Long term mortality in sepsis survivors: a population-based study during 15 years

Long term mortality in sepsis survivors: a population-based study during 15 years | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Long term mortality in sepsis survivors: a population-based study during 15 years Carol Lorencio, Emili Vela, Elisabeth Esteban-Torné, Clara Reina, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8340179/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Sepsis, defined as organ dysfunction due to a dysregulated host response to infection, remains a major global health burden. Sepsis short-term mortality have decreased due to advances in early recognition, standardized management and improved referral pathways. However, the long-term prognosis of sepsis survivors remains poorly understood, particularly in Europe, where studies are limited by small sample sizes or short follow-up. This study aimed to evaluate long-term mortality—defined as death within two years after hospital discharge—among sepsis survivors in Catalonia over a 15-year period, and to identify factors associated with increased long-term mortality. Methods A retrospective population-based study was conducted using the Catalan Minimum Basic Dataset of Acute-Care Hospitals. Sepsis cases were identified from 2005 to 2019 using ICD-9-CM and ICD-10-CM codes for infection and acute organ dysfunction. Patients who died during hospitalization, were transferred, or represented readmission episodes were excluded. Survivors were longitudinally followed for two years after discharge, with vital status obtained from the Central Registry of Insured Persons. Comorbidities were assessed using the Charlson index. Long-term mortality predictors were analyzed using logistic regression and Cox proportional hazards models. Results Among 296,554 hospital admissions for sepsis, 237,075 (79.9%) patients survived to discharge. Of these, 42% (99,571) died within two years. Long-term mortality increased with age (from 5.8% in patients 84 years; p < 0.0001) and with comorbidity (21%, 38%, 51% and 67% for Charlson index 0, 1–2, 3–4 and ≥ 5, respectively; p < 0.0001). Neoplasia (HR = 2.011), liver cirrhosis (HR = 1.562) and dementia (HR = 1.204) were the comorbidities most strongly associated with mortality. Longer hospital stays were also associated with increased mortality. A progressive decline in long-term mortality was observed during 2017–2019. Conclusions Long-term mortality among sepsis survivors remains alarmingly high, with over 40% dying within two years after discharge. These findings highlight the need to extend sepsis care beyond the acute episode, focusing on post-sepsis syndrome prevention, improved continuity of care, and structured follow-up—potentially including multidisciplinary and telemonitoring strategies—to reduce long-term morbidity and mortality. Identifying high-risk subgroups could optimize resource allocation and target interventions to those most likely to benefit. Sepsis Sepsis mortality Sepsis long-term mortality Sepsis survivors Sepsis epidemiology Post-sepsis syndrome. Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Sepsis, defined as organ dysfunction resulting from a dysregulated immune response to infection [1] , represents a major global health challenge as recognized by the World Health Organization [2] . Epidemiological data underscores the magnitude of its impact: the annual incidence of sepsis is estimated at 200–420 cases per 100,000 population [3] , affecting more than 45 million individuals worldwide each year [4] and continues to rise [3] . Beyond its increasing incidence, sepsis is associated with substantial mortality, being the direct caused of one death every 2.8 seconds globally [4] . Hospital deaths attributable to sepsis surpass those from other major conditions such as ischemic heart disease and acute cerebrovascular disease [5] , accounting for approximately 50% of all-caused in-hospital mortality [6] . Furthermore, sepsis imposes the greatest economic burden and is responsible for the highest healthcare expenditure among pathological entities in developed nations [4] . Efforts to improve the prognosis of sepsis have centered on standardizing and simplifying its therapeutic management [7] , with strong evidence emphasizing the necessity of early diagnosis and prompt initiation of antibiotic therapy and organ failure management [7] . Health systems have also focused on optimizing resources by implementing rapid referral algorithms to ensure that septic patients with higher care needs are identified and transferred swiftly to advanced care settings [8] . Likely as a consequence of these comprehensive strategies, in-hospital mortality due to sepsis has markedly decreased in recent years [3] . Improvements that save lives in the acute phase could inadvertently contribute to a growth of population with complex health needs and ongoing medical challenges. Although short-term sepsis mortality is well studied, data on long-term impact remain limited, unlike the situation with other diseases, where long-term outcomes are more commonly assessed [9] . The few existing European studies on this subject typically involve small cohorts or have limited follow-up periods after hospital discharge, limiting their ability to draw robust conclusions about true long-term outcomes [10,11] . Therefore, the objective of this study is to analyze the long-term mortality, defined as mortality within 2 years after hospital discharge, of all patients who survived a hospital admission for sepsis in the population of Catalonia over a 15-year period. Additionally, the study aims to identify the factors associated with increased long-term mortality in this population, in order to facilitate targeted interventions for patients at higher risk.​ This approach aims to fill the current evidence gap with a comprehensive, population-based analysis and extended follow-up, providing new insights into the lasting impact of sepsis survival in this region. Methods Design & Interventions The hospitalization rate was defined as annual admissions per 100.000 population. Crude overall and specific hospitalization rates by age and sex were calculated. All patients who survived a hospitalization for sepsis were identified and longitudinally followed for up to 2 years after hospital discharge. Vital status at two years and the date of death (if applicable) were obtained from the Central Registry of Insured Persons (RCA), which in turn receives this information from the Spanish National Statistics Institute (INE). Data sources A retrospective analysis was conducted from hospital discharge records from the Minimum Basic Data Set Acute-Care Hospitals (CMBD-HA in Catalan language) of the Catalan Health System (CatSalut). CMBD-HA is a mandatory population-based registry covering all public and private acute-care hospitals in Catalonia, enabling resource evaluation, healthcare planning and payment management. All codes are provided directly by the patient’s treating physicians and subsequently verified by the technical secretariat of each health center. To ensure data quality, the CMBD-HA input data are systematically validated internally in CatSalut with an automated data validation system that checks its congruity and identifies potential errors or inconsistencies between variables. Furthermore, as this information is used for provider payment purposes, external audits are regularly performed to ensure the quality and reliability of the data. The data set contains demographic and clinical information for patient care episodes, including one primary and secondaries diagnosis, procedures and status on discharge. Official reports from the register