Introduction
In the treatment of severe sepsis, timely and effective antimicrobial therapy (AT) as well as source control is crucial and has become a key element in the resuscitation bundles proposed by the Surviving Sepsis Campaign (SSC)[
1]. The SSC guidelines recommend obtaining blood cultures and applying intravenous broad-spectrum antimicrobials within 1 hour after the onset of severe sepsis or septic shock; the guidelines also recommend initiating surgical source control within 12 hours[
1]. Numerous studies have shown that a delay of AT and inappropriate initial AT in this condition is associated with poor outcome[
2‐
6]. One retrospective study in patients with septic shock suggests an increase of patient mortality between 7 and 8% per hour within the first 6 hours after onset of arterial hypotension[
3]. There is also evidence that delayed surgery is associated with lower survival rates[
7‐
9], but the appropriate time frame remains poorly defined[
10].
In numerous retrospective and before-and-after studies, improved adherence to the sepsis bundles was associated with improved patient outcome[
4,
11‐
14]. A meta-analysis suggests that among the individual elements of the resuscitation bundle, timely and appropriately administered antimicrobials are the most important predictors for survival[
15]. However, compliance with sepsis guideline recommendations is poor[
16]. In a Spanish multicenter trial, only 18.4% of the studied patients received AT within the first hour of severe sepsis or septic shock. The administration of antimicrobials within 1 hour was independently associated with a lower risk of hospital death[
6].
Application of antimicrobials without microbiological evidence of infection might be associated with an unfavorable outcome[
17]. Likewise, starting AT in patients with severe sepsis before obtaining blood cultures was among the factors that were associated with higher hospital mortality[
4]. Compliance with the recommendation to draw two pairs of blood cultures before AT, however, was only in the range of 54.4 to 64.5% of patients[
4,
13,
18].
Most of the previous studies investigating the timing of antimicrobials and the compliance with the SSC sepsis bundles reported only ICU mortality rates, focused mainly on patients treated in the emergency department or in the ICU, and did not evaluate the impact of delayed source control on patient outcome[
3,
5,
17,
19,
20]. However, many of these patients may be admitted also from general wards or the operating room and may require effective surgical and other measures of source control. We therefore extended our assessment of infection control measures to include these patients as well. The primary aim of our cohort study was to prospectively test the hypothesis that a delay in AT and source control after onset of sepsis-related organ dysfunction impacts patient outcome. In addition, we aimed to assess compliance with recent best-practice recommendations for the diagnosis and therapy of sepsis.
Discussion
This prospective observational trial included 1,011 evaluable patients with severe sepsis from a large group of academic and nonacademic hospitals. The main finding of this study was that surgical source control within the first 6 hours was associated with 16% lower 28-day mortality. This finding is of interest since the SSC guidelines recently increased the window for source control from 6 hours[
25] to 12 hours[
1] after diagnosis. This decision is based on a single study in patients with necrotizing soft tissue infection, where a delay of surgery >14 hours was associated with an increased risk of death[
7]. However, this study by Boyer and colleagues did not examine the effect of shorter delays on mortality. While current data suggest that delayed surgery adversely affects outcome[
26,
27], studies to allow the determination of an optimal time point of surgical source control are rare. A retrospective analysis of patients with fecal peritonitis did not confirm a relationship between duration until source control and mortality[
28]. However, overall mortality in this study was very low with 19.1% and only 24-hour time intervals were reported. Our data are more consistent with an observational study of children reporting that all patients who received surgical debridement for necrotizing fasciitis at later than 3 hours died[
8]. Likewise, a study in patients with perforated peptic ulcers found that each hour delay in surgical source control increases 30-day mortality by 2%[
9]. Clearly, more data on the relationship between time to source control and patient outcome are needed. In the interim, surgical source control should be performed as soon as possible.
