Critical Care Medicine:
Empiric Antibiotic Treatment Reduces Mortality in Severe Sepsis and Septic Shock From the First Hour: Results From a Guideline-Based Performance Improvement Program*
Ferrer, Ricard MD, PhD1; Martin-Loeches, Ignacio MD, PhD2; Phillips, Gary MAS3; Osborn, Tiffany M. MD, MPH4; Townsend, Sean MD5; Dellinger, R. Phillip MD, FCCP, FCCM6; Artigas, Antonio MD, PhD2; Schorr, Christa RN, MSN6; Levy, Mitchell M. MD, FCCP, FCCM7
1Department of Intensive Care, Mútua Terrassa University Hospital, CIBER Enfermedades Respiratorias, Barcelona, Spain.
2Critical Care Center, Sabadell Hospital, CIBER Enfermedades Respiratorias, Corporacion Sanitaria Universitaria Parc Tauli, Autonomous University of Barcelona, Sabadell, Spain.
3The Ohio State University Center for Biostatistics, Columbus, OH.
4Department of Surgery and Emergency Medicine, Division of Acute Care Surgery, Surgical/Trauma Critical Care, Barnes Jewish Hospital, Washington University, St. Louis, MO.
5California Pacific Medical Center, San Francisco, CA.
6Brown University/Rhode Island Hospital, Providence, RI.
7Cooper University Hospital, Camden, NJ.
* See also p. 1931.
Dr. Levy had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).
Initial funding for the Surviving Sepsis Campaign (from 2002 to 2006) was through unrestricted educational grants from Eli Lilly, Edwards Lifesciences, Phillips Medical Systems, and the Coalition for Critical Care Excellence (Society of Critical Care Medicine). There was no involvement by the sponsors in the development, data analysis, or manuscript preparation of the current study. No additional funding has been received since that time or during the analysis and development of the current study and manuscript.
Dr. Ferrer served as board member for Laboratorios Ferrer and lectured for Merck, Sharp and Dohme, and Pfizer. His institution received grant support from Instituto de Salud Carlos III. Mr. Phillips received support for participation in review activities from the Rhode Island Hospital, a Lifespan Partner. His institution received grant support from the National Institutes of Health Grant and Murdoch Children’s Research Institution. Dr. Osborn consulted for Institute of Healthcare Improvement (sepsis consultant on quality initiative); and received support for travel from American College of Emergency Physicians (Scientific Assembly 2011, 2012, 2013. Dr. Townsend received support for article research from the Gordon and Betty Moore Foundation. Dr. Dellinger received support for travel for the meeting of Surviving Sepsis Campaign (SSC) steering committee. Dr. Artigas served as board member for Ferrer Farma, consulted for Hill Rom, and lectured for Pulsion. His institution received grant support from Pulsion. The remaining authors have disclosed that they do not have any potential conflicts of interest.
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Objectives: Compelling evidence has shown that aggressive resuscitation bundles, adequate source control, appropriate antibiotic therapy, and organ support are cornerstone for the success in the treatment of patients with sepsis. Delay in the initiation of appropriate antibiotic therapy has been recognized as a risk factor for mortality. To perform a retrospective analysis on the Surviving Sepsis Campaign database to evaluate the relationship between timing of antibiotic administration and mortality.
Design: Retrospective analysis of a large dataset collected prospectively for the Surviving Sepsis Campaign.
Setting: One hundred sixty-five ICUs in Europe, the United States, and South America.
Patients: A total of 28,150 patients with severe sepsis and septic shock, from January 2005 through February 2010, were evaluated.
Interventions: Antibiotic administration and hospital mortality.
Measurements and Main Results: A total of 17,990 patients received antibiotics after sepsis identification and were included in the analysis. In-hospital mortality was 29.7% for the cohort as a whole. There was a statically significant increase in the probability of death associated with the number of hours of delay for first antibiotic administration. Hospital mortality adjusted for severity (sepsis severity score), ICU admission source (emergency department, ward, vs ICU), and geographic region increased steadily after 1 hour of time to antibiotic administration. Results were similar in patients with severe sepsis and septic shock, regardless of the number of organ failure.
Conclusions: The results of the analysis of this large population of patients with severe sepsis and septic shock demonstrate that delay in first antibiotic administration was associated with increased in-hospital mortality. In addition, there was a linear increase in the risk of mortality for each hour delay in antibiotic administration. These results underscore the importance of early identification and treatment of septic patients in the hospital setting.
