American Journal of Emergency Medicine 44 (2021) 56–61

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American Journal of Emergency Medicine

journal homepage: www.elsevier.com/locate/ajem

Treatment of suspected sepsis and septic shock in children with chronic

disease seen in the pediatric emergency department
Emily Hegamyer ⁎, Nadine Smith, Amy D. Thompson, Andrew D. Depiero
Division of Emergency Medicine, Department of Pediatrics, Nemours, Alfred I. Dupont Hospital for Children. 1600 Rockland Road, Wilmington, DE 19803, United States of America

a r t i c l e i n f o a b s t r a c t

Article history: Background: Research demonstrates that timely recognition and treatment of sepsis can significantly improve pe-
Received 2 November 2020 diatric patient outcomes, especially regarding time to intravenous fluid (IVF) and antibiotic administration. Fur-
Received in revised form 10 January 2021 ther research suggests that underlying chronic disease in a septic pediatric patient puts them at higher risk for
Accepted 11 January 2021 poor outcomes.
Objective: To compare treatment time for suspected sepsis and septic shock in pediatric patients with chronic dis-
ease versus those without chronic disease seen in the Pediatric Emergency Department (PED).
Keywords:
Sepsis
Methods: We reviewed patient data from a pediatric sepsis outcomes dataset collected at two tertiary care pedi-
Pediatric atric hospital sites from January 2017–December 2018. Patients were stratified into two groups: those with and
Chronic disease without chronic disease, defined as any patient with at least one of eight chronic health conditions. Inclusion
Intravenous access criteria: patients seen in the PED ultimately diagnosed with sepsis or septic shock, patient age 0 to 20 years
Antimicrobial therapy and time zero for identification of sepsis in the PED. Exclusion criteria: time zero unavailable, inability to deter-
Fluid resuscitation mine time of first IVF or antibiotic administration or patient death within the PED. Primary analysis included
comparison of time zero to first IVF and antibiotic administration between each group.
Results: 312 patients met inclusion criteria. 169 individuals had chronic disease and 143 did not. Median time to
antibiotics in those with chronic disease was 41.9 min versus 43.0 min in patients without chronic disease (p =
0.181). Time to first IVF in those with chronic disease was 22.0 min versus 12.0 min in those without (p = 0.010).
Those with an indwelling line/catheter (n = 40) received IVF slower than those without (n = 272), with no sig-
nificant difference in time to antibiotic administration by indwelling catheter status (p = 0.063). There were no
significant differences in the mode of identification of suspected sepsis or septic shock between those with versus
without chronic disease (p = 0.27).
Conclusions: Study findings suggest pediatric patients with chronic disease with suspected sepsis or septic shock
in the PED have a slower time to IVF administration but equivocal use of sepsis recognition tools compared to pa-
tients without chronic disease.
© 2021 Elsevier Inc. All rights reserved.

1. Background recognition and treatment of pediatric sepsis and its role in improving
overall outcomes [7-10].
Pediatric sepsis is a leading cause of morbidity, mortality and The principle of early recognition and treatment of pediatric sepsis
healthcare utilization worldwide. Globally, there are 1.2 million cases has since become the basis for the development of multiple sepsis rec-
of pediatric sepsis annually with sepsis accounting for more than 4% of ognition tools in use across the United States within Pediatric Emer-
all pediatric hospitalizations in high-income countries [1-6]. The major- gency Departments (PED), which are often centered on abnormal vital
ity of pediatric patients who die from sepsis present with or develop re- signs suggestive of impending shock or end organ dysfunction [11,12].
fractory shock or multiple organ dysfunction and death occuring within Several research studies have demonstrated that timely recognition
48 to 72 h of treatment, underscoring the significance of early and treatment of pediatric sepsis with the help of these tools within
the PED can significantly improve patient outcomes, in particular in
regards to expedient administration of intravenous fluids (IVF) and an-
tibiotics [11,12]. Both early administration of antimicrobrials and rapid
⁎ Corresponding author.
E-mail addresses: [email protected] (E. Hegamyer),
volume resuscitation strategies within one hour of septic shock recogni-
[email protected] (N. Smith), [email protected] (A.D. Thompson), tion have been established as two key factors in the initial treatment of
[email protected] (A.D. Depiero). pediatric sepsis influencing patient outcomes, including both mortality

