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Impact of compliance with infection management guidelines on outcome in patients with severe sepsis: a prospective observational multi-center study

Impact of compliance with infection management guidelines on outcome in patients with severe... Introduction: Current sepsis guidelines recommend antimicrobial treatment (AT) within one hour after onset of sepsis-related organ dysfunction (OD) and surgical source control within 12 hours. The objective of this study was to explore the association between initial infection management according to sepsis treatment recommendations and patient outcome. Methods: In a prospective observational multi-center cohort study in 44 German ICUs, we studied 1,011 patients with severe sepsis or septic shock regarding times to AT, source control, and adequacy of AT. Primary outcome was 28-day mortality. Results: Median time to AT was 2.1 (IQR 0.8 – 6.0) hours and 3 hours (-0.1 – 13.7) to surgical source control. Only 370 (36.6%) patients received AT within one hour after OD in compliance with recommendation. Among 422 patients receiving surgical or interventional source control, those who received source control later than 6 hours after onset of OD had a significantly higher 28-day mortality than patients with earlier source control (42.9% versus 26.7%, P <0.001). Time to AT was significantly longer in ICU and hospital non-survivors; no linear relationship was found between time to AT and 28-day mortality. Regardless of timing, 28-day mortality rate was lower in patients with adequate than non-adequate AT (30.3% versus 40.9%, P < 0.001). Conclusions: A delay in source control beyond 6 hours may have a major impact on patient mortality. Adequate AT is associated with improved patient outcome but compliance with guideline recommendation requires improvement. There was only indirect evidence about the impact of timing of AT on sepsis mortality. Introduction cultures and applying intravenous broad-spectrum anti- In the treatment of severe sepsis, timely and effective microbials within 1 hour after the onset of severe sepsis antimicrobial therapy (AT) as well as source control is or septic shock; the guidelines also recommend initiating crucial and has become a key element in the resuscitation surgical source control within 12 hours [1]. Numerous bundles proposed by the Surviving Sepsis Campaign (SSC) studies have shown that a delay of AT and inappropriate [1]. The SSC guidelines recommend obtaining blood initial AT in this condition is associated with poor outcome [2-6]. One retrospective study in patients with septic shock * Correspondence: [email protected] suggests an increase of patient mortality between 7 and Department of Anesthesiology and Intensive Care Medicine, Jena University 8% per hour within the first 6 hours after onset of arterial Hospital, 07740 Jena, Germany hypotension [3]. There is also evidence that delayed surgery The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07740 Jena, Germany Full list of author information is available at the end of the article © 2014 Bloos et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Bloos et al. Critical Care 2014, 18:R42 Page 2 of 10 http://ccforum.com/content/18/2/R42 is associated with lower survival rates [7-9], but the appro- networks. The objectives of the study, inclusion and priate time frame remains poorly defined [10]. exclusion criteria, and the documentation procedures In numerous retrospective and before-and-after studies, were discussed in several national meetings before the improved adherence to the sepsis bundles was associated start of the study. The study was designed as a pragmatic with improved patient outcome [4,11-14]. A meta-analysis studywithaminimalcasereportformtoallow forthe suggests that among the individual elements of the re- participation of hospitals without research staff. This suscitation bundle, timely and appropriately administered study served as a run-in study for a cluster-randomized antimicrobials are the most important predictors for trial assessing whether a multifaceted educational program survival [15]. However, compliance with sepsis guideline accelerates the onset of AT and improves survival (Med- recommendations is poor [16]. In a Spanish multicenter ical Education for Sepsis Source Control and Antibiotics trial, only 18.4% of the studied patients received AT within MEDUSA, ClinicalTrials.gov Identifier NCT01187134). the first hour of severe sepsis or septic shock. The adminis- tration of antimicrobials within 1 hour was independently Patients associated with a lower risk of hospital death [6]. Between December 2010 and April 2011, all consecutive Application of antimicrobials without microbiological adult patients treated in the ICU for proven or suspected evidence of infection might be associated with an unfavor- infection with at least one new organ dysfunction related able outcome [17]. Likewise, starting AT in patients with to the infection were eligible for inclusion. Organ dysfunc- severe sepsis before obtaining blood cultures was among tions were defined as follows: acute encephalopathy, the factors that were associated with higher hospital thrombocytopenia defined as a platelet count <100,000/μl mortality [4]. Compliance with the recommendation to or a drop in platelet count >30% within 24 hours, arterial draw two pairs of blood cultures before AT, however, was oxygen partial pressure <10 kPa (75 mmHg) when breath- only in the range of 54.4 to 64.5% of patients [4,13,18]. ing room air or partial pressure of arterial oxygen/fraction Most of the previous studies investigating the timing of inspired oxygen ratio <33 kPa (<250 mmHg), renal of antimicrobials and the compliance with the SSC sepsis dysfunction defined as oliguria (diuresis ≤0.5 ml/kg body bundles reported only ICU mortality rates, focused mainly weight/hour) despite adequate fluid resuscitation or an on patients treated in the emergency department or in the increase of serum creatinine more than twice the ICU, and did not evaluate the impact of delayed source local reference value, metabolic acidosis with a base control on patient outcome [3,5,17,19,20]. However, many excess < −5 mmol/l or a serum lactate >1.5 times the local of these patients may be admitted also from general wards reference value, and arterial hypotension defined as sys- or the operating room and may require effective surgical tolic arterial blood pressure <90 mmHg or mean arterial and other measures of source control. We therefore blood pressure <70 mmHg for >1 hour despite adequate extended our assessment of infection control measures fluid loading or vasopressor therapy at any dosage to to include these patients as well. The primary aim of maintain higher blood pressures [21]. Patients who re- our cohort study was to prospectively test the hypothesis ceived initial infection control measures for sepsis in that a delay in AT and source control after onset of sepsis- another hospital and patients who did not receive full related organ dysfunction impacts patient outcome. In life-sustaining treatment were excluded. The study was addition, we aimed to assess compliance with recent best- reviewed and approved by the local ethics committees, practice recommendations for the diagnosis and therapy which waived the need for informed consent because of the of sepsis. observational nature of the study (see Acknowledgements). The study was also approved by the local data protection Methods boards. Study design This prospective study was designed as a longitudinal Data collection multicenter observational cohort study in 42 German hos- Onset of severe sepsis or septic shock was defined as the pitals to determine the time to AT, surgical source control time of first infection-related organ dysfunction as docu- and compliance with sepsis recommendations related to mented in the patient file. Patient location at time of AT in patients with suspected severe sepsis or septic shock onset of severe sepsis was defined as the patient location and its impact on 28-day, ICU, and hospital mortality. Par- where the first infection-related organ dysfunction was ticipation of hospitals was voluntary but was restricted to documented. For patients who developed severe sepsis hospitals involved in the primary care of sepsis patients outside the ICU, this could be the prehospital setting, and committed to participate in a quality improvement the emergency department, the hospital ward, or the process. Hospitals without ICUs were excluded from operating room. Time and type of first AT as well as pre- this study. Potential study centers were recruited by existing AT were also recorded from the medical records. regional and national research and quality improvement Any AT prescribed up to 24 hours before the onset of Bloos et al. Critical Care 2014, 18:R42 Page 3 of 10 http://ccforum.com/content/18/2/R42 organ dysfunction but for the current infectious episode stateof blood culturewithdrawalwereonlyincluded was considered previous AT. Perioperative antimicrobial into the final model if they were associated with 28-day prophylaxis was not regarded as specific AT for sepsis. mortality at P < 0.20. Goodness of fit was assessed by the Change of empirical AT was assessed on day 5. Initial AT c-statistic and the Hosmer-Lemeshow test. was defined as inadequate if escalation had occurred within the first 5 days. For each patient, a blinded arbitrator Results assessed whether the initial AT complied with German Participating centers and patients guideline recommendations [22]. Source control was Hospital and ICU characteristics of the 44 participating defined as removal of an anatomic source of infection centers are shown in Table 1. A total of 1,048 patients either by surgery or intervention (that is, computed were included during the 5-month study period. Of these, tomography-guided drainage). Source control was defined 37 patients were excluded for missing values in 28-day as inadequate if the technical procedure was unsuccessful. mortalityortimetoAT, resultingin1,011 evaluable Time to source control was obtained from the medical patients. Approximately one-half of the patients (n =504, record. Other factors included serum lactate and procalci- 49.9%) were treated for surgical reasons. Organ dysfunc- tonin at the time of onset of severe sepsis, number of tions on the day of study inclusion were shock (n =632, blood culture sets taken, and ICU and hospital mortality. 