The hospital mortality rate was 12.5% and was more than two-fold higher (11.4% vs 25.6%) in non-POA cases. A substantial proportion surviving the hospitalization were discharged to home (52.3%) or other forms of supportive care including skilled nursing facilities, rehabilitation, and long-term care (28.0%). Non-POA patients had lower rates of discharge to home (34.9%) than POA patients (55.7%). Among only the survivors, non-POA cases had lower rates of discharge to home (47%) than POA patients (62.7%), some of which was influenced by discharge to other long-term care settings (non-POA: 46.1% and POA: 31.7%) and the remainder due to the higher mortality rates observed.
On average, non-POA sepsis cases spent nearly double the amount time in the hospital, in the ICU, and on mechanical ventilation compared with sepsis POA cases, that is, from 7.7 to 17.6 days, from 5.2 to 10.1 days, and from 6.6 to 10.1 days, respectively. Cause of sepsis was generally not specified, with 96.7% of the events classified as “other,” postoperative infection at 2.1%, burn at 0.1%, and trauma at 0.9%. As expected, there were more postoperative infections in cases with sepsis not POA (5.4%). Mean patient costs were considerable at $21,568, and when stratified, POA was $18,023 and a staggering $51,022 for non-POA. Although outliers may have skewed the results, the median costs demonstrated a three-fold increase in costs for non-POA cases ($10,371 vs $32,085, respectively).
To further explore the differences in sepsis outcomes and costs, an analysis by sepsis severity among cases with sepsis overall and by POA was conducted as a secondary objective. The study found a distribution of severity levels with the majority classified as sepsis without organ dysfunction (51.2%) followed by 19.1% for severe sepsis and 29.7% for septic shock. Details on the sepsis-related outcomes by sepsis severity and sepsis at the point of admission are summarized in Table 3.
Overall, the mortality rates as well as the healthcare resource use and costs increased as severity increased. The mortality rate overall by sepsis severity was 5.6%, 14.9%, and 34.3% for sepsis without organ dysfunction, severe sepsis, and septic shock, respectively. Despite the high mortality rates, LOS increased from 7.7 to 12.6 days, and the costs of sepsis increased from $16,324 to $38,298 from sepsis without organ dysfunction to septic shock. A clear trend toward increased resource use and costs and poor clinical outcomes was associated with increasing severity (Table 3). The largest driver of better clinical outcomes was less severity as demonstrated by a larger range in mortality rates by severity level as compared to stratifying by POA status. Mortality ranged from 5.6% to 14.9% to 34.3% for the overall cohort for sepsis without organ dysfunction, severe sepsis, and septic shock, respectively. This trend followed when severity levels were also stratified by POA status (13.8%, 30.7%, 48.5% for non-POA vs 4.5%, 12.9%, 31.2% for POA diagnosis) (Table 3). Costs, however, were more influenced by stratification by POA diagnosis. Those with sepsis not POA had higher mean costs overall ($51,022 as compared to POA at $18,023). This trend also followed when POA status was stratified by severity ($39,336 to $60,672 to $60,671 for non-POA patients and $13,384 to $19,851 to $31,704 for non-POA patients by severity level: sepsis without organ dysfunction, severe sepsis, and septic shock, respectively). Readmission rates ranged from ~10% to 16% regardless of severity or sepsis POA.
Despite increased costs and worse outcomes with increasing sepsis severity on a case-by-case basis, the aggregate costs for sepsis without organ dysfunction were the greatest. This is due to the higher prevalence of sepsis without organ failures (n = 1,346,824) compared with severe sepsis (n = 412,736) or septic shock (n = 518,010) over the ~7-year evaluation period. The higher prevalence of sepsis without organ failures accounted for higher aggregate costs (and LOS) ~$22 billion (LOS~10.4 million d), compared with ~$10.2 billion (LOS~4.1 million d) and $19.8 billion (LOS~6.5 million d) for severe sepsis and septic shock, respectively.
