Circulating bioactive adrenomedullin as a marker of sepsis, septic shock and critical illness

Abstract

Background: Biomarkers can be of help to understand critical illness and to identify and stratify sepsis. Adrenomedullin is a vasoactive hormone, with reported prognostic and potentially therapeutic value in sepsis. The primary aim of this study was to investigate the association of circulating bioactive adrenomedullin (bio-ADM) levels at intensive care unit (ICU) admission with mortality in sepsis patients and in a general ICU population. Secondary aims included the association of bio-ADM with organ failure and the ability of bio-ADM to identify sepsis.

Methods: In this retrospective observational study, adult patients admitted to one of four ICUs during 2016 had admission bio-ADM levels analysed. Age-adjusted odds ratios (OR) with 95% CI for log-2 transformed bio-ADM, and Youden's index derived cut-offs were calculated. The primary outcome was 30-day mortality, and secondary outcomes included the need for organ support and the ability to identify sepsis.

Results: Bio-ADM in 1867 consecutive patients were analysed; 632 patients fulfilled the sepsis-3 criteria of whom 267 had septic shock. The median bio-ADM in the entire ICU population was 40 pg/mL, 74 pg/mL in sepsis patients, 107 pg/mL in septic shock and 29 pg/mL in non-septic patients. The association of elevated bio-ADM and mortality in sepsis patients and the ICU population resulted in ORs of 1.23 (95% CI 1.07-1.41) and 1.22 (95% CI 1.12-1.32), respectively. The association with mortality remained after additional adjustment for lactate in sepsis patients. Elevated bio-ADM was associated with an increased need for dialysis with ORs of 2.28 (95% CI 2.01-2.59) and 1.97 (95% CI 1.64-2.36) for the ICU population and sepsis patients, respectively, and with increased need of vasopressors, OR 1.33 (95% CI 1.23-1.42) (95% CI 1.17-1.50) for both populations. Sepsis was identified with an OR of 1.78 (95% CI 1.64-1.94) for bio-ADM, after additional adjustment for severity of disease. A bio-ADM cut-off of 70 pg/mL differentiated between survivors and non-survivors in sepsis, but a Youden's index derived threshold of 108 pg/mL performed better.

Conclusions: Admission bio-ADM is associated with 30-day mortality and organ failure in sepsis patients as well as in a general ICU population. Bio-ADM may be a morbidity-independent sepsis biomarker.

Keywords: Adrenomedullin; Bioactive adrenomedullin; Biomarkers; Critical illness; Cut-off; Sepsis; Septic shock.

Fig. 1

Flow chart of ICU admissions, admission samples and consent. ICU: Intensive care unit

Fig. 2

Distribution of bio-ADM in the ICU population, Sepsis cohort and Non-sepsis cohort. X-axis logarithmic with base 2. The dotted line represents a concentration of 70 pg/mL. ICU: intensive care unit; bio-ADM: circulating bioactive adrenomedullin

Fig. 3

Kaplan–Meier curves for the ICU population and the sepsis cohort according to quartiles of bio-ADM. The range of bio-ADM (pg/mL) in the quartiles in the ICU populations was < 21; 21–40; 40–86; > 86 and in the sepsis cohort < 42; 42–74; 74–145; > 145. The p values were derived from the log-rank test. ICU: intensive care unit; bio-ADM: circulating bioactive adrenomedullin; Q1: quartile 1; Q2: quartile 2; Q3: quartile 3 Q4: quartile 4

Fig. 4

Kaplan–Meier curves for the ICU population and the sepsis cohort according to bio-ADM admission levels above or below 70 pg/mL and according to an Youden’s index derived cut-off of 108 pg/mL for the sepsis cohort. The p values were derived from the log-rank test. ICU: intensive care unit; bio-ADM: circulating bioactive adrenomedullin