Abstract

Background
Septic shock remains an important cause of death and disability in children. Optimal care requires
early recognition and treatment.
Methods
We evaluated a retrospective cohort of children (age <19) treated in our emergency department
(ED) for septic shock during 2008–2012 to investigate the association between timing of
antibiotic therapy and outcomes. The exposures were (1) receipt of empiric antibiotics in ≤1 hour
and (2) receipt of appropriate antibiotics in ≤1 hour. The primary outcome was development of
new or progressive multiple system organ dysfunction syndrome (NP-MODS). The secondary
outcome was mortality.
Results

Among 321 patients admitted to intensive care, 48% (n = 153) received empiric antibiotics in ≤1
hour. These patients were more ill at presentation with significantly greater median pediatric
index of mortality 2 (PIM2) scores and were more likely to receive recommended resuscitation in
the ED (61% vs 14%); however, rates of NP-MODS (9% vs 12%) and hospital mortality (7% vs
4%) were similar to those treated later.

Early, appropriate antibiotics were administered to 33% (n = 67) of patients with identified or
suspected bacterial infection. These patients had significantly greater PIM2 scores but similar
rates of NP-MODS (15% vs 15%) and hospital mortality (10% vs 6%) to those treated later.
Conclusions
Critically ill children with septic shock treated in a children's hospital ED who received
antibiotics in ≤1 hour were significantly more severely ill than those treated later, but they did
not have increased risk of NP-MODS or death.

Septic shock is an important cause of death and long-term morbidity in US children [1]. The
prevalence of pediatric septic shock has increased, but prior to programs for early recognition
and treatment, mortality had remained unchanged [2–4]. Delay in treatment of shock and
subsequent development of acute multiorgan failure increases risk of death [4].

Early resuscitation of shock to mitigate or prevent progression of organ failure was

demonstrated to decrease mortality in adults in 2001 [5]. Early recognition of shock followed
by timely treatment of the underlying cause and rapid reversal of cardiovascular insufficiency
using protocol-based care is now accepted as standard medical practice. These goals are the
cornerstone of the Surviving Sepsis Campaign (SSC) [6].

An important aspect of early goal directed therapy is the rapid administration of antibiotics.
The SSC endorses administering antibiotics within 1 hour of shock recognition [6]. However,
rapid antibiotic therapy is a nuanced factor because not all patients with septic shock have
bacterial infections, and among those with treatable bacterial infections, the initial coverage
may be inadequate. Delaying treatment with appropriate antibiotics is associated with
increased mortality in adults [7].

Our children's hospital emergency department (ED) has an ongoing quality improvement
program for early recognition and treatment of pediatric septic shock [8]. This program has
been in place since 2007, and adherence to recommended interventions including rapid
antibiotic administration has increased over time [8]. In the present study, we evaluate
whether administration of empiric and appropriate antibiotics in the ED within 1 hour from
identification of shock is associated with decreased development of new or progressive
multiple organ dysfunction syndrome (NP-MODS) compared with those treated later. We
also describe infectious etiologies in children presenting to our ED with septic shock as well
as the choice and timing of empiric antibiotic therapy.

METHODS
Study Design and Setting

We evaluated the relationship between timing of antibiotic administration for treatment of

septic shock and outcomes of children requiring admission to the pediatric intensive care unit
(PICU). We retrospectively identified patients presenting to the ED with septic shock
between 2008 and 2012, and we reviewed the hospital course and clinical outcomes. The
study was conducted at Primary Children's Hospital (PCH), a tertiary care pediatric hospital
with 40 000 ED visits per year and 2000 PICU admissions per year. The University of Utah
Institutional Review Board approved the study and waived requirement for informed consent.

Participant Selection Criteria

Initial patient selection was from the PCH Pediatric Septic Shock Project Database, which
was established with initiation of the PCH ED Septic Shock Guidelines in 2007. Patient
records were flagged for initial review and possible inclusion in this database if they met any
of the following broad criteria: (1) triage in the ED to “emergent” status, (2) lactate drawn
during ED course, (3) PICU admission within 12 hours of presentation to ED, (4) repeat
visits to the ED within 48 hours of initial visit, and (5) having a “rapid response” called on a
patient within 12 hours of admission from the ED to an inpatient ward for management of
sepsis. After initial screening, patients were retained in this database if their condition met the
American College of Critical Care Medicine (ACCM)/Pediatric Advanced Life Support
(PALS) definition of septic shock: known or suspected infection accompanied by temperature
abnormalities, vital sign abnormalities based on PALS vital sign parameters for age, and
physical exam consistent with deficit in end-organ perfusion [9–11]. The ACCM/PALS
definition was used because of its usefulness in bedside diagnosis and treatment in real time
[12]. We included subjects for the present study if they were ≤18 years of age and were
admitted from the PCH ED directly to the PICU between January 2008 and December 2012.

