide support for statistical analysis.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


1. Salluh JI, Soares M. ICU severity of illness scores: APACHE, SAPS and MPM. Curr Opin Crit Care 2014;20:557–65.10.1097/MCC.0000000000000135Search in Google Scholar PubMed

2. Kuzniewicz MW, Vasilevskis EE, Lane R, Dean ML, Trivedi NG, Rennie DJ, et al. Variation in ICU risk-adjusted mortality: impact of methods of assessment and potential confounders. Chest 2008;133:1319–27.10.1378/chest.07-3061Search in Google Scholar PubMed

3. Murphy-Filkins R, Teres D, Lemeshow S, Hosmer DW. Effect of changing patient mix on the performance of an intensive care unit severity-of-illness model: how to distinguish a general from a specialty intensive care unit. Crit Care Med 1996;24:1968–73.10.1097/00003246-199612000-00007Search in Google Scholar PubMed

4. Balmelli C, Drexler B, Mueller C. Utile or futile: biomarkers in the ICU. Crit Care 2011;15:131.10.1186/cc10056Search in Google Scholar PubMed PubMed Central

5. Giulia B, Luisa A, Concetta S, Bruna LS, Chiara B, Marcello C. Procalcitonin and community-acquired pneumonia (CAP) in children. Clin Chim Acta 2015;451:215–8.10.1016/j.cca.2015.09.031Search in Google Scholar PubMed

6. Yeh JH, Huang CT, Liu CH, Ruan SY, Tsai YJ, Chien YC, et al. Cautious application of pleural N-terminal pro-B-type natriuretic peptide in diagnosis of congestive heart failure pleural effusions among critically ill patients. PLoS One 2014;9:e115301.10.1371/journal.pone.0115301Search in Google Scholar PubMed PubMed Central

7. Sweeney TE, Khatri P. Generalizable biomarkers in critical care: toward precision medicine. Crit Care Med 2017;45:934–9.10.1097/CCM.0000000000002402Search in Google Scholar PubMed PubMed Central

8. Agnello L, Bellia C, Di Gangi M, Lo Sasso B, Calvaruso L, Bivona G, et al. Utility of serum procalcitonin and C-reactive protein in severity assessment of community-acquired pneumonia in children. Clin Biochem 2016;49:47–50.10.1016/j.clinbiochem.2015.09.008Search in Google Scholar PubMed

9. Valenzuela-Sánchez F, Valenzuela-Méndez B, Rodríguez-Gutiérrez JF, Estella-García Á, González-García MÁ. New role of biomarkers: mid-regional pro-adrenomedullin, the biomarker of organ failure. Ann Transl Med 2016;4:329.10.21037/atm.2016.08.65Search in Google Scholar PubMed PubMed Central

10. Pilotto A, Dini S, Veronese N, Daragjati J, Miolo M, Mion MM, et al. Multidimensional Prognostic Index (MPI) and proadrenomedullin plasma levels in predicting one-month mortality risk in older patients hospitalized with community-acquired pneumonia (CAP): a prospective study. Panminerva Med 2018. Doi: 10.23736/S0031-0808.18.03408-0. [Epub ahead of print].10.23736/S0031-0808.18.03408-0Search in Google Scholar PubMed

11. Koyama T, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Shindo TJ. Adrenomedullin-RAMP2 system in vascular endothelial cells. Atheroscler Thromb 2015;22:647–53.10.5551/jat.29967Search in Google Scholar

12. Eto T. A review of the biological properties and clinical implications of adrenomedullin and proadrenomedullin N-terminal 20 peptide (PAMP), hypotensive and vasodilating peptides. Peptides 2001;22:1693–711.10.1016/S0196-9781(01)00513-7Search in Google Scholar

13. Pio R, Martinez A, Unsworth EJ, Kowalak JA, Bengoechea JA, Zipfel PF, et al. Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. J Biol Chem 2001;276:12292–300.10.1074/jbc.M007822200Search in Google Scholar

14. Lewis LK, Smith MW, Brennan SO, Yandle TG, Richards AM, Nicholls MG. Degradation of human adrenomedullin (1–52) by plasma membrane enzymes and identification of metabolites. Peptides 1997;18:733–9.10.1016/S0196-9781(97)00005-3Search in Google Scholar

15. Martínez A, Oh HR, Unsworth EJ, Bregonzio C, Saavedra JM, Stetler-Stevenson WG, et al. Matrix metalloproteinase-2 cleavage of adrenomedullin produces a vasoconstrictor out of a vasodilator. Biochem J 2004;383:413–8.10.1042/BJ20040920Search in Google Scholar PubMed PubMed Central

16. Morgenthaler NG, Struck J, Alonso C, Bergmann A. Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clin Chem 2005;51:1823–9.10.1373/clinchem.2005.051110Search in Google Scholar PubMed

17. Self WH, Storrow AB, Hartmann O, Barrett TW, Fermann GJ, Maisel AS, et al. Plasma bioactive adrenomedullin as a prognostic biomarker in acute heart failure. Am J Emerg Med 2016;34:257–62.10.1016/j.ajem.2015.10.033Search in Google Scholar PubMed PubMed Central

18. Nishikimi T. Adrenomedullin in the kidney-renal physiological and pathophysiological roles. Curr Med Chem 2007;14:1689–99.10.2174/092986707780830943Search in Google Scholar PubMed

19. Bernal-Morell E, García-Villalba E, Vera MD, Medina B, Martinez M, Callejo V, et al. Usefulness of midregional pro-adrenomedullin as a marker of organ damage and predictor of mortality in patients with sepsis. J Infect 2018;76:249–57.10.1016/j.jinf.2017.12.003Search in Google Scholar PubMed