Sepsis is a worldwide syndrome that affects over 700,000 patients per year in the United States (1), with a high fatality rate, significant morbidity, and socioeconomic cost (2). Compelling evidence has shown that aggressive resuscitation bundles, adequate source control, appropriate antibiotic therapy, and organ support are cornerstones for the success in the treatment of patients with sepsis (3). Delay in the initiation of appropriate antibiotic therapy has been recognized as a risk factor for mortality. This assumption is not a new paradigm since Ehrlich’s concept of “hit hard and fast” was first described in the early 1900 (4). More recently, Kumar et al (5) conducted in the United States and Canada a retrospective cohort study in 2,731 septic shock patients and found that effective antimicrobial administration within the first hour of documented hypotension was associated with 79.9% survival to hospital discharge. Treatment protocols targeting the rapid administration of appropriate antibiotics are now recognized as a key measure in the initial care of patients presenting with severe sepsis and septic shock (6).
Based on this evidence, the Surviving Sepsis Campaign (SSC) Guidelines recommended that after the recognition of severe sepsis or septic shock, IV broad-spectrum antibiotics should be administered as early as possible and always within 1 hour (for patients identified on the general medical wards) or 3 hours (for patients identified in the emergency department [ED]) (7). Nevertheless, these results need to be confirmed and the optimal timing of antibiotic administration remains uncertain in patients with sepsis. Therefore, the aim of this study was to analyze the association between timing of antibiotic administration and mortality to evaluate whether an optimal time window for empiric antibiotic administration could be found in these patients with severe sepsis and septic shock. Because of the global nature of the SSC, we also aimed to describe cultural differences in empiric antibiotic treatment for severe sepsis and septic shock.
MATERIAL AND METHODS
Sites and Patient Selection
The process of participation in the SSC is described in detail elsewhere (8). Eligible subjects were those admitted to an ICU having a suspected site of infection, two or more systemic inflammatory response syndrome criteria, and one or more organ dysfunction criteria (9). Clinical and demographic characteristics and time of presentation with severe sepsis or septic shock criteria were collected for analysis of time-based measures. Time of presentation was determined through chart review and defined in instructions to site data collectors on the Campaign website and educational materials. For patients enrolled from the ED, the time of presentation was defined as the time of triage. For patients admitted to the ICU from the medical and surgical wards and for patients in the ICU at the time of diagnosis, the time of presentation was determined by chart review for the diagnosis of severe sepsis. The patient was considered to have a nosocomial infection if severe sepsis or septic shock was discovered in the ICU more than 72 hours after admission or if severe sepsis or septic shock was discovered in the ward and the patient had been in the ward more than 72 hours prior to sepsis identification. Otherwise, the patient was considered to have a community infection.
Data were entered into the SSC database locally at individual hospitals into preestablished, unmodifiable fields documenting performance data and the time of specific actions and findings. Data stripped of private health information were submitted every 30 days to the secure master SSC server at the Society of Critical Care Medicine (Mount Prospect, IL) via file transfer protocol or as comma-delimited text files attached to e-mail submitted to the Campaign’s server.
Institutional Review Board Approval
The global SSC improvement initiative was approved by the Cooper University Hospital Institutional Review Board (Camden, NJ) as meeting criteria for exempt status.
Analysis Set Construction
The analysis set was constructed from the subjects entered into the SSC database from January 2005 through February 2010. Inclusion was limited to sites with at least 20 subjects and at least 3 months of subject enrollment.
Antibiotics and Time to Administration
Once severe sepsis or septic shock was identified using the screening criteria established in the SSC initiative, patients were eligible for antibiotics. All dates and times in the SSC database are based on the time of presentation. Time to first antibiotic administration is reported as the difference between time of presentation (as recorded in the database and described above) and first antibiotic administration (also entered into the database through chart review by institutional data collector). For each antibiotic given to a particular patient, the name of the antibiotic and time of administration were recorded in the database. Patients could receive none, one, or multiple antibiotics. Throughout the rest of this manuscript, antibiotic administration implies the patient’s first antibiotic. Subjects who did not receive any antibiotics in the first 6 hours, those with missing time of antibiotic administration, or subjects who were receiving antibiotics prior to presentation of severe sepsis were excluded from the data analysis.
Since the study’s goal was not to predict hospital mortality but rather to identify the role of timing of antibiotic administration on survival, we used a risk factor modeling approach to determine which covariates to add to the model—a generalized estimating equation (GEE) population averaged logistic regression. Logistic regression was used to analyze hospital mortality since the database has complete information on the time to antibiotic administration on all subjects and their mortality status (no censoring). Time to only the patient’s first antibiotics was entered into the model as a categorical variable, and only covariates that acted as either a confounder or an effect modifier were included. A confounder was identified when its addition to the model changed the odds ratio associated with the time to antibiotic administration by more than 10% in either direction, without considering statistical significance. A covariate that had a statistically significant interaction (p < 0.05) with antibiotic administration was considered to be an effect modifier. Table S1 (Supplemental Digital Content 1, http://links.lww.com/CCM/A900) in the online appendix lists the 51 covariates that were considered possible confounders and effect modifiers. GEE population averaged logistic regression was used since patients are nested within a particular ICU. This method takes into account the variability within and between ICUs and uses this inherent correlation when estimating the SEs that are used to test model coefficients. The hierarchical nature of the SSC data lends itself to this type of analysis. All analyses were run using Stata 12.1 (Stata Corporation, College Station, TX).
