Although sepsis was described more than 2,000 years ago, and clinicians still struggle to define it, there is no “gold standard,” and multiple competing approaches and terms exist. Challenges include the ever-changing knowledge base that informs our understanding of sepsis, competing views on which aspects of any potential definition are most important, and the tendency of most potential criteria to be distributed in at-risk populations in such a way as to hinder separation into discrete sets of patients. We propose that the development and evaluation of any definition or diagnostic criteria should follow four steps: 1) define the epistemologic underpinning, 2) agree on all relevant terms used to frame the exercise, 3) state the intended purpose for any proposed set of criteria, and 4) adopt a scientific approach to inform on their usefulness with regard to the intended purpose. Usefulness can be measured across six domains: 1) reliability (stability of criteria during retesting, between raters, over time, and across settings), 2) content validity (similar to face validity), 3) construct validity (whether criteria measure what they purport to measure), 4) criterion validity (how new criteria fare compared to standards), 5) measurement burden (cost, safety, and complexity), and 6) timeliness (whether criteria are available concurrent with care decisions). The relative importance of these domains of usefulness depends on the intended purpose, of which there are four broad categories: 1) clinical care, 2) research, 3) surveillance, and 4) quality improvement and audit. This proposed methodologic framework is intended to aid understanding of the strengths and weaknesses of different approaches, provide a mechanism for explaining differences in epidemiologic estimates generated by different approaches, and guide the development of future definitions and diagnostic criteria.
1Department of Critical Care Medicine, The Clinical Research, Investigation, and Systems Modeling of Acute illness (CRISMA) Center, University of Pittsburgh School of Medicine, Pittsburgh, PA.
2Department of Surgery, Emory University School of Medicine, Atlanta, GA.
3Department of Pediatrics, Hofstra-North Shore-LIJ School of Medicine, Cohen Children’s Medical Center, New Hyde Park, NY.
4Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, MA.
5Department of Medicine, Brigham and Women’s Hospital, Boston, MA.
6Division of Pulmonary/Critical Care Medicine, Alpert Medical School at Brown University, Providence, RI.
7Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Critical Care, Emory University School of Medicine, Atlanta, GA.
8Departments of Surgery and Emergency Medicine, Washington University School of Medicine, St. Louis, MO.
9Department of Pediatrics, Pediatric Critical Care Medicine, University of Washington; Center for Child Health Behavior and Development, Seattle Children’s Research Institute, Seattle, WA.
Drs. Angus and Seymour and were supported, in part, by grants from the National Institutes of Health (NIH) (GM104022, GM107650, and HL123020). Dr. Seymour received support for article research from the NIH and he received funding from Beckman Coulter. His institution received funding from the NIH. Dr. Coopersmith disclosed other support (He was the president of the Society of Critical Care Medicine [SCCM] when the manuscript was submitted. Salary support for effort was paid to Emory University for this position. He also receives grant support from the NIH paid to Emory University unrelated to this paper. He also receives salary support from the Centers for Disease Control and Prevention [CDC] related to sepsis surveillance). Dr. Deutschman disclosed receiving other support from WFSICC (hotel expenses, meeting PA), SCCM (Honorarium, travel expenses for presentation), and SCCM (reimbursement for attending meetings, accommodations at annual meeting). He received funding from the CDC, North Shore LIJ Health System, and the Department of Anesthesiology, Stanford University. Dr. Klompas’ institution received funding from the CDC. Dr. Levy’s institution received grant support from ImmuneExpress (Gene Analysis for early identification of sepsis). Dr. Martin received support for article research from the NIH and received funding from CR Bard and Medscape. His institution received funding from the CDC, NIH, FDA, and Baxter Healthcare. Dr. Osborn disclosed receiving other support from the Barnes Jewish Hospital. Her institution received funding from Cheetah Inc. and ImaCor Inc. Dr. Watson disclosed receiving other support from the University of Washington and University of Pittsburgh UPMC and he received funding from the CDC (paid travel funds for a meeting to discuss sepsis monitoring). His institution received funding from the NIH/NICHD, SCCM, and the Seattle Children's Hospital. The remaining authors have disclosed that they do have no potential conflicts of interest.
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