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. 

In This Article

Discussion

Our systematic review evaluated over 50 variables and derived scores in studies on over 150,000 patients from diverse global settings. To our knowledge, this is the largest systematic review assessing a broad range of variables associated with severity of infection in children.[115] The majority of included studies in this review described features among septic children associated with higher mortality. We found evidence of increased odds of mortality for septic patients with severe acute malnutrition, chronic conditions, oncologic disorders, hypotension, use of inotropes, mechanical ventilation, decreased level of consciousness, and lower GCS. In addition, we found significant differences in VIS, base deficit, pH, lactate, platelets, fibrinogen, urea, creatinine, albumin, potassium, ALT, and procalcitonin between nonsurvivors and survivors. These findings provide support for using the above measures of organ dysfunction as hallmarks of sepsis and serve to inform data-driven development of revised pediatric sepsis criteria.

Our study evaluated data from 35 countries in diverse geographic regions and income levels of the World Bank Income classification.[18] This is important given that up to 85% of all sepsis cases and related deaths occur in lower income and middle-income countries.[2] However, although 18 included studies were conducted in LIC and LMIC countries, these represented only 1.8% (2,784/154,674) of the patients analyzed. The lower representation of LIC/LMIC patients may have resulted in our findings being more applicable to HIC/UMIC settings as a result of distinct causes of sepsis,[116] limited access to and availability of treatments,[117] and higher mortality rates[2] in patients with sepsis from LMIC/LIC settings. Large studies in LMIC/LIC settings remain challenging to perform due to the lack of comprehensive registries, electronic health records, and limited laboratory resources, which has important implications for the derivation, dissemination, and uptake of a revised definition of pediatric sepsis.

Only a small proportion of eligible studies (8/81, 9.9%), contributing 1.3% of included patients (2078/154,674), was from pre-ICU settings. This may have resulted in underrepresentation of early clinical variables used to differentiate self-limited febrile illness from critical illness and that may be important in sepsis definitions designed for the pre-ICU phase of illness.[118] Considering that most children with sepsis initially present to non-ICU settings, it is imperative that the future work of the Pediatric Sepsis Definition Taskforce also develops and validates tools for the recognition of sepsis outside of the ICU.

Previous sepsis definitions, such as the 2001 Consensus Conference[22] and 2005 IPSCC[3] definitions, included markers of organ dysfunction such as lactate, but their inclusion was the result of a consensus process and was never formally validated. The present systematic review allows prioritization of markers showing robust association with mortality for future revisions of sepsis criteria. Interestingly, bilirubin, used as the sole marker of liver dysfunction in the adult-adapted pSOFA score, was not associated with mortality, whereas another marker of liver dysfunction, ALT, performed well. In addition, measures of metabolic failure (increased serum lactate, acidosis, and base deficit) were confirmed as relevant markers despite not being part of the SOFA score. This review assessed individual variables as well as illness severity and organ dysfunction scores that incorporate combinations of the studied variables. This is an important contribution as many of the studied scores were derived and validated in critically ill children but not specifically studied in those with sepsis.

This review has several limitations. The first is that several variables included in the meta-analysis demonstrated significant heterogeneity. However, since the purpose of this review was to identify potential variables for use in an updated definition of pediatric sepsis rather than draw conclusions regarding a treatment effect, the actual effect size and its associated I 2 value may be less relevant. Second, our pragmatic approach resulted in the inclusion of studies with different definitions of sepsis. Although this may have limited our ability to find associations of some variables with our outcomes of interest, it may also have contributed to the robustness of the associations for other variables. Finally, for continuous variables, we were not able to determine thresholds for the development of sepsis or for mortality due to lack of data. However, we determined overall mean values for survivors and nonsurvivors for variables with a significant mean difference that could provide initial thresholds in the data validation phase of the Pediatric Sepsis Definition Taskforce project.

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