Long-Term Survival Following Sepsis
Results of a single-center registry study with four year follow-up
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Background: There have not yet been any prospective registry studies in Germany with active investigation of the long-term survival of patients with sepsis.
Methods: The Jena Sepsis Registry (JSR) included all patients with a diagnosis of sepsis in the four intensive care units of Jena University Hospital from January 2011 to December 2015. Long-term survival 6–48 months after diagnosis was documented by asking the treating general practitioners. The survival times were studied with Kaplan-Meier estimators. Cox regressions were calculated to show associations between possible predictors and survival time.
Results: 1975 patients with sepsis or septic shock were included. The mean time of observation was 730 days. For 96.4% of the queries to the general practitioners, information on long-term survival was available. Mortality in the intensive care unit was 34% (95% confidence interval [32; 37]), and in-hospital mortality was 45% [42; 47]. The overall mortality six months after diagnosis was 59% [57; 62], the overall mortality 48 months after diagnosis was 74% [72; 78]. Predictors of shorter survival were age, nosocomial origin of sepsis, diabetes, cerebrovascular disease, duration of stay in the intensive care unit, and renal replacement therapy.
Conclusion: The nearly 75% mortality four years after diagnosis indicates that changes are needed both in the acute treatment of patients with sepsis and in their multi-sector long-term care. The applicability of these findings may be limited by their having been obtained in a single center.
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (1). The clinical diagnosis is made in the presence of infection-related dysfunction at least one of the following: lung, kidney, liver, cardiovascular system, blood count, or CNS (eTable 1). Based on an analysis of national figures for ICD-10-GM-coded hospital discharge diagnoses, 136 542 people in Germany suffered from (severe) sepsis during 2015 (according to the “Sepsis-1 definition” , eTable 1). This corresponds to 158 cases of (severe) sepsis per 100 000 inhabitants, and 41.7 % of the patients involved died in hospital (3). Worldwide, the estimated figure for 2017 is 49 million patients affected—significantly more than previously estimated (4). About 11 million patients do not survive (5). However, due to major international differences in coding and documentation, the state of the data is uncertain. For the purposes of monitoring epidemiological indicators therefore, Rhee et al. (6) recommend the identification of clinical cases from patient records.
Owing to a multiplicity of physical and psychological sequelae, the disease burden of sepsis survivors is not restricted to the period of acute care in hospital (7). Although the direct impact on long-term survival is currently a matter of debate (7, 8), the post-acute phase of sepsis is attracting increasing attention. To date, only a small amount of data on long-term survival after sepsis is available in Germany, based on small study populations (9, 10) or limited to 90-day mortality, as in a quality management program of the University Hospital Greifswald (11).
The Jena Sepsis Registry (JSR) at Jena University Hospital, a tertiary care center for about one million people in the state of Thuringia, was founded to meet the need for both clinical case identification and reliable capture of data on long-term survival. Since (like 90% of the population ) most patients who survive sepsis are treated by their family doctors, the latter were chosen as the source of information on long-term survival.
The primary goal of the JSR was the systematic registration of sepsis patients in the intensive care units of a German university hospital, collecting data on clinical information, care parameters, in-hospital mortality, and long-term survival up to 48 months. In addition, the intention was to identify potential predictors of long-term survival on the basis of these data.
In accordance with the definition of a clinical registry (13), all patients over 18 years of age who were treated in one of the four surgical and medical intensive care units of Jena University Hospital between 1 January 2011 and 15 December 2015 were included (in 2015, there were 72 beds with 3835 cases of treatment in these ICUs). The inclusion criterion was “severe sepsis” or septic shock as defined by the first Sepsis Consensus Conference of 1992 (“sepsis-1”) (2) (see eTable 1). Screening for signs of infection and organ dysfunction was done manually by four trained study assistants under physician supervision, based on a patient data management system (PDMS). There were no exclusion criteria. The web-based open-source software OpenClinica (14) was used for documentation. The documented baseline set of data at the time of diagnosis included infection site, APACHE II (15) and SOFA (16) scores, comorbidities, and subsequent microbiological pathogen identification (Table 1a, eTable 2). For patients discharged from hospital, mode of transfer, therapeutic and diagnostic procedures performed, and the number of treatment and ventilation days were also collected (Table 1b).
For patients with septic shock by the sepsis-1 definition, the maximum blood lactate value within the 24 hours after diagnosis was post-documented from the PDMS, enabling comparison for this subgroup with the current, sepsis-3 definition (1) (eTable 1). It should be noted that the current sepsis-3 definition has dispensed with the term “severe sepsis,” replacing it with “sepsis.” In this article, we therefore use the form “(severe) sepsis.”