Our observation that early AT of the underlying infection of sepsis before onset of organ dysfunction is associated with a trend towards lower 28-day mortality in the range of 6% supports the importance of early recognition and antimicrobial treatment of infection underlying sepsis[
1]. The finding that the median time to antimicrobial treatment was about 40 minutes shorter in survivors than in nonsurvivors confirms other studies[
18,
29]. Median times to antimicrobial administration were 2.1 hours after diagnosis of severe sepsis or septic shock and thus exceeded guideline recommendations[
1]. Similar delays have been reported in other studies[
5,
13,
18,
20,
30,
31]. In contrast to our data, a number of studies demonstrated an association between patient outcome and time to AT in patients with severe infections[
2,
32‐
35]. Like other studies[
6,
20], we could not confirm the data of Kumar and coworkers in patients with septic shock that suggested an increase of 7.6% in hospital mortality per hour delay in AT[
3]. This may be related to differences in the patient population or study methodology. Kumar and colleagues focused their work on patients with septic shock and observed a median time to AT of 6 hours – three times longer than what we and other studies have observed[
3].
There are some other considerations that may explain the different findings about time to AT and its association with mortality. Firstly, some studies used the time until adequate AT[
3,
5,
34] rather than time to first AT, as we did. We rather applied an approach similar to Puskarich and colleagues because it seems unreasonable to assess the quality of primary care with microbiological data that are not available for the treating physician at that time[
20]; other studies also used this design[
2,
17,
36]. Furthermore, the underlying pathogen may remain unknown and alternative definitions of adequacy such as guideline adherence[
3,
34] need to replace the microbiological definition of adequacy anyhow. Secondly, the definition of the starting time for the duration until AT is defined significantly different across the available studies and includes hospital[
33,
35] or ICU admission[
2], onset of arterial hypotension[
3,
34], and the time when cultures were obtained[
17,
36]. We have chosen onset of infection-related organ dysfunction since this is a clinical feature that should trigger initiation of primary sepsis care. All of the chosen starting times may overlook that significant organ dysfunction occurred before the defined time. These considerations suggest that the investigation of the impact of timing of AT on patient outcome is limited in observational studies.
The concept of early empirical AT has recently been challenged. Puskarich and colleagues did not find an increase in mortality with each hour delay in AT in emergency department patients with septic shock[
20]. In a before-and-after-study in critically ill surgical patients, AT initiated only after microbiological confirmation was associated with a lower mortality rate than early empirical AT[
17]. However, the overall long delays to antimicrobial administration in both groups (11 and 17.7 hours, respectively) limit interpretation of results from that study[
37].
In general, compliance with sepsis guideline recommendations was poor. Only one-third of patients received their first antimicrobial agent according to current guideline recommendations before or within 1 hour of diagnosis of severe sepsis. Blood cultures before AT were taken in 649 (64.2%) patients; however, two sets of blood cultures were obtained in only one-half of these patients. Choice of antimicrobials complied with German recommendations for empirical AT[
22] in 75% of cases. Nevertheless, in about 40% of patients the treating physicians considered first AT as inadequate and escalated AT within the first 5 days. Overall, 28-day mortality of these patients was considerably increased. The association between adequacy of AT and patient outcome remained significant regardless of whether AT was given earlier or later than 1 hour after onset of severe sepsis. This was also true for the 588 patients not requiring surgical or interventional source control. Therefore it seems unlikely that AT was deemed inadequate and changed because the patient deteriorated for reasons unrelated to the microbiological inappropriateness of AT, such as inadequate surgical source control. Increased mortality in patients with inappropriate initial AT has also been observed in other studies[
38,
39]. Recent data from the EUROBACT study concluded that infections with multiresistant organisms are associated with a delay of appropriate AT and increased mortality[
40].
Current guidelines recommend at least two sets of blood cultures before starting AT[
1]. In our study, two-thirds of patients had blood cultures drawn before AT. However, only one set was drawn in about 50% of those patients. Drawing blood cultures before initiation of broad-spectrum antimicrobials was associated with a lower risk of death in the SSC database[
4] but not in our study. This may be explained by the much larger sample size in the SSC database.
