Opinion
EDITORIAL
Context and Implications of the New Pediatric Sepsis Criteria
Erin F. Carlton, MD, MSc; Mallory A. Perry-Eaddy, PhD, RN; Hallie C. Prescott, MD, MSc
Sepsis has been recognized as an important cause of morbid-
ity and mortality for more than 2800 years.1 Derived from the
Greek word sepo (σηπω, translated as “I rot,”), sepsis appears in
writings of Homer, Hippocrates, Aristotle, and Galen.1,2 Concep-
tually, sepsis denotes a “line in
the sand” within the broad
Editorial spectrum of host-microbe in-
teractions. It indicates that not
Related articles only is the microbe unwanted
(in contrast to the many mi-
crobes that live on and within us and contribute to health and
digestion),3 but the host’s attempts to eradicate the microbe are
resulting in collateral damage.
Despite existing in the medical lexicon for millennia, sep-
sis was not formally defined until the 1992 American College
of Chest Physicians and Society of Critical Care Medicine
Consensus Conference.4 Now referred to as Sepsis-1, the sep-
sis definition was viewed by the consensus conference as an
overabundant inflammatory response to infection, a sys-
temic inflammatory response syndrome (SIRS), requiring 2 or
more abnormalities of temperature, heart rate, respiratory rate,
or white blood cell count. An updated definition in the early
2000s (Sepsis-2)5 expanded on the potential signs of an over-
abundant inflammatory response but was otherwise similar
to Sepsis-1.
Pediatric-specific sepsis criteria were subsequently
developed by an expert panel during the International Pedi-
atric Sepsis Consensus Conference (IPSCC) and published in
2005.6 Similar to adult definitions (Sepsis-1/2),4,5 pediatric
sepsis was defined by 2 or more SIRS criteria in the setting of
confirmed or suspected infection, with severe sepsis denot-
ing sepsis complicated by organ failure, and septic shock
indicating sepsis with severe cardiovascular dysfunction.
Acknowledging differences in pediatric physiology, the IPSCC
definitions diverged from adult criteria to require at least 1
SIRS criteria be abnormal temperature or white blood cell
count and to use age-specific SIRS criteria.
The adult sepsis definitions underwent a third update in
2016 (Sepsis-3), which departed from the SIRS-based
definition.7 Sepsis was reconceptualized as life-threatening
acute organ dysfunction secondary to a dysregulated host
response to infection. The prior notion of sepsis as an over-
abundant inflammatory response was deemed too narrow—a
recognition informed, in part, by dozens of negative trials of
anti-inflammatory agents to treat sepsis.8 At the same time,
SIRS criteria were removed from the definition because they
may merely reflect a noninjurious host response to infection.
In contrast to prior definitions based on expert consen-
sus, Sepsis-3 used a data-driven approach to select the crite-
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ria for organ dysfunction. After analyzing data from nearly 1
million patients treated in 177 hospitals, the panel recom-
mended using an increase in the Sequential (sepsis-related)
Organ Failure Assessment (SOFA) score of at least 2 points to
define life-threatening acute organ dysfunction. This recom-
mendation was based on both predictive validity and feasibil-
ity of implementing SOFA scoring.
The Process for Developing the Pediatric Sepsis Criteria
Although Sepsis-3 criteria were not proposed for use in chil-
dren, there has been increasing recognition that—in children
as well as in adults—sepsis is more appropriately viewed as
infection-triggered acute organ dysfunction.9 Therefore, in
2019, the Society of Critical Care Medicine appointed an
international, multiprofessional task force to update the pe-
diatric sepsis criteria. The Phoenix sepsis criteria,9 presented
in this issue of JAMA,10 were selected through a modified
Delphi consensus process and informed by several task force–
led studies (Figure).9,11,12
First, the task force fielded an international survey to de-
termine how clinicians diagnose sepsis in practice.9 There
were 2835 respondents from 6 global regions, including
14% from lower-income settings. None of the existing
definitions (IPSCC, Sepsis-3, World Health Organization
[WHO]) were perceived as useful by the majority of respon-
dents across all 6 domains of use (recognition, early recogni-
tion, disease classification, prognostication, benchmarking,
epidemiology, and trial enrollment). Furthermore, 71% of re-
spondents believed the term sepsis should be limited to chil-
dren with infection-related organ dysfunction. Next, the task
force completed a systematic review and meta-analysis to
evaluate associations between patient and clinical features with
(1) development of sepsis among children with infection and
(2) mortality among children with sepsis.11 Review of 16 stud-
ies (9629 children) evaluating sepsis and 71 studies (154 674
children) evaluating outcomes confirmed that organ dysfunc-
tion is strongly associated with both sepsis and mortality. Over-
all, these studies supported a transition from SIRS-based to or-
gan dysfunction–based criteria for pediatric sepsis.