Microbiology Definitions

Patients with a “primary bacterial” infection had a culture taken on the day of hospitalization
(urine, blood, cerebral spinal fluid [CSF], other sterile body fluid, or a wound culture) that
grew pathogenic bacteria. Bacteria were classified as pathogenic if determined to be the cause
of septic shock based on review of clinician documentation. A “primary respiratory bacterial
infection” required the following: a respiratory sample from either an endobronchial brush
specimen, a tracheal aspirate, or a bronchial alveolar lavage that met Centers for Disease
Control and Prevention criteria for a respiratory infection, and presence of an infiltrate on
chest imaging [12]. Patients with “presumed primary bacterial” infections were defined as
those with clinical documentation indicating a likely bacterial infection with a full treatment
course of antibiotics but no positive culture. These included community-acquired pneumonia,
aspiration pneumonia, intestinal and intra-abdominal infections, and life-threatening skin and
soft tissue infection. Intra-abdominal infections include perforated bowel from any cause
including appendicitis or necrotizing enterocolitis. Patients were determined to have a
“primary viral” infection if bacterial cultures were negative and a viral respiratory panel or
viral polymerase chain reaction (PCR) study was positive. Patients without an infectious
source identified were classified as no source identified.

Exposures and Outcome

The principle exposure was receipt of empiric antibiotics ≤1 hour after recognition of septic
shock in the ED, compared with later administration among all patients admitted to the PICU.
Time to antibiotics was determined by time from triage in the ED to initial administration of
medication. We additionally compared receipt of appropriate antibiotics in ≤1 hour among
those with infections for which antibiotic therapy is recommended. These patients may have
required additional or changed antibiotic therapy from the initial, empiric choice. Antibiotics
were considered appropriate if the bacteria isolated were susceptible to the regimen given.
For presumed bacterial infections, the antibiotics were considered appropriate when the
spectrum of activity of the regimen was at least as broad as that recommended by the
Infectious Disease Society of America clinical guidelines for bacterial pneumonia, skin and
soft tissue infections, and intra-abdominal infections [14–16].

The primary outcome was development of NP-MODS. Given the relatively low pediatric
mortality rate, surrogate measures of disease severity are often used. Sepsis is associated with
MODS, and NP-MODS has been used as a surrogate measure in this way [17–19]. New or
progressive multiple system organ dysfunction syndrome was defined as the development of
2 or more organ dysfunctions during the hospitalization that were not present on the initial
day of admission, or worsening of organ failures present on admission. Organ dysfunction
present on hospital day 1 was presumed to be present on arrival. Assessment was based on
cardiovascular, pulmonary, renal, neurologic, hematologic, and hepatic function, based on the
patient's worst parameter during a specified time period (Supplementary Table 1) [18, 19].
Death was not part of NP-MODS assessment.

We assessed NP-MODS on days 1, 2, 5, 8, 12, 16, and 18 (or until hospital discharge,
whichever was sooner). Data were abstracted from the Intermountain Enterprise Data
Warehouse and by manual chart review. The ED course and compliance with the SSC
recommendations was recorded [6]. Additional outcome measures including mortality, PICU
and hospital length of stay, and hospital resource utilization were captured. All data were
stored within the University of Utah Division of Pediatric Critical Care Data Coordinating
Center secure server.

Statistical Analysis

Standard descriptive statistics were used to summarize patient characteristics. Groups were
compared by exposure, using χ2 test for categorical variables and Wilcoxon rank-sum test for
continuous variables. A binomial logistic regression was used to estimate the relationship
between receipt of early antibiotics and odds of NP-MODS (primary outcome) as well as
mortality (secondary outcome), adjusting for severity of illness with pediatric index of
mortality 2 scores (PIM2). Findings were considered statistically significant if P value was
<.05. The Bonferroni adjustment was used for restriction of significance when multiple
pairwise comparisons were made between groups. All data were analyzed using SPSS
(Chicago, Illinois) software, 19th version.

