Criteria for Pediatric Sepsis

A Systematic Review and Meta-Analysis by the Pediatric Sepsis Definition Taskforce

Kusum Menon, MD, MSc; Luregn J. Schlapbach, MD, FCICM, PhD; Samuel Akech, MBChB, MMED, DPhil; Andrew Argent, MBBCh, MD(Paeds); Paolo Biban, MD; Enitan D. Carrol, MBChB, MD; Kathleen Chiotos, MD, MSCE; Mohammod Jobayer Chisti, MBBS, MMed, PhD; Idris V. R. Evans, MD, MSc; David P. Inwald, MB BChir, PhD; Paul Ishimine, MD; Niranjan Kissoon, MD; Rakesh Lodha, MD; Simon Nadel, MRCP; Cláudio Flauzino Oliveira, MD; Mark Peters, MBChB, PhD; Benham Sadeghirad, PharmD, MPH, PhD; Halden F. Scott, MD, MSCS; Daniela C. de Souza, MD; Pierre Tissieres, MD, DSc; R. Scott Watson, MD, MPH; Matthew O. Wiens, PharmD, PhD; James L. Wynn, MD; Jerry J. Zimmerman, MD, PhD; Lauren R. Sorce, RN, PhD

Disclosures

Crit Care Med. 2022;50(1):21-36.

Abstract and Introduction

Abstract

Objective: To determine the associations of demographic, clinical, laboratory, organ dysfunction, and illness severity variable values with: 1) sepsis, severe sepsis, or septic shock in children with infection and 2) multiple organ dysfunction or death in children with sepsis, severe sepsis, or septic shock.

Data Sources: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from January 1, 2004, and November 16, 2020.

Study Selection: Case-control studies, cohort studies, and randomized controlled trials in children greater than or equal to 37-week-old postconception to 18 years with suspected or confirmed infection, which included the terms "sepsis," "septicemia," or "septic shock" in the title or abstract.

Data Extraction: Study characteristics, patient demographics, clinical signs or interventions, laboratory values, organ dysfunction measures, and illness severity scores were extracted from eligible articles. Random-effects meta-analysis was performed.

Data Synthesis: One hundred and six studies met eligibility criteria of which 81 were included in the meta-analysis. Sixteen studies (9,629 patients) provided data for the sepsis, severe sepsis, or septic shock outcome and 71 studies (154,674 patients) for the mortality outcome. In children with infection, decreased level of consciousness and higher Pediatric Risk of Mortality scores were associated with sepsis/severe sepsis. In children with sepsis/severe sepsis/septic shock, chronic conditions, oncologic diagnosis, use of vasoactive/inotropic agents, mechanical ventilation, serum lactate, platelet count, fibrinogen, procalcitonin, multi-organ dysfunction syndrome, Pediatric Logistic Organ Dysfunction score, Pediatric Index of Mortality-3, and Pediatric Risk of Mortality score each demonstrated significant and consistent associations with mortality. Pooled mortality rates varied among high-, upper middle-, and lower middle-income countries for patients with sepsis, severe sepsis, and septic shock (p < 0.0001).

Conclusions: Strong associations of several markers of organ dysfunction with the outcomes of interest among infected and septic children support their inclusion in the data validation phase of the Pediatric Sepsis Definition Taskforce.

Introduction

Infections account for 26.5% of the global burden of disease^[1] and 25% of deaths in children worldwide.^[2] However, the clinical manifestations of these infections vary from minimal symptoms to multiple organ failure and death. The currently accepted definitions of sepsis, severe sepsis, and septic shock were developed and refined using different criteria to help identify, treat, and study patients with infections who are at higher risk of significant morbidity and mortality.^[3,4] However, specific variables identifying children with sepsis and their resulting outcomes have never been rigorously evaluated in a systematic review.