https://doi.org/10.1016/j.ajem.2021.01.026
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E. Hegamyer, N. Smith, A.D. Thompson et al. American Journal of Emergency Medicine 44 (2021) 56–61

rate and hospital length of stay [3,6,7,13-16]. These treatments are often in EHR, time of initiation of sepsis order set, time of first antibiotic ad-
prompted by early recognition of septic shock or organ dysfunction due ministration and first IVF bolus administration and chronic disease sta-
to sepsis recognition tools demonstrating clinical and vital signs tus. Every patient chart was reviewed in detail within the EHR by study
changes [12,17-25]. staff to evaluate for both inclusion and exclusion criteria and to confirm
In addition to early administration of both IVF and antibiotics, under- all documentation within the original sepsis outcomes data set.
lying patient risk factors such as high-risk medical conditions are For this study, patients were stratified into one of two groups: those
another key variable influencing pediatric sepsis outcomes, often with chronic disease and those without chronic disease. The health con-
also integrated within electronic health record (EHR) sepsis alerts ditions of those patients defined as having chronic disease were
along with vital sign abnormalities. This includes chronic disease, predetermined by the IPSO collaborative guidelines set forth for the in-
encompassing the pediatric population of individuals with at least one stitutional sepsis outcomes data set and include the following condi-
significant chronic condition in two or more body systems or those tions: malignancy, asplenia (including all sickle cell disease patients),
with a single dominant chronic condition [26]. Overall, comorbid illness bone marrow transplant, indwelling catheter (defined as any central ve-
was present in 34% of all children hospitalized for sepsis in the United nous line including peripherally inserted central catheters), solid organ
States between 2004 and 2012 with multiple comorbid illnesses identi- transplant, immunocompromised, severe mental retardation cerebral
fied as a key factor associated with higher odds of both mortality palsy (MRCP) and technology dependence (defined as an individual
and longer hospital length of stay [2]. Additionally, multiple research with tracheostomy, ventriculoperitoneal shunt or enteral feeding tube).
studies have shown that chronically ill children have a higher overall Study participants were classified as those with versus without
burden of disease from sepsis with a higher risk for poor outcomes chronic disease through detailed chart review by study staff, who
[3,6,7,13,14,27]. Thus the importance of a prioritized mechanism for reviewed the EHR and medical history for each individual to identify un-
the early recognition and treatment of suspected sepsis or septic derlying medical conditions. Each medical condition was then catego-
shock in pediatric chronic disease patients is evident, as it may signifi- rized into any of the applicable eight chronic disease conditions (e.g. a
cantly impact overall outcomes for these individuals. leukemia patient with a central line falls into the categories of malig-
The primary objective of this study is determination of the degree to nancy, indwelling catheter and immunocompromised). Any individual
which this optimization of sepsis treatment of patients with chronic dis- with at least one of these eight health conditions was classified in this
ease is currently taking place in the Pediatric Emergency Department. study as an individual with chronic disease.
This study compares the initial time to first IV fluid bolus and IV antibi- The primary outcome of the study was to examine the time to first
otic administration for suspected sepsis or septic shock between pediat- IVF bolus and time to first intravenous antibiotic administration from
ric patients age 0 to 20 years old with chronic disease and those without functional time zero of suspected sepsis or septic shock identification
chronic disease. in the PED in those with chronic disease versus those without chronic
disease. Functional time zero for identification of suspected sepsis or
2. Methods septic shock was defined as the first time in which concern for sepsis
or septic shock occurred and for this study includes the following five
This study was a multi-site retrospective study including patients categories considered to be key markers for process improvement re-
