Clinical Investigations

Impact of time to antibiotics on survival in patients with severe

sepsis or septic shock in whom early goal-directed therapy was
initiated in the emergency department*
David F. Gaieski, MD; Mark E. Mikkelsen, MD, MSCE; Roger A. Band, MD;
Jesse M. Pines, MD, MBA, MSCE; Richard Massone, MD; Frances F. Furia, MD; Frances S. Shofer, PhD;
Munish Goyal, MD

Objective: To study the association between time to antibiotic tibiotics was 42 mins (interquartile range, 0 –93 mins). There was
administration and survival in patients with severe sepsis or no significant association between time from triage or time from
septic shock in whom early goal-directed therapy was initiated in qualification for early goal-directed therapy to antibiotics and
the emergency department. mortality when assessed at different hourly cutoffs. When ana-
Design: Single-center cohort study. lyzed for time from triage to appropriate antibiotics, there was a
Setting: The emergency department of an academic tertiary significant association at the <1 hr (mortality 19.5 vs. 33.2%;
care center from 2005 through 2006. odds ratio, 0.30 [95% confidence interval, 0.11– 0.83]; p ⴝ .02)
Patients: Two hundred sixty-one patients undergoing early time cutoff; similarly, for time from qualification for early goal-
goal-directed therapy. directed therapy to appropriate antibiotics, a significant associ-
Interventions: None. ation was seen at the <1 hr (mortality 25.0 vs. 38.5%; odds
Measurements and Main Results: Effects of different time ratio, 0.50 [95% confidence interval, 0.27– 0.92]; p ⴝ .03) time
cutoffs from triage to antibiotic administration, qualification for cutoff.
early goal-directed therapy to antibiotic administration, triage to Conclusions: Elapsed times from triage and qualification for
appropriate antibiotic administration, and qualification for early early goal-directed therapy to administration of appropriate anti-
goal-directed therapy to appropriate antibiotic administration on microbials are primary determinants of mortality in patients with
in-hospital mortality were examined. The mean age of the 261 severe sepsis and septic shock treated with early goal-directed
patients was 59 ⴞ 16 yrs; 41% were female. In-hospital mortality therapy. (Crit Care Med 2010; 38:1045–1053)
was 31%. Median time from triage to antibiotics was 119 mins KEY WORDS: sepsis; early goal-directed therapy; antimicrobial
(interquartile range, 76 –192 mins) and from qualification to an- timing; appropriateness; outcomes; resuscitation

I t has been estimated that one limited. Antibiotic therapy has long stay (3). However, in a study by Kumar
patient presents to an emer- been one of the mainstays of treatment. et al (5), examining the duration of
gency department (ED) in the New therapies have emerged in the past hypotension until the administration of
United States with severe sepsis decade, including early goal-directed appropriate antimicrobials in patients
or septic shock every minute, and mor- therapy (EGDT), which uses an algo- with septic shock, each hour’s delay to
tality ranges from 25% to 50% (1, 2). rithmic resuscitation strategy, system- antibiotic administration was associ-
Until recently, treatment options were atically measuring and correcting cen- ated with, on average, a 7.6% increase
tral venous pressure, mean arterial in mortality. Therefore, what priority
pressure, and central venous oxygen early antibiotic administration should
*See also p. 1211. saturation (ScvO2) at the most proximal be given in an algorithmic resuscitation
From the Department of Emergency Medicine
(DFG, JMP, RAB, RM, FFF, FSS), Division of Pulmonary,
phase of critical infection (3). In a ran- strategy remains unclear.
Allergy, and Critical Care, Department of Medicine domized, single-center trial, EGDT pro- The Surviving Sepsis Campaign’s
(MEM), the Center for Clinical Epidemiology and Bio- duced a 16% absolute reduction in in- 2008 “International guidelines for the
statistics (JMP, MEM), and the Leonard Davis Institute hospital mortality. In patients with management of severe sepsis and septic
for Health Economics (JMP), University of Pennsylva- hemodynamic instability, the initial shock” recommend that appropriate an-
nia, Philadelphia, PA; and the Department of Emer-
gency Medicine (MG), Washington Hospital Center, steps of care, including establishing timicrobial therapy be administered
Georgetown University School of Medicine, Washing- vascular access and fluid resuscitation, within 1 hr of recognition of severe
ton, DC. may take precedence over early antibi- sepsis or septic shock (4). The recom-
The authors have not disclosed any potential con- otic administration (4). It is notable mendation was primarily based on the
flicts of interest.
For information regarding this article, E-mail:
that in the original EGDT trial, 13.7% study by Kumar et al (5) and on one
[email protected] of the patients in the EGDT group and other retrospective study (6). Given the
Copyright © 2010 by the Society of Critical Care 7.6% of the patients in the standard competing demands that exist in many
Medicine and Lippincott Williams & Wilkins therapy group did not receive antibiot- EDs, administration of antimicrobial
DOI: 10.1097/CCM.0b013e3181cc4824 ics during the first 6 hrs of their ED therapy within this 1-hr time frame can

