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

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Abstract

Background

Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial.

Methods

AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock.

Results

Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5–148.1 pg/ml]. Initial SOFA score was 7 [IQR 5–10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9–2.9]; adjusted HR 1.6 [CI 1.1–2.5]) and between bio-ADM levels and SOFA score ( p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5–9.8).

Conclusions

AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial.

Trial registration

ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015.

Electronic supplementary material

The online version of this article (10.1186/s13054-018-2243-2) contains supplementary material, which is available to authorized users.

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Most cited references 19

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Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study

Mirjam Christ-Crain, Nils Morgenthaler, Joachim Struck … (2005)

Introduction Measurement of biomarkers is a potential approach to early assessment and prediction of mortality in patients with sepsis. The aim of the present study was to evaluate the prognostic value of mid-regional pro-adrenomedullin (MR-proADM) levels in a cohort of medical intensive care patients and to compare it with other biomarkers and physiological scores. Method We evaluated blood samples from 101 consecutive critically ill patients admitted to the intensive care unit and from 160 age-matched healthy control individuals. The patients had initially been enrolled in a prospective observational study investigating the prognostic value of endocrine dysfunction in critically ill patients ("PEDCRIP" Study). The prognostic value of MR-proADM levels was compared with those of two physiological scores and of various biomarkers (for example C-reactive Protein, IL-6, procalcitonin). MR-proADM was measured in EDTA plasma from all patients using a new sandwich immunoassay. Results On admission, 53 patients had sepsis, severe sepsis, or septic shock, and 48 had systemic inflammatory response syndrome. Median MR-proADM levels on admission (nmol/l [range]) were 1.1 (0.3–3.7) in patients with systemic inflammatory response syndrome, 1.8 (0.4–5.8) in those with sepsis, 2.3 (1.0–17.6) in those with severe sepsis and 4.5 (0.9–21) in patients with septic shock. In healthy control individuals the median MR-proADM was 0.4 (0.21–0.97). On admission, circulating MR-proADM levels in patients with sepsis, severe sepsis, or septic shock were significantly higher in nonsurvivors (8.5 [0.8–21.0]; P < 0.001) than in survivors (1.7 [0.4–17.6]). In a receiver operating curve analysis of survival of patients with sepsis, the area under the curve (AUC) for MR-proADM was 0.81, which was similar to the AUCs for IL-6, Acute Physiology and Chronic Health Evaluation II score and Simplified Acute Physiology Score II. The prognostic value of MR-proADM was independent of the sepsis classification system used. Conclusion MR-proADM may be helpful in individual risk assessment in septic patients.

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Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis

Rossella Marino, Joachim Struck, Alan Maisel … (2014)

Introduction The incidence of death among patients admitted for severe sepsis or septic shock is high. Adrenomedullin (ADM) plays a central role in initiating the hyperdynamic response during the early stages of sepsis. Pilot studies indicate an association of plasma ADM with the severity of the disease. In the present study we utilized a novel sandwich immunoassay of bioactive plasma ADM in patients hospitalized with sepsis in order to assess the clinical utility. Methods We enrolled 101 consecutive patients admitted to the emergency department with suspected sepsis in this study. Sepsis was defined by fulfillment of at least two systemic inflammatory response syndrome (SIRS) criteria plus clinical suspicion of infection. Plasma samples for ADM measurement were obtained on admission and for the next four days. The 28-day mortality rate was recorded. Results ADM at admission was associated with severity of disease (correlation with Acute Physiology and Chronic Health Evaluation II (APACHE II) score: r = 0.46; P <0.0001). ADM was also associated with 28-day mortality (ADM median (IQR): survivors: 50 (31 to 77) pg/mL; non-survivors: 84 (48 to 232) pg/mL; P <0.001) and was independent from and additive to APACHE II (P = 0.02). Cox regression analysis revealed an additive value of serial measurement of ADM over baseline assessment for prediction of 28-day mortality (P < 0.01). ADM was negatively correlated with mean arterial pressure (r = -0.39; P <0.0001), and it strongly discriminated those patients requiring vasopressor therapy from the others (ADM median (IQR): no vasopressors 48 (32 to 75) pg/mL; with vasopressors 129 (83 to 264) pg/mL, P <0.0001). Conclusions In patients admitted with sepsis, severe sepsis or septic shock plasma ADM is strongly associated with severity of disease, vasopressor requirement and 28-day mortality.