The task force next completed a cohort study to identify
and validate organ dysfunction–based pediatric sepsis cri-
teria.12 To support this task, they assembled a granular data-
base from 6 US and 4 international sites, located in Bangladesh,
China, Colombia, and Kenya. Nearly 175 000 children in the
derivation cohort and 50 000 children in the validation co-
hort with confirmed or suspected infection were included. Data
from all care settings in the 24 hours after presentation were
used, including emergency department, inpatient, and inten-
sive care units.
(Reprinted) JAMA Published online January 21, 2024 E1
 Opinion Editorial
Figure. Process to Develop the Phoenix Pediatric Sepsis Criteria
International survey
How do clinicians diagnose sepsis?
No existing definitions were deemed useful across all 6 domains of use
by the majority of the 2835 respondents.
71% of respondents felt the term sepsis should be limited to children
with infection-related organ dysfunction.
Systematic review and meta-analysis of factors associated with sepsis
What factors are associated with sepsis among children with infection?
Review of 16 studies (9629 children) confirmed that organ dysfunction
is strongly associated with sepsis diagnosis.
What factors are associated with poor outcomes among children with sepsis?
Review of 71 studies (154 674 children) confirmed that organ dysfunction
is strongly associated with mortality.
Cohort study to develop and validate pediatric sepsis criteria
For each of 8 organ systems, which existing criteria best predict
hospital mortality?
The best performing criteria were identified for each of 8 individual organ
systems, from 5 existing scoring systems: International Pediatric Sepsis
Consensus Conference (IPSCC), Pediatric Logistic Organ Dysfunction (PELOD-2),
Pediatric Organ Dysfunction Information Update Mandate (PODIUM),
pediatric SOFA, and Proulx.
Which organ system dysfunctions best predict hospital mortality among
children with infection?
A 4-system model including cardiovascular, coagulation, neurologic, and
respiratory systems achieved similar discrimination as the full 8-system model.
Taskforce consensus process
How should pediatric sepsis be identified in practice?
The 4-system model was prioritized for clinical use and converted
to Phoenix Sepsis Score.
Septic shock requires ≥1 point in the cardiovascular system.
The 8-system model may be useful for research and was converted
to Phoenix-8 Score.
This figure displays the systematic program of inquiry used to develop the
Phoenix sepsis criteria. The task force completed an international survey,9 a
systematic review and meta-analysis,11 and a cohort study,12 which together
informed the consensus selection of the Phoenix Sepsis Score.10
The overarching goal of the cohort study was to deter-
mine which organ dysfunction criteria best predict mortality
among children with proven or suspected infection. First, the
best criteria for predicting in-hospital mortality were identi-
fied for each of 8 individual organ systems (cardiovascular, co-
agulation, endocrine, hepatic, immunologic, neurological, kid-
ney, respiratory), drawn from 5 existing scoring systems: IPSCC,
Pediatric Logistic Organ Dysfunction-2 (PELOD-2), Pediatric
Organ Dysfunction Information Update Mandate (PODIUM),
pediatric SOFA, and Proulx. Next, these best-performing cri-
teria for each individual organ system were considered for in-
clusion in an overall model predicting in-hospital mortality.
A 4-system model (including cardiovascular, coagulation, neu-
rological, and respiratory systems) achieved similar discrimi-
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nation as the full 8-system model. The task force selected the
4-system model due to its simplicity and translated this model
into an integer score (Phoenix Sepsis Score) to facilitate imple-
mentation into practice.
The Definitions
The Phoenix sepsis criteria defines sepsis as life-threatening
organ dysfunction of the respiratory, cardiovascular, coagu-
lation, and/or neurological systems, demonstrated by a Phoenix
Sepsis Score of at least 2, in the setting of confirmed or sus-
pected infection (Table).10 Septic shock was defined as sepsis
with at least 1 point in the cardiovascular category (blood lactate
≥5 mmol/L [≥45.05 mg/dL], hypotension for age, or vasoac-
tive use). These thresholds were selected based on group con-
sensus, requiring more than 80% agreement among more than
80% of the task force.
