International Consensus Criteria for Pediatric Sepsis and Septic Shock | Critical Care Medicine | JAMA

Key Points

Question 
How should children with suspected infection at higher risk of mortality, indicative of sepsis, be identified?

Findings 
Using an international survey, systematic review, and analysis of more than 3 million pediatric health care encounters, and consensus process, new criteria for sepsis and septic shock in children were developed. Pediatric sepsis in children (<18 years) with suspected infection was identified by at least 2 points in the novel Phoenix Sepsis Score, including dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems; and septic shock as sepsis with at least 1 cardiovascular point in the Phoenix Sepsis Score.

Meaning 
The new criteria for pediatric sepsis and septic shock are globally applicable.

Importance 
Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children.

Objective 
To update and evaluate criteria for sepsis and septic shock in children.

Evidence Review 
The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria.

Findings 
Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4—respiratory, cardiovascular, coagulation, and/or neurological—organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively.

Conclusions and Relevance 
The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

In 2017, an estimated 25 million children experienced sepsis worldwide, leading to more than 3 million deaths.¹ Many pediatric survivors of sepsis have ongoing physical, cognitive, emotional, and psychological sequelae, which may have long-term effects on them and their families.^2-4 The risk of developing sepsis during the early years of life exceeds that of any other age group, with the most disproportionate effect among children in lower-resource settings.⁵ The World Health Organization resolution on sepsis called for dedicated efforts to improve diagnosis, prevention, and management of sepsis, all of which require use of criteria that accurately identify those with infection who are at high risk of adverse outcomes and death.^6,7 However, such criteria are lacking for children.

The most recent criteria specific to pediatric sepsis were published in 2005 by the International Pediatric Sepsis Consensus Conference (IPSCC) and have been widely incorporated in clinical practice, research, quality improvement, and policy efforts.^8,9 Similar to criteria for adult sepsis at the time—the 2001 Society of Critical Care Medicine, European Society of Intensive Care Medicine, American College of Chest Physicians, American Thoracic Society, and Surgical Infection Society International Sepsis Definitions Consensus Conference (Sepsis-2)¹⁰—which developed a second recommendation, the IPSCC criteria were based on expert opinion and characterized sepsis as suspected or confirmed infection in the presence of the systemic inflammatory response syndrome (SIRS). Severe sepsis was defined as sepsis with cardiovascular or respiratory organ dysfunction or dysfunction of at least 2 other organ systems. Septic shock was defined as sepsis with hypotension, need for vasoactive medications, or evidence of impaired perfusion despite resuscitation with 40 mL/kg or more of intravenous fluid boluses.

In 2016, the Third International Consensus Conference for Sepsis and Septic Shock (Sepsis-3) revised criteria for sepsis and septic shock in adults using data from nearly 150 000 patients with suspected infection in the US and Germany.¹¹ The Sepsis-3 definition differentiated sepsis from uncomplicated infection by the presence of life-threatening organ dysfunction caused by a dysregulated host response to infection and identified sepsis using an increase in the Sequential Organ Failure Assessment (SOFA) score by at least 2 points in patients with suspected infection.¹² Septic shock was identified in patients with sepsis with vasopressor use to maintain mean arterial blood pressure of 65 mm Hg or higher and serum lactate level more than 2 mmol/L (18.02 mg/dL) in the absence of hypovolemia.¹³ These criteria were not developed with pediatric data nor validated or broadly adapted for children.

Sepsis in children has important differences from that in adults, including age-specific variability of vital signs, developmental age-dependent immune function, and differences in pediatric-specific comorbidities, epidemiology, and outcomes.^14-17 Due to the high morbidity and mortality caused by sepsis in children worldwide, sepsis criteria should be derived and validated specifically for diagnosis in children.