This analysis of over 2.5 million U.S. sepsis cases demonstrates substantial burden while elucidating the vast heterogeneity of sepsis epidemiology, outcomes, and costs by severity level, including cases where sepsis was not diagnosed until after admission (non-POA). The overall inpatient mortality rate was 12.5% representing a slightly lower estimate as compared to the 2013 Nationwide Inpatient Sample of 14.7–16.3% (6), but when examining the data closer, a wide range of mortality rates exists: 11.4% for POA and 25.6% for non-POA, whereas mortality rates by severity ranged from 5.6% for sepsis without organ dysfunction, 14.9% for severe sepsis, and 34.2% for septic shock. Costs followed this same pattern: $18,023 for POA compared with $51,022 for non-POA, a 322% increase, wherein the cost per case of severe sepsis and septic shock were 50% and 235% higher, respectively, compared with sepsis without organ failures (Table 3).
The greatest costs were observed in non-POA sepsis ranging from $39,336 in sepsis without organ dysfunction, $60,672 in severe sepsis, and $68,671 for septic shock per case. These higher costs could in part be attributable to delayed sepsis diagnosis and treatment (e.g., sepsis cases diagnosed within 48 hr of admission but not at baseline) and sepsis complicating other acute medical conditions (e.g., sepsis onset that is delayed beyond 48 hr of admission). It is well known that delayed sepsis diagnosis and/or treatment adversely affect sepsis outcomes (9–15) emphasizing the need for early diagnosis even after admission. In this regard, sepsis diagnosis and/or treatment is frequently delayed during inpatient admissions. A more detailed analysis on a case-by-case basis is needed to determine what proportion of non-POA patients would be characterized as delayed sepsis diagnosis compared with new-onset after hospital admission. Non-POA combines those cases of sepsis that were missed during initial screening (most of these cases would presumably be caught within the first 24 hr of admission) with cases of new onset (e.g., complication of surgery or relating to central catheters, aspiration, etc). This dataset is unable to discriminate one from the other. Nonetheless, any delay in the diagnosis of sepsis typically carries a worse prognosis, and for this reason, the non-POA cohort would be of particular interest for further study.
Regardless of the factors influencing non-POA diagnosis and treatment, the costs of care within this cohort were 2–3× higher than the POA cohort. A related study using data from the multicenter Sepsis Early Recognition and Response Initiative (SERRI) (16) found a similar proportion of sepsis cases identified at admission of almost 85% (compared with our estimate of almost 87%). The SERRI mortality rates reported were slightly higher with an overall mortality rate of 17.2% (ours at 12.5%) and 14.1% (ours at 11.1%) and 38.6% (ours at 25.6%) for those with sepsis POA and non-POA, respectively. Costs reported were of similar magnitude and directionally aligned with the findings of our study. Thus, the Premier healthcare cohort data presented here are consistent with previous reports which serves to validate its results.
Another interesting finding was the higher aggregate cost and LOS for those presenting with milder forms of sepsis. The aggregate costs and LOS for sepsis without organ failure was higher than for either severe sepsis or septic shock, which is in keeping with prior studies showing that the aggregate mortality of the sepsis without organ failure is higher than for either severe sepsis or septic shock (3). Most published studies to date have focused on severe sepsis and septic shock (e.g., the new Sepsis-3 definition ) when in fact milder sepsis manifestations account for most sepsis cases and represents the largest disease burden (3). It follows that future research aimed at reducing overall sepsis clinical and financial burden should aim to include this cohort.
The ability to detect and treat sepsis early, before progression to organ failure, leads to less mortality and ultimately less costs (9). Specifically, a body of evidence demonstrates that early sepsis identification and treatment lead to decreased sepsis severity (10–12), mortality (3 , 9 , 11 , 13 , 14), and costs (9 , 18 , 19). Given that a vast majority of sepsis cases initially fall within the “mild” category (i.e., not manifesting with overt organ failures or circulatory shock), and because inherent delays in the detection and treatment of sepsis are common, there is an urgent need for new technologies that aid physicians in earlier detection of sepsis in order to begin treatment as soon as possible.
