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Prognostic Value of Secretoneurin in Patients With Severe Sepsis and Septic Shock: Data From the Albumin Italian Outcome Sepsis Study

Røsjø, Helge, MD, PhD1; Masson, Serge, PhD2; Caironi, Pietro, MD3,4; Stridsberg, Mats, MD, PhD5; Magnoli, Michela, Stat D2; Christensen, Geir, MD, PhD, MHA6; Moise, Gabriella, MD7; Urbano, Maria, Cristina, MD8; Gattinoni, Luciano, MD, FRCP9; Pesenti, Antonio, MD10,11; Latini, Roberto, MD2; Omland, Torbjørn, MD, PhD, MPH1for the ALBIOS Biomarkers Study Investigators

doi: 10.1097/CCM.0000000000003050
Online Clinical Investigations

Objectives: Secretoneurin directly influences cardiomyocyte calcium handling, and circulating secretoneurin levels seem to improve risk prediction in patients with myocardial dysfunction by integrating information on systemic stress, myocardial function, and renal function. Accordingly, in this study, we hypothesized that secretoneurin would improve risk prediction in patients with sepsis and especially in patients with septic shock as these patients are more hemodynamically unstable.

Design: Multicenter, interventional randomized clinical trial.

Setting: Multicenter, pragmatic, open-label, randomized, prospective clinical trial testing fluid administration with either 20% human albumin and crystalloids or crystalloid solutions alone in patients with severe sepsis or septic shock (The Albumin Italian Outcome Sepsis).

Patients or Subjects: In total, 540 patients with septic shock and 418 patients with severe sepsis.

Interventions: Either 20% human albumin and crystalloids or crystalloid solutions alone.

Measurements and Main Results: We measured secretoneurin on days 1, 2, and 7 after randomization and compared the prognostic value of secretoneurin for ICU and 90-day mortality with established risk indices and cardiac biomarkers in septic shock and severe sepsis. High secretoneurin levels on day 1 were associated with age and serum concentrations of lactate, bilirubin, creatinine, and N-terminal pro-B-type natriuretic peptide. Adjusting for established risk factors and cardiovascular biomarkers, secretoneurin levels on day 1 were associated with ICU (odds ratio, 2.27 [95% CI, 1.05–4.93]; p = 0.04) and 90-day mortality (2.04 [1.02–4.10]; p = 0.04) in patients with septic shock, but not severe sepsis without shock. Secretoneurin levels on day 2 were also associated with ICU (3.11 [1.34–7.20]; p = 0.008) and 90-day mortality (2.69 [1.26–5.78]; p = 0.01) in multivariate regression analyses and improved reclassification in patients with septic shock, as assessed by the net reclassification index. Randomized albumin administration did not influence the associations between secretoneurin and outcomes.

Conclusions: Secretoneurin provides early and potent prognostic information in septic patients with cardiovascular instability.

1Division of Medicine, Akershus University Hospital, Lørenskog, Norway and Center for Heart Failure Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

2Department of Cardiovascular Research, IRCCS – Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy.

3Department of Anesthesia and Critical Care, Azienda-Ospedaliero Universitaria S. Luigi Gonzaga, Orbassano, Italy.

4Dipartimento di Oncologia, Università degli Studi di Torino, Turin, Italy.

5Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

6Institute for Experimental Medical Research, Ullevål and Center for Heart Failure Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

7Department of Anesthesia and Critical Care, Ospedale Città di Sesto San Giovanni, Sesto San Giovanni, Italy.

8Ospedale della Misericordia, Grosseto, Italy.

9Department of Anesthesiology, Emergency and Intensive Care Medicine, University of Göttingen, Göttingen, Germany.

10Dipartimento di Anestesia, Rianimazione ed Emergenza Urgenza, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy.

11Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.

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A complete list of centers and investigators participating in the Albumin Italian Outcome Sepsis substudy has been published elsewhere: Masson S, Caironi P, Spanuth E, et al; ALBIOS Study Investigators: Presepsin (soluble CD14 subtype) and procalcitonin levels for mortality prediction in sepsis: Data from the Albumin Italian Outcome Sepsis trial. Crit Care 2014; 18:R6.

The Albumin Italian Outcome Sepsis trial was funded by a grant from the Agenzia Italiana del Farmaco (AIFA) (grant FARM6JS3R5, 2006). This project was also funded by Akershus University Hospital, the Research Council of Norway, the University of Oslo, and the South-Eastern Norway Regional Health Authority. Supported, in part, by funding from the Italian Ministry of Health (Ricerca Finalizzata, grant number RF-2011-02348358). Roche Diagnostics (Rotkreuz, Switzerland) provided in kind reagents for measuring N-terminal pro B-type natriuretic peptide and high-sensitive cardiac troponin T.

Dr. Røsjø received personal fees from Novartis and CardiNor AS. Dr. Røsjø disclosed that this project was funded by Akershus University Hospital, the Research Council of Norway, the University of Oslo, and the South-Eastern Norway Regional Health Authority. Roche Diagnostics (Rotkreuz, Switzerland) provided in kind reagents for measuring N-terminal pro B-type natriuretic peptide and high sensitive cardiac troponin T. Dr. Røsjø has financial interests in CardiNor AS, which holds the license to commercialize secretoneurin. Drs. Masson’s and Caironi’s institutions received funding from the AIFA (grant FARM6JS3R5, 2006) and the Italian Ministry of Health (Ricerca Finalizzata, grant number RF-2011-02348358). Dr. Caironi received funding from Bbraun (lecture honoraria), Grifols (lecture honoraria and grant: Albumin Awards Program Grifols Award), and Ortho Diagnostic (lecture honoraria). Dr. Stridsberg received personal fees from CardiNor AS. Drs. Røsjø, Stridsberg, and Omland are partners in a patent filed by the University of Oslo regarding the use of secretoneurin as a biomarker in patients with cardiovascular disease and patients with critical illness. Dr. Christensen disclosed that he is a partner in a patent filed by the University of Oslo regarding the use of secretoneurin as a biomarker in patients with cardiovascular disease and patients with critical illness and has financial interests in CardiNor AS, which holds the license to commercialize secretoneurin. Dr. Urbano received support for article research from the National Institutes of Health and disclosed work for hire. Dr. Gattinoni received funding from Grifols (jury member for Albumin Grifols Award) and expert testimony in legal trials. Dr. Pesenti’s institution received funding from AIFA Official Italian agency for drug safety and studies, and he received funding from Xenios and Baxter. Dr. Omland’s institution received funding from Akershus University Hospital, Research Council of Norway, University of Oslo, and the South-Eastern Norway Regional Health Authority, and he received funding from Roche Diagnostics, Abbott Diagnostics, Bayer, Novartis, and CardiNor. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Helge Røsjø, MD, PhD, Division of Medicine, Akershus University Hospital, Sykehusveien 25, 1478 Lørenskog, Norway. E-mail: helge.rosjo@medisin.uio.no

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