The IPSCC criteria for pediatric sepsis include many children with mild illness severity, and recent literature supports that the SIRS criteria do not reliably identify children with infection at risk of poor outcomes.^18,19 Furthermore, studies have reported discrepancies in how the criteria are applied clinically, which limit accurate characterization of sepsis disease burden.²⁰ Finally, the global applicability of IPSCC criteria for populations in lower-resource settings, where disease burden remains greatest, has not been rigorously evaluated.^21-23

Insights from the process of developing and validating Sepsis-3 in adults and subsequent validation studies provided guidance to inform the revision of pediatric sepsis criteria.^24,25 Sepsis criteria for children should be based on robust, readily available data from diverse clinical settings. Sepsis-3 used the preexisting SOFA score, but the sensitivity and positive predictive value of pediatric organ dysfunction scores^26-29 for children with infection are unclear.³⁰ In addition, although sepsis research has focused on patients requiring intensive care, 80% of pediatric patients with sepsis initially present to emergency department or regular inpatient care settings. Therefore, data spanning the entire hospital care continuum should be considered in pediatric patients with sepsis.³¹

This article follows the Guidelines on Modifying the Definition of Diseases.³² A task force was assembled in 2019 by the SCCM to update criteria for pediatric sepsis (eTable 1 in Supplement 1). A diverse panel in terms of discipline, gender, and health care setting was considered essential. Pediatric experts in intensive care, emergency medicine, infectious diseases, general pediatrics, informatics, nursing, neonatology, and research were approached based on their expertise and experience in sepsis, ensuring that health care settings with different resources and geography on 6 continents were represented. The task force included 35 nurse and physician experts from Australia, Bangladesh, Brazil, Canada, France, India, Italy, Japan, Switzerland, South Africa, United Kingdom, and the United States.

A 3-pronged approach (eMethods 1 in Supplement 1) was used to develop the new criteria, including (1) a global survey of 2835 clinicians,³³ (2) a systematic review and meta-analysis (eMethods 3 in Supplement 1),^34,35 and (3) a data-driven derivation and validation study,³⁶ which culminated in a modified Delphi consensus process by the entire task force. At each step, the task force included data from lower- and higher-resource settings and considered the challenges related to limited resources (eMethods 2 in Supplement 1). The global survey and systematic review informed the design of the derivation and validation study, the results of which were used in the consensus process to arrive at the final criteria for pediatric sepsis. During the consensus process, results of analyses were presented to the members of the task force for review, discussion, and vote using REDCap surveys. Consensus was defined as more than 80% agreement of more than 80% of the task force members for any given question. If this threshold was not reached, further discussion (and data analysis where necessary) ensued, followed by additional rounds of voting until consensus was reached (eMethods 4 in Supplement 1). Preterm neonates (<37 weeks’ gestation at birth) and newborns who remained hospitalized after birth were excluded due to challenges with defining organ dysfunction in neonates born prematurely and because of the unique context of perinatally acquired infections.^37,38

The global survey highlighted concern about inconsistent availability of diagnostic tests and therapeutic tools across settings and a need for new criteria applicable to clinical care, benchmarking, quality improvement, epidemiology, and research.³³ The survey also confirmed the preferred use of the term sepsis by pediatric clinicians to refer to children with infection-associated organ dysfunction rather than with infection-associated SIRS, indicating widespread adoption of the Sepsis-3 conceptual framework.

The systematic review and meta-analysis examined the association of individual clinical and laboratory criteria with the development of sepsis or increased risk of adverse outcomes, including organ dysfunction scores.³⁴ This confirmed the choice of using validated measures of organ dysfunction for the development of sepsis and septic shock criteria for children.

An international, multicenter, electronic health record database was developed using data from health systems in 6 higher-resource sites (all in the US) and 4 lower-resource sites in Bangladesh, China, Colombia, and Kenya. This database included more than 3 million hospital encounters of patients younger than 18 years across various hospital locations (eg, emergency department, regular inpatient care area, intensive care unit), excluding birth hospitalizations and children whose postconceptional age was younger than 37 weeks.³⁶ Data from each encounter were available from presentation through discharge or death and were divided into derivation and validation data sets, stratified by resource setting (higher vs lower). The Sepsis-3 conceptual definitions of sepsis as life-threatening organ dysfunction caused by infection and septic shock as sepsis leading to cardiovascular dysfunction,¹² broadly acceptable in a global survey of clinicians and researchers caring for children,³³ were used as starting points by the task force.