The present study showed lower readmission rates at 30 days compared with other published studies. Prescott et al (20) 2014 found that survivors of hospitalization for severe sepsis had 30-, 60-, and 365-day hospital readmission rates of 26.5%, 41%, and 63.0%, respectively, compared with the current findings for severe sepsis at 30 days of 12.3%. These lower rates could reflect more current data (Prescott et al  represent data from 1992 to 2006) in which hospitals have been implementing early sepsis identification programs and follow-up clinics for sepsis patients and the demographics of the population as Prescott et al (20) was focused on a Medicare only population with a mean age of 78.6 years old.
There are several limitations to this study many of which are common to observational database research. This study relied on International Classification of Diseases and DRG coding provided by the hospitals to Premier. Although coding variations exist within and across hospitals, the degree to which coding variation may affect this analysis is unknown. Hospitals that submit data to Premier may differ from nonreporting hospitals due to the fact that Premier hospitals submit data to drive quality efforts, thus affecting the ability to generalize results to all U.S. hospitals. In comparison with the American Hospital Association (AHA) hospitals, the Premier hospitals have a similar distribution of geography, urbanicity, and teaching focus, whereas the size of the hospitals suggest that Premier hospitals are larger (21). However, the number of cases over the 7-year study period yields ~ 350,000 cases per year. Assuming Premier hospitals represent 20% of U.S. hospitals, this results in ~1.7 M sepsis hospitalizations per year, which is consistent with the most recent national estimates provided by Rhee et al (22). The 2018 AHA statistics show a difference in cost with smaller hospitals incurring greater cost per hospitalization (23). The findings of this study may underestimate the clinical and economic burden among smaller hospitals.
Last, the use of diagnosis codes to identify sepsis cases differs from clinical definitions. Cases which were clinically septic and/or treated for sepsis may have been missed by coders who go through medical records retrospectively for billing purposes, and therefore, the volume of sepsis patients and the total cohort costs reported here are likely underreported. The optimal method for accurately capturing sepsis cases from an epidemiologic perspective may be best through clinical criteria, but databases like the Premier dataset lack such details. The literature regarding the accuracy of sepsis diagnostic coding versus the use of clinical criteria for reporting of epidemiology does differ, but the use of the Premier dataset using specific sepsis diagnosis codes of case identification may better reflect the economic burden by avoiding dilution in the study with nonsepsis cases (22 , 24). In addition, recent updates to the sepsis definitions (from Sepsis-2 to Sepsis-3) have introduced new classifications of sepsis severity, which may result in shifts in coding as the ICD-10 diagnosis and DRG codes are not evolving with the clinical definitions of sepsis. The new definitions remove the concept of severe sepsis leaving only two classifications: sepsis and septic shock. Future diagnostic codes and database analyses will need to address the new definitions and to determine the clinical utility of the new Sepsis-3 criteria in terms of sepsis detection especially given how such definitions may impact diagnosis codes and allocated DRG codes used for payment.
Early recognition and prompt treatment of sepsis remain the pivotal steps in reducing the overall burden of sepsis-related hospitalization. Our study focuses on the heterogeneity of sepsis cases and highlights less severe sepsis (sepsis without organ dysfunction), which accounts for the majority of cases and costs. By applying a nationally representative dataset, we could focus on differences within the sepsis population and understand the varying outcomes and costs when sepsis is POA and evaluated by severity level. The quantification of this granularity suggests an opportunity, both clinically and economically, to reduce the burden of sepsis in the United States, particularly through efforts to enhance early identification and treatment of patients in the earliest phases of sepsis.
1. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology
of severe sepsis
in the United States: Analysis of incidence
, outcome, and associated costs of care. Crit Care Med 2001; 29:1303–1310
2. Martin GS, Mannino DM, Eaton S, et al. The epidemiology
in the United States from 1979 through 2000. N Engl J Med 2003; 348:1546–1554
3. Liu V, Escobar GJ, Greene JD, et al. Hospital deaths in patients with sepsis
from 2 independent cohorts. JAMA 2014; 312:90–92
4. Martin GS. Sepsis
, severe sepsis
and septic shock
: Changes in incidence
, pathogens and outcomes. Expert Rev Anti Infect Ther 2012; 10:701–706
5. Hall MJ, Williams SN, DeFrances CJ, et al. Inpatient Care for Septicemia or Sepsis
: A Challenge for Patients And Hospitals, 2000–2008. National Center for Health Statistics. Data Brief No. 62. June 2011. Available at: http://www.cdc.gov/nchs/data/databriefs/db62.pdf
. Accessed June 24, 2016
6. HCUP National Inpatient Sample (NIS): Healthcare Cost
and Utilization Project (HCUP), 2013. Rockville, MD. Agency for Healthcare Research and Quality, Available at: at www.hcup-us.ahrq.gov/nisoverview.jsp
. Accessed June 24, 2016
9. Judd WR, Stephens DM, Kennedy CA. Clinical and economic impact of a quality improvement initiative to enhance early recognition and treatment of sepsis
. Ann Pharmacother 2014; 48:1269–1275
10. Whiles BB, Deis AS, Simpson SQ. Increased time to initial antimicrobial administration is associated with progression to septic shock
in severe sepsis
patients. Crit Care Med 2017; 45:623–629
11. Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality
in severe sepsis
and septic shock
from the first hour: Results from a guideline-based performance improvement program. Crit Care Med 2014; 42:1749–1755
12. Filbin MR, Arias SA, Camargo CA Jr, et al. Sepsis
visits and antibiotic utilization in U.S. emergency departments*. Crit Care Med 2014; 42:528–535
13. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock
. Crit Care Med 2006; 34:1589–1596
14. Liu VX, Fielding-Singh V, Greene JD, et al. The timing of early antibiotics and hospital mortality
. Am J Respir Crit Care Med 2017; 196:856–863
15. Pruinelli L, Westra BL, Yadav P, et al. Delay within the 3-hour surviving sepsis
campaign guideline on mortality
for patients with severe sepsis
and septic shock
. Crit Care Med 2018; 46:500–505
16. Jones SL, Ashton CM, Kiehne LB, et al. Outcomes and resource use of sepsis
-associated stays by presence on admission, severity, and hospital type. Med Care 2016; 54:303–310
17. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis
and septic shock
-3). JAMA 2016; 315:801–810
18. Ost DE, Hall CS, Joseph G, et al. Decision analysis of antibiotic and diagnostic strategies in ventilator-associated pneumonia. Am J Respir Crit Care Med 2003; 168:1060–1067
19. Houck PM, Bratzler DW, Nsa W, et al. Timing of antibiotic administration and outcomes for Medicare patients hospitalized with community-acquired pneumonia. Arch Intern Med 2004; 164:637–644
20. Prescott HC, Langa KM, Liu V, et al. Increased 1-year healthcare use in survivors of severe sepsis
. Am J Respir Crit Care Med 2014; 190:62–69
22. Rhee C, Dantes R, Epstein L, et al; CDC Prevention Epicenter Program: Incidence
and trends of sepsis
in US hospitals using clinical vs claims data, 2009-2014. JAMA 2017; 318:1241–1249
24. Jafarzadeh SR, Thomas BS, Marschall J, et al. Quantifying the improvement in sepsis
diagnosis, documentation, and coding: The marginal causal effect of year of hospitalization on sepsis
diagnosis. Ann Epidemiol 2016; 26:66–70
Keywords:Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
cost; epidemiology; incidence; sepsis; shock; mortality