seen in the PED of two pediatric tertiary care center sites. Both sites garding pediatric sepsis outcomes: sepsis screen prompt in EHR based
are suburban free standing tertiary care children's hospitals, each with on the patient's shock score (prompted by a shock score of ≥45 and in-
a separate PED, one of which is located in Wilmington, DE with a yearly cludes text box with suggestion to consider sepsis in the patient and di-
PED volume of 60,000 patients and the other in Orlando, FL with a yearly rect link to sepsis order set), sepsis huddle (prompted by a shock score
PED volume of approximately 40,000. of ≥45 and often initiated by the bedside RN, requiring bedside evalua-
Data for this study were part of an institution wide pediatric sepsis tion and documentation in the EHR by both the attending physician
outcomes data set collected at each site from January 2017 through De- and bedside RN), sepsis order set initiation (includes laboratory, intra-
cember 2018. The information within the data set was initially extracted venous fluid and antibiotic orders), first antibiotic administration or
by a researcher whose primary role within both institutions is to obtain first IVF bolus administration. The shock score for each patient is
patient information for the sepsis outcomes data set from the EHR using based primarily on institutional vital sign parameters determined by a
predetermined institutional guidelines with specifications of which multidisciplinary committee across both study sites with five extra
data points to include. The same EHR system is used at both study sites. points added if patient is labeled to have a “complex medical history”
The sepsis outcomes data set includes all Pediatric Emergency De- within the EHR. Vital sign parameters and shock score calculation
partment patients seen from January 2017 through December 2018 at were the same at both study sites. The functional time zero documented
both study sites, with individual patient encounters initially extracted for each patient encounter within our study data set was based on
from the EHR using a set of eight inclusion criteria to capture patients which of the aforementioned five categories occurred first in the PED,
with suspected sepsis or septic shock [28]. These criteria are reflective identified upon chart review within the EHR by study staff as the pre-
of the sepsis definitions as determined by a multidisciplinary national sumed first moment at which a medical provider suspected sepsis or
expert advisory committee of the Children's Hospital Association's Im- septic shock.
proving Pediatric Sepsis Outcomes (IPSO) collaborative and include Secondary outcome measures included goal met of first IVF bolus
the following: positive sepsis screen plus treatment, positive sepsis hud- and antibiotic administration within 60 min of the time at which sepsis
dle, severe sepsis order set use or other infectious disease order set use or septic shock was suspected (i.e. functional time zero) in those with
plus treatment, ICU admission plus treatment, lactate measured plus chronic disease versus those without chronic disease and time to first
treatment, pressor plus treatment, or severe sepsis/septic shock ICD- IVF bolus and antibiotic administration in those with an indwelling
10 codes or other sepsis ICD-10 codes plus treatment where treatment catheter versus those without an indwelling catheter. Data were also
is defined as IV antibiotics and two boluses or one bolus and pressor analyzed to determine if there was a statistically significant difference
within six hours and blood culture within 72 h of antibiotics and boluses between the number of underlying chronic medical conditions and
(or bolus/pressor) [28]. Any patient meeting at least one set of criteria the time to first IVF bolus and antibiotic administration after functional
was included in the data set. time zero.
Data points for each patient encounter included in this study were Inclusion criteria for this study were any patient seen in the PED
abstracted from the institution wide pediatric sepsis outcomes data with suspected sepsis or septic shock based on at least 1 of the 8 criteria
set and include, if applicable: patient age, time of arrival to the Emer- as defined by the sepsis outcomes data set [28], in addition to functional
gency Department, sepsis huddle time, time of sepsis screen prompt time zero for identification of sepsis or septic shock occurring in the PED

