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Original Investigation | Caring for the Critically Ill Patient

Developing a New Definition and Assessing New Clinical Criteria for Septic Shock For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

Manu Shankar-Hari, MD, MSc1,2; Gary S. Phillips, MAS3; Mitchell L. Levy, MD4; Christopher W. Seymour, MD, MSc5; Vincent X. Liu, MD, MSc6; Clifford S. Deutschman, MD7,8,9; Derek C. Angus, MD, MPh5,10; Gordon D. Rubenfeld, MD, MSc11,12; Mervyn Singer, MD, FRCP13 ; for the Sepsis Definitions Task Force
[+] Author Affiliations
1Division of Asthma, Allergy, and Lung Biology, King’s College London, London, United Kingdom
2Department of Critical Care Medicine, Guy’s and St Thomas’ NHS Foundation Trust, London SE17EH, United Kingdom
3The Ohio State University College of Medicine, Department of Biomedical Informatics, Center for Biostatistics, Columbus
4Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island
5Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care and Emergency Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
6Division of Research, Kaiser Permanente, Oakland, California
7Department of Pediatrics, Hofstra-North Shore-Long Island Jewish-Hofstra School of Medicine, Steven and Alexandra Cohen Children’s Medical Center, New Hyde Park, New York
8Department of Molecular Medicine, Hofstra-North Shore-Long Island Jewish-Hofstra School of Medicine, Steven and Alexandra Cohen Children’s Medical Center, New Hyde Park, New York
9Feinstein Institute for Medical Research, Manhasset, New York
10Associate Editor, JAMA
11Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada
12Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
13Bloomsbury Institute of Intensive Care Medicine, University College London, London, United Kingdom
JAMA. 2016;315(8):775-787. doi:10.1001/jama.2016.0289.
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Importance  Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition.

Objective  To develop a new definition and clinical criteria for identifying septic shock in adults.

Design, Setting, and Participants  The Society of Critical Care Medicine and the European Society of Intensive Care Medicine convened a task force (19 participants) to revise current sepsis/septic shock definitions. Three sets of studies were conducted: (1) a systematic review and meta-analysis of observational studies in adults published between January 1, 1992, and December 25, 2015, to determine clinical criteria currently reported to identify septic shock and inform the Delphi process; (2) a Delphi study among the task force comprising 3 surveys and discussions of results from the systematic review, surveys, and cohort studies to achieve consensus on a new septic shock definition and clinical criteria; and (3) cohort studies to test variables identified by the Delphi process using Surviving Sepsis Campaign (SSC) (2005-2010; n = 28 150), University of Pittsburgh Medical Center (UPMC) (2010-2012; n = 1 309 025), and Kaiser Permanente Northern California (KPNC) (2009-2013; n = 1 847 165) electronic health record (EHR) data sets.

Main Outcomes and Measures  Evidence for and agreement on septic shock definitions and criteria.

Results  The systematic review identified 44 studies reporting septic shock outcomes (total of 166 479 patients) from a total of 92 sepsis epidemiology studies reporting different cutoffs and combinations for blood pressure (BP), fluid resuscitation, vasopressors, serum lactate level, and base deficit to identify septic shock. The septic shock–associated crude mortality was 46.5% (95% CI, 42.7%-50.3%), with significant between-study statistical heterogeneity (I2 = 99.5%; τ2 = 182.5; P < .001). The Delphi process identified hypotension, serum lactate level, and vasopressor therapy as variables to test using cohort studies. Based on these 3 variables alone or in combination, 6 patient groups were generated. Examination of the SSC database demonstrated that the patient group requiring vasopressors to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L (18 mg/dL) after fluid resuscitation had a significantly higher mortality (42.3% [95% CI, 41.2%-43.3%]) in risk-adjusted comparisons with the other 5 groups derived using either serum lactate level greater than 2 mmol/L alone or combinations of hypotension, vasopressors, and serum lactate level 2 mmol/L or lower. These findings were validated in the UPMC and KPNC data sets.

Conclusions and Relevance  Based on a consensus process using results from a systematic review, surveys, and cohort studies, septic shock is defined as a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone. Adult patients with septic shock can be identified using the clinical criteria of hypotension requiring vasopressor therapy to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation.

