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Empiric Antibiotic Treatment Reduces Mortality in Severe Sepsis and Septic Shock From the First Hour

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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. Retrospective analysis of a large dataset collected prospectively for the Surviving Sepsis Campaign. One hundred sixty-five ICUs in Europe, the United States, and South America. A total of 28,150 patients with severe sepsis and septic shock, from January 2005 through February 2010, were evaluated. Antibiotic administration and hospital mortality. 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. 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.
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Critical Care Medicine www.ccmjournal.org 1
grant support from Pulsion. The remaining authors have disclosed that
they do not have any potential conflicts of interest.
For information regarding this article, E-mail: mitchell_levy@brown.edu
Objectives: Compelling evidence has shown that aggressive
resuscitation bundles, adequate source control, appropriate anti-
biotic 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 pro-
spectively 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 depart-
ment, ward, vs ICU), and geographic region increased steadily
after 1 hour of time to antibiotic administration. Results were simi-
lar 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
1Department of Intensive Care, Mútua Terrassa University Hospital, CIB ER
Enfermedades Respiratorias, Barcelona, Spain.
2Critical Care Center, Sabadell Hospital, CIBER Enfermedades Respi-
ratorias, 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, Wash-
ington University, St. Louis, MO.
5California Pacific Medical Center, San Francisco, CA.
6Brown University/Rhode Island Hospital, Providence, RI.
7Cooper University Hospital, Camden, NJ.
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 UR L cita-
tions 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 Life-
sciences, 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 prepara-
tion 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 sup-
port for participation in review activities from the Rhode Island Hospi-
tal, 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); 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) steer-
ing committee. Dr. Artigas served as board member for Ferrer Farma;
consulted for Hill Rom; and lectured for Pulsion. His institution received
Copyright © 2014 by the Society of Critical Care Medicine and Lippincott
Williams & Wilkins
DOI: 10.1097/CCM.0000000000000330
Empiric Antibiotic Treatment Reduces Mortality
in Severe Sepsis and Septic Shock From the
First Hour: Results From a Guideline-Based
Performance Improvement Program
Ricard Ferrer, MD, PhD1; Ignacio Martin-Loeches, MD, PhD2; Gary Phillips, MAS3;
Tiffany M. Osborn, MD, MPH4; Sean Townsend, MD5; R. Phillip Dellinger, MD, FCCP, FCCM6;
Antonio Artigas, MD, PhD2; Christa Schorr, RN, MSN6; Mitchell M. Levy, MD, FCCP, FCCM7
Copyright (c) Society of Critical Care Medicine and Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited
Ferrer et al
2 www.ccmjournal.org XXX2014•VolumeXX•NumberXXX
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 set-
ting. (Crit Care Med 2014; XX:00–00)
Key Words: antibiotics; knowledge translation; performance
improvement; performance metrics; sepsis; septic shock; severe
sepsis
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 resus-
citation bundles, adequate source control, appropriate anti-
biotic 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 rec-
ognized 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 retrospec-
tive 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 depart-
ment [ED]) (7). Nevertheless, these results need to be con-
firmed 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 discov-
ered 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 Collection
Data were entered into the SSC database locally at individual
hospitals into preestablished, unmodifiable fields document-
ing 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 (Cam-
den, 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 collec-
tor). 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.
Statistical Analysis
Since the study’s goal was not to predict hospital mortal-
ity but rather to identify the role of timing of antibiotic
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Feature Article
Critical Care Medicine www.ccmjournal.org 3
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 hos-
pital 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 vari-
able, 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 associ-
ated with the time to antibiotic administration by more than
10% in either direction, without considering statistical signifi-
cance. 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 regres-
sion 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 Corpora-
tion, College Station, TX).
RESULTS
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 peri-
ods 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 obser-
vations. Hospital mortality is
32.0% in the first hour of anti-
biotic 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 sever-
ity 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 loca-
tion (Europe, United States, South America), infection source
(pneumonia, urinary tract infection, abdominal, etc.), vari-
ous 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 pro-
portion 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 fail-
ure (40.1%). After 1 hour, hospital mortality steadily increases
with a delay in antibiotic timing. The prevalence of nosoco-
mial 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 dys-
function 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
Figure 1. Patient enrollment diagram.