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Adrenomedullin reduces endothelial hyperpermeability.

Stefan Hippenstiel, Martin Witzenrath, Bernd Schmeck … (2002)

Endothelial hyperpermeability induced by inflammatory mediators is a hallmark of sepsis and adult respiratory distress syndrome. Increased levels of the regulatory peptide adrenomedullin (ADM) have been found in patients with systemic inflammatory response. We analyzed the effect of ADM on the permeability of cultured human umbilical vein endothelial cell (HUVEC) and porcine pulmonary artery endothelial cell monolayers. ADM dose-dependently reduced endothelial hyperpermeability induced by hydrogen peroxide (H2O2), thrombin, and Escherichia coli hemolysin. Moreover, ADM pretreatment blocked H2O2-related edema formation in isolated perfused rabbit lungs and increased cAMP levels in lung perfusate. ADM bound specifically to HUVECs and porcine pulmonary artery endothelial cells and increased cellular cAMP levels. Simultaneous inhibition of cAMP-degrading phosphodiesterase isoenzymes 3 and 4 potentiated ADM-dependent cAMP accumulation and synergistically enhanced ADM-dependent reduction of thrombin-induced hyperpermeability. However, ADM showed no effect on endothelial cGMP content, basal intracellular Ca2+ levels, or the H2O2-stimulated, thrombin-stimulated, or Escherichia coli hemolysin-stimulated Ca2+ increase. ADM diminished thrombin- and H2O2-related myosin light chain phosphorylation as well as stimulus-dependent stress fiber formation and gap formation in HUVECs, suggesting that ADM may stabilize the barrier function by cAMP-dependent relaxation of the microfilament system. These findings identify a new function of ADM and point to ADM as a potential interventional agent for the reduction of vascular leakage in sepsis and adult respiratory distress syndrome.

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Author and article information

Contributors

Alexandre Mebazaa: alexandre.mebazaa@aphp.fr

Christopher Geven: christopher.geven@radboudumc.nl

Alexa Hollinger:

ORCID: http://orcid.org/0000-0001-6799-1652

+41 78 674 71 30 , alexa.hollinger@usb.ch

Xavier Wittebole: xavier.wittebole@uclouvain.be

Benjamin Glen Chousterman: benjamin.chousterman@aphp.fr

Alice Blet: aliceblet@gmail.com

Etienne Gayat: etienne.gayat@aphp.fr

Oliver Hartmann: hartmann@sphingotec.de

Paul Scigalla: PScigalla@adrenomed.com

Joachim Struck: struck@sphingotec.de

Andreas Bergmann: bergmann@sphingotec.de

Massimo Antonelli: Massimo.Antonelli@unicatt.it

Albertus Beishuizen: b.beishuizen@mst.nl

Jean-Michel Constantin: jmconstantin@chu-clermontferrand.fr

Charles Damoisel: charles.damoisel@aphp.fr

Nicolas Deye: nicolas.deye@aphp.fr

Salvatore Di Somma: salvatore.disomma@ospedalesantandrea.it

Thierry Dugernier: Thierry.DUGERNIER@cspo.be

Bruno François: realim@unilim.fr

Stephane Gaudry: stephanegaudry@gmail.com

Vincent Huberlant: vhuberlant@hotmail.com

Jean-Baptiste Lascarrou: jeanbaptiste.lascarrou@chu-nantes.fr

Gernot Marx: gmarx@ukaachen.de

Emmanuelle Mercier: emercier@med.univ-tours.fr

Haikel Oueslati: haikel.oueslati@sls.aphp.fr

Peter Pickkers: Peter.Pickkers@radboudumc.nl

Romain Sonneville: romain.sonneville@bch.aphp.fr

Matthieu Legrand: Matthieu.legrand@aphp.fr

Pierre-François Laterre: pierre-francois.laterre@uclouvain.be

Journal

Journal ID (nlm-ta): Crit Care

Title: Critical Care

Publisher: BioMed Central (London )

