By Betty Tran, MD, MSc, Editor
Assistant Professor of Medicine, Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago
Dr. Tran reports no financial relationships relevant to this field of study.
Over the past few decades, improvement in the care of patients with sepsis has resulted in a reduced in-hospital mortality rate.1,2 Although this achievement is compelling and has led to increasing numbers of sepsis survivors, their post-hospitalization course often is fraught with physical, cognitive, and overall functional decline as well as decreased quality of life that can persist for years after their acute sepsis episode.3,4 The full effect of these post-sepsis health consequences on patients and the healthcare system has yet to be fully elucidated.
Given the growing focus on readmission penalties for hospitals, the need to understand patterns of healthcare use in sepsis survivors has gained momentum to assess whether readmissions could be prevented.
Furthermore, an understanding of the healthcare needs in this population theoretically could inform targeted interventions to reduce the readmission rate and preclude the development or progression of complications.
LIFE AFTER THE HOSPITAL: POST-SEPSIS TRAJECTORY
Despite reductions in in-hospital mortality for sepsis, later (31 days to two years) mortality in sepsis survivors is significant. A systematic review of 43 studies cited a one-year post-acute sepsis hospitalization mortality rate of 16.1% (95% confidence interval [CI], 14.1-18.1%), although there was significant heterogeneity among the studies included and concerns for residual confounding.5
A more recent study that employed a “doubly robust” analysis with a regression model for mortality and propensity score matching for covariates showed that in adults > 65 years of age, sepsis was associated independently with an absolute increase in mortality of 22.1% (95% CI, 17.5%-26.7%) relative to adults not hospitalized and 10.4% (95% CI, 5.4%-15.4%) relative to adults hospitalized for a non-sepsis infection.6
For the population of sepsis survivors, readmissions to the acute hospital setting are frequent. Recently, several large, observational cohort studies have examined the readmission rates for sepsis survivors and have reported very similar findings across different hospital settings. Using data from 21 community-based hospitals in the Kaiser Permanente Northern California network, Liu et al reported that of 5,479 sepsis patients who survived to hospital discharge, 17.9% experienced a readmission within 30 days, with almost half admitted at least once in the year following discharge.7
Similarly, Prescott et al observed that 26.5% of the 1,083 severe sepsis survivors in the Health and Retirement Study required readmission within 30 days, with 41% readmitted within 90 days, and 63% at some point in the year following the index hospitalization.8 This finding of approximately one in five sepsis survivors requiring readmission within 30 days of hospital discharge is reported in other studies involving single- and multi-hospital systems.9-14 Compared to patients hospitalized for a non-sepsis reason, the odds of 30-day readmission after a sepsis hospitalization were 1.51 times greater (95%CI, 1.38-1.66), even after adjusting for pre-sepsis characteristics and center-level effects.15
Based on a study by Prescott et al, a hospitalization for severe sepsis is a significant transition point. Compared to the year prior to their acute hospitalization, sepsis survivors spent more days (median 16 vs. seven days; P < 0.001) and a higher proportion of days alive (median 9.6% vs. 1.9%; P < 0.001) admitted to inpatient facilities such as hospitals, long-term acute care, and skilled nursing.8
This change in facility days is similar to that observed in otherwise similar patients hospitalized for a non-sepsis reason. But when considering a higher sepsis cohort mortality, sepsis survivors demonstrated a steeper decline in number of days spent at home and a steeper rise in days alive in an inpatient facility.8
Infection was a common reason for readmission. In the Kaiser Permanente study, between 28.3% and 42.7% of readmissions were for infectious reasons (including sepsis).7
In two studies at the Hospital University of Pennsylvania, infection was the most common reason for 30-day readmissions, accounting for 46-69.2% of the 30-day readmissions, with skin/soft tissue infections and pneumonia the most common reasons for readmission.9,14
In a Veterans Affairs study of 90-day readmissions after sepsis hospitalization, infection accounted for 22.2% of readmissions in patients > 65 years of age compared to 15.8% in younger patients.16 Interestingly, although perhaps not surprisingly, the proportion of readmissions because of infection in this study was much greater among patients discharged to nursing facilities (either as a chronic inhabitant or acutely), accounting for about one-fourth of all readmissions compared to patients discharged home.16
Readmissions after a sepsis hospitalization are noteworthy in that they carry high mortality and are costly. In a study by Ortego et al of 269 survivors of septic shock, 33% of the 63 patients readmitted within 30 days required ICU care and 16% ultimately expired or transitioned to hospice.9
In a similar study by Sun et al of 30-day hospital readmissions after sepsis, 39% received ICU care and 14.4% died or transitioned to hospice.14