RESULTS

Three hundred twenty-one patients met study criteria, and select demographic and clinical
features are presented in Table 1. Bacterial infections were identified in 154 (48%) patients
with septic shock. Presumed bacterial and viral infections accounted for 51 (16%) and 50
(16%) patients, respectively. The remaining 66 (21%) patients had no source of infection
identified. Table 1 reports patient groups by infectious etiology. Those without an infectious
pathogen identified were significantly more likely to have a complex chronic condition [20]
compared with all other groups. Those with documented bacterial infections had significantly
longer median hospital length of stay than those with presumed bacterial, viral, or no
infection identified. New or progressive multiple system organ dysfunction syndrome was
significantly more common in those with documented bacterial infections compared with
children without a source of infection identified and those with viral infections.

Table 1.
Select Patient Demographic and Clinical Characteristics by Infection Typea

Presumed No P Value
Bacterial Bacterial Viral Infection Compares
Infection Infection N Infection Identified All
Characteristic N = 154 = 51 N = 50 N = 66 Groups

Demographic
Characteristics

65 (13– 106 (33– 81 (21–

Age, months 156) 159) 23 (4–128) 163) .01

Race .45
 Presumed No P Value
Bacterial Bacterial Viral Infection Compares
Infection Infection N Infection Identified All
Characteristic N = 154 = 51 N = 50 N = 66 Groups

White 109 (71) 35 (69) 30 (60) 49 (74)

Hispanic 20 (13) 7 (14) 6 (12) 6 (9)

Other 25 (16) 9 (18) 14 (28) 11 (17)

Male 78 (51) 22 (43) 28 (55) 37 (56) .49

Study years .19

2007–10 77 (50) 26 (51) 17 (34) 28 (42)

2010–12 77 (50) 25 (49) 33 (66) 38 (58)

Clinical
Characteristics

Tracheostomy
dependence 9 (6) 5 (10) 5 (10) 9 (14) .29

CCC [ 18] 45 (29) 18 (35) 10 (20) 31 (47) .01

Number of CCC 0 (0,1) 0 (0, 1) 0 (0, 0) 1 (0, 1) .01

Antibiotics given
in ED 148 (96) 50 (98) 50 (100) 59 (89) .03

Received empiric
antibiotics ≤1
hour 77 (50) 18 (35) 18 (36) 40 (61) .01

Minutes to initial 60 (42, 75 (37, 74 (44,

antibiotics 100) 120) 101) 55 (32, 88) .1

Appropriate
antibiotics ≤1 Not Not
hour 56 (37) 11 (23) applicable applicable .23
 Presumed No P Value
Bacterial Bacterial Viral Infection Compares
Infection Infection N Infection Identified All
Characteristic N = 154 = 51 N = 50 N = 66 Groups

Minutes to
appropriate 92 (50, 100 (65, Not Not
antibiotics 238) 192) applicable applicable .65

1.6 (1.2, 1.4 (1.0, 1.3 (1.0, 1.8 (1.2,

PIM2 ED 4.0) 3.1) 3.8) 5.1) .09

Mechanical
ventilation
during
admission 61 (40) 16 (31) 9 (18)b 16 (24) .02

Vasoactive
medications
during
admission 58 (38) 17 (33) 6 (12)b 20 (30) .01

Length of PICU 1.9 (0.9, 1.7 (0.9, 1.7 (0.7, 1.7 (0.7,
stay, days 6.3) 3.9) 2.9) 4.0) .34

Length of
hospital stay, 7.1 (4.0, 4.9 (3.2, 3.7b (2.5, 4.4b (2.2,
days 13.2) 10.7) 6.2) 9.9) <.01

Death 10 (7) 3 (6) 0 4 (6) .34

Greatest organ
dysfunction on
any PICU day 2 (1,2) 1 (0, 2)b 1 (0, 1)b 1 (1, 2)b <.01

NP-MODS 25 (16) 5 (10) 1 (2)b 3 (5)b <.01

Abbreviations: CCC, complex chronic condition; ED, emergency department; IQR,

interquartile range; MODS, multiple organ dysfunction syndrome; NP-MODS,
new or progressive multiple organ dysfunction syndrome; PICU, pediatric
intensive care unit; PIM2, pediatric index of mortality 2.
a Data are presented as either n (%) or median (IQR).
b Significantly different than bacterial infection, P < .008 for pairwise comparisons.