76.4%), lactacidosis (n = 424, 51.3%), acute renal failure Severity of disease was assessed by the Simplified Acute (n = 307, 37.2%) thrombocytopenia (n = 238, 28.8%), pul- Physiology Score II and the Sequential Organ Failure monary dysfunction (n = 492, 65.8%), and septic encephal- Assessment score on the day of sepsis diagnosis [23,24]. opathy (n = 338, 41.2%). A total 85.1% of the patients had Data were collected by a web-based electronic case more than one organ failure. Patient characteristics are report form using OpenClinica® (OpenClinica, LLC, shown in Table 2. The overall 28-day mortality was 34.8%; Waltham, MA, USA). Data integrity was confirmed by ICU mortality and hospital mortality were 33.0% and data checks within the database, resulting in queries to 41.4%, respectively. There was no association of academic the investigator where applicable. Additionally, onset of versus nonacademic hospitals or hospital size with 28-day infection-related organ dysfunction and subsequent AT mortality. were checked for plausibility by the MEDUSA study staff and discussed with the study center staff where applicable. Timing and adequacy of antimicrobial therapy Three hundred and seventy (36.6%) patients received anti- Statistical analysis microbials within 1 hour of the onset of organ dysfunction; The primary endpoint was survival status at day 28 after onset of severe sepsis. Categorical data are expressed as Table 1 Characteristics of participating hospitals and ICUs absolute or relative frequencies; the chi-square or Fisher's (n = 44) exact test was used for inferential statistics. Continuous Hospital Data data are expressed as the median and interquartile range; University hospital 10 (22.7%) the Mann–Whitney U test was used for inferential sta- Level of care tistics. Missing data were not replaced by calculation. We divided patients according to the timing of antimicro- Primary care hospitals 14 (31.8%) bial treatment into the following groups: previous AT, 0 Secondary care hospitals 12 (27.3%) to 1 hours, 1 to 3 hours, 3 to 6 hours and >6 hours [6]. Tertiary care hospitals 18 (40.9%) Patients were grouped by time to source control into two Hospital beds 581 (416 to 1,055) groups: within 6 hours or >6 hours [25]. Odds ratios (OR) Number of ICUs 2 (1 to 4) with 95% confidence intervals (CI) for the risk of death Inhospital biochemistry laboratory 43 (97.7%) within 28 days depending on time to AT or time to source control were calculated by univariate and multivariate lo- Inhospital microbiology department 30 (68 to 2%) gistic regression only in those patients were treatment was ICU beds 15 (10 to 29) started after onset of organ dysfunction. In patients with ICU patients per annum 1,200 (900 to 2,050) sepsis, prior research has identified the initial Sequential Emergency department Organ Failure Assessment score, age, and serum lactate Emergency department available 37 (84.1%) [20] as confounders for the risk of death. These parame- Lactate available within 1 hour 38 (86.4%) ters were therefore included in the multivariable logistic regression analysis to calculate adjusted ORs. In addition, Broad-spectrum antibiotics available 36 (81.8%) indication for source control, escalation as well as de- Prehospital emergency physician available 39 (88.6%) escalation of empirical AT within 5 days, presence of Data are shown as number (percentage) for categorical data or median community acquired infection, focus of infection, and (interquartile range) for continuous data. Bloos et al. Critical Care 2014, 18:R42 Page 4 of 10 http://ccforum.com/content/18/2/R42 Table 2 Patient characteristics 28-day survivors (n = 659) 28 day nonsurvivors (n = 352) All patients (n = 1,011) P value Male 413 (62.7%) 221 (62.8%) 634 (62.7%) 0.972 Age (years) 68 (55 to 75) 72 (64 to 79) 69 (58 to 77) <0.001 ICU admission 0.254 Elective surgery 74 (11.2%) 42 (11.9%) 116 (11.5%) Emergency surgery 255 (38.7%) 118 (33.5%) 373 (36.9%) Trauma 10 (1.5%) 5 (1.4%) 15 (1.5%) Medical 304 (46.1%) 183 (52%) 487 (48.2%) Other 16 (2.4%) 4 (1.1%) 20 (2%) Patient location at onset of sepsis 0.426 Emergency department 93 (14.1%) 47 (13.4%) 140 (13.9%) ICU 366 (55.6%) 214 (60.8%) 580 (57.4%) Operating theatre 63 (9.6%) 22 (6.2%) 85 (8.4%) Hospital ward 80 (12.2%) 41 (11.6%) 121 (12%) Prehospital 12 (1.8%) 4 (1.1%) 16 (1.6%) IMC 44 (6.7%) 24 (6.8%) 68 (6.7%) Infection 0.22 Community acquired 300 (45.5%) 143 (40.6%) 443 (43.8%) ICU/IMC acquired 170 (25.8%) 91 (25.9%) 261 (25.8%) Hospital acquired 189 (28.7%) 118 (33.5%) 307 (30.4%) Source of infection (multiple responses possible) Intra-abdominal 228 (34.7%) 138 (39.2%) 366 (36.3%) 0.167 Pneumonia 221 (33.7%) 130 (36.9%) 351 (34.9%) 0.311 Urogenital 92 (14.0%) 30 (8.5%) 122 (12.1%) 0.011 Upper airway 59 (9.0%) 24 (6.8%) 83 (8.2%) 0.228 Bones/soft tissue 47 (7.2%) 25 (7.1%) 72 (7.1%) 0.966 Other 67 (11.7%) 38 (10.7%) 105 (10.4%) 0.863 Unknown 25 (3.8%) 25 (7.1%) 50 (5%) 0.022 ICU length of stay (days) 11 (4 to 26) 7 (4 to 13) 11 (4 to 24) 0.003 Hospital length of stay (days) 32 (19 to 52) 18 (14.5 to 21.5) 32 (19 to 52) 0.011 SOFA score 9 (7 to 11) 11 (9 to 15) 10 (8 to 12) <0.001 SAPS II 45 (34 to 56) 54 (45 to 68) 48 (37 to 60) <0.001 Lactate maximum (mmol/l) 2.3 (1.3 to 3.9) 4.0 (2 to 8.1) 2.7 (1.5 to 4.9) <0.001 Procalcitonin (ng/ml) 6.3 (1.6 to 25) 7.0 (2.2 to 21.9) 6.5 (1.8 to 22.8) 0.465 Categorical data are expressed as absolute or relative frequencies (number (percentage); continuous data are expressed as median (interquartile range). SOFA score, lactate, and procalcitonin refer to the day of sepsis onset. P value refers to differences between survivors and nonsurvivors. IMC, intermediate care unit; SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment. among these, 186 (18.4%) patients received antimicrobials care wards, 2.7 (1.5 to 5. 2) hours in hospital wards, 2.3 in the first hour and 184 patients (18.2%) received antimi- (0.6 to 7.3) hours in ICUs, 2.2 (1.4 to 3.0) hours prehospital, crobials prior to onset of organ dysfunction. Six hundred 2.0 (1.0 to 3.5) hours in emergency departments, and 1.1 and forty-one (63.3%) patients received their first AT more (0.2 to 4.7) hours in operating theatres. Three hundred and than 1 hour after onset of organ dysfunction (Figure 1). twenty-one patients were admitted to the ICU with septic Median time to AT was 2.1 (interquartile range: 0.8 to 6) shock. Median time to AT was 2.1 (1.0 to 5.0) hours in hours in all patients and 2.8 (interquartile range: 1.0 to 2.8) this subgroup. The 28-day mortality was 34.9% in the 186 hours for patients that received their AT after development patients who received AT during the first hour and 36.2% of organ dysfunction. Median times by location where in 641 patients when AT was given more than 1 hour sepsis developed were 2.8 (1 to 7.2) hours in intermediate after onset of the first sepsis-related organ dysfunction Bloos et al. Critical Care 2014, 18:R42 Page 5 of 10 http://ccforum.com/content/18/2/R42 Table 3 Time to antimicrobial therapy and source control according to survival Survivors Nonsurvivors P value Time to antimicrobial therapy (hours) 28-day survival 2.0 (0.6 to 5.6) 2.5 (1.0 to 6.6) 0.112 (n = 659) (n = 352) ICU survival 2.0 (0.7 to 5.4) 2.8 (0.9 to 7.0) 0.023 (n = 667) (n = 329) Hospital survival 2.0 (0.6 to 5.1) 2.8 (0.9 to 7.0) 0.020 (n = 581) (n = 329) 10 Time to source control (hours) 28-day survival 2.0 (−0.5 to 10.1) 5.7 (0.4 to 18.0) 0.004 (n = 286) (n = 139) 184 186 249 162 230 0 ICU survival 2.0 (−0.6 to 9.1) 6.0 (0.5 to 19.9) <0.001 (n = 286) (n = 132) previous 0−1 1−3 3−6 AT not AT within 6h Hospital survival 2.0 (−0.5 to 9.3) 5.5 (0.4 to 18.9) 0.001 Time to antimicrobial therapy (hrs) (n = 249) (n = 166) Figure 1 Twenty-eight-day mortality according to time to Data are shown as median and interquartile range. antimicrobial therapy. Numbers in the bars represent number of patients in this group. Previous AT, patients who received antimicrobial therapy (AT) before onset of infection-related organ dysfunction. first 5 days in 423 (41.9%) patients. Therapy was escalated more often in patients receiving antimicrobials not in (P = 0.76). For the subgroup of 370 patients who received compliance with guideline recommendations (125 of 245, AT within 1 hour, 28-day mortality was 32.4% compared 51%) than in patients treated in compliance with guide- with 36.2% for those 641 patients receiving delayed AT lines (298 of 762, 39.1%; P < 0.01). For 96 patients (9.5%), (P = 0.227). There was no linear relationship between time AT was de-escalated within 5 days. The 28-day mortality to AT and 28-day mortality (Figure 1). There was also no rate was 22.9% in patients with de-escalation compared association between time to AT and risk of death within with 36.0% in patients without de-escalation (P = 0.01). 28 days (OR per hour increase of time to AT: 1.0 (95% CI: For 587 (58.1%) patients, AT was deemed adequate. 1.0 to 1.0), P = 0.482) in those 849 patients that received In patients with inadequate AT, the 28-day mortality their AT after the first organ dysfunction. Considering a rate was significantly higher compared with adequately mean time to AT of 6.1 (± standard deviation 9.5) hours, treated patients (40.9% vs. 30.3%, P < 0.001; Table 4). the data would allow one to identify an effect OR of 1.02 This increased risk was also evident when patients re- per hour increase with an alpha level of 0.05 and a power ceived AT within the first hour: in patients receiving of 0.8. AT within 1 hour, 28-day mortality was 26.9% (32/119) The 28-day mortality was lower (29.9%) in patients when this AT was deemed adequate compared with who developed severe sepsis or septic shock while being 48.5% (32/66) for patients with inadequate AT; likewise, in treated with antimicrobials compared with a mortality rate patients receiving AT later than 1 hour, 28-day mortality of 35.9% in the patients who were treated only after was 31.2% (146/468) for adequate compared with 42.7% diagnosis, although the difference was not statistically (118/278) for an inadequate AT (P < 0.001). Among 588 significant (P = 0.121). Time to first AT was longer for patients not requiring surgical or interventional source nonsurvivors than survivors (Table 3). This difference control, 101/335 (30.1%) patients with adequate AT and reached statistical significance for ICU mortality (P = 0.023) 112/253 (44.3%) patients with inadequate AT died within and hospital mortality (P = 0.02) but not for 28-day mortal- 28 days (P <0.001). ity (P = 0.112). For 763 (75.5%) patients, the initial empir- By multivariable analysis, inadequate empirical AT ical therapy complied with the German recommendations (OR (95% CI): 1.44 (1.05 to 1.99)) as well as age (OR (95% for AT. The 28-day mortality was 34.9% in the compliant CI): 1.04 (1.03 to 1.06)), initial Sequential Organ Failure group and 34.3% in the noncompliant group (P = 0.869). Assessment score (OR (95% CI): 1.18 (1.13 to 1.24)) and The most frequently used empirical antimicrobial maximum serum lactate levels on the day of diagnosis of agents were piperacillin/tazobactam or ampicillin/sulbac- severe sepsis or septic shock (OR (95% CI): 1.09 (1.05 to tam (26.7%), followed by imipenem/cilastatin (8.2%) and 1.14)) were significantly associated with an increased risk meropenem (7.8%). Empirical AT was escalated within the of death. Adjusted for these and further covariates, a delay 28 days mortality (%) Bloos et al. Critical Care 2014, 18:R42 Page 6 of 10 http://ccforum.com/content/18/2/R42 Table 4 Patient population stratified by adequacy of Table 5 Multivariate logistic regression model for the empirical antimicrobial therapy impact of patient-related factors on 28-day mortality Variable Odds ratios P value Adequate AT Inadequate AT P value (95% CI) (n = 587) (n = 423) All patients (n = 725) Age 70 (58 to 77) 69 (57 to 76.2) 0.458 Time to antimicrobial therapy >1 hour 0.81 (0.54 to 1.23) 0.323 Infection 0.048 Initial SOFA score 1.19 (1.13 to 1.26) <0.001 Community acquired 276 (47%) 166 (39.2%) Age 1.04 (1.03 o 1.06) <0.001 ICU/IMC acquired 144 (24.5%) 117 (27.7%) Maximum lactate (day 1) 1.09 (1.04 to 1.14) <0.001 Hospital acquired 167 (28.4%) 140 (33.1%) Intra-abdominal focus 1.08 (0.75 to 1.57) 0.670 28-day mortality 178 (30.3%) 173 (40.9%) <0.001 