Crit Care Med 2010 Vol. 38, No. 4 1045

be a difficult task to accomplish unless present study. More than 150 data points ter reliability comparing one investigator’s
specific protocols are implemented to were collected per patient. Severity of illness (DFG’s) assignment of time from triage to
streamline ordering and delivery of an- was calculated using an ED Acute Physiol- antibiotics with those of the other data entry
tibiotics. The 2006 Emergency Depart- ogy and Chronic Health Evaluation II score personnel was calculated using Cohen’s kappa
(3, 9, 10). There were no specific recommen- calculation.
ment Management Guidelines (7) cre-
dations in the EGDT protocol regarding an- Data Analysis. Descriptive data are pre-
ated by the ED-SEPSIS Working Group tibiotic timing or type; however, an ED- sented as mean (SD) for continuous data,
state, “Although there are insufficient based severe sepsis antibiogram (Appendix medians with interquartile ranges (IQRs) for
data to conclude that delays on the or- B) was available for guidance in antibiotic time variables, and frequencies and percents
der of hours are deleterious, adminis- choice if desired. Data were recorded using for categorical data. We compared in-
tration of antibiotics within the time of standard database software (Access; Mi- hospital mortality in patients receiving an-
ED care and as soon as possible once crosoft Corporation, Redmond, WA). The tibiotics at different time cutoffs, using
there is a reasonable suspicion of severe retrospective study was completed in accor- Fisher’s exact test. We examined time to
sepsis/septic shock will likely increase dance with established standards for chart antibiotics in four ways: elapsed time from
the chance of favorable outcome com- reviews in emergency medicine (11, 12). triage to antibiotic administration; from
Data entry on standardized forms was done qualification for EGDT to antibiotic admin-
pared with later administration.”
by five data entry personnel (one emergency istration; from triage to appropriate antibi-
We studied the impact of antibiotic medicine attending; one critical care fellow; otic administration; and from qualification
timing on survival in patients receiving two emergency medicine residents; and one for EGDT to appropriate antibiotic adminis-
a standardized resuscitation algorithm medical student), including four authors tration. Timing cutoffs included: ⱕ1 hr vs.
(EGDT) for severe sepsis or septic shock (DFG, RM, FFF, MEM), who were trained ⬎1 hr; ⱕ2 hrs vs. ⬎2 hrs; ⱕ3 hrs vs. ⬎3 hrs;
in our ED. We hypothesized that earlier before the start of the study. Each person ⱕ4 hrs vs. ⬎4 hrs; and ⱕ5 hrs vs. ⬎5 hrs.
administration of antimicrobial therapy entered a minimum of 30 charts, using a pri- Multivariable logistic regression was
in patients receiving EGDT (within the ori-determined rules, available in a standard- used to adjust for potential confounding in
time frame recommended by the Sur- ized glossary, for data entry in each category, the association between time to antibiotics
viving Sepsis Campaign) would be asso- including triage time, time of qualification for and in-hospital mortality. We considered
EGDT, time of initial antibiotic administra- age, Acute Physiology and Chronic Health
ciated with improved survival.
tion, appropriateness of antibiotic selection, Evaluation II score, initial lactate, initial
