Research

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, MSc; Gary S. Phillips, MAS; Mitchell L. Levy, MD; Christopher W. Seymour, MD, MSc; Vincent X. Liu, MD, MSc;
Clifford S. Deutschman, MD; Derek C. Angus, MD, MPh; Gordon D. Rubenfeld, MD, MSc; Mervyn Singer, MD, FRCP; for the Sepsis Definitions Task Force

Editorial page 757

IMPORTANCE Septic shock currently refers to a state of acute circulatory failure associated Author Audio Interview at
with infection. Emerging biological insights and reported variation in epidemiology challenge jama.com
the validity of this definition.
Related articles pages 762 and
801
OBJECTIVE To develop a new definition and clinical criteria for identifying septic shock in adults.
Supplemental content at
jama.com
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 Author Affiliations: Author
or lower. These findings were validated in the UPMC and KPNC data sets. affiliations are listed at the end of this
article.

CONCLUSIONS AND RELEVANCE Based on a consensus process using results from a systematic Group Information: Members of the
Sepsis Definitions Task Force are
review, surveys, and cohort studies, septic shock is defined as a subset of sepsis in which listed at the end of this article.
underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of
Corresponding Author: Manu
mortality than sepsis alone. Adult patients with septic shock can be identified using the clinical Shankar-Hari, MD, MSc, Department
criteria of hypotension requiring vasopressor therapy to maintain mean BP 65 mm Hg or greater of Critical Care Medicine, Guy’s and St
and having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation. Thomas’ NHS Foundation Trust,
London SE1 7EH, United Kingdom
JAMA. 2016;315(8):775-787. doi:10.1001/jama.2016.0289 (manu.shankar-hari@kcl.ac.uk).

