Elsevier

Annals of Emergency Medicine

Volume 70, Issue 4, October 2017, Pages 553-561.e1
Annals of Emergency Medicine

Infectious disease/original research
Potential Impact of the 2016 Consensus Definitions of Sepsis and Septic Shock on Future Sepsis Research

https://doi.org/10.1016/j.annemergmed.2017.04.007Get rights and content

Study objective

The influence of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) on the conduct of future sepsis research is unknown. We seek to examine the potential effect of the new definitions on the identification and outcomes of patients enrolled in a sepsis trial.

Methods

This was a post hoc analysis of the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial of early goal-directed therapy that recruited 1,591 adult patients presenting to the emergency department (ED) with early septic shock diagnosed by greater than or equal to 2 systemic inflammatory response syndrome criteria and either refractory hypotension or hyperlactatemia. The proportion of participants who would have met the Sepsis-3 criteria for quick Sequential Organ Failure Assessment (qSOFA) score, sepsis (an increased Sequential Organ Failure Assessment score ≥2 because of infection) and septic shock before randomization, their baseline characteristics, interventions delivered, and mortality were determined.

Results

There were 1,139 participants who had a qSOFA score of greater than or equal to 2 at baseline (71.6% [95% confidence interval {CI} 69.4% to 73.8%]). In contrast, 1,347 participants (84.7% [95% CI 82.9% to 86.4%]) met the Sepsis-3 criteria for sepsis. Only 1,010 participants were both qSOFA positive and met the Sepsis-3 criteria for sepsis (63.5% [95% CI 61.1% to 65.8%]). The Sepsis-3 definition for septic shock was met at baseline by 203 participants (12.8% [95% CI 11.2% to 14.5%]), of whom 175 (86.2% [95% CI 81.5% to 91.0%]) were also qSOFA positive. Ninety-day mortality for participants fulfilling the Sepsis-3 criteria for sepsis and septic shock was 20.4% (95% CI 18.2% to 22.5%) (274/1,344) and 29.6% (95% CI 23.3% to 35.8% [60/203]) versus 9.4% (95% CI 5.8% to 13.1%) (23/244) and 17.1% (95% CI 15.1% to 19.1% [237/1,388]), respectively, for participants not meeting the criteria (risk differences 11.0% [95% CI 6.2% to 14.8%] and 12.5% [95% CI 6.3% to 19.4%], respectively).

Conclusion

Most ARISE participants did not meet the Sepsis-3 definition for septic shock at baseline. However, the majority fulfilled the new sepsis definition and mortality was higher than for participants not fulfilling the criteria. A quarter of participants meeting the new sepsis definition did not fulfill the qSOFA screening criteria, potentially limiting its utility as a screening tool for sepsis trials with patients with suspected infection in the ED. The implications of the new definitions for patients not eligible for recruitment into the ARISE trial are unknown.

Introduction

Editor’s Capsule Summary

What is already known on this topic

International consensus sepsis definitions have recently changed (Third International Consensus Definitions for Sepsis and Septic Shock [Sepsis-3]). The effect of this change on identification and outcomes of patients compared with that of previous sepsis definitions (Sepsis-2) is unknown.

What question this study addressed

How do categories of patients classified by both Sepsis-2 and -3 criteria compare both in terms of definitional overlap and outcomes?

What this study adds to our knowledge

Most patients who met the Sepsis-2 definitions of severe sepsis or septic shock did not meet the Sepsis-3 criteria for septic shock. A quarter of patients meeting Sepsis-3 criteria did not fulfill quick Sequential Organ Failure Assessment (qSOFA) criteria.

How this is relevant to clinical practice

qSOFA appears to have limited utility as a sepsis screening tool in the emergency department. Sepsis-3 may miss patients considered to have sepsis by Sepsis-2 definitions.