and time of appropriate antibiotic administra- systolic blood pressure, initial temperature,
tion (Appendix C). One author (DFG) met reg- and amount of intravenous fluid given dur-
MATERIALS AND METHODS
ularly (at least once a month) with each data ing the first 6 hrs and over the total ED stay
Study Design and Setting. After obtaining abstractor to review data entry and to resolve as potential confounders. Potential con-
approval from our Institutional Review Board, conflicts about data coding and timing inter- founders were determined a priori and were
we conducted a retrospective analysis of a co- vals. The research hypothesis was generated forced into the final model. We present the
hort of patients with severe sepsis and septic after data entry was completed and, therefore, adjusted odds ratio for in-hospital mortality
shock treated with EGDT in the Hospital of the data abstractors were blinded to the hy- and 95% confidence interval. Statistical sig-
the University of Pennsylvania’s ED between pothesis of this study. Kappa value of interra- nificance was defined as a p value ⬍.05. To
January 5, 2005, and December 31, 2006. The
Hospital of the University of Pennsylvania is
an urban, tertiary care medical center with an Table 1. Baseline characteristics of patients (n ⫽ 261)
annual ED volume of approximately 55,000
adult patients. Variable Value SD or IQR Range
Inclusion Criteria. Inclusion criteria in-
cluded 1) inclusion in the severe sepsis and Age, yrs 59 16.1 22–101
septic shock database; 2) initiation of EGDT Female gender, % 41
(defined as algorithmic volume resuscitation, Race
placement of central venous catheter, and Black, % 48
measurement of central venous pressure, White, % 43
mean arterial pressure, and ScvO2) during the Other, % 9
patient’s ED stay. APACHE II score 17.9 6.4
Data Collection. The data used in this Qualified for EGDT at presentation to ED, % 47
study were part of a prospective quality im- SIRS criteria
provement initiative to evaluate the impact Temperature, °F 99.2 2.7 91.7–107.0
of an EGDT program on survival in patients Heart rate, beats/min 115.2 25.9 30–182
with severe sepsis and septic shock in the Respiratory rate, breaths/min 22.1 7.3 6–64
Partial pressure of CO2, mm Hg 34.5 11.4 12–95
Hospital of the University of Pennsylvania
White blood count, per mm3 14.7 10.9 0.1–90.5
ED (see Appendix A for EGDT protocol).
Early goal-directed therapy criteria
Generally accepted definitions of severe sep-
Systolic blood pressure, mm Hg 107.8 27.2 32–173
sis and septic shock were used (Appendix B) Lactate, mmol/L 5.6 3.6 0.8–26.5
(8). Patients qualified for EGDT if they had: Baseline laboratory values
1) cryptic septic shock, defined as severe Hemoglobin, mg/dL 11.8 2.9 2.8–19.8
sepsis with a lactate ⱖ4 mmol/L as a marker Platelets, per mm3 233.0 156.0 5–1098
of significant tissue hypoperfusion; or 2) CO2, mg/dL 20.6 6.5 1–56
septic shock as defined in Appendix B (3). International normalized ratio 1.46 0.59 1–⬎50
The EGDT program started actively treating Total bilirubin, mg/dL 2.5 4.0 0.1–26.6
patients in January 2005, and two authors
(DFG, MG) were contacted by pager or e- IQR, interquartile range; APACHE, Acute Physiology and Chronic Health Evaluation; EGDT, early
mail about all of the patients included in the goal-directed therapy; ED, emergency department; SIRS, systemic inflammatory response syndrome.