(Reprinted) 775

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 Research Original Investigation
C
onsensus definitions, generated in 19911 and revisited in
2001,2 describe septic shock as a state of cardiovascu-
lar dysfunction associated with infection and unex-
plained by other causes. The increasing availability of large elec-
tronic health record (EHR) data sets, registries, national case mix
programs, trial data sets, and claims databases using Interna-
tional Classification of Diseases codes have since generated mul-
tiple observational studies reporting septic shock epidemiol-
ogy. However, variable interpretation and application of the
consensus definitions1,2 have contributed to variable esti-
mates of both incidence and outcomes.3-8 It is unclear to what
extent these variations represent true differences or an artifact
attributable to inconsistent use of definitions.8,9 Furthermore,
emerging insights into sepsis pathophysiology10-13 warrant a re-
view of the current septic shock definition and the criteria used
to identify it clinically.
Against this background, the Society of Critical Care Medi-
cine (SCCM) and the European Society of Intensive Care Med
(ESICM) convened an international task force to review defini-
tions of sepsis and septic shock in January 2014. To support the
task force deliberations on redefining septic shock, a series of
activities was performed: a systematic review and meta-
analysis of criteria used in observational studies reporting sep-
sis epidemiology in adults; a Delphi study to achieve consen-
sus; cohort studies using the Surviving Sepsis Campaign (SSC)
registry; and subsequent testing of the applicability of the new
criteria in patients with suspected infection from 2 large EHR-
derived data sets. The aims of this study were to develop an up-
dated septic shock definition and to derive clinical criteria for
identifying patients with septic shock meeting this updated defi-
nition. Specifically, this updated definition and these criteria are
intended to provide a standard classification to facilitate clini-
cal care, future clinical research, and reporting.
Methods
In this article, “definition” refers to a description of septic shock
and “clinical criteria” to variables used to identify adult pa-
tients with septic shock.
Task Force
The SCCM and ESICM each nominated cochairs of the task force
and provided unrestricted funding support toward the work con-
ducted. The 2 cochairs then selected 17 other task force partici-
pants based on their scientific expertise in sepsis epidemiol-
ogy, clinical trials, and basic or translational research. Task force
participants are listed at the end of the article. The task force
retained complete autonomy for all decisions. ESICM and SCCM
had no role in study design, conduct, or analysis but were con-
sulted for peer review and endorsement of the manuscript.14
Systematic Review and Meta-analysis
The aims of the systematic review were to assess the differ-
ent criteria used to identify adult patients with septic shock
and whether these criteria were associated with differences in
reported outcomes. MEDLINE was searched using search
terms, MeSH headings, and combinations of sepsis, septic shock,
776 JAMA February 23, 2016 Volume 315, Number 8 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
New Definition and Criteria for Septic Shock
and epidemiology and limits of human studies; adults 19 years
or older; English-language publications; and publication dates
between January 1, 1992 (1991 definitions1), and December 25,
2015. For full-text review, only noninterventional studies re-
porting sepsis epidemiology and all-cause mortality were in-
cluded. Randomized clinical trials were excluded, because the
additional inclusion and exclusion criteria might confound the
effect of criteria on mortality (the study objective).8 To avoid
variability in outcomes related to specific pathogens, specific
patient groups, and interventional before-and-after studies,
studies reporting these populations were also excluded. Data
were extracted on cohort recruitment period, cohort charac-
teristics, setting, criteria used to identify septic shock, and acute
mortality. Detailed methods, including search strategy, are pre-
sented in eMethods 1 and eTable 1 in the Supplement.
Delphi Study
To generate consensus on the septic shock definition and cri-
teria, 3 face-to-face meetings, 3-round sequential pretested
questionnaires, and email discussions among the task force par-
ticipants were conducted. One task force member did not par-
ticipate in these surveys because of lack of content expertise,
and 1 did not respond to the first 2 surveys. Questionnaires were
developed, refined, and administered consisting of single- and
multiple-answer questions, free-text comments, and a 5-point
Likert agreement scale. For consensus discussions and not-
ing agreement, the 5-point Likert agreement scales were
grouped at the tails of the scale choices (ie, “strongly dis-
agree” grouped with “disagree”; “strongly agree” grouped with
“agree”). All outputs from the systematic review, surveys, and
the results of cohort studies were made available to partici-
pants throughout the Delphi study.
In the first round (August 2014), using 26 questions in 4
domains, agreement and opinions were explored on (1) com-
ponents of the new septic shock definition; (2) variables and
their cutoffs identified by the systematic review; (3) defini-
tions of, and criteria for, hypotension, persistent hypoten-
sion, adequacy of resuscitation, and resuscitation end points;
and (4) septic shock severity scoring. In the second round
(November 2014), 4 questions were used to generate state-
ments for key terms (persistent hypotension, adequacy of re-
suscitation, and septic shock) and to reach agreement on test
variables and outcomes for subsequent analysis of predictive
validity. The objectives of the third round (January 2015) were
to establish a consensus definition of septic shock and re-
lated clinical criteria. In the third survey, the task force mem-
bers were given 4 choices for the septic shock updated crite-
ria ([1] serum lactate level alone; [2] hypotension alone;
[3] vasopressor-dependent hypotension or serum lactate