ISSN (Print): 1364-8535

ISSN (Electronic): 1466-609X

Publication date (Electronic): 21 December 2018

Publication date PMC-release: 21 December 2018

Publication date Collection: 2018

Volume: 22

Electronic Location Identifier: 354

Affiliations

[1 ]Department of Anesthesiology, Burn and Critical Care Medicine, AP-HP, Saint Louis and Lariboisière University Hospitals, 2 rue A. Paré, 75010 Paris, France

[2 ]Inserm 942, Paris, France

[3 ]ISNI 0000 0001 2217 0017, GRID grid.7452.4, University Paris Diderot, ; Paris, France

[4 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Intensive Care Medicine, , Radboud University Medical Center, ; Geert Grooteplein Zuid 10, 6500 HB Nijmegen, The Netherlands

[5 ]GRID grid.410567.1, Department of Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, , University Hospital Basel, ; Basel, Switzerland

[6 ]ISNI 0000 0004 0461 6320, GRID grid.48769.34, Department of Critical Care Medicine, , St Luc University Hospital, Université Catholique de Louvain, ; Brussels, Belgium

[7 ]sphingotec GmbH, Hennigsdorf, Germany

[8 ]Adrenomed AG, Hennigsdorf, Germany

[9 ]ISNI 0000 0004 1760 4193, GRID grid.411075.6, Fondazione Policlinico Universitario A. Gemelli, ; Rome, Italy

[10 ]Department of Intensive Care, Medische Spectrum Twente, Enschede, The Netherlands

[11 ]ISNI 0000 0004 0639 4151, GRID grid.411163.0, Department of Perioperative Medicine, , University Hospital of Clermont-Ferrand, ; Clermont-Ferrand, France

[12 ]ISNI 0000 0004 1757 123X, GRID grid.415230.1, Sant’ Andrea Hospital, ; Rome, Italy

[13 ]Clinique St Pierre, Ottignies, Belgium

[14 ]ISNI 0000 0001 1481 5225, GRID grid.412212.6, ICU Department, CHU Dupuytren, ; Limoges, France

[15 ]INSERM CIC 1435/UMR 1092, Limoges, France

[16 ]ISNI 0000 0001 0273 556X, GRID grid.414205.6, Hôpital Louis Mourier, ; Colombes, France

[17 ]GRID grid.413908.7, Hôpital Jolimont, ; Haine-St-Paul, Belgium

[18 ]ISNI 0000 0004 0472 0371, GRID grid.277151.7, Centre Hospitalier Universitaire de Nantes, ; Nantes, France

[19 ]ISNI 0000 0000 8653 1507, GRID grid.412301.5, Klinik für Operative Intensivmedizin und Intermediate Care, Universitätsklinikum der RWTH, ; Aachen, Germany

[20 ]ISNI 0000 0004 1765 1600, GRID grid.411167.4, CHU de Tours, ; Tours, France

[21 ]ISNI 0000 0000 8588 831X, GRID grid.411119.d, Hopital Bichat Claude-Bernard, ; Paris, France

[22 ]ISNI 0000 0004 0461 6320, GRID grid.48769.34, Department of Critical Care Medicine, , Saint Luc University Hospital, Université Catholique de Louvain, ; Avenue Hippocrate 10, 1200 Brussels, Belgium

Author information

Alexa Hollinger http://orcid.org/0000-0001-6799-1652

Article

Publisher ID: 2243

DOI: 10.1186/s13054-018-2243-2

PMC ID: 6305573

PubMed ID: 30583748

SO-VID: bb839216-21a5-4064-8c4a-5ed762c0c81d

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.