Does Sepsis Case Mix Heterogeneity Prevent Outcome Comparisons?

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. 2288 www.ccmjournal. org December 2016 • Volume 44 • Number 12 Licensing ourselves to hyperbole, sepsis may be one of the most diverse syndromes in the modern clinical vocabulary (1). For starters, it is a syndrome with etiologic agents not only across three taxonomic kingdoms of life (bacteria, protozoa, and fungi) but also outside of the taxonomy of life (viruses). Multiplying the possible flavors of sepsis, many of these pathogens can infect a variety of human tissues, and each infective episode can in turn induce different combinations of systemic inflammatory responses and distant organ failures. Just how many flavors of sepsis can there be? As a simple thought experiment, let us ignore the rainbow of etiologic agents, assume one source of infection per sepsis episode and narrow the field of organ dysfunctions to five. To get the total number of sepsis combinations under these stipulations, we multiply the five infection sources by the 11 different combinations of systemic inflammatory response syndrome (SIRS) criteria that meet a definition of sepsis by the 31 combinations of organ dysfunctions (Fig. 1). This gives us 1,705 shades of sepsis, admittedly only the tip of the iceberg given that we have ignored the myriad of etiologic agents. Yet, like choosing which variation of beige to paint your dining room, the important question is whether there is any meaningful difference between these myriad tones of sepsis? The article published in this issue of Critical Care Medicine by Shankar-Hari et al (2) adds to a body of evidence suggesting that there “is” a meaningful difference. To summarize, the article is a cohort study of the 241,603 adults admitted with a diagnosis of infection to a general critical care unit in England from 2000 to 2012. Systemic inflammatory response and organ dysfunction criteria were extracted from physiologic data within the first 24 hours of critical care admission and hospital mortality was the primary outcome. The study uses data from the Case Mix Programme, a high quality, professionally and independently maintained database of nearly every patient of every general critical care unit in the United Kingdom (3). The analyses examine the unadjusted hospital mortality of sepsis from many different angles: source of infection, quantity and combination of SIRS criteria, and quantity and combination of organ dysfunctions. The results display a wide range of hospital mortality along every facet. For source of infection, hospital mortality was lowest for genitourinary infections (19.4%) and highest for cardiovascular infections (44.2%). For SIRS criteria, even within groupings of two and three total criteria met within the first 24 hours of critical care admission, different combinations were associated with wide within-group variation in unadjusted hospital mortality (from approximately 20–40%, estimating from the graphs). Similarly, among different combinations of organ dysfunctions, there is a considerable range of unadjusted hospital mortality rates. From this data, the investigators create four risk categories of organ dysfunction combinations, grouped by the associated hospital mortality rates rather than the sum or physiologic relationships of organ dysfunctions. They demonstrate that within each risk category, hospital mortality has followed a similar downward trend from 2000 to 2012, an observation that increases confidence in the notion that overall sepsis mortality is improving due to changes in care rather than increases in diagnosis of less severe cases. Furthermore, the investigators use these risk categories to hypothesize an explanation as to why the hospital mortality from sepsis in England was on average 1.5 times higher than that reported in a well-known study over the same time period in Australia and New Zealand (4). Their analyses suggest that the sepsis case mix in England represents a higher risk case mix than that found in Australia and New Zealand. However, while they illustrate that overall mortality reported in Australia and New Zealand is similar to the mortality from risk category 2 sepsis in England, we do not see the risk categories of the Australia and New Zealand data, limiting any direct comparisons. The study by Shankar-Hari et al (2) graphically depicts the wide variations in unadjusted hospital mortality of a wide variety sepsis syndromes defined by various combinations of infection source, SIRS criteria, and organ dysfunctions. Although this is an important and well-presented reminder of the significant variety under the umbrella of sepsis, many of the concepts are not new. The notion that increasing numbers of abnormal vital signs and organ dysfunctions was associated with increased mortality in sepsis was demonstrated in the early clinical studies of sepsis from the mid-1990s (5–7). Furthermore, the effects Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000001933 Does Sepsis Case Mix Heterogeneity Prevent Outcome Comparisons? *