The organ-specific subscores of 8 existing pediatric organ dysfunction scores^26-29 were calculated using data from the first 24 hours of presentation to the hospital and were compared to ascertain those that were best able to discriminate in-hospital mortality (including in the emergency department) among children with suspected infection, defined as those receiving systemic antimicrobials and undergoing microbiological testing. The best-performing subscores were used as inputs in stacked regression models to determine their association with in-hospital mortality.³⁶ When subscores performed similarly, the task force voted to determine which to include in the final models.

The final model, which incorporated levels of dysfunction for 4—cardiovascular, respiratory, neurological, and coagulation—organ systems, had comparable performance with a score generated from an 8-organ system model that also included renal, hepatic, endocrine, and immunological dysfunction (Phoenix-8 Score³⁶). The final 4-organ system model was supported by the task force based on performance and parsimony and was translated into an integer-based score, the Phoenix Sepsis Score (Table), to optimize utility. Thresholds in the score for sepsis and septic shock were set through the consensus process involving the entire task force, based on sensitivity and positive predictive value. Once completed, the recommendations were circulated to endorsing societies.

Sepsis in children was identified using the Phoenix sepsis criteria, which was 2 or more points in the Phoenix Sepsis Score, indicating potentially life-threatening organ dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems in children with suspected or confirmed infection (Table, Box 1, and eTables 2 and 3 in Supplement 1). Children with suspected infection in the first 24 hours of presentation had in-hospital mortality of 0.7% (1049 of 144 379) in higher-resource settings and 3.6% (1016 of 28 605) in lower-resource settings. Among these children, a Phoenix Sepsis Score of at least 2 in the first 24 hours of presentation occurred in 7.1% (10 243 of 144 379) in higher-resource settings and 5.4% (1549 of 28 605) in lower-resource settings and identified children at a higher risk of death (in-hospital mortality of 7.1% [726 of 10 243] in higher-resource settings and 28.5% [441 of 1549] in lower-resource settings; eFigure 2 in Supplement 1). The threshold of Phoenix Sepsis Score of at least 2 points had higher positive predictive value and higher or comparable sensitivity for in-hospital mortality in children with confirmed or suspected infection in the first 24 hours when compared with the IPSCC definition of sepsis (ie, SIRS with suspected or confirmed infection) and severe sepsis (ie, IPSCC sepsis with IPSCC-based organ dysfunction criteria) in the main analysis and in multiple sensitivity analyses.³⁶

Box Section Ref ID

Pediatric septic shock was identified in children with sepsis by at least 1 point in the cardiovascular component of the Phoenix Sepsis Score (ie, severe hypotension for age, blood lactate >5 mmol/L, or receipt of vasoactive medication; Figure). Because vasoactive medications may not be available in some clinical settings,³⁹ this approach allowed the identification of septic shock in the absence of such resources. The prevalence of septic shock among children with sepsis was 53.7% (5502 of 10 243) in higher-resource settings and 81.3% (1260 of 1549) in lower-resource settings and was associated with in-hospital mortality of 10.8% (593 of 5502) and 33.5% (422 of 1260), respectively.

Children meeting Phoenix sepsis criteria included those with organ dysfunction limited to the primary infected organ (eg, isolated respiratory dysfunction in a child with pneumonia), and those with Phoenix Sepsis Scores that indicated organ dysfunction remote from the primary site of infection (eg, respiratory dysfunction in a child with meningitis). However, children with sepsis and organ dysfunction remote from the primary site of infection, which includes patients with septic shock and those with multiorgan dysfunction, represent an important, distinct subset of children with sepsis (eFigures 1 and 2 in Supplement 1). Children with sepsis and remote organ dysfunction had higher mortality (8.0% [700 of 8728] and 32.3% [427 of 1320] in higher- and lower-resource settings, respectively) and represented 85.2% (8728 of 10 243) and 85.2% (1320 of 1549) of children with sepsis in higher- and lower-resource settings, respectively. In contrast, children with a Phoenix Sepsis Score of at least 2 who had organ dysfunction limited to the primary site of infection had a mortality of 1.7% and 6.1% in higher- and lower-resource settings, respectively.

