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      Risk Factors at Index Hospitalization Associated With Longer-term Mortality in Adult Sepsis Survivors

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      , MSc, PhD, FRCA, FFICM 1 , 2 , 3 , , , PhD 3 , , PhD 3 , , MD 4 , , MPhil 3
      JAMA Network Open
      American Medical Association

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          Key Points

          Question

          Which generic and sepsis-specific patient characteristics, known during index critical care admission for sepsis, are independently associated with long-term mortality in sepsis survivors?

          Findings

          In this cohort study of 94 748 adult sepsis survivors, age, male sex, 1 or more severe comorbidities, prehospitalization dependency, nonsurgical status, acute severity of illness, site of infection, and organ dysfunction were independently associated with long-term mortality.

          Meaning

          Generic and sepsis-specific risk factors, known during index critical care admission for sepsis, could be used to identify a higher-risk sepsis survivor population for targeted strategies aimed at reducing the excess risk of long-term mortality.

          Abstract

          This cohort study investigates the generic and sepsis-specific patient characteristics that are associated with long-term mortality in patients who survive hospitalization for sepsis.

          Abstract

          Importance

          Sepsis survivors, defined as adult patients who survived to hospital discharge following a critical care unit admission for sepsis, are at increased risk of long-term mortality. Identifying factors independently associated with long-term mortality, known during critical care admission for sepsis, could inform targeted strategies to reduce this risk.

          Objective

          To assess, in adult sepsis survivors, factors independently associated with long-term mortality, known during their index critical care admission for sepsis, meeting Third International Consensus Definitions for Sepsis and Septic Shock criteria.

          Design, Setting, and Participants

          This cohort study included a nationally representative sample of 94 748 adult sepsis survivors from 192 critical care units in England. Participants were identified from consecutive critical care admissions between April 1, 2009, and March 31, 2014, with survival status ascertained as of March 31, 2015. Statistical analyses were completed in June 2017.

          Exposures

          Generic patient characteristics (age, sex, ethnicity, severe comorbidities [defined using the Acute Physiology and Chronic Health Evaluation II method], dependency, surgical status, and acute illness severity [scored using the Acute Physiology and Chronic Health Evaluation II acute physiology component]) and sepsis-specific patient characteristics (site of infection, number of organ dysfunctions, and septic shock status) known during index critical care admission for sepsis.

          Main Outcomes and Measures

          Long-term mortality in adult sepsis survivors with maximum follow-up of 6 years. Adjusted hazard ratios (HRs) were estimated using Cox regression for both generic and sepsis-specific patient characteristics.

          Results

          Sepsis survivors had a mean (SD) age of 61.3 (17.0) years, 43 584 (46.0%) were female, and 86 056 (90.8%) were white. A total of 46.3% had respiratory site of infection. By 1 year from hospital discharge, 15% of sepsis survivors had died, with 6% to 8% dying per year over the subsequent 5 years. Age, sex, race/ethnicity, severe comorbidities, dependency, nonsurgical status, and site of infection were independently associated with long-term mortality. Compared with single-organ dysfunction, having 2 or 3 organ dysfunctions was associated with increased risk of long-term mortality (adjusted HR, 1.07; 95% CI, 1.01-1.13; and adjusted HR, 1.18; 95% CI, 1.03-1.14, respectively), while having 4 organ dysfunctions or more was not associated with increased risk. Unexpectedly, the Acute Physiology and Chronic Health Evaluation acute physiology component score had an incremental association with long-term mortality (adjusted HR, 1.11 for every 5-point increase; 95% CI, 1.08-1.13). The adjusted HR for septic shock was 0.89 (95% CI, 0.85-0.92).

          Conclusions and Relevance

          This study suggests that generic and sepsis-specific risk factors, known during index critical care admission for sepsis, could identify a high-risk sepsis survivor population for biological characterization and designing interventions to reduce long-term mortality.

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          Most cited references12

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          Time to Treatment and Mortality during Mandated Emergency Care for Sepsis.

          Background In 2013, New York began requiring hospitals to follow protocols for the early identification and treatment of sepsis. However, there is controversy about whether more rapid treatment of sepsis improves outcomes in patients. Methods We studied data from patients with sepsis and septic shock that were reported to the New York State Department of Health from April 1, 2014, to June 30, 2016. Patients had a sepsis protocol initiated within 6 hours after arrival in the emergency department and had all items in a 3-hour bundle of care for patients with sepsis (i.e., blood cultures, broad-spectrum antibiotic agents, and lactate measurement) completed within 12 hours. Multilevel models were used to assess the associations between the time until completion of the 3-hour bundle and risk-adjusted mortality. We also examined the times to the administration of antibiotics and to the completion of an initial bolus of intravenous fluid. Results Among 49,331 patients at 149 hospitals, 40,696 (82.5%) had the 3-hour bundle completed within 3 hours. The median time to completion of the 3-hour bundle was 1.30 hours (interquartile range, 0.65 to 2.35), the median time to the administration of antibiotics was 0.95 hours (interquartile range, 0.35 to 1.95), and the median time to completion of the fluid bolus was 2.56 hours (interquartile range, 1.33 to 4.20). Among patients who had the 3-hour bundle completed within 12 hours, a longer time to the completion of the bundle was associated with higher risk-adjusted in-hospital mortality (odds ratio, 1.04 per hour; 95% confidence interval [CI], 1.02 to 1.05; P<0.001), as was a longer time to the administration of antibiotics (odds ratio, 1.04 per hour; 95% CI, 1.03 to 1.06; P<0.001) but not a longer time to the completion of a bolus of intravenous fluids (odds ratio, 1.01 per hour; 95% CI, 0.99 to 1.02; P=0.21). Conclusions More rapid completion of a 3-hour bundle of sepsis care and rapid administration of antibiotics, but not rapid completion of an initial bolus of intravenous fluids, were associated with lower risk-adjusted in-hospital mortality. (Funded by the National Institutes of Health and others.).
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            Long Term Outcomes Following Hospital Admission for Sepsis Using Relative Survival Analysis: A Prospective Cohort Study of 1,092 Patients with 5 Year Follow Up

