We have new sepsis criteria for children…now what?

Sepsis in children continues to be a major public health problem, with millions of children affected by death and disability every year worldwide.^1–5 Defining pediatric sepsis, however, has been problematic. The previous criteria developed by the International Pediatric Sepsis Consensus Conference in 2005⁶ based on systemic inflammatory response syndrome (SIRS) criteria had low specificity, low sensitivity, did not allow for risk stratification in both lower- and higher-resource settings, and were discordant with clinician-based diagnosis of sepsis.^7,8 In 2019, the Society of Critical Care Medicine (SCCM) Pediatric Sepsis Definition Task Force was convened to update the pediatric sepsis definition and the operational criteria to diagnose sepsis. The Task Force included a diverse group of experts, including specialists in critical care, emergency medicine, infectious disease, nursing, pharmacists, and informatics from both high and low resource settings. For this endeavor, the Task Force performed an international survey of almost 3,000 clinicians and conducted a large systematic review of associations between markers of organ dysfunction and outcome in children with infection.⁹³ Informed by the findings from the survey and the systematic review, they applied interpretable machine learning models to pediatric electronic health record (EHR) data–3.6 million encounters from 10 hospitals in 5 countries. The goal was to operationalize the concept of sepsis as a “suspected infection with life-threatening organ dysfunction”⁸ by deriving and validating models to discriminate mortality using individual organ dysfunction subscores among children with suspected infection.³ The two best-performing models were then evaluated by the Task Force. One model, which included variables for cardiovascular, respiratory, neurologic, and coagulation organ dysfunction, was selected via a modified Delphi consensus process given its greater simplicity and lower dependence on laboratory values. This model was then translated into an integer-based score, the Phoenix Sepsis Score (PSS), that was found to have better performance than previous organ scoring systems at nearly all clinical sites. Again through a Delphi consensus process, members of the Task Force chose a PSS of >=2 as the threshold for sepsis in children with suspected or confirmed infection, and sepsis plus at least one cardiovascular point to define septic shock. The new Phoenix criteria and score were presented in the 2024 SCCM Annual Congress in Phoenix, Arizona, and published simultaneously in a pair of articles in JAMA.^5,8

The diagnosis and management of sepsis can occur at any point along the acute care continuum: pre-hospital, the emergency department, the acute care wards, or the intensive care unit. Importantly, sepsis is not a singular phenomenon that occurs at a single time point. Generally, the course of sepsis and, by extension, its management, can be divided into two time periods: pre-diagnosis and post-diagnosis. In the pre-diagnosis stage, sepsis must be screened for among patients at risk, and those who achieve a high-enough level of suspicion for sepsis (either based on clinician judgment alone or clinician judgment informed by an algorithm or a data-driven tool) should receive empiric therapy and organ support as needed until a diagnosis of sepsis is confirmed or refuted. The management of sepsis should be guided by clinical best practice guidelines, such as the Surviving Sepsis Guidelines for Children,¹⁰ including fluid balance, antimicrobial duration, nutrition initiation, blood product administration, vasoactive use, need for extracorporeal therapies, etc. The Phoenix criteria for sepsis were designed to define the transition between pre-diagnosis and post-diagnosis, and not for use in decision-making in the pre-diagnosis/screening phase. Developing accurate early screening criteria remains an active area of work and improvement in all acute care settings. The new criteria were designed instead to define the start of a post-diagnosis phase that is more concordant with clinician diagnosis of sepsis. This consistency can be leveraged to implement best clinical practices for management. The new criteria will also facilitate more consistent patient cohorts for benchmarking, quality improvement, and research in all acute care settings, including the acute care wards, an improvement over SIRS-based criteria. Even with increased consistency in patient identification, sepsis is increasingly being recognized as having potential subtypes that may have different risks or responses to treatments.¹¹ With new diagnostic criteria now in place, an important next focus of study should be the definition of these subtypes of sepsis. Although a central tenet of the SCCM Pediatric Sepsis Task Force was that organ dysfunction is relevant for any form of sepsis, it is important to assess the performance of the Phoenix criteria and PSS in subgroups of infected patients who may differ from the general population of patients with infection and sepsis.