In the validation study, children meeting the Phoenix cri-
teria for sepsis in higher- and lower-resourced settings had 7%
and 29% in-hospital mortality, respectively, or 8-fold higher
than all children with infection. Children meeting Phoenix
criteria for septic shock had 11% and 34% mortality, respec-
tively. Overall, the Phoenix criteria out performed all other cri-
teria, including IPSCC, for predicting in-hospital mortality.
The Meaning
The Phoenix sepsis criteria were created to improve clinical
care, research, and benchmarking. They were informed by
a systematic program of inquiry that intentionally incorpo-
rated diverse stakeholders and perspectives, from panel
composition to inclusions in the survey, meta-analysis, and
cohort studies. The broad applicability of sepsis definitions is
important, particularly given the disproportionate burden of
sepsis and sepsis-related mortality experienced in lower
resourced settings13—a point highlighted by the 3-fold differ-
ence in mortality between US and international sites in the
validation study. Continued efforts to decrease this large gap
are paramount.
With the Phoenix criteria, pediatric sepsis is redefined as
life-threatening organ dysfunction in the setting of infection.
The organ dysfunction criteria selected are both data driven
and pragmatic. As the field incorporates these criteria, there
are several points to consider. First, the SIRS criteria are not
included in the Phoenix definition but have value in clinical
care particularly for assessing the presence of infection. The
Phoenix criteria were developed and validated among chil-
dren with proven or suspected infection. However, recogniz-
ing and confirming infection remains a challenge, with up to
a third of patients diagnosed with sepsis having a noninfec-
tious illness in hindsight.14 The SIRS criteria remain useful for
assessing the presence of infection.7 Second, while Sepsis-3 re-
quires at least 2 new SOFA points, Phoenix scoring does not
specify that organ dysfunction must be new. Chronic organ dys-
function may indicate increased risk of mortality but be less
responsive to acute treatments for sepsis. Enrollment into clini-
cal trials should thus be mindful of acute vs chronic organ dys-
function. Third, kidney dysfunction (which is included in the
IPSCC definition of severe sepsis and associated with mortal-
ity in prior studies of pediatric sepsis15,16) was not included in
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 Editorial Opinion

Table. Comparison of Phoenix Pediatric Sepsis Criteria With International Pediatric Sepsis Consensus Conference Criteria

International Pediatric Sepsis Consensus Conference criteria Phoenix pediatric sepsis criteria
Sepsis
Definition SIRS in the setting of a suspected or confirmed infection: Life-threatening organ dysfunction in the setting of suspected
≥2 SIRS criteria, of which 1 must be temperature or or confirmed infection, defined as ≥2 points on the Phoenix
white blood cell count Sepsis Score
Criteria Pediatric SIRS Criteria Organ dysfunction may include
• Core temperature • Respiratory (PaO2:FIO2 or SpO2:FIO2)
• White blood cell count • Cardiovascular (vasoactive medications, lactate, age-specific
• Heart rate MAP
• Respiratory rate • Coagulation (platelets, INR, D-dimer, fibrinogen)
• Neurologic systems (Glasgow Coma Scale)
Severe sepsis
Definition Sepsis with at least 1 of the following: cardiovascular organ Term no longer used now that sepsis definition requires organ
dysfunction, acute respiratory distress syndrome, dysfunction
or ≥2 other organ dysfunctions.
Criteria Organ dysfunctions include
• Respiratory (PaO2:FIO2 ratio, PaCO2, FIO2, mechanical ventilation)
• Neurological (Glasgow Coma Scale)
• Hematologic (platelet count, INR)
• Kidney (serum creatinine)
• Hepatic (bilirubin, alanine aminotransferase)
Septic shock
Definition Sepsis and cardiovascular organ dysfunctiona Sepsis with ≥1 point in the cardiovascular systemb
Abbreviations: FIO2, fraction of inspired oxygen; INR, international normalized for age) or need for vasoactive or at least 2 of the following: unexplained
ratio; MAP, mean arterial pressure; PaCO2, atrial partial pressure of carbon metabolic acidosis; arterial lactate >2 times the upper limit of normal; oliguria;
dioxide; PaO2, atrial partial pressure of oxygen; SIRS, Systemic Inflammatory prolonged capillary refill; or core to peripheral temperature gap.
