A multifaceted educational intervention improved anti-infectious measures but had no effect on mortality in patients with severe sepsis

Daniel Schwarzkopf, Claudia Tanja Matthaeus-Kraemer, Daniel O Thomas-Rüddel, Hendrik Rüddel, Bernhard Poidinger, Friedhelm Bach, Herwig Gerlach, Matthias Gründling, Matthias Lindner, Christian Scheer, Philipp Simon, Manfred Weiss, Konrad Reinhart, Frank Bloos, MEDUSA study group, Gernot Marx, Achim Schindler, Tobias Schürholz, Heike Schlegel-Höfner, Gunther Lehmann, Annett Sander, Steffen Friese, Christian Scholz, Pia Fischer, Christina Fuchs, Lutz Becher, Norbert Salewsky, Torsten Schreiber, Anton Goldmann, Didier Keh, Katrin Schmid, Winfried Menning, Renate Steuckart, Robert Barz, Karin Dey, Meike Fahrenholz, Martin Müller, Susanne Toussaint, Jörg Brederlau, Dirk Buschmann, Ingo Gummelt, J Hoeschen, Marion Klaproth, Ina Vedder, Ulrike Bachmann-Holdau, Jürgen Eiche, Rolf Hauschild, Martina Lange, Davia Herrmann-Karbaum, Annette Lubasch, Marcus Rücker, Christian Icke, Alexander Lucht, Andreas Meier-Hellmann, Jan Wagner, Olaf Arnold, Steffen Kästner, Tobias Clausen, Michael Sternkopf, Robert Voswinckel, T Benndorf, Christel Eiserloh, Gerhard Kuhnle, Mathias Koch, Manuela Gerber, Liane Guderian, Sven-Olaf Kuhn, Gerd Scheiber, Frank Bloos, Stefanie D'Aria, Thees Lemke, Birgit Michaelsen, Dirk Schädler, Nina Schulz-Ruhtenberg, Norbert Weiler, Martin Anetseder, Zoran Textor, Udo Kaisers, Matthias Löbe, Frank Meineke, Christine Pausch, Christoph Engel, Georg Braun, Nicole Jensen, Werner Gegenfurtner, Alexander Meinhardt, Robert Schmitt, Andrea Teichert, Klaus-Dieter Becker, Anja Diers, Florian Jelschen, Andreas Weyland, Frieder Knebel, Thomas Kupfer, Rüdinger Sinz, Petra Bautz, Annemarie Fischer, Armin Seibel, Christoph Fleischhacker, Helene Häberle, Philipp Henn, Friederike Mezger, Peter Rosenberger, Reimer Riessen, Silvia Ziegler, Eberhard Barth, Hendrik Bracht, I Heymann, A Hinder, R Sens, Christof Lascho, Henriette Micke, Falk Schmidt, Stefanie Schilling, Gabriele Wöbker, Daniel Schwarzkopf, Claudia Tanja Matthaeus-Kraemer, Daniel O Thomas-Rüddel, Hendrik Rüddel, Bernhard Poidinger, Friedhelm Bach, Herwig Gerlach, Matthias Gründling, Matthias Lindner, Christian Scheer, Philipp Simon, Manfred Weiss, Konrad Reinhart, Frank Bloos, MEDUSA study group, Gernot Marx, Achim Schindler, Tobias Schürholz, Heike Schlegel-Höfner, Gunther Lehmann, Annett Sander, Steffen Friese, Christian Scholz, Pia Fischer, Christina Fuchs, Lutz Becher, Norbert Salewsky, Torsten Schreiber, Anton Goldmann, Didier Keh, Katrin Schmid, Winfried Menning, Renate Steuckart, Robert Barz, Karin Dey, Meike Fahrenholz, Martin Müller, Susanne Toussaint, Jörg Brederlau, Dirk Buschmann, Ingo Gummelt, J Hoeschen, Marion Klaproth, Ina Vedder, Ulrike Bachmann-Holdau, Jürgen Eiche, Rolf Hauschild, Martina Lange, Davia Herrmann-Karbaum, Annette Lubasch, Marcus Rücker, Christian Icke, Alexander Lucht, Andreas Meier-Hellmann, Jan Wagner, Olaf Arnold, Steffen Kästner, Tobias Clausen, Michael Sternkopf, Robert Voswinckel, T Benndorf, Christel Eiserloh, Gerhard Kuhnle, Mathias Koch, Manuela Gerber, Liane Guderian, Sven-Olaf Kuhn, Gerd Scheiber, Frank Bloos, Stefanie D'Aria, Thees Lemke, Birgit Michaelsen, Dirk Schädler, Nina Schulz-Ruhtenberg, Norbert Weiler, Martin Anetseder, Zoran Textor, Udo Kaisers, Matthias Löbe, Frank Meineke, Christine Pausch, Christoph Engel, Georg Braun, Nicole Jensen, Werner Gegenfurtner, Alexander Meinhardt, Robert Schmitt, Andrea Teichert, Klaus-Dieter Becker, Anja Diers, Florian Jelschen, Andreas Weyland, Frieder Knebel, Thomas Kupfer, Rüdinger Sinz, Petra Bautz, Annemarie Fischer, Armin Seibel, Christoph Fleischhacker, Helene Häberle, Philipp Henn, Friederike Mezger, Peter Rosenberger, Reimer Riessen, Silvia Ziegler, Eberhard Barth, Hendrik Bracht, I Heymann, A Hinder, R Sens, Christof Lascho, Henriette Micke, Falk Schmidt, Stefanie Schilling, Gabriele Wöbker

