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

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.

Keywords: Biomarker; Outcome; Sepsis-2; Sepsis-3.

Conflict of interest statement

Authors’ information

Sponsor

sphingotec GmbH

Neuendorfstraße 15a

16761 Hennigsdorf

Germany

Principal investigators

Prof. Dr. Alexandre Mebazaa, Head

Department of Anesthesiology and Critical Care Medicine

AP-HP, Saint Louis and Lariboisière University Hospitals

Paris, France

Tel: + 33 1 49 95 80 83

Fax: + 33 1 49 95 80 71

Prof. Pierre-François Laterre, Head of Clinical Service

Saint Luc University Hospital at the Université Catholique de Louvain

Brussels, Belgium

Tel: + 32 2764 27 35

Fax: + 32 2764 89 28

Ethics approval and consent to participate

The present study was conducted in France, Belgium, The Netherlands, Italy, and Germany. The study protocol was approved by the local ethics committees, and the study was conducted in accordance with Directive 2001/20/EC as well as good clinical practice (International Conference on Harmonization Harmonized Tripartite Guideline version 4 of May 1, 1996, and decision of November 24, 2006) and the Declaration of Helsinki. Patients were included from June 2015 to May 2016.

Consent for publication

Not applicable.

Competing interests

AM has received speaker’s honoraria from Novartis, Orion, and Servier and fees as a member of the advisory board and/or steering committee from Cardiorentis, Adrenomed, sphingotec, Sanofi, Roche, Abbott, and Bristol-Myers Squibb. EG has received consulting fees from Adrenomed, Roche Diagnostics, and Magnisense and lecture fees from Edwards Lifesciences. AB is the managing director of sphingotec GmbH and holds shares in it. OH and JS are employees of sphingotec GmbH, the company that developed and holds patent rights in the bio-ADM assay. BF has received consulting fees from Aridis, Ferring, Arsanis, Inotrem, and Lascco. PP serves as a consultant for and has received consulting fees from Adrenomed. The other authors report no conflicts of interest. ML has received lecture fees from Alere, Fresenius, and Gilead Sciences and consulting fees from Adrenomed. PFL has received consulting fees from Adrenomed, Ferring, and Lascco. The other authors report no conflicts of interest.

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Figures

Fig. 1

Twenty-eight-day Kaplan-Meier survival curves of low versus high biologically active adrenomedullin at admission, based on a cutoff value of 70 pg/ml, in (a) sepsis, and (b) septic shock patients

Fig. 2

Association between the changes of biologically active adrenomedullin (bio-ADM) levels over 48 h and mortality. HR between high-high (HH) (levels of bio-ADM remained high) and high-low (HL) (levels of bio-ADM declining over 48 h) 4.9 (95% CI 2.5–9.8; HR of LL 1.1 [0.52–2.4]). Only a small number (n = 16, 2.7%; 28-day survival rate 68.8%) of patients who presented with a low bio-ADM concentration upon admission had higher bio-ADM level on day 2 (low-high (LH) group), which is why this group is not represented in the figure

Fig. 3

Association between biologically active adrenomedullin levels upon admission and (a) length of total organ support over the first 7 days (p < 0.0001), (b) length of vasopressor/inotropic support over the first 7 days (p < 0.0001), (c) overall need for vasopressor support (p < 0.0001), and (d) total fluid balance over the initial 48 h (p = 0.0001)

Fig. 4

The absolute Sequential Organ Failure Assessment (SOFA) scores at (a) admission, (b) day 2, and (c) day 7 for groups high-high (HH; i.e., above 70 pg/ml at baseline and day 2), high-low (HL), and low-low (LL), excluding patients who died within 7 days. p Value for differences between HH vs. LL: p < 0.0001 for all days; p value for HH vs. HL: p < 0.0001 for all days; p Values for HL vs. LL: p < 0.0001, 0.6016, and 0.9969 for days 1, 3, and 7, respectively. Of note, the number of patients is less at day 2 than at day 7 because there were more values missing at day 2 owing to the fact that discharged patients (mostly at day 7) were given a SOFA score of 0. Furthermore, only a small number (n = 16, 2.7%) of patients who presented with a low bio-ADM concentration upon admission had a higher bio-ADM level on day 2 (low-high [LH] group), which is why this group is not represented in the figure. Median (IQR) SOFA scores for the LH group were 7.5 (6.0–9.8), 9.0 (4.0–11.2), and 4.0 (0.0–6.5) for admission, day 2, and day 7, respectively