New Definitions for Sepsis and Septic Shock: Continuing Evolution but With Much Still to Be Done

The diagnosis of sepsis is not a new concern. Indeed, as early as 700 BCE, the Greeks recognized Σήψις (sepsis), referring to decomposition or rot, as a life-threatening condition associated with infection and high riskofdeath.Theprimarycriterion for sepsis has historically been progressive organ system dysfunction resulting frominfection.Because theonlyavailable therapies for this condition, antimicrobials and supportive care, are not specific, therewas little concern about developingmore detailed standards for diagnosis. Over the past 30 years, 2 major factors have led to a perceived need for better definitions. In particular, the increasing sophistication, at least in high-income countries, of modalities available for organ support in critical care units, including ventilators and dialysis, has resulted in growing numbers of patients with sepsis receiving care in intensive care units (ICUs) and enhanced awareness of the frequency and high costs associated with this condition. In addition, greater understanding of the underlying pathophysiologic mechanisms responsible for cellular dysfunction in experimental models and in patients with severe infection has accelerated the need for better entry criteria in clinical trials using therapies specifically directed toward molecular events thought to contribute to sepsis-associated morbidity and mortality. In this issue of JAMA, the Sepsis Definitions Task Force presents 3 articles: the updated definitions for sepsis and sepsis shock1 and 2 supporting reports with evidence for derivation and validation of these new definitions.2,3 In their Special Communication, Singer and colleagues1 describe the importance, process used, issues addressed, key findings from the evidence, and synthesis to develop the third iteration of consensus conference definitions for sepsis and septic shock and present the new definitions in detail. Previous versions of these definitions date from 1992 and 2003.4,5 A major underpinning for the present effort was the use of analyses in large cohorts to provide quantitative information in support of the revised criteria. The accompanying report by Seymour and colleagues2 assesses the predictive validity of the Sequential [Sepsisrelated] Organ Failure Assessment score (SOFA), systemic inflammatory response syndrome (SIRS) criteria, and the Logistic Organ Dysfunction System (LODS) score and derived a new score called quickSOFA (qSOFA) in a primary cohort that included 148907 patient encounters with suspected sepsis and a confirmatory analysis that included 706399 out-ofhospital and hospital patient encounters at 165 US and non-US hospitals. The investigators found that among ICU encounters with suspected infection (n = 7932), the predictive validity for in-hospital mortality of SOFA (area under the receiver operating characteristic curve [AUROC], 0.74 [95% CI, 0.73-0.76]) was not significantly different than that derived from the more complex LODS (AUROC, 0.75 [95% CI, 0.73-0.76]) but was superior to that from SIRS (AUROC, 0.64 [95% CI, 0.62-0.66]), supporting use of SOFA in clinical criteria for sepsis. Among patient encounters with suspected infection outside the ICU (n = 66522), qSOFA had high predictive validity for in-hospital mortality (AUROC, 0.81 [95% CI, 0.80-0.82]) that was statistically greater than that for SIRS (AUROC, 0.76 [95% CI, 0.75-0.77]), suggesting that it may have utility as a prompt to consider possible sepsis. In the other accompanying report, Shankar-Hari and colleagues3 describe the process of developing a new definition and clinical criteria for identifying septic shock in adults. The authors conducted a systematic review and meta-analysis of 92 studies informing a Delphi process that created the new definition, then tested the variables identified by the Delphi process in cohort studies (Surviving Sepsis Campaign [n = 28 150; University of Pittsburgh Medical Center [n = 1 309025], and Kaiser Permanente Northern California [n = 1847 165]). According to the new definitions, sepsis is now defined as evidence of infection plus life-threatening organ dysfunction, clinically characterized by an acute change of 2 points or greater in the SOFA score. The new clinical criteria for septic shock include sepsis with fluid-unresponsive hypotension, serum lactate level greater than 2 mmol/L, and the need for vasopressors to maintain mean arterial pressure of 65 mmHg or greater. A major change in the new definitions is the elimination of mention of SIRS. Components of SIRS include tachycardia, tachypnea, hyperthermia or hypothermia, and abnormalities in peripheral white blood cell count. Many studies have shown that the presence of SIRS is nearly ubiquitous in hospitalized patients and occurs in many benign conditions, both related and not related to infection, and thus is not adequately specific for the diagnosis of sepsis.6 It is a strength of the consensus definition that it no longer includes SIRS. Patients with infections and organ dysfunction are exceptionally heterogeneous in terms of demographic characteristics, underlying conditions, microbiology, and other clinically relevant factors.7 The updated definition for sepsis, Related articles pages 762, 775 and 801 Opinion