Evidence for a Causal Link Between Sepsis and Long-term Mortality: a Systematic Review of Epidemiologic Studies

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.