1046 Crit Care Med 2010 Vol. 38, No. 4

calculate the probability of death, we used a tality for culture-positive patients who We found no relationship between
marginal standardization approach wherein did not receive appropriate initial anti- time from triage to administration of
we used the estimates from the multivari- biotics in the ED was 50.0% (p ⫽ .15). antibiotics and mortality outcome after
able logistic regression to determine the av- adjusting for potential confounders.
erage predicted probability of death for a
The lack of relationship between time of
given group (13). Statistical analyses were
performed using SAS (version 9.1; SAS In-
antibiotic administration and mortality
Table 2. Source of infection
stitute, Cary, NC) and STATA (version 10; outcome extended to ⬎5 hrs from tri-
StataCorp, College Station, TX) statistical Source Percent age to antibiotic administration. Simi-
software. larly, we found no relationship between
Respiratory 30.6 time from qualification for EGDT to
RESULTS Genitourinary 22.8 antibiotic administration and mortality.
Gastrointestinal 19.7 In the analysis examining time from
Primary bacteremia 14.9
The average age of the 261 patients Skin/soft tissue 7.5
triage to appropriate antibiotic admin-
receiving EGDT studied was 59 ⫾ 16 Central venous catheter 5.9 istration, mortality was significantly
yrs; 41% were female; 48% were black, Central nervous system 2.4 decreased when antibiotics were given
and 43% were white. Forty-seven per- Surgical site 2.0 in ⱕ1 hr vs. ⬎1 hr. Finally, in the
cent (n ⫽ 123) of the patients qualified Endocarditis 1.6 analysis examining time from qualifica-
Other 5.8
for EGDT at triage; 53% (n ⫽ 138) Total 306 sites tion for EGDT to appropriate antibiot-
qualified later during their ED stay. ics, mortality was significantly de-
Cryptic shock was the qualifying diag- Forty-three patients had two or more primary creased when antibiotics were given in
nostic category for 48% (n ⫽ 126) of sources. ⱕ1 hr vs. ⬎1 hr (Tables 4–7; Figs. 1– 4).
the patients; septic shock was the qual-
ifying diagnostic category for the re-
maining 52% (n ⫽ 135). Mean Acute Table 3. Culture results
Physiology and Chronic Health Evalua-
Number Percent
tion II score was 17.9 ⫾ 6.4 (Table 1).
All patients received antibiotics dur- Total patients 261
ing their ED course. The median length Culture-negative patients 113 43.3
of time from triage to antibiotics was Culture-positive patients 148 56.7
119 mins (IQR, 76 –192 mins); from Urine 71 27.2
Blood 83 31.8
qualification for EGDT to antibiotics
Other 50 19.2
was 42 mins (IQR, 0 –93 mins); from Polymicrobial 25 9.6
triage to appropriate antibiotics was Multiple sources 42 16.1
127 mins (IQR, 79 –224 mins); and from Total positive cultures 204 N/A
qualification for EGDT to appropriate Gram-positive organisms 67 25.7
Enterococcus 18 6.9
antibiotics was 47 mins (IQR, 0 –108 Streptococcus pneumoniae 14 5.4
mins). Kappa value of interrater reli- MSSA 14 5.4
ability for time to antibiotics ⫽ 0.91. MRSA 8 3.1
The most common sources of infection Group B Streptococcus 5 2.0
Streptococcus viridans 4 1.5
were: respiratory (30.6%), genitouri-
Other staphylococci 3 1.2
nary (22.8%), gastrointestinal (19.7%), (S. hominis, S. lugdunensis)
and primary bacteremia (14.9%) (Table Group A Streptococcus 1 0.4
2). Cultures were positive in 148 Gram-negative organisms 96 36.6
(56.7%) patients. Our ED antibiogram Escherichia coli 30 11.5
Klebsiella 21 8.0
was followed in all of the culture-
Pseudomonas species 15 5.7
negative cases (Appendix B); 126 Citrobacter 6 2.3
(85.1%) of the culture-positive cases re- Acinetobacter 5 1.9
ceived appropriate initial antibiotic Enterobacter species 5 1.9
coverage during their ED stay; 22 Proteus mirabilis 4 1.5
Haemophilus influenzae 2 0.8
(14.9%) of the culture-positive cases Serratia 2 0.8
were initially given inappropriate anti- Stenotrophomonas 1 0.4
biotics. Two patients who initially re- Morganella 1 0.4
ceived inappropriate antibiotics were Other gram-negative organisms 4 1.5
Anaerobic organisms 9 3.4
subsequently given appropriate antibi-
Clostridium difficile 4 1.5
otics before transfer from the ED. Bacteroides fragilis 3 1.2
In-hospital mortality was 31.0% for Other Clostridia 1 0.4
the cohort as a whole; it was 35.1% for Fungi 6 2.3
culture-positive patients vs. 25.7% (p ⫽ Candida albicans 5 1.9
Candid glabrata 1 0.4
.11) for culture-negative patients (Table Legionella species 1 0.4
3). Mortality for culture-positive pa-
tients who received appropriate initial MSSA, methicillin-sensitive Staphylococcus aureus; MRSA, methicillin-resistant S. aureus; N/A,
antibiotics in the ED was 32.5%; mor- not applicable.

