Hello, and thank you so much for the invitation to speak today. My name is Erin Carlton, and I'm an assistant professor in the Division of Pediatric Critical Care Medicine and faculty investigator in the Susan B. Meister Child Health Evaluation and Research Center at the University of Michigan. And today I'm going to speak with you on pediatric sepsis definitions, do they matter? I have no conflict of interest or disclosures to report. Today we will discuss how sepsis is defined in children, do these definitions matter, and what's coming next in terms of pediatric sepsis definitions. Each year, there are an estimated 1.2 million cases of pediatric sepsis worldwide. In the United States, this results in approximately 75,000 hospitalizations for severe sepsis, demonstrating the significant health impact that sepsis has on children. There are many different definitions for sepsis, including those used at the bedside clinically, those used for administrative purposes, and those used for research, such as in clinical trials. No single definition is going to be perfect for all scenarios, and because of this, there are varying definitions which are used. The concept of sepsis has been discussed for centuries as evidence in the writings of Homer and Hippocrates. However, it wasn't until 1992 that a formal consensus definition was developed. Since that time, there have been updates to the original definition, the addition of administrative or coding-based definitions, and the introduction of pediatric sepsis definitions in 2005. The first modern definition of sepsis came in 1992 with sepsis 1, which defined SERS, or the systemic inflammatory response syndrome, and organ dysfunction as they related to infection. Almost a decade later, sepsis 2 continued with this model of infection and inflammation, expounding on the SERS diagnostic criteria. Most recently, in 2016, the third international consensus definitions for sepsis and septic shock, or sepsis 3, redefined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection. It's important to note that the SERS criteria used in sepsis 1 and sepsis 2 were no longer included in the definition. In 2005, the International Pediatric Sepsis Consensus Conference published a modified definition for severe sepsis and septic shock for the pediatric population. So why are different definitions necessary for children? First, we have to consider the physiologic impact of age. Clinical variables such as vital signs are significantly affected by the normal physiologic changes which occur throughout childhood. The normal heart rate, respiratory rate, and blood pressure are different for a four-month-old, four-year-old, and 14-year-old. Therefore, our definitions must take this into account and use age-specific parameters. Secondly, the clinical presentation of a disease process is different for children. Tachycardia and tachypnea are often early, if not the first symptoms of illness, while decline in blood pressure is a late manifestation. With that, the previously used definitions of SERS could include children who are having a normal and appropriate physiologic response to illness with increased heart rate and respiratory rates. Alternatively, because shock definitions in the adult population required hypotension, those definitions may exclude some children in shock who do not have adequate perfusion or oxygen delivery but were not yet hypotensive. With these differences in mind, the International Consensus Conference on Pediatric Sepsis constructed and published the first pediatric sepsis definition in 2005. Specifically, the group's goal was to develop definitions and criteria for the components of the sepsis continuum that could be consistently applied to children. Using a similar framework of sepsis 1 and sepsis 2 definitions, the group created pediatric-specific definitions for SERS, sepsis, severe sepsis, and septic shock. Recognizing the impact of a child's age, the group developed age-specific criteria for organ dysfunction and, as shown in this table, for SERS variables. Additionally, it's important to note that because of the normal response of tachycardia and tachypnea in the pediatric population, the guidelines required either the presence of temperature abnormality or white blood cell count abnormality to be present for a child to meet SERS criteria. There have not been updates to the pediatric definition of sepsis since 2005, but with the new adult definitions published in 2016, could the pediatric equivalent of sepsis 3 be applied to children? Doctors Maddox and Santosh Pinchot evaluated this in a cohort of nearly 9,000 children hospitalized in a pediatric ICU and demonstrated that the PSOPA score could be applied to a PICU population. These pediatric sepsis 3 definitions identified a group of children with high mortality and microbiologic characteristics or the presence of bacterial or viral infections similar to prior studies of pediatric severe sepsis. In addition to the clinical diagnosis of sepsis, the ability to define it in administrative claims databases would allow researchers and policymakers to evaluate sepsis through a different mechanism or a different lens. Given