Response Syndrome; SpO2, oxygen saturation as measured by pulse oximetry. b
The Phoenix definition of cardiovascular organ dysfunction includes severe
a
The International Pediatric Sepsis Consensus Conference Criteria definition of hypotension for age; venous or arterial blood lactate value of more than 5
cardiovascular organ dysfunction is despite 40 mL/kg or more isotonic fluid in mmol/L (>45.05 mg/dL), or need for vasoactive medication.
1 hour, hypotension (<5% percentile for age or systolic blood pressure <2 SD

the Phoenix criteria. Research studies should consider using
the full 8-system model to further assess the implications of
restricting to 4-organ systems.
Fourth, the cohort study considered only data from the first
24 hours of presentation and had high rates of missingness at
some sites. Additional validation, particularly for hospital-
onset sepsis, is warranted. Fifth, like Sepsis-3, the Phoenix cri-
teria identify a sicker subset of patients than prior SIRS-based
criteria. Some may worry this higher threshold could delay
management of patients not meeting sepsis criteria. Just as
patients with chest pain and a troponin leak warrant moni-
toring and treatment (but are not prioritized for immediate
heart catheterization)—patients with infection need monitor-
ing and treatment. Improvements in care should thus be judged
not only by improved outcomes among patients with sepsis
but also by decreased progression to sepsis among patients
with infection.
The Phoenix sepsis criteria identify children with life-
threatening organ dysfunction in the setting of infection. This
sepsis definition is supported by a robust body of research, in-
clusive of diverse geographic and resource settings. These new
definitions and shared conceptual understanding of pediat-
ric sepsis will support improvements in the management, re-
search, and outcomes of children with sepsis worldwide.

ARTICLE INFORMATION
Author Affiliations: Department of Pediatrics,
University of Michigan, Ann Arbor (Carlton);
Susan B. Meister Child Health Evaluation and
Research, Ann Arbor, Michigan (Carlton); University
of Connecticut School of Nursing, Storrs
(Perry-Eaddy); Department of Pediatrics, University
of Connecticut School of Medicine, Farmington
(Perry-Eaddy); Pediatric Intensive Care Unit,
Connecticut Children’s, Hartford (Perry-Eaddy);
Department of Internal Medicine, University of
Michigan, Ann Arbor (Prescott); VA Center for
Clinical Management Research, Ann Arbor,
Michigan (Prescott).
Corresponding Author: Hallie C. Prescott, MD,
MSc, 2800 Plymouth Rd, North Campus Research
Center, Bldg 16, 341E, Ann Arbor, MI 48109-2800
(hprescot@med.umich.edu).
Published Online: January 21, 2024.
doi:10.1001/jama.2023.27979
Conflict of Interest Disclosures: Dr Prescott
reported serving as cochair of the Surviving Sepsis
Campaign Adult Guidelines panel and receiving
grant funding and/or salary support from the
National Institutes of Health (NIH), the Centers for
Disease Control and Prevention, Agency for
Healthcare Research and Quality, Veterans Affairs,
and Blue Cross Blue Shield of Michigan. Dr Carlton
reported serving on the Pediatric Surviving Sepsis
Campaign Guideline committee, receiving grant
support from the NIH. Dr Perry-Eaddy reported
receiving grant support from the NIH.
Funding/Support: This material is the result of
work supported with resources and use of facilities
at the Ann Arbor VA Medical Center.
Role of the Funder/Sponsor: The funder had no
role in the preparation, review, or approval of the
manuscript; and decision to submit the manuscript
for publication.
Disclaimer: This content does not represent the
views of the Department of Veterans Affairs or the
US government.
REFERENCES
1. Geroulanos S, Douka ET. Historical perspective of
the word “sepsis”. Intensive Care Med. 2006;32
(12):2077-2077. doi:10.1007/s00134-006-0392-2
2. Hernández-Botero J, Pérez MF. The history of
sepsis from Ancient Egypt to the XIX century. In:
Azevedo L, ed. Sepsis—An Ongoing and Significant
Challenge. IntertechOpen; 2012.
3. Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK,
Lynch SV, Knight R. Current understanding of the
human microbiome. Nat Med. 2018;24(4):392-400.
doi:10.1038/nm.4517
4. Bone RC, Balk RA, Cerra FB, et al; The
ACCP/SCCM Consensus Conference Committee.
American College of Chest Physicians/Society of
Critical Care Medicine. Definitions for sepsis and

jama.com (Reprinted) JAMA Published online January 21, 2024 E3

© 2024 American Medical Association. All rights reserved.

Downloaded from jamanetwork.com by Luis Carvalho on 01/21/2024
 Opinion Editorial
organ failure and guidelines for the use of
innovative therapies in sepsis. Chest. 1992;101(6):
1644-1655. doi:10.1378/chest.101.6.1644
5. Levy MM, Fink MP, Marshall JC, et al;
SCCM/ESICM/ACCP/ATS/SIS. 2001
SCCM/ESICM/ACCP/ATS/SIS International Sepsis
Definitions Conference. Crit Care Med. 2003;31(4):
1250-1256. doi:10.1097/01.CCM.0000050454.
01978.3B
6. Goldstein B, Giroir B, Randolph A; International
Consensus Conference on Pediatric Sepsis.
International Pediatric Sepsis Consensus
Conference: definitions for sepsis and organ
dysfunction in pediatrics. Pediatr Crit Care Med.
2005;6(1):2-8. doi:10.1097/01.PCC.0000149131.
72248.E6
7. Singer M, Deutschman CS, Seymour CW, et al.
The Third International Consensus Definitions for
Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315
(8):801-810. doi:10.1001/jama.2016.0287
8. Marshall JC. Why have clinical trials in sepsis
failed? Trends Mol Med. 2014;20(4):195-203. doi:
10.1016/j.molmed.2014.01.007
E4 JAMA Published online January 21, 2024 (Reprinted)
© 2024 American Medical Association. All rights reserved.
Downloaded from jamanetwork.com by Luis Carvalho on 01/21/2024
9. Morin L, Hall M, de Souza D, et al; Pediatric
Sepsis Definition Taskforce. The current and future
state of pediatric sepsis definitions: an international
survey. Pediatrics. 2022;149(6):e2021052565. doi:
10.1542/peds.2021-052565
10. Schlapbach LJ, Watson RS, Sorce LR, et al.
International consensus criteria for pediatric sepsis
and septic shock. JAMA. Published online January 21,
2024. doi:10.1001/jama.2024.0179
11. Menon K, Schlapbach LJ, Akech S, et al;
Pediatric Sepsis Definition Taskforce of the Society
of Critical Care Medicine. Criteria for pediatric
sepsis—a systematic review and meta-analysis by
the Pediatric Sepsis Definition Taskforce. Crit Care
Med. 2022;50(1):21-36. doi:10.1097/CCM.
0000000000005294
12. Rudd KE, Johnson SC, Agesa KM, et al. Global,
regional, and national sepsis incidence and
mortality, 1990-2017: analysis for the Global Burden
of Disease Study. Lancet. 2020;395(10219):200-211.
doi:10.1016/S0140-6736(19)32989-7
13. Sanchez-Pinto LN, Bennett TD, DeWitt PE, et al.
Development and validation of the Phoenix criteria
for pediatric sepsis and septic shock. JAMA. Published
online January 21, 2024. doi:10.1001/jama.2024.0196
14. Klein Klouwenberg PM, Cremer OL, van Vught
LA, et al. Likelihood of infection in patients with
presumed sepsis at the time of intensive care unit
admission: a cohort study. Crit Care. 2015;19(1):319.
doi:10.1186/s13054-015-1035-1
15. Starr MC, Banks R, Reeder RW, et al; Life After
Pediatric Sepsis Evaluation (LAPSE) Investigators.
Severe acute kidney injury is associated with
increased risk of death and new morbidity after
pediatric septic shock. Pediatr Crit Care Med. 2020;
21(9):e686-e695. doi:10.1097/PCC.
0000000000002418
16. Fitzgerald JC, Basu RK, Akcan-Arikan A, et al;
Sepsis Prevalence, Outcomes, and Therapies Study
Investigators and Pediatric Acute Lung Injury and
Sepsis Investigators Network. Acute kidney injury in
pediatric severe sepsis: an independent risk factor
for death and new disability. Crit Care Med. 2016;44
(12):2241-2250. doi:10.1097/CCM.
0000000000002007
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