The Phoenix criteria for pediatric sepsis and septic shock, developed with an international survey, a systematic review, analyses of more than 3 million pediatric encounters, and a modified Delphi consensus process, were designed to reliably identify children with sepsis for the purpose of clinical care, benchmarking, quality improvement, epidemiology, and research in pediatric sepsis. The method used to develop the criteria leveraged knowledge gained by the Sepsis-3 process while incorporating novel elements, using a globally diverse task force and relying on data from diverse health care systems. SIRS should no longer be used to diagnose sepsis in children, and because any life-threatening condition is severe, the term severe sepsis is redundant. The Phoenix criteria were intended to be globally applicable and were named in reference to the symbolic meaning of the mythological phoenix and the location where the criteria were presented during the 2024 SCCM Congress (Phoenix, Arizona).

In recent years, many health care institutions caring for adults have implemented SOFA-based extraction procedures in their electronic health care records to identify patients with sepsis, improve sepsis care, and facilitate more accurate coding and billing.⁴⁰ The Phoenix Sepsis Score could achieve the same goals for children across diverse settings.

The Phoenix Sepsis Score incorporated sepsis-defining organ dysfunction associated with increased risk of death. Although this score only included 4 organ systems, the model was sensitive with good positive predictive value when compared with the more complex Phoenix-8 Score. The task force prioritized parsimony, performance, and feasibility across different resource settings and thus limited the number of organ systems used to differentiate sepsis and septic shock from infection without sepsis. Although the 4 organs in the Phoenix Sepsis Score are most commonly involved in sepsis, this does not diminish the crucial importance of the assessment and management of other organ dysfunction.⁴¹ Clinicians and researchers can identify and classify additional organ dysfunctions (eg, kidney or hepatic dysfunction), with the Phoenix-8 Score.³⁶

The Phoenix sepsis criteria accurately identified sepsis in data sets from lower-resource settings,³⁶ which should facilitate international dissemination and data collection for future studies. The restriction to 4 organ systems reduces requirements for laboratory investigation and data collection. Although serum lactate was included in the Phoenix Sepsis Score and may not be available in some settings, the modeling and global survey provide rationale for its inclusion as an essential test whenever possible, even in lower-resource settings.²² The task force acknowledges that organ support such as mechanical ventilation or vasoactive medications may not be available in some lower-resource settings, in which case other score items such as a low arterial oxygen saturation to fraction of inspired oxygen (Sao₂:Fio₂) ratio or low mean arterial blood pressure can be used. In addition, the availability of coagulation parameters may be limited in areas of the world with fewer resources than the sites included in this study; however, there is enough redundancy in the score that it still performs well in identifying children with sepsis when coagulation parameters are not reported.

The Phoenix criteria for sepsis and septic shock were intended to identify life-threatening organ dysfunction due to infection in children. They were not designed for screening children at risk for developing sepsis or early identification of children with suspected sepsis. Thus, it is imperative to continue to develop sepsis screening and early warning tools to correctly identify patients at higher risk of developing sepsis, in both outpatient and inpatient settings, which may lead to early interventions that could decrease the morbidity and mortality associated with pediatric sepsis. The development of such tools is a future goal of the SCCM Pediatric Sepsis Definition Task Force.⁴²

The Phoenix criteria have the potential to advance pediatric sepsis quality improvement initiatives,⁴³ although not all patients meeting these criteria will have bacterial infections (eg, those with viral infections such as adenovirus or dengue). Efforts to enhance antimicrobial stewardship integrated into quality improvement work should therefore include both measures of timely antimicrobial administration as well as its appropriateness.^44,45

