The definitions of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock were formulated by consensus during a meeting of the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) in 1991 [1]. Sepsis was defined as SIRS due to infection, presumed or confirmed. When sepsis was associated with organ dysfunction, hypoperfusion, or hypotension, it was defined as severe sepsis. Septic shock was designated as sepsis-induced hypotension persisting despite adequate fluid resuscitation.

These definitions were revised in 2001 during the International Sepsis Definitions Conference [2]. The 2001 task force expanded the lists of diagnostic criteria for SIRS and organ dysfunction. However, they did not revise for the definition of sepsis due to a lack of supporting evidence. Practically, the definitions of sepsis, septic shock, and organ dysfunction have remained unchanged for more than two decades.

Given these circumstances, a task force was appointed by the European Society of Intensive Care Medicine (ESICM) and the SCCM to prepare new definitions of sepsis. The clinical criteria for sepsis were formulated by a data-driven approach. The task force performed systematic review and metaanalysis of sepsis studies, a Delphi study, and cohort studies using the Surviving Sepsis Campaign registry [3]. The 2016 SCCM/ESICM task force introduced a new bedside clinical score, quick Sequential Organ Failure Assessment (qSOFA), which consists of three parameters (respiratory rate ≥22/min, altered mentation, and systolic blood pressure [BP] ≤100 mmHg). Patients with at least two of these three clinical variables are more likely to experience poor outcomes typical of sepsis [4]. The term “severe sepsis” was considered to be superfluous and has been discarded. Instead, the Sequential (sepsis-related) Organ Failure Assessment (SOFA) was chosen to measure organ dysfunction due to reliability and simplicity [5]. Organ dysfunction is represented by increase in SOFA score of 2 points or more. Septic shock was defined as vasopressor requirement to maintain mean arterial pressure ≥65 mmHg and serum lactate level >2 mmol/L (18 mg/dl) in the absence of hypovolemia.

The efforts of the task force that derived and validated the Sepsis-3 definitions should be appreciated. Nevertheless, there are concerns regarding the Sepsis-3 definitions. Most problematically, the health data utilized for the Sepsis-3 were almost exclusively derived from the United States and Germany. The primary cohort at the University of Pittsburgh Medical Center (UPMC) with suspected infection included 148,907 encounters. European descents comprised most of the cohort (76%), with African-Americans making up the second largest group (14%). East Asian descents make up one of remaining 10% population. Therefore, generalizability of Sepsis-3 definitions to East Asian descents has not been validated.

In 2012, the Korean Society of Critical Care Medicine (KSCCM) and the Japanese Society of Intensive Care Medicine (JSICM) published a joint study, the fever and antipyretics in critically ill patients evaluation (FACE) study which evaluated the relationships between fever, antipyretic treatment, and mortality in patients admitted to the intensive care unit (ICU) [6]. In the FACE study, patients were classified into two groups depending on the presence of sepsis at the time of ICU admission according to Sepsis-2 criteria. We hypothesized that it would be possible to evaluate the validity of Sepsis-3 criteria and the differential power of Sepsis-3 criteria in Koreans using of FACE study data.

Sepsis is a clinical syndrome that comprises physiologic, biologic, and biochemical abnormalities caused by inflammatory responses to invading microorganisms. The first international consensus conference in 1991 and subsequent revision in 2001 relied mainly on expert opinion to generate a clinical definition of sepsis [2,7]. Advances in the understanding of the pathophysiology of sepsis and the increasing availability of large electronic health record data sets, registries, and trial data sets enabled the application of an evidence-based approach to formulate new definitions of sepsis and septic shock. However, the lack of regional diversity among the patient sample upon which the Sepsis-3 criteria are based inspired us to evaluate the utility of these new sepsis definitions using data collected for the FACE study data.

The FACE study was a binational study performed in Korea and Japan, where most of population are East Asian descents. For the present study, we selected Korean participants of the FACE study. In the FACE study, patients were identified as with or without sepsis according to Sepsis-2 criteria at the time of ICU admission, which allowed us to figure out easily which patients harbored infection at the time of ICU admission [6].

