LABORATORIO DE URGENCIAS

International Consensus Criteria for Pediatric Sepsis and Septic Shock

 
The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force:
Luregn J. Schlapbach, MD, PhD; R. Scott Watson, MD, MPH; Lauren R. Sorce, PhD, RN; et alAndrew C. Argent, MD, MBBCh, MMed; Kusum Menon, MD, MSc; Mark W. Hall, MD; Samuel Akech, MBChB, MMED, PhD; David J. Albers, PhD; Elizabeth R. Alpern, MD, MSCE; Fran Balamuth, MD, PhD, MSCE; Melania Bembea, MD,PhD; Paolo Biban, MD; Enitan D. Carrol, MBChB, MD; Kathleen Chiotos, MD; Mohammod Jobayer Chisti, MBBS, MMed, PhD; Peter E. DeWitt, PhD; Idris Evans, MD, MSc; Cláudio Flauzino de Oliveira, MD, PhD; Christopher M. Horvat, MD, MHA; David Inwald, MB,PhD;  Paul Ishimine, MD; Juan Camilo Jaramillo-Bustamante, MD; Michael Levin, MD, PhD;  Rakesh Lodha, MD; Blake Martin, MD; Simon Nadel, MBBS; Satoshi Nakagawa, MD; Mark J. Peters, PhD; Adrienne G. Randolph, MD, MS; Suchitra Ranjit, MD; Margaret N. Rebull, MA; Seth Russell, MS; Halden F. Scott, MD; Daniela Carla de Souza, MD, PhD;  Pierre Tissieres, MD, DSc; Scott L. Weiss, MD, MSCE; Matthew O. Wiens, PharmD, PhD; James L. Wynn, MD; Niranjan Kissoon, MD; Jerry J. Zimmerman, MD, PhD; L. Nelson Sanchez-Pinto, MD;  Tellen D. Bennett, MD, MS

                                                                                                        JAMA. 2024;331(8):665-674. doi:10.1001/jama.2024.0179

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.

Limitations of Current Criteria for Sepsis 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

The Process of Developing and Validating New Criteria for Sepsis in Children
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, 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.

Results

Criteria to Identify Children With Sepsis
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; Figure 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

Criteria to Identify Children With Septic Shock
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.

Organ Dysfunction Remote From the Primary Site of Infection
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.

Discussion

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).

Considerations
* Use of the Phoenix Pediatric Sepsis Criteria
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.
* Organ Dysfunctions Not Included in the Phoenix Sepsis Score
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
* Lower-Resource Settings
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.
* Identification of Children at Risk of Sepsis
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
* Quality Improvement and Antimicrobial Stewardship
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

Development Toward Phenotype-Based Sepsis Criteria
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

Limitations
* 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

Conclusions

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.

References

1.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)32989-7PubMedGoogle ScholarCrossref

2.Zimmerman  JJ, Banks  R, Berg  RA,  et al; Life After Pediatric Sepsis Evaluation (LAPSE) Investigators.  Critical illness factors associated with long-term mortality and health-related quality of life morbidity following community-acquired pediatric septic shock.   Crit Care Med. 2020;48(3):319-328. doi:10.1097/CCM.0000000000004122PubMedGoogle ScholarCrossref

3.Carlton  EF, Gebremariam  A, Maddux  AB,  et al.  New and progressive medical conditions after pediatric sepsis hospitalization requiring critical care. JAMA Pediatr. 2022;176(11):
e223554. doi:10.1001/jamapediatrics.2022.3554 ArticlePubMedGoogle ScholarCrossref

4.Carlton  EF, Barbaro  RP, Iwashyna  TJ, Prescott  HC.  Cost of pediatric severe sepsis hospitalizations.   JAMA Pediatr. 2019;173(10):986-987. doi:10.1001/jamapediatrics.2019.2570 ArticlePubMedGoogle ScholarCrossref

5.Souza  DC, Jaramillo-Bustamante  JC, Céspedes-Lesczinsky  M,  et al.  Challenges and health-care priorities for reducing the burden of paediatric sepsis in Latin America: a call to action. Lancet Child Adolesc Health. 2022;6(2):129-136. doi:10.1016/S2352-4642(21)00341-2 PubMedGoogle ScholarCrossref

6.Reinhart  K, Daniels  R, Kissoon  N, Machado  FR, Schachter  RD, Finfer  S.  Recognizing sepsis as a global health priority—a WHO resolution.   N Engl J Med. 2017;377(5):414-417. doi:10.1056/NEJMp1707170PubMedGoogle ScholarCrossref