The positive bacterial cultures were as follows: 72 blood, 25 urine, 12 CSF, 10 stool, and 8
sterile body fluid infections. The remaining infections were respiratory and soft tissue
infections. A summary of the isolated organisms is in Supplementary Table 2. The most
common bacterial species were streptococcal (n = 42), staphylococcal (n = 25), and Gram-
negative species (n = 66), of which 19 patients had Escherichia coli infections. Among those
with a viral infection, 47 had a respiratory illness with rhinovirus isolated in 36% (n = 17)
and respiratory syncytial virus isolated in 21% (n = 10). Two patients had enterovirus
meningitis, and 1 had cytomegalovirus viremia. There were 4 children with bacterial diarrhea
for which antibiotic treatment is not recommended. Of the patients with a bacterial infection
for which antibiotic treatment is indicated, 145 (72%) of the bacterial pathogens were
sensitive to ceftriaxone, which is the empiric antibiotic therapy recommended in the PCH ED
septic shock guideline.

Table 2 compares demographic and clinical features of patients who received empiric
antibiotics in ≤1 hour (N = 153) to those treated later (N = 168). Those treated in ≤1 hour
were more likely to receive initial resuscitation compliant with the SSC guidelines (61% vs
14%). They also had significantly greater risk of mortality estimated by PIM2 score, but
neither mortality (7% vs 4%) nor development of NP-MODS (9% vs 12%) differed
significantly from those treated after 1 hour. This nonsignificant relationship was also found
among the subset of the cohort for whom antibiotic treatment is indicated, with mortality
rates 11% vs 6% (relative risk [RR], 1.65; 95% confidence interval [CI], 0.65–4.18) and
development of NP-MODS 15% vs 18% (RR, 0.81; 95% CI, 0.43–1.51), among those treated
in ≤1 hour vs after 1 hour, respectively.

Table 2.
Comparison of Demographic and Clinical Features of Patients Who Received
Empiric Antibiotics in ≤1 Hour or Longera

Empiric Antibiotics Empiric Antibiotics

Variable ≤1 Hour N = 153 >1 Hour N = 168 PValue

Age years 5.0 (1.3, 12.9) 6.1 (1.1, 13.1) .79

Minutes to initial 40 (22, 50) 95 (75, 138) <.001

 Empiric Antibiotics Empiric Antibiotics
Variable ≤1 Hour N = 153 >1 Hour N = 168 PValue

antibiotics

Any CCC 54 (35) 50 (30) .30

Infection Type .01

Bacterial 77 (50) 77 (46)

Presumed bacterial 18 (20) 33 (12)

Viral 18 (12) 32 (19)

No infectious source
identified 40 (26) 26 (16)

ED care compliant with

sepsis guidelines 94 (61) 23 (14) <.001

PIM2 in ED 1.9 (1.3, 4.7) 1.3 (1.0, 3.5) .001

Mechanical ventilation 55 (36) 47 (28) .13

Vasoactive medications 53 (35) 48 (29) .24

PICU length of stay 2.1 (0.8, 6.1) 1.6 (0.9, 3.6) .10

Hospital length of stay 6.9 (3.0, 12.4) 4.7 (3.0, 9.6) .10

Death 10 (7) 7 (4) .34

Greatest organ dysfunction

on any PICU day 1 (1, 2) 1 (1, 2) .04

NP-MODS 14 (9) 20 (12) .42

Abbreviations: CCC, complex chronic condition; ED, emergency department; IQR,

interquartile range; MODS, multiple organ dysfunction syndrome; NP-MODS,
new or progressive multiple organ dysfunction syndrome; PICU, pediatric
intensive care unit; PIM2, pediatric index of mortality 2.
a Data are presented as either n (%) or median (IQR).
Table 3 compares patients with bacterial infections for which antibiotic treatment is indicated
who received early appropriate antibiotics in ≤1 hour (N = 67) to those treated after 1 hour
(N = 134). This excludes patients with viral infections and no source of infection identified as
well as those with bacterial infections for which treatment is not recommended (n = 4). Those
receiving appropriate antibiotics in ≤1 hour were also more likely to receive initial
resuscitation compliant with the SSC guidelines (69% vs 17%). They also had significantly
greater risk of mortality estimated by PIM2 score and higher rates of mechanical ventilation.
However, when adjusting for severity of illness using PIM2, neither mortality (10% vs 6%)
nor development of NP-MODS (15% vs 15%) differed significantly between groups.