Our study has strengths and weaknesses. Strengths include the prospective data collection and multicenter design. Unlike previous studies, our study used short-term prospective data collection and is therefore not influenced by secular trends. Furthermore, reporting of times to AT not only in the ICU but also in other locations as well as outside the hospital and inclusion of medical centers with all levels of care increases the generalizability of our results. Although we enrolled over 1,000 patients, the sample size may not have been large enough to detect small differences in outcome; moreover, we cannot rule out that eligible patients were not included in the study because of limited resources. We also did not include patients who were not referred to the ICU. However, it is unlikely that many such patients were missed since in Germany the majority of patients with organ dysfunction are referred to an ICU or intermediate care unit.
We did not assess adequacy of AT by means of microbiological susceptibility testing results because many of the included hospitals lacked the staff to report such data for a study. Instead, we used the pragmatic approach to ask physicians to record any change of AT within 5 days, which was defined a priori as an indication of inadequate initial therapy. Despite the fact that we found this association also in nonsurgical patients, we cannot rule out that AT was changed because the patient deteriorated for reasons that were not related to the microbiological inappropriateness of AT. Except for serum lactate measurements, which were obtained in 95.2% of the patients at baseline, we did not assess the compliance with other guideline recommendations and therefore cannot rule out that mortality rates were potentially influenced by unmeasured effects; for instance, timely fluid resuscitation or appropriate use of other supportive measures.
Acknowledgements
Financial support was received from the German Federal Ministry of Education and Research via the integrated research and treatment Center for Sepsis Control and Care (FKZ 01EO1002).
In addition to the authors, the following investigators and institutions participated in the MEDUSA study: Department of Intensive Care Medicine, University Hospital Aachen (G Marx, T Schürholz); Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Hospital Altenburger Land, Altenburg (M Blacher, M Kretzschmar); Department of Anesthesiology and Intensive Care Medicine, Ilm-Kreis-Kliniken Arnstadt-Ilmenau, Arnstadt (H Schlegel-Höfner); Department of Anesthesiology and Intensive Care Medicine, HELIOS Klinikum Aue (P Fischer); Department of Anesthesiology and Intensive Care Medicine, Zentralklinik Bad Berka GmbH, Bad Berka (T Schreiber); Department of Anesthesiology and Intensive Care Medicine, Hufelandkrankenhaus GmbH, Bad Langensalza (R Steuckart); Department of Anesthesiology and Intensive Care Medicine, Bundeswehrkrankenhaus Berlin (H Bubser, K Dey); Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Vivantes Klinikum Neukölln, Berlin (H Gerlach); Department of Intensive Care Medicine, HELIOS Kliniken Berlin-Buch, Berlin (J Brederlau); Department of Anesthesiology and Intensive Care Medicine, Charité Berlin (C Spies); Department of Anesthesiology and Intensive Care and Emergency Medicine, HELIOS Klinikum Emil von Behring, Berlin (A Lubasch, O Franke); Department of Anesthesiology, Intensive Care Medicine, Emergency Medicine, and Pain Therapy, Ev. Krankenhaus Bielefeld (F Bach); Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, HELIOS St. Josefs-Hospital Bochum–Linden, Bochum (U Bachmann-Holdau); Department of Anesthesiology and Intensive Care Medicine, St. Georg Hospital Eisenach (J Eiche); Department of Anesthesiology and Intensive Care Medicine, Waldkrankenhaus Rudolf Elle GmbH, Eisenberg (M Lange, D Volkert); Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Helios Klinikum Erfurt (A Meier-Hellmann); Department of Anesthesiology and Intensive Care Medicine, Catholic Hospital St. Johann Nepomuk Erfurt (T Clausen); Department of