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Figure 1.
Study Identification and Selection Process Used in the Systematic Review

aNonduplicate references from other sources included review articles.3,108110 See eMethods 1 in the Supplement for further details of search strategy.

bRefers to records that were excluded after reference screening of full text articles. The screening criteria for full text inclusion were reporting of all case sepsis epidemiology in adult populations without specific assessment of interventions. The qualitative review assessed sepsis and septic shock definitions and criteria. The records included in the qualitative review (92 studies57,19107) are presented in eTable 2 in the Supplement. The quantitative review assessed septic shock criteria and mortality.

cRefers to the records included for quantitative assessment of septic shock mortality and the heterogeneity by criteria using random-effects meta-analysis (44 studies57,1959) (eTable 2 in the Supplement).

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Figure 2.
Random-Effects Meta-analysis of Studies Identified in the Systematic Review, Reporting Septic Shock Mortality

Forty-four studies report septic shock–associated mortality57,1959 and were included in the quantitative synthesis using random-effects meta-analysis. The Surviving Sepsis Campaign (SSC) database analyses with similar data are reported in 2 studies6,29; therefore, only one of these was used in the meta-analysis reported.6 Levy et al report 3 septic shock subsets,6 Klein Klowenberg et al report 2 (restrictive and liberal),7 Zahar et al report 3 (community-acquired, ICU-acquired, and nosocomial infection–associated septic shock),30 and Phua et al report 2 groups,32 which were treated as separate data points in the meta-analysis. Studies under “consensus definition” cite the Sepsis Consensus Definitions.1,2 The categorization used to assess heterogeneity does not fully account for septic shock details in individual studies.

SI conversion factor: To convert serum lactate values to mg/dL, divide by 0.111.

aData obtained from GiViTI database provided by Bertolini et al (published 20158).

bThe mortality data of Group 1 patients (new septic shock population) and the overall potential septic shock patient populations (n = 18 840) described in the manuscript from the current study using the Surviving SSC database are also included in the meta-analysis. Septic shock–specific data were obtained from Australian & New Zealand Intensive Care Society Adult Patient Database (ANZICS), from a previously published report.22 This results in 52 data points for random-effects meta-analysis.

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Figure 3.
Selection of Surviving Sepsis Campaign Database Cohort

Hypotension was defined as mean arterial pressure less than 65 mm Hg. Vasopressor therapy to maintain mean arterial pressure of 65 mm Hg or higher is treated as a binary variable. Serum lactate level greater than 2 mmol/L (18 mg/dL) is considered abnormal. The “after fluids” field in the Surviving Sepsis Campaign (SSC) database was considered equivalent to adequate fluid resuscitation. “Before fluids” refers to patients who did not receive fluid resuscitation. Serum lactate level greater than 2 mmol/L after fluid resuscitation but without hypotension or need for vasopressor therapy (group 4) is defined as “cryptic shock.” Missing serum lactate level measurements (n = 4419 [15.7%]) and patients with serum lactate levels greater than 4 mmol/L (36 mg/dL) who did not receive fluids as per SSC guidelines (n = 790 [2.8%]) were excluded from full case analysis. Of the 22 941 patients, 4101 who were coded as having severe sepsis were excluded. Thus, the remaining 18 840 patients were categorized within septic shock groups 1 to 6.

aPatients with screening serum lactate levels coded as greater than 2 mmol/L (n=3342) were included in the missing-data analysis.

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Figure 4.
Serum Lactate Level Analysis

Adjusted odds ratio for actual serum lactate levels for the entire septic shock cohort (N = 18 840). The covariates used in the regression model include region (United States and Europe), location where sepsis was suspected (emergency department, ward, or critical care unit), antibiotic administration, steroid use, organ failures (pulmonary, renal, hepatic, and acutely altered mental state), infection source (pneumonia, urinary tract infection, abdominal, meningitis, and other), hyperthermia (>38.3°C), hypothermia (<36°C), chills with rigor, tachypnea (>20/min), leukopenia (<4000 cells/µL), hyperglycemia (plasma glucose >120 mg/dL [6.7 mmol/L]), platelet count <100 ×103/μL, and coagulopathy (eMethods 3 in the Supplement). The adjusted odds ratio (OR) for the 6 groups presented in eTable 7 in the Supplement and the adjusted OR for the individual variables (lactate, vasopressor therapy, and fluids) are reported in eTable 8 in the Supplement. To convert serum lactate values to mg/dL, divide by 0.111.

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