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
Authors: Rüddel Hendrik , Thomas-Rüddel Daniel O. , Reinhart Konrad , Bach Friedhelm , Gerlach Herwig , Lindner Matthias , Marshall John C. , Simon Philipp , Weiss Manfred , Bloos Frank , Schwarzkopf Daniel ,   the MEDUSA study group, Marx Gernot , Schindler Achim , Schürholz Tobias , Schlegel‑Höfner Heike , Lehmann Gunther , Sander Annett , Friese Steffen , Scholz Christian , Fischer Pia , Fuchs Christina , Becher Lutz , Salewsky Norbert , Schreiber Torsten , Goldmann Anton , Keh Didier , Schmid Katrin , Menning Winfried , Steuckart Renate , Barz Robert , Dey Karin , Fahrenholz Meike , Müller Martin , Gerlach Herwig , Toussaint Susanne , Brederlau Jörg , Bach Friedhelm , Buschmann Dirk , Gummelt Ingo , Hoeschen J. , Klaproth Marion , Vedder Ina , Bachmann‑Holdau Ulrike , Eiche Jürgen , Hauschild Rolf , Lange Martina , Herrmann‑Karbaum Davia , Lubasch Annette , Rücker Marcus , Icke Christian , Lucht Alexander , Meier‑Hellmann Andreas , Wagner Jan , Arnold Olaf , Kästner Steffen , Clausen Tobias , Sternkopf Michael , Voswinckel Robert , Benndorf T. , Eiserloh Christel , Kuhnle Gerhard , Koch Mathias , Gerber Manuela , Gründling Matthias , Guderian Liane , Kuhn Sven‑Olaf , Scheer Christian , Scheiber Gerd , Matthäus‑Krämer Claudia , Poidinger Bernhard , D’Aria Stefanie , Lemke Thees , Michaelsen Birgit , Schädler Dirk , Schulz‑Ruhtenberg Nina , Weiler Norbert , Anetseder Martin , Textor Zoran , Kaisers Udo , Simon Philipp , Löbe Matthias , Meineke Frank , Pausch Christine , Engel Christoph , Braun Georg , Jensen Nicole , Gegenfurtner Werner , Meinhardt Alexander , Schmitt Robert , Teichert Andrea , Becker Klaus‑Dieter , Diers Anja , Jelschen Florian , Weyland Andreas , Knebel Frieder , Kupfer Thomas , Sinz Rüdinger , Bautz Petra , Fischer Annemarie , Seibel Armin , Fleischhacker Christoph , Häberle Helene , Henn Philipp , Mezger Friederike , Rosenberger Peter , Riessen Reimer , Ziegler Silvia , Barth Eberhard , Bracht Hendrik , Heymann I. , Hinder A. , Sens R. , Weiss Manfred , Lascho Christof , Micke Henriette , Schmidt Falk , Schilling Stefanie , Wöbker Gabriele 
Published: February 2022

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