After considerable discussion and debate, the task force defined sepsis as infection-associated organ dysfunction regardless of the site of infection. However, in terms of pathophysiology and management, patients with isolated organ dysfunction due to local infection-related tissue damage likely differ from those with organ dysfunction remote from the site of infection, eg, those who have shock and/or multiorgan dysfunction and a substantially higher mortality.⁴⁶ Children with this systemic form of sepsis may harbor distinct targets for translational and clinical research to understand its evolution and optimal treatment.⁴⁶ Given the heterogeneity of sepsis, studies should be designed to incorporate phenotype-based criteria reflective of individual biology and that may identify patient subgroups that are more likely to benefit from specific therapeutic interventions.^47-49

First, the Phoenix sepsis criteria inherently represent a simplification of the complex biological processes leading to sepsis in children and the heterogeneity of the condition in terms of host, pathogen, and contextual factors (Box 2). Second, identification of “infection” by proxy markers such as microbiological testing and antibiotics is affected by resource availability and local practice. Third, similar to Sepsis-3, we have not attempted to characterize specific markers of dysregulated host response, nor have we validated findings on data sets of higher biological resolution such as those including multiomics data. Fourth, the data from higher-resource settings were derived exclusively from children’s hospitals in the US, so they may not be representative of or generalizable to children in other higher-resource countries. Fifth, death as a primary end point in children with infection, while pragmatic, does not account for infection-associated morbidity, and does not include the long-term effects on children and their families. Sixth, the 24-hour presentation window used in the development of the criteria excluded children who developed sepsis as a result of health care–associated infections.⁵⁰ Seventh, the temporal sequence of infection followed by organ dysfunction and death does not prove causality, and dynamic measures of physiology may reflect deteriorating patients more accurately than static or single-time point assessments used in the criteria. Eighth, the new criteria incorporated treatments delivered in response to sepsis (eg, vasoactive medications) and may not have accounted for other therapies (eg, sedation) that could have influenced organ dysfunction. Ninth, preterm neonates and term newborns who were hospitalized directly after birth were excluded from this study, so these pediatric sepsis criteria do not apply to those patients.

Box Section Ref ID

The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

Accepted for Publication: January 4, 2024.

Published Online: January 21, 2024. doi:10.1001/jama.2024.0179

Corresponding Author: R. Scott Watson, MD, MPH, Department of Pediatrics, University of Washington, 4800 Sand Point Way NE, M/S FA.2.112, Seattle, WA 98105 ([email protected]).

Author Contributions: Drs Sanchez-Pinto and Bennett had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Schlapbach, Watson, Sorce, and Argent contributed equally. Drs Sanchez-Pinto and Bennett contributed equally.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: All authors.

Obtained funding: All authors.

Administrative, technical, or material support: All authors.

Supervision: All authors.

Other – Analysis of data, input into evaluation and drafting manuscript: Nadel.

Other – Data processing and harmonization: Martin.

Other: Schlapbach, Watson, Sorce, Argent, Menon, Hall, Albers, Alpern, Balamuth, Bembea, Biban, Chisti, DeWitt, Evans, de Oliveira, Horvat, Ishimine, Jaramillo-Bustamante, Lodha, Nakagawa, Peters, Randolph, Ranjit, Rebull, Russell, Scott, de Souza, Tissieres, Weiss, Wiens, Wynn, Kissoon, Zimmerman, Sanchez-Pinto, Bennett.