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E. Hegamyer, N. Smith, A.D. Thompson et al. American Journal of Emergency Medicine 44 (2021) 56–61

and patient age from 0 to 20 years old. Multiple patient encounters for Table 1
the same individual were included in this study if the appropriate inclu- Age of Study Participants

sion criteria were met. Chronic Disease No Chronic Disease P valuea

Exclusion criteria included any patient who bypassed the PED, death n (%) n (%)
within the PED, functional time zero for suspected sepsis or septic shock Age 0.000
occurring outside the PED, or inability to determine functional time 0d to <1y 4 (2.4) 32 (22.4)
zero, time of first IVF bolus or first antibiotic administration. Addition- 1y to <5y 31 (18.3) 37 (25.9)
5y to <13y 86 (50.9) 39 (27.3)
ally, patients transferred from outside facilities were excluded given
13y to 20y 48 (28.4) 35 (24.5)
the inability to reliably confirm documentation of antibiotic and IVF ad- Total, N 169 143
ministration prior to PED arrival. Patients were also excluded if they re- a
P-value based on Pearson Chi-Square test
ceived antibiotics in the PED prior to functional time zero, but not if they
received intravenous fluids.
Descriptive statistical analysis is presented as medians with inter-
Table 2
quartile ranges for continuous variables. Continuous variables were
Chronic disease subcategory.
compared with the Wilcoxon rank sum test and categorical variables
with the Pearson Chi Square test. Statistical software used for data anal- Chronic Disease Category Total (N, % of Chronic Disease patients)
ysis is R (version 3.6.1) and SPSS Statistics (version 25). This study was Severe MRCP a
114 (67.4)
approved by the Nemours Institutional Review Board (IRB) Committee. Technology Dependentb 114 (67.4)
Indwelling Catheterc 40 (23.7)
Immunocompromised 39 (23.1)
Malignancy 25 (14.8)
3. Results
Solid Organ Transplant 9 (5.3)
Aspleniad 6 (3.6)
A total of 368 patients seen in the Pediatric Emergency Department Bone Marrow Transplant 1 (0.5)
across both study sites were initially identified from the study data set a
Severe mental retardation/cerebral palsy
as potential participants in this study. Three hundred and twelve indi- b
Defined as an individual with tracheostomy, ventriculoperitoneal shunt or enteral
viduals ultimately met inclusion criteria, 169 of whom had chronic dis- feeding tube
c
ease and 143 without chronic disease (Fig. 1). Table 1 provides age Defined as any central venous line including peripherally inserted central catheter
d
Includes all sickle cell disease patients
specific demographic information of those patients with versus without
chronic disease in this study population, demonstrating that the older
the patient the more likely they are to have chronic disease (p = 0.000).
Among those patients with chronic disease, the majority (N = 114, the second and third most commonly used categories of functional
67.4%) had severe mental retardation cerebral palsy (MRCP), technol- time zero, respectively. The sepsis huddle was initiated among 10.7%
ogy dependence or both. Twenty-three percent (N = 40) of patients (N = 18) of patients with chronic disease versus 17.5% (N = 25) pa-
had an indwelling catheter and thirty-nine patients (23.1%) were im- tients without chronic disease. Only 9.1% (N = 13) of patients without
munocompromised. Twenty-five patients (14.8%) had an underlying chronic disease had the sepsis order set initiated versus 11.2% (N =
malignancy while the rest of patients fell into one of the final three cat- 19) of those with chronic disease. There was no significant difference
egories, including prior bone marrow transplant, asplenia and/or prior found between those with chronic disease versus without chronic dis-
history of solid organ transplant (Table 2). ease in relationship to any of the five categories of functional time
Data were examined looking at each of the five categories for func- zero (p = 0.27). See Fig. 2.
tional time zero in those with chronic disease versus those without One of the key areas of focus for this study was the time from func-
chronic disease. The most frequently identified functional time zero tional time zero to actual administration of first IVF bolus and antibiotic
was the sepsis screen EHR prompt based on patient shock score with administration among the two patient groups. The median time to first
35.5% (N = 60) use among those with chronic disease and 32.2% IVF bolus administration from functional time zero in those with
(N = 46) use in those without chronic disease. This was followed by chronic disease was longer (22.0 min) than for those patients without
the time of first IVF bolus and time of first antibiotic administration as chronic disease (12.0 min), a statistically significant difference (p =

Fig. 1. Participant Inclusion and Categorization.

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E. Hegamyer, N. Smith, A.D. Thompson et al. American Journal of Emergency Medicine 44 (2021) 56–61

60 min from the time of identification of sepsis or suspected sepsis

within the PED.
With respect to the goal of first IVF bolus administration within
60 min, a higher percentage of patients without chronic disease 87.4%
(N = 125) met the IVF bolus administration goal versus the antibiotic
administration goal. Among those with chronic disease, 81.7% (N =
138) of patients met the goal for IVF bolus administration with an over-
all success rate of 84.3% (N = 263) among all patients. Again, there was
no significant difference in meeting the IVF bolus administration goal
among those with versus without chronic disease (p = 0.211).

