Elke et al. Critical Care (2018) 22:147 https://doi.org/10.1186/s13054-018-2084-z LETTER Open Access Identification of developing multiple organ failure in sepsis patients with low or moderate SOFA scores 1* 2,3 4 5 Gunnar Elke , Frank Bloos , Darius Cameron Wilson , Patrick Meybohm and the SepNet Critical Care Trials Group An early identification of sepsis patients likely to progress vs. 4 [3–5] dysfunctional organs; P < 0.01; 6.3 ± 1.3 towards multiple organ failure is crucial in order to initiate vs. 10.2 ± 4.7 points; P < 0.01). targeted therapeutic strategies to decrease mortality. Our Area under the receiver operating characteristic curve recent publication highlighted the greater accuracy of (AUROC) and Cox regression analysis indicated that mid-regional proadrenomedullin (MR-proADM) com- MR-proADM had the highest accuracy in predicting pro- pared with conventional biomarkers and clinical scores in gression towards sepsis-related multiple organ failure predicting 28-day mortality in patients with initially low mortality in both groups (Fig. 1). High initial concentra- (≤7 points; N = 240) or moderate (8–13 points; N =653) tions in non-surviving patients with low or moderate Sepsis-related Organ Failure Assessment (SOFA) scores SOFA scores resulted in a high progression rate towards , thus confirming results from smaller investigations multiple organ failure (N = 6; 100.0% and N = 25; 52.1%), [2, 3]. This additional post hoc analysis aimed to further with similar results found in patients with increasing describe the non-surviving patient population of both sub- concentrations over the first 24 h (e.g. moderate SOFA groups and identify those likely to progress towards population: N = 15; 57.8%). Conversely, mortality in pa- sepsis-related multiple organ failure. tients with low MR-proADM concentrations was pre- In our study, patients with low SOFA scores had a dominantly due to non-sepsis-related causes (N = 14; lower 28-day mortality rate (N = 35; 14.6% vs. N = 60.9%), with a low subsequent progression rate towards 181; 27.7%) and incidence of septic shock (N = sepsis-related multiple organ failure in the total patient 87; 36.7% vs. N = 399; 61.5%) compared to those population with continuously low concentrations over with moderate values. Nevertheless, multiple organ the first 24 h (N = 3; 1.4%). failure was the most common cause of death irre- Results suggest that initially high or increasing spective of initial SOFA classification (low vs. mod- MR-proADM concentrations may help to identify pa- erate SOFA: N = 16; 45.7% vs. N = 79; 43.6%). tients with a high risk of progression towards Patients with low SOFA scores tended to take lon- sepsis-related multiple organ failure. Elevated microcir- ger to progress towards multiple organ failure (10 culation dysfunction and endothelial permeability may [6–18] vs. 7 [3–11] days) and had an increasing therefore play a significant role in driving the develop- number of dysfunctional organs (identified by ment of further organ dysfunction, as described previ- organ-specific SOFA scores ≥2) and an increasing ously . Further studies in larger patient populations overall SOFA score (e.g. diagnosis to day 7: 2 [1–2] are essential to confirm these hypotheses. * Correspondence: firstname.lastname@example.org Department of Anaesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3 Haus 12, 24105 Kiel, Germany Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Elke et al. Critical Care (2018) 22:147 Page 2 of 3 ab Fig. 1 Prediction of sepsis-related multiple organ failure in low (≤7 points) and moderate (8–13 points) SOFA severity patient populations. Cox regression and AUROC analysis for 28-day mortality due to sepsis-related multiple organ failure. Univariate Cox regression was compared for each biomarker and clinical score in the (a) low (≤7 points) and (b) moderate (8–13 points) SOFA severity subgroups. Multivariate Cox regression analysis was corrected for age and the presence of comorbidities. Abbreviations: APACHE II Acute Physiology and Chronic Health Evaluation II (score), AUROC area under the receiver operating characteristic curve, CI confidence interval, CRP C-reactive protein, HR hazard ratio, IQR interquartile range, LR likelihood ratio, MOF multiple organ failure, MR-proADM mid-regional proadrenomedullin, N number, PCT procalcitonin, SAPS II Simplified Acute Physiology Score II, SOFA Sepsis-related Organ Failure Assessment Funding Ethics approval and consent to participate The SISPCT trial infrastructure was partially funded by grant 01 KI 0106 from the The study protocol of the Placebo Controlled Trial of Sodium Selenite and German Federal Ministry of Education and Research. Biosyn (Germany) and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT) was Thermo Fisher (Germany) provided study medication and financial support via approved by the ethics board of Jena University Hospital (Internal File No. unrestricted grants. For the purpose of this secondary analysis of the SISPCT 2242–03/08). Written informed consent was obtained from all patients or trial, no specific funding was received. Neither for the original SISPCT trial nor their legal representatives. for this secondary analysis did the funding organizations have any role in the design and conduct of the trial; collection, management, analysis, or Consent for publication interpretation of the data; preparation, review, or approval of the manuscript; or No individual participant data are reported that would require consent to decision to submit the manuscript for publication. publish from the participant (or legal parent or guardian for children). Competing interests Availability of data and materials FB reported receiving lecture honoraria from biosyn, Gilead, and CSL Behring The datasets used or analyzed during the present study are available from and public funding for the SISPCT trial to his department by the German the corresponding author on reasonable request. Federal Ministry of Education and Research as well as unrestricted research grants for the SISPCT trial by biosyn and Thermo Fisher Scientific. DCW is an employee of B·R·A·H·M·S GmbH. All other authors declared that they have no Authors’ contributions competing interests. GE was the primary author and editor of the manuscript. FB was the principal investigator for the SISPCT trial. All authors collected the study data and contributed to the evaluation and interpretation of data as well as Publisher’sNote writing and editing of the manuscript, performing the statistical analysis of Springer Nature remains neutral with regard to jurisdictional claims in data, and critically reviewing and approving the final manuscript. published maps and institutional affiliations. Elke et al. Critical Care (2018) 22:147 Page 3 of 3 Author details Department of Anaesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3 Haus 12, 24105 Kiel, Germany. Deparment of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Center for Sepsis Control & Care (CSCC), Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. B·R·A·H·M·S GmbH, Hennigsdorf, Neuendorfstr. 25, 16761 Hennigsdorf, Germany. Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Received: 15 May 2018 Accepted: 24 May 2018 References 1. Elke G, Bloos F, Wilson DC, et al. The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis - a secondary analysis of a large randomised controlled trial. Crit Care. 2018;22:79. 2. Andaluz-Ojeda D, Nguyen HB, Meunier-Beillard N, et al. Superior accuracy of mid-regional proadrenomedullin for mortality prediction in sepsis with varying levels of illness severity. Ann Intensive Care. 2017;7:15. 3. Bernal-Morell E, García-Villalba E, Vera MDC, et al. Usefulness of midregional pro-adrenomedullin as a marker of organ damage and predictor of mortality in patients with sepsis. J Inf Secur. 2018;76:249–57. 4. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for Sepsis and septic shock (Sepsis-3). JAMA. 2016;315:801–10. 5. Ince C, Mayeux PR, Nguyen T, et al. The endothelium in Sepsis. Shock. 2016; 45:259–70.
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Published: Jun 5, 2018