of insured persons maintained by CatSalut were used to estimate crude and specific hospitalization rates (universal coverage for 7.570.430 inhabitants in 2019). Patients & Coding Sepsis cases were defined as infection and at least one associated acute organ dysfunction at discharge diagnosis. In Catalonia, the diagnostic coding system changed in January 2018 from ICD-9-CM to ICD-10-CM. In this way, ICD-9 CM codes were used until December 31, 2017, and ICD-10-CM were used subsequently. Using ICD-9-CM and ICD-10-CM codes, all hospitalized patients with an infection and an organ dysfunction were detected following the Angus et al methodology [12] , over a 15-year period (January 2005 to December 2019). All ICD-9-CM diagnostic codes used for detection of infection-related organ dysfunction have been provided in the Additional file 1, and refer to acute dysfunction of any organ as a result of sepsis, since each of them is associated with the diagnosis of infection or sepsis. All of these used codes were translated into the new coding system (CID-10-CM) as of 2018. All patients who died during their hospital stay were excluded. To avoid overlaps, patients who were transferred from one acute-care hospital to another during the same sepsis episode we excluded. Hospital readmission episodes were excluded from the analysis. All patients who survived to hospital admission were included in the study, and their survival was assessed two years after hospital discharge, obtaining data of RCA. As information was not available regarding if patients were treated in the intensive Care Unit (ICU) or regular ward, ICU admission was directly deduced from obtaining codes of procedures typically used in ICU management (Additional file 1). The Charlson comorbidity index (ChI) was used to assess the presence of underlying comorbidities. The ICD-9-CM codes used to identify acute organ dysfunction and infectious processes are listed in Supplementary Material. With ICD-10-CM codification system, all used codes to identify acute organ dysfunction were equated to ICD-10-CM system. Statistical analysis Continuous and discrete variables were compared using analysis of variance and the Chisquare test, respectively. Multivariate logistic regression, adjusted for other significant variables, was used to analyze long-term mortality risk; variables were entered one by one and retained when their significance was < 0.10 and were clinically plausible. Survival analysis was performed using the Kaplan–Meier method. Subsequently, using the variables with a significant difference between categories (Gehan test), a multivariate model was constructed by calculating Cox proportional hazards with robust standard errors. Data analysis was performed using R 4.4.0. software (R foundation for Statistical Computing). Ethics The study was approved by the Ethics Committee of Hospital de Mataró and the Maresme Health Consortium (code CEIC_20/18) on March 21, 2018, with a waiver of informed consent. All study procedures were conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Results Characteristics of surviving patients Of 11,916,974 discharges from all Catalan acute-care hospitals during the study period (2005–2019), 296,554 were admitted for sepsis (2.49% of all hospital admissions). Of all of them, 237,075 (79.9%) survived hospital admission. Among the survivors at hospital discharge, 55.9% (132,514) were men and their mean age was 72.3 (± 18.7) years (Fig. 1). A moderate degree of comorbidity was observed between survivors, with a mean ChI of 2.36 (± 2.12). Only 12.8% of the surviving patients had high comorbidity (ChI ≥5). The most frequently observed chronic diseases among surviving patients were chronic kidney disease (29.1%), chronic obstructive pulmonary disease (25.5%), uncomplicated diabetes mellitus (22.9%), active neoplasms (25%) and congestive heart failure (21.2%). The most frequent septic source was the genitourinary (41.6%), followed by the respiratory (32%), unknown origin (11.4%), abdomen-biliary focus (10.1%), related to intravascular devices (7.5%), skin and soft tissues (4.6%), endocarditis (1.1%) and infection of the central nervous system (0.78%). Their mean length of hospital stay was 15.5 (± 24.8) days. The main baseline characteristics of included patients are showed in table 1. Long-term mortality Of the 237,075 sepsis cases who survived hospital admission for sepsis, 42% (99,571 patients) died within 2 years after hospital discharge. Characteristics of those who died before 2 years were analyzed. Long-term mortality following sepsis was higher in men (43% vs 40%, p < 0.0001) and was closely related to the patient's age, increasing markedly with advanced age groups (5.8%, 11%, 27%, 35%, 45% and 62% in those who were discharged from the hospital at an age 84 years, respectively (p < 0,0001) (Fig. 2). Long-term mortality was also related to patient comorbidity at the time of hospital discharge and it also increased significantly as ChI increased, being of 21%, 38%, 51% and 67% for patients without comorbidities (ChI = 0), with low comorbidity (ChI 1–2), with moderate comorbidity (ChI 3–4), and with high comorbidity (ChI ≥ 5), respectively (p < 0.0001) (Fig. 3). The comorbidities present at hospital discharge with the greatest impact on long-term mortality were the presence of neoplasia (mortality at 2 years = 67%, p < 0.0001, HR = 2.011), liver cirrhosis (mortality at 2 years = 55%, p < 0.0001, HR = 1.562) and dementia (mortality at 2 years = 62%, p < 0.0001, HR = 1.204) (Fig. 4). Additionally, 2-years mortality was also related to the length of stay of previous hospital admission, with increased numbers in longer stays: Mortality was significantly higher among patients who required hospital admission for more than 2 weeks (between 15 and 21 days of stay: HR = 1.18, CI = 1.152–1.209, between 22 and 28 days of stay: HR = 1.241, CI = 1.204–1.279, and hospital stays > 28 days: HR = 1.299, CI = 1.263–1.337) (Fig. 4). Finally, mortality has been changing during the study period, with a progressive and significant decrease over the final years. Thus, the long-term mortality of patients discharged in 2017, 2018 and 2019 was 39.1% (HR = 0.929, CI = 0.891–0.97), 35.9% (HR = 0.857, CI = 0.821–0.895) and 34.86% (HR = 0.83, CI = 0.792–0.87), respectively (Fig. 4). Discussion In recent years, sepsis management has primarily focused on restoring organ perfusion and cellular oxygenation during the early stages of the disease, with the goal of reducing early mortality. Advances in early detection [13] and initial resuscitation and management [14] have together contributed to a significant reduction in in-hospital mortality from sepsis [3] . However, there is a scarcity of studies evaluating long-term mortality in sepsis survivors, and those that do exist are limited by small sample sizes [15] or relatively short follow-up periods after the acute episode [16] . To the best of current knowledge, this study represents the largest epidemiological investigation in this area, with a 15-year registry that includes over 296,000 sepsis cases who survived a hospital admission for sepsis. Furthermore, the follow-up period in this study is the longest reported to date, assessing mortality up to 2 years after hospital discharge. Despite substantial advances in reducing in-hospital mortality [3] , this study shows that long-term mortality among patients who survive hospitalization remains high, exceeding 40% 2 years after discharge. Although the epidemiological nature of this study does not allow for establishing causality, we have found that mortality was associated with age, comorbidity and length of stay, findings that are consistent with the limited existing