The 2016 sepsis definition update in adult patients (Sepsis-3) included a systematic review of reported criteria used to identify adults with septic shock.^[5] This review focused on hemodynamic criteria, was primarily limited to studies from upper middle-income countries (UMICs) and high-income countries (HICs), and specifically excluded pediatric studies. Furthermore, results of adult trials cannot be extrapolated to children because of differences in epidemiology,^[6] mortality rates,^[7] underlying diseases,^[8] disease-specific outcomes,^[9,10] and differing responses to therapy.^[11,12]

Therefore, the Society of Critical Care Medicine (SCCM) convened the Pediatric Sepsis Definition Taskforce to evaluate, develop, and validate criteria for the identification of sepsis in children. As part of this process, the Taskforce conducted a systematic review with the explicit goal of determining the ability of demographic, clinical, laboratory, organ dysfunction, and illness severity variables to capture children with more severe infections. For this purpose, we assessed association of these variables with: 1) sepsis, severe sepsis, or septic shock in children with suspected or confirmed infection and 2) with new or progressive multiple organ dysfunction (NPMODS) or mortality in children with sepsis, severe sepsis, or septic shock.

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Table 1. Characteristics of All Included Studies
Characteristic	Studies in Meta-Analysis (n = 81), n (%)	Patients From Meta-Analysis (n = 154,674), n (%)	Narrative Studies (n = 25), n (%)	Patients From Narrative Studies (n = 5,812)
Publication year
2004–2008	8 (9.9)	7,861 (5.1)	6 (24.0)	374 (6.4)
2009–2012	5 (6.2)	1,499 (0.1)	0 (0)	0 (0)
2013–2016	13 (16.0)	53,340 (34.4)	7 (28.0)	1,046 (18.0)
2017–2020	55 (67.9)	91,974 (59.4)	12 (48.0)	4,392 (75.6)
Participating sites
1	58 (71.6)	17,937 (11.6)	22 (88.0)	4,185 (72.0)
2–5	3 (3.7)	1,281 (0.8)	0 (0)	0 (0)
6–10	6 (7.4)	2,035 (1.3)	0 (0)	0 (0)
> 10	14 (17.3)	133,421 (86.3)	3 (12.0)	1,627 (28.8)
Region of primary site^a
North America	15 (18.5)	136,120 (88.0)	8 (32.0)	2,312 (39.8)
Latin America and Caribbean	13 (16.0)	3,387 (2.2)	2 (8.0)	57 (1.0)
Europe and Central Asia	13 (16.0)	3,807 (2.5)	7 (28.0)	694 (11.9)
East Asia and Pacific	19 (23.5)	8,053 (5.2)	1 (4.0)	1,510 (26.0)
South Asia	14 (17.3)	1,585 (1.0)	3 (12.0)	249 (4.3)
Middle East and North Africa	5 (6.2)	541 (0.3)	3 (12.0)	585 (10.1)
Sub-Saharan Africa	2 (2.5)	1,181 (0.8)	1 (4.0)	405 (7.0)
World Bank Income classification
High income country	33 (40.7)	142,364 (92.0)	14 (56.0)	4,351 (7.5)
Upper middle-income country	30 (37.0)	9,377 (6.1)	5 (20.0)	528 (9.1)
Lower middle-income country	17 (21.0)	1,812 (1.2)	6 (24.0)	923 (15.9)
Lower income country	1 (1.2)	1,121 (0.7)	0 (0)	0 (0)
Study design
Randomized controlled trial^b	1 (1.2)^a	50 (0.03)	0 (0)	0 (0)
Prospective cohort	38 (46.9)	9,634 (6.2)	14 (56.0)	1,160 (20.0)
Retrospective cohort	37 (45.7)	145,291 (94.1)	10 (40.0)	4,130 (71.1)
Case-control	5 (6.2)	499 (0.3)	1 (4.0)	72 (1.2)
Primary study setting^c
PICU	68 (84.0)	136,599 (88.3)	21 (84.0)	5,072 (87.3)
Emergency department	8 (9.9)	2,078 (1.3)	4 (16.0)	932 (16.0)
Ward	7 (8.6)	12,423 (8.0)	0 (0)	0 (0)
Other	3 (3.7)	3,574 (2.3)	0 (0)	0 (0)

^aSite of the corresponding author and or location of research ethics approval using the World Bank Classification of 2019–2020.
^bSecondary analysis of a randomized controlled trial.
^cTwo settings were unspecified and one included all hospital locations. In addition, some studies included more than one specified study location resulting in a total of more than 81 study locations.