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Ferrer et al
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TABLE 1. Patient Characteristics by Timing in Hours to the First Antibiotic
Patient
Characteristic,
n (%)
Antibiotic Timing (Hr)
pa
0.0–1.0 1.0–2.0 2.0–3.0 3.0–4.0 4.0–5.0 5.0–6.0 > 6.0
n4,728 4,595 3,020 1,734 1,037 640 2,239
Hospital mortality 1,512 (32.0) 1,292 (28.1) 863 (28.6) 517 (29.8) 337 (32.5) 234 (36.6) 885 (39.6) < 0.001
Severity sepsis
score, median
(IQR)
58 (42–73) 50 (36–66) 49 (35–64) 49 (35–66) 51 (37–68) 53 (38–69) 57 (40–71) < 0.001
Nosocomial
infection
812 (17.2) 357 (7.8) 229 (7.6) 173 (10.0) 128 (12.3) 89 (13.9) 403 (18.0) < 0.001
Septic shock 3,289 (69.6) 2,880 (62.7) 1,847 (61.2) 1,047 (60.4) 684 (66.0) 441 (68.9) 1,370 (61.3) < 0.001
Hospital LOS,
median days
(IQR)
13 (6.4–25) 10 (5.6–19) 10.0 (5.6–19) 11 (5.9–20) 12 (5.9–23) 12 (6.3–22) 14 (7.3–29) < 0.001
ICU LOS, median
days (IQR)
5.1 (2.4–11) 4.1 (2.1–8.9) 4.2 (2.1–8.8) 4.3 (2.0–9.5) 4.9 (2.4–11) 4.6 (2.1–10) 6.7 (2.8–15) < 0.001
LOS prior to ICU,
median days
(IQR)
0.1 (0.0–0.8) 0.1 (0.0–0.3) 0.1 (0.0–0.3) 0.1 (0.0–0.4) 0.2 (0.0–0.5) 0.2 (0.0–0.7) 0.2 (0.0–1.4) < 0.001
Location where sepsis identified
ED 3,028 (64.0) 3,716 (80.9) 2,424 (80.3) 1,322 (76.2) 727 (70.1) 417 (65.2) 1,294 (57.9) < 0.001
ED mortality 797 (26.3) 935 (25.2) 629 (26.0) 352 (26.6) 209 (28.8) 132 (31.7) 404 (31.2) < 0.001
Ward 1,198 (25.3) 680 (14.8) 469 (15.5) 326 (18.8) 244 (23.5) 177 (27.7) 689 (30.8) < 0.001
Ward mortality 481 (40.2) 274 (40.3) 195 (41.6) 131 (40.8) 94 (38.5) 83 (46.9) 332 (48.2) < 0.001
ICU 502 (10.6) 199 (4.3) 127 (4.2) 86 (5.0) 66 (6.4) 46 (7.2) 253 (11.3) < 0.001
ICU mortality 234 (46.6) 83 (41.7) 39 (30.7) 34 (39.5) 34 (51.5) 19 (41.3) 149 (58.9) < 0.001
Site of infection
Pneumonia 2,388 (50.5) 2,308 (50.2) 1,398 (46.3) 729 (42.0) 430 (41.5) 252 (39.4) 982 (43.9) < 0.001
Urinary tract
infection
1,076 (22.8) 1,332 (29.0) 950 (31.5) 518 (29.9) 273 (26.3) 164 (25.6) 444 (19.9) < 0.001
Abdominal 914 (19.3) 738 (16.1) 545 (18.1) 387 (22.3) 225 (21.7) 146 (22.8) 550 (24.6) < 0.001
Meningitis 101 (2.1) 57 (1.2) 39 (1.3) 23 (1.3) 16 (1.5) 5 (0.8) 36 (1.6) 0.002
Skin 294 (6.2) 294 (6.4) 212 (7.0) 119 (6.9) 66 (6.4) 35 (5.5) 113 (5.1) 0.040
Bone 46 (1.0) 57 (1.2) 48 (1.6) 28 (1.6) 7 (0.7) 9 (1.4) 37 (1.7) 0.075
Wound 206 (4.4) 242 (5.3) 124 (4.1) 78 (4.5) 50 (4.8) 20 (3.1) 95 (4.3) 0.080
Catheter 169 (3.6) 157 (3.4) 106 (3.5) 75 (4.3) 37 (3.6) 29 (4.5) 88 (3.9) 0.596
Endocarditis 46 (1.0) 42 (0.9) 33 (1.1) 15 (0.9) 14 (1.4) 11 (1.7) 26 (1.2) 0.548
