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

Oscar H M Lundberg, Maria Lengquist, Martin Spångfors, Martin Annborn, Deborah Bergmann, Janin Schulte, Helena Levin, Olle Melander, Attila Frigyesi, Hans Friberg, Oscar H M Lundberg, Maria Lengquist, Martin Spångfors, Martin Annborn, Deborah Bergmann, Janin Schulte, Helena Levin, Olle Melander, Attila Frigyesi, Hans Friberg

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.

Conflict of interest statement

OL, ML, MS, MA, HL, AF and HF declare that they have no competing interests, no financial or any other interests in SphingoTec GmbH and have not been in any way influenced by SphingoTec GmbH in writing this research paper. OM is listed as an inventor on a patent on bio-ADM in dementia prediction. SphingoTec GmbH is the owner of the patent. DB and JS are employed by SphingoTec GmbH and participate in the company’s employee stock option program. Bioactive ADM was analysed free of charge by SphingoTec GmbH, Neuendorfstrae 15A, 16761 Hennigsdorf, Germany.

Figures

Fig. 1
Fig. 1
Flow chart of ICU admissions, admission samples and consent. ICU: Intensive care unit
Fig. 2
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
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 86 and in the sepsis cohort 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
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

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