Table 3.
Comparison of Demographic and Clinical Features of Patients Who Received
Appropriate Antibiotics in ≤1 Hour or Longera,b

Appropriate Appropriate
Antibiotics ≤1 Hour N Antibiotics >1 Hour N
Variable = 67 = 134 PValue

Age years 4.7 (1, 13.1) 6.3 (1.4, 13.4) .38

Minutes to appropriate
antibiotics 43 (26, 53) 153 (95, 329) <.01

Any CCC [12] 25 (37) 36 (27) .13

Infection Type .08

Bacterial 56 (84) 95 (71)

Presumed bacterial 11 (16) 37 (28)

ED care compliant with

sepsis guidelines 46 (69) 23 (17) <.001

PIM2 in ED 2.2 (1.4, 5.0) 1.4 (1.0, 2.7) <.001

PIM2 in PICU 1.4 (1.1, 5.7) 1.2 (1.0, 3.4) <.03

Mechanical ventilation 34 (52) 41 (31) .005

 Appropriate Appropriate
Antibiotics ≤1 Hour N Antibiotics >1 Hour N
Variable = 67 = 134 PValue

Vasoactive medications 26 (39) 48 (36) .68

ICU length of stay 2.5 (0.9, 7.6) 1.6 (0.9, 4.0) .12

Hospital length of stay 8.9 (3.8, 14.2) 6.0 (3.7, 11.3) .13

Death 7 (10) 6 (6) .27c

Greatest organ
dysfunction on any
PICU day 2 (1, 3) 1 (1,2) .005

NP-MODS 10 (15) 20 (15) .89c

Abbreviations: CCC, complex chronic condition; ED, emergency department; ICU,

intensive care unit; IQR, interquartile range; MODS, multiple organ dysfunction
syndrome; NP-MODS, new or progressive multiple organ dysfunction syndrome;
PICU, pediatric ICU; PIM2, pediatric index of mortality 2.
a Data are presented as either n (%) or median (IQR).
bInfections for which antibiotics are not recommended such as shigellosis are
excluded n = 4.
c Adjusted for PIM2 in ED.

Figure 1a compares development of NP-MODS in the ICU by hours elapsed to

empiric antibiotic treatment among all patients (including patients with viral
infections and no source identified). Almost half (n = 153) of patients received
empiric antibiotics within 1 hour, 118 (37%) between 1 and 2 hours, 26 (8%)
between 2 and 3 hours, 10 (3%) between hours 3 and 4, and 14 (4%) in greater
than 4 hours. In total, 93% of patients received antibiotics within 3 hours of
presentation. When comparing hourly interval to empiric antibiotics, there were no
significant differences in development of NP-MODS.
Figure 1.

View largeDownload slide

(a) Empiric antibiotic timing and development of new or progressive multiple organ dysfunction syndrome (NP-
MODS). Patients who developed NP-MODS versus time from emergency department arrival to empiric
antibiotics in hourly increments among all patients. The percentage of patients who developed NP-MODS
(lighter portion) within each hour are reflected numerically above each bar. (b) Appropriate antibiotic timing
and development of new or progressive multiple organ dysfunction syndrome (NP-MODS). Patients who
developed NP-MODS versus time from emergency department arrival to appropriate antibiotics in hourly
increments among patients with an infection for which antibiotics are recommended. This cohort is a subset of
the study cohort and appropriateantibiotic administration may have required additional or changed drug from
that empirically administered. The percentage of patients who developed NP-MODS (lighter portion) within
each hour are reflected numerically above each bar.

Figure 1b compares development of NP-MODS by hours elapsed until appropriate antibiotic

treatment among the subset of patients with infections for which treatment is recommended.
Sixty-seven (33%) patients received appropriate antibiotics within 1 hour, 56 (28%) patients
between 1 and 2 hours, 16 (8%) patients between 2 and 3 hours, 15 (7%) patients between
hours 3 and 4, and 47 (23%) in greater than 4 hours. When comparing hourly interval to
appropriate antibiotics, there were no significant differences in development of NP-MODS.

DISCUSSION

Almost two thirds of children with septic shock admitted to the PICU from the ED had a
definite or presumed bacterial infection. Among all children, those receiving empiric
antibiotics ≤1 hour were significantly more severely ill at presentation to the ED but did not
differ with respect to NP-MODS or mortality compared with those treated later. Among those
with an infection treatable by antibiotics, children receiving appropriate antibiotics in ≤1
hour were also significantly more severely ill at presentation to the ED but did not have
greater rates of NP-MODS or mortality compared with those treated later.