Device 54 (1.1) 51 (1.1) 43 (1.4) 24 (1.4) 16 (1.5) 9 (1.4) 22 (1.0) 0.704
Other infection 260 (9.7) 528 (11.5) 399 (13.2) 216 (12.5) 145 (14.0) 95 (14.8) 337 (15.7) < 0.001
Baseline acute organ dysfunction
Cardiovascular 4,221 (89.3) 4,123 (89.7) 2,689 (89.0) 1,510 (87.1) 888 (85.6) 541 (84.5) 1,800 (80.5) < 0.001
Pulmonary 1,456 (30.8) 1,120 (24.4) 610 (20.2) 383 (22.1) 240 (23.1) 145 (22.7) 681 (30.5) < 0.001
Renal 1,824 (38.6) 1,717 (37.4) 1,139 (37.7) 644 (37.1) 415 (40.0) 238 (37.2) 890 (39.8) 0.002
Hepatic 393 (8.3) 415 (9.0) 285 (9.4) 170 (9.8) 107 (10.3) 74 (11.6) 280 (12.5) < 0.001
Hematologic 1,171 (24.8) 904 (19.7) 706 (23.4) 405 (23.4) 251 (24.2) 175 (27.3) 595 (26.6) < 0.001
(
Continued
)
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Feature Article
Critical Care Medicine www.ccmjournal.org 5
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).
DISCUSSION
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 anti-
biotic administration from the first through the sixth hour
after patient identification This relationship between delay
in antibiotic administration and mortality has been demon-
strated 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 (num-
ber of organ failure) and whether sepsis was identified in the
ED, on the wards, or in the ICU. This study demonstrates, for
Number of acute organ dysfunction
1 1,898 (40.1) 2,078 (45.2) 1,363 (45.1) 777 (44.8) 458 (44.2) 275 (43.0) 942 (42.1)
< 0.001
2 1,653 (35.0) 1,587 (34.5) 1,060 (35.1) 608 (35.1) 358 (34.5) 227 (35.5) 732 (32.7)
3 847 (17.9) 681 (14.8) 436 (14.4) 268 (15.5) 154 (14.9) 99 (15.5) 387 (17.3)
4 265 (5.6) 207 (4.5) 131 (4.3) 68 (3.9) 51 (4.9) 31 (4.8) 134 (6.0)
5 65 (1.4) 42 (0.9) 30 (1.0) 13 (0.8) 16 (1.5) 8 (1.3) 41 (1.8)
Cardiovascular
No cardiovascular
dysfunction
376 (7.9) 379 (8.3) 265 (8.8) 168 (9.7) 115 (11.1) 57 (8.9) 349 (15.6)
< 0.001
Cardiovascular
dysfunction no
hypertension
803 (17.0) 1,004 (21.8) 659 (21.8) 402 (23.2) 174 (16.8) 116 (18.1) 403 (18.0)
Total shock 3,549 (75.1) 3,212 (69.9) 2,096 (69.4) 1,164 (67.2) 748 (72.1) 467 (73.0) 1,484 (66.4)
Lactate > 4 260 (5.5) 332 (7.2) 249 (8.3) 117 (6.8) 64 (6.2) 26 (4.1) 114 (5.1)
Vasopressors
only
2,273 (48.1) 1,938 (42.2) 1,309 (43.3) 769 (44.4) 522 (50.3) 346 (54.1) 1,126 (50.4)
Lactate > 4 and
vasopressors
1,016 (21.5) 942 (20.5) 538 (17.8) 278 (16.0) 162 (15.6) 95 (14.8) 244 (10.9)
IQR = interquartile range, LOS = length of stay, ED = emergency department.
ap value based on Pearson chi-square test for categorical variables and Wilcox rank-sum test for continuous variables.