literature [15] , and that suggest that sepsis survivors remain clinically fragile after the acute episode, experiencing lasting sequelae that negatively affect both their quality of life and life expectancy. Patients who survive an ICU admission often experience prolonged functional and cognitive decline that persists for months beyond hospital discharge [17] . This condition, known as post–intensive care syndrome (PICS) [18] , is associated with increased long-term morbidity and mortality, as well as higher healthcare costs [19] . In patients with sepsis, PICS—or post-sepsis syndrome [20] —is particularly devastating [15] : about two-thirds remain dependent three years after hospital discharge [15], with physical impairments such as muscle loss, dysphagia, respiratory disorders or pain. Additionally, many suffer major psychological sequelae, including cognitive deficits and sleep disturbances [15] . These long-lasting effects contribute to the high burden of morbidity and mortality observed in sepsis survivors [15] . Risk factors that have been associated with PICS include length of ICU stay, duration of mechanical ventilation, muscle weakness, poor glycemic control, delirium, deep sedation, and use of neuromuscular blockers or glucocorticoids [18] . These considerations suggest that, to improve the overall prognosis of sepsis survivors, efforts must extend beyond early detection and initial management to also optimize post-acute care aimed at reducing long-term morbidity. Preventing the risk factors linked to post-sepsis syndrome is critical, yet significant challenges remain. Despite clinical guidelines, common practices such as oversedation [21] , inadequate nutritional support [22] , underdiagnosed delirium [23] , and limited physiotherapy access [24] , still persist widely in clinical settings. Addressing these modifiable risk factors is essential to improve long-term outcomes for sepsis survivors and reduce the burden of chronic impairments following critical illness. While efforts should mainly focus on preventing post-sepsis syndrome development during the ICU stay, this is not always achievable. When post-sepsis syndrome does occur, close follow-up of affected patients is essential to minimize its impact, manage symptoms, and identify potential complications early on. In this context, effective follow-up by the primary care physician after hospital discharge is crucial. Primary care providers play a central role in directing patient treatment and coordinating a multidisciplinary team - including nutritionists, physiotherapists, psychologists, nurses, and others- who are all integral to supporting the patients’ recovery. The high long-term mortality observed among sepsis survivors in this study suggests not only a significant decline in health status at hospital discharge but may also indicate suboptimal continuity of care by primary care services after hospitalization. Numerous studies suggest that close follow-up by primary care physicians after hospital discharge may be associated with reduced risk of readmission and improved long-term mortality in medical patients, although the evidence specific to sepsis survivors is limited and of low quality due to the predominance of observational studies and risk of bias [25] . In response to these findings, various post-hospitalization follow-up programs—including rehabilitation and care coordination interventions—have been implemented, showing promising results in reducing readmissions and mortality, as well as improving physical function and psychological symptoms in sepsis survivors [26] . However, most available studies are small and heterogeneous in their interventions, which limits the generalizability of the results [25] . Therefore, high-quality prospective studies are needed to evaluate the impact of follow-up interventions across all domains of post-sepsis impairment, particularly cognitive impairment [26] . This study reports a slight decrease in long-term mortality among sepsis survivors during the last three years. Although this observational study cannot establish causality, it could be related to the implementation of these post-hospitalization follow-up programs. Given the need for ongoing follow-up of sepsis survivors, telemonitoring programs have gained popularity in recent years and could play a crucial role in tracking clinical progress and early identifying potential complications. Despite challenges, telemonitoring offers an effective way to provide continuous care and facilitate timely interventions that may improve long-term outcomes in this vulnerable population [27] . This study emphasizes that the long-term prognosis of patients with sepsis varies based on patient-related factors such as age, sex and comorbidities, as well as other elements like the length of hospital stay. Identifying high-risk subgroups for long-term mortality could facilitate the development of predictive survival models tailored for sepsis. Such models could assist in decision-making during ICU admission and promote rational, efficient use of healthcare resources. While multiple studies have developed predictive models to estimate in-hospital mortality in septic patients [28] , no widely applicable predictive models currently exist for long-term mortality. The few existing predictive models either do not allow estimating mortality in such a long period after hospital discharge [29] , limiting their generalizability and utility for long-term prognosis assessment. It is appropriate to note that one of the limitations of the study is its retrospective design, which inherently introduces potential biases such as selection bias and limits the ability to establish causality. Additionally, the restriction of data to patients admitted up to the end of 2019 is a significant limitation, as it excludes the period during which the COVID-19 pandemic led to major changes in hospital operations and patient management. During the pandemic, sepsis patients were frequently transferred to non-specialized units or experienced delays in ICU admission, which could have affected outcomes and the generalizability of findings to subsequent years, as evidenced by multiple studies [30] . Another important limitation of this study is the inability to establish causality, as it is an epidemiological study relying on administrative and diagnostic coding data. Although a validated methodology was used to define cases, there remains a risk of bias due to inconsistencies in case identification and coding processes. ICU admission was inferred from procedure codes, and although in this setting procedures related to critically or semi-critically ill patients are mostly performed in ICU, this is not the case in all instances. Consequently, the percentage of patients admitted to the ICU may be overestimated due to selection bias. The study design also does not allow for identifying the specific causes of late mortality in sepsis survivors. Understanding these causes could clarify which aspects of post-ICU syndrome most strongly affect comorbidity and prognosis, thereby enabling targeted follow-up, monitoring and treatment. Finally, the study was conducted within the population of Catalonia, which limits the generalizability of the results. Findings may not be applicable to other regions or countries with different socioeconomic conditions or healthcare systems. Conclusions Long-term mortality in sepsis survivors remains alarmingly high, with more than 40% of patients dying within 2 years after hospital discharge. Despite substantial advances in early recognition and acute management, the prognosis of sepsis survivors continues to be poor. These results highlight the need to extend sepsis