Urogenital focus 0.65 (0.36 to 1.14) 0.143 SOFA score 9 (7 to 12) 10 (8 to 12) 0.002 Unknown focus 1.26 (0.57 to 2.78) 0.574 ICU length of stay 8.5 (4 to 22) 14 (5 to 28) <0.001 Community-acquired infection 0.89 (0.65 to 1.22) 0.484 Lactate maximum (mmol/l) 2.5 (1.5 to 4.7) 2.9 (1.6 to 5) 0.09 Inadequate empiric antimicrobial therapy 1.44 (1.05 to 1.99) 0.026 Procalcitonin (ng/ml) 6.3 (1.7 to 21) 6.6 (1.9 to 27.9) 0.497 No de-escalation of antimicrobials 1.17 (0.66 to 2.14) 0.597 within 5 days Inadequacy was defined as escalation of AT within 5 days. Categorical data are expressed as absolute and relative frequencies (number (percentage)) and are Surgical source control required (n = 234) compared by the Pearson test; continuous data are expressed as median Time to antimicrobial therapy >1 hour 0.80 (0.38 to 1.72) 0.552 (interquartile range) and are compared by the Kruskal–Wallis test. SOFA score, lactate, and procalcitonin refer to the day of sepsis onset. AT, antimicrobial Initial SOFA score 1.19 (1.08 to 1.31) <0.001 therapy; IMC, intermediate care ward; SOFA, Sequential Organ Failure Age 1.06 (1.03 to 1.08) <0.001 Assessment. Maximum lactate (day 1) 1.08 (1.00 to 1.13) 0.046 Time to source control >6 hours 2.36 (1.22 to 4.71) 0.012 in the administration of AT more than 1 hour after onset Intra-abdominal focus 1.08 (0.54 to 2.18) 0.822 of organ dysfunction (OR (95% CI): 0.96 (0.69 to 1.33)) Urogenital focus 0.43 (0.12 to 1.34) 0.165 was not associated with an increased 28-day mortality Unknown focus –– (Table 5). Likewise, no association between time to AT Community-acquired infection 1.08 (0.58 to 2.04) 0.800 and outcome was seen in the subgroup of patients with- Inadequate empiric antimicrobial therapy 1.17 (0.61 to 2.24) 0.646 out need for surgical or interventional source control (Table 5). No de-escalation of antimicrobials 0.94 (0.33 to 2.81) 0.909 within 5 days No surgical source control required (n = 424) Blood culture testing Time to antimicrobial therapy >1 hour 0.69 (0.39 to 1.21) 0.189 Blood cultures were taken before AT in 649 (64.2%) Initial SOFA score 1.19 (1.11 to 1.28) <0.001 patients, and 48.8% of these cultures were positive. In 269 patients (41.4% of patients from whom blood cultures Age 1.04 (1.02 to 1.06) <0.001 were drawn), only one set of blood cultures was obtained. Maximum lactate (day 1) 1.12 (1.05 to 1.20) 0.001 In the 317 positive blood cultures, 187 (62.1%) showed Intra-abdominal focus 1.72 (0.93 to 3.19) 0.083 Gram-positive bacteria, 127 (42.2%) showed Gram-negative Urogenital focus 0.95 (0.47 to 1.86) 0.875 bacteria, and 20 (6.6%) showed fungi; 32 (10.6%) of the Unknown focus 1.67 (0.70 to 3.98) 0.243 positive blood cultures revealed more than one pathogen. Community-acquired infection 1.03 (0.64 to 1.65) 0.904 Among the 317 patients with a positive blood culture, Inadequate empiric antimicrobial therapy 1.52 (0.95 to 2.42) 0.078 63.3% received antimicrobials before onset of organ dys- No de-escalation of antimicrobials 2.71 (1.02 to 8.40) 0.061 function and 103 (33.7%) received antimicrobials after on- within 5 days set of organ dysfunction. The 28-day mortality in these Adjusted odds ratios and 95% confidence intervals (CIs) for 28-day mortality. groups was 35.9% and 31.5%, respectively (P =0.440). Only patients with initiation of antimicrobial therapy as well as source control after development of organ dysfunction and with complete observations in all variables are entered into this analysis. Parameters not included due to result Time and adequacy to source control in the monovariate analysis: surgical or interventional source control required (P = 0.223), status of blood culture withdrawal (P = 0.779), pulmonary focus Surgical (84.8%) or interventional (15.9%) source control (P = 0.491), other focus than intra-abdominal, pulmonary, urogenital or unknown was performed in 422 patients: overall median time to (P = 0.691). Inadequate antimicrobial therapy was defined as escalation of empiric source control was 3 (–0.1 to 13.7) hours and 6 (2 to 20) antimicrobial therapy within 5 days. All models showed a good separation of the outcome (c-statistic >0.7) and a good calibration (P >0.05 in the Hosmer–Lemeshow hours, respectively, in those patients where source con- test (pHLT)). SOFA, Sequential Organ Failure Assessment. Goodness of fit: c =0.76, trol was initiated after development of organ dysfunction pHLT = 0.904. Against previous antimicrobial therapy and antimicrobials within c d 1 hour after infection-related onset of organ dysfunction. Per point increase. Per (n = 314). One hundred and fifty-eight of 314 patients e f g year. Per mmol/l. Goodness of fit: c = 0.79, pHLT = 0.733. Insufficient sample size (50.3%) received source control within 6 hours after onset h in this subgroup. Goodness of fit: c = 0.77, pHLT = 0.887. of infection-related organ dysfunction. The time to source Bloos et al. Critical Care 2014, 18:R42 Page 7 of 10 http://ccforum.com/content/18/2/R42 control was significantly longer in nonsurvivors than in to antimicrobial administration were 2.1 hours after diag- survivors (Table 3). In 55 patients (13.3%), source control nosis of severe sepsis or septic shock and thus exceeded was assessed as being inadequate. The 28-day mortality guideline recommendations [1]. Similar delays have been was 65.5% in patients with inadequate source control reported in other studies [5,13,18,20,30,31]. In contrast to compared with 26.7% in patients with adequate source con- our data, a number of studies demonstrated an association trol (P <0.01). There was no direct relationship between between patient outcome and time to AT in patients with time to source control and risk of death within 28 days (OR severe infections [2,32-35]. Like other studies [6,20], we per hour increase of time to source control: 1.0 (95% CI: 1. could not confirm the data of Kumar and coworkers in to 1.0), P = 0.725). Patients who had surgical source control patients with septic shock that suggested an increase of delayed for more than 6 hours had a significantly higher 7.6% in hospital mortality per hour delay in AT [3]. This 28-day mortality (42.9% vs. 26.7%, P <0.001); this delay was may be related to differences in the patient population or independently associated with an increased risk of death study methodology. Kumar and colleagues focused their (Table 5). There was neither a statistically significant inter- work on patients with septic shock and observed a median action nor a collinearity between time to AT and time to time to AT of 6 hours – three times longer than what we source control. and other studies have observed [3]. There are some other considerations that may explain Discussion the different findings about time to AT and its association This prospective observational trial included 1,011 eva- with mortality. Firstly, some studies used the time until luable patients with severe sepsis from a large group of adequate AT [3,5,34] rather than time to first AT, as we academic and nonacademic hospitals. The main finding did. We rather applied an approach similar to Puskarich of this study was that surgical source control within the first and colleagues because it seems unreasonable to assess 6 hours was associated with 16% lower 28-day mortality. the quality of primary care with microbiological data that This finding is of interest since the SSC guidelines recently are not available for the treating physician at that time increased the window for source control from 6 hours [25] [20]; other studies also used this design [2,17,36]. Further- to 12 hours [1] after diagnosis. This decision is based on a more, the underlying pathogen may remain unknown and single study in patients with necrotizing soft tissue infec- alternative definitions of adequacy such as guideline ad- tion, where a delay of surgery >14 hours was associated herence [3,34] need to replace the microbiological defin- with an increased risk of death [7]. However, this study by ition of adequacy anyhow. Secondly, the definition of the Boyer and colleagues did not examine the effect of shorter starting time for the duration until AT is defined signifi- delays on mortality. While current data suggest that cantly different across the available studies and includes delayed surgery adversely affects outcome [26,27], studies hospital [33,35] or ICU admission [2], onset of arterial to allow the determination of an optimal time point of hypotension [3,34], and the time when cultures were surgical source control are rare. A retrospective analysis of obtained [17,36]. We have chosen onset of infection-related patients with fecal peritonitis did not confirm a relation- organ dysfunction since this is a clinical feature that should ship between duration until source control and mortality trigger initiation of primary sepsis care. All of the chosen [28]. However, overall mortality in this study was very low starting times may overlook that significant organ dysfunc- with 19.1% and only 24-hour time intervals were reported. tion occurred before the defined time. These considerations Our data are more consistent with an observational study suggest that the investigation of the impact of timing of of children reporting that all patients who received surgical AT on patient outcome is limited in observational studies. debridement for necrotizing fasciitis at later than 3 hours The concept of early empirical AT has recently been died [8]. Likewise, a study in patients with perforated peptic challenged. Puskarich and colleagues did not find an ulcers found that each hour delay in surgical source control increase in mortality with each hour delay in AT in emergency department patients with septic shock [20]. increases 30-day mortality by 2% [9]. Clearly, more data on the relationship between time to source control and patient In a before-and-after-study in critically ill surgical patients, outcome are needed. In the interim, surgical source control AT initiated only after microbiological confirmation was associated with a lower mortality rate than early empirical should be performed as soon as possible. Our observation that early AT of the underlying infection AT [17]. However, the overall long delays to antimicrobial of sepsis before onset of organ dysfunction is associated administration in both groups (11 and 17.7 hours, respect- ively) limit interpretation of results from that study [37]. with a trend towards lower 28-day mortality in the range of 6% supports the importance of early recognition and In general, compliance with sepsis guideline recommen- antimicrobial treatment of infection underlying sepsis [1]. dations was poor. Only one-third of patients received their first antimicrobial agent according to current guideline The finding that the median time to antimicrobial treat- ment was about 40 minutes shorter in survivors than in recommendations before or within 1 hour of diagnosis nonsurvivors confirms other studies [18,29]. Median times of severe sepsis. Blood cultures before AT were taken in Bloos et al. Critical Care 2014, 18:R42 Page 8 of 10 http://ccforum.com/content/18/2/R42 649 (64.2%) patients; however, two sets of blood cultures this association also in nonsurgical patients, we cannot were obtained in only one-half of these patients. Choice of rule out that AT was changed because the patient deterio- antimicrobials complied with German recommendations