Table 2. Patient Characteristics for All Included Studies
Characteristic	Studies in Meta-Analysis (n = 81), n (%)	Patients in Meta-Analysis (n = 154,674), n (%)	Narrative Studies (n = 25), n (%)	Patients in Narrative Studies (n = 5,812), n (%)
Age groups included^a
Neonates (0–30 d)	41 (50.6)	127,574 (82.5)	11 (44.0)	3,657 (62.9)
Babies (31–90 d)	70 (86.4)	151,730 (98.1)	22 (88.0)	1,510 (26.0)
Infants (91 d to 1 yr)	80 (98.8)	154,452 (99.9)	24 (96.0)	5,719 (98.4)
Toddlers (2–5 yr)	79 (97.5)	154,380 (99.8)	24 (96.0)	5,812 (100)
School age (6–12 yr)	73 (90.1)	152,810 (98.8)	22 (88.0)	5,652 (97.2)
Adolescents (13–16 yr)	62 (76.5)	151,283 (97.8)	19 (76.0)	5,248 (90.3)
Young adults (17–18 yr)	44 (54.3)	144,616 (93.5)	13 (52.0)	3,757 (64.6)
Population studied
Bronchiolitis	1 (1.2)	72 (0.0)	0 (0)
Meningococcal infections	2 (2.5)	1,151 (0.7)	1 (4.0)	151 (2.6)
Pneumonia	1 (1.2)	222 (0.1)	1 (4.0)	160 (2.8)
Diarrheal illness	2 (2.5)	270 (0.2)	0 (0)	0 (0)
Severe acute malnutrition	1 (1.2)	50 (0.0)	0 (0)	0 (0)
Bone marrow transplant	0 (0)	0 (0)	1 (4.0)	567 (9.8)
Oncology—general	4 (4.9)	768 (0.5)	1 (4.0)	99 (1.7)
Oncology—febrile neutropenia	1 (1.2)	151 (0.1)	0 (0)	0 (0)
Emergency department patients	5 (6.2)	1,664 (1.1)	4 (16.0)	740 (12.7)
Hospital ward patients	6 (7.4)	24,778 (16.0)	0 (0)	0 (0)
Any PICU admission	58 (71.6)	125,539 (81.2)	17 (68.0)	4,095 (70.5)
Sepsis definition used^b
2001 SCCM/ACCP criteria	7 (8.6)	2,317 (1.5)	2 (8.0)	93 (1.6)
2005 International Pediatric Sepsis Consensus Conference	57 (70.4)	56,377 (36.4)	17 (68.0)	5,274 (90.7)
ACCM 2002	2 (2.5)	126 (0.1)	1 (4.0)	57 (0.1)
ACCM 2007	1 (1.2)	1,299 (0.8)	1 (4.0)	71 (1.2)
International Classification of Diseases, 9th Edition codes	6 (7.4)	86,594 (56.0)	0 (0)	0 (0)
Bone criteria	2 (2.5)	431 (0.3)	2 (8.0)	166 (2.9)
Sepsis-3	2 (2.5)	7,091 (4.6)	0 (0)	0 (0)
Other	4 (4.9)^c	439 (0.3)	2 (8.0)^d	151 (2.6)

