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Effect of a multifaceted educational intervention for anti-infectious measures on sepsis mortality: a cluster randomized trial

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Abstract

Purpose

Guidelines recommend administering antibiotics within 1 h of sepsis recognition but this recommendation remains untested by randomized trials. This trial was set up to investigate whether survival is improved by reducing the time before initiation of antimicrobial therapy by means of a multifaceted intervention in compliance with guideline recommendations.

Methods

The MEDUSA study, a prospective multicenter cluster-randomized trial, was conducted from July 2011 to July 2013 in 40 German hospitals. Hospitals were randomly allocated to receive conventional continuous medical education (CME) measures (control group) or multifaceted interventions including local quality improvement teams, educational outreach, audit, feedback, and reminders. We included 4183 patients with severe sepsis or septic shock in an intention-to-treat analysis comparing the multifaceted intervention (n = 2596) with conventional CME (n = 1587). The primary outcome was 28-day mortality.

Results

The 28-day mortality was 35.1% (883 of 2596 patients) in the intervention group and 26.7% (403 of 1587 patients; p = 0.01) in the control group. The intervention was not a risk factor for mortality, since this difference was present from the beginning of the study and remained unaffected by the intervention. Median time to antimicrobial therapy was 1.5 h (interquartile range 0.1–4.9 h) in the intervention group and 2.0 h (0.4–5.9 h; p = 0.41) in the control group. The risk of death increased by 2% per hour delay of antimicrobial therapy and 1% per hour delay of source control, independent of group assignment.

Conclusions

Delay in antimicrobial therapy and source control was associated with increased mortality but the multifaceted approach was unable to change time to antimicrobial therapy in this setting and did not affect survival.