level; [4] vasopressor-dependent hypotension and serum lac-
tate level) and were asked to provide their first and second
choices. The cumulative first or second choices were used to
agree on the reported septic shock criteria.
Questionnaire items were accepted if agreement ex-
ceeded 65%. Choices for which agreement was less than 65%
were rediscussed to achieve consensus or were eliminated, as
appropriate to achieve the project aims. The survey question-
naires are presented in eMethods 2 in the Supplement.
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New Definition and Criteria for Septic Shock
Cohort Studies
The institutional review boards of Cooper University Hospital
(Camden, New Jersey),15 University of Piitsburgh Medical Cen-
ter (UPMC; a network of hospitals in western Pennsylvania),
and Kaiser Permanente Northern California (KPNC)16 pro-
vided ethics approvals for research using the SSC and EHR data
sets, respectively.
The SSC registry includes data collected from 218 hospi-
tals in 18 countries on 28 150 patients with suspected infec-
tion who, despite adequate fluid resuscitation as judged by
the collecting sites, still had 2 or more systemic inflamma-
tory response syndrome criteria and 1 or more organ dysfunc-
tion criteria (eMethods 3 in the Supplement). The SSC data-
base setup, inclusion, and reporting items are described in
detail elsewhere.6,17 To select clinical criteria for the new sep-
tic shock definition, an analysis data set was created that in-
cluded all patients with a serum lactate level measurement or
a mean arterial pressure less than 65 mm Hg after fluids, or who
received vasopressors.
For external validation, mortality was determined using the
same clinical criteria in patients with suspected infection
(cultures taken, antibiotics commenced) within 2 large EHR da-
tabases from UPMC (12 hospitals, 2010-2012, n = 1 309 025) and
KPNC (20 hospitals, 2009-2013, n = 1 847 165). Three variables
(hypotension, highest serum lactate level, and vasopressor
therapy as a binary variable [yes/no]) were extracted from these
2 data sets during the 24-hour period after infection was sus-
pected. Descriptive analyses, similar to those performed on the
SSC data set, were then undertaken. Because of constraints on
data availability, hypotension was considered present if sys-
tolic blood pressure was 100 mm Hg or less for any single mea-
surement taken during the 24-hour period after infection was
suspected. Serum lactate levels were measured in 9% of in-
fected patients at UPMC and in 57% of those at KPNC after imple-
mentation of a sepsis quality improvement program.
Statistics
Meta-analysis
A random effects meta-analysis of septic shock mortality by
study-specific septic shock criteria and sepsis definitions was
performed. Two meta-regression models of septic shock mor-
tality were tested with the covariates: sepsis definition, crite-
ria for shock, mid–cohort-year of study population, single cen-
ter or multicenter, and World Health Organization member
state regions.18 These 2 models (with and without per capita
intensive care unit beds) were generated to account for inter-
national cohorts and countries for which per capita intensive
care unit bed data were unavailable (See eMethods 1 in the
Supplement for details).
Cohort Studies
Hospital mortality was used as the primary outcome for deri-
vation and descriptive validation analysis. Using the 3 dichoto-
mous variables identified in round 2 of the Delphi process, the
SSC cohort was divided into 6 groups and the variables tested
either alone or in combination: (1) hypotension (mean arte-
rial pressure <65 mm Hg) after fluid administration; (2) vaso-
pressor therapy; and (3) serum lactate level greater than
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Copyright 2016 American Medical Association. All rights reserved.
Original Investigation Research
Figure 1. Study Identification and Selection Process Used
in the Systematic Review
1017 Records identified and screened
982 MEDLINE
35 Other sources a
915 Excluded
894 Did not meet screening
criteria
21 Duplicate
102 Met full-text review criteria
36 Excluded b
16 Specific population
10 Included all age groups
10 Interventional study
26 New records included from
reference search of full-text
articles
92 Included for qualitative synthesis
of definitions and criteria
44 Reported septic shock–specific mortality
for quantitative synthesis c
a
Nonduplicate references from other sources included review articles.3,108-110
See eMethods 1 in the Supplement for further details of search strategy.
b
Refers 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 studies5-7,19-107) are presented in eTable 2 in the Supplement. The
quantitative review assessed septic shock criteria and mortality.
c
Refers to the records included for quantitative assessment of septic shock
mortality and the heterogeneity by criteria using random-effects
meta-analysis (44 studies5-7,19-59) (eTable 2 in the Supplement).
2 mmol/L or 2 mmol/L or less (to convert serum lactate val-
ues to mg/dL, divide by 0.111). Hypotension was assumed when
vasopressor therapy was being administered, generating 6 dis-
tinct potential septic shock patient groups using the 3 se-
lected variables (eTable 5 in the Supplement). Analyses were
performed using either the 6 groups or the 3 dichotomous vari-
ables as the risk factor. Subsequent analyses using the serum
lactate level as a categorical variable were performed using a
χ2 test of trend for mortality.
Currently, there are no gold standard septic shock criteria for
predictive validity comparisons.8 Thus, these analyses aimed to
identify a patient population that has the attributes of the newly
proposed definition, which includes higher mortality compared
with other patient populations commonly reported as having sep-
tic shock in the literature identified by the systematic review.
Therefore, the independent relationship between the 3 poten-
tial criterion variables (hypotension, serum lactate level, and va-
sopressor therapy) agreed on the second round of the Delphi pro-
cess and a future outcome (hospital mortality) was tested using
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 Research Original Investigation New Definition and Criteria for Septic Shock