rated for reasons that were not related to the microbio- for empirical AT [22] in 75% of cases. Nevertheless, in logical inappropriateness of AT. Except for serum lactate about 40% of patients the treating physicians considered measurements, which were obtained in 95.2% of the pa- first AT as inadequate and escalated AT within the first tients at baseline, we did not assess the compliance with 5 days. Overall, 28-day mortality of these patients was other guideline recommendations and therefore cannot considerably increased. The association between adequacy rule out that mortality rates were potentially influenced by of AT and patient outcome remained significant regardless unmeasured effects; for instance, timely fluid resuscitation of whether AT was given earlier or later than 1 hour after or appropriate use of other supportive measures. onsetofseveresepsis. This was alsotruefor the588 pa- tients not requiring surgical or interventional source con- Conclusions trol. Therefore it seems unlikely that AT was deemed More data on the relationship between time to source inadequate and changed because the patient deteriorated control and patient outcome are needed. In the interim, for reasons unrelated to the microbiological inappropriate- surgical source control should be performed as soon as ness of AT, such as inadequate surgical source control. In- possible. Adequacy of empirical AT is important for the creased mortality in patients with inappropriate initial AT survival in sepsis, and choice of initial AT is an important has also been observed in other studies [38,39]. Recent data decision in the therapy of these patients. There was only from the EUROBACT study concluded that infections indirect evidence about the impact of timing of AT on with multiresistant organisms are associated with a delay sepsis mortality but evidence about this issue varies of appropriate AT and increased mortality [40]. significantly among the available studies. Randomized Current guidelines recommend at least two sets of controlled trials are thus necessary to further elucidate blood cultures before starting AT [1]. In our study, two- the impact of AT timing on survival. Quality improvement thirds of patients had blood cultures drawn before AT. initiatives should not be restricted to severe sepsis but However, only one set was drawn in about 50% of those should also focus on the timely recognition and adequate patients. Drawing blood cultures before initiation of treatment of infections to prevent their progress to severe broad-spectrum antimicrobials was associated with a sepsis. lower risk of death in the SSC database [4] but not in our study. This may be explained by the much larger Key messages sample size in the SSC database. Our study has strengths and weaknesses. Strengths  A delay of surgical or interventional source control include the prospective data collection and multicenter of more than 6 hours was associated with increased design. Unlike previous studies, our study used short-term mortality. prospective data collection and is therefore not influenced  Although survivors had a shorter time to AT than by secular trends. Furthermore, reporting of times to AT nonsurvivors, there was no significant association or not only in the ICU but also in other locations as well as linear relationship between time to AT and survival. outside the hospital and inclusion of medical centers with  An inadequate empiric AT was associated with an all levels of care increases the generalizability of our results. increased mortality. Although we enrolled over 1,000 patients, the sample size  Compliance with guidelines regarding anti-infectious may not have been large enough to detect small differences measures regarding timing and choice of empiric in outcome; moreover, we cannot rule out that eligible AT, withdrawal of blood cultures, and de-escalation patients were not included in the study because of limited of AT should be improved. resources. We also did not include patients who were not Abbreviations referred to the ICU. However, it is unlikely that many such AT: antimicrobial therapy; CI: confidence interval; OR: odds ratio; SSC: Surviving patients were missed since in Germany the majority of pa- Sepsis Campaign. tients with organ dysfunction are referred to an ICU or Competing interests intermediate care unit. The authors declare that they have no competing interests. We did not assess adequacy of AT by means of micro- Authors’ contribution biological susceptibility testing results because many of All authors made substantive intellectual contributions to the manuscript. FB the included hospitals lacked the staff to report such data and KR conceived and designed the study, drafted the manuscript, and were for a study. Instead, we used the pragmatic approach to 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 ask physicians to record any change of AT within 5 days, responsible for the conduct of the study and helped to revise the manuscript. which was defined apriori as an indication of inad- CE and HH participated in the study design and the statistical data analysis and equate initial therapy. Despite the fact that we found helped to revise the manuscript. JCM, SH, and CH participated in the assessment Bloos et al. Critical Care 2014, 18:R42 Page 9 of 10 http://ccforum.com/content/18/2/R42 of the data analysis and revised the manuscript. All authors read and approved Saxony-Anhalt, EC of the medical association of Bavaria, EC of the medical the final manuscript. 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, Acknowledgements EC of the medical association of Baden-Württemberg, EC of the Ulm University, Financial support was received from the German Federal Ministry of EC of the Ernst-Moritz-Arndt-University Greifswald, EC of the medical association Education and Research via the integrated research and treatment Center for of Lower Saxony, EC of the medical association of Saxony, EC of the medical Sepsis Control and Care (FKZ 01EO1002). association of North Rhine, EC of the Eberhard-Karls University Tübingen, EC of In addition to the authors, the following investigators and institutions the Carl-Gustav-Carus University Dresden, EC of the RWTH Aachen, EC of the participated in the MEDUSA study: Department of Intensive Care Medicine, Friedrich-Wilhelm-University Bonn, and EC of the medical association of University Hospital Aachen (G Marx, T Schürholz); Department of Hamburg. Anesthesiology, Intensive Care Medicine, and Pain Therapy, Hospital Altenburger Land, Altenburg (M Blacher, M Kretzschmar); Department of Anesthesiology Author details and Intensive Care Medicine, Ilm-Kreis-Kliniken Arnstadt-Ilmenau, Arnstadt Department of Anesthesiology and Intensive Care Medicine, Jena University (H Schlegel-Höfner); Department of Anesthesiology and Intensive Care Medicine, Hospital, 07740 Jena, Germany. The Integrated Research and Treatment HELIOS Klinikum Aue (P Fischer); Department of Anesthesiology and Intensive Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07740 Care Medicine, Zentralklinik Bad Berka GmbH, Bad Berka (T Schreiber); Department Jena, Germany. Institute for Medical Informatics, Statistics and Epidemiology, of Anesthesiology and Intensive Care Medicine, Hufelandkrankenhaus GmbH, Bad University of Leipzig, Leipzig, Germany. Department of Surgery and the Li Langensalza (R Steuckart); Department of Anesthesiology and Intensive Care Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Medicine, Bundeswehrkrankenhaus Berlin (H Bubser, K Dey); Department of Toronto, Ontario, Canada. Infection Control Program, Geneva University Anesthesiology, Intensive Care Medicine, and Pain Therapy, Vivantes Klinikum Hospitals and Medical School, Geneva, Switzerland. Department of Neukölln, Berlin (H Gerlach); Department of Intensive Care Medicine, HELIOS Anesthesiology and Intensive Care Medicine, University Hospital Leipzig, Kliniken Berlin-Buch, Berlin (J Brederlau); Department of Anesthesiology and Leipzig, Germany. Department of Internal Medicine, University Hospital Intensive Care Medicine, Charité Berlin (C Spies); Department of Anesthesiology Tübingen, Tübingen, Germany. Department of Anesthesiology and Intensive and Intensive Care and Emergency Medicine, HELIOS Klinikum Emil von Care Medicine, Charité Berlin, Berlin, Germany. Department of Behring, Berlin (A Lubasch, O Franke); Department of Anesthesiology, Anesthesiology and Intensive Care Medicine, Bundeswehrkrankenhaus Berlin, Intensive Care Medicine, Emergency Medicine, and Pain Therapy, Ev. Berlin, Germany. Department of Anesthesiology, University Hospital Ulm, Krankenhaus Bielefeld (F Bach); Department of Anesthesiology, Intensive Care Ulm, Germany. Department of Anesthesiology, Intensive Care Medicine, Medicine, and Pain Therapy, HELIOS St. Josefs-Hospital Bochum–Linden, and Pain Therapy, Vivantes Klinikum Neukölln, Berlin, Germany. Department Bochum (U Bachmann-Holdau); Department of Anesthesiology and Intensive of Anesthesiology and Intensive Care Medicine, University Medical Center Care Medicine, St. Georg Hospital Eisenach (J Eiche); Department of Schleswig-Holstein, Campus Kiel, Kiel, Germany. Department of Anesthesiology and Intensive Care Medicine, Waldkrankenhaus Rudolf Elle Anesthesiology, Intensive Care Medicine, Emergency Medicine, and Pain GmbH, Eisenberg (M Lange, D Volkert); Department of Anesthesiology, Intensive Therapy, Hospital Oldenburg, Oldenburg, Germany. Department of Care Medicine, and Pain Therapy, Helios Klinikum Erfurt (A Meier-Hellmann); Anesthesiology and Intensive Care Medicine, University Hospital Carl Gustav Department of Anesthesiology and Intensive Care Medicine, Catholic Hospital Carus, Dresden, Germany. Department of Anesthesiology and Intensive St. Johann Nepomuk Erfurt (T Clausen); Department of Internal Medicine, Care Medicine, Hospital Saarbrücken, Saarbrücken, Germany. Department of Bürgerhospital Friedberg (A Niedenthal, M Sternkopf); Department of Anesthesiology and Intensive Care Medicine, St. Georg Hospital Eisenach, Anesthesiology and Intensive Care Medicine, GeoMed Klinikum Gerolzhofen Eisenach, Germany. Department of Anesthesiology and Intensive Care (H Schulz); Department of Anesthesiology, Intensive Care Medicine, and Pain Medicine, SRH Waldklinikum Gera, Gera, Germany. Institute of Medical Therapy, Klinik am Eichert, Göppingen (S Rauch); Department of Anesthesiology Statistics, Computer Sciences and Documentation, Jena University Hospital, and Intensive Care Medicine, Ernst-Moritz-Arndt-University Greifswald Jena, Germany. (M Gründling); Department of Anesthesiology and Intensive Care Medicine, Helios St. Elisabeth Klinik Hünfeld (N Knöck); Department of Anesthesiology and Received: 4 November 2013 Accepted: 25 February 2014 Intensive Care Medicine, Ilm-Kreis-Kliniken Arnstadt–Ilmenau, Ilmenau (G Scheiber); Published: 3 March 2014 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 References (E Berendes, S Nicolas); Department of Anesthesiology and Intensive Care 1. 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Impact of compliance with infection management guidelines on outcome in patients with severe sepsis: a prospective observational multi-center study

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Springer Journals
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Copyright © 2014 by Bloos et al.; licensee BioMed Central Ltd.