care beyond the acute episode, prioritizing strategies to prevent and manage post-sepsis syndrome, ensure adequate continuity of care, and promote structured follow-up after hospital discharge. Primary care physicians, multidisciplinary teams, and approaches such as telemonitoring may help reduce long-term morbidity and mortality in this vulnerable population. Identifying high-risk subgroups can optimize healthcare resource allocation and target long-term support to those who benefit most. Abbreviations CatSalut: Catalan Health System. CMBD-HA: Minimum Basic Data Set Acute-Care Hospitals in Catalan language. ChI: Charlson comorbidity index. ICU: Intensive Care Unit. INE: Spanish National Statistics Institute, in Spanish language. PICS: post–intensive care syndrome. RCA: Central Registry of Insured Persons, in Spanish language. Declarations Ethics approval and consent to participate: The study was approved by the Ethics Committee of Hospital de Mataró and the Maresme Health Consortium (code CEIC_20/18) on March 21, 2018, with a waiver of informed consent. All study procedures were conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Consent for publication: not applicable Availability of data and materials: The data that support the findings of this study are available from the Information Areas Department of the Catalan Health Service (CatSalut), but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are, however, available from the authors upon reasonable request and with permission of CatSalut. Competing interests : The authors declare that they have no competing interests Funding: not applicable Authors' contributions: C.L. contributed to the conception and design of the study, interpreted the data and wrote the main manuscript. E.V. was responsible for the statistical analysis and prepared figures. E.E.-T & J.C.Y. contributed to the conception and design of the study, interpreted the data and contributed to the critical revision of the manuscript. C.R., A.H.-P., R.F.-S., J.T., P.C.-R., J.C.R., A.R., A.A., P.G., R.F. contributed to the critical revision of the manuscript. Acknowledgements : Sepsis and Septic Shock Working Group of the Catalan Society of Intensive and Critical Care Medicine (SOCMIC). References Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. 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Klein Klouwenberg PMC, Spitoni C, van der Poll T, Bonten MJ, Cremer OL; MARS consortium. Predicting the clinical trajectory in critically ill patients with sepsis: a cohort study. Crit Care. 2019 Dec 12;23(1):408. Li A, Ling L, Qin H, Arabi YM, Myatra SN, Egi M, Kim JH, Nor MBM, Son DN, Fang WF, Wahyuprajitno B, Hashmi M, Fruq MO, Patjanasoontorn B, Al Bahrani MJ, Shrestha BR, Shrestha U, Nafees KMK, Sann KK, Palo JEM, Mendsaikhan N, Konkayev A, Detleuxay K, Chan YH, Du B, Divatia JV, Koh Y, Phua J; MOSAICS II Study Group; Asian Critical Care Clinical Trials Group. Prognostic evaluation of quick sequential organ failure assessment score in ICU patients with sepsis across different income settings. Crit Care. 2024 Jan 23;28(1):30. Szatmary P, Arabi YM, Brown RM, Chen Y, Coopersmith CM, Deng JC, Estenssoro E, Fowler RA, Gong MN, Hodgson CL, Kissoon N, Koh Y, Machado FR, Martin-Loeches I, McAuley DF, Nseir S, Phua J, Phua GC, Riviello ED, Salluh JI, et al. Non-COVID-19 intensive care admissions during the pandemic: a multinational registry-based study. Intensive Care Med . 2023 Jun;49(6):665-678. Table Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.pdf SupplementalAppendixAdditionalFile1.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Distribution by age and gender, Catalunya, 2005 – 2019.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8340179/v1/fdcc752c653f27948674aa5c.png"},{"id":99318932,"identity":"d8dc7713-0356-4e98-93de-9bcb40626969","added_by":"auto","created_at":"2025-12-31 16:35:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":68752,"visible":true,"origin":"","legend":"\u003cp\u003eSepsis long-term surviving according to age, Catalunya, 2005 – 2019.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8340179/v1/3342a4e552a6dc1f8879da81.png"},{"id":99316932,"identity":"0bd88ad4-f0d3-47fb-aafa-d8ddd7fd58c1","added_by":"auto","created_at":"2025-12-31 16:29:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":67063,"visible":true,"origin":"","legend":"\u003cp\u003eSepsis long-term surviving according to comorbidities (Charlson Index (ChI)), Catalunya, 2005 – 2019.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8340179/v1/5099f620d5c2834fcdd46065.png"},{"id":99188793,"identity":"f63bbb1d-4e82-4e99-b4f1-3e9d90b1405d","added_by":"auto","created_at":"2025-12-30 00:20:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":85813,"visible":true,"origin":"","legend":"\u003cp\u003eLong-term mortality risk factors in surviving patients. Catalunya 20015 – 2019. (HR= Hazard Ratio)\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8340179/v1/c13185ba496c495b88ae168b.png"},{"id":100356224,"identity":"d216cb0f-02e9-4a19-8a3f-d8f29ea666db","added_by":"auto","created_at":"2026-01-16 06:57:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":852080,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8340179/v1/a896b88c-aab0-4cbb-9c39-2f638c8ddf66.pdf"},{"id":99316172,"identity":"5c950430-56f3-4c5f-880b-38f915684cab","added_by":"auto","created_at":"2025-12-31 16:27:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":50843,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8340179/v1/70cc5d7a729fa2e51e7abada.pdf"},{"id":99317843,"identity":"fe93a68d-3b17-490b-adb0-7c6299a8ea0e","added_by":"auto","created_at":"2025-12-31 16:30:48","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":40613,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalAppendixAdditionalFile1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8340179/v1/b31c5d4de48c41c75a099399.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Long term mortality in sepsis survivors: a population-based study during 15 years","fulltext":[{"header":"Background","content":"\u003cp\u003eSepsis, defined as organ dysfunction resulting from a dysregulated immune response to infection\u003csup\u003e[1]\u003c/sup\u003e, represents a major global health challenge as recognized by the World Health Organization\u003csup\u003e[2]\u003c/sup\u003e. Epidemiological data underscores the magnitude of its impact: the annual incidence of sepsis is estimated at 200\u0026ndash;420 cases per 100,000 population\u003csup\u003e[3]\u003c/sup\u003e, affecting more than 45\u0026nbsp;million individuals worldwide each year \u003csup\u003e[4]\u003c/sup\u003e and continues to rise\u003csup\u003e[3]\u003c/sup\u003e. Beyond its increasing incidence, sepsis is associated with substantial mortality, being the direct caused of one death every 2.8 seconds globally\u003csup\u003e[4]\u003c/sup\u003e. Hospital deaths attributable to sepsis surpass those from other major conditions such as ischemic heart disease and acute cerebrovascular disease \u003csup\u003e[5]\u003c/sup\u003e, accounting for approximately 50% of all-caused in-hospital mortality\u003csup\u003e[6]\u003c/sup\u003e. Furthermore, sepsis imposes the greatest economic burden and is responsible for the highest healthcare expenditure among pathological entities in developed nations\u003csup\u003e[4]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEfforts to improve the prognosis of sepsis have centered on standardizing and simplifying its therapeutic management\u003csup\u003e[7]\u003c/sup\u003e, with strong evidence emphasizing the necessity of early diagnosis and prompt initiation of antibiotic therapy and organ failure management\u003csup\u003e[7]\u003c/sup\u003e. Health