The 2016 SCCM/ESICM task force for Sepsis-3 developed qSOFA, as a way to facilitate the identification of patients potentially at risk of dying from sepsis. The qSOFA score is easy to calculate since it has only three components (respiratory rate ≥22/min, altered mentation, and systolic BP ≤100 mmHg). A qSOFA score ≥2 is associated with poor outcomes due to sepsis. The qSOFA score was originally recommended as for assessment of patients outside the ICU [3-5]. It has since been prospectively studied in several settings including the emergency department (ED) and ICU with conflicting results. In a 2018 meta-analysis of 38 studies that included patients from the ED, wards, and ICU, qSOFA showed poor sensitivity compared to SIRS for predicting mortality from sepsis [8]. In addition, a retrospective analysis of 184,875 ICU patients with infection-related admission reported that qSOFA was inferior to SOFA for predicting in-hospital mortality [9]. These findings are consistent with the results of the present study. We did not detect statistically significant differences between patients with or without sepsis by Sepsis-2 criteria with qSOFA score ≥2 criterion (55.4% vs. 49.1%) (Table 3). qSOFA was originally developed as an assessment tool for patients outside the ICU. Because FACE study exclusively included patients who were expected to stay in the ICU for more than 48 hours, the weak performance of qSOFA in the present study is not surprising. In addition, the AUROC of discriminatory capacity for ICU and 28-day mortality showed that qSOFA score was inferior not only to SOFA and but also to SIRS in predicting both parameters (Figure 2). qSOFA may therefore not be as robust as originally anticipated. Among the three parameters comprising qSOFA, “altered mentality” showed the lowest positive rate in sepsis patients who met both Sepsis-2 and Sepsis-3 definition criteria. All things considered, clinicians should keep in mind that qSOFA was originally designed not as a diagnostic tool but rather as a predictive tool that calculates the risk of death from sepsis.

The term “severe sepsis,” which describes sepsis with tissue hypoperfusion and/or organ dysfunction, is no longer in use in Sepsis-3 [2]. Instead, organ dysfunction is defined as an increase of two or more points in the SOFA score. Patients who fulfill these criteria have a predicted mortality of 10% or more. All patients enrolled in the FACE study satisfied the criterion of SOFA score greater than 2 points. The median values of SOFA in the with-sepsis and without-sepsis groups were 9 and 7, respectively (Table 3). This finding implies that FACE patients are characterized by high degree of organ dysfunction, which might in turn explain the higher ICU and 28-day mortality rates of sepsis patients (26.2% and 31.0%) and sepsis with organ dysfunction (27.5% and 32.5%). Septic shock patients had ICU and 28-day mortality rates of 40.8% and 43.4%, respectively (Figure 1). This is consistent with the estimates by the 2016 SCCM/ESICM task force. In their analysis, the mortality rate of septic shock patients was greater than 40% [10,11].

A limited number of studies evaluated the mortality rates of patients with sepsis using large samples of Korean patients. In a prospective, multicenter, observation study that included 1,192 adult patients admitted to 22 participating ICUs of 12 university hospitals in Korea, the 28-day mortality rate was 23.0% according to Sepsis-2 septic shock criteria [12]. The new Sepsis-3 definition of septic shock estimates 40% of mortality rate among septic shock patients, therefore, new definition may represent more severe disease than the previous definition. Another observational, prospective, multi-center registry study performed by 10 EDs at tertiary hospitals in Korea found that the 28-day mortality rate of septic shock patients defined according to Sepsis-3 criteria was 25.1%, which is far lower than the mortality rate observed in the present study and that observed by the 2016 SCCM/ESICM task force [13]. To our best knowledge, this is the first study to present data regarding the mortality rates of patients with sepsis, sepsis with organ dysfunction, and septic shock as defined by Sepsis-3 criteria using a large sample of Korean ICU patients.

In conclusion, the concordance rates for sepsis between Sepsis-2 and Sepsis-3 criteria were low, which might be associated with the weak performance of qSOFA. The mortality rate of Korean patients with septic shock was consistent with estimates by the 2016 SCCM/ESICM task force. Not only SOFA but also SIRS was better than qSOFA in predicting ICU and 28-day mortality in Korean ICU patients.