A total of 28,150 patients with severe sepsis and septic shock from 165 ICUs were evaluated. Four hundred fifty-seven patients (457) received no antibiotics, 832 received antibiotics but were missing the timing of the antibiotics, and 8,871 patients received antibiotics prior to suspected sepsis. These patients were removed from the analysis set; thus, a total of 17,990 patients received antibiotics and were included in the analysis of time-to-antibiotic administration and mortality (Fig. 1).
Table 1 summarizes patient characteristics by antibiotic timing in 1-hour time periods up to 6 hours. All patients that received antibiotics after 6 hours were grouped together in this table since they only represented 12% of the observations. Hospital mortality is 32.0% in the first hour of antibiotic administration, drops to 28.1% in the second hours, and then steadily increases after that. It peaks at 39.6% in those receiving antibiotics after 6 hours. The median sepsis severity score (SSS) is the highest in the first hour compared with all other time points. The SSS was developed and validated on the SSC database and includes the elements available in the database such as location where sepsis was suspected (ED, ward, or ICU), geographic location (Europe, United States, South America), infection source (pneumonia, urinary tract infection, abdominal, etc.), various organ failures, hypotension (resolved and unresolved), mechanical ventilation, and other clinical characteristics (T. Osborn et al, unpublished observation, 2013). In the first hour, patients tend to have a higher proportion of severe sepsis/septic shock identified in the ICU (10.6%), compared with the same patients in the other time periods, higher mortality (46.6%) when severe sepsis/septic shock is identified in the ICU, higher proportion of pulmonary organ failure (30.8%), higher proportion of nosocomial infection (21.9%), higher septic shock (69.6%), longer hospital and ICU length of stays (13 and 5.1 d, respectively), and the lowest proportion of a single organ failure (40.1%). After 1 hour, hospital mortality steadily increases with a delay in antibiotic timing. The prevalence of nosocomial infection decreases during the first 3 hours of antibiotics administration and then increases when administered after 4 hours. The proportion of patients with 1 baseline organ dysfunction is highest in the first hour and then decreases with a delay in antibiotics.
Figure 2 and the odds ratios in Table 2 are based on the same adjusted GEE population averaged logistic regression model. The model is adjusted for SSS, ICU admission source (ED, ward, vs ICU), and geographic region (Europe, United States, and South America). The relationship between hospital mortality and time to first antibiotic administration was fairly robust once we controlled for these three covariates, thus no additional covariates (for a list, see Table S1, Supplemental Digital Content 1, http://links.lww.com/CCM/A900) either confounded nor were effect modifiers of the relationship between hospital mortality and time to first antibiotic. The regression model uses the same seven time periods as shown in Table 1. Figure 2 illustrates the trend in hospital mortality over timing to first antibiotic, relative to suspicion of sepsis. Table 2 shows that the adjusted hospital mortality odds ratios steadily increase from 1.00 to 1.52 as time to antibiotic administration increases from 0 to greater than 6 hours where 0–1 hour is the referent group. The probability of mortality increases from 24.6% to 33.1% and is based on a subject having the following characteristics: from the United States, admission source is the ED, and the SSS is 52 (median of all observations).
The results of this study confirm, in the largest population of patients with severe sepsis and septic shock reported to date, that delay in antibiotic administration was associated with increased in-hospital mortality. In addition, we confirm the increasing risk associated with delay—there was a linear increase in the risk of mortality for each hour delay in antibiotic administration from the first through the sixth hour after patient identification This relationship between delay in antibiotic administration and mortality has been demonstrated before by Kumar et al (5). However, the population in that study was patients with septic shock, and the delay was from the onset of hypotension. Our study findings are distinct and unique in the population studied and the location of these patients in the hospital: similar results were found in patients with either severe sepsis or septic shock, and consistent results were also seen when patients were stratified by severity (number of organ failure) and whether sepsis was identified in the ED, on the wards, or in the ICU. This study demonstrates, for the first time, that delay in antibiotic administration has a significant negative impact on survival across all areas in the hospital and across levels of illness severity (organ dysfunction).