Information on long-term survival at 6, 12, 24, 36, and 48 months after diagnosis was collected by trained study assistants who contacted the treating primary care physicians by telephone. In addition to the date of death, the place of death was also recorded (see eMethod).
The first part of the analysis was descriptive (Table 1a, Table 1b, eTable 2). Survival times were presented using Kaplan-Meier estimators, as recommended by Pocock et al. (17) (Figure). Cox regressions were calculated to show associations between possible predictors and survival time (for details see eMethod).
Between January 2011 and December 2015, 1975 patients with (severe) sepsis or septic shock were identified and included (median annual number of cases: n = 388). Median age was 66 years (interquartile range [IQR] 58–76), and 65.2% of patients were male. In all, 90.4% were mechanically ventilated, with a median duration of ventilation of 250.8 hours (IQR 34.3–381.3). Further characteristics can be found in Table 1a and Table 1b, and information on microbiological findings in eTable 2.
For data collection on long-term survival, 2600 contacts with primary care physicians were documented, some of them after multiple attempts, at the relevant follow-up timepoints between 6 and 48 months after diagnosis. In 2507 of these contacts (96.4%), information on survival was obtained; 93 contacts (3.6%) brought no result. In these cases, no information was available to the primary care physician—usually because patients had either changed their doctor or moved away.
Mortality was 34.3% in the intensive care unit (ICU) (95% confidence interval: [32.2; 36.4]) and 44.7% in hospital [42.5; 46.9]. The criteria for septic shock by the sepsis-3 definition applied to a smaller proportion of patients (48.6%) than the criteria by the sepsis-1 definition (74.4%). The group fulfilling the sepsis-3 definition showed higher in-hospital mortality (eTable 3).
Of the n = 1093 patients who survived their hospital stay, 38.9% were discharged home, 32.3% to another hospital, 23% to a rehabilitation facility, and 5.8% to a nursing home. For n = 327 of the patients who died after discharge, the place of death was known: 200 (61.2%) died in hospital, 49 (15.0%) in a nursing home, 47 (14.4%) at home, and 31 (9.4%) in a rehabilitation facility.
The Figure shows survival time curves over the 4 years from the time of diagnosis; eTable 3 shows cumulative mortality over the long term. Median follow-up was 730 days (= 24 months). After 70 days [55 days; 88 days], half of the patients had died (median survival time). One year after diagnosis the survival rate was 36% [34; 38], and after 4 years it was 25% [22; 28]. The Figure shows in addition how survival varies depending on key strata by sex, age tertile, and APACHE II score (as a measure of severity of disease at inclusion). A more detailed account of potential predictors of long-term survival identified in univariate and multiple Cox regression models is presented in Table 2. In multiple Cox regression, the following were found to be predictors of reduced long-term survival: age; hospital-acquired infection (infection source); diabetes and cerebrovascular disease (comorbidities); and length of stay in the ICU and renal replacement therapy (care parameters). In contrast, the classification “Reason for ICU admission: emergency surgery” was associated with improved long-term survival (all p ≤ 0.05). Associations with clinical variables at study inclusion for the entire patient population are shown in eTable 4. Among others, variables relating to sepsis severity stand out as predictors of acute death.
This paper describes the systematic and prospective documentation of almost 2000 patients treated in intensive care units for (severe) sepsis or septic shock, with up to 4 years’ follow-up. High acute and long-term mortality were revealed: 44.6% of sepsis patients died during their stay in hospital and another 19.1% within the first year after diagnosis. Median survival after sepsis diagnosis was 70 days.
The age and sex distribution of the patients included in the JSR are within the range of large population-based studies of sepsis patients in Germany (3, 18) and the USA (6). Against the background of the increased mortality rates when the new sepsis-3 definition of septic shock is applied, this new definition proved to be highly selective, confirming findings in the recent literature (18, 19, 20). As to the effect of the sepsis definition employed on (severe) sepsis, no conclusion can be drawn on the basis of our data. However, based on the results of a large British comparative study (21), we assume that application of the sepsis-3 definition would not have led to significant change, because the patient overlap is very large.
In-hospital and ICU mortality rates are comparable with results from national diagnosis-related group (DRG) analysis (22) and a German multicenter point prevalence study (19) (eTable 3). However, the German estimates are significantly higher than those reported in large retrospective cohort studies of >10 000 patients in Australia/New Zealand and the United Kingdom, which give ICU and in-hospital mortality rates of 16% and 24% (23) and 24% and 32% (for 2012) (24), respectively.