Crit Care Med 2010 Vol. 38, No. 4 1047

Table 4. In-hospital mortality: Triage to ED antibiotics the incidence is increasing. The optimal
treatment strategy is constantly evolv-
Adjusted
ing and includes initial resuscitation,
Mortality, Difference, Probability rapid diagnosis, timely administration
Cutoffs Number % % OR 95% CI p of Death of appropriate antibiotics, source iden-
tification and control, and meticulous
ⱕ1 hr 46 26.1 6.0 0.51 0.21–1.22 .13 .20 vs. .28 ED and intensive care unit (ICU) man-
⬎1 hr 215 32.1 agement. The question of how antibi-
ⱕ2 hrs 136 30.9 0.3 0.72 0.38–1.37 .30 .25 vs. .28 otic administration should be priori-
⬎2 hrs 125 31.2
ⱕ3 hrs 187 29.4 5.7 0.64 0.32–1.29 .21 .25 vs. .31 tized in the initial resuscitation
⬎3 hrs 74 35.1 sequence of patients with severe sepsis
ⱕ4 hrs 217 30.0 6.4 0.80 0.35–1.84 .59 .27 vs. .29 and septic shock has been unanswered.
⬎4 hrs 44 36.4 We hypothesized that earlier antibiotic
ⱕ5 hrs 237 32.1 ⫺11.2 0.86 0.56–6.15 .31 .28 vs. .16
⬎5 hrs 24 20.8
administration would be associated
with lower in-hospital mortality in pa-
ED, emergency department; OR, odds ratio; CI, confidence interval. tients treated with a uniform resuscita-
tion strategy (EGDT). We examined
Table 5. In-hospital mortality: Qualified for EGDT to ED antibiotics time from triage to antibiotic adminis-
tration (a commonly tracked perfor-
Adjusted mance measure) and time from quali-
fication for EGDT to antibiotic admin-
Mortality, Difference, Probability istration, which is much more in keep-
Cutoffs Number % % OR 95% CI p of Death
ing with the Surviving Sepsis Cam-
ⱕ1 hr 154 26.6 10.8 0.58 0.31–1.08 .09 .22 vs. .34
paign’s recommendation of rapid
⬎1 hr 107 37.4 antibiotic administration after recogni-
ⱕ2 hrs 218 29.8 7.4 0.77 0.34–1.70 .51 .26 vs. .34 tion of severe sepsis or septic shock.
⬎2 hrs 43 37.2 The results of our study identify three
ⱕ3 hrs 239 30.1 10.8 0.62 0.23–1.69 .36 .26 vs. .39 important factors in the relationship
⬎3 hrs 22 40.9
ⱕ4 hrs 252 30.6 13.9 0.77 0.17–3.59 .74 .27 vs. .37 between mortality and timing of antibi-
⬎4 hrs 9 44.4 otic administration in severe sepsis and
ⱕ5 hrs 257 31.1 ⫺6.1 1.33 0.12–14.20 .82 .27 vs. .24 septic shock: 1) the time the patient
⬎5 hrs 4 25.0 qualified for EGDT; 2) the length of
time from triage to administration of
EGDT, early goal-directed therapy; ED, emergency department; OR, odds ratio; CI, confidence
interval.
appropriate antibiotics; and 3) the
length of time from qualification for
EGDT to administration of appropriate
Table 6. In-hospital mortality: Time from triage to appropriate antibiotics
antibiotics. Based on the results of this
Adjusted study, we recommend that practitio-
ners administer appropriate antibiotics
Mortality, Difference, Probability as rapidly as possible once there is a
Cutoffs Number % % OR 95% CI p of Death reasonable suspicion of severe sepsis
and septic shock and place a high pri-
ⱕ1 hr 41 19.5 13.7 0.30 0.11–0.83 .02 .13 vs. .29 ority on developing systems to stream-
⬎1 hr 220 33.2
ⱕ2 hrs 124 28.2 5.4 0.54 0.29–1.03 .06 .22 vs. .31 line their timely administration. Appro-
⬎2 hrs 137 33.6 priate antibiotics should be given
ⱕ3 hrs 172 27.9 9.2 0.53 0.27–1.01 .05 .23 vs. .34 within 1 hr of qualification for EGDT.
⬎3 hrs 89 37.1 Of note, in our study, there were only
ⱕ4 hrs 200 28.5 10.8 0.62 0.31–1.24 .18 .25 vs. .34
⬎4 hrs 61 39.3
five patients (four of whom died) who
ⱕ5 hrs 218 30.7 1.8 0.82 0.37–1.79 .62 .27 vs. .29 received inappropriate antibiotics
⬎5 hrs 43 32.6 within 1 hr of triage and only 10 pa-
tients (five of whom died) who received
OR, odds ratio; CI, confidence interval. inappropriate antibiotics within 1 hr of
qualification for EGDT. Given this, the
mortality benefit of timely antibiotics is
These findings were supported by the DISCUSSION likely driven by the timely administra-
sensitivity analyses at other time cut- tion of appropriate antibiotics.
offs. Similar results were seen when the Severe sepsis and septic shock are Our findings support the recommen-
patients were divided into two catego- vexing healthcare problems in the dations on timeliness of antibiotic ad-
ries (patients with cryptic shock and United States and around the world. ministration published by the Surviving
patients with septic shock), which were There is a large burden of disease and Sepsis Campaign. Their recommenda-
subsequently analyzed as described pre- high mortality; outcomes have, until tions are based primarily on expert
viously (not shown in tables). recently, remained relatively static, and opinion and the results of two retro-

