Application of the Third International Consensus Definitions for Sepsis (Sepsis-3) Classification: a retrospective population-based cohort study

Summary

Background

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) present clinical criteria for the classification of patients with sepsis. We investigated incidence and long-term outcomes of patients diagnosed with these classifications, which are currently unknown.

Methods

We did a retrospective analysis using data from 30 239 participants from the USA who were aged at least 45 years and enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Patients were enrolled between Jan 25, 2003, and Oct 30, 2007, and we identified hospital admissions from Feb 5, 2003, to Dec 31, 2012, and applied three classifications: infection and systemic inflammatory response syndrome (SIRS) criteria, elevated sepsis-related organ failure assessment (SOFA) score from Sepsis-3, and elevated quick SOFA (qSOFA) score from Sepsis-3. We estimated incidence during the study period, in-hospital mortality, and 1-year mortality.

Findings

Of 2593 first infection events, 1526 met SIRS criteria, 1080 met SOFA criteria, and 378 met qSOFA criteria. Incidence was 8·2 events (95% CI 7·8–8·7) per 1000 person-years for SIRS, 5·8 events (5·4–6·1) per 1000 person-years for SOFA, and 2·0 events (1·8–2·2) per 1000 person-years for qSOFA. In-hospital mortality was higher for patients with an elevated qSOFA score (67 [23%] of 295 patients died) than for those with an elevated SOFA score (125 [13%] of 960 patients died) or who met SIRS criteria (128 [9%] of 1392 patients died). Mortality at 1 year after discharge was also highest for patients with an elevated qSOFA score (29·4 deaths [95% CI 22·3–38·7] per 100 person-years) compared with those with an elevated SOFA score (22·6 deaths [19·2–26·6] per 100 person-years) or those who met SIRS criteria (14·7 deaths [12·5–17·2] per 100 person-years).

Interpretation

SIRS, SOFA, and qSOFA classifications identified different incidences and mortality. Our findings support the use of the SOFA and qSOFA classifications to identify patients with infection who are at elevated risk of poor outcomes. These classifications could be used in future epidemiological assessments and studies of patients with infection.

Funding

National Institute for Nursing Research, National Center for Research Resources, and National Institute of Neurological Disorders and Stroke.

Introduction

Sepsis—life-threatening organ dysfunction due to a dysregulated response to infection—is a major public health problem worldwide.1, 2, 3, 4 Although mortality due to sepsis has improved, sepsis remains a leading cause of death, with in-hospital mortality ranging from 12% to 26%.3, 4, 5, 6, 7 Advances in clinical care and research for sepsis have been hampered by disparate terminology for and approaches to the definition of sepsis and its components.⁸

The European Society of Intensive Care Medicine and Society for Critical Care Medicine proposed the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) to standardise sepsis terminology.8, 9, 10, 11 Previous iterations of the international consensus definitions for sepsis focused on the systemic inflammatory response to infection.12, 13 For Sepsis-3, the task force considered several candidate criteria with less focus on systemic inflammation.¹⁰ Using several large hospital databases, Seymour and colleagues⁹ examined the ability of three classifications to identify patients with infection who were at high risk of mortality: high risk was defined as two or more systemic inflammatory response syndrome (SIRS) criteria (the previous standard for definition of sepsis), two or more points on the sepsis-related organ failure assessment (SOFA) score, or two or more points on the empirically derived quick SOFA (qSOFA) score. An elevated SOFA score was the best discriminator of patients with infection who had a high risk of death while in intensive care. By contrast, an elevated qSOFA score (based on respiratory rate, altered mentation, and blood pressure) was best able to identify patients with a high risk of death in hospital but not in intensive care. These analyses were unable to establish the incidence of elevated SOFA and qSOFA scores or SIRS criteria, and were unable to assess how SIRS criteria and the revised Sepsis-3 classifications (based on SOFA and qSOFA) performed with respect to long-term outcomes; a population-based cohort is the best design to formulate such estimates.

Research in context

Evidence before this study

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) task force released revised classifications in February, 2016. As part of this initiative, several manuscripts were published that described the conclusions of the task force, assessed the validity of candidate clinical criteria with respect to inpatient outcomes, and presented a revised framework for evaluating sepsis definitions. We searched PubMed up to Nov 9, 2016, for papers related to the identification of sepsis. We searched for the terms “sepsis” and “validation”, “sepsis” and “definition”, or “sepsis” and “identification”. We found a wide range of studies pertinent to the definition of sepsis, but few assessments of the revised Sepsis-3 classifications. Two single-centre studies have examined the Sepsis-3 classifications in patients admitted with sepsis in intensive care units in Brazil (n=957) and the USA (n=214), with results showing increased mortality in patients who met the revised criteria compared with those identified by the old criteria. The study in Brazil found that the revised criteria had greater accuracy for identification of patients at high risk of mortality, whereas the US study found similar prognostic value for the revised and old criteria. These studies had limited sample sizes and lacked robust data on individual patients. All previous validation efforts to date have also not incorporated outcome and baseline data outside of the inpatient setting.

Added value of this study

Because previous analyses were restricted to inpatients, they could not provide data on incidence or post-discharge outcomes for the revised classifications. We used data from one of the largest contemporary population-based cohorts in the USA. The revised classifications identified distinct populations with different incidence, and mortality at 28 days and 1 year. Compared with patients with infection who met systemic inflammatory response syndrome (SIRS) criteria or who had elevated sepsis-related organ failure assessment (SOFA) scores, those who met quick SOFA (qSOFA) criteria had the highest in-hospital mortality, 28-day mortality, and 1-year mortality after discharge. Models that included variables for SOFA and qSOFA classifications showed the greatest improvements in discrimination and reclassification for both in-hospital and 1-year mortality.

Implications of all the available evidence

The revised sepsis classifications derived by the Sepsis-3 task force are useful for identifying patients at increased risk of poor outcomes during hospital stays. In addition to serving as an in-hospital screening tool, the revised classifications might also be useful for the characterisation and identification of patients with infection who are at increased risk of poor outcomes after discharge. Further study is needed to establish whether widespread use of the revised classifications would lead to improved outcomes.

Using data from one of the largest contemporary population-based longitudinal cohorts in the USA, we compared incidence, short-term mortality, and long-term mortality for patients with infection who met the revised Sepsis-3 classifications and the previously established SIRS criteria. We postulated that these classifications would identify different populations, show different trends in incidence and outcomes, and be useful for identifying patients with infection at high risk of mortality.