The JSR also showed a lower long-term survival rate than the few international prospective long-term studies of sepsis patients treated in intensive care: The multicenter Finnsepsis study reported a 2-year mortality of 44.9% (25), and another multicenter study, from Scotland, reported a mortality rate of 61% for the 5-year period after diagnosis (26). In a single-center Canadian study, by the end of 10 years 67% of patients had died (27) (eTable 5).
Even if one looks at just studies with similar design (prospective inclusion of sepsis patients treated in intensive care), comparability both with the JSR and with each other is limited by several factors:
- Case identification: The retrospective case identification used in large studies based on routine data is only comparable in a limited way to prospective clinical patient enrollment because of the limited validity of sepsis coding: Studies in the United States by Rhee et al. and Gaieski et al. (6, 28) found up to 3.5-fold differences in incidence and mortality when they compared health insurance claims data with clinical record data. Even for (automated) clinical case identification from electronic patient records, which is to be preferred, Rhee et al. (6) reported a positive predictive value of only 70.4% in comparison with manual clinical validation as the gold standard.
- Patient population: As measured by the APACHE II score (25), the mean initial severity of sepsis patients in the JSR was higher than that in the above-mentioned English (24) and Australian cohorts (score >25 only in about 18%) (23). This is problably related to a higher age and a higher rate of comorbidities: The mean age in these studies was 2 to 3 years lower than the mean age of patients in the JSR. Patients in the Canadian and Finnish papers cited above with similar APACHE II scores were also notably younger, with mean ages of 58 and 60.4 years, respectively (25, 27).
- Care: International differences are also noticeable with regard to care structures. The median length of stay in an ICU/hospital is reported as 4/21 days for the United Kingdom (29), 3.2/13.5 days for Australia (23), and 6.9/19.2 days for Canada (27). This compares with 15.9/33.2 days in the JSR. In addition, an international comparison showed Germany to have the highest number of intensive care beds in relation to population size. In the Anglophone countries, capacities are significantly lower (30). In 2008, a comparative cross-sectional study showed that the intensive care admission rate was ten times lower in the United Kingdom than in Germany (216/100 000 versus 2353/100 000 inhabitants) (21). Moreover, in the United States an average of 6.2% of patients discharged from hospital are transferred directly to a hospice (6). In Germany, this is true for only 0.3% of patients (3). Thus, more sepsis patients appear to die in the hospital in Germany than in the US, which inevitably increases hospital mortality rates.
In addition to recording mortality rates, the JSR investigated a number of clinical variables for a possible association with survival (Table 2, eTable 4). All the associations noted have been previously described in the literature. These include, first, clinical variables that cannot be influenced by optimization of acute care, such as age and chronic pre-existing conditions (31). Secondly, indicators of sepsis severity at diagnosis, such as APACHE II and SOFA scores (29), and the presence of septic shock were shown to be predictors of acute survival. Length of stay in the ICU and the need for renal replacement therapy, as additional care parameters assessed (32), were associated with decreased long-term survival. They too should be understood as an expression of the severity of sepsis.
One of the initiatives to improve acute care in Germany has been started at Greifswald University Hospital. There, a quality management program reduced 90-day mortality from 64.2% to 45% (11) (eTable 3). The key point is staff training in early detection and implementation of evidence-based treatment protocols including (among other things) immediate antibiotic administration and collection of blood for culture. Since hospital-acquired infections were also negatively associated with long-term survival in the JSR (33), the introduction of hospital-wide access to an infectious disease consultatant seems to be another possible measure to reduce severe cases of hospital-acquired sepsis (34).
To better understand and treat the long-term consequences of sepsis (35) will require trans-sectoral initiatives and structured outpatient care. In the JSR, long-term survival was assessed on the basis of primary care physician records with only minimal data loss. In contrast, contacting patients directly by telephone resulted in a failure rate of almost 30% after 5 years in one Scottish study (26). The Ohio State University Sepsis Registry was even closed in 2011 due to inadequate follow-up rates (36).
The findings derived from the JSR are limited by the facts that it is a single center dataset and that data collection is confined to mortality over the long term, precluding any conclusions about long-term morbidity. Although the JSR findings show parallels to national or multicenter data (e.g., regarding demographic characteristics or hospital mortality), the extent to which the results are comparable with other locations remains unclear. The lack of an appropriate control group means that no conclusions can be drawn about whether sepsis survival has increased long-term mortality rates in our population. However, indications from the recent literature suggest that it has: The US observational studies by Prescott et al. (37) and Wang et al. (e1) respectively showed increased mortality up to 2 years after sepsis among patients over age 65, and up to 5 years after sepsis among those over age 45, compared with the control group. Most comparable with the present work is a single-center prospective cohort study from Australia (38), which found, in comparison with national mortality tables, a (probably) sepsis-induced increase in mortality rates for up to 2 years after sepsis (eTable 5).
