Emerging Role of Adrenomedullin as Sepsis Prognostic Marker


Sepsis represents an important and global health problem. It affects 27–30 million people every year, 7–9 million of these die. Sepsis occurs when the body uncontrolled response to an infection injures its own tissues and organs. If it is not quickly recognised and treated, it may led to septic shock, multiorgan failure and death. Together with clinical signs, a series of biomarkers can be very useful in the early diagnosis of sepsis. Adrenomedullin (ADM) is one of these biomarkers, not only important for sepsis diagnosis but also particularly useful for prognosis. ADM is a hormone secreted by endothelial cells, involved in regulation of the endothelium barrier and vascular tone, so playing a decisive role in the inflammation process. The mid regional‐proadrenomedullin (MR‐proADM) is the molecule detected in septic patients because it is more stable than ADM and is released in an equimolar ratio of the active portion. MR‐proADM is capable to identify disease severity and progression, more accurately than other biomarkers and clinical scores. Inclusion of MR‐proADM assay in clinical routine could help the clinicians to manage septic patients especially by identifying their mortality risk.

Key Concepts

  • Sepsis is considered one of the most important public health concern with high rates of morbidity, mortality and resource consuming worldwide;
  • Sepsis is defined as uncontrolled immune response against infections;
  • A fast diagnosis of sepsis is necessary to promptly initiate the appropriate treatment;
  • Several biomarkers are adopted in clinical settings for sepsis diagnosis and prognosis, but the ‘gold standard’ has not found yet;
  • Mid Regional‐proAdrenomedullin (MR‐proADM) is a novel promising biomarker of prognosis associated to sepsis severity playing an important role in the initial evaluation and clinical management of septic patient.

Keywords: sepsis; biomarkers; clinical scores; mid regional pro‐adrenomedullin; prognosis

Figure 1. Structure of ADM gene located on chromosome 11: it is formed by four exons and three introns. The mRNA encodes proadrenomedullin: this one has four vasoactive peptides: ADM, aminoterminal peptide of proadrenomedullin (PAMP), adrenotensin and mid‐regional proadrenomedullin (MR‐proADM).


Al Shuaibi M, Bahu RR, Chaftari AM, et al. (2013) Pro‐adrenomedullin as a novel biomarker for predicting infections and response to antimicrobials in febrile patients with hematologic malignancies. Clinical Infectious Diseases 56: 943–950.

Allaker RP, Grosvenor PW, McAnerney DC, et al. (2006) Mechanisms of adrenomedullin antimicrobial action. Peptides 27: 661–666.

Andaluz‐Ojeda D, Bobillo F, Iglesias V, et al. (2012) A combined score of pro‐ and anti‐inflammatory interleukins improves mortality prediction in severe sepsis. Cytokine 57: 332–336.

Andaluz‐Ojeda D, Cicuéndez R, Calvo D, et al. (2015) Sustained value of proadrenomedullin as mortality predictor in severe sepsis. Journal of Infection 71: 136–139.

Angeletti S, Dicuonzo G, Fioravanti M, et al. (2015) Procalcitonin, MR‐proadrenomedullin, and cytokines measurement in sepsis diagnosis: advantages from test combination. Disease Markers 2015: 1–14.

Assicot M, Gendrel D, Carsin H, et al. (1993) High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 341: 515–518.

Billeter A, Turina M, Seifert B, et al. (2009) Early serum procalcitonin, interleukin‐6, and 24‐hour lactate clearance: useful indicators of septic infections in severely traumatized patients. World Journal of Surgery 33: 558–566.

Brain SD and Grant AD (2004) Vascular actions of calcitonin gene‐related peptide and adrenomedullin. Physiological Reviews 84: 903–934.

Charles PE, Péju E, Dantec A, et al. (2017) Mid‐regional pro‐adrenomedullin elevation upon ICU admission predicts the outcome of septic patients and is correlated with upcoming fluid overload. Shock 48: 418–426.

Chenevier‐Gobeaux C, Borderie D, Weiss N, et al. (2015) Presepsin (sCD14‐ST), an innate immune response marker in sepsis. Clinica Chimica Acta 450: 97–103.

Christ‐Crain M, Morgenthaler NG, Struck J, et al. (2005) Mid‐regional pro‐adrenomedullin as a prognostic marker in sepsis: an observational study. Critical Care 9: R816–R824.

Churpek MM, Snyder A, Han X, et al. (2017) Quick sepsis‐related organ failure assessment, systemic inflammatory iesponse syndrome, and early warning scores for detecting clinical deterioration in infected patients outside the Intensive Care Unit. American Journal of Respiratory and Critical Care Medicine 195: 906–911.

Dagher GA, Saadeldine M, Bachir R, et al. (2015) Descriptive analysis of sepsis in a developing country. International Journal of Emergency Medicine 8: 19.