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Medicine & Public Health; Intensive / Critical Care Medicine; Emergency Medicine
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1364-8535
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10.1186/cc13755
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24589043
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Abstract

Introduction: Current sepsis guidelines recommend antimicrobial treatment (AT) within one hour after onset of sepsis-related organ dysfunction (OD) and surgical source control within 12 hours. The objective of this study was to explore the association between initial infection management according to sepsis treatment recommendations and patient outcome. Methods: In a prospective observational multi-center cohort study in 44 German ICUs, we studied 1,011 patients with severe sepsis or septic shock regarding times to AT, source control, and adequacy of AT. Primary outcome was 28-day mortality. Results: Median time to AT was 2.1 (IQR 0.8 – 6.0) hours and 3 hours (-0.1 – 13.7) to surgical source control. Only 370 (36.6%) patients received AT within one hour after OD in compliance with recommendation. Among 422 patients receiving surgical or interventional source control, those who received source control later than 6 hours after onset of OD had a significantly higher 28-day mortality than patients with earlier source control (42.9% versus 26.7%, P <0.001). Time to AT was significantly longer in ICU and hospital non-survivors; no linear relationship was found between time to AT and 28-day mortality. Regardless of timing, 28-day mortality rate was lower in patients with adequate than non-adequate AT (30.3% versus 40.9%, P < 0.001). Conclusions: A delay in source control beyond 6 hours may have a major impact on patient mortality. Adequate AT is associated with improved patient outcome but compliance with guideline recommendation requires improvement. There was only indirect evidence about the impact of timing of AT on sepsis mortality. Introduction cultures and applying intravenous broad-spectrum anti- In the treatment of severe sepsis, timely and effective microbials within 1 hour after the onset of severe sepsis antimicrobial therapy (AT) as well as source control is or septic shock; the guidelines also recommend initiating crucial and has become a key element in the resuscitation surgical source control within 12 hours [1]. Numerous bundles proposed by the Surviving Sepsis Campaign (SSC) studies have shown that a delay of AT and inappropriate [1]. The SSC guidelines recommend obtaining blood initial AT in this condition is associated with poor outcome [2-6]. One retrospective study in patients with septic shock * Correspondence: [email protected] suggests an increase of patient mortality between 7 and Department of Anesthesiology and Intensive Care Medicine, Jena University 8% per hour within the first 6 hours after onset of arterial Hospital, 07740 Jena, Germany hypotension [3]. There is also evidence that delayed surgery The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07740 Jena, Germany Full list of author information is available at the end of the article © 2014 Bloos et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Bloos et al. Critical Care 2014, 18:R42 Page 2 of 10 http://ccforum.com/content/18/2/R42 is associated with lower survival rates [7-9], but the appro- networks. The objectives of the study, inclusion and priate time frame remains poorly defined [10]. exclusion criteria, and the documentation procedures In numerous retrospective and before-and-after studies, were discussed in several national meetings before the improved adherence to the sepsis bundles was associated start of the study. The study was designed as a pragmatic with improved patient outcome [4,11-14]. A meta-analysis studywithaminimalcasereportformtoallow forthe suggests that among the individual elements of the re- participation of hospitals without research staff. This suscitation bundle, timely and appropriately administered study served as a run-in study for a cluster-randomized antimicrobials are the most important predictors for trial assessing whether a multifaceted educational program survival [15]. However, compliance with sepsis guideline accelerates the onset of AT and improves survival (Med- recommendations is poor [16]. In a Spanish multicenter ical Education for Sepsis Source Control and Antibiotics trial, only 18.4% of the studied patients received AT within MEDUSA, ClinicalTrials.gov Identifier NCT01187134). the first hour of severe sepsis or septic shock. The adminis- tration of antimicrobials within 1 hour was independently Patients associated with a lower risk of hospital death [6]. Between December 2010 and April 2011, all consecutive Application of antimicrobials without microbiological adult patients treated in the ICU for proven or suspected evidence of infection might be associated with an unfavor- infection with at least one new organ dysfunction related able outcome [17]. Likewise, starting AT in patients with to the infection were eligible for inclusion. Organ dysfunc- severe sepsis before obtaining blood cultures was among tions were defined as follows: acute encephalopathy, the factors that were associated with higher hospital thrombocytopenia defined as a platelet count <100,000/μl mortality [4]. Compliance with the recommendation to or a drop in platelet count >30% within 24 hours, arterial draw two pairs of blood cultures before AT, however, was oxygen partial pressure <10 kPa (75 mmHg) when breath- only in the range of 54.4 to 64.5% of patients [4,13,18]. ing room air or partial pressure of arterial oxygen/fraction Most of the previous studies investigating the timing of inspired oxygen ratio <33 kPa (<250 mmHg), renal of antimicrobials and the compliance with the SSC sepsis dysfunction defined as oliguria (diuresis ≤0.5 ml/kg body bundles reported only ICU mortality rates, focused mainly weight/hour) despite adequate fluid resuscitation or an on patients treated in the emergency department or in the increase of serum creatinine more than twice the ICU, and did not evaluate the impact of delayed source local reference value, metabolic acidosis with a base control on patient outcome [3,5,17,19,20]. However, many excess < −5 mmol/l or a serum lactate >1.5 times the local of these patients may be admitted also from general wards reference value, and arterial hypotension defined as sys- or the operating room and may require effective surgical tolic arterial blood pressure <90 mmHg or mean arterial and other measures of source control. We therefore blood pressure <70 mmHg for >1 hour despite adequate extended our assessment of infection control measures fluid loading or vasopressor therapy at any dosage to to include these patients as well. The primary aim of maintain higher blood pressures [21]. Patients who re- our cohort study was to prospectively test the hypothesis ceived initial infection control measures for sepsis in that a delay in AT and source control after onset of sepsis- another hospital and patients who did not receive full related organ dysfunction impacts patient outcome. In life-sustaining treatment were excluded. The study was addition, we aimed to assess compliance with recent best- reviewed and approved by the local ethics committees, practice recommendations for the diagnosis and therapy which waived the need for informed consent because of the of sepsis. observational nature of the study (see Acknowledgements). The study was also approved by the local data protection Methods boards. Study design This prospective study was designed as a longitudinal Data collection multicenter observational cohort study in 42 German hos- Onset of severe sepsis or septic shock was defined as the pitals to determine the time to AT, surgical source control time of first infection-related organ dysfunction as docu- and compliance with sepsis recommendations related to mented in the patient file. Patient location at time of AT in patients with suspected severe sepsis or septic shock onset of severe sepsis was defined as the patient location and its impact on 28-day, ICU, and hospital mortality. Par- where the first infection-related organ dysfunction was ticipation of hospitals was voluntary but was restricted to documented. For patients who developed severe sepsis hospitals involved in the primary care of sepsis patients outside the ICU, this could be the prehospital setting, and committed to participate in a quality improvement the emergency department, the hospital ward, or the process. Hospitals without ICUs were excluded from operating room. Time and type of first AT as well as pre- this study. Potential study centers were recruited by existing AT were also recorded from the medical records. regional and national research and quality improvement Any AT prescribed up to 24 hours before the onset of Bloos et al. Critical Care 2014, 18:R42 Page 3 of 10 http://ccforum.com/content/18/2/R42 organ dysfunction but for the current infectious episode stateof blood culturewithdrawalwereonlyincluded was considered previous AT. Perioperative antimicrobial into the final model if they were associated with 28-day prophylaxis was not regarded as specific AT for sepsis. mortality at P < 0.20. Goodness of fit was assessed by the Change of empirical AT was assessed on day 5. Initial AT c-statistic and the Hosmer-Lemeshow test. was defined as inadequate if escalation had occurred within the first 5 days. For each patient, a blinded arbitrator Results assessed whether the initial AT complied with German Participating centers and patients guideline recommendations [22]. Source control was Hospital and ICU characteristics of the 44 participating defined as removal of an anatomic source of infection centers are shown in Table 1. A total of 1,048 patients either by surgery or intervention (that is, computed were included during the 5-month study period. Of these, tomography-guided drainage). Source control was defined 37 patients were excluded for missing values in 28-day as inadequate if the technical procedure was unsuccessful. mortalityortimetoAT, resultingin1,011 evaluable Time to source control was obtained from the medical patients. Approximately one-half of the patients (n =504, record. Other factors included serum lactate and procalci- 49.9%) were treated for surgical reasons. Organ dysfunc- tonin at the time of onset of severe sepsis, number of tions on the day of study inclusion were shock (n =632, blood culture sets taken, and ICU and hospital mortality. 