From Pediatric Sepsis Epidemiologic Data to Improved Clinical Outcomes*

Pediatric sepsis contributes disproportionately to global sepsis cases and mortality. It is estimated to have contributed to more than 3 million deaths in children and adolescents globally in 2017 (1). Although these are staggering numbers, the current estimates rely on many assumptions and imputation methods (2). Sepsis is primarily a disease of the socioeconomically disadvantaged populations; yet, data are scant, especially from the Global South, and much of what we "know" about pediatric sepsis is extrapolated from the adult sepsis literature as well as a few global reviews and estimates (3–5) In this issue of Pediatric Critical Care Medicine, Liu et al (6), undertook a regional, prospective cohort study in 12—of the 31 invited to participate—PICUs in tertiary care hospitals located in Southwest China. This study aimed to directly measure the prevalence of pediatric (non-neonatal) severe sepsis and septic shock and associated hospital outcomes over a 1-year period (April 2022 to March 2023). Across participating PICUs, the prevalence of severe sepsis/septic shock was 3.3% and was associated with an 11.2% inpatient mortality. This is notably less than the global point prevalence study—Sepsis Prevalence, Outcomes, and Therapies—which reported an 8.2% prevalence of severe sepsis/septic shock and 25% mortality (7). A study we conducted more than a decade (September 2010 to August 2011) earlier in 11 regional hospitals in the Jiangsu region of China, revealed similar findings except for higher inpatient mortality (8); the case fatality rate for children with sepsis was 3.5% (53/1530) and, in children with severe sepsis/septic shock, it was 10-fold higher (34.6% [53/153]) (8). Although it seems that not much has changed in the intervening decade, the current report by Liu et al (6) adds to our understanding of the intractable burden of pediatric sepsis in China. Furthermore, it highlights the need for both a national sepsis database and action plan, and facility-level quality improvement and education initiatives. Despite this contribution, there are some critical aspects of the study by Liu et al (6), that render the findings difficult to interpret as well as challenging to compare across sites; thus, the potential impact is limited. The approach to sepsis management between centers was not protocolized, but rather left to "the experience of the physician." Although the experienced physician with an intimate knowledge of contemporary sepsis management is capable of providing superb care, it is unlikely that all physicians across 12 centers would deliver a similar standard of care. Thus, without protocolized sepsis treatment within and across centers, it is impossible to draw meaningful conclusions about the potential effect of specific interventions on clinical outcomes. For instance, it is difficult to decipher whether the 11% inpatient mortality observed in Liu et al (6), signals an improvement in high-quality sepsis care and/or earlier sepsis recognition compared with the 2011 study, or whether the 34% inpatient mortality associated with septic shock from 2011 reflects a sicker cohort. It is even more problematic to compare pediatric sepsis outcomes in Liu et al (6) to findings from other regions of the world; the authors insightfully acknowledge that "[t]he results of the study in Southwest China cannot represent the characteristics of pediatric sepsis in the whole China." Additionally, "usual care" in participating centers in Liu et al (6) deviated significantly from the current international, pediatric Surviving Sepsis Campaign guidelines (4). This is most evident in the liberal use of adjunctive sepsis therapies, which may be explained by physician preference, "experience," or bias (4). For example in this cohort, 82% of subjects received methylprednisolone, 51% received albumin infusions, and 51% received IV immunoglobulin, despite the fact that there are currently no high-quality data to support the routine use of these therapies (4). Interestingly, in the Liu et al (6) cohort, approximately the same proportion of subjects received fluid resuscitation (46.9%) as received vasoactive support (46.6%); however, per existing Surviving Sepsis Campaign (4), World Health Organization (9), and Pediatric Advanced Life Support (10) sepsis guidelines, fluid administration is the first step in sepsis resuscitation while vasoactive medications are reserved for "fluid-refractory" cases. This degree of practice variation is certainly not unique to these centers and likely speaks to the lack of primary pediatric sepsis data and, therefore, the scarcity of strong, evidenced-based pediatric guidelines (4). It may also be, in part, because pediatric sepsis in China has unique characteristics and may require a tailored management approach that deviates from the recommendations provided by the Surviving Sepsis Campaign