systems have also focused on optimizing resources by implementing rapid referral algorithms to ensure that septic patients with higher care needs are identified and transferred swiftly to advanced care settings\u003csup\u003e[8]\u003c/sup\u003e. Likely as a consequence of these comprehensive strategies, in-hospital mortality due to sepsis has markedly decreased in recent years\u003csup\u003e[3]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eImprovements that save lives in the acute phase could inadvertently contribute to a growth of population with complex health needs and ongoing medical challenges. Although short-term sepsis mortality is well studied, data on long-term impact remain limited, unlike the situation with other diseases, where long-term outcomes are more commonly assessed\u003csup\u003e[9]\u003c/sup\u003e. The few existing European studies on this subject typically involve small cohorts or have limited follow-up periods after hospital discharge, limiting their ability to draw robust conclusions about true long-term outcomes\u003csup\u003e[10,11]\u003c/sup\u003e. Therefore, the objective of this study is to analyze the long-term mortality, defined as mortality within 2 years after hospital discharge, of all patients who survived a hospital admission for sepsis in the population of Catalonia over a 15-year period. Additionally, the study aims to identify the factors associated with increased long-term mortality in this population, in order to facilitate targeted interventions for patients at higher risk.​\u003c/p\u003e \u003cp\u003eThis approach aims to fill the current evidence gap with a comprehensive, population-based analysis and extended follow-up, providing new insights into the lasting impact of sepsis survival in this region.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign \u0026amp; Interventions\u003c/h2\u003e \u003cp\u003eThe hospitalization rate was defined as annual admissions per 100.000 population. Crude overall and specific hospitalization rates by age and sex were calculated. All patients who survived a hospitalization for sepsis were identified and longitudinally followed for up to 2 years after hospital discharge. Vital status at two years and the date of death (if applicable) were obtained from the Central Registry of Insured Persons (RCA), which in turn receives this information from the Spanish National Statistics Institute (INE).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData sources\u003c/h3\u003e\n\u003cp\u003e A retrospective analysis was conducted from hospital discharge records from the Minimum Basic Data Set Acute-Care Hospitals (CMBD-HA in Catalan language) of the Catalan Health System (CatSalut). CMBD-HA is a mandatory population-based registry covering all public and private acute-care hospitals in Catalonia, enabling resource evaluation, healthcare planning and payment management. All codes are provided directly by the patient\u0026rsquo;s treating physicians and subsequently verified by the technical secretariat of each health center. To ensure data quality, the CMBD-HA input data are systematically validated internally in CatSalut with an automated data validation system that checks its congruity and identifies potential errors or inconsistencies between variables. Furthermore, as this information is used for provider payment purposes, external audits are regularly performed to ensure the quality and reliability of the data. The data set contains demographic and clinical information for patient care episodes, including one primary and secondaries diagnosis, procedures and status on discharge. Official reports from the register of insured persons maintained by CatSalut were used to estimate crude and specific hospitalization rates (universal coverage for 7.570.430 inhabitants in 2019).\u003c/p\u003e\n\u003ch3\u003ePatients \u0026 Coding\u003c/h3\u003e\n\u003cp\u003eSepsis cases were defined as infection and at least one associated acute organ dysfunction at discharge diagnosis. In Catalonia, the diagnostic coding system changed in January 2018 from ICD-9-CM to ICD-10-CM. In this way, ICD-9 CM codes were used until December 31, 2017, and ICD-10-CM were used subsequently. Using ICD-9-CM and ICD-10-CM codes, all hospitalized patients with an infection and an organ dysfunction were detected following the Angus et al methodology\u003csup\u003e[12]\u003c/sup\u003e, over a 15-year period (January 2005 to December 2019). All ICD-9-CM diagnostic codes used for detection of infection-related organ dysfunction have been provided in the Additional file 1, and refer to acute dysfunction of any organ as a result of sepsis, since each of them is associated with the diagnosis of infection or sepsis. All of these used codes were translated into the new coding system (CID-10-CM) as of 2018. All patients who died during their hospital stay were excluded. To avoid overlaps, patients who were transferred from one acute-care hospital to another during the same sepsis episode we excluded. Hospital readmission episodes were excluded from the analysis. All patients who survived to hospital admission were included in the study, and their survival was assessed two years after hospital discharge, obtaining data of RCA.\u003c/p\u003e \u003cp\u003eAs information was not available regarding if patients were treated in the intensive Care Unit (ICU) or regular ward, ICU admission was directly deduced from obtaining codes of procedures typically used in ICU management (Additional file 1). The Charlson comorbidity index (ChI) was used to assess the presence of underlying comorbidities. The ICD-9-CM codes used to identify acute organ dysfunction and infectious processes are listed in Supplementary Material. With ICD-10-CM codification system, all used codes to identify acute organ dysfunction were equated to ICD-10-CM system.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous and discrete variables were compared using analysis of variance and the Chisquare test, respectively. Multivariate logistic regression, adjusted for other significant variables, was used to analyze long-term mortality risk; variables were entered one by one and retained when their significance was \u0026lt;\u0026thinsp;0.10 and were clinically plausible. Survival analysis was performed using the Kaplan\u0026ndash;Meier method. Subsequently, using the variables with a significant difference between categories (Gehan test), a multivariate model was constructed by calculating Cox proportional hazards with robust standard errors. Data analysis was performed using R 4.4.0. software (R foundation for Statistical Computing).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics\u003c/h3\u003e\n\u003cp\u003e The study was approved by the Ethics Committee of Hospital de Matar\u0026oacute; and the Maresme Health Consortium (code CEIC_20/18) on March 21, 2018, with a waiver of informed consent. All study procedures were conducted in accordance with the Declaration of Helsinki and its subsequent amendments.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of surviving patients\u003c/h2\u003e \u003cp\u003e Of 11,916,974 discharges from all Catalan acute-care hospitals during the study period (2005\u0026ndash;2019), 296,554 were admitted for sepsis (2.49% of all hospital admissions). Of all of them, 237,075 (79.9%) survived hospital admission. Among the survivors at hospital discharge, 55.9% (132,514) were men and their mean age was 72.3 (\u0026plusmn;\u0026thinsp;18.7) years (Fig.