76.4%), lactacidosis (n = 424, 51.3%), acute renal failure Severity of disease was assessed by the Simplified Acute (n = 307, 37.2%) thrombocytopenia (n = 238, 28.8%), pul- Physiology Score II and the Sequential Organ Failure monary dysfunction (n = 492, 65.8%), and septic encephal- Assessment score on the day of sepsis diagnosis [23,24]. opathy (n = 338, 41.2%). A total 85.1% of the patients had Data were collected by a web-based electronic case more than one organ failure. Patient characteristics are report form using OpenClinica® (OpenClinica, LLC, shown in Table 2. The overall 28-day mortality was 34.8%; Waltham, MA, USA). Data integrity was confirmed by ICU mortality and hospital mortality were 33.0% and data checks within the database, resulting in queries to 41.4%, respectively. There was no association of academic the investigator where applicable. Additionally, onset of versus nonacademic hospitals or hospital size with 28-day infection-related organ dysfunction and subsequent AT mortality. were checked for plausibility by the MEDUSA study staff and discussed with the study center staff where applicable. Timing and adequacy of antimicrobial therapy Three hundred and seventy (36.6%) patients received anti- Statistical analysis microbials within 1 hour of the onset of organ dysfunction; The primary endpoint was survival status at day 28 after onset of severe sepsis. Categorical data are expressed as Table 1 Characteristics of participating hospitals and ICUs absolute or relative frequencies; the chi-square or Fisher's (n = 44) exact test was used for inferential statistics. Continuous Hospital Data data are expressed as the median and interquartile range; University hospital 10 (22.7%) the Mann–Whitney U test was used for inferential sta- Level of care tistics. Missing data were not replaced by calculation. We divided patients according to the timing of antimicro- Primary care hospitals 14 (31.8%) bial treatment into the following groups: previous AT, 0 Secondary care hospitals 12 (27.3%) to 1 hours, 1 to 3 hours, 3 to 6 hours and >6 hours [6]. Tertiary care hospitals 18 (40.9%) Patients were grouped by time to source control into two Hospital beds 581 (416 to 1,055) groups: within 6 hours or >6 hours [25]. Odds ratios (OR) Number of ICUs 2 (1 to 4) with 95% confidence intervals (CI) for the risk of death Inhospital biochemistry laboratory 43 (97.7%) within 28 days depending on time to AT or time to source control were calculated by univariate and multivariate lo- Inhospital microbiology department 30 (68 to 2%) gistic regression only in those patients were treatment was ICU beds 15 (10 to 29) started after onset of organ dysfunction. In patients with ICU patients per annum 1,200 (900 to 2,050) sepsis, prior research has identified the initial Sequential Emergency department Organ Failure Assessment score, age, and serum lactate Emergency department available 37 (84.1%) [20] as confounders for the risk of death. These parame- Lactate available within 1 hour 38 (86.4%) ters were therefore included in the multivariable logistic regression analysis to calculate adjusted ORs. In addition, Broad-spectrum antibiotics available 36 (81.8%) indication for source control, escalation as well as de- Prehospital emergency physician available 39 (88.6%) escalation of empirical AT within 5 days, presence of Data are shown as number (percentage) for categorical data or median community acquired infection, focus of infection, and (interquartile range) for continuous data. Bloos et al. Critical Care 2014, 18:R42 Page 4 of 10 http://ccforum.com/content/18/2/R42 Table 2 Patient characteristics 28-day survivors (n = 659) 28 day nonsurvivors (n = 352) All patients (n = 1,011) P value Male 413 (62.7%) 221 (62.8%) 634 (62.7%) 0.972 Age (years) 68 (55 to 75) 72 (64 to 79) 69 (58 to 77) <0.001 ICU admission 0.254 Elective surgery 74 (11.2%) 42 (11.9%) 116 (11.5%) Emergency surgery 255 (38.7%) 118 (33.5%) 373 (36.9%) Trauma 10 (1.5%) 5 (1.4%) 15 (1.5%) Medical 304 (46.1%) 183 (52%) 487 (48.2%) Other 16 (2.4%) 4 (1.1%) 20 (2%) Patient location at onset of sepsis 0.426 Emergency department 93 (14.1%) 47 (13.4%) 140 (13.9%) ICU 366 (55.6%) 214 (60.8%) 580 (57.4%) Operating theatre 63 (9.6%) 22 (6.2%) 85 (8.4%) Hospital ward 80 (12.2%) 41 (11.6%) 121 (12%) Prehospital 12 (1.8%) 4 (1.1%) 16 (1.6%) IMC 44 (6.7%) 24 (6.8%) 68 (6.7%) Infection 0.22 Community acquired 300 (45.5%) 143 (40.6%) 443 (43.8%) ICU/IMC acquired 170 (25.8%) 91 (25.9%) 261 (25.8%) Hospital acquired 189 (28.7%) 118 (33.5%) 307 (30.4%) Source of infection (multiple responses possible) Intra-abdominal 228 (34.7%) 138 (39.2%) 366 (36.3%) 0.167 Pneumonia 221 (33.7%) 130 (36.9%) 351 (34.9%) 0.311 Urogenital 92 (14.0%) 30 (8.5%) 122 (12.1%) 0.011 Upper airway 59 (9.0%) 24 (6.8%) 83 (8.2%) 0.228 Bones/soft tissue 47 (7.2%) 25 (7.1%) 72 (7.1%) 0.966 Other 67 (11.7%) 38 (10.7%) 105 (10.4%) 0.863 Unknown 25 (3.8%) 25 (7.1%) 50 (5%) 0.022 ICU length of stay (days) 11 (4 to 26) 7 (4 to 13) 11 (4 to 24) 0.003 Hospital length of stay (days) 32 (19 to 52) 18 (14.5 to 21.5) 32 (19 to 52) 0.011 SOFA score 9 (7 to 11) 11 (9 to 15) 10 (8 to 12) <0.001 SAPS II 45 (34 to 56) 54 (45 to 68) 48 (37 to 60) <0.001 Lactate maximum (mmol/l) 2.3 (1.3 to 3.9) 4.0 (2 to 8.1) 2.7 (1.5 to 4.9) <0.001 Procalcitonin (ng/ml) 6.3 (1.6 to 25) 7.0 (2.2 to 21.9) 6.5 (1.8 to 22.8) 0.465 Categorical data are expressed as absolute or relative frequencies (number (percentage); continuous data are expressed as median (interquartile range). SOFA score, lactate, and procalcitonin refer to the day of sepsis onset. P value refers to differences between survivors and nonsurvivors. IMC, intermediate care unit; SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment. among these, 186 (18.4%) patients received antimicrobials care wards, 2.7 (1.5 to 5. 2) hours in hospital wards, 2.3 in the first hour and 184 patients (18.2%) received antimi- (0.6 to 7.3) hours in ICUs, 2.2 (1.4 to 3.0) hours prehospital, crobials prior to onset of organ dysfunction. Six hundred 2.0 (1.0 to 3.5) hours in emergency departments, and 1.1 and forty-one (63.3%) patients received their first AT more (0.2 to 4.7) hours in operating theatres. Three hundred and than 1 hour after onset of organ dysfunction (Figure 1). twenty-one patients were admitted to the ICU with septic Median time to AT was 2.1 (interquartile range: 0.8 to 6) shock. Median time to AT was 2.1 (1.0 to 5.0) hours in hours in all patients and 2.8 (interquartile range: 1.0 to 2.8) this subgroup. The 28-day mortality was 34.9% in the 186 hours for patients that received their AT after development patients who received AT during the first hour and 36.2% of organ dysfunction. Median times by location where in 641 patients when AT was given more than 1 hour sepsis developed were 2.8 (1 to 7.2) hours in intermediate after onset of the first sepsis-related organ dysfunction Bloos et al. Critical Care 2014, 18:R42 Page 5 of 10 http://ccforum.com/content/18/2/R42 Table 3 Time to antimicrobial therapy and source control according to survival Survivors Nonsurvivors P value Time to antimicrobial therapy (hours) 28-day survival 2.0 (0.6 to 5.6) 2.5 (1.0 to 6.6) 0.112 (n = 659) (n = 352) ICU survival 2.0 (0.7 to 5.4) 2.8 (0.9 to 7.0) 0.023 (n = 667) (n = 329) Hospital survival 2.0 (0.6 to 5.1) 2.8 (0.9 to 7.0) 0.020 (n = 581) (n = 329) 10 Time to source control (hours) 28-day survival 2.0 (−0.5 to 10.1) 5.7 (0.4 to 18.0) 0.004 (n = 286) (n = 139) 184 186 249 162 230 0 ICU survival 2.0 (−0.6 to 9.1) 6.0 (0.5 to 19.9) <0.001 (n = 286) (n = 132) previous 0−1 1−3 3−6 AT not AT within 6h Hospital survival 2.0 (−0.5 to 9.3) 5.5 (0.4 to 18.9) 0.001 Time to antimicrobial therapy (hrs) (n = 249) (n = 166) Figure 1 Twenty-eight-day mortality according to time to Data are shown as median and interquartile range. antimicrobial therapy. Numbers in the bars represent number of patients in this group. Previous AT, patients who received antimicrobial therapy (AT) before onset of infection-related organ dysfunction. first 5 days in 423 (41.9%) patients. Therapy was escalated more often in patients receiving antimicrobials not in (P = 0.76). For the subgroup of 370 patients who received compliance with guideline recommendations (125 of 245, AT within 1 hour, 28-day mortality was 32.4% compared 51%) than in patients treated in compliance with guide- with 36.2% for those 641 patients receiving delayed AT lines (298 of 762, 39.1%; P < 0.01). For 96 patients (9.5%), (P = 0.227). There was no linear relationship between time AT was de-escalated within 5 days. The 28-day mortality to AT and 28-day mortality (Figure 1). There was also no rate was 22.9% in patients with de-escalation compared association between time to AT and risk of death within with 36.0% in patients without de-escalation (P = 0.01). 28 days (OR per hour increase of time to AT: 1.0 (95% CI: For 587 (58.1%) patients, AT was deemed adequate. 1.0 to 1.0), P = 0.482) in those 849 patients that received In patients with inadequate AT, the 28-day mortality their AT after the first organ dysfunction. Considering a rate was significantly higher compared with adequately mean time to AT of 6.1 (± standard deviation 9.5) hours, treated patients (40.9% vs. 30.3%, P < 0.001; Table 4). the data would allow one to identify an effect OR of 1.02 This increased risk was also evident when patients re- per hour increase with an alpha level of 0.05 and a power ceived AT within the first hour: in patients receiving of 0.8. AT within 1 hour, 28-day mortality was 26.9% (32/119) The 28-day mortality was lower (29.9%) in patients when this AT was deemed adequate compared with who developed severe sepsis or septic shock while being 48.5% (32/66) for patients with inadequate AT; likewise, in treated with antimicrobials compared with a mortality rate patients receiving AT later than 1 hour, 28-day mortality of 35.9% in the patients who were treated only after was 31.2% (146/468) for adequate compared with 42.7% diagnosis, although the difference was not statistically (118/278) for an inadequate AT (P < 0.001). Among 588 significant (P = 0.121). Time to first AT was longer for patients not requiring surgical or interventional source nonsurvivors than survivors (Table 3). This difference control, 101/335 (30.1%) patients with adequate AT and reached statistical significance for ICU mortality (P = 0.023) 112/253 (44.3%) patients with inadequate AT died within and hospital mortality (P = 0.02) but not for 28-day mortal- 28 days (P <0.001). ity (P = 0.112). For 763 (75.5%) patients, the initial empir- By multivariable analysis, inadequate empirical AT ical therapy complied with the German recommendations (OR (95% CI): 1.44 (1.05 to 1.99)) as well as age (OR (95% for AT. The 28-day mortality was 34.9% in the compliant CI): 1.04 (1.03 to 1.06)), initial Sequential Organ Failure group and 34.3% in the noncompliant group (P = 0.869). Assessment score (OR (95% CI): 1.18 (1.13 to 1.24)) and The most frequently used empirical antimicrobial maximum serum lactate levels on the day of diagnosis of agents were piperacillin/tazobactam or ampicillin/sulbac- severe sepsis or septic shock (OR (95% CI): 1.09 (1.05 to tam (26.7%), followed by imipenem/cilastatin (8.2%) and 1.14)) were significantly associated with an increased risk meropenem (7.8%). Empirical AT was escalated within the of death. Adjusted for these and further covariates, a delay 28 days mortality (%) Bloos et al. Critical Care 2014, 18:R42 Page 6 of 10 http://ccforum.com/content/18/2/R42 Table 4 Patient population stratified by adequacy of Table 5 Multivariate logistic regression model for the empirical antimicrobial therapy impact of patient-related factors on 28-day mortality Variable Odds ratios P value Adequate AT Inadequate AT P value (95% CI) (n = 587) (n = 423) All patients (n = 725) Age 70 (58 to 77) 69 (57 to 76.2) 0.458 Time to antimicrobial therapy >1 hour 0.81 (0.54 to 1.23) 0.323 Infection 0.048 Initial SOFA score 1.19 (1.13 to 1.26) <0.001 Community acquired 276 (47%) 166 (39.2%) Age 1.04 (1.03 o 1.06) <0.001 ICU/IMC acquired 144 (24.5%) 117 (27.7%) Maximum lactate (day 1) 1.09 (1.04 