7.Kissoon  N, Reinhart  K, Daniels  R, Machado  MFR, Schachter  RD, Finfer  S.  Sepsis in children: global implications of the World Health Assembly resolution on sepsis.   Pediatr Crit Care Med. 2017;18(12):e625-e627. doi:10.1097/PCC.0000000000001340PubMedGoogle ScholarCrossref

8.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.E6PubMedGoogle ScholarCrossref

9.Gebara  BM.  Values for systolic blood pressure.   Pediatr Crit Care Med. 2005;6(4):500. doi:10.1097/01.PCC.0000164344.07588.83PubMedGoogle ScholarCrossref

10.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.0000050454.01978.3BPubMedGoogle ScholarCrossref

11.Seymour  CW, Liu  VX, Iwashyna  TJ,  et al.  Assessment of clinical criteria for sepsis: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).   JAMA. 2016;315(8):762-774. doi:10.1001/jama.2016.0288 ArticlePubMedGoogle ScholarCrossref

12.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 ArticlePubMedGoogle ScholarCrossref

13.Shankar-Hari  M, Phillips  GS, Levy  ML,  et al; Sepsis Definitions Task Force.  Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).   JAMA. 2016;315(8):775-787. doi:10.1001/jama.2016.0289 ArticlePubMedGoogle ScholarCrossref

14.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 Australia and New Zealand, 2002-13: a multicentre retrospective cohort study.   Lancet Infect Dis. 2015;15(1):46-54. doi:10.1016/S1473-3099(14)71003-5PubMedGoogle ScholarCrossref

15.Watson  RS, Carcillo  JA, Linde-Zwirble  WT, Clermont  G, Lidicker  J, Angus  DC.  The epidemiology of severe sepsis in children in the United States.   Am J Respir Crit Care Med. 2003;167(5):695-701. doi:10.1164/rccm.200207-682OCPubMedGoogle ScholarCrossref

16.de Souza  DC, Gonçalves Martin  J, Soares Lanziotti  V,  et al; SPREAD PED Investigators and the Instituto Latino Americano de Sepsis Network.  The epidemiology of sepsis in paediatric intensive care units in Brazil (the Sepsis PREvalence Assessment Database in Pediatric population, SPREAD PED): an observational study.   Lancet Child Adolesc Health. 2021;5(12):873-881. doi:10.1016/S2352-4642(21)00286-8PubMedGoogle ScholarCrossref

17.Weiss  SL, Fitzgerald  JC, Pappachan  J,  et al; Sepsis Prevalence, Outcomes, and Therapies (SPROUT) Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network.  Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study.   Am J Respir Crit Care Med. 2015;191(10):1147-1157. doi:10.1164/rccm.201412-2323OCPubMedGoogle ScholarCrossref

18.Scott  HF, Deakyne  SJ, Woods  JM, Bajaj  L.  The prevalence and diagnostic utility of systemic inflammatory response syndrome vital signs in a pediatric emergency department  Acad Emerg Med. 2015;22(4):381-389. doi:10.1111/acem.12610PubMedGoogleScholarCrossref

19.Schlapbach  LJ, Straney  L, Bellomo  R, MacLaren  G, Pilcher  D.  Prognostic accuracy of age-adapted SOFA, SIRS, PELOD-2, and qSOFA for in-hospital mortality among children with suspected infection admitted to the intensive care unit.   Intensive Care Med. 2018;44(2):179-188. doi:10.1007/s00134-017-5021-8PubMedGoogle ScholarCrossref

20.Weiss  SL, Fitzgerald  JC, Maffei  FA,  et al; SPROUT Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators Network.  Discordant identification of pediatric severe sepsis by research and clinical definitions in the SPROUT international point prevalence study. Crit Care. 2015;19(1):325.doi:10.1186/s13054-015-1055-xPubMedGoogle ScholarCrossref

21.Wiens  MO, Larson  CP, Kumbakumba  E,  et al.  Application of sepsis definitions to pediatric patients admitted with suspected infections in Uganda.   Pediatr Crit Care Med. 2016;17(5):400-405. doi:10.1097/PCC.0000000000000708PubMedGoogle ScholarCrossref

22.Carrol  ED, Ranjit  S, Menon  K,  et al; Society of Critical Care Medicine’s Pediatric Sepsis Definition Taskforce.  Operationalizing appropriate sepsis definitions in children worldwide: considerations for the Pediatric Sepsis Definition Taskforce.   Pediatr Crit Care Med. 2023;24(6):e263-e271. doi:10.1097/PCC.0000000000003263PubMedGoogle ScholarCrossref