\u0026nbsp;1). A moderate degree of comorbidity was observed between survivors, with a mean ChI of 2.36 (\u0026plusmn;\u0026thinsp;2.12). Only 12.8% of the surviving patients had high comorbidity (ChI \u0026ge;5). The most frequently observed chronic diseases among surviving patients were chronic kidney disease (29.1%), chronic obstructive pulmonary disease (25.5%), uncomplicated diabetes mellitus (22.9%), active neoplasms (25%) and congestive heart failure (21.2%).\u003c/p\u003e \u003cp\u003eThe most frequent septic source was the genitourinary (41.6%), followed by the respiratory (32%), unknown origin (11.4%), abdomen-biliary focus (10.1%), related to intravascular devices (7.5%), skin and soft tissues (4.6%), endocarditis (1.1%) and infection of the central nervous system (0.78%). Their mean length of hospital stay was 15.5 (\u0026plusmn;\u0026thinsp;24.8) days. The main baseline characteristics of included patients are showed in table 1.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLong-term mortality\u003c/h3\u003e\n\u003cp\u003eOf the 237,075 sepsis cases who survived hospital admission for sepsis, 42% (99,571 patients) died within 2 years after hospital discharge. Characteristics of those who died before 2 years were analyzed. Long-term mortality following sepsis was higher in men (43% vs 40%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and was closely related to the patient's age, increasing markedly with advanced age groups (5.8%, 11%, 27%, 35%, 45% and 62% in those who were discharged from the hospital at an age\u0026thinsp;\u0026lt;\u0026thinsp;15 years, 15\u0026ndash;44 years, 45\u0026ndash;64 years, 65\u0026ndash;74 years, 75\u0026ndash;84 years and \u0026gt;\u0026thinsp;84 years, respectively (p\u0026thinsp;\u0026lt;\u0026thinsp;0,0001) (Fig.\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eLong-term mortality was also related to patient comorbidity at the time of hospital discharge and it also increased significantly as ChI increased, being of 21%, 38%, 51% and 67% for patients without comorbidities (ChI\u0026thinsp;=\u0026thinsp;0), with low comorbidity (ChI 1\u0026ndash;2), with moderate comorbidity (ChI 3\u0026ndash;4), and with high comorbidity (ChI \u0026ge; 5), respectively (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Fig.\u0026nbsp;3).\u003c/p\u003e \u003cp\u003eThe comorbidities present at hospital discharge with the greatest impact on long-term mortality were the presence of neoplasia (mortality at 2 years\u0026thinsp;=\u0026thinsp;67%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, HR\u0026thinsp;=\u0026thinsp;2.011), liver cirrhosis (mortality at 2 years\u0026thinsp;=\u0026thinsp;55%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, HR\u0026thinsp;=\u0026thinsp;1.562) and dementia (mortality at 2 years\u0026thinsp;=\u0026thinsp;62%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, HR\u0026thinsp;=\u0026thinsp;1.204) (Fig.\u0026nbsp;4).\u003c/p\u003e \u003cp\u003eAdditionally, 2-years mortality was also related to the length of stay of previous hospital admission, with increased numbers in longer stays: Mortality was significantly higher among patients who required hospital admission for more than 2 weeks (between 15 and 21 days of stay: HR\u0026thinsp;=\u0026thinsp;1.18, CI\u0026thinsp;=\u0026thinsp;1.152\u0026ndash;1.209, between 22 and 28 days of stay: HR\u0026thinsp;=\u0026thinsp;1.241, CI\u0026thinsp;=\u0026thinsp;1.204\u0026ndash;1.279, and hospital stays\u0026thinsp;\u0026gt;\u0026thinsp;28 days: HR\u0026thinsp;=\u0026thinsp;1.299, CI\u0026thinsp;=\u0026thinsp;1.263\u0026ndash;1.337) (Fig.\u0026nbsp;4).\u003c/p\u003e \u003cp\u003eFinally, mortality has been changing during the study period, with a progressive and significant decrease over the final years. Thus, the long-term mortality of patients discharged in 2017, 2018 and 2019 was 39.1% (HR\u0026thinsp;=\u0026thinsp;0.929, CI\u0026thinsp;=\u0026thinsp;0.891\u0026ndash;0.97), 35.9% (HR\u0026thinsp;=\u0026thinsp;0.857, CI\u0026thinsp;=\u0026thinsp;0.821\u0026ndash;0.895) and 34.86% (HR\u0026thinsp;=\u0026thinsp;0.83, CI\u0026thinsp;=\u0026thinsp;0.792\u0026ndash;0.87), respectively (Fig.\u0026nbsp;4).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn recent years, sepsis management has primarily focused on restoring organ perfusion and cellular oxygenation during the early stages of the disease, with the goal of reducing early mortality. Advances in early detection\u003csup\u003e[13]\u003c/sup\u003e and initial resuscitation and management\u003csup\u003e[14]\u003c/sup\u003e have together contributed to a significant reduction in in-hospital mortality from sepsis\u003csup\u003e[3]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, there is a scarcity of studies evaluating long-term mortality in sepsis survivors, and those that do exist are limited by small sample sizes\u003csup\u003e[15]\u003c/sup\u003e or relatively short follow-up periods after the acute episode\u003csup\u003e[16]\u003c/sup\u003e. To the best of current knowledge, this study represents the largest epidemiological investigation in this area, with a 15-year registry that includes over 296,000 sepsis cases who survived a hospital admission for sepsis. Furthermore, the follow-up period in this study is the longest reported to date, assessing mortality up to 2 years after hospital discharge.\u003c/p\u003e \u003cp\u003eDespite substantial advances in reducing in-hospital mortality\u003csup\u003e[3]\u003c/sup\u003e, this study shows that long-term mortality among patients who survive hospitalization remains high, exceeding 40% 2 years after discharge. Although the epidemiological nature of this study does not allow for establishing causality, we have found that mortality was associated with age, comorbidity and length of stay, findings that are consistent with the limited existing literature\u003csup\u003e[15]\u003c/sup\u003e, and that suggest that sepsis survivors remain clinically fragile after the acute episode, experiencing lasting sequelae that negatively affect both their quality of life and life expectancy.\u003c/p\u003e \u003cp\u003ePatients who survive an ICU admission often experience prolonged functional and cognitive decline that persists for months beyond hospital discharge \u003csup\u003e[17]\u003c/sup\u003e. This condition, known as post\u0026ndash;intensive care syndrome (PICS)\u003csup\u003e[18]\u003c/sup\u003e, is associated with increased long-term morbidity and mortality, as well as higher healthcare costs\u003csup\u003e[19]\u003c/sup\u003e. In patients with sepsis, PICS\u0026mdash;or post-sepsis syndrome\u003csup\u003e[20]\u003c/sup\u003e\u0026mdash;is particularly devastating\u003csup\u003e[15]\u003c/sup\u003e: about two-thirds remain dependent three years after hospital discharge\u003csup\u003e[15],\u003c/sup\u003e with physical impairments such as muscle loss, dysphagia, respiratory disorders or pain. Additionally, many suffer major psychological sequelae, including cognitive deficits and sleep disturbances\u003csup\u003e[15]\u003c/sup\u003e. These long-lasting effects contribute to the high burden of morbidity and mortality observed in sepsis survivors\u003csup\u003e[15]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRisk factors that have been associated with PICS include length of ICU stay, duration of mechanical ventilation, muscle weakness, poor glycemic control, delirium, deep sedation, and use of neuromuscular blockers or glucocorticoids\u003csup\u003e[18]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThese considerations suggest that, to improve the overall prognosis of sepsis survivors, efforts must extend beyond early detection and initial management to also optimize post-acute care aimed at reducing long-term morbidity.