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Severity and Timing of Onset Drive Economic Costs and Clinical Outcomes With Sepsis*

Kempker, Jordan A., MD, MSc; Martin, Greg S., MD, MSc

doi: 10.1097/CCM.0000000000003376
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Division of Pulmonary, Allergy, Critical Care Medicine and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA

*See also p. 1889.

Drs. Kempker and Martin contributed to the writing of this article.

Supported, in part, by grants from the National Institutes of Health’s National Center for Advancing Translational Science (to Dr. Martin; UL1 TR-002378) and the Agency for Healthcare Quality and Research (to Dr. Kempker; K08 HS-025240).

Dr. Kempker’s institution received funding from the Agency for Healthcare Research and Quality (AHRQ) (K08 HS-025240), and he received support for article research from the AHRQ. Dr. Martin’s institution received funding from National Institutes of Health (NIH) and Bristol-Myers Squibb; he received funding from Grifols; and he received support for article research from the NIH.

The newest article by Paoli et al (1), published in this issue of Critical Care Medicine, adds to the body of literature on sepsis epidemiology using the increasingly available pool of large clinical and administrative databases to characterize the financial burden of sepsis in the United States. This particular study (1) uses data from Premier, Inc (Charlotte, NC), a U.S. healthcare improvement company that provides analytics and other services to its hospital alliance members (2). The 2010–2016 data in the study by Paoli et al (1) represent an approximately 20% nonrandom sample of U.S. hospitalizations, capturing greater than 2.5 million sepsis hospitalizations using a combination of International Classification of Diseases, 9th Edition, International Classification of Diseases, 10th Edition, and Diagnosis-Related Group (DRG) case-finding definitions. These recent data demonstrate important, recurrent themes in sepsis epidemiology: sepsis disproportionately affects older adults (mean age, 65 yr), sepsis is predominantly community acquired (87%), sepsis is expensive (mean hospital costs $21,500), and sepsis is associated with high hospital mortality (one in eight patients) and high rates of 30-day readmission for survivors (one in eight patients). Importantly, there are two axes along which the investigators add novel information to the field of sepsis epidemiology: comparisons of “aggregate” costs by sepsis severity and comparisons of sepsis outcomes and resource utilization by “present on admission” (POA) status.

The investigators analyze their data by sepsis severity, using administrative coding that is consistent with the sepsis, severe sepsis, and septic shock classifications in existence before Sepsis-3 (3). The finding that increasing sepsis severity is associated with increasingly worse outcomes and higher costs is intuitively correct and a check on internal validity and is expanded with provocative assertions regarding the societal burden of sepsis under its earlier clinical definitions. Although sepsis without organ dysfunction was associated with shorter length of stay, lower costs, and lower hospital mortality than more severe forms of sepsis, given that it accounted for 55% of the sepsis cases, it accounted for the highest aggregated cost and hospital bed utilization. This highlights an important aspect of the evolution to the Sepsis-3 definition where sepsis requires organ dysfunction, and less ill patients are simply “infected,” and in the process altering the epidemiologic estimates of “sepsis” and challenging epidemiologists, providers, and policy makers to translate across the definitional, clinical, and administrative categorizations.

Before delving into the analyses of sepsis by POA status, background on the creation of POA indicators is important. These indicators arose from the 2005 Deficit Reduction Act, which called for the ongoing identification of conditions that are “high cost or high volume or both, result in the assignment of a case to a DRG that has a higher payment when present as a secondary diagnosis and could reasonably have been prevented through the application of evidence-based guidelines” (4). The intent of the regulation was to encourage hospitals to avoid these conditions by not reimbursing for hospital-acquired (i.e., not POA) conditions that may have been preventable. Since its operationalization in 2008, the Centers for Medicare and Medicaid Services (CMS) has not paid hospitals for the costs associated with these conditions when they are included among the secondary diagnoses of the discharge record without a POA designation. CMS requires hospitals to record POA indicators on all hospital discharge diagnoses, and although sepsis is not explicitly on this list, six of the 14 categories of hospital-acquired conditions are related to sepsis, such as catheter- associated urinary tract infections, vascular catheter-associated infections, and surgical site infections (5). An important caveat to the POA system acknowledged by the authors is that POA sepsis may include community-acquired and healthcare-associated sepsis identified at admission, whereas not POA sepsis may include hospital-acquired sepsis as well as any other sepsis case that was not recognized at the time of admission. In 2015, an article in this journal laid the foundation for deconstructing the POA groups with respect to sepsis. That study used the 2012 University HealthSystem Consortium data of greater than 3.3 million discharges, demonstrating that sepsis cases were 63% community-acquired, 26% healthcare-associated (combined 89% POA), and 11% hospital-acquired, with the last group being defined by infection not POA (6). These results are consistent with the findings by Paoli et al (1) of 87% of sepsis being POA, which likely reflects a mixture of community-acquired and healthcare-associated sepsis. Additionally, the supposition by Paoli et al (1) that the not POA status represents a delayed sepsis diagnosis remains speculative as this analysis cannot distinguish later onset hospital-acquired sepsis from sepsis that was POA but for which the diagnosis was not evident at admission.