to 1.14) <0.001 Hospital acquired 167 (28.4%) 140 (33.1%) Intra-abdominal focus 1.08 (0.75 to 1.57) 0.670 28-day mortality 178 (30.3%) 173 (40.9%) <0.001 Urogenital focus 0.65 (0.36 to 1.14) 0.143 SOFA score 9 (7 to 12) 10 (8 to 12) 0.002 Unknown focus 1.26 (0.57 to 2.78) 0.574 ICU length of stay 8.5 (4 to 22) 14 (5 to 28) <0.001 Community-acquired infection 0.89 (0.65 to 1.22) 0.484 Lactate maximum (mmol/l) 2.5 (1.5 to 4.7) 2.9 (1.6 to 5) 0.09 Inadequate empiric antimicrobial therapy 1.44 (1.05 to 1.99) 0.026 Procalcitonin (ng/ml) 6.3 (1.7 to 21) 6.6 (1.9 to 27.9) 0.497 No de-escalation of antimicrobials 1.17 (0.66 to 2.14) 0.597 within 5 days Inadequacy was defined as escalation of AT within 5 days. Categorical data are expressed as absolute and relative frequencies (number (percentage)) and are Surgical source control required (n = 234) compared by the Pearson test; continuous data are expressed as median Time to antimicrobial therapy >1 hour 0.80 (0.38 to 1.72) 0.552 (interquartile range) and are compared by the Kruskal–Wallis test. SOFA score, lactate, and procalcitonin refer to the day of sepsis onset. AT, antimicrobial Initial SOFA score 1.19 (1.08 to 1.31) <0.001 therapy; IMC, intermediate care ward; SOFA, Sequential Organ Failure Age 1.06 (1.03 to 1.08) <0.001 Assessment. Maximum lactate (day 1) 1.08 (1.00 to 1.13) 0.046 Time to source control >6 hours 2.36 (1.22 to 4.71) 0.012 in the administration of AT more than 1 hour after onset Intra-abdominal focus 1.08 (0.54 to 2.18) 0.822 of organ dysfunction (OR (95% CI): 0.96 (0.69 to 1.33)) Urogenital focus 0.43 (0.12 to 1.34) 0.165 was not associated with an increased 28-day mortality Unknown focus –– (Table 5). Likewise, no association between time to AT Community-acquired infection 1.08 (0.58 to 2.04) 0.800 and outcome was seen in the subgroup of patients with- Inadequate empiric antimicrobial therapy 1.17 (0.61 to 2.24) 0.646 out need for surgical or interventional source control (Table 5). No de-escalation of antimicrobials 0.94 (0.33 to 2.81) 0.909 within 5 days No surgical source control required (n = 424) Blood culture testing Time to antimicrobial therapy >1 hour 0.69 (0.39 to 1.21) 0.189 Blood cultures were taken before AT in 649 (64.2%) Initial SOFA score 1.19 (1.11 to 1.28) <0.001 patients, and 48.8% of these cultures were positive. In 269 patients (41.4% of patients from whom blood cultures Age 1.04 (1.02 to 1.06) <0.001 were drawn), only one set of blood cultures was obtained. Maximum lactate (day 1) 1.12 (1.05 to 1.20) 0.001 In the 317 positive blood cultures, 187 (62.1%) showed Intra-abdominal focus 1.72 (0.93 to 3.19) 0.083 Gram-positive bacteria, 127 (42.2%) showed Gram-negative Urogenital focus 0.95 (0.47 to 1.86) 0.875 bacteria, and 20 (6.6%) showed fungi; 32 (10.6%) of the Unknown focus 1.67 (0.70 to 3.98) 0.243 positive blood cultures revealed more than one pathogen. Community-acquired infection 1.03 (0.64 to 1.65) 0.904 Among the 317 patients with a positive blood culture, Inadequate empiric antimicrobial therapy 1.52 (0.95 to 2.42) 0.078 63.3% received antimicrobials before onset of organ dys- No de-escalation of antimicrobials 2.71 (1.02 to 8.40) 0.061 function and 103 (33.7%) received antimicrobials after on- within 5 days set of organ dysfunction. The 28-day mortality in these Adjusted odds ratios and 95% confidence intervals (CIs) for 28-day mortality. groups was 35.9% and 31.5%, respectively (P =0.440). Only patients with initiation of antimicrobial therapy as well as source control after development of organ dysfunction and with complete observations in all variables are entered into this analysis. Parameters not included due to result Time and adequacy to source control in the monovariate analysis: surgical or interventional source control required (P = 0.223), status of blood culture withdrawal (P = 0.779), pulmonary focus Surgical (84.8%) or interventional (15.9%) source control (P = 0.491), other focus than intra-abdominal, pulmonary, urogenital or unknown was performed in 422 patients: overall median time to (P = 0.691). Inadequate antimicrobial therapy was defined as escalation of empiric source control was 3 (–0.1 to 13.7) hours and 6 (2 to 20) antimicrobial therapy within 5 days. All models showed a good separation of the outcome (c-statistic >0.7) and a good calibration (P >0.05 in the Hosmer–Lemeshow hours, respectively, in those patients where source con- test (pHLT)). SOFA, Sequential Organ Failure Assessment. Goodness of fit: c =0.76, trol was initiated after development of organ dysfunction pHLT = 0.904. Against previous antimicrobial therapy and antimicrobials within c d 1 hour after infection-related onset of organ dysfunction. Per point increase. Per (n = 314). One hundred and fifty-eight of 314 patients e f g year. Per mmol/l. Goodness of fit: c = 0.79, pHLT = 0.733. Insufficient sample size (50.3%) received source control within 6 hours after onset h in this subgroup. Goodness of fit: c = 0.77, pHLT = 0.887. of infection-related organ dysfunction. The time to source Bloos et al. Critical Care 2014, 18:R42 Page 7 of 10 http://ccforum.com/content/18/2/R42 control was significantly longer in nonsurvivors than in to antimicrobial administration were 2.1 hours after diag- survivors (Table 3). In 55 patients (13.3%), source control nosis of severe sepsis or septic shock and thus exceeded was assessed as being inadequate. The 28-day mortality guideline recommendations [1]. Similar delays have been was 65.5% in patients with inadequate source control reported in other studies [5,13,18,20,30,31]. In contrast to compared with 26.7% in patients with adequate source con- our data, a number of studies demonstrated an association trol (P <0.01). There was no direct relationship between between patient outcome and time to AT in patients with time to source control and risk of death within 28 days (OR severe infections [2,32-35]. Like other studies [6,20], we per hour increase of time to source control: 1.0 (95% CI: 1. could not confirm the data of Kumar and coworkers in to 1.0), P = 0.725). Patients who had surgical source control patients with septic shock that suggested an increase of delayed for more than 6 hours had a significantly higher 7.6% in hospital mortality per hour delay in AT [3]. This 28-day mortality (42.9% vs. 26.7%, P <0.001); this delay was may be related to differences in the patient population or independently associated with an increased risk of death study methodology. Kumar and colleagues focused their (Table 5). There was neither a statistically significant inter- work on patients with septic shock and observed a median action nor a collinearity between time to AT and time to time to AT of 6 hours – three times longer than what we source control. and other studies have observed [3]. There are some other considerations that may explain Discussion the different findings about time to AT and its association This prospective observational trial included 1,011 eva- with mortality. Firstly, some studies used the time until luable patients with severe sepsis from a large group of adequate AT [3,5,34] rather than time to first AT, as we academic and nonacademic hospitals. The main finding did. We rather applied an approach similar to Puskarich of this study was that surgical source control within the first and colleagues because it seems unreasonable to assess 6 hours was associated with 16% lower 28-day mortality. the quality of primary care with microbiological data that This finding is of interest since the SSC guidelines recently are not available for the treating physician at that time increased the window for source control from 6 hours [25] [20]; other studies also used this design [2,17,36]. Further- to 12 hours [1] after diagnosis. This decision is based on a more, the underlying pathogen may remain unknown and single study in patients with necrotizing soft tissue infec- alternative definitions of adequacy such as guideline ad- tion, where a delay of surgery >14 hours was associated herence [3,34] need to replace the microbiological defin- with an increased risk of death [7]. However, this study by ition of adequacy anyhow. Secondly, the definition of the Boyer and colleagues did not examine the effect of shorter starting time for the duration until AT is defined signifi- delays on mortality. While current data suggest that cantly different across the available studies and includes delayed surgery adversely affects outcome [26,27], studies hospital [33,35] or ICU admission [2], onset of arterial to allow the determination of an optimal time point of hypotension [3,34], and the time when cultures were surgical source control are rare. A retrospective analysis of obtained [17,36]. We have chosen onset of infection-related patients with fecal peritonitis did not confirm a relation- organ dysfunction since this is a clinical feature that should ship between duration until source control and mortality trigger initiation of primary sepsis care. All of the chosen [28]. However, overall mortality in this study was very low starting times may overlook that significant organ dysfunc- with 19.1% and only 24-hour time intervals were reported. tion occurred before the defined time. These considerations Our data are more consistent with an observational study suggest that the investigation of the impact of timing of of children reporting that all patients who received surgical AT on patient outcome is limited in observational studies. debridement for necrotizing fasciitis at later than 3 hours The concept of early empirical AT has recently been died [8]. Likewise, a study in patients with perforated peptic challenged. Puskarich and colleagues did not find an ulcers found that each hour delay in surgical source control increase in mortality with each hour delay in AT in emergency department patients with septic shock [20]. increases 30-day mortality by 2% [9]. Clearly, more data on the relationship between time to source control and patient In a before-and-after-study in critically ill surgical patients, outcome are needed. In the interim, surgical source control AT initiated only after microbiological confirmation was associated with a lower mortality rate than early empirical should be performed as soon as possible. Our observation that early AT of the underlying infection AT [17]. However, the overall long delays to antimicrobial of sepsis before onset of organ dysfunction is associated administration in both groups (11 and 17.7 hours, respect- ively) limit interpretation of results from that study [37]. with a trend towards lower 28-day mortality in the range of 6% supports the importance of early recognition and In general, compliance with sepsis guideline recommen- antimicrobial treatment of infection underlying sepsis [1]. dations was poor. Only one-third of patients received their first antimicrobial agent according to current guideline The finding that the median time to antimicrobial treat- ment was about 40 minutes shorter in survivors than in recommendations before or within 1 hour of diagnosis nonsurvivors confirms other studies [18,29]. Median times of severe sepsis. Blood cultures before AT were taken in Bloos et al. Critical Care 2014, 18:R42 Page 8 of 10 http://ccforum.com/content/18/2/R42 649 (64.2%) patients; however, two sets of blood cultures this association also in nonsurgical patients, we