In this edition of Pediatric Hospital Medicine, Tripathi et al. present a retrospective cohort study describing the prevalence of sepsis by Phoenix criteria and validating the performance of the PSS to predict mortality in children with suspected or confirmed COVID-19 or Multisystem Inflammatory Syndrome in Children (MIS-C).¹² They did this by performing a secondary analysis of the SCCM Viral Infection and Respiratory Illness Universal Study (VIRUS). COVID19 and MIS-C are potentially distinct subgroups of infection-related conditions that were not included in the original Phoenix cohort who can receive different treatments than the general population of sepsis, including immunomodulators and novel antivirals. Despite these potential differences, the Phoenix criteria and the PSS were able to discriminate most of the children with COVID19 or MIS-C who died during their hospitalization. There was, however, a notable difference between the VIRUS cohort compared to the original Phoenix dataset. The mortality was overall lower in the VIRUS cohort (sepsis 4.6%; septic shock 5.4%) than among the children meeting Phoenix sepsis criteria (for high resource settings: sepsis 7.1%; septic shock 10.8%), which resulted in a relatively higher area under the receiver operating characteristic curve (AUROC) and lower area under the precision-recall curve (AUPRC) in the VIRUS cohort. Notably, an even lower mortality rate was seen in children with MIS-C (2.5%), despite MIS-C pathophysiology often being associated with significant cardiovascular dysfunction. There are several potential explanations for these findings. First, it is possible that once identified, specific treatments (i.e. antivirals, immunomodulators) for COVID19 and/or MIS-C reduced mortality risk more effectively than typical therapies do for other forms of sepsis and septic shock. Second, it is possible that the VIRUS cohort did contain enough positive cases to validate the performance of the criteria with confidence. Fewer than 100 events (deaths) occurred in the VIRUS cohort, below the threshold recommended by experts for validation of models and scores.¹³ Third, the source of the VIRUS data is a registry, rather than directly from EHR systems as in the Phoenix dataset. This is important because the PSS was derived and validated using the highest values in the first 24 hours of an encounter. The current study assumes that the values needed to capture the highest possible score in a 24-hour timeframe have been entered into the registry in order to mimic data collection appropriately, and that the 24 hours entered into the registry were also the first 24 hours of the encounter, as there are no timestamps in the VIRUS registry. Fourth, increased vigilance during the pandemic might have led to faster detection and treatment of COVID19 and/or MIS-C in children, thereby resulting in lower mortality. Finally, during the pandemic there was a reduced exposure to other infections, and so a reduced number of co-infections could have made these patients lower risk.

While recent articles have found that Phoenix criteria had strong test characteristics in children identified with suspected sepsis in the ED,¹⁴ transported to ICU,¹⁵ and hospitalized with cancer,¹⁶ this study in a lower-mortality population of children with COVID and MIS-C found it had a lower AUPRC. Nevertheless, this study supports the central tenet that organ dysfunction is relevant for discriminating risk of mortality in any form of sepsis and that the Phoenix criteria and the PSS may be useful tools to assess risk of mortality for children with any type of suspected infection or infection-related condition. This study adds to the important work being done to evaluate the test characteristics of the Phoenix criteria in relevant subpopulations. This includes children who develop sepsis in the inpatient wards. In a recently published study, we found that patients who were admitted to the inpatient ward for more than 72 hours prior to PICU admission, had a suspected hospital-acquired infection, and met Phoenix sepsis criteria within 24 hours of PICU admission, mortality was substantially higher than the overall PICU sepsis mortality rate (19.9% vs 9%).¹⁷ How we incorporate that information into our practice throughout the spectrum of sepsis care across the acute care continuum remains the next big question ripe for investigation: (1) How will the Phoenix sepsis criteria and the PSS drive interventions, and how does this protocolized sepsis care intersect with other important values like resource stewardship? (2) How will the Phoenix sepsis criteria and PSS integrate into established rapid response systems? (3) How does the score perform in acute care environments when included tests may not be ordered, documentation may be delayed, and new onset sepsis is rare? (4) How will we handle the repeated measures and alert challenges of transitioning from a score that was derived based on the worst value in a 24 hour period to implementations that result in continuously recalculated scores with new EHR data?¹⁸ We look forward to the important Phoenix sepsis criteria and PSS work to come.