Table 1. Summary of Septic Shock Definitions and Criteria Reported in the Studies Identified by the Systematic Reviewa

Septic Shock Case Definitions and Corresponding Variables Reported in Literature

Consensus Definitions Other Definitions
Other Description
Criteria Bone et al1 Levy et al2 SSC111 Trial-based112 of Criteria Variables
Infection Suspected or proven Suspected or proven Suspected or proven Suspected or proven Bacteremia, culture
positive; CDC definitions
for infection
SIRS criteria, No. 2 One or more of 24 2 3 NA
variablesb
Septic shock Sepsis-induced State of acute circulatory Sepsis-induced Cardiovascular Precoded data using
description hypotension despite failure characterized hypotension persisting dysfunction defined as ICD-9 and ICD-10 codesc
adequate resuscitation by persistent arterial despite adequate hypotension despite
OR receiving hypotension after fluid resuscitation adequate resuscitation
vasopressors/Inotropes adequate resuscitation or need for vasopressors
plus presence of unexplained by
perfusion abnormalities other causes
Hypotension, mm Hg
Systolic BP <90 <90 <90 <90 <100
Decrease Decrease >40 Decrease >40 Decrease >40 NA<70 >50% decrease in
in systolic BP hypertension
MAP No <60 <70 Hypotension lasting <65
>1 h after resuscitation
Adequate resuscitation Not defined Not defined Goals set as CVP Not defined After resuscitation fluids
definition 8-12 mm Hg; urine (0.5 L; 1 L; 1.5 L;
output ≥0.5 mL/kg/h; 20 mL/kg ideal
ScvO2 >70% body weight
Vasopressor use Yes (not absolute Yes (CVS SOFA score) Yes (not absolute Yes (not absolute Vasoactive drugs required
requirement) requirement) requirement) for >30 min
Hypoperfusion Hypoperfusion Tissue hypoperfusion Tissue hypoperfusion No description Serum lactate
abnormalities abnormality defined as defined as serum lactate defined as >2.5 mmol/L; base deficit
lactic acidosis; oliguria; >1 mmol/L or delayed infection-induced >5 mEq/L, alkaline
low Glasgow Coma Score capillary refill hypotension, elevated reserve <18 mEq/L;
serum lactate CVP <8; PCWP <12
(>4 mmol/L), or oliguria
Data points from 39 (75) 13 (25)
included studies,
No. (%)d
Sample size, No. 158 354 8125
Mortality by septic 47.2 (42.7-51.7) 44.2 (38.5-49.9)
shock definition using
random-effects meta
analysis, % (95% CI)
I2, %e 99.6 95.9
τ2f 191.21 94.9
P value heterogeneity <.001 <.001
c
Abbreviations: BP, blood pressure; CDC, Centers for Disease Control and Different ICD-9 codes are reported to identify septic shock in the literature.
Prevention; CVP, central venous pressure; CVS, cardiovascular system; These include shock without trauma code 785.50 with all subcodes (785.51,
ICD, International Classification of Diseases; MAP, mean arterial pressure; 785.52, 785.59), hypotension code 458 with subcodes (458.0, 458.8 458.9),
NA, not applicable; PCWP, pulmonary capillary wedge pressure; SBP, systolic cardiovascular failure code 427.5 and the nonspecific low blood pressure
blood pressure; ScvO2, central venous oxygen saturation; SIRS, systemic code 796.3.
inflammatory response syndrome; SOFA, Sequential [Sepsis-related] Organ d
Studies reporting 2 or more subsets,6,7,30,32 current study (whole population
Failure Assessment; SSC, Surviving Sepsis Campaign. and Group 1), and GiViTI database account for 52 data points from 44 studies.
SI conversion factor: To convert serum lactate values to mg/dL, divide by 0.111. See Figure 2 notes for further details.
a
The summary table was generated from eTable 2 data from 92 studies.5-7,19-107 e 2
I is the percentage of between-study heterogeneity that is attributable to a
b
Levy et al highlight an extended variable list as a replacement for SIRS criteria true variability in septic shock mortality, rather than sampling variation,
consisting of general (n = 7); inflammatory (n = 5); hemodynamic (n = 3); implying heterogeneity.
organ dysfunction (n = 7) and tissue perfusion (n = 2) variables.2 f
τ2 refers to the between-study variance within groups in random-effects
meta-analysis.