Patients with bacterial infections had greater illness severity at presentation, were more likely
to receive antibiotics in ≤1 hour and resuscitation in compliance with the SSC guidelines,
and had significantly greater NP-MODS compared with children with viral infections or no
infectious source identified. They also had significantly longer lengths of hospital stay. This
is likely related to the pathophysiology of bacterial infections with greater activation of an
inflammatory response [21, 22]. This is also consistent with other studies showing culture-
positive bacterial infections associated with increased morbidity [23].
Among those with bacterial infections as the etiology of septic shock, the majority (72%) of
isolates were sensitive to empiric therapy. This is similar to a report by Weiss et al [24] who
showed that the majority (78%) of pediatric septic shock patients treated in a single children's
hospital also received appropriate initial antibiotic therapy.

We hypothesized that rapid administration (≤1 hour) of empiric antibiotics would be

associated with decreased NP-MODS. We were surprised to find that although children
treated in ≤1 hour presented more severely ill, they were more likely to receive SSC
compliant care and had similar risk of NP-MODS and death compared with those treated
later. Failure to demonstrate a benefit from timely empiric antibiotics may be due to
increased error in measurement of patients likely to benefit from the exposure because only
62% had an infection for which antibiotics would be expected to improve the child's status.

We also tested whether rapid appropriate antibiotic administration was associated with
decreased risk of NP-MODS. Again, we found that children treated in ≤1 hour were more
severely ill at presentation to the ED compared with those with delayed antibiotics, but there
were no statistical differences in development of NP-MODS or mortality by time of antibiotic
administration or type of infection (presumed or culture positive bacterial infections). Our
findings differ from the majority of reports involving adult patients, showing delay to
appropriate antibiotic administration and increased mortality [23, 25–27]. The recent study by
Weiss et al [24] of children with septic shock suggested improved mortality and patient
outcomes if appropriate antibiotic therapy was delivered within 3 hours of shock recognition.
We did not find a similar mortality benefit.

Our study has important differences compared with the report by Weiss et al [24]. The
majority of our patients received antibiotics in ≤3 hours (93% vs 60%), and receipt of
appropriate antibiotics in ≤1 hour was almost 3 times greater in our patients (33% vs 12%)
[11]. Although both cohorts had similar rates of comorbid conditions and similar rates and
infection types, the overall mortality (5% vs 12%, P= .08), support with mechanical
ventilation (32% vs 62%, P < .001), receipt of vasoactive medications (31% vs 74%, P <
.001), and ICU length of stay (2 vs 9 median days), were all greater in the previous report.
However, we included only patients directly admitted to the PICU from the ED, used a
slightly different definition of septic shock (ACCM/PALS [9] vs Goldstein et al [10]), and
our patients had lower risk of mortality measured by PIM2 scores on presentation to the ICU
after treatment in the ED. Thus, our patients may have been less severely ill at recognition of
shock, but they also likely benefitted from more rapid treatment, as evidenced by lack of
disease progression toward NP-MODS and death. More importantly, because the majority of
our patients received antibiotics in <3 hours, we had inadequate power to determine a
difference at the 3-hour cutoff.

Our study has several limitations. First, as a retrospective study evaluating appropriate
antibiotic choices, we recognize that it is not always possible to predict the pathogen and
appropriate antibiotic choice in real time. Second, because this is a single-center study, results
may not be generalizable to other care settings. Third, there is a link between early receipt of
antibiotics and the delivery of care consistent with the SSC guidelines, suggesting that
clinical assessment of illness severity drives the intensity of care and is likely linked to
subsequent development of NP-MODS and mortality. Larger, multicenter studies are needed
to identify the ideal time goal for early appropriate antibiotic therapy that impacts pediatric
patient outcomes.

CONCLUSIONS

More than half of children presenting to the ED with septic shock requiring intensive care
had a definite or presumed bacterial infection, and the recommended empiric antibiotic
treatment at our hospital was appropriate in 72% of cases. Those treated with appropriate
antibiotics in ≤1 hour were more ill when presenting to the ED with greater PIM2 scores, but
they were also more likely to receive rapid resuscitation compliant with SSC guidelines.
Despite increased illness severity on presentation, patients treated in ≤1 hour did not have an
increased disease progression as quantified by NP-MODS or death. Because the natural
history of untreated septic shock is development of multiple organ failure and death, our
findings support the premise that early recognition and treatment of shock, including
administration of timely, appropriate antibiotics, remains pivotal.