this, in 2001, Dr. Angus and colleagues developed the first criteria to identify patients with severe sepsis using the International Classification of Diseases, or ICD-9, codes. They defined severe sepsis as the presence of infection, specifically bacterial or fungal infection, and at least one organ dysfunction. Following this original definition, there have been other schemas developed which required simultaneous use of sepsis or bacteremia rather than infection alone in addition to organ dysfunction. Finally, there are specific ICD-9 and now ICD-10 codes for sepsis, severe sepsis, and septic shock, which can be used to identify a patient cohort. But do these definitions matter? Are there differences in the patient populations identified and in the clinical outcomes seen depending on how a group of patients with severe sepsis is identified? The short answer is yes, definitions matter. In this study, Dr. Malamuth and team examined the ability of different ICD-9 coding strategies to identify severe sepsis and septic shock as defined by the international consensus criteria at six U.S. children's hospitals. They found that sepsis-specific codes had a much higher sensitivity and specificity to identify children with severe sepsis compared to coding strategies that used infection plus organ dysfunction. In addition, the definition of sepsis used can result in the identification of different groups of children. In a study of nearly 7,500 children, Dr. Lindell and team compared the performance of three identification methods. First, the Angus criteria of infection plus organ dysfunction. Second, the Martin criteria of sepsis or bacteremia plus organ dysfunction. And third, explicit or specific severe sepsis or septic shock codes. They then compared these to a cohort of children identified using the consensus criteria. As shown in this figure, they identified overlapping but distinct patient groups. Additionally, children identified using sepsis-specific codes were more similar to the cohort identified using the consensus criteria in terms of mortality, severity of illness, and resource utilization compared to both the Martin and Angus cohorts. Finally, using a nationally representative U.S. database, my colleagues and I measured the cost of pediatric sepsis hospitalizations. And as shown in this table, there's over $150 million difference in nationwide hospitalization cost estimates depending on the definition used. So while prior studies show the difference in sepsis definitions, another important question is how often does the physician diagnosis of sepsis agree with consensus criteria? The Sprout study, an international point prevalence study of PICU severe sepsis, screened almost 7,000 PICU patients for severe sepsis using the consensus criteria. Additionally, they independently asked the attending physician if each patient met criteria for severe sepsis or septic shock. They found only 43% of patients with severe sepsis or septic shock were concurrently identified by both the attending physician and the consensus criteria. This discrepancy suggests research studies using consensus criteria may be less generalizable to the overall PICU population diagnosed with sepsis. But what is next for pediatric sepsis definitions? Recently, the Society of Critical Care Medicine convened the Pediatric Sepsis Definition Task Force to evaluate, develop, and finally validate criteria to identify sepsis in children. As an early step, the task force completed a systematic review and meta-analysis to determine how well specific clinical, demographic, laboratory, illness severity, and organ dysfunction variables can identify children with sepsis and how these variables are associated with organ dysfunction and mortality in children with severe sepsis or septic shock. Of the approximately 12,000 records screened, 81 studies were included in the meta-analysis. And among these, consensus conference criteria were by far the most often used sepsis criteria occurring in about 70% of the 81 studies included. The group identified specific variables associated with the development of sepsis in children with infections. Additionally, among children with sepsis, severe sepsis, or septic shock, they identified variables associated with specific outcomes including mortality and organ dysfunction. The authors concluded that these data support the inclusion of such variables in the next step of data valuation for the Pediatric Sepsis Definition Task Force. This is really outstanding work, and I'm very much looking forward to the next steps and ultimately the final product of the new Pediatric Sepsis Definitions. So in summary, Pediatric Sepsis Definitions differ, and with that can result in variability in reported epidemiology, patient outcomes, healthcare utilization, and cost. And as stated by the consensus conference group back in 2005, Pediatric Sepsis Definitions should be considered a work in progress, and they will require continuous refinement and changes as our knowledge about pediatric sepsis grows. Thank you so much for the opportunity to present and for listening to my presentation today.

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