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

BackgroundAdrenomedullin (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.MethodsAdrenOSS-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.ResultsCirculating 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).ConclusionsAdrenOSS-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 registrationClinicalTrials.gov, NCT02393781. Registered on March 19, 2015.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2243-2) contains supplementary material, which is available to authorized users.

Added value of serial bio-adrenomedullin measurement in addition to lactate for the prognosis of septic patients admitted to ICU

“…Anyway, normalization of lactate is associated with improved outcome [4]. We have recently shown that plasma levels of bio-adrenomedullin (bio-ADM), a peptide regulating vascular integrity and endothelial function, were associated with patient outcome during sepsis [5]. Interestingly, we observed that patients with elevated bio-ADM levels at admission and with low bio-ADM levels 2 days later had similar outcome to patients with persistently low bio-ADM levels.…”

“…The AdrenOSS-1 study is a prospective observational study conducted in 24 centers within 5 European countries and included 583 septic patients from June 2015 to May 2016 [5]. The primary endpoint was 28-day mortality.…”

“…We evaluated the relationship between the association of initial evolution of lactate plasma levels and bio-ADM level at 24 h and outcome in patients for whom both markers were available at admission and 1 day later ("24 h"). As described previously, bio-ADM levels below or above 70 pg/mL were considered respectively as low and high [5].…”

“…Accordingly, our data suggest that measurement of bio-ADM in addition to lactate may help physicians to refine risk stratification and therefore to guide resuscitation during sepsis. 23 (24) Catheter ( Central venous pressure (mmHg) 8 [5][6][7][8][9][10][11][12] 8 [5][6][7][8][9][10][11][12][13] 7 [3][4][5][6][7][8][9][10][11] Fig. 1 Impact of 24 h lactate and bio-ADM values in patients with elevated lactate level at admission.…”

Sepsis diagnosis and monitoring – procalcitonin as standard, but what next?

“…In patients with bio-ADM > 70 pg mL -1 at admission, decrease in bio-ADM below 70 pg mL -1 at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). Constantly elevated bio-ADM at day 2 was linked to prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR = 4.9, 95% CI: 2.5-9.8) [49]. Preclinical work performed with the non-neutralizing ADM-binding antibody adrecizumab in animal models of septic shock revealed improved vascular barrier function, reduced vasopressor dosage and organ dysfunction and increased survival.…”