Using data from the Healthcare Cost and Utilization Project (HCUP) state inpatient databases from California, Florida, and New York, Goodwin et al estimated that the mean cost for each readmission within 30 days after a sepsis hospitalization was $25,505 (standard deviation, $38,765).11 In this study, a minority of sepsis survivors, 25.4% who were readmitted two or more times, accounted for 77.3% of all readmissions, with a cumulative cost of $877.6 million (78.2% of all readmission costs).11
Using data from California’s HCUP, Chang et al found that the median cost for a 30-day readmission after a hospitalization for sepsis was $18,794 (interquartile range, $10,260-$35,386), compared to $14,075 for acute myocardial infarction and $8,973 for congestive heart failure.12
RISK FACTORS FOR READMISSION AND HEALTHCARE USE AFTER SURVIVING SEPSIS
In one of the earliest studies by Liu et al, factors associated with 30-day readmission included severity of illness (based on Laboratory Acute Physiology Scores, version 2), comorbid disease burden (based on Comorbidity Point Scores, version 2), index hospital length of stay (LOS), and need for ICU care, with the dominant contributor identified as prior comorbid conditions with a relative contribution of 73.9%.7
The dominant contributor (at 64.2%) to high healthcare use (defined as > 15% of living days spent in a hospital, subacute nursing facility, or long-term acute care) after a sepsis episode was a history of high use pre-sepsis.7
As the authors noted, both risk factors were present prior to hospitalization for sepsis. It is highly plausible that these factors not only increase the risk for higher healthcare use post-sepsis but also the risk for developing sepsis at all.
Multiple other studies have confirmed comorbid conditions and pre-sepsis healthcare use as risk factors for 30-day readmissions.9,11,12,14-15 Demographic factors also have been implicated, including age,9,11-12 gender,11-12 race (black and/or Native American),11,12 socioeconomic status,12,17 insurance status,10,11 and residence in a metropolitan area.12
Some factors related to the actual hospitalization for sepsis, such as longer hospital LOS9,11 and severity of illness,7,10 are associated with an increased risk for 30-day readmissions. In a study from Barnes-Jewish Hospital, Zilberberg et al found that among the 32% of severe sepsis/septic shock survivors who required readmission within 30 days, risk factors for increased risk of readmission included infection with an extended beta-lactamase organism or Bacteroides spp (although these were infrequent events at around 3%) and experiencing acute kidney injury or failure (odds ratio, 1.951; 95% CI, 1.297-2.933).13 Interestingly, risk factors related to the index hospitalization were not observed consistently across all studies, nor were they cited as the predominant contributors to readmission rates.
Regarding hospital-level factors, Goodwin et al found that for each tertile increase in annual sepsis case volume, the risk of 30-day readmission increased.11 In addition, increased hospital sepsis mortality rates were associated with more readmissions.11 Similar findings were reported by two other studies, which also noted that hospitals with higher severe sepsis volume were more likely to be teaching or university hospitals and to offer trauma services.10,12
Although this may seem contrary to the notion that higher volume centers possess greater experience and resources, several explanations may account for these observations: higher volume centers likely care for sicker patients, and residual confounding could exist despite adjustments for age, comorbidities, and acute organ failure; reduced in-hospital sepsis mortality at higher volume centers could translate to more readmissions because there is a larger pool of sepsis survivors at risk for readmission (as opposed to septic patients dying before hospital discharge); and higher volume centers are more likely to receive outside hospital transfers, some at quite a distance away, which could result in more fragmented post-hospital follow-up local care when these patients return home.11
POTENTIAL EXPLANATIONS AND INTERVENTION PLANNING
Collectively, these studies paint a grim picture of the post-sepsis hospitalization trajectory. However, as with observational studies in general, causality is difficult to unravel, and it is unclear how much of the increased mortality and morbidity with frequent readmissions is attributable to the sepsis episode itself vs. pre-existing risk factors that increase the risk for both sepsis and the sequelae of later mortality and complications.
Certainly, many risk factors that contribute significantly to readmission rates and healthcare use described here are not related to the sepsis event, but rather are “present on admission.” This suggests that a pre-sepsis health trajectory is highly significant in determining the post-sepsis course. In addition, death is a competing outcome with hospital readmissions. This may explain why fewer risk factors surrounding the index hospitalization for sepsis are associated with readmission rates; more severe cases of sepsis result in higher short-term mortality.
From a biologic standpoint, we know that sepsis represents a complex interplay between baseline health status/functioning, risk factors for infection, genetics, a dysregulated immune response, propensity to develop acute organ failure, the healthcare setting, and treatment response. The exact biologic mechanisms by which sepsis survivors experience faster declines are not clear.
