title: Evidence for a causal link between sepsis and long-term mortality: a systematic review of epidemiologic studies.
abstract: BACKGROUND
  In addition to acute hospital mortality, sepsis is associated with higher risk of death following hospital discharge. We assessed the strength of epidemiological evidence supporting a causal link between sepsis and mortality after hospital discharge by systematically evaluating the available literature for strength of association, bias, and techniques to address confounding.
  
  
  METHODS
  We searched Medline and Embase using the following 'mp' terms, MESH headings and combinations thereof - sepsis, septic shock, septicemia, outcome. Studies published since 1992 where one-year post-acute mortality in adult survivors of acute sepsis could be calculated were included. Two authors independently selected studies and extracted data using predefined criteria and data extraction forms to assess risk of bias, confounding, and causality. The difference in proportion between cumulative one-year mortality and acute mortality was defined as post-acute mortality. Meta-analysis was done by sepsis definition categories with post-acute mortality as the primary outcome.
  
  
  RESULTS
  The literature search identified 11,156 records, of which 59 studies met our inclusion criteria and 43 studies reported post-acute mortality. In patients who survived an index sepsis admission, the post-acute mortality was 16.1% (95% CI 14.1, 18.1%) with significant heterogeneity (p < 0.001), on random effects meta-analysis. In studies reporting non-sepsis control arm comparisons, sepsis was not consistently associated with a higher hazard ratio for post-acute mortality. The additional hazard associated with sepsis was greatest when compared to the general population. Older age, male sex, and presence of comorbidities were commonly reported independent predictors of post-acute mortality in sepsis survivors, challenging the causality relationship. Sensitivity analyses for post-acute mortality were consistent with primary analysis.
  
  
  CONCLUSIONS
  Epidemiologic criteria for a causal relationship between sepsis and post-acute mortality were not consistently observed. Additional epidemiologic studies with recent patient level data that address the pre-illness trajectory, confounding, and varying control groups are needed to estimate sepsis-attributable additional risk and modifiable risk factors to design interventional trials.
authors.affiliation: Guy's and St Thomas' NHS Foundation Trust, ICU support Offices, 1st Floor, East Wing, St Thomas' Hospital, London, SE1 7EH, UK. Manu.Shankar-Hari@kcl.ac.uk.|Division of Asthma, Allergy and Lung Biology, Kings College London, London, SE1 9RT, UK. Manu.Shankar-Hari@kcl.ac.uk.
authors.forename: Manu
authors.initials: M
authors.lastname: Shankar-Hari
authors.affiliation: Guy's and St Thomas' NHS Foundation Trust, ICU support Offices, 1st Floor, East Wing, St Thomas' Hospital, London, SE1 7EH, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Ambler
authors.affiliation: Guy's and St Thomas' NHS Foundation Trust, ICU support Offices, 1st Floor, East Wing, St Thomas' Hospital, London, SE1 7EH, UK.
authors.forename: Viyaasan
authors.initials: V
authors.lastname: Mahalingasivam
authors.affiliation: Guy's and St Thomas' NHS Foundation Trust, ICU support Offices, 1st Floor, East Wing, St Thomas' Hospital, London, SE1 7EH, UK.|Division of Asthma, Allergy and Lung Biology, Kings College London, London, SE1 9RT, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jones
authors.affiliation: Intensive Care National Audit & Research Centre, Napier House, 24 High Holborn, London, WC1V 6AZ, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Rowan
authors.affiliation: Interdepartmental Division of Critical Care Medicine, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, D5 03, Toronto, Ontario, M4N 3M5, Canada.
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Rubenfeld
mesh_terms: D000328:Adult; D015984:Causality; D016021:Epidemiologic Studies; D017052:Hospital Mortality / Q000639:trends; D006801:Humans; D010351:Patient Discharge / Q000706:statistics & numerical data; D012151:Resuscitation / Q000379:methods / Q000706:statistics & numerical data; D018805:Sepsis / Q000401:mortality* / Q000628:therapy*; D016896:Treatment Outcome
keywords: Bias; Causality; Confounding factors (epidemiology); Mortality; Sepsis