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Acknowledgements

MEDUSA contributing sites and site investigators, alphabetical by site

University Hospital RWTH Aachen, Department of Intensive Care Medicine: Gernot Marx, Achim Schindler, Tobias Schürholz; Ilm-Kreis-Kliniken Arnstadt, Department of Anesthesiology and Intensive Care Medicine: Heike Schlegel-Höfner, Gunther Lehmann, Annett Sander, Steffen Friese, Christian Scholz; Helios Hospital Aue, Department of Anesthesiology and Intensive Care Medicine: Pia Fischer; Zentralklinik Bad Berka GmbH, Department of Anaesthesia and Intensive Care Medicine: Christina Fuchs, Lutz Becher, Norbert Salewsky, Torsten Schreiber; Charité Berlin, Department of Anesthesiology and Operative Intensive Care Medicine: Anton Goldmann, Didier Keh, Katrin Schmid; Hufeland-Klinikum Bad Langensalza, Department of Anesthesiology and Intensive Care Medicine: Winfried Menning, Renate Steuckart; Bundeswehrkrankenhaus Berlin, Department of Anesthesiology and Intensive Care Medicine: Robert Barz, Karin Dey, Meike Fahrenholz, Martin Müller; Vivantes Klinikum Neukölln-Berlin, Department of Anesthesiology, Surgical Intensive Care Medicine, and Pain Therapy: Herwig Gerlach, Susanne Toussaint; Helios Hospital Berlin-Buch, Department of Intensive Care Medicine: Jörg Brederlau; Ev. Hospital Bielefeld, Department of Anesthesiology, Emergency and Intensive Care Medicine, and Pain Therapy: Friedhelm Bach, Dirk Buschmann, Ingo Gummelt, J. Hoeschen, Marion Klaproth, Ina Vedder; HELIOS-Hospital St. Josefs-Hospital Bochum-Linden, Department of Anesthesiology: Ulrike Bachmann-Holdau; St. Georg Hospital Eisenach, Department of Anesthesiology and Intensive Care Medicine: Jürgen Eiche, Rolf Hauschild; Hospital Rudolf Elle, Eisenberg, Department of Anesthesiology and Intensive Care Medicine: Martina Lange, Davia Herrmann-Karbaum; Helios-Hospital Emil-von Behring, Department of Interdisciplinary Intensive Care and Emergency Medicine: Annette Lubasch, Marcus Rücker; Helios-Hospital Erfurt, Department of Anesthesiology and Intensive Care Medicine: Christian Icke, Alexander Lucht, Andreas Meier-Hellmann, Jan Wagner; Catholic Hospital St. Johann Nepomuk Erfurt, Department of Anesthesiology and Intensive Care Medicine: Olaf Arnold, Steffen Kästner, Tobias Clausen; Hospital Friedberg, Department of Internal Medicine: Michael Sternkopf, Robert Voswinckel; SRH Waldklinikum Gera, Department of Anesthesiology and Intensive Care Medicine: T. Benndorf, Christel Eiserloh, Gerhard Kuhnle, Mathias Koch; University Hospital Greifswald, Department of Anesthesiology and Intensive Care Medicine: Manuela Gerber, Matthias Gründling, Liane Guderian, Sven-Olaf Kuhn, Christian Scheer; Hospital Ilmenau; Department of Anesthesiology and Intensive Care Medicine: Gerd Scheiber; Jena University Hospital, Center for Sepsis Control & Care/Department of Anesthesiology and Intensive Care Medicine: Frank Bloos, Susann Christink, Martina Kortegast, Claudia Matthäus-Krämer, Marcel Mücke, Bernhard Poidinger, Hendrik-Rüddel, Ulrike Redlich, Daniel Schwarzkopf, Daniel Thomas-Rüddel, Christel Volkmer; University Hospital Kiel, Department of Anesthesiology and Intensive Care Medicine: Stefanie D’Aria, Thees Lemke, Birgit Michaelsen, Dirk Schädler, Nina Schulz-Ruhtenberg, Norbert Weiler; Hospital Landshut-Achdorf, Department of Anesthesiology and Surgical Intensive Care Medicine: Martin Anetseder, Zoran Textor; University Hospital Leipzig, Department of Anesthesiology and Intensive Care Medicine: Udo Kaisers, Philipp Simon; Hospital Meiningen, Department of Intensive Care and Emergency Medicine: Georg Braun, Nicole Jensen, Werner Gegenfurtner, Alexander Meinhardt, Robert Schmitt, Andrea Teichert; Saale-Unstrut-Hospital Naumburg, Department of Anesthesiology and Intensive Care Medicine: Klaus-Dieter Becker; Hospital Oldenburg, Department of Anesthesiology, Intensive Care Medicine; Emergency Medicine, and Pain Therapy: Anja Diers, Florian Jelschen, Andreas Weyland; Thüringen-Klinik Pößneck, Department of Anesthesiology and Intensive Care Medicine: Frieder Knebel, Thomas Kupfer; Asklepios Hospital Radeberg, Department of Intensive Care and Emergency Medicine: Rüdinger Sinz; Thüringen-Kliniken Saalfeld, Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy: Petra Bautz, Annemarie Fischer; Ev. Jung-Stilling Hospital Siegen, Department of Anesthesiology, Intensive Care, and Emergency Medicine: Armin Seibel, Christoph Fleischhacker; University Hospital Tübingen; Department of Anesthesiology: Helene Häberle, Philipp Henn, Friederike Mezger, Peter Rosenberger; University Hospital Tübingen; Dept of Internal Medicine: Reimer Riessen, Silvia Ziegler; University Hospital Medical School Ulm, Clinic of Anaesthesiology: Eberhard Barth, Hendrik Bracht, I. Heymann, A. Hinder, R. Sens, Manfred Weiss; Hufeland Hospital Weimar; Department of Anesthesiology and Intensive Care Medicine: Christof Lascho, Henriette Micke, Falk Schmidt; Helios Hospital Wuppertal. Department of Intensive Care Medicine: Stefanie Schilling, Gabriele Wöbker.

Clinical data collection and management

Matthias Löbe, Frank Meineke, Christine Pausch, Christoph Engel (Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig); statistical support for protocol development: Heike Hoyer (Institute for Medical Statistics, Information, and Documentation: Jena University Hospital); statistical support for implementation of the multiple imputation method: S. Grund, A. Robitzsch (Leibnitz Institute for Science and Mathematics Education, University Kiel).

Author information

Authors and Affiliations

  1. Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany

    Frank Bloos, Hendrik Rüddel, Daniel Thomas-Rüddel, Daniel Schwarzkopf, Claudia Matthäus-Krämer, Bernhard Poidinger & Konrad Reinhart

  2. Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany

    Frank Bloos, Hendrik Rüddel, Daniel Thomas-Rüddel, Bernhard Poidinger & Konrad Reinhart

  3. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany

    Christine Pausch & Christoph Engel

  4. Service Prévention et Contrôle de l’Infection, Hôpitaux Universitaires de Genève, Geneva, Switzerland

    Stephan Harbarth

  5. Department of Anaesthesia and Intensive Care Medicine, Zentralklinik Bad Berka GmbH, Bad Berka, Germany

    Torsten Schreiber

  6. Department of Anesthesiology and Intensive Care Medicine, University Hospital Greifswald, Greifswald, Germany

    Matthias Gründling & Christian Scheer

  7. Department of Surgery and the Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Ontario, Canada

    John Marshall

  8. Department of Anesthesiology and Intensive Care Medicine, University Hospital Leipzig, Leipzig, Germany

    Philipp Simon & Udo X. Kaisers

  9. Division of Pulmonary and Critical Care Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA

    Mitchell M. Levy

  10. Department of Anesthesiology, University Hospital Ulm, Ulm, Germany

    Manfred Weiss

  11. Department of Anesthesiology and Intensive Care Medicine, University Hospital Oldenburg, Oldenburg, Germany

    Andreas Weyland

  12. Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Therapy, Vivantes Hospital Neukölln, Berlin, Germany