4. Discussion
Fig. 2. Functional Time Zero Frequencies.
This multi-site retrospective study examined identification and
treatment of suspected sepsis or septic shock in pediatric ED patients
with and without chronic disease, as those patients with underlying
0.010). The time to first antibiotic administration from functional time chronic disease carry a higher burden of disease from sepsis and argu-
zero was shorter (41.9 min) in those patients with chronic disease ver- ably require at least equivocal if not more aggressive recognition and
sus those patients without chronic disease (43.0 min), which was not a treatment for sepsis than non-chronic disease patients in the PED
significant difference (Table 3). [3,6,7,17,18]. Primary results from this study demonstrate a marginally
Among those patients with chronic disease, one specific factor often faster antibiotic administration time from functional time zero in the
felt to possibly influence time to administration of both IVF and antibi- PED among those patients with chronic disease, yet a significantly
otics in those with sepsis or suspected sepsis is the presence of an in- slower median time to first IVF bolus administration.
dwelling catheter. In this study it was found that the time from One significant factor that may influence the time to administration
functional time zero to first IVF bolus administration was longer of both antibiotics and the first IVF bolus is intravenous access, which is
(20.0 min) for patients with an indwelling catheter versus those with- often found to be more difficult among those patients with chronic dis-
out an indwelling catheter (16.5 min), although this difference is not ease and may in part explain the longer IVF administration time among
significant (p = 0.735). The opposite was noted in regards to first anti- these patients seen in this study. Another element to consider is the
biotic administration from functional time zero, with a median time of presence of an indwelling catheter, which was present in 23.7% of pa-
33.0 min to administration in those with an indwelling catheter versus tients in our study, meaning these individuals had pre-established intra-
43.0 min in those without an indwelling catheter (p = 0.063). See venous access prior to PED arrival. One might hypothesize that this
Table 4. would allow for faster intravenous access and earlier administration of
When examining the number of medical conditions present for each either IVF or antibiotics among these individuals. Yet IVF administration
participant, no significant difference in time to first antibiotic adminis- was actually longer in those patients with an indwelling catheter with
tration from functional time zero was found (p = 0.254), based on a no significant differences in either time to antibiotic or IVF administra-
subdivision of study participants into two comparison groups of those tion between those with and without an indwelling catheter. One expla-
with only one or no chronic medical condition versus those with greater nation may be the ease with which bedside staff are able to access an
than or equal to two conditions. There was a significant difference indwelling catheter versus placing a peripheral IV, as the process is
among these same patient groups in the time to first IVF bolus adminis- often a sterile procedure that needs to be performed by trained staff
tration from functional time zero with regard to the presence of either members. Overall, these results suggest that intravenous access in
one or no chronic medical conditions versus greater than or equal to those patients presenting with suspected sepsis or septic shock in the
two chronic medical conditions (p = 0.014). Those with only one or PED, albeit via an indwelling catheter or peripheral access, is a key
no chronic medical conditions received IVF faster than those with at area for improvement, particularly among those pediatric patients
least two underlying chronic medical conditions. See Fig. 3. with chronic disease.
Additionally, we further examined the institutional goal of both first The finding that overall time to antibiotic administration was almost
IVF bolus and antibiotic administration within 60 min of functional time twice as long as IVF in both those with and without chronic disease was
zero for patients with suspected sepsis or septic shock. When looking at unexpected. This is presumptively related to the easier availability of IVF
functional time zero to first antibiotic administration, the study demon- versus antibiotics in the PED, the latter in some cases requiring delivery
strated having met the goal among those with chronic disease in 68.6% from a location outside the Pediatric Emergency Department, such as a
(N = 116) of patients versus 51.4% (N = 55) of those patients without centralized hospital pharmacy. Additionally, the finding may reflect the
chronic disease. There was no significant difference between meeting decision by bedside clinical staff to first administer IVF versus antibi-
the 60 min goal of antibiotic administration between those with versus otics, assuming both were readily available. There was not a standard-
without chronic disease (p = 0.716). Overall, 67.6% (N = 211) of all ized protocol at either study site regarding the order of IVF versus
study participants met the goal of antibiotic administration within antibiotic administration, a decision which may also be influenced by

Table 3
Time to Antibiotic and IVF Administration in Patients With versus Without Chronic Disease

Chronic Disease (N = 169) No Chronic Disease (N = 143) P Valuea

b
Time Zero to Antibiotic
(minutes) 41.9 (17.5–73.0) 43.0 (26.0–81.9) p = 0.181
Time Zero to IVFb (minutes)
22.0 (1.0–50.0) 12.0 (0.0–29.0) p = 0.010
a
P-values based on Wilcoxon Rank Sum test.
b
Data presented as median values with interquartile range.