\u003c/p\u003e \u003cp\u003ePreventing the risk factors linked to post-sepsis syndrome is critical, yet significant challenges remain. Despite clinical guidelines, common practices such as oversedation\u003csup\u003e[21]\u003c/sup\u003e, inadequate nutritional support\u003csup\u003e[22]\u003c/sup\u003e, underdiagnosed delirium\u003csup\u003e[23]\u003c/sup\u003e, and limited physiotherapy access\u003csup\u003e[24]\u003c/sup\u003e, still persist widely in clinical settings. Addressing these modifiable risk factors is essential to improve long-term outcomes for sepsis survivors and reduce the burden of chronic impairments following critical illness.\u003c/p\u003e \u003cp\u003eWhile efforts should mainly focus on preventing post-sepsis syndrome development during the ICU stay, this is not always achievable. When post-sepsis syndrome does occur, close follow-up of affected patients is essential to minimize its impact, manage symptoms, and identify potential complications early on. In this context, effective follow-up by the primary care physician after hospital discharge is crucial. Primary care providers play a central role in directing patient treatment and coordinating a multidisciplinary team - including nutritionists, physiotherapists, psychologists, nurses, and others- who are all integral to supporting the patients\u0026rsquo; recovery. The high long-term mortality observed among sepsis survivors in this study suggests not only a significant decline in health status at hospital discharge but may also indicate suboptimal continuity of care by primary care services after hospitalization.\u003c/p\u003e \u003cp\u003eNumerous studies suggest that close follow-up by primary care physicians after hospital discharge may be associated with reduced risk of readmission and improved long-term mortality in medical patients, although the evidence specific to sepsis survivors is limited and of low quality due to the predominance of observational studies and risk of bias\u003csup\u003e[25]\u003c/sup\u003e. In response to these findings, various post-hospitalization follow-up programs\u0026mdash;including rehabilitation and care coordination interventions\u0026mdash;have been implemented, showing promising results in reducing readmissions and mortality, as well as improving physical function and psychological symptoms in sepsis survivors\u003csup\u003e[26]\u003c/sup\u003e. However, most available studies are small and heterogeneous in their interventions, which limits the generalizability of the results\u003csup\u003e[25]\u003c/sup\u003e. Therefore, high-quality prospective studies are needed to evaluate the impact of follow-up interventions across all domains of post-sepsis impairment, particularly cognitive impairment\u003csup\u003e[26]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study reports a slight decrease in long-term mortality among sepsis survivors during the last three years. Although this observational study cannot establish causality, it could be related to the implementation of these post-hospitalization follow-up programs.\u003c/p\u003e \u003cp\u003eGiven the need for ongoing follow-up of sepsis survivors, telemonitoring programs have gained popularity in recent years and could play a crucial role in tracking clinical progress and early identifying potential complications. Despite challenges, telemonitoring offers an effective way to provide continuous care and facilitate timely interventions that may improve long-term outcomes in this vulnerable population\u003csup\u003e[27]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study emphasizes that the long-term prognosis of patients with sepsis varies based on patient-related factors such as age, sex and comorbidities, as well as other elements like the length of hospital stay. Identifying high-risk subgroups for long-term mortality could facilitate the development of predictive survival models tailored for sepsis. Such models could assist in decision-making during ICU admission and promote rational, efficient use of healthcare resources.\u003c/p\u003e \u003cp\u003eWhile multiple studies have developed predictive models to estimate in-hospital mortality in septic patients\u003csup\u003e[28]\u003c/sup\u003e, no widely applicable predictive models currently exist for long-term mortality. The few existing predictive models either do not allow estimating mortality in such a long period after hospital discharge\u003csup\u003e[29]\u003c/sup\u003e, limiting their generalizability and utility for long-term prognosis assessment.\u003c/p\u003e \u003cp\u003eIt is appropriate to note that one of the limitations of the study is its retrospective design, which inherently introduces potential biases such as selection bias and limits the ability to establish causality. Additionally, the restriction of data to patients admitted up to the end of 2019 is a significant limitation, as it excludes the period during which the COVID-19 pandemic led to major changes in hospital operations and patient management. During the pandemic, sepsis patients were frequently transferred to non-specialized units or experienced delays in ICU admission, which could have affected outcomes and the generalizability of findings to subsequent years, as evidenced by multiple studies\u003csup\u003e[30]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAnother important limitation of this study is the inability to establish causality, as it is an epidemiological study relying on administrative and diagnostic coding data. Although a validated methodology was used to define cases, there remains a risk of bias due to inconsistencies in case identification and coding processes. ICU admission was inferred from procedure codes, and although in this setting procedures related to critically or semi-critically ill patients are mostly performed in ICU, this is not the case in all instances. Consequently, the percentage of patients admitted to the ICU may be overestimated due to selection bias.\u003c/p\u003e \u003cp\u003eThe study design also does not allow for identifying the specific causes of late mortality in sepsis survivors. Understanding these causes could clarify which aspects of post-ICU syndrome most strongly affect comorbidity and prognosis, thereby enabling targeted follow-up, monitoring and treatment.\u003c/p\u003e \u003cp\u003eFinally, the study was conducted within the population of Catalonia, which limits the generalizability of the results. Findings may not be applicable to other regions or countries with different socioeconomic conditions or healthcare systems.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eLong-term mortality in sepsis survivors remains alarmingly high, with more than 40% of patients dying within 2 years after hospital discharge. Despite substantial advances in early recognition and acute management, the prognosis of sepsis survivors continues to be poor. These results highlight the need to extend sepsis care beyond the acute episode, prioritizing strategies to prevent and manage post-sepsis syndrome, ensure adequate continuity of care, and promote structured follow-up after hospital discharge. Primary care physicians, multidisciplinary teams, and approaches such as telemonitoring may help reduce long-term morbidity and mortality in this vulnerable population. Identifying high-risk subgroups can optimize healthcare resource allocation and target long-term support to those who benefit most.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCatSalut: Catalan Health System.\u003c/p\u003e\n\u003cp\u003eCMBD-HA: Minimum Basic Data Set Acute-Care Hospitals in Catalan language.\u003c/p\u003e\n\u003cp\u003eChI: Charlson comorbidity index.\u003c/p\u003e\n\u003cp\u003eICU: Intensive Care Unit.\u003c/p\u003e\n\u003cp\u003eINE: Spanish National Statistics Institute, in Spanish language.\u003c/p\u003e\n\u003cp\u003ePICS: post\u0026ndash;intensive care syndrome.