guidelines (4). Conceptually, sepsis is characterized by a dysfunctional host response to a presumed or proven infection that leads to organ dysfunction and failure (11). The present definition for pediatric sepsis, however, is based on systemic inflammatory response syndrome (SIRS) criteria and it lacks specificity and sensitivity, which has led to confusion in identifying and classifying children with sepsis (11–13). The current definition also has poor discriminant validity; SIRS criteria are frequently present in hospitalized patients including those without infection and those who never experience a poor outcome (9–11). In this cohort study, Liu et al (6) used the International Pediatric Sepsis Consensus Conference definition for pediatric severe sepsis and septic shock, which are based on the presence of SIRS criteria (14). In a recent retrospective cohort study of over 1800 children admitted to PICUs in China with an infection, an age-adapted Sequential Organ Failure Assessment (SOFA) was better at predicting in-hospital mortality and more sensitive for identifying children with severe infection as compared with SIRS criteria (12). Liu et al (12) reported that both a low pediatric critical incident score and an elevated pediatric SOFA score were associated with sepsis mortality, though this is difficult to interpret when applied to a sepsis cohort defined by SIRS criteria. The definition of sepsis in children is now undergoing a reappraisal that may help to standardize the reporting of sepsis. The greatest strengths of epidemiologic studies like the one conducted by Liu et al (6) are to establish the baseline prevalence of a disease, measure associated outcomes, and identify opportunities for quality improvement initiatives targeting quality of care and patient outcomes. The diverse treatment approaches and variation in practice between tertiary hospital PICUs observed in Liu et al (6) suggest the need for quality improvement initiatives that target standardization of sepsis care based on international guidelines and physician education (8). Hospital-based sepsis management protocols have been shown to standardize care and improve outcomes, including mortality, hospital length of stay, and decreased organ dysfunction, in children with severe sepsis and septic shock (15–18). Most of these studies have focused on the timely, appropriate administration of a sepsis bundle that typically includes obtaining a blood culture, providing fluid resuscitation, and administering early antibiotics (15–18). In a retrospective cohort study in pediatric patients with sepsis conducted in 54 New York State hospitals (n = 1179), completion of a sepsis bundle within 1-hour was associated with a significantly lower risk-adjusted odds of in-hospital mortality (0.59; 95% CI, 0.38–0.93) (18). Available evidence shows a strong and consistent association: sepsis protocol implementation and adherence reduce variability in care and improve patient outcomes. Although strong quality improvement initiatives can improve patient outcomes, protocolized management alone is not enough to end pediatric sepsis mortality. Sepsis is a complex interplay between the host and pathogen (9); it is a heterogeneous clinical entity characterized by differences inpatient comorbidities (47% in Liu et al [6]) and infectious etiologies, and outcomes are affected by access to care, provider knowledge, monitoring capabilities, and resource availability across and within regions that demands context-specific approaches to care delivery. Furthermore, distinct sepsis endotypes, which are subtypes defined by a distinct functional or pathobiological mechanism, may manifest varying responses to therapy depending on the endotype (19,20). Protocolized treatment is preferred in most instances when the goal is to deliver high-quality care, compare treatment strategies, and test the efficacy of interventions; however, there will likely always be some role for a personalized, thoughtful approach to pediatric sepsis management. There is no question that pediatric sepsis is serious and life-threatening, resulting in high morbidity and mortality worldwide (1). Sepsis epidemiologic data are valuable; a "pediatric sepsis-specific database" and the use of the existing pediatric sepsis common data elements (14) would standardize data collection and allow for pooling of data across sites and studies, thus increasing the power and generalizability of the results. To improve patient outcomes, however, what is desperately needed are pediatric sepsis quality improvement initiatives, as well as a better understanding of the pathobiology of sepsis in different patient populations from both the Global North and South. Much needs to be done both locally and globally as outlined in the World Health Organization 2017 resolution on sepsis (21). The enormity of the socioeconomic burden of sepsis to children and families demands a concerted effort.