TABLE 1. (Continued). Patient Characteristics by Timing in Hours to the First Antibiotic
Patient
Characteristic,
n (%)
Antibiotic Timing (Hr)
pa
0.0–1.0 1.0–2.0 2.0–3.0 3.0–4.0 4.0–5.0 5.0–6.0 > 6.0
Figure 2. Predicted hospital mortality and the associated 95% CIs for
time to first antibiotic administration. The results are adjusted by the sepsis
severity score (SSS), ICU admission source (emergency department [ED],
ward, vs ICU), and geographic region (Europe, United States, and South
America). Probability of hospital mortality is based on the subject having
the following specific characteristics: the patient is from the United States,
admission source is the ED, and the SSS is 52 (median of all observations).
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Ferrer et al
6 www.ccmjournal.org XXX2014•VolumeXX•NumberXXX
the first time, that delay in antibiotic administration has a sig-
nificant negative impact on survival across all areas in the hos-
pital and across levels of illness severity (organ dysfunction).
The most important finding from our study is the sur-
vival 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 mor-
tality 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 reduc-
tion 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 anti-
biotic 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 diag-
nosis; odds ratio, 0.67; 95% CI, 0.50–0.90; p = 0.008). Kumar
et al (5) demonstrated that every additional hour without anti-
biotics 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 antibi-
otic 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 vari-
ables, including time-to-antibiotic treatment, followed by a
mortality reduction.
Recent studies report low compliance with prompt adminis-
tration 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 adminis-
tration 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 pneu-
monia. 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.
TABLE 2. Adjusted Hospital Mortality Odds Ratio and Probability of Mortality for Time to
Antibiotics Based on a Generalized Estimating Equation Population Averaged Logistic
Regression Model
Time to
Antibiotics (Hr) ORa95% CI p
Probability of
Mortality (%)b95% CI
0–1c1.00 24.6 23.2–26.0
1–2 1.07 0.97–1.18 0.165 25.9 24.5–27.2
2–3 1.14 1.02–1.26 0.021 27.0 25.3–28.7
3–4 1.19 1.04–1.35 0.009 27.9 25.6–30.1
4–5 1.24 1.06–1.45 0.006 28.8 25.9–31.7
5–6 1.47 1.22–1.76 < 0.001 32.3 28.5–36.2
> 6 1.52 1.36–1.70 < 0.001 33.1 30.9–35.3
OR = odds ratio.
aHospital mortality odds ratio referent group is 0–1 hr for the time to antibiotics and is adjusted by the sepsis severity score (SSS), ICU admission source (ED,
ward, vs ICU), and geographic region (Europe, United States, and South America).
bProbability of hospital mortality is estimated using the generalized estimating equation population averaged logistic regression model and is based on the
subject having the following characteristics: from the United States, admission source is the ED, and the SSS is 52 (median of all observations).
cAntibiotics administered in the first hour are the referent group and thus the odds ratio by definition is 1.00 while the 95% CI and the p value are not generated
by the regression model.
Copyright (c) Society of Critical Care Medicine and Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited
Feature Article
Critical Care Medicine www.ccmjournal.org 7
Our study has several limitations. As with any retrospec-
tive 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 appropriate-
ness since this variable is commonly based on culture data avail-
able 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 administra-
tion 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 associa-
tion 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 lit-
erature, sepsis is a time-dependent condition (like acute myo-
cardial infarction or stroke) and should be recognized as an
urgent situation that requires immediate response.
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... However, the cost impact of early detection and treatment of sepsis is less known. 10 Despite updated diagnostic criteria, early detection of sepsis is still complicated by the lack of reliable biomarkers. 11 A large number of biomarkers have been evaluated clinically as possible prognostic markers for sepsis; procalcitonin and C-reactive protein have been most frequently investigated. ...
... The risk for in-hospital mortality was also a continuous variable determined by the total number of hours to treatment compared with diagnosis for current practice. The time-dependent in-hospital mortality was extrapolated from the results of Ferrer et al, 10 and different risk equations were estimated for patients who develop or who do not develop septic shock. The risk equations were estimated in 2 steps. ...