Moving beyond the nuances of the terminology, the investigators report provocative differences between sepsis POA and sepsis not POA. Sepsis not POA was associated with a two-fold higher hospital mortality (26% vs 11%), a lower rate of discharge to home among survivors (47% vs 63%), longer stays in the ICU (10.1 vs 5.2 d), and higher average hospital costs ($51,000 vs $18,000). In interpreting these comparisons, bear in mind the issues of severity of illness adjustment and reverse causality. In regard to the first issue, these estimates are not adjusted for the underlying severity of illness of the patients, and the data demonstrate that sepsis not POA patients had a higher prevalence of comorbidities, notably congestive heart failure, chronic kidney disease, atrial fibrillation, and active cancer. Therefore, it may be possible that the worse outcomes and higher resource utilization of the sepsis not POA group are in part due to residual confounding of the increase severity of underlying illness of these patients. Reverse causality refers to the interpreted direction of causal connections, in this case between POA status and increased resource utilization. One possible interpretation of the association is that in comparison with sepsis POA, sepsis not POA leads to increases in ICU and hospital lengths of stay and resultant costs. Conversely, an alternative explanation of the observed associations is that increased stays in the hospital and/or ICU lead to hospital-acquired sepsis. From one point of view, to be concerned with which interpretation is correct may be purely academic. The large magnitude of the differences between sepsis POA and sepsis not POA is sufficient to consider sepsis not POA as a distinct and major problem. Furthermore, when contemplating potential sepsis prevention strategies, even though sepsis not POA represents a minority of sepsis cases, it potentially represents those cases that are most amenable to developing such strategies given the accessibility of this at-risk population during the risk period (7).

In conclusion, this article (1) makes two important points using opposite constructs to make arguments for the public health importance of sepsis. On one hand, the authors conclude that severe infections (“sepsis” by the original definition, called “sepsis without organ dysfunction” in this publication) represents a dominant burden to society despite its lower risk and burden to the individual due to its high prevalence in relation to other more severe forms of sepsis. Conversely, the authors point out that sepsis POA presents a large burden despite its lower prevalence when compared with sepsis not POA, due to its markedly worse outcomes and higher resource utilization. These considerations are most relevant to those making policy and hospital administration decisions. In this regard, the Centers for Disease Control and Prevention, the National Hospital Safety Network, and CMS continue to affect policies directed to the prevention of community- and hospital-acquired infections that precede all forms of sepsis (8). Emerging research questions remain as to what community- and systems-based interventions may further disrupt the continuum from infection to sepsis.

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1. Paoli CJ, Reynolds MA, Sinha M, et al. Epidemiology and Costs of Sepsis in the United States—An Analysis Based on Timing of Diagnosis and Severity Level. Crit Care Med 2018; 46:1889–1897
2. Premier Inc: About Us. Available at: Accessed July 4, 2018
3. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315:801–810
4. Centers for Medicare & Medicaid: Hospital-Acquired Conditions (Present on Admission Indicator). Available at: Accessed July 4, 2018
5. Centers for Medicare & Medicaid: Hospital-Acquired Conditions. Available at: Accessed July 4, 2018
6. Page DB, Donnelly JP, Wang HE. Community-, healthcare-, and hospital-acquired severe sepsis hospitalizations in the university healthsystem consortium. Crit Care Med 2015; 43:1945–1951
7. Kempker JA, Wang HE, Martin GS. Sepsis is a preventable public health problem. Crit Care 2018; 22:116
8. Dantes RB, Epstein L. Combatting sepsis: A public health perspective. Clin Infect Dis 2018 May 29. [Epub ahead of print]

data science; epidemiology; health economics; sepsis

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