ACCM = American College of Critical Care Medicine, ACCP = American College of Chest Physicians, SCCM = Society of Critical Care Medicine.
^aValues for age groups from eligible articles were included in category that provided the closest approximation to the classification used in the article. Articles could have patients from more than one age group resulting in totals being > 100%.
^b1. Bone RC, et al: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992; 101:1644–1655. 2. Levy et al (22). 3. Carcillo JA, et al: Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med 2002; 30:1365–1378. 4. Goldstein et al (3). 5. Brierley J, et al: Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009; 37:666–688. 6. Singer M, et al: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:801–810.
^cThree papers referred to hospital guidelines and one defined sepsis as tachycardia plus hypothermia (35.0°C) or hyperthermia (38.5°C), or abnormal WBC count plus poor peripheral perfusion (mean arterial pressure 50 mm Hg and/or absent peripheral pulses or capillary refilling time 3 s) in the absence of clinical dehydration.
^dOne paper used Carrol ED, et al: The role of RANTES in meningococcal disease. J Infect Dis 2000; 182:363–366 and one referenced Abraham E, et al: Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: Time for a re-evaluation. Crit Care Med 2000; 28:232–235.

Table 3. Summary of Variables With Significant Associations With Outcomes of Interest
Variable	No. of Studies	No. of Participants With Outcome^a	No. of Participants Without Outcome^a	Pooled Estimate^b (95% CI)	Mean Value in Two Groups^c	p for Heterogeneity	I ² Value (%)
Variables significantly associated with outcome of sepsis, severe sepsis, or septic shock
Decreased LOC	4	172/369	354/2,565	9.8 (5.8–16.7)		0.080	55.7
PRISM score	2	1,695	3,612	6.0 (4.0–8.0)	9.5 vs 3.5	< 0.0001	93.3
Variables significantly associated with outcome of mortality
Demographic variables
Severe acute malnutrition	3	30/135	57/450	4.7 (1.4–16.3)		0.094	57.8
Chronic conditions	11	859/1,464	13,013/25,664	2.4 (1.4–4.1)		< 0.0001	85.7
Oncologic conditions	8^d	104/402	616/2,422	2.3 (1.7–3.1)		0.63	0.0
Clinical variables
Hypotension	4	1,013/1,910	10,828/41,283	2.3 (1.8–2.9)		0.052	61.1
Vasoactive agents	20	623/739	1,831/3,475	6.5 (4.2–10.0)		< 0.0001	59.7
Vasoactive-inotropic score	6	175	468	23.5 (3.4–43.6)	49.3 vs 20.4	< 0.0001	87.5
Stroke index	3	165	295	0.2 (0.1–0.4)	1.8 vs 1.7	0.42	0.0
Mechanical ventilation	30	2,778/3,350	22,874/51,151	11.0 (7.4–16.3)		< 0.0001	84.2
Decreased LOC	3	1,147/1,813	10,975/38,744	4.1 (2.9–5.9)		0.22	33.6
Glasgow Coma Scale	3	134	176	–4.0 (–6.2 to –1.8)	6.6 vs 11.0	0.10	56.5
Laboratory variables
pH	4	203	334	–0.10 (–0.14 to –0.05)	7.21 vs 7.31	0.077	56.1
Lactate (mmol/L)	17	900	3,867	1.9 (1.2–2.6)	4.6 vs 2.7	< 0.0001	94.4
Base deficit	6	570	2,377	–3.2 (–5.8 to –0.6)	–9.1 vs –5.9	< 0.0001	98.1
Urea (mg/dL)	4	326	1,750	1.5 (0.7–2.3)	9.4 vs 6.2	0.075	56.6
Creatinine (μmol/L)	8	471	2,148	13.0 (4.6–21.5)	62.4 vs 42.8	< 0.0001	89.0
Potassium (meq/L)	3	268	1,447	0.2 (0.02–0.44)	4.5 vs 4.3	0.92	0.0
Platelet count (10⁹/L)	14	585	3,196	–87 (–107 to –67)	90 vs 178	< 0.0001	90.9
Fibrinogen (g/L)	5	324	2,503	–1.5 (–2.5 to –0.6)	2.0 vs 3.6	< 0.0001	97.9
Albumin (g/L)	3	237	563	–4.3 (–8.4 to –0.2)	31.0 vs 35.4	< 0.0001	92.5
Procalcitonin (ng/ml)	9	463	1,266	4.0 (2.0–6.0)	7.8 vs 4.8	< 0.0001	92.2
Alanine aminotransferase (units/L)	3	298	1,262	10.1 (4.0–16.2)	97.3 vs 65.8	0.46	0.0
Organ dysfunction and illness severity variables
No. of organ dysfunctions	4	1,065	4,683	0.9 (0.3–1.5)	3.4 vs 2.5	< 0.0001	92.6
Renal dysfunction	4	77/160	84/323	4.0 (1.0–18.4)		< 0.0001	86.2
Multiple organ dysfunction syndrome	9^c	388/467	816/1,986	7.8 (3.9–15.6)		< 0.0001	75.2
PELOD	12^c	442	1,748	6.1 (2.5–9.8)	16.7 vs 8.7	< 0.0001	97.7
PELOD-2	3	110	1,320	8.7 (5.7–11.6)	10.4 vs 1.2	< 0.0001	91.2
Sequential Organ Failure Assessment	2	95	647	3.8 (2.7–4.9)	9.9 vs 5.9	0.16	50.4
Pediatric Sequential (Sepsis-related) Organ Failure Assessment	4	595	756	4.8 (3.7–5.8)	10.0 vs 4.2	0.52	0.0
PRISM	19	821	3,871	11.0 (5.6–16.5)	22.5 vs 11.5	< 0.0001	99.6
PIM-2	2	63	397	12.1 (9.3–14.9)	35.6 vs 18.0	0.33	0.0
PIM-3	5^c	245	1,455	7.8 (2.5–13.1)		< 0.0001	89.1