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We sought to determine the association between time to initial antibiotics and mortality of patients with septic shock treated with an emergency department-based early resuscitation protocol. Preplanned analysis of a multicenter randomized controlled trial of early sepsis resuscitation. Three urban U.S. emergency departments. Adult patients with septic shock. A quantitative resuscitation protocol in the emergency department targeting three physiological variables: central venous pressure, mean arterial pressure, and either central venous oxygen saturation or lactate clearance. The study protocol was continued until all end points were achieved or a maximum of 6 hrs. Data on patients who received an initial dose of antibiotics after presentation to the emergency department were categorized based on both time from triage and time from shock recognition to initiation of antibiotics. The primary outcome was inhospital mortality. Of 291 included patients, mortality did not change with hourly delays in antibiotic administration up to 6 hrs after triage: 1 hr (odds ratio [OR], 1.2; 0.6-2.5), 2 hrs (OR, 0.71; 0.4-1.3), 3 hrs (OR, 0.59; 0.3-1.3). Mortality was significantly increased in patients who received initial antibiotics after shock recognition (n = 172 [59%]) compared with before shock recognition (OR, 2.4; 1.1-4.5); however, among patients who received antibiotics after shock recognition, mortality did not change with hourly delays in antibiotic administration. In this large, prospective study of emergency department patients with septic shock, we found no increase in mortality with each hour delay to administration of antibiotics after triage. However, delay in antibiotics until after shock recognition was associated with increased mortality.
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To study the association between time to antibiotic administration and survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Single-center cohort study. The emergency department of an academic tertiary care center from 2005 through 2006. Two hundred sixty-one patients undergoing early goal-directed therapy. None. Effects of different time cutoffs from triage to antibiotic administration, qualification for early goal-directed therapy to antibiotic administration, triage to appropriate antibiotic administration, and qualification for early goal-directed therapy to appropriate antibiotic administration on in-hospital mortality were examined. The mean age of the 261 patients was 59 +/- 16 yrs; 41% were female. In-hospital mortality was 31%. Median time from triage to antibiotics was 119 mins (interquartile range, 76-192 mins) and from qualification to antibiotics was 42 mins (interquartile range, 0-93 mins). There was no significant association between time from triage or time from qualification for early goal-directed therapy to antibiotics and mortality when assessed at different hourly cutoffs. When analyzed for time from triage to appropriate antibiotics, there was a significant association at the <1 hr (mortality 19.5 vs. 33.2%; odds ratio, 0.30 [95% confidence interval, 0.11-0.83]; p = .02) time cutoff; similarly, for time from qualification for early goal-directed therapy to appropriate antibiotics, a significant association was seen at the < or =1 hr (mortality 25.0 vs. 38.5%; odds ratio, 0.50 [95% confidence interval, 0.27-0.92]; p = .03) time cutoff. Elapsed times from triage and qualification for early goal-directed therapy to administration of appropriate antimicrobials are primary determinants of mortality in patients with severe sepsis and septic shock treated with early goal-directed therapy.
Article
Sepsis bundles have been developed to improve patient outcomes by combining component therapies. Valid bundles require effective components with additive benefits. Proponents encourage evaluation of bundles, both as a whole and based on the performance of each component. Assess the association between outcome and the utilization of component therapies in studies of sepsis bundles. Database searches (January 1980 to July 2008) of PubMed, Embase, and the Cochrane Library, using the terms sepsis, bundles, guidelines, and early goal directed therapy. Inclusion required comparison of septic adults who received bundled care vs. nonprotocolized care. Survival and use rates for individual interventions were abstracted. Eight unblinded trials, one randomized and seven with historical controls, were identified. Sepsis bundles were associated with a consistent (I2 = 0%, p = .87) and significant increase in survival (odds ratio, 1.91; 95% confidence interval, 1.49-2.45; p < .0001). For all studies reporting such data, there were consistent (I2 = 0%, p > or = .64) decreases in time to antibiotics, and increases in the appropriateness of antibiotics (p < or = .0002 for both). In contrast, significant heterogeneity was seen across trials for all other treatments (antibiotic use within a specified time period; administration of fluids, vasopressors, inotropes, and packed red blood cells titrated to hemodynamic goals; corticosteroids and human recombinant activated protein C use) (all I2 > or = 67%, p < .002). Except for antibiotics, sepsis bundle components are still being investigated for efficacy in randomized controlled trials. Bundle use was associated with consistent and significant improvement in survival and antibiotic use. Use of other bundle components changed heterogeneously across studies, making their impact on survival uncertain. However, this analysis should be interpreted cautiously as these studies were unblinded, and only one was randomized.