Conflict of Interest Disclosures: Dr Schlapbach reported receiving grants from Medical Research Future Funds (MRFF), National Health and Research Council (NHMRC), NOMIS Foundation, and Swiss Personalized Health Network (SPHN) outside the submitted work. Dr Watson reported receiving support to his institution from the National Institutes of Health (NIH) and nonfinancial support from the SCCM during the conduct of the study. Dr Argent reported receiving payments for providing expert evidence for medicolegal matters in South Africa. Dr Menon reported receiving grants from the Canadian Institutes of Health Research (CIHR) funding outside the submitted work. Dr Hall reported serving on the data and safety monitoring board for Abbvie and on a subboard of the American Board of Pediatrics; receiving nonfinancial support from Sobi and Partner Therapeutics and personal fees from Kiadis Licensing that is unrelated to the submitted work. Dr Balamuth reported receiving grants from the NIH and the Children’s Hospital of Philadelphia Research Institute, Global Lyme Alliance, and the Kleberg Foundation. Dr Bembea reported receiving grants from the National Institute of Child Health and Human Development (NICHD), Grifols Research, Department of Defense, and the National Heart, Lung, and Blood Institute (NHLBI) to her institution outside the submitted work. Dr Carrol reported serving on the committee for UK National Institute for Health and Care Excellence (NICE) sepsis guidelines 2016 and SCCM International guidelines for pediatric sepsis. Dr Chiotos reported receiving grants from Centers for Disease Control and Prevention (CDC) and the Agency for Healthcare Research and Quality (AHRQ) outside the submitted work and serving as a member of the Infectious Diseases Society of America (IDSA) Sepsis Taskforce. Dr Horvat reported receiving grants from the NICHD and grants from National Institute of Neurological Disorders and Stroke (NINDS) outside the submitted work. Dr Martin reported receiving grants from the Thrasher Research Fund outside the submitted work. Dr Nakagawa reported receiving grants from the Japan Blood Products Organization outside the submitted work. Dr Peters reported receiving grants from the National Institute of Health and Care Research UK for clinical trials from the Heath Technology Assessment, Research for Patient Benefit, and Programme Grants for Applied Research programmes outside of the submitted work. Dr Randolph reported serving as the chair of the International Sepsis Forum; receiving institutional grants from the CDC, NIH, and NIAID; serving as a section editor of UpToDate and on the advisory board of ThermoFisher Pediatric; attending a scientific advisory meeting for Volition Inc; and receiving nonfinancial support from Illumina Inc in the form of reagents to Boston Children’s Hospital outside the submitted work. Dr Scott reported receiving grants from AHRQ outside the submitted work. Dr Tissieres reported receiving grants from Baxter, honoraria from a Baxter symposium, advisory fees from Sedana, ThermoFisher, and Sanofi outside the submitted work. Dr Wynn reported serving as a consultant to Sobi outside the submitted work. Dr Zimmerman reported receiving grants from Immunexpress, research funding and personal fees and royalties from Elsevier Publishing, and royalties outside the submitted work. Dr Bennett reported receiving grants from the National Center for Advancing Translational Sciences and the NHLBI outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by the SCCM and grant R01HD105939 from the NICHD to Drs Bennett and Sanchez-Pinto. Data for the Kenya site was collected with support of the Wellcome Trust to the Kenya Major Overseas Programme (Nos. 092654 and 203077).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force: See Supplement 2.

Disclaimer: Dr Sorce reported being an elected member of the executive committee and serves as president-elect of the SCCM 2023-2024 and president 2024-2025. The research presented is that of the authors and does not represent the opinions of the SCCM.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank Kathy Vermoch, MPH, Lori Harmon, MBA, and Lynn Retford at the SCCM for their invaluable assistance throughout this project; Rebeca Mozun, MD, PhD, University Children’s Hospital Zurich, Switzerland, for help with creating the figures; and Clifford S. Deutschman, MS, MD, and Derek C. Angus, MD, MPH, for their invaluable guidance in developing and conducting the work of the task force. None mentioned herein received compensation beyond their salaries.

Additional Information: A list of endorsing societies can be found at Representatives from the following organizations were members of the task force: American College of Emergency Physicians (Ishimine), Associação de Medicina Intensiva Brasileira (Flauzino de Oliveira), European Society of Paediatric and Neonatal Intensive Care (Schlapbach), Infectious Diseases Society of America (Chiotos), Pediatric Infectious Diseases Society (Chiotos), World Federation of Pediatric Intensive and Critical Care Societies (Argent).