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E. Hegamyer, N. Smith, A.D. Thompson et al. American Journal of Emergency Medicine 44 (2021) 56–61

Table 4
Time to Antibiotic and IVF Administration in Patients With Indwelling Catheter versus Without Indwelling Catheter

Indwelling Catheter (N = 40) No Indwelling Catheter (N = 272) P Valuea

Time Zero to Antibioticb

(min) 33.0 (11.3–49.8) 43.0 (23.0–81.8) p = 0.063
Time Zero to IVF2 (min)
20.0 (0.0–45.5) 16.5 (0.0–39.8) p = 0.735
a
P-values based on Wilcoxon Rank Sum test
b
Data presented as median values with interquartile range

the presence of one versus multiple sites of intravenous access, data we Finally, while our study found no significant difference in the time
did not have available for this study. The access to and administration of from functional time zero to antibiotic administration for suspected
antibiotics should be an ongoing area for process improvement in the sepsis or septic shock between patients with none or one and those
PED, especially in regards to meeting goals for the early treatment of with two or more chronic medical conditions, there was a significant
suspected sepsis or septic shock. difference in time to IVF administration, with longer time to IVF admin-
Furthermore, we found no significant differences in meeting institu- istration in those with two or more chronic medical conditions. This is
tional goals for time to administration of IVF and antibiotics under reflective of the primary study results in which IVF administration
60 min between those with chronic disease versus those without from functional time zero was overall longer in those with chronic dis-
chronic disease. That being said, the institutional goals for antibiotic ease and suggests the possibility that increased medical complexity and
and IVF administration within 60 min were met only in 67.6% and certain conditions may affect these outcomes more than others (e.g.
84.3% of all participants, respectively. This again demonstrates contin- MRCP versus asplenia). We were unable to analyze the latter hypothesis
ued areas for overall improvement in early identification and treatment in depth within our particular study given the small number of patients
of suspected sepsis or septic shock within the PED, particularly in in each category of chronic disease among our participants, but this re-
regards to antibiotic administration. mains an area of potential interest for future studies.
The results of this study show no significant differences between
those patients with chronic disease versus those without in regards to 5. Limitations
the documented mode of identification for suspected sepsis or septic
shock (i.e. functional time zero), including a sepsis huddle, sepsis There were several limitations to this study. One limitation is the in-
order set, EHR prompt based on shock score or the time to first IVF clusion of both time to IVF bolus and antibiotic administration as a cat-
bolus or antibiotic administration. Thus there does not appear to be egory of functional time zero, with the concern that the distribution of
one method of identification for suspected sepsis or septic shock that median times would subsequently be towards lower values. To further
is utilized more frequently for those in the study population with evaluate this, we reanalyzed the data without including these two cate-
chronic disease. One may also extrapolate that those individuals with gories as a functional time zero and found no significant changes in the
chronic disease did not necessarily present with more vital sign abnor- study results in regards to significant differences and overall median
malities, as those modes of identification for suspected sepsis or septic values for time to administration of IVF and antibiotics.
shock based on shock score (i.e. abnormal vital signs) were not used An additional limitation to this study was the inability to examine
more frequently in a statistically significant manner among this patient the data by each chronic condition due to small sample size within
population in the study. each category. As referenced above, it may be possible, for example,

Fig. 3. Time to Antibiotic and IVF Administration versus Number of Chronic Disease Conditions *Greater than or equal to two conditions **Less than or equal to one condition.

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that the underlying condition of severe MRCP is a more significant factor [6] Schlapbach LJ, Straney L, Alexander J, et al. ANZICS Paediatric study group: mortality
related to invasive infections, sepsis, and septic shock in critically ill children in
in time to administration of IVF and antibiotic administration than Australia and New Zealand, 2002-13: a multicentre retrospective cohort study. Lan-
asplenia. cet Infect Dis. 2015;15:46–54.
Finally, this study had a relatively small sample size due to the rela- [7] Morin L, Ray S, Wilson C, et al. ESPNIC refractory septic shock definition taskforce the
infection systemic inflammation Sepsis section of ESPNIC: refractory septic shock in
tively small representation of pediatric sepsis patients in the PED pa- children: a European Society of Paediatric and Neonatal Intensive Care definition. In-
tient population in the two sites during the study's time frame. This tensive Care Med. 2016;42:1948–57.
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