Sepsis, a syndrome of physiologic, pathologic, and biochemical abnormalities induced by infection, is a major public health concern, accounting for more than $20 billion (5.2%) of total US hospital costs in 2011.¹ The reported incidence of sepsis is increasing,^2,3 likely reflecting aging populations with more comorbidities, greater recognition,⁴ and, in some countries, reimbursement-favorable coding.⁵ Although the true incidence is unknown, conservative estimates indicate that sepsis is a leading cause of mortality and critical illness worldwide.^6,7 Furthermore, there is increasing awareness that patients who survive sepsis often have long-term physical, psychological, and cognitive disabilities with significant health care and social implications.⁸

Background: Sepsis and septic shock remain drivers for mortality in critically ill patients. The heterogeneity of the syndrome hinders the generation of reproducible numbers on mortality risks. Consequently, mortality rates range from 15 to 56%. We aimed to update and extend the existing knowledge from meta-analyses and estimate 30- and 90-day mortality rates for sepsis and septic shock separately, stratify rates by region and study type and assess mortality rates across different sequential organ failure assessment (SOFA) scores.Methods: We performed a systematic review of articles published in PubMed or in the Cochrane Database, between 2009 and 2019 in English language including interventional and observational studies. A meta-analysis of pooled 28/30- and 90-day mortality rated separately for sepsis and septic shock was done using a random-effects model. Time trends were assessed via Joinpoint methodology and for the assessment of mortality rate over different SOFA scores, and linear regression was applied.Results: Four thousand five hundred records were identified. After title/abstract screening, 783 articles were assessed in full text for eligibility. Of those, 170 studies were included. Average 30-day septic shock mortality was 34.7% (95% CI 32.6–36.9%), and 90-day septic shock mortality was 38.5% (95% CI 35.4–41.5%). Average 30-day sepsis mortality was 24.4% (95% CI 21.5–27.2%), and 90-day sepsis mortality was 32.2% (95% CI 27.0–37.5%). Estimated mortality rates from RCTs were below prospective and retrospective cohort studies. Rates varied between regions, with 30-day septic shock mortality being 33.7% (95% CI 31.5–35.9) in North America, 32.5% (95% CI 31.7–33.3) in Europe and 26.4% (95% CI 18.1–34.6) in Australia. A statistically significant decrease of 30-day septic shock mortality rate was found between 2009 and 2011, but not after 2011. Per 1-point increase of the average SOFA score, average mortality increased by 1.8–3.3%.Conclusion: Trends of lower sepsis and continuous septic shock mortality rates over time and regional disparities indicate a remaining unmet need for improving sepsis management. Further research is needed to investigate how trends in the burden of disease influence mortality rates in sepsis and septic shock at 30- and 90-day mortality over time.

SUMMARY: Sepsis is among the most common causes of death in hospitals. It arises from the host response to infection. Currently, diagnosis relies on nonspecific physiological criteria and culture-based pathogen detection. This results in diagnostic uncertainty, therapeutic delays, the mis- and overuse of antibiotics, and the failure to identify patients who might benefit from immunomodulatory therapies. There is a need for new sepsis biomarkers that can aid in therapeutic decision making and add information about screening, diagnosis, risk stratification, and monitoring of the response to therapy. The host response involves hundreds of mediators and single molecules, many of which have been proposed as biomarkers. It is, however, unlikely that one single biomarker is able to satisfy all the needs and expectations for sepsis research and management. Among biomarkers that are measurable by assays approved for clinical use, procalcitonin (PCT) has shown some usefulness as an infection marker and for antibiotic stewardship. Other possible new approaches consist of molecular strategies to improve pathogen detection and molecular diagnostics and prognostics based on transcriptomic, proteomic, or metabolic profiling. Novel approaches to sepsis promise to transform sepsis from a physiologic syndrome into a group of distinct biochemical disorders and help in the development of better diagnostic tools and effective adjunctive sepsis therapies.