2 generalized estimating equation population-averaged logistic
regression models with exchangeable correlation structure,
where hospital site was the panel variable.
The first model used the potential septic shock groups 1 to
6 derived from these variables (eTable 5 in the Supplement), with
group 1 as the referent group and adjusted for other covariates
to assess true mortality difference between these groups. The sec-
ond model assessed the independent association of these 3 po-
tential criterion variables on hospital mortality adjusted for other
covariates. These models also included an a priori adjustment
variable for covariates including region (United States and
Europe), location where sepsis was suspected (emergency de-
partment, ward, or critical care unit), antibiotic administration,
steroid use, organ dysfunction (pulmonary, renal, hepatic, and
acutely altered mental state), infection source (pneumonia, uri-
nary tract infection, abdominal, meningitis and other), hyper-

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New Definition and Criteria for Septic Shock Original Investigation Research

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

Reporting Septic Shock Mortality

Patients With
Septic Shock Septic Shock, Mortality, %
Source Deaths, No. No. (95% CI)
Consensus Definition
Degoricija et al,46 2006 90 125 72.0 (64.1-79.9)
Angkasekwinai et al,38 2007 41 78 52.6 (41.5-63.6)
Nesseler et al,27 2013 30 93 32.3 (22.8-41.8)
Sakr et al,25 2013 85 145 58.6 (50.6-66.6)
23
Goncalves-Pereira et al, 2014 418 856 48.8 (45.5-52.2)
Leligdowicz et al,5 2014 4146 7974 52.0 (50.9 -53.1)
Ortiz et al,19 2014 144 319 45.1 (39.7-50.6)
Hypotension
Laupland et al,47 2004 81 159 50.9 (43.2-58.7)
Gaspraovic et al,45 2006 44 129 34.1 (25.9-42.3)
Shapiro et al,44 2006 15 53 28.3 (16.2-40.4)
Povoa et al,35 2009 202 458 44.1 (39.6-48.7)
7
Klein Klowenberg et al, 2012 52 98 53.1 (43.2-62.9)
Kaukonen et al,22 2014 14 609 51 079 28.6 (28.2-29.0)
Hypotension + Perfusion Abnormalities and/or Vasopressor Therapy
Rangel-Frausto et al,56 1995 51 110 46.4 (37.0-55.7)
Salvo et al,55 1995 27 33 81.8 (68.7-95.0) Forty-four studies report septic
Alberti et al,52 2002 752 1180 63.8 (60.7-67.0) shock–associated mortality5-7,19-59
Hypotension + Vasopressor Therapy and were included in the quantitative
Rodriguez et al,31 2001 129 283 45.6 (39.8-51.4) synthesis using random-effects
Silva et al,48 2004 106 203 52.2 (45.3-59.1) meta-analysis. The Surviving
Laupland et al,49 2005 28 57 49.1 (36.5-61.8) Sepsis Campaign (SSC) database
Vincent et al,43 2006 250 462 54.1 (49.6-58.7)
analyses with similar data are
Karlsson et al,40 2007 90 363 24.8 (20.4-29.2)
reported in 2 studies6,29; therefore,
Sakr et al,39 2007 250 462 54.1 (49.6-58.7)
only one of these was used in the
Kauss et al,34 2010 185 255 72.5 (67.1-78.0)
meta-analysis reported.6 Levy et al
Levy et al,6 2010 915 2494 36.7 (34.8-38.6)
32
Phua et al, 2011 441 939 47.0 (44.3-49.7) report 3 septic shock subsets,6
Ogura et al,20 2014 117 282 41.5 (35.7-47.2) Klein Klowenberg et al report 2