23.Sankar  J, Dhochak  N, Kumar  K, Singh  M, Sankar  MJ, Lodha  R.  Comparison of International Pediatric Sepsis Consensus Conference versus Sepsis-3 definitions for children presenting with septic shock to a tertiary care center in India: a retrospective study.   Pediatr Crit Care Med. 2019;20(3):e122-e129. doi:10.1097/PCC.0000000000001864PubMedGoogle ScholarCrossref

24.Raith  EP, Udy  AA, Bailey  M,  et al; Australian and New Zealand Intensive Care Society (ANZICS) Centre for Outcomes and Resource Evaluation (CORE).  Prognostic accuracy of the SOFA Score, SIRS Criteria, and qSOFA score for in-hospital mortality among adults with suspected infection admitted to the intensive care unit.   JAMA. 2017;317(3):290-300. doi:10.1001/jama.2016.20328 ArticlePubMedGoogle ScholarCrossref

25.Machado  FR, Nsutebu  E, AbDulaziz  S,  et al.  Sepsis 3 from the perspective of clinicians and quality improvement initiatives.   J Crit Care. 2017;40:315-317. doi:10.1016/j.jcrc.2017.04.037PubMedGoogle ScholarCrossref

26.Schlapbach  LJ, Weiss  SL, Bembea  MM,  et al; Pediatric Organ Dysfunction Information Update Mandate (PODIUM) Collaborative.  Scoring systems for organ dysfunction and multiple organ dysfunction: the PODIUM Consensus Conference.   Pediatrics. 2022;149(1)(suppl 1):S23-S31. doi:10.1542/peds.2021-052888DPubMedGoogle ScholarCrossref

27.Leteurtre  S, Duhamel  A, Salleron  J, Grandbastien  B, Lacroix  J, Leclerc  F; Groupe Francophone de Réanimation et d’Urgences Pédiatriques (GFRUP).  PELOD-2: an update of the pediatric logistic organ dysfunction score.   Crit Care Med. 2013;41(7):1761-1773. doi:10.1097/CCM.0b013e31828a2bbdPubMedGoogle ScholarCrossref

28.Matics  TJ, Sanchez-Pinto  LN.  Adaptation and validation of a pediatric Sequential Organ Failure Assessment score and evaluation of the Sepsis-3 definitions in critically ill children.   JAMA Pediatr. 2017;171(10):e172352. doi:10.1001/jamapediatrics.2017.2352
ArticlePubMedGoogle ScholarCrossref

29.Bembea  MM, Agus  M, Akcan-Arikan  A,  et al.  Pediatric Organ Dysfunction Information Update Mandate (PODIUM) contemporary organ dysfunction criteria: executive summary.   Pediatrics. 2022;149(1)(suppl 1):S1-S12. doi:10.1542/peds.2021-052888BPubMedGoogle ScholarCrossref

30.Schlapbach  LJ, Goertz  S, Hagenbuch  N,  et al; Swiss Pediatric Sepsis Study Group.  Organ dysfunction in children with blood culture-proven sepsis: comparative performance of four scores in a national cohort study.   Pediatr Crit Care Med. Published online October 25, 2023. doi:10.1097/PCC.0000000000003388PubMedGoogle ScholarCrossref

31.Balamuth  F, Scott  HF, Weiss  SL,  et al; Pediatric Emergency Care Applied Research Network (PECARN) PED Screen and PECARN Registry Study Groups.  Validation of the pediatric sequential organ failure assessment score and evaluation of Third International Consensus definitions for sepsis and septic shock definitions in the pediatric emergency department. JAMA Pediatr. 2022;176(7):672-678.doi:10.1001/jamapediatrics.2022.1301Article PubMedGoogle ScholarCrossref

32.Doust  J, Vandvik  PO, Qaseem  A,  et al; Guidelines International Network (G-I-N) Preventing Overdiagnosis Working Group.  Guidance for modifying the definition of diseases: a checklist.   JAMA Intern Med. 2017;177(7):1020-1025. doi:10.1001/jamainternmed.2017.1302
ArticlePubMedGoogle ScholarCrossref

33.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.2021-052565PubMed<a href="https://scholar.google.com/scholar_lookup?title=The%20current%20and%20future%20state%20of%20pediatric%20sepsis%20definitions%3A%20an%20international%20survey.&author=L%20Morin&author=M%2