1048 Crit Care Med 2010 Vol. 38, No. 4

Table 7. In-hospital mortality: Time from qualification for early goal-directed therapy to appropriate spective studies (5, 6). The first study
antibiotics demonstrated a logarithmic relation-
ship between the duration of hypoten-
Adjusted
sion before administration of appropri-
Mortality, Difference, Probability ate antimicrobials and mortality in
Cutoffs Number % % OR 95% CI p of Death patients admitted to the ICU with septic
shock. Direct admissions from the ED
ⱕ1 hr 144 25.0 13.5 0.50 0.27–0.92 0.03 .20 vs. .35 accounted for 44.4% of the patients in-
⬎1 hr 117 38.5 cluded. In this study, each hour’s delay
ⱕ2 hrs 201 28.4 11.6 0.57 0.27–1.15 0.12 .24 vs. .38
⬎2 hrs 60 40.0
from the onset of hypotension to ad-
ⱕ3 hrs 220 28.6 15.3 0.47 0.22–1.01 0.05 .24 vs. .43 ministration of appropriate antibiotics
⬎3 hrs 41 43.9 was associated with an average increase
ⱕ4 hrs 232 29.3 15.5 0.49 0.20–1.18 0.11 .25 vs. .42 in in-hospital mortality of 7.6% (5). The
⬎4 hrs 29 44.8 second study found that delaying anti-
ⱕ5 hrs 238 29.8 13.7 0.48 0.18–1.25 0.13 .25 vs. .43
⬎5 hrs 23 43.5 fungal therapy for ⬎12 hrs after the
initial positive fungal culture was
OR, odds ratio; CI, confidence interval. drawn was an independent predictor of
hospital mortality (6).
How early is early enough for anti-
biotic administration in severe sepsis
and septic shock? A handful of recent
studies have attempted to answer this
question. For example, a retrospective
analysis of patients with severe pneu-
monia resulting from Legionella pneu-
mophilia, found that delays to antibi-
otic administration ⬎8 hrs from ICU
admission were associated with in-
creased mortality (14). Another retro-
spective study examining predictors of
30-day mortality in critically ill patients
with cancer with septic shock found
that mortality was increased when time
from ICU admission to first antibiotic
administration was ⬎2 hrs (15). Fi-
nally, the Finnsepsis Study Group (16)
examined how early treatment guide-
lines, including early antibiotic admin-
Figure 1. Number of patients and mortality at hourly intervals based upon time from triage to
istration and early hemodynamic opti-
antibiotics.
mization, were being adopted in the
treatment of septic shock in Finland.
They examined 92 patients with septic
shock admitted from the ED to the ICU,
dividing them into patients receiving
antibiotics in ⬍3 hrs vs. ⬎3 hrs from
ED admission. They found that a “de-
layed start of antibiotics was the most
significant individual early treatment
variable resulting in increased mortal-
ity.” However, compliance with EGDT
screening and resuscitation end points
was unsatisfactory in their cohort: lac-
tate measurement occurred during the
first 6 hrs in 58%; antibiotics were
given in ⬍3 hrs in 53%; central venous
pressure was measured during the first
6 hrs in 37%; mean arterial pressure
⬎65 mm Hg was achieved in 74%; and
ScvO2 was measured within 6 hrs in
19.6%. This variability of care makes it
Figure 2. Number of patients and mortality at hourly intervals based upon time from qualification for hard to generalize from the patients
early goal-directed therapy (EGDT) to antibiotics. with septic shock in their cohort to a