GiViTI database, 2015a 15 935 26 295 60.6 (60.0-61.2) (restrictive and liberal),7 Zahar et al
Hypotension + Vasopressor Therapy + Serum Lactate Level >2 mmol/L report 3 (community-acquired,
Group 1b 3602 8520 42.3 (41.2-43.3) ICU-acquired, and nosocomial
Hypotension + Perfusion Abnormalities + Vasopressor Therapy infection–associated septic shock),30
Lundberg et al,54 1998 19 41 46.3 (31.1-61.6) and Phua et al report 2 groups,32
Levy et al,6 2010 3428 7436 46.1 (45.0-47.2) which were treated as separate
26
Quenot et al, 2013 728 1495 48.7 (46.2-51.2) data points in the meta-analysis.
Hypotension ± Vasopressor Therapy or Metabolic Abnormalities Studies under “consensus definition”
Peake et al,36 2009 75 324 23.1 (18.6-27.7) cite the Sepsis Consensus
Hypotension or Vasopressor Therapy Definitions.1,2 The categorization
Dahmash et al,59 1993 14 36 38.9 (23.0-54.8) used to assess heterogeneity does
McLauchlan et al,58 1995 73 101 72.3 (63.5-81.0) not fully account for septic shock
Pittet et al,57 1995 7 12 58.3 (30.4-86.2) details in individual studies.
Schoenberg et al,53 1998 32 80 40.0 (29.3-50.7)
Engel et al,42 2007 119 190 62.6 (55.8-69.5) SI conversion factor: To convert
Esteban et al,41 2007 27 59 45.8 (33.1-58.5) serum lactate values to mg/dL, divide
Khwannimit and Bhuayanontachai,37 2009 164 303 54.1 (48.5-59.7) by 0.111.
Moore et al,33 2011 22 61 36.1 (24.0-48.1) a
Data obtained from GiViTI database
Zahar et al,30 2011 (community) 215 530 40.6 (36.3-44.8) provided by Bertolini et al
Zahar et al,30 2011 (ICU) 123 232 53.0 (47.1-59.0) (published 20158).
Zahar et al,30 2011 (nosocomial) 233 580 40.2 (36.1-44.2) b
7 The mortality data of Group 1
Klein Klowenberg et al, 2012 29 47 61.7 (47.8-75.6)
Park et al,28 2012 228 740 30.8 (27.5-34.1) patients (new septic shock
Hypotension or Serum Lactate Any Value or Vasopressor Therapy population) and the overall
Liu et al,21 2014 827 2536 32.6 (30.8-34.4) potential septic shock patient
SSC database,16 2016b 6556 18 840 34.8 (34.1-35.5) populations (n = 18 840) described
International Classification of Diseases Codes in the manuscript from the current
Annane et al,51 2003 13 269 26 172 50.7 (50.1-51.3) study using the Surviving SSC
Flaatten,50 2004 457 1562 29.3 (27.1-31.6) database are also included in the
Whittaker et al,24 2013 117 321 36.4 (31.2-41.7) meta-analysis. Septic shock–specific
Serum Lactate Level >4 mmol/L data were obtained from Australian
Levy et al,6 2010 242 811 29.8 (26.7-33.0) & New Zealand Intensive Care
Phua et al,32 2011 219 466 47.0 (42.0-52.0) Society Adult Patient Database
Overall (I2 = 99.5%; P = .000) 46.5 (42.7-50.3) (ANZICS), from a previously
0 20 40 60 80 100 published report.22 This results in
Mortality, % (95% CI) 52 data points for random-effects
meta-analysis.

thermia (>38.3°C), hypothermia (<36°C), chills with rigor, tachyp- (plasma glucose level >120 mg/dL [6.7 mmol/L), platelet count
nea (>20/min), leukopenia (<4000 cells/μL), hyperglycemia <100 ×103/μL, and coagulopathy.