Debiane L, Hachem RY, Al Wohoush I, et al. (2014) The utility of proadrenomedullin and procalcitonin in comparison to C‐reactive protein as predictors of sepsis and bloodstream infections in critically ill patients with cancer. Critical Care Medicine 42: 2500–2507.

Dellinger RP, Levy MM, Rhodes A, et al. (2013) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Critical Care Medicine 41: 580–637.

Endo Y, Suzuki G, Takahashi T, et al. (2012) Usefulness of presepsin in the diagnosis of sepsis in a multicenter prospective study. Journal of Infection and Chemotherapy 18: 891–897.

Elke G, Bloos F, Wilson DC, et al. (2018) The use of mid‐regional proadrenomedullin to identify disease severity and treatment response to sepsis ‐ a secondary analysis of a large randomised controlled trial. Critical Care 22: 79.

Gille J, Ostermann H, Dragu A, et al. (2017) MR‐proADM: a new biomarker for early diagnosis of sepsis in burned patients. Journal of Burn Care & Research 38: 290–298.

Hinson JP, Kapas S and Smith DM (2000) Adrenomedullin, a multifunctional regulatory peptide. Endocrine Reviews 21: 138–167.

Hirata Y, Mitaka C, Sato K, et al. (1996) Increased circulating adrenomedullin, a novel vasodilatory peptide, in sepsis. Journal of Clinical Endocrinology and Metabolism 81: 1449–1453.

Ishimitsu T, Kojima M, Kangawa K, et al. (1994) Genomic structure of human adrenomedullin gene. Biochemical and Biophysical Research Communications 203: 631–639.

Kitamura K, Kangawa K, Kawamoto M, et al. (1993) Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochemical and Biophysical Research Communications 192: 553–560.

de Kruif MD, Lemaire LC, Giebelen IA, et al. (2008) The influence of corticosteroids on the release of novel biomarkers in human endotoxemia. Intensive Care Medicine 34: 518–522.

Kweon OJ, Choi JH, Park SK, et al. (2014) Usefulness of presepsin (sCD14subtype) measurements as a new marker for the diagnosis and prediction of disease severity of sepsis in the Korean population. Journal of Critical Care 29: 965–970.

Lewis LK, Smith MW, Yandle TG, et al. (1998) Adrenomedullin (1‐52) measured in human plasma by radioimmunoassay: plasma concentration, adsorption, and storage. Clinical Chemistry 44: 571–577.

Limper M, De Kruif MD, Duit AJ, et al. (2010) The diagnostic role of procalcitonin and other biomarkers in discriminating infectious from non‐infectious fever. Journal of Infection 60: 409–416.

Linscheid P, Seboek D, Zulewski H, et al. (2005) Autocrine/paracrine role of inflammation‐mediated calcitonin gene‐related peptide and adrenomedullin expression in human adipose tissue. Endocrinology 146: 2699–2708.

Mancini N, Carletti S, Ghidoli N, et al. (2010) The era of molecular and other non‐culture‐based methods in diagnosis of sepsis. Clinical Microbiology Reviews 23: 235–251.

Maruna P, Nedelníková K and Gürlich R (2000) Physiology and genetics of procalcitonin. Physiological Research 49: S57–S61.

Okashah AS, El‐Sawy MM, Beshay BN, et al. (2014) Ratio of neutrophil to lymphocyte counts as a simple marker for sepsis and severe sepsis in Intensive Care Unit. Research and Opinion in Anesthesia & Intensive Care 2: 39–45.

Pepys MB and Hirschfield GM (2003) C‐reactive protein: a critical update. Journal of Clinical Investigation 111: 1805–1812.

Petilla V, Hynninen M, Takkunen O, et al. (2002) Predictive value of procalcitonin and interleukin 6 in critically ill patients with suspected sepsis. Intensive Care Medicine 28: 1220–1225.

Pierrakos C and Vincent JL (2010) Sepsis biomarkers: a review. Critical Care 14: R15.

Pio R, Martinez A, Unsworth EJ, et al. (2001) Complement factor H is a serum‐binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. Journal of Biological Chemistry 276: 12292–12300.

Raynes JG (2015) Acute‐phase proteins. In: eLS. John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0000497.pub2.

Saeed K, Wilson DC, Bloos F, et al. (2019) The early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi‐centre derivation and validation study. Critical Care 23: 40.

Valenzuela Sanchez F, Valenzuela Mendez B, Bohollo de Austria R, et al. (2015a) Diagnostic and prognostic usefulness of mid‐regional pro‐adrenomedullin levels in patients with severe sepsis. Intensive Care Medicine Experimental 3: A306.