An international task force of experts in sepsis pathophysiology recently generated a new set of definitions for sepsis and septic shock (Third International Consensus Definitions for Sepsis and Septic Shock [Sepsis-3]).1 The impetus for revising the definitions was awareness that elements of the 1991 and 2001 consensus conference definitions,2, 3 which incorporated the requirement for 2 or more systemic inflammatory response syndrome (SIRS) criteria, were outdated and did not accurately identify patients with presumed sepsis and septic shock. Data from Australia and New Zealand suggested that 1 in 8 patients admitted to the ICU with infection and new organ failure did not fulfill the SIRS criteria for defining sepsis, despite having substantial mortality.4

The new Sepsis-3 definitions use the Sequential Organ Failure Assessment (SOFA)5 score to identify sepsis and septic shock. Moreover, they provide a screening tool, the quick Sequential Organ Failure Assessment (qSOFA) score, to assist in the rapid identification of patients with suspected infection who are at higher risk of mortality. Lacking a criterion standard test for diagnosing sepsis, the qSOFA screening tool and the revised definitions for sepsis and septic shock were based on a systematic literature review, a Delphi study, and retrospective analyses of the Surviving Sepsis Campaign database and 5 electronic health record databases for adult patients with suspected infection in 167 US hospitals and 1 German hospital.6 The underlying goal was to develop definitions that would lead to more timely identification and resuscitation of patients with sepsis, in particular those with poor outcomes, more reliable epidemiologic data, and less heterogeneity in populations included in clinical sepsis trials.

The potential research implications of adopting the proposed new definitions for the screening, identification, and inclusion of patients in sepsis trials have not yet been evaluated, in particular for trials involving prompt recognition and early resuscitation. It is not known how the populations of patients included in recent sepsis trials using previous definitions might differ from those likely to be included in future equivalent trials using the new definitions. The effect on key trial design features such as feasibility, sample size calculations, and recruitment is also unknown. Moreover, it is uncertain how informative comparisons of results across trials might be influenced by the variability in selection of patients if different definitions are used.

We sought to explore the utility and potential effects of the new Sepsis-3 definitions for qSOFA, sepsis, and septic shock on the screening, identification, recruitment, and outcomes of participants, using data from patients previously enrolled in a large, multicenter, randomized, clinical trial conducted in patients presenting to the emergency department (ED) with early septic shock.

Section snippets

Study Design and Setting

We conducted a post hoc analysis of the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial to determine the proportion of patients enrolled with the SIRS-based criteria that met the new Sepsis-3 definitions for qSOFA, sepsis, and septic shock before randomization; their baseline characteristics; interventions delivered; and outcomes, including mortality, duration of organ support, and ICU and hospital length of stay.7

ARISE was a large, multicenter, randomized trial of early

Characteristics of Study Subjects

Of 1,591 participants included in the ARISE study, 1,139 (71.6% [69.4% to 73.8%]) met 2 or more qSOFA bedside screening criteria before randomization (qSOFA positive) (Figure). The remaining 452 participants (28.4% [26.2% to 30.6%]) were qSOFA negative.

The Sepsis-3 criteria for sepsis were present in 1,347 participants (84.7% [82.9% to 86.4%]) (sepsis positive). A total of 1,010 participants (63.5% [61.1% to 65.8%]) were both qSOFA positive and met the Sepsis-3 definition for sepsis. However,

Limitations

First, our study was limited to patients presenting to the ED with early septic shock who were eligible for recruitment into the ARISE trial. The number of patients who may have met the new SOFA-based definitions for sepsis and septic shock but did not meet the SIRS-based ARISE entry criteria is not known and potentially underestimates the number of patients eligible for future septic shock trials.4 The assumption that missing data were within normal limits may also underestimate the potential

Discussion

We found that most ARISE participants fulfilled the Sepsis-3 definition for sepsis before randomization. Accordingly, baseline characteristics and outcomes were similar. However, only 1 in 8 participants met the new definition for septic shock in a trial in which patients were specifically selected because of refractory hypotension (hemodynamic shock), a blood lactate level greater than or equal to 4 mmol/L (cryptic shock), or both. In contrast, more than two thirds of participants enrolled in

References (10)

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Please see page 554 for the Editor’s Capsule Summary of this article.

Supervising editor: Alan E. Jones, MD

Author contributions: SLP, AD, and RB conceived the study. MB conducted the statistical analyses. SLP drafted the article and all authors contributed substantially to its revision. SLP takes responsibility for the paper as a whole.

All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist.

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Investigators in the Australasian and Resuscitation in Sepsis Evaluation (ARISE) trial and their affiliations are listed in the Appendix.

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