The most important finding from our study is the survival benefit associated with prompt antibiotic administration in severe sepsis and septic shock. The potential influence of delayed antibiotic therapy was first evaluated in patients with community-acquired pneumonia. In the early-1990, McGarvey and Harper (10) demonstrated that care processes that included antibiotic delivery within 4 hours were associated with lower pneumonia mortality at two community hospitals. More recently, Houck et al (11) described that among 13,771 patients who had not received outpatient antibiotic agents, antibiotic administration within 4 hours of arrival at the hospital was associated with reduced in-hospital mortality (6.8% vs 7.4%; adjusted odds ratio [AOR], 0.85; 95% CI, 0.74–0.98) and mortality within 30 days of admission (11.6% vs 12.7%; AOR, 0.85; 95% CI, 0.76–0.95). Kahn et al (12) observed a 4% point reduction in 30-day mortality among Medicare patients who received antibiotics within 4 hours of admission and appropriate oxygen therapy. Interestingly, this work highlights not only the early administration of antibiotics but also correlates the process of care with better outcomes. In a study of 261 patients in the ED, Gaieski et al (13) confirmed the association with timing of antibiotic therapy and mortality in patients with severe sepsis or septic shock. In our previous prospective observational study in 77 ICUs (14) based on propensity scores and adjusting for other treatments, we reported that among 2,796 severe sepsis/septic shock patients, empiric antibiotic treatment reduced mortality (treatment within 1 hr vs no treatment within first 6 hr of diagnosis; odds ratio, 0.67; 95% CI, 0.50–0.90; p = 0.008). Kumar et al (5) demonstrated that every additional hour without antibiotics increased the risk for death in septic shock patients by 7.6% during the first 6 hours. It is important to point out that this was a retrospective study over 15 years, and recruitment rates were relatively low, with 2,154 patients included from 10 sites (14 ICUs). Only 12% of patients had received antibiotics within the first hour. In addition, Kumar et al (5) focused on septic shock patients with appropriate antibiotic treatment. Our data demonstrate that the association between timing of antibiotic administration and mortality is not only true for patients with septic shock but also for patients with severe sepsis.
The relationship of prompt antibiotic and better outcomes might represent a surrogate marker for the quality of care in a broader sense. Other important sepsis treatments have shown time-dependency, like quantitative resuscitation (15) or source control (16). In fact, the meta-analysis of Barochia et al (3) showed that the implementation of SSC bundles was followed by an improvement in most of the sepsis process-of-care variables, including time-to-antibiotic treatment, followed by a mortality reduction.
Recent studies report low compliance with prompt administration of antimicrobial therapy. In these reports, although the SSC proposals were implemented, the mean delay to first infusion of antibiotics remained in excess of 3 hours (17), and as many as 68% of patients did not receive their first dose within this period (18). In addition, Kumar et al (5) reported that delays in administration of antibiotics are common: 79% of patients did not receive antibiotics until the onset of hypotension, and of those patients, only 14.5% received them within the first hour of hypotension. Only 32.5% received antibiotics by 3 hours and only 51.4% by 6 hours. It is important to note here that there is controversy about performance metrics for antibiotic timing in patients with pneumonia. In a retrospective review of patients with community-acquired pneumonia, Welker et al (19) demonstrated that while performance metrics decreased time to first antibiotic dose from 8 to 4 hours, there was also an associated reduction in the accuracy of diagnosis of pneumonia by ED physicians.
Our study has several limitations. As with any retrospective study, there is potential for residual confounding. Second, in our report, the main goal of the study was to evaluate only timing of initial antibiotic administration and not appropriateness since this variable is commonly based on culture data available only after 24–96 hours. Therefore, we could not assess the appropriateness of antibiotic therapy in this patient population. Inappropriate or inadequate antibiotic choices may confound our results. Current SSC guidelines recommend administration of broad-spectrum antibiotics, and our results demonstrate adherence to this recommendation, which might reduce, but not eliminate the likelihood of inadequate coverage. Additionally, this was a retrospective review that did not allow for analysis of the reasons for delay or the cause of the delay in antibiotic administration. We are unable, in the SSC database, to ascertain whether the delay in antibiotic administration was because of order writing, pharmacy delay, or other system factors.
In conclusion, this study demonstrates a significant association between delay in antibiotic administration over the first 6 hours after identification of patients with severe sepsis and septic shock and increasing mortality. These results underscore the importance of early identification and treatment of septic patients in the hospital setting. As mentioned often in the literature, sepsis is a time-dependent condition (like acute myocardial infarction or stroke) and should be recognized as an urgent situation that requires immediate response.
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antibiotics; knowledge translation; performance improvement; performance metrics; sepsis; septic shock; severe sepsis
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