Crit Care Med 2010 Vol. 38, No. 4 1049

 of Kumar et al, and we hypothesize that
the reason for this is threefold: 1) in the
study of Kumar et al, the median time
to appropriate antibiotics was 6 hrs
(IQR ⫽ 2–15 hrs), whereas in our study,
it was just over 2 hrs (127 mins [IQR,
79 –224 mins]); 2) resuscitation strate-
gies were heterogeneous over time and
location in the study of Kumar et al,
whereas a single, algorithmic hemody-
namic optimization strategy initiated in
the ED was used in all patients in our
study; and 3) the study of Kumar et al
benefited from a much larger sample
size.
Results of animal studies using an
intra-abdominal sepsis model suggest a
critical inflection point between 12 and
Figure 3. Number of patients and mortality at hourly intervals based upon time from triage to
15 hrs after induction of septic shock;
appropriate antibiotics. this inflection point coincides with the
onset of persistent hypotension and the
development of significant lactic acido-
sis. When antibiotic administration is
delayed beyond this point, mortality in-
creases dramatically (17). Our data are
consistent with this finding and suggest
that a similar inflection point exists in
patients presenting to the ED with se-
vere infections, who qualify for goal-
directed hemodynamic optimization
strategies. This inflection point may co-
incide with triage (47% of our patients
qualified for EGDT at triage) or may
develop during the initial hours of eval-
uation and treatment in the ED (53% of
our patients qualified at some point af-
ter triage). When appropriate antibiot-
ics are administered before or coinci-
dent with this inflection point,
Figure 4. Number of patients and mortality at hourly intervals based upon time from qualification for mortality is significantly lower than
early goal-directed therapy (EGDT) to appropriate antibiotics. when appropriate antibiotic adminis-
tration is delayed beyond that point.
Our findings support the Surviving
group of patients managed with a more to the ICU. Within this aggressive, uni- Sepsis Campaign’s recommendation of
uniform resuscitation strategy. form resuscitation strategy at the most antibiotic administration within 1 hr of
How do our findings diverge from proximal point of critical infection, recognition of septic shock and suggest
those of prior studies investigating the time from qualification for EGDT to that the recommendations from the
relationship between time to antibiotics appropriate antibiotic administration ED-SEPSIS Working Group that “ad-
and mortality in patients with septic had a significant effect on in-hospital ministration of antibiotics within the
shock? All 261 patients in our cohort mortality outcome. This effect was not time of ED care and as soon as possible
underwent hemodynamic optimization present when time from triage to anti- once there is a reasonable suspicion of
during the first 6 hrs of their hospital biotic administration was analyzed; this severe sepsis/septic shock will likely in-
presentation. This included assessment suggests that the commonly used per- crease the chance of favorable outcome
of serum lactate, early volume resusci- formance measure of time from triage compared with later administration”
tation, and invasive monitoring for cen- to antibiotics in diseases such as pneu- are not rigorous enough given our cur-
tral venous pressure, mean arterial monia needs to be modified to take into rent understanding of the role of appro-
pressure, and ScvO2. Despite variations account the appropriateness of the an- priate antibiotics in the treatment of
in presentation, the median time from tibiotics that were given and the patho- life-threatening severe sepsis.
triage to antibiotics was 119 mins, physiological implications of the time This study has several limitations. It
97.6% received antibiotics within 6 hrs of onset of hemodynamic instability. was performed at a single center using
of triage, and all of the patients received We did not find the logarithmic a uniform, algorithmic resuscitation
antibiotics before transfer from the ED changes in mortality seen in the study strategy, and caution should be taken in

1050 Crit Care Med 2010 Vol. 38, No. 4

generalizing these results to the treat- general, the delivery of antibiotics for hospital mortality. Antimicrob Agents
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gency department management guidelines.
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Ann Emerg Med 2006; 48:28 –54
data from multiple perspectives, we tration of potentially life-saving antibi- 8. Levy MM, Fink MP, Marshall JC, et al: Inter-
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results are confounded by these pa- intravenous push vs. those that require Definitions Conference. Intensive Care Med
tients being at higher risk of death; infusion over an extended time frame. 2003; 29:530 –538
however, this confounding should bias Also, the central antibiotics in an institu- 9. Nguyen HB, Corbett SW, Menes K, et al:
toward the null. It is possible that dif- tion’s severe sepsis and septic shock an- Early goal-directed therapy, corticosteroid,
ferences in times to EGDT end points tibiogram must be immediately available and recombinant human activated protein C
for the treatment of severe sepsis and septic
not considered in this analysis played a in the ED and ICUs, eliminating delays to
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thor met with the other data abstrac- Implementation and outcomes of the Mul-
tors on a regular basis to address ques- ACKNOWLEDGMENTS tiple Urgent Sepsis Therapies (MUST) pro-
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emergency medicine: The blessing and the
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APPENDIX A: THE HOSPITAL OF THE UNIVERSITY OF APPENDIX B: A PRIORI RULES
PENNSYLVANIA’S SEVERE SEPSIS PATHWAY FOR DEFINING SEPTIC SHOCK,
CRYPTIC SHOCK, AND
QUALIFICATION FOR EARLY
GOAL-DIRECTED THERAPY,
ASSIGNING TIMES TO
QUALIFICATION FOR EARLY
GOAL-DIRECTED THERAPY AND
ANTIBIOTIC ADMINISTRATION,
AND ASSESSING
APPROPRIATENESS OF
ANTIBIOTIC ADMINISTRATION