    Herwig Gerlach

  13. Department of Intensive Care Medicine, University Hospital RWTH Aachen, Aachen, Germany

    Tobias Schürholz

  14. Department of Anesthesiology and Intensive Care Medicine, University Hospital Rostock, Rostock, Germany

    Tobias Schürholz

  15. Department of Anesthesiology, Intensive Care, Transfusion and Emergency Medicine and Pain Therapy, Bethel Hospital Bielefeld, Bielefeld, Germany

    Friedhelm Bach

  16. Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany

    Reimer Riessen

  17. Department of Anesthesiology and Intensive Care Medicine, Hospital of the Bundeswehr Berlin, Berlin, Germany

    Karin Dey

  18. Department of Anesthesiology and Intensive Care Medicine, University Medical Center Kiel, Kiel, Germany

    Norbert Weiler

  19. Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Helios Hospital Erfurt, Erfurt, Germany

    Andreas Meier-Hellmann

  20. Department of Anesthesiology and Intensive Care Medicine, University Hospital Tübingen, Tübingen, Germany

    Helene H. Häberle

  21. Department of Intensive Care Medicine, Helios Hospital Wuppertal, Wuppertal, Germany

    Gabriele Wöbker

  22. University Hospital Ulm, Ulm, Germany

    Udo X. Kaisers

Authors
  1. Frank Bloos
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  2. Hendrik Rüddel
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  3. Daniel Thomas-Rüddel
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  4. Daniel Schwarzkopf
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  5. Christine Pausch
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  6. Stephan Harbarth
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  7. Torsten Schreiber
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  8. Matthias Gründling
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  9. John Marshall
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  10. Philipp Simon
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  11. Mitchell M. Levy
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  12. Manfred Weiss
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  13. Andreas Weyland
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  14. Herwig Gerlach
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  15. Tobias Schürholz
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  16. Christoph Engel
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  17. Claudia Matthäus-Krämer
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  18. Christian Scheer
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  19. Friedhelm Bach
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  20. Reimer Riessen
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  21. Bernhard Poidinger
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  22. Karin Dey
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  23. Norbert Weiler
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  25. Helene H. Häberle
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  26. Gabriele Wöbker
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  27. Udo X. Kaisers
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  28. Konrad Reinhart
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Corresponding author

Correspondence to Konrad Reinhart.

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Conflicts of interest

All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Bloos reported receiving lecture honoraria from biosyn, Gilead, and CSL Behring. Dr. Harbarth reported receiving personal fees from Johnson & Johnson and Novartis and grants from Pfizer and BioMerieux. Dr. Levy reported receiving grants and personal fees from ImmuneExpress. Prof. Reinhart reported receiving grants and non-financial support from biosyn AG and Thermofischer/BRAHMS, being a shareholder of InflaRx Jena, and receiving personal fees from Adrenomed. Dr. Schuerholz reported grants and personal fees from Astellas Pharma, grants from B Braun Melsungen and Köhler Chemie, personal fees from Bayer Healthcare. Dr. Weyland reported receiving recruitment fees from Jena University Hospital for another trial.

Dr. Bach, Dr. Dey, Dr. Engel, Dr. Gerlach, Dr. Gründling, Dr. Häberle, Dr. Kaisers, Dr. Marshall, C. Matthäus-Krämer, Dr. Meier-Hellmann, Dr. Poidinger, Dr. Riessen, Dr. Rüddel, Dr. Scheer, Dr. Schreiber, D. Schwarzkopf, Dr. Simon, Dr. Thomas-Rüddel, Dr. Weiler, Dr. Weiss, and Dr. Woebker reported no conflicts of interest.

Funding/support

The study was funded by the German Federal Ministry of Education and Research via the integrated research and treatment center “Center for Sepsis Control and Care” (FKZ 01EO1002).

Additional information

Members of the MEDUSA study group are listed in the "Acknowledgements".

Take-home message: This first cluster-randomized controlled multicenter clinical trial addressing the effect of time to empirical antimicrobial therapy on 28-day mortality was unable to reduce time to antimicrobial therapy in the intervention group. Although the intervention itself did not affect survival, time to first antimicrobial therapy and time to source control were both associated with mortality.

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Bloos, F., Rüddel, H., Thomas-Rüddel, D. et al. Effect of a multifaceted educational intervention for anti-infectious measures on sepsis mortality: a cluster randomized trial. Intensive Care Med 43, 1602–1612 (2017). https://doi.org/10.1007/s00134-017-4782-4

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