title: 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).
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Division of Asthma, Allergy, and Lung Biology, King's College London, London, United Kingdom2Department of Critical Care Medicine, Guy's and St Thomas' NHS Foundation Trust, London SE17EH, United Kingdom.
authors.forename: Manu
authors.initials: M
authors.lastname: Shankar-Hari
authors.affiliation: The Ohio State University College of Medicine, Department of Biomedical Informatics, Center for Biostatistics, Columbus.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Phillips
authors.affiliation: Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island.
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Levy
authors.affiliation: Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care and Emergency Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Seymour
authors.affiliation: Division of Research, Kaiser Permanente, Oakland, California.
authors.forename: Vincent X
authors.initials: VX
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Hofstra-North Shore-Long Island Jewish-Hofstra School of Medicine, Steven and Alexandra Cohen Children's Medical Center, New Hyde Park, New York8Department of Molecular Medicine, Hofstra-North Shore-Long Island Jewish-Hofstra Sch.
authors.forename: Clifford S
authors.initials: CS
authors.lastname: Deutschman
authors.affiliation: Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care and Emergency Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania10Associate Editor, JAMA.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Angus
authors.affiliation: Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada12Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Rubenfeld
authors.affiliation: Bloomsbury Institute of Intensive Care Medicine, University College London, London, United Kingdom.
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
mesh_terms: D000328:Adult; D026683:Advisory Committees; D015415:Biomarkers / Q000097:blood; D001795:Blood Pressure Determination; D015331:Cohort Studies; D032921:Consensus; D003697:Delphi Technique; D005440:Fluid Therapy; D006801:Humans; D007022:Hypotension / Q000175:diagnosis; D007773:Lactates / Q000097:blood; D064887:Observational Studies as Topic; D012151:Resuscitation / Q000379:methods; D012196:Review Literature as Topic; D012772:Shock, Septic / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology / Q000628:therapy; D014662:Vasoconstrictor Agents / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D007773:Lactates; D014662:Vasoconstrictor Agents