Valenzuela Sanchez F, Valenzuela Mendez B, Rodríguez Gutierrez JF, et al. (2015b) Initial levels of MR‐proadrenomedullin: a predictor of severity in patients with influenza a virus pneumonia. Intensive Care Medicine Experimental 3: A832.

Vila G, Resl M, Stelzeneder D, et al. (2008) Plasma NT‐proBNP increases in response to LPS administration in healthy men. Journal of Applied Physiology 105: 1741–1745.

Sehrawat S and Rouse BT (2017) Immunity to infections. In: eLS. John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0000478.pub3.

Seymour CW, Liu VX, Iwashyna TJ, et al. (2016) Assessment of clinical criteria for sepsis: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis‐3). JAMA 315: 762–774.

Singer M, Deutschman CS, Seymour CW, et al. (2016) The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis‐3). JAMA 315: 801–810.

Sridharan P and Chamberlain RS (2013) The efficacy of procalcitonin as a biomarker in the management of sepsis: slaying dragons or tilting at windmills? Surgical Infections 14: 489–511.

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

Sugo S, Minamino N and Kangawa K (1994) Endothelial cells actively synthesize and secrete adrenomedullin. Biochemical and Biophysical Research Communications 201: 1160–1166.

Sugo S, Minamino N, Shoji H, et al. (1995) Interleukin‐1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells. Biochemical and Biophysical Research Communications 207: 25–32.

Tamayo E, Fernández A, Almansa R, et al. (2011) Pro‐and anti‐inflammatory responses are regulated simultaneously from the first moments of septic shock. European Cytokine Network 22: 82–87.

Vincent JL and Moreno R (2010) Clinical review: scoring systems in the critically ill. Critical Care 14: 207.

Vincent JL, Donadello K and Schmit X (2011) Biomarkers in the critically ill patient: C‐reactive protein. Critical Care Clinics 27: 241–251.

Wacharasint P, Nakada TA, Boyd JH, et al. (2012) Normal‐range blood lactate concentration in septic shock is prognostic and predictive. Shock 38: 4–10.

Walsh TJ, Martinez A, Peter J, et al. (1998) Antimicrobial activity of adrenomedullin and its gene‐related peptides. Clinical Infection Disease 23: 96.

Williams JM, Greenslade JH, McKenzie JV, et al. (2017) Systemic inflammatory response syndrome, quick sequential organ function assessment, and organ dysfunction: insights from a prospective database of ED patients with infection. Chest 151: 586–596.

Yaegashi Y, Shirakawa K, Sato N, et al. (2005) Evaluation of a newly identified soluble CD14 subtype as a marker for sepsis. Journal of Infection and Chemotherapy 11: 234–238.

Further Reading

Decker S, Sigl A, Grumaz C, et al. (2017) Immune‐response patterns and next generation sequencing diagnostics for the detection of mycoses in patients with septic shock—results of a combined clinical and experimental investigation. International Journal of Molecular Sciences 18: 1796.

Geven C, Kox M and Pickkers P (2018) Adrenomedullin and adrenomedullin‐targeted therapy as treatment strategies relevant for sepsis. Frontiers in Immunology 9: 292.

Legramante JM, Mastropasqua M, Susi B, et al. (2017) 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 12: e0187702.

Liu D, Xie L, Zhao H, et al. (2016) Prognostic value of mid‐regional pro‐adrenomedullin (MR‐proADM) in patients with community‐acquired pneumonia: a systematic review and meta‐analysis. BMC Infectious Diseases 16: 232.

Önal U, Valenzuela‐Sánchez F, Vandana K, et al. (2018) Mid‐Regional pro‐Adrenomedullin (MR‐proADM) as a biomarker for sepsis and septic shock: narrative review. Health 6: 110.

Sen P, Demirdal T, Nemli SA, et al. (2018) Infection markers as predictors of bacteremia in an Intensive Care Unit: a prospective study. Pakistan Journal of Medical Sciences 34: 1517.

Travaglino F, De Berardinis B, Magrini L, et al. (2012) Utility of Procalcitonin (PCT) and mid regional pro‐Adrenomedullin (MR‐proADM) in risk stratification of critically ill febrile patients in Emergency Department (ED). A comparison with APACHE II score. BMC Infectious Diseases 12: 184.

Viaggi B, Poole D, Tujjar O, et al. (2018) Mid regional pro‐adrenomedullin for the prediction of organ failure in infection. Results from a single centre study. PLoS One 13: e0201491.

Vincent JL (2007) Septicaemic shock. In: eLS. John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0002223.pub2.

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Lia, Maria Stella, Angeletti, Silvia, Bernardini, Sergio, and Minieri, Marilena(Jan 2020) Emerging Role of Adrenomedullin as Sepsis Prognostic Marker. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028883]