Some proposed hypotheses undergoing further investigation include accelerated aging of the immune system, persistent inflammation post-recovery from sepsis, impaired immune system functions, and imbalances in the gastrointestinal microbiota in sepsis leading to higher risk of subsequent infection.18 In addition, the sequelae of hospitalization, including disrupted sleep, poor nourishment, pain, stress, and physical deconditioning, could place already vulnerable patients at increased risk for readmissions in the short term.10
This could explain the findings that many risk factors for readmission are not unique to sepsis, and that many hospital admissions, even for non-sepsis reasons, result in a change in healthcare use after discharge.8
When discussing potential areas for intervention, it is difficult to see how many reported risk factors are easily modifiable. Nonetheless, acknowledgement of the factors that increase the risk of readmission for sepsis survivors can identify patients who may need additional resources at discharge or require closer surveillance in a formal care coordination program.
Disparities in readmissions regarding race and socioeconomic status call for a closer look at whether there are disparities in the quality of care delivered, but also highlight aspects of care, such as social support, health literacy, and chronic disease management, that warrant closer attention to prevent readmissions.11
Other components with the potential to reduce readmissions include an antibiotic stewardship program during the acute hospitalization and post-discharge, a continuous rehabilitation program to help with functional impairment, early and frequent follow-up, and timely access to providers to manage new complications as they arise.9
Finally, given the finding that comorbid conditions and age (up to a certain point, beyond which few very elderly patients are readmitted) are risk factors for readmissions, interventions focused on how palliative care is approached and discussed during and after a sepsis hospitalization could affect readmission rates, especially in the elderly.
SUMMARY
Sepsis survivors experience a difficult health trajectory following their acute illness, with high rates of mortality, hospital readmissions, and healthcare use. However, the causal role of sepsis for the observed sequelae of mortality and morbidity is unclear. A more thorough understanding of the clinical and biologic mechanisms underpinning the long-term health consequences post-sepsis are needed to design interventions to help prevent or treat these outcomes.
REFERENCES
- Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546-1554.
- Kumar G, Kumar N, Taneja A, et al. for the Milwaukee Initiative in Critical Care Outcomes Research Group of Investigators. Nationwide trends of severe sepsis in the 21st century (2000-2007). Chest 2011;140:1223-1231.
- Yende S, Angus DC. Long-term outcomes from sepsis. Curr Infect Dis Rep 2007;9:382-386.
- Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010;304:1787-1794.
- Shankar-Hari M, Ambler M, Mahalingasivam V, et al. Evidence for a causal link between sepsis and long-term mortality: A systematic review of epidemiologic studies. Crit Care 2016;20:101.
- Prescott HC, Osterholzer JJ, Langa KM, et al. Late mortality after sepsis: A propensity matched cohort study. BMJ 2016;353:i2375.
- Liu V, Lei X, Prescott HC, et al. Hospital readmission and healthcare utilization following sepsis in community settings. J Hosp Med 2014;9:502-507.
- 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.
- Ortego A, Gaieski DF, Fuchs BD, et al. Hospital-based acute care use in survivors of septic shock. Crit Care Med 2015;43:729-737.
- Donnelly JP, Hohmann SF, Wang HE. Unplanned readmissions after hospitalization for severe sepsis at academic medical center-affiliated hospitals. Crit Care Med 2015;43:1916-1927.
- Goodwin AJ, Rice DA, Simpson KN, Ford DW. Frequency, cost and risk factors for readmissions among severe sepsis survivors. Crit Care Med 2015;43:738-746.
- Chang DW, Tseng C, Shapiro MF. Rehospitalizations following sepsis: Common and costly. Crit Care Med 2015;43:2085-2093.
- Zilberberg MD, Shorr AF, Micek ST, Kollef MH. Risk factors for 30-day readmission among patients with culture-positive severe sepsis and septic shock: A retrospective cohort study. J Hosp Med 2015;10:678-685.
- Sun A, Netzer G, Small DS, et al. Association between index hospitalization and hospital readmission in sepsis survivors. Crit Care Med 2016;44:478-487.
- Jones TK, Fuchs BD, Small DS, et al. Post-acute care use and hospital readmission after sepsis. Ann Am Thorac Soc 2015;12:904-913.
- Prescott HC. Variation in postsepsis readmission patterns: A cohort study of Veterans Affairs beneficiaries. Ann Am Thorac Soc 2017;14:230-237.
- Schnegelsberg A, Mackenhauer J, Nibro HL, et al. Impact of socioeconomic status on mortality and unplanned readmission in septic intensive care unit patients. Acta Anaesthesiologica Scandinavica 2016;60:465-475.
- Shankar-Hari M, Rubenfeld GD. Understanding long-term outcomes following sepsis: Implications and challenges. Curr Infect Dis Rep 2016;18:37.
The need to understand patterns of healthcare use in sepsis survivors has gained momentum to assess whether readmissions could be prevented.
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