LOC = level of consciousness, PELOD = pediatric logistic organ dysfunction, PIM = Pediatric Index of Mortality, PRISM = Pediatric Risk of Mortality.
^aNumbers reported are totals for those with and without the listed outcome for each parameter for continuous variables. For categorical variables, the numbers shown are the number with the parameter over the total with or without the outcome of interest.
^bPooled estimate is for the odds ratio for categorical variables and the mean difference for continuous variables.
^cThe mean values of nonsurvivors versus survivors are provided for all continuous variables.
^dThe study by Thakkar et al (23) reported on two nonoverlapping cohorts of medical and surgical patients that were, therefore, analyzed separately and counted as two studies.

Authors and Disclosures

Kusum Menon, MD, MSc¹, Luregn J. Schlapbach, MD, FCICM, PhD², Samuel Akech, MBChB, MMED, DPhil³, Andrew Argent, MBBCh, MD(Paeds)⁴, Paolo Biban, MD⁵, Enitan D. Carrol, MBChB, MD⁶, Kathleen Chiotos, MD, MSCE⁷, Mohammod Jobayer Chisti, MBBS,, MMed, PhD⁸, Idris V. R. Evans, MD, MSc⁹, David P. Inwald, MB BChir, PhD¹⁰, Paul Ishimine, MD¹¹, Niranjan Kissoon, MD¹², Rakesh Lodha, MD¹³, Simon Nadel, MRCP¹⁴, Cláudio Flauzino Oliveira, MD¹⁵, Mark Peters, MBChB, PhD¹⁶, Benham Sadeghirad, PharmD, MPH,, PhD¹⁷, Halden F. Scott, MD, MSCS¹⁸, Daniela C. de Souza, MD¹⁹, Pierre Tissieres, MD, DSc²⁰, R. Scott Watson, MD, MPH²¹, Matthew O. Wiens, PharmD, PhD^22,23, James L. Wynn, MD²⁴, Jerry J. Zimmerman, MD, PhD²¹ and Lauren R. Sorce, RN, PhD²⁵ for the Pediatric Sepsis Definition Taskforce of the Society of Critical Care Medicine