Internal Medicine, Bürgerhospital Friedberg (A Niedenthal, M Sternkopf); Department of Anesthesiology and Intensive Care Medicine, GeoMed Klinikum Gerolzhofen (H Schulz); Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Klinik am Eichert, Göppingen (S Rauch); Department of Anesthesiology and Intensive Care Medicine, Ernst-Moritz-Arndt-University Greifswald (M Gründling); Department of Anesthesiology and Intensive Care Medicine, Helios St. Elisabeth Klinik Hünfeld (N Knöck); Department of Anesthesiology and Intensive Care Medicine, Ilm-Kreis-Kliniken Arnstadt–Ilmenau, Ilmenau (G Scheiber); Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel (N Weiler); Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, HELIOS-Klinikum Krefeld GmbH, Krefeld (E Berendes, S Nicolas); Department of Anesthesiology and Intensive Care Medicine, Hospital Landshut–Achdorf, Landshut (M Anetseder, Z Textor); Department of Anesthesiology and Intensive Care Medicine, University Hospital Leipzig (U Kaisers, P Simon); Department of Intensive Care and Emergency Medicine, Hospital Meiningen (G Braun); Department of Anesthesiology and Intensive Care Medicine, Saale-Unstrut-Klinikum Naumburg (K Becker); Department of Anesthesiology and Intensive Care Medicine, Südharz-Krankenhaus Nordhausen (R Laubinger, U Klein); Department of Anesthesiology and Intensive Care Medicine, Thüringen-Klinik Pößneck (F Knebel); Department of Intensive Care and Emergency Medicine, ASKLEPIOS-ASB Krankenhaus Radeberg (R Sinz); Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Thüringen-Kliniken ‘Georgius Agricola’, Saalfeld/Saale (A Fischer); Department of Anesthesiology and Intensive Care Medicine, Diakonie-Klinikum Schwäbisch Hall, Schwäbisch Hall (K Hornberger, K Rosenhagen); Department of Anesthesiology and Intensive Care and Emergency Medicine, Ev. Jung-Stilling-Krankenhaus, Siegen (A Seibel); Department of Anesthesiology and Intensive Care Medicine, SRH Zentralklinikum Suhl (W Schummer); Department of Internal Medicine, University Hospital Tübingen (A Heininger); Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Sophien- und Hufeland-Klinikum gGmbH, Weimar (C Lascho, F Schmidt); Department of Intensive Care Medicine, HELIOS Klinikum Wuppertal (G Wöbker).
The following ethics bodies approved the study: Ethics Committee (EC) of the Friedrich-Schiller-University (primary vote), EC of the medical association of Thuringia, EC of the medical association of Bavaria, EC of the Christian-Albrechts-University Kiel, EC of the medical association of Saxony-Anhalt, EC of the medical association of Bavaria, EC of the medical association of Westphalia-Lippe and the Westphalian Wilhelms-University Munster, EC of the University Leipzig, EC of the University Witten/Herdecke, EC of the medical association of Saarland, EC of the medical association of Hesse, EC of the medical association of Baden-Württemberg, EC of the Ulm University, EC of the Ernst-Moritz-Arndt-University Greifswald, EC of the medical association of Lower Saxony, EC of the medical association of Saxony, EC of the medical association of North Rhine, EC of the Eberhard-Karls University Tübingen, EC of the Carl-Gustav-Carus University Dresden, EC of the RWTH Aachen, EC of the Friedrich-Wilhelm-University Bonn, and EC of the medical association of Hamburg.
Competing interests
The authors declare that they have no competing interests.
Authors’ contribution
All authors made substantive intellectual contributions to the manuscript. FB and KR conceived and designed the study, drafted the manuscript, and were responsible for the grant funding. DaS, DT-R, HR, PS, RR, DK, KD, MW, ST, DiS, AW, MR, KS, JE, GK, and UK participated in the acquisition of the data, were responsible for the conduct of the study and helped to revise the manuscript. CE and HH participated in the study design and the statistical data analysis and helped to revise the manuscript. JCM, SH, and CH participated in the assessment of the data analysis and revised the manuscript. All authors read and approved the final manuscript.