The strength of the JSR is its follow-up period, which for a prospective observational study is quite long even by international standards, and its relatively high number of cases and data completeness, required by many authors as an indicator of quality (8). It seems possible that this approach to data collection may be transferable to other locations. This is currently under way in the Mid-German Sepsis Cohort (39): This multicenter patient cohort study also addresses, on the basis of extensive interviews, the issue of long-term morbidity in sepsis patients.
For the specific setting of a German tertiary care center, results regarding the long-term survival of almost 2000 patients who received a diagnosis and intensive treatment for sepsis are now available. Prospective case identification produced data of high quality. Primary care physician records proved to be a practicable data source for long-term registry projects.
As indicated by the WHO Sepsis Resolution (40), the reduced survival rates after sepsis, even in the long term, underscore the need for additional efforts, both hospital-based and on a wider intersectoral basis, to further reduce the number of preventable sepsis-associated deaths and to improve the long-term care of sepsis survivors.
Many colleagues and co-workers have contributed over the years to make the Jena Sepsis Registry possible. Data collection and clinical testing: Dr. Frank Bloos, Petra Bloos, Anke Braune, Daniela Fergen, Anja Haucke, Susan Kerth, Steffi Kolanos, Karina Knuhr-Kohlberg, Dr. Katrin Ludewig, Almut Noack, Ulrike Redlich, Dr. Daniel Thomas-Rüddel, Sandra Töpel, Christel Volkmer. Technical support: Cornelia Eichhorn, Michelle Kaufmann, Matthias Löbe, Dr. Frank Meineke, Florian Rissner. Conception: Dr. Friederike Müller.
Conflict of interest statement
Professor Vollmar owns shares in Medtronic.
Professor Scherag has received financial support from Rudolf Presl GmbH & Co. Klinik Bavaria Rehabilitations KG for a research project.
The other authors declare that there is no conflict of interest.
Manuscript received on 7 April 2020, revised version accepted on 24 June 2020
Dr. med. Konrad Schmidt
Institut für Allgemeinmedizin, Universitätsklinikum Jena
Bachstr. 18, 07743 Jena, Germany
Cite this as:
Schmidt K, Gensichen J, Fleischmann-Struzek C, Bahr V, Pausch C, Sakr Y, Reinhart K, Vollmar HC, Thiel P, Scherag A, Gantner J, Brunkhorst FM: Long-term survival following sepsis—results of a single-center registry study with four year follow-up.
Dtsch Arztebl Int 2020; 117: 775–82. DOI: 10.3238/arztebl.2020.0775
For eReferences please refer to:
Center for Sepsis Control and Care (CSCC), Jena University Hospital: Dr. med. Konrad Schmidt, Dr. med. Carolin Fleischmann-Struzek, Dr. rer. nat. Christine Pausch, Prof. Dr. med. Konrad Reinhart, Dr. med. Paul Thiel, Prof. Dr. rer. physiol. André Scherag, Prof. Dr. med. Frank M. Brunkhorst
Institute of General Practice and Family Medicine, Jena University Hospital: Dr. med. Konrad Schmidt, Prof. Dr. med. Jochen Gensichen, Prof. Dr. med. Horst Christian Vollmar, Dr. med. Paul Thiel
Institute of General Practice, Charité–Universitätsmedizin Berlin: Dr. med. Konrad Schmidt
Institute of General Practice and Family Medicine, Munich University Hospital, Ludwig-Maximilians-Universität München: Prof. Dr. med. Jochen Gensichen
Center for Clinical Studies, Jena University Hospital : Viola Bahr, Prof. Dr. med. Frank M. Brunkhorst
Clinic for Anaesthesiology and Intensive Care Medicine, Jena University Hospital : Prof. Dr. med. Yasser Sakr, Prof. Dr. med. Konrad Reinhart
Institute for Medical Informatics, Statistics and Epidemiology (IMISE), Leipzig University: Dr. rer. nat. Christine Pausch
Institute of General Practice and Family Medicine, Ruhr-University Bochum: Prof. Dr. med. Horst Christian Vollmar
Institute of Medical Statistics, Computer Science and Data Sciences, Jena University Hospital: Prof. Dr. rer. physiol. André Scherag, Julia Gantner
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