Supplementary Data

Supplementary materials are available at the Journal of The Pediatric Infectious Diseases
Society online (http://jpids.oxfordjournals.org).

Acknowledgments
We thank Dr. Roni Lane (Department of Pediatrics, University of Utah) for outstanding
leadership of the Primary Children's Sepsis Work group and careful review of this
manuscript. We also thank Tanya Stout (Primary Children's Hospital, Department of Systems
Improvement) for contributions to the septic shock database used in this study.

Disclaimer. S. G. A. had full access to all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data analysis.

Financial support. This work was supported in part by the Primary Children's Foundation
Clinical Excellence Grants Program, which provided support for data collection and
management.

Potential conflicts of interest. All authors: No reported conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

References
1
Watson

RS

,
Carcillo

JA

,
Linde-Zwirble

WT

et al.
.
The epidemiology of severe sepsis in children in the United States
.
Am J Respir Crit Care Med

2003
;
167
:
695
–
701
.
Google Scholar
Crossref
PubMed

2
Hartman

ME

,
Linde-Zwirble

WT

,
Angus

DC

,
Watson

RS

.
Trends in the epidemiology of pediatric severe sepsis
.
Pediatr Crit Care Med

2013
;
14
:
686
–
93
.
Google Scholar
Crossref
PubMed

3
Balamuth

,
Weiss

SL

,
Neuman

MI

et al.
.
Pediatric severe sepsis in U.S
.
children's hospitals. Pediatr Crit Care Med

2014
;
15
:
798
–
805
.
Google Scholar
Crossref

4
Kutko

MC

,
Calarco

MP

,
Flaherty

MB

et al.
.
Mortality rates in pediatric septic shock with and without multiple organ system failure
.
Pediatr Crit Care Med

2003
;
4
:
333
–
7
.
Google Scholar
Crossref
PubMed

5
Rivers

,
Nguyen

,
Havstad

et al.
.
Early goal-directed therapy in the treatment of severe sepsis and septic shock
.
N Engl J Med

2001
;
345
:
1368
–
77
.
Google Scholar
Crossref
PubMed

6
Dellinger

RP

,
Levy
MM

,
Rhodes

et al.
.
Surviving sepsis campaign: international guidelines for management of severe sepsis and
septic shock: 2012
.
Crit Care Med

2013
;
41
:
580
–
637
.
Google Scholar
Crossref
PubMed

7
Kumar

,
Ellis

,
Arabi

et al.
.
Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in
human septic shock
.
Chest

2009
;
136
:
1237
–
48
.
Google Scholar
Crossref
PubMed

8
Larsen

GY

,
Mecham

,
Greenberg

.
An emergency department septic shock protocol and care guideline for children initiated at
triage
.
Pediatrics

2011
;
127
:
e1585
–
92
.
Google Scholar
Crossref
PubMed

9
Zaritsky

AL

,
Nadkarni
V

,
Hickey

RW

et al.
.
2005 American Heart Association (AHA) guidelines for cardiopulmonary resuscitation
(CPR) and emergency cardiovascular care (ECC) of pediatric and neonatal patients: pediatric
basic life support
.
Pediatrics

2006
;
117
:
e989
–
1004
.
Google Scholar
Crossref
PubMed

10
Goldstein

,
Giroir

,
Randolph

.
International pediatric sepsis consensus conference: definitions for sepsis and organ
dysfunction in pediatrics
.
Pediatr Crit Care Med

2005
;
6
:
2
–
8
.
Google Scholar
Crossref
PubMed

11
Brierley

,
Carcillo

JA

,
Choong

et al.
.
Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock:
2007 update from the American College of Critical Care Medicine
.
Crit Care Med

2009
;
37
:
666
–
88
.
Google Scholar
Crossref
PubMed

12
Kuch

BA
,
Carcillo

JA

,
Han

YY

,
Orr

RA

.
Definitions of pediatric septic shock
.
Pediatr Crit Care Med

2005
;
6
:
501
.
Google Scholar
Crossref
PubMed

13
Centers for Disease Control and Prevention
.
CDC/NHSN Surveillance Definitions for Specific Types of Infections Website
.
Available at: http://www.cdc.gov/nhsn/PDFs/pscManual/17pscNosInfDef_current.pdf
.
Accessed December 1, 2014
.
14
Solomkin

