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Bioactive Adrenomedullin, Organ Support Therapies, and Survival in the Critically Ill

Results from the French and European Outcome Registry in ICU Study

Lemasle, Léa MD1; Blet, Alice MD, PhD1,2; Geven, Christopher MD3; Cherifa, Ményssa MSc4; Deniau, Benjamin MD1,2,5; Hollinger, Alexa MD1,2,6; Fournier, Marie-Céline RN1; Monnet, Xavier MD, PhD7; Rennuit, Isabelle MD8; Darmon, Michael MD, PhD4,5,9; Laterre, Pierre-François MD, PhD10; Struck, Joachim PhD11; Hartmann, Oliver PhD11; Bergmann, Andreas PhD11; Mebazaa, Alexandre MD, PhD1,2,5; Gayat, Etienne MD, PhD1,2,5

doi: 10.1097/CCM.0000000000004044
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Objectives: Adrenomedullin has vascular properties and elevated plasma adrenomedullin levels were detected in sepsis. We assessed, in septic and nonseptic ICU patients, the relation between circulating adrenomedullin, the need for organ support and mortality, using an assay of bioactive adrenomedullin.

Design: Prospective multicenter observational cohort study.

Setting: Data from the French and euRopean Outcome reGistry in ICUs study.

Patients: Consecutive patients admitted to intensive care with a requirement for invasive mechanical ventilation and/or vasoactive drug support for more than 24 hours following ICU admission and discharged from ICU were included.

Interventions: Clinical and biological parameters were collected at baseline, including bioactive-adrenomedullin. Status of ICU survivors was assess until 1 year after discharge. The main outcome was the need for organ support, including renal replacement therapy and/or for inotrope(s) and/or vasopressor(s). Secondary endpoints were the ICU length of stay and the 28-day all-cause mortality.

Measurements and Main Results: Median plasma bioactive adrenomedullin (n = 2,003) was 66.6 pg/mL (34.6–136.4 pg/mL) and the median Simplified Acute Physiology Score II score 49 (36–63). Renal replacement therapy was needed in 23% and inotropes(s) and/or vasopressor(s) in 77% of studied patients. ICU length of stay was 13 days (7–21 d) and mortality at 28 days was 22 %. Elevated bioactive adrenomedullin independently predicted 1) the need for organ support (odds ratio, 4.02; 95% CI, 3.08–5.25) in ICU patients whether admitted for septic or nonseptic causes and 2) the need for renal replacement therapy (odds ratio, 4.89; 3.83–6.28), and for inotrope(s) and/or vasopressor(s) (odds ratio, 3.64; 2.84–4.69), even in patients who were not on those supports at baseline. Elevated bioactive adrenomedullin was also associated with a prolonged length of stay (odds ratio, 1.85; 1.49–2.29) and, after adjustment for Simplified Acute Physiology Score II, with mortality (odds ratio, 2.31; 1.83–2.92).

Conclusions: Early measurement of bioactive adrenomedullin is a strong predictor of the need of organ support and of short-term mortality in critically ill patients.

1Department of Anesthesia, Burn and Critical Care, University Hospitals Saint-Louis - Lariboisière, AP-HP, Paris, France.

2UMR-S 942, Inserm, Paris, France.

3Department of Intensive Care Medicine, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.

4ECSTRA team, Biostatistics and clinical epidemiology, UMR 1153 (center of epidemiology and biostatistic Sorbonne Paris Cité, CRESS), INSERM, Paris, France.

5Paris Diderot University, Sorbonne Paris Cité, Paris, France.

6Department of Anesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Basel, Switzerland.

7Medical ICU, Bicêtre Hospital, Paris-Sud University Hospitals, Inserm UMR_S999, Paris-Sud University, Le Kremlin-Bicêtre, France.

8Department of Anesthesiology and Critical Care, Beaujon Hospital, Assistance Publique Hôpitaux de Paris University, Clichy, France.

9Medical ICU, Saint-Louis University Hospital, AP-HP, Paris, France.

10Medical–Surgical ICU, Cliniques Saint-Luc, Brussels, Belgium.

11Sphingotec GmbH, Neuendorfstraße 15A, 16761, Hennigsdorf, Germany.

This work was performed at Department of Anesthesia, Burn and Critical Care, University Hospitals Saint-Louis - Lariboisière, AP-HP, Paris, France.

Drs. Lemasle and Blet contributed equally to this work.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Dr. Geven and his institution have received funding from Adrenomed AG. Dr. Monnet received support for article research from Assistance publique hôpitaux de Paris. Drs. Struck and Hartmann received funding from sphingotec GmbH (employees). Dr. Hartmann disclosed off-label product use of biomarker assay for adrenomedullin. Dr. Bergmann disclosed he is a member of the Adrenomed Board (but he receives no financial compensation). Dr. Mebazaa’s institution received funding from Adrenomed (paid to ship the samples), and he received funding from the Steering Committee of Adrenoss-2 (member). The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: etienne.gayat@aphp.fr

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