20. Legramante JM, Mastropasqua M, Susi B, Porzio O, Mazza M, Miranda Agrippino G, et al. Prognostic performance of MR-pro-adrenomedullin in patients with community acquired pneumonia in the Emergency Department compared to clinical severity scores PSI and CURB. PLoS One 2017;12:e0187702.10.1371/journal.pone.0187702Search in Google Scholar PubMed PubMed Central

21. Tzikas S, Keller T, Ojeda FM, Zeller T, Wild PS, Lubos E, et al. MR-proANP and MR-proADM for risk stratification of patients with acute chest pain. Heart 2013;99:388–95.10.1136/heartjnl-2012-302956Search in Google Scholar PubMed

22. Khan SQ, O’Brien RJ, Struck J, Quinn P, Morgenthaler N, Squire I, et al. 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;49:1525–32.10.1016/j.jacc.2006.12.038Search in Google Scholar PubMed

23. Breslow MJ, Badawi O. Severity scoring in the critically ill: part 1 – interpretation and accuracy of outcome prediction scoring systems. Chest 2012;141:245–52.10.1378/chest.11-0330Search in Google Scholar PubMed

24. Lilly CM, Zuckerman IH, Badawi O, Riker RR. Benchmark data from more than 240,000 adults that reflect the current practice of critical care in the United States. Chest 2011;140:1232–42.10.1378/chest.11-0718Search in Google Scholar PubMed

25. Sekulic AD, Trpkovic SV, Pavlovic AP, Marinkovic OM, Ilic AN. Scoring systems in assessing survival of critically ill ICU patients. Med Sci Monit 2015;21:2621–9.10.12659/MSM.894153Search in Google Scholar PubMed PubMed Central

26. Suberviola B, Castellanos-Ortega A, Ruiz Ruiz A, Lopez-Hoyos M, Santibañez M. Hospital mortality prognostication in sepsis using the new biomarkers suPAR and proADM in a single determination on ICU admission. Intensive Care Med 2013;39:1945–52.10.1007/s00134-013-3056-zSearch in Google Scholar PubMed

27. Elke G, Bloos F, Wilson DC, Brunkhorst FM, Briegel J, Reinhart K, et al. The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis – a secondary analysis of a large randomised controlled trial. Crit Care 2018;22:79.10.1186/s13054-018-2001-5Search in Google Scholar PubMed PubMed Central

28. De La Torre-Prados MV, Garcia-De La Torre A, Enguix A, Mayor-Reyes M, Nieto-González M, Garcia-Alcantara A. Mid-regional pro-adrenomedullin as prognostic biomarker in septic shock. Minerva Anestesiol 2016;82:760–6.Search in Google Scholar

29. Andaluz-Ojeda D, Nguyen HB, Meunier-Beillard N, Cicuéndez R, Quenot JP, Calvo D, et al. Superior accuracy of mid-regional proadrenomedullin for mortality prediction in sepsis with varying levels of illness severity. Ann Intensive Care 2017;7:1510.1186/s13613-017-0238-9Search in Google Scholar PubMed PubMed Central

30. Shankar-Hari M, Harrison DA, Rubenfeld GD, Rowan K. Epidemiology of sepsis and septic shock in critical care units: comparison between sepsis-2 and sepsis-3 populations using a national critical care database. Br J Anaesth 2017;119:626–36.10.1093/bja/aex234Search in Google Scholar PubMed

31. Schoe A, Schippers EF, Struck J, Ebmeyer S, Klautz RJ, de Jonge E, et al. Postoperative pro-adrenomedullin levels predict mortality in thoracic surgery patients: comparison with Acute Physiology and Chronic Health Evaluation IV Score. Crit Care Med 2015;43:373–81.10.1097/CCM.0000000000000709Search in Google Scholar PubMed

32. Simon TP, Martin L, Doemming S, Humbs A, Bruells C, Kopp R, et al. Plasma adrenomedullin in critically ill patients with sepsis after major surgery: a pilot study. J Crit Care 2017;38:68–72.10.1016/j.jcrc.2016.10.017Search in Google Scholar PubMed

33. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 1993;192:553–60.10.1006/bbrc.1993.1451Search in Google Scholar PubMed

34. Schonauer R, Els-Heindl S, Beck-Sickinger AG. Adrenomedullin – new perspectives of a potent peptide hormone. J Pept Sci 2017;23:472–85.10.1002/psc.2953Search in Google Scholar PubMed

35. Temmesfeld-Wollbrück B, Hocke AC, Suttorp N, Hippenstiel S. Adrenomedullin and endothelial barrier function. Thromb Haemost 2007;98:944–51.10.1160/TH07-02-0128Search in Google Scholar PubMed

36. Vigué B, Leblanc PE, Moati F, Pussard E, Foufa H, Rodrigues A, et al. Mid-regional pro-adrenomedullin (MR-proADM), a marker of positive fluid balance in critically ill patients: results of the ENVOL study. Crit Care 2016;20:363.10.1186/s13054-016-1540-xSearch in Google Scholar PubMed PubMed Central

37. García-Ponce A, Chánez Paredes S, Castro Ochoa KF, Schnoor M. Regulation of endothelial and epithelial barrier functions by peptide hormones of the adrenomedullin family. Tissue Barriers 2016;4:e1228439.10.1080/21688370.2016.1228439Search in Google Scholar PubMed PubMed Central

38. Hinson JP, Kapas S, Smith DM. Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev 2000;21:138–67.10.1210/edrv.21.2.0396Search in Google Scholar PubMed

Received: 2018-06-21
Accepted: 2018-07-21
Published Online: 2018-08-29
Published in Print: 2019-03-26

©2019 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 1.3.2024 from
Scroll to top button