Abstract

Sepsis is a major reason for preventable hospital deaths. A cluster-randomized controlled trial on an educational intervention did not show improvements of sepsis management or outcome. We now aimed to test an improved implementation strategy in a second intervention phase in which new intervention hospitals (former controls) received a multifaceted educational intervention, while controls (former intervention hospitals) only received feedback of quality indicators. Changes in outcomes from the first to the second intervention phase were compared between groups using hierarchical generalized linear models controlling for possible confounders. During the two phases, 19 control hospitals included 4050 patients with sepsis and 21 intervention hospitals included 2526 patients. 28-day mortality did not show significant changes between study phases in both groups. The proportion of patients receiving antimicrobial therapy within one hour increased in intervention hospitals, but not in control hospitals. Taking at least two sets of blood cultures increased significantly in both groups. During phase 2, intervention hospitals showed higher proportion of adequate initial antimicrobial therapy and de-escalation within 5 days. A survey among involved clinicians indicated lacking resources for quality improvement. Therefore, quality improvement programs should include all elements of sepsis guidelines and provide hospitals with sufficient resources for quality improvement.Trial registration: ClinicalTrials.gov, NCT01187134. Registered 23 August 2010, https://www.clinicaltrials.gov/ct2/show/study/NCT01187134 .

Conflict of interest statement

Dr. Schwarzkopf has nothing to disclose. Dr. Matthäus-Krämer has nothing to disclose. Dr. Thomas-Rüddel reports grants from BMBF, outside the submitted work. Dr. Rüddel has nothing to disclose. Dr. Poidinger has nothing to disclose. Dr. Bach has nothing to disclose. Dr. Gerlach has nothing to disclose. Dr. Gründling reports grants from BMBF, outside the submitted work. Dr. Lindner has nothing to disclose. Dr. Scheer has nothing to disclose. Dr. Simon reports personal fees from InfectoPharm, outside the submitted work. Dr. Weiss has nothing to disclose. Dr. Reinhart is shareholder with less of 0.5% of InflaRx NV a Jena /Germany based Biotech Company that evaluates a immunmodulatory approach for the adjunctive treatment of COVID-19. Dr. Bloos reports grants from German Federal Ministry of Education and Research, during the conduct of the study; personal fees from Baxter, outside the submitted work.

© 2022. The Author(s).

Figures

Figure 1
Figure 1
Inclusion of hospitals and patients.
Figure 2
Figure 2
Difference-in-differences analysis of primary and secondary outcomes. Analyses based on data of 40 participating hospitals. Adjusted odds-ratios and p-values result from hierarchical generalized linear models with a logit link adjusted for the covariates age, sex, origin of infection, focus of infection, location at onset of infection and vasopressor use during the first 12 h. Difference-in-differences tested by an interaction effect between study phase and group (control vs. intervention). No. of patients gives the number of cases with complete data both on outcome and confounders compared to the total number of cases were the respective outcome was measured. Intraclass correlations (ICC): 28-day-mortality, ICC = 0.02; Antimicrobial therapy before ODF or within 1 h, ICC = 0.08; Antimicrobial therapy within 1 h after ODF, ICC = 0.04; At least 2 sets of blood cultures, ICC = 0.06; Blood cultures before beginning of antimicrobial therapy, ICC = 0.08; Surgical source control before ODF or within 6 h, ICC = 0.05; Surgical source control after ODF within 6 h, ICC = 0.03. ODF: Organ dysfunction. Data on phase 1 have been previously published.
Figure 3
Figure 3
Comparison between groups during phase 2 of the trial regarding appropriateness and de-escalation of antimicrobial therapy. Analyses based on data of 29 participating hospitals. (a) Adjusted odds-ratios and p-values result from hierarchical generalized linear models with a logit link adjusted for the covariates age, sex, origin of infection, focus of infection, location at onset of infection and vasopressor use during the first 12 h. Since definitions of measures were changed between phases, no difference-in-difference analysis was possible. No. of patients gives the number of cases with complete data both on outcome and confounders compared to the total number of cases were the respective outcome was measured. Intraclass correlations (ICC): Appropriate initial antimicrobial therapy, ICC = 0.03; De-escalation within 5 days, ICC = 0.03. (b) Barplot on appropriateness of initial antimicrobial treatment. (c) Barplot on change of antimicrobial treatment within five days after sepsis onset.

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