JS

,
Mazuski

JE

,
Bradley

JS

et al.
.
Diagnosis and management of complicated intra-abdominal infection in adults and children:
guidelines by the Surgical Infection Society and the Infectious Diseases Society of America
.
Clin Infect Dis

2010
;
50
:
133
–
64
.
Google Scholar
Crossref
PubMed

15
Bradley

JS

,
Byington

CL

,
Shah

SS

et al.
.
The management of community-acquired pneumonia in infants and children older than 3
months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and
the Infectious Diseases Society of America
.
Clin Infect Dis

2011
;
53
:
e25
–
76
.
Google Scholar
Crossref
PubMed

16
Stevens

DL

,
Bisno

AL

,
Chambers

HF

et al.
.
Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014
update by the Infectious Diseases Society of America
.
Clin Infect Dis

2014
;
59
:
e10
–
52
.
Google Scholar
Crossref
PubMed

17
Proulx

,
Fayon
M

,
Farrell

et al.
.
Epidemiology of sepsis and multiple organ dysfunction syndrome in children
.
Chest

1996
;
109
:
1033
–
7
.
Google Scholar
Crossref
PubMed

18
Doughty

,
Carcillo

,
Kaplan

et al.
.
The compensatory anti-inflammatory cytokine interleukin 10 response in pediatric sepsis-
induced multiple organ failure
.
Chest

1998
;
113
:
1625
–
31
.
Google Scholar
Crossref
PubMed

19
Lacroix

,
Hébert

PC

,
Hutchison

JS

et al.
.
Transfusion strategies for patients in pediatric intensive care units
.
N Engl J Med

2007
;
356
:
1609
–
19
.
Google Scholar
Crossref
PubMed

20
Feudtner

,
Christakis
DA

,
Connell

FA

.
Pediatric deaths attributable to complex chronic conditions: a population-based study of
Washington State, 1980–1997
.
Pediatrics

2000
;
106
:
205
–
9
.
Google Scholar
PubMed

21
Lisboa

,
Seligman

,
Diaz

et al.
.
C-reactive protein correlates with bacterial load and appropriate antibiotic therapy in
suspected ventilator-associated pneumonia
.
Crit Care Med

2008
;
36
:
166
–
71
.
Google Scholar
Crossref
PubMed

22
Deis

JN

,
Creech

CB

,
Estrada

CM

,
Abramo

TJ

.
Procalcitonin as a marker of severe bacterial infection in children in the emergency
department
.
Pediatr Emerg Care

2010
;
26
:
51
–
60
.
Google Scholar
Crossref
PubMed

23
Gaieski

DF
,
Mikkelsen

ME

,
Band

RA

et al.
.
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
.
Crit Care Med

2010
;
38
:
1045
–
53
.
Google Scholar
Crossref
PubMed

24
Weiss

SL

,
Fitzgerald

JC

,
Balamuth

et al.
.
Delayed antimicrobial therapy increases mortality and organ dysfunction duration in pediatric
sepsis
.
Crit Care Med

2014
;
42
:
2409
–
17
.
Google Scholar
Crossref
PubMed

25
Kumar

,
Roberts

,
Wood

KE

et al.
.
Duration of hypotension before initiation of effective antimicrobial therapy is the critical
determinant of survival in human septic shock
.
Crit Care Med

2006
;
34
:
1589
–
96
.
Google Scholar
Crossref
PubMed

26
Paul
M

,
Shani

,
Muchtar

et al.
.
Systematic review and meta-analysis of the efficacy of appropriate empiric antibiotic therapy
for sepsis
.
Antimicrob Agents Chemother

2010
;
54
:
4851
–
63
.
Google Scholar
Crossref
PubMed

27
Varula

,
Karisson

,
Parvianinen

et al.
.
Community-acquired septic shock: early management and outcome in a nationwide study in
Finland
.
Acta Anaesthesiol Scand

2007
;
51
:
1320
–
6
.
Google Scholar
Crossref
PubMed

28
Ferrer

,
Martin-Loeches

,
Phillips

et al.
.
Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first
hour: results from a guideline-based performance improvement program
.
Crit Care Med

2014
;
42
:
1749
–
55
.