cannot were obtained in only one-half of these patients. Choice of rule out that AT was changed because the patient deterio- antimicrobials complied with German recommendations rated for reasons that were not related to the microbio- for empirical AT [22] in 75% of cases. Nevertheless, in logical inappropriateness of AT. Except for serum lactate about 40% of patients the treating physicians considered measurements, which were obtained in 95.2% of the pa- first AT as inadequate and escalated AT within the first tients at baseline, we did not assess the compliance with 5 days. Overall, 28-day mortality of these patients was other guideline recommendations and therefore cannot considerably increased. The association between adequacy rule out that mortality rates were potentially influenced by of AT and patient outcome remained significant regardless unmeasured effects; for instance, timely fluid resuscitation of whether AT was given earlier or later than 1 hour after or appropriate use of other supportive measures. onsetofseveresepsis. This was alsotruefor the588 pa- tients not requiring surgical or interventional source con- Conclusions trol. Therefore it seems unlikely that AT was deemed More data on the relationship between time to source inadequate and changed because the patient deteriorated control and patient outcome are needed. In the interim, for reasons unrelated to the microbiological inappropriate- surgical source control should be performed as soon as ness of AT, such as inadequate surgical source control. In- possible. Adequacy of empirical AT is important for the creased mortality in patients with inappropriate initial AT survival in sepsis, and choice of initial AT is an important has also been observed in other studies [38,39]. Recent data decision in the therapy of these patients. There was only from the EUROBACT study concluded that infections indirect evidence about the impact of timing of AT on with multiresistant organisms are associated with a delay sepsis mortality but evidence about this issue varies of appropriate AT and increased mortality [40]. significantly among the available studies. Randomized Current guidelines recommend at least two sets of controlled trials are thus necessary to further elucidate blood cultures before starting AT [1]. In our study, two- the impact of AT timing on survival. Quality improvement thirds of patients had blood cultures drawn before AT. initiatives should not be restricted to severe sepsis but However, only one set was drawn in about 50% of those should also focus on the timely recognition and adequate patients. Drawing blood cultures before initiation of treatment of infections to prevent their progress to severe broad-spectrum antimicrobials was associated with a sepsis. lower risk of death in the SSC database [4] but not in our study. This may be explained by the much larger Key messages sample size in the SSC database. Our study has strengths and weaknesses. Strengths  A delay of surgical or interventional source control include the prospective data collection and multicenter of more than 6 hours was associated with increased design. Unlike previous studies, our study used short-term mortality. prospective data collection and is therefore not influenced  Although survivors had a shorter time to AT than by secular trends. Furthermore, reporting of times to AT nonsurvivors, there was no significant association or not only in the ICU but also in other locations as well as linear relationship between time to AT and survival. outside the hospital and inclusion of medical centers with  An inadequate empiric AT was associated with an all levels of care increases the generalizability of our results. increased mortality. Although we enrolled over 1,000 patients, the sample size  Compliance with guidelines regarding anti-infectious may not have been large enough to detect small differences measures regarding timing and choice of empiric in outcome; moreover, we cannot rule out that eligible AT, withdrawal of blood cultures, and de-escalation patients were not included in the study because of limited of AT should be improved. resources. We also did not include patients who were not Abbreviations referred to the ICU. However, it is unlikely that many such AT: antimicrobial therapy; CI: confidence interval; OR: odds ratio; SSC: Surviving patients were missed since in Germany the majority of pa- Sepsis Campaign. tients with organ dysfunction are referred to an ICU or Competing interests intermediate care unit. The authors declare that they have no competing interests. We did not assess adequacy of AT by means of micro- Authors’ contribution biological susceptibility testing results because many of All authors made substantive intellectual contributions to the manuscript. FB the included hospitals lacked the staff to report such data and KR conceived and designed the study, drafted the manuscript, and were for a study. Instead, we used the pragmatic approach to 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 ask physicians to record any change of AT within 5 days, responsible for the conduct of the study and helped to revise the manuscript. which was defined apriori as an indication of inad- CE and HH participated in the study design and the statistical data analysis and equate initial therapy. Despite the fact that we found helped to revise the manuscript. JCM, SH, and CH participated in the assessment Bloos et al. Critical Care 2014, 18:R42 Page 9 of 10 http://ccforum.com/content/18/2/R42 of the data analysis and revised the manuscript. All authors read and approved Saxony-Anhalt, EC of the medical association of Bavaria, EC of the medical the final manuscript. 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, Acknowledgements EC of the medical association of Baden-Württemberg, EC of the Ulm University, Financial support was received from the German Federal Ministry of EC of the Ernst-Moritz-Arndt-University Greifswald, EC of the medical association Education and Research via the integrated research and treatment Center for of Lower Saxony, EC of the medical association of Saxony, EC of the medical Sepsis Control and Care (FKZ 01EO1002). association of North Rhine, EC of the Eberhard-Karls University Tübingen, EC of In addition to the authors, the following investigators and institutions the Carl-Gustav-Carus University Dresden, EC of the RWTH Aachen, EC of the participated in the MEDUSA study: Department of Intensive Care Medicine, Friedrich-Wilhelm-University Bonn, and EC of the medical association of University Hospital Aachen (G Marx, T Schürholz); Department of Hamburg. Anesthesiology, Intensive Care Medicine, and Pain Therapy, Hospital Altenburger Land, Altenburg (M Blacher, M Kretzschmar); Department of Anesthesiology Author details and Intensive Care Medicine, Ilm-Kreis-Kliniken Arnstadt-Ilmenau, Arnstadt Department of Anesthesiology and Intensive Care Medicine, Jena University (H Schlegel-Höfner); Department of Anesthesiology and Intensive Care Medicine, Hospital, 07740 Jena, Germany. The Integrated Research and Treatment HELIOS Klinikum Aue (P Fischer); Department of Anesthesiology and Intensive Center for Sepsis Control and Care (CSCC), Jena University Hospital, 07740 Care Medicine, Zentralklinik Bad Berka GmbH, Bad Berka (T Schreiber); Department Jena, Germany. Institute for Medical Informatics, Statistics and Epidemiology, of Anesthesiology and Intensive Care Medicine, Hufelandkrankenhaus GmbH, Bad University of Leipzig, Leipzig, Germany. Department of Surgery and the Li Langensalza (R Steuckart); Department of Anesthesiology and Intensive Care Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Medicine, Bundeswehrkrankenhaus Berlin (H Bubser, K Dey); Department of Toronto, Ontario, Canada. Infection Control Program, Geneva University Anesthesiology, Intensive Care Medicine, and Pain Therapy, Vivantes Klinikum Hospitals and Medical School, Geneva, Switzerland. Department of Neukölln, Berlin (H Gerlach); Department of Intensive Care Medicine, HELIOS Anesthesiology and Intensive Care Medicine, University Hospital Leipzig, Kliniken Berlin-Buch, Berlin (J Brederlau); Department of Anesthesiology and Leipzig, Germany. Department of Internal Medicine, University Hospital Intensive Care Medicine, Charité Berlin (C Spies); Department of Anesthesiology Tübingen, Tübingen, Germany. Department of Anesthesiology and Intensive and Intensive Care and Emergency Medicine, HELIOS Klinikum Emil von Care Medicine, Charité Berlin, Berlin, Germany. Department of Behring, Berlin (A Lubasch, O Franke); Department of Anesthesiology, Anesthesiology and Intensive Care Medicine, Bundeswehrkrankenhaus Berlin, Intensive Care Medicine, Emergency Medicine, and Pain Therapy, Ev. Berlin, Germany. Department of Anesthesiology, University Hospital Ulm, Krankenhaus Bielefeld (F Bach); Department of Anesthesiology, Intensive Care Ulm, Germany. Department of Anesthesiology, Intensive Care Medicine, Medicine, and Pain Therapy, HELIOS St. Josefs-Hospital Bochum–Linden, and Pain Therapy, Vivantes Klinikum Neukölln, Berlin, Germany. Department Bochum (U Bachmann-Holdau); Department of Anesthesiology and Intensive of Anesthesiology and Intensive Care Medicine, University Medical Center Care Medicine, St. Georg Hospital Eisenach (J Eiche); Department of Schleswig-Holstein, Campus Kiel, Kiel, Germany. Department of Anesthesiology and Intensive Care Medicine, Waldkrankenhaus Rudolf Elle Anesthesiology, Intensive Care Medicine, Emergency Medicine, and Pain GmbH, Eisenberg (M Lange, D Volkert); Department of Anesthesiology, Intensive Therapy, Hospital Oldenburg, Oldenburg, Germany. Department of Care Medicine, and Pain Therapy, Helios Klinikum Erfurt (A Meier-Hellmann); Anesthesiology and Intensive Care Medicine, University Hospital Carl Gustav Department of Anesthesiology and Intensive Care Medicine, Catholic Hospital Carus, Dresden, Germany. Department of Anesthesiology and Intensive St. Johann Nepomuk Erfurt (T Clausen); Department of Internal Medicine, Care Medicine, Hospital Saarbrücken, Saarbrücken, Germany. Department of Bürgerhospital Friedberg (A Niedenthal, M Sternkopf); Department of Anesthesiology and Intensive Care Medicine, St. Georg Hospital Eisenach, Anesthesiology and Intensive Care Medicine, GeoMed Klinikum Gerolzhofen Eisenach, Germany. Department of Anesthesiology and Intensive Care (H Schulz); Department of Anesthesiology, Intensive Care Medicine, and Pain Medicine, SRH Waldklinikum Gera, Gera, Germany. Institute of Medical Therapy, Klinik am Eichert, Göppingen (S Rauch); Department of Anesthesiology Statistics, Computer Sciences and Documentation, Jena University Hospital, and Intensive Care Medicine, Ernst-Moritz-Arndt-University Greifswald Jena, Germany. (M Gründling); Department of Anesthesiology and Intensive Care Medicine, Helios St. Elisabeth Klinik Hünfeld (N Knöck); Department of Anesthesiology and Received: 4 November 2013 Accepted: 25 February 2014 Intensive Care Medicine, Ilm-Kreis-Kliniken Arnstadt–Ilmenau, Ilmenau (G Scheiber); Published: 3 March 2014 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 References (E Berendes, S Nicolas); Department of Anesthesiology and Intensive Care 1. 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Critical Care – Springer Journals

Published: Mar 3, 2014

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