Definitions of Septic Shock and Cryp-

tic Shock. Generally accepted defini-
tions of severe sepsis and septic shock
were used: 1) severe sepsis was defined
as two or more systemic inflammatory
response syndrome criteria: tempera-
ture ⬍96°F or ⬎100.4°F; heart rate
⬎90 beats/min; respiratory rate ⬎20
breaths/min or PaCO2 ⬍32 mm Hg; and
white blood cell count ⬍4000/mm3,
⬎12,000/mm3, or ⬎10% bands; a pre-
sumed or documented source of infec-
tion; and at least one organ dysfunc-
tion, including change in mental
status, acute renal dysfunction, plate-
lets ⬍100/mm3, lactate ⬎3 mmol/L,
and total bilirubin ⬎4 mg/dL among
others; septic shock was defined as two
or more systemic inflammatory re-
sponse syndrome criteria, a presumed
or documented source of infection, and
a systolic blood pressure (SBP) ⱕ90
mm Hg after a fluid challenge of 20 to
30 mL/kg over 30 mins; a patient was
also considered to be in septic shock if
their SBP remained at least 40 mm Hg
below a well-documented baseline SBP
CVC, central venous catheter; IJV, internal jugular vein; SVC, superior vena cava; Apache, Acute after 20- to 30-mL/kg fluid challenge
Physiology and Chronic Evaluation; SAR, senior assistant resident; MICU, medical intensive care unit; over 30 mins (8); conversely, if a patient
SIRS, systemic inflammatory response syndrome; HR, heart rate; RR, respiratory rate; WBC, white had a well-documented baseline low
blood cell, SBP, systolic blood pressure; NS, normal saline; MAP, mean arterial pressure; PRBC, packed SBP (between 75 and 90 mm Hg), then
red blood cell; CVP, central venous pressure; ACTH, adrenocorticotropic hormone.
they were not considered to be in septic
shock if their blood pressure was in this
range. Cryptic shock was defined as se-
vere sepsis with a lactate ⱖ4 mmol/L as
a marker of significant tissue hypoper-
fusion (3).
Definition of Qualified at Triage. Pa-
tients were classified as “qualifying for
EGDT at triage” if they were hypoten-
sive in triage and remained so during
their initial intravenous fluid resuscita-
tion in the ED (20 –30 mL/kg); if they
became hypotensive during the first
60 mins after triage and that hypoten-
sive reading occurred after adequate
initial fluid resuscitation (20 –30 mL/

1052 Crit Care Med 2010 Vol. 38, No. 4

kg); or if they had an elevated serum using the same time zero points given for which the causative pathogens were
lactate (ⱖ4 mmol/L as a marker of sig- previously, and defining time of appro- sensitive in vitro; 2) in cases of polymi-
nificant tissue hypoperfusion) result priate antibiotic administration as the time crobial infection, all pathogens felt to
available on the ED electronic medical the antibiotic covering the causative organ- be contributing to severe sepsis or sep-
record within 1 hr of triage. If these ism was started, up to 36 hrs after triage or tic shock had to be covered by antibi-
criteria were not met and the patient qualification; if the time of administration otics for which the organisms were sen-
qualified at a later point, they were clas- of appropriate antibiotics was ⬎36 hrs from sitive in vitro; and 3) in cases of
sified as “not qualifying for EGDT at time zero, the time to administration was culture-negative severe sepsis or septic
triage.” considered 36 hrs. shock, broad-spectrum antibiotics ap-
Time From Triage to Antibiotic Ad- Appropriate Antibiotics. Appropriate propriate for the presumed site of in-
ministration. For analysis of time from antibiotics were defined as: 1) antibiotics fection.
triage to antibiotic administration,
time zero was considered triage time or
room time, whichever time was earlier,
APPENDIX C: EMERGENCY DEPARTMENT SEVERE SEPSIS
and time of antibiotic administration
ANTIBIOGRAM
was considered the time the first anti-
biotic was started by the nurse caring
for the patient.
For analysis of time from qualifica-
tion for EGDT to antibiotic administra-
tion, time zero for cryptic shock was
considered the time the lactate value
ⱖ4 mmol/L was received on the ED
electronic medical record and for septic
shock was the time of the first hypoten-
sive reading (SBP ⱕ90 mm Hg or ⬎40
mm Hg below baseline) after adequate
volume resuscitation (20 –30 mL/kg) or
the time of onset of hypotension if the
SBP was always ⱕ90 mm Hg or ⬎40
mm Hg below baseline during the ini-
tial resuscitation. For these patients,
time of antibiotic administration was
considered the time the first antibiotic
was started by the nurse caring for the
patient. Time from triage to appropriate
antibiotic administration and time from
qualification for EGDT to appropriate
antibiotic administration were defined PCN, penicillin; CNS, central nervous system; ETOH, ethyl alcohol; TPN, total parenteral nutrition.

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