Adverse effects of delayed antimicrobial treatment and surgical source control in adults with sepsis: results of a planned secondary analysis of a cluster-randomized controlled trial
Hendrik Rüddel, Daniel Thomas‐Rüddel, Konrad Reinhart, Friedhelm Bach, Herwig Gerlach, Matthias Lindner, John C. Marshall, Philipp Simon, Manfred Weiß, Frank Bloos, Daniel Schwarzkopf, the MEDUSA study group, Gernot Marx, Achim W. Schindler, Tobias Schürholz, Heike Schlegel‐Höfner, Günther Lehmann, Annett Sander, Steffen Friese, Christian W. 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, Herwig Gerlach, Susanne Toussaint, Jörg Brederlau, Friedhelm Bach, 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 Lücht, 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, Matthias Gründling, Liane Guderian, Sven‐Olaf Kuhn, Christian Scheer, Gerd Scheiber, Claudia Matthäus‐Krämer, Bernhard Poidinger, Stefanie D’Aria, Thees Lemke, Birgit Michaelsen, Dirk Schädler, Nina Schulz‐Ruhtenberg, Norbert Weiler, Martin Anetseder, Zoran Textor, Udo X. Kaisers, Philipp Simon, 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, A. Weyland, Frieder Knebel, Thomas Kupfer, Rüdinger Sinz, Petra Bautz, Annemarie Fischer
Abstract
BACKGROUND: Timely antimicrobial treatment and source control are strongly recommended by sepsis guidelines, however, their impact on clinical outcomes is uncertain. METHODS: We performed a planned secondary analysis of a cluster-randomized trial conducted from July 2011 to May 2015 including forty German hospitals. All adult patients with sepsis treated in the participating ICUs were included. Primary exposures were timing of antimicrobial therapy and delay of surgical source control during the first 48 h after sepsis onset. Primary endpoint was 28-day mortality. Mixed models were used to investigate the effects of timing while adjusting for confounders. The linearity of the effect was investigated by fractional polynomials and by categorizing of timing. RESULTS: Analyses were based on 4792 patients receiving antimicrobial treatment and 1595 patients undergoing surgical source control. Fractional polynomial analysis identified a linear effect of timing of antimicrobials on 28-day mortality, which increased by 0.42% per hour delay (OR with 95% CI 1.019 [1.01, 1.028], p ≤ 0.001). This effect was significant in patients with and without shock (OR = 1.018 [1.008, 1.029] and 1.026 [1.01, 1.043], respectively). Using a categorized timing variable, there were no significant differences comparing treatment within 1 h versus 1-3 h, or 1 h versus 3-6 h. Delays of more than 6 h significantly increased mortality (OR = 1.41 [1.17, 1.69]). Delay in antimicrobials also increased risk of progression from severe sepsis to septic shock (OR per hour: 1.051 [1.022, 1.081], p ≤ 0.001). Time to surgical source control was significantly associated with decreased odds of successful source control (OR = 0.982 [0.971, 0.994], p = 0.003) and increased odds of death (OR = 1.011 [1.001, 1.021]; p = 0.03) in unadjusted analysis, but not when adjusted for confounders (OR = 0.991 [0.978, 1.005] and OR = 1.008 [0.997, 1.02], respectively). Only, among patients with septic shock delay of source control was significantly related to risk-of death (adjusted OR = 1.013 [1.001, 1.026], p = 0.04). CONCLUSIONS: Our findings suggest that management of sepsis is time critical both for antimicrobial therapy and source control. Also patients, who are not yet in septic shock, profit from early anti-infective treatment since it can prevent further deterioration. Trial registration ClinicalTrials.gov ( NCT01187134 ). Registered 23 August 2010, NCT01187134.