1 Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada.
2 Pediatric and Neonatal ICU, University Children's Hospital Zurich, Zurich, Switzerland, and Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia.
3 KEMRI Wellcome Trust Research Program, Nairobi, Kenya.
4 Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital and University of Cape Town, Cape Town, South Africa.
5 Department of Paediatrics, Verona University Hospital, Verona, Italy.
6 Department of Clinical Infection Microbiology and Immunology, University of Liverpool Institute of Infection, Veterinary and Ecological Sciences, Liverpool, United Kingdom.
7 Children's Hospital of Philadelphia, Philadelphia, PA.
8 International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.
9 Department of Critical Care Medicine, University of Pittsburgh School of Medicine, and The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Pittsburgh, PA.
10 Paediatric Intensive Care Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
11 Departments of Emergency Medicine and Pediatrics, University of California San Diego School of Medicine, La Jolla, CA.
12 Department of Pediatrics, University of British Columbia and British Columbia Children's Hospital, Vancouver, BC, Canada.
13 All India Institute of Medical Sciences, Delhi, India.
14 St. Mary's Hospital, Imperial College Healthcare NHS Trust, and Imperial College London, London, United Kingdom.
15 Associação de Medicina Intensiva Brasileira, São Paulo, Brazil.
16 University College London Great Ormond Street Institute of Child Health, London, United Kingdom.
17 Departments of Anesthesia and Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
18 Departments of Pediatrics and Emergency Medicine, University of Colorado School of Medicine, Aurora, CO.
19 Departments of Pediatrics, Hospital Sírio-Libanês and Hospital Universitário da Universidade de São Paulo, São Paolo, Brazil.
20 Pediatric Intensive Care, AP-HP Paris Saclay University, Bicêtre Hospital, Le Kremlin-Bicêtre, France.
21 Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA.
22 University of British Columbia, Vancouver, BC, Canada.
23 Mbarara University of Science and Technology, Mbarara, Uganda.
24 Department of Pediatrics, University of Florida, Gainesville, FL.
25 Ann & Robert H. Lurie Children's Hospital and Department of Pediatrics, Northwestern University Feinberg School of Medicine, Lurie Children's Pediatric Research & Evidence Synthesis Center (PRECIISE): A JBI Affiliated Group, Chicago, IL.

Address requests for reprints to
Kusum Menon, MD, MSc, Rm 3446, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada. E-mail: menon@cheo.on.ca

Dr. Menon has a Canadian Institutes of Health Research grant for the study of corticosteroids in pediatric septic shock. Dr. Menon's institution received funding from Crowdsourcing; he disclosed that he is a principal investigator on an international trial on Steroids in Pediatric Sepsis Shock. Drs. Menon and Watson received funding from Society of Critical Care Medicine. Dr. Argent received funding from the World Federation of Pediatric Intensive and Critical Care Societies as a part of the process of working with the Pediatric Sepsis Definitions working group. Dr. Biban received funding from Chiesi and Getinge. Dr. Nadel received funding from Abbvie. Dr. Sadeghirad received funding from the Pre-Interventional Preventative Risk Assessment AG, Mitacs Canada, and Accelerate internship in partnership with Nestlé Canada. Dr. Scott's institution received funding from the Agency for Healthcare Research and Quality (AHRQ K08HS025696); he received support for article research from the AHRQ. Dr. Tissieres received funding from Sedana, Inotrem, and Baxter. Dr. Wynn received funding from the National Institutes of Health (NIH) (R01GM128452; R01HD089939, R01HD097081, R43EB029863). Dr. Zimmerman's institution received funding from the NIH, the National Institute of Child Health and Human Development, and Immunexpress; he received funding from Elsevier Publishing. The remaining authors have disclosed that they do not have any potential conflicts of interest.