Sepsis-3: What is the Meaning of a Definition?

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The recent publication of Sepsis-3–the latest iteration of an effort to define sepsis–has evoked an impressive response (1). To date it has been viewed more than one million times on the JAMA website, making it one of the most highly accessed articles there in recent years. It has also generated a flurry of commentaries–some supportive, some opposing, and almost all thoughtful (2–4). Indeed recognizing as the original paper did that the new definition is simply the next step in the evolution of a challenging process, the controversy is as important as the Sepsis-3 document in clarifying what has been accomplished and what remains undone.
According to the Merriam-Webster Dictionary, a definition is “…an explanation of the meaning of a word…”. Sepsis to the Greeks denoted a range of processes characterized by putrefaction and a foul smell (5). With the identification of the pathogenic role of microorganisms in disease, sepsis has come to take on a meaning related to the consequences of infection. This meaning has changed as our understanding of the biology of infection and the host response has evolved. In the early 1970s, Stedman’s Medical Dictionary defined sepsis as “…the presence of pus-forming organisms in the bloodstream…”, however this definition rapidly became obsolete with the discovery that the adverse sequelae of infection arose through the activation of a host response, rather than as a consequence of the intrinsic toxicity of the microorganism or its products. A new definition was needed. In 1991, a consensus conference of the SCCM and ACCP suggested that sepsis is “…the systemic host response to invasive infection …” (6). Further cognizant of the fact that an identical clinical response could be evoked by non-infectious stimuli, they proposed a neologism, the systemic inflammatory response syndrome (SIRS), to denote the response independent of its cause. Time and reflection rendered this definition inadequate.
While sepsis might arise from the host response, it was not the response per se (presumably an appropriate and adaptive process evolved to overcome infection) but rather the adverse clinical consequences of that response. The biologic complexity of that response was such that it defied simple description as excessive inflammation, immunoparalysis, or any other of a number of reductionist terms. These considerations shaped the current definition of sepsis as put forward in Sepsis 3.0–“…life-threatening organ dysfunction caused by a dysregulated host response to infection.”
The new definition has face validity: it describes a potentially lethal disorder whose clinical presentation is organ dysfunction. It reflects current biologic understanding in classifying the response as dysregulated, and resisting the temptation to interpret beyond what we currently know. Its major shortcoming, to my mind, is that in its emphasis on the response to infection, it excludes other disorders–pancreatitis, heat shock, ischemia-reperfusion injury, endotoxemia–that are elicited through the same biologic pathways and result in a similar clinical presentation, yet are non-infectious in cause.
A definition is fundamental to effective communication. It provides a common foundation for approaching a problem, and in medicine, provides a means of discriminating not only what something is but as importantly, what it is not. If we define cancer as “a disease resulting from the uncontrolled proliferation of abnormal cells,” we differentiate cancer from normal processes of growth, or the controlled proliferation of hematopoietic cells that occurs in response to infection. In this strict sense of a definition, the Sepsis-3 definition has moved the field forward by emphasizing the primary role of organ dysfunction as the pathologic feature of the host response, and by adopting a more sanguine and less confident perspective on the nature of that response–dysregulated, rather than pro-inflammatory, immunoparalytic, or uncontrolled.

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