            Background Sepsis is a leading cause of death in intensive care units and is increasing in incidence. Current trials of novel therapeutic approaches for sepsis focus on 28-day mortality as the primary outcome measure, but excess mortality may extend well beyond this time period. Methods We used relative survival analysis to examine excess mortality in a cohort of 1,028 patients admitted to a tertiary referral hospital with sepsis during 2007–2008, over the first 5 years of follow up. Expected survival was estimated using the Ederer II method, using Australian life tables as the reference population. Cumulative and interval specific relative survival were estimated by age group, sex, sepsis severity and Indigenous status. Results Patients were followed for a median of 4.5 years (range 0–5.2). Of the 1028 patients, the mean age was 46.9 years, 52% were male, 228 (22.2%) had severe sepsis and 218 (21%) died during the follow up period. Mortality based on cumulative relative survival exceeded that of the reference population for the first 2 years post admission in the whole cohort and for the first 3 years in the subgroup with severe sepsis. Independent predictors of mortality over the whole follow up period were male sex, Indigenous Australian ethnicity, older age, higher Charlson Comorbidity Index, and sepsis-related organ dysfunction at presentation. Conclusions The mortality rate of patients hospitalised with sepsis exceeds that of the general population until 2 years post admission. Efforts to improve outcomes from sepsis should examine longer term outcomes than the traditional primary endpoints of 28-day and 90-day mortality.
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              A Tutorial on Multilevel Survival Analysis: Methods, Models and Applications

              Summary Data that have a multilevel structure occur frequently across a range of disciplines, including epidemiology, health services research, public health, education and sociology. We describe three families of regression models for the analysis of multilevel survival data. First, Cox proportional hazards models with mixed effects incorporate cluster-specific random effects that modify the baseline hazard function. Second, piecewise exponential survival models partition the duration of follow-up into mutually exclusive intervals and fit a model that assumes that the hazard function is constant within each interval. This is equivalent to a Poisson regression model that incorporates the duration of exposure within each interval. By incorporating cluster-specific random effects, generalised linear mixed models can be used to analyse these data. Third, after partitioning the duration of follow-up into mutually exclusive intervals, one can use discrete time survival models that use a complementary log–log generalised linear model to model the occurrence of the outcome of interest within each interval. Random effects can be incorporated to account for within-cluster homogeneity in outcomes. We illustrate the application of these methods using data consisting of patients hospitalised with a heart attack. We illustrate the application of these methods using three statistical programming languages (R, SAS and Stata).
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                Author and article information

                Journal
                JAMA Netw Open
                JAMA Netw Open
                JAMA Netw Open
                JAMA Network Open
                American Medical Association
                2574-3805
                31 May 2019
                May 2019
                31 May 2019
                : 2
                : 5
                : e194900
                Affiliations
                [1 ]Intensive Care Unit Support Offices, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
                [2 ]School of Immunology & Microbial Sciences, King’s College London, London, United Kingdom
                [3 ]Intensive Care National Audit & Research Centre, London, United Kingdom
                [4 ]Interdepartmental Division of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
                Author notes
                Article Information
                Accepted for Publication: April 13, 2019.
                Published: May 31, 2019. doi:10.1001/jamanetworkopen.2019.4900
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Shankar-Hari M et al. JAMA Network Open.
                Corresponding Author: Manu Shankar-Hari, MSc, PhD, FRCA, FFICM, ICU Critical Care Offices, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London SE17EH, United Kingdom ( manu.shankar-hari@ 123456kcl.ac.uk ).
                Author Contributions: Drs Shankar-Hari and Harrison had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: Shankar-Hari, Harrison, Rubenfeld, Rowan.
                Acquisition, analysis, or interpretation of data: Shankar-Hari, Harrison, Ferrando-Vivas, Rowan.
                Drafting of the manuscript: Shankar-Hari, Rubenfeld, Rowan.
                Critical revision of the manuscript for important intellectual content: All authors.
                Statistical analysis: Shankar-Hari, Harrison, Ferrando-Vivas.
                Obtained funding: Shankar-Hari.
                Administrative, technical, or material support: Rowan.
                Supervision: Harrison, Rubenfeld, Rowan.
                Conflict of Interest Disclosures: None reported.
                Funding/Support: Dr Shankar-Hari is supported by National Institute for Health Research Clinician Scientist Award CS-2016-16-011.
                Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Disclaimer: The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health and Social Care. Dr Rubenfeld, a JAMA Network Open associate editor, was not involved in the editorial review of or the decision to publish this article.
                Additional Information: The data used in this study are accessible on request from the UK national intensive care admissions data set managed by the Intensive Care National Audit and Research Centre.
                Article
                zoi190206
                10.1001/jamanetworkopen.2019.4900
                6547123
                31150081
                36ac6ff6-5689-4731-a6a3-27afa7e81af6
                Copyright 2019 Shankar-Hari M et al. JAMA Network Open.

                This is an open access article distributed under the terms of the CC-BY License.

                History
                : 21 January 2019
                : 12 April 2019
                : 13 April 2019
                Categories
                Research
                Original Investigation
                Online Only
                Critical Care Medicine

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