\u003c/p\u003e\n\u003cp\u003eRCA: Central Registry of Insured Persons, in Spanish language.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e The study was approved by the Ethics Committee of Hospital de Matar\u0026oacute; and the Maresme Health Consortium (code CEIC_20/18) on March 21, 2018, with a waiver of informed consent. All study procedures were conducted in accordance with the Declaration of Helsinki and its subsequent amendments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u0026nbsp;not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e The data that support the findings of this study are available from the Information Areas Department of the Catalan Health Service (CatSalut), but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are, however, available from the authors upon reasonable request and with permission of CatSalut.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: The authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003e\u0026nbsp;C.L. contributed to the conception and design of the study, interpreted the data and wrote the main manuscript. E.V. was responsible for the statistical analysis and prepared figures. E.E.-T \u0026amp; J.C.Y. contributed to the conception and design of the study, interpreted the data and contributed to the critical revision of the manuscript. C.R., A.H.-P., R.F.-S., J.T., P.C.-R., J.C.R., A.R., A.A., P.G., R.F. contributed to the critical revision of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: Sepsis and Septic Shock Working Group of the Catalan Society of Intensive and Critical Care Medicine (SOCMIC).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSinger M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10.\u003c/li\u003e\n \u003cli\u003eGlobal report on the epidemiology and burden of sepsis: current evidence, identifying gaps and future directions. 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Effectiveness of targeted post-acute interventions and follow-up services for sepsis survivors: a systematic review. Crit Care. 2025 Aug 8;29(1):351. \u003c/li\u003e\n \u003cli\u003eLeggett N, Ali Abdelhamid Y, Bicknell E, Booth S, Carmody J, Deane AM, Farley KJ, Karahalios A, Merolli M, Haines KJ. Virtual Peer Support for ICU Survivors Is Feasible, and May Improve Outcomes for ICU Survivors: Results from the icuRESOLVE-D (icu Recovery Solutions Co-Designed through SurVivor Engagement - Digital) Pilot Randomised Controlled Trial. Am J Respir Crit Care Med. 2024 Sep 23.\u003c/li\u003e\n \u003cli\u003eKlein Klouwenberg PMC, Spitoni C, van der Poll T, Bonten MJ, Cremer OL; MARS consortium. Predicting the clinical trajectory in critically ill patients with sepsis: a cohort study. Crit Care. 2019 Dec 12;23(1):408. \u003c/li\u003e\n \u003cli\u003eLi A, Ling L, Qin H, Arabi YM, Myatra SN, Egi M, Kim JH, Nor MBM, Son DN, Fang WF, Wahyuprajitno B, Hashmi M, Fruq MO, Patjanasoontorn B, Al Bahrani MJ, Shrestha BR, Shrestha U, Nafees KMK, Sann KK, Palo JEM, Mendsaikhan N, Konkayev A, Detleuxay K, Chan YH, Du B, Divatia JV, Koh Y, Phua J; MOSAICS II Study Group; Asian Critical Care Clinical Trials Group. Prognostic evaluation of quick sequential organ failure assessment score in ICU patients with sepsis across different income settings. Crit Care. 2024 Jan 23;28(1):30. \u003c/li\u003e\n \u003cli\u003eSzatmary P, Arabi YM, Brown RM, Chen Y, Coopersmith CM, Deng JC, Estenssoro E, Fowler RA, Gong MN, Hodgson CL, Kissoon N, Koh Y, Machado FR, Martin-Loeches I, McAuley DF, Nseir S, Phua J, Phua GC, Riviello ED, Salluh JI, et al. Non-COVID-19 intensive care admissions during the pandemic: a multinational registry-based study. \u003cem\u003eIntensive Care Med\u003c/em\u003e. 2023 Jun;49(6):665-678.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Sepsis, Sepsis mortality, Sepsis long-term mortality, Sepsis survivors, Sepsis epidemiology, Post-sepsis syndrome.","lastPublishedDoi":"10.21203/rs.3.rs-8340179/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8340179/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSepsis, defined as organ dysfunction due to a dysregulated host response to infection, remains a major global health burden. Sepsis short-term mortality have decreased due to advances in early recognition, standardized management and improved referral pathways. However, the long-term prognosis of sepsis survivors remains poorly understood, particularly in Europe, where studies are limited by small sample sizes or short follow-up. This study aimed to evaluate long-term mortality\u0026mdash;defined as death within two years after hospital discharge\u0026mdash;among sepsis survivors in Catalonia over a 15-year period, and to identify factors associated with increased long-term mortality.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e A retrospective population-based study was conducted using the Catalan Minimum Basic Dataset of Acute-Care Hospitals. Sepsis cases were identified from 2005 to 2019 using ICD-9-CM and ICD-10-CM codes for infection and acute organ dysfunction. Patients who died during hospitalization, were transferred, or represented readmission episodes were excluded. Survivors were longitudinally followed for two years after discharge, with vital status obtained from the Central Registry of Insured Persons. Comorbidities were assessed using the Charlson index. Long-term mortality predictors were analyzed using logistic regression and Cox proportional hazards models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong 296,554 hospital admissions for sepsis, 237,075 (79.9%) patients survived to discharge. Of these, 42% (99,571) died within two years. Long-term mortality increased with age (from 5.8% in patients\u0026thinsp;\u0026lt;\u0026thinsp;15 years to 62% in those\u0026thinsp;\u0026gt;\u0026thinsp;84 years; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and with comorbidity (21%, 38%, 51% and 67% for Charlson index 0, 1\u0026ndash;2, 3\u0026ndash;4 and \u0026ge;\u0026thinsp;5, respectively; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Neoplasia (HR\u0026thinsp;=\u0026thinsp;2.011), liver cirrhosis (HR\u0026thinsp;=\u0026thinsp;1.562) and dementia (HR\u0026thinsp;=\u0026thinsp;1.204) were the comorbidities most strongly associated with mortality. Longer hospital stays were also associated with increased mortality. A progressive decline in long-term mortality was observed during 2017\u0026ndash;2019.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eLong-term mortality among sepsis survivors remains alarmingly high, with over 40% dying within two years after discharge. These findings highlight the need to extend sepsis care beyond the acute episode, focusing on post-sepsis syndrome prevention, improved continuity of care, and structured follow-up\u0026mdash;potentially including multidisciplinary and telemonitoring strategies\u0026mdash;to reduce long-term morbidity and mortality. Identifying high-risk subgroups could optimize resource allocation and target interventions to those most likely to benefit.\u003c/p\u003e","manuscriptTitle":"Long term mortality in sepsis survivors: a population-based study during 15 years","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-30 00:19:55","doi":"10.21203/rs.3.rs-8340179/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a6099707-edcb-491e-8bd4-9b39bbc506b7","owner":[],"postedDate":"December 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-28T09:11:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-30 00:19:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8340179","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8340179","identity":"rs-8340179","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}