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 Research Original Investigation New Definition and Criteria for Septic Shock

Table 2. Random Effects Meta-Analysis by Septic Shock Criteria Groups

Mortality, No. of Events/ Heterogeneity
Septic Shock Case Definition Criteriaa No.b No. of Patients (%) [95% CI]c Statisticd df P Value I2, %e τ2f
Consensus definitions cited (no description) 7 4954/9590 53.2 6 <.001 88.7 39.9
(51.6) [46.3-56.9]
Hypotension 6 15 003/51 976 100.5 5 <.001 95.0 129.5
(39.8) [30.1-49.5]
Hypotension + perfusion abnormalities and/or 3 830/1323 20.4 2 <.001 90.2 155.8
vasopressor therapy (63.3) [48.3-78.4]
Hypotension + vasopressor therapy 11 18 446/32 095 919.8 10 <.001 98.9 195.8
(48.9) [40.5-57.4]
Hypotension + vasopressor therapy 1 3602/8520 0
+ serum lactate level >2 mmol/L (42.3) [41.2-43.3]
Hypotension + perfusion abnormalities 3 4175/8972 3.4 2 .19 40.5 1.33
+ vasopressor therapy (47.0) [45.0-49.0]
Hypotension ± vasopressor therapy 1 75/324 0
or metabolic abnormalities (23.1) [18.6-27.7]
Hypotension or vasopressor therapy 13 1286/2971 165.3 12 <.001 92.7 142.3
(48.4) [41.3-55.5]
Hypotension or serum lactate any value 2 7383/21 376 4.9 1 .03 79.4 1.9
or vasopressor therapy (33.9) [31.8-36.0]
International Classification of Diseases codes 3 13 843/28 055 343.8 2 <.001 99.4 205.6
(38.9) [22.5-55.2]
Serum lactate level >4 mmol/L 2 461/1277 32.6 1 .005 96.9 142.6
(38.3) [21.5-55.1]
Overall 52 70 058/166 479 11026.7 51 <.001 99.5 182.5
(46.5) [42.7-50.3]
Abbreviation: df, degree of freedom. Bertolini et al8 and the current septic shock study resulting in 52 data points
SI conversion factor: To convert serum lactate values to mg/dL, divide by 0.111. (further information provided in Figure 2 legend).
d
a
Interpretation of the operationalization described for criteria to detect a septic The categorization used to assess heterogeneity does not fully account for
shock case in individual studies reporting septic shock mortality. septic shock details in individual studies.
e
b
Number of data points from studies included in the systematic review shown Percentage of between-study heterogeneity attributable to true variability in
in Figure 2 (see Figure 2 legend). septic shock mortality, rather than sampling variation, implying heterogeneity.
f
c
Septic shock mortality was reported by 44 studies. Four studies report septic τ2 refers to the between-study variance within groups in random-effects
shock subsets6,7,30,32; data obtained from GiViTi database provided by meta-analysis.

These models were used to estimate acute hospital mor-
tality odds ratios (ORs) and adjusted ORs for mortality per-unit
increase in the serum lactate level using continuous natural
log–transformed serum lactate level. The operating character-
istics (sensitivity/specificity over hospital mortality curves;
positive and negative predictive values) of different serum
lactate cutpoints (2, 3, and 4 mmol/L) were also tested using
the logistic regression model. Multiple imputations (n = 20)
were used to assess the statistical effect of missing serum lac-
tate values.
P < .05 (2-sided) was considered statistically significant. All
analyses were performed using Stata version 13.1 (StataCorp).
Results
Systematic Review and Meta-analysis
The systematic review identified 44 studies (166 479
patients) reporting septic shock mortality5-7,19-59 from a total
of 92 studies reporting sepsis cohorts between 1987 and
20155-7,19-107 (Figure 1; eTable 2 in the Supplement). Different
shock criteria were used for systolic blood pressure
(<90 mm Hg; <100 mm Hg; decrease >40 mm Hg; or decrease
>50% of baseline value if hypertensive), mean arterial
pressure (<70; <65; <60 mm Hg), serum lactate level (>4,
>2.5, >2, >1 mmol/L) and base deficit (−5 mmol/L) (Table 1;
eTable 2 in the Supplement). Temporal relationships
between resuscitation status and end points to shock diagno-
sis were seldom reported. The studies differed in the descrip-
tion of resuscitation, persistent hypotension, and in their
vasopressor definitions when using the cardiovascular
Sequential [Sepsis-related] Organ Failure Assessment (SOFA)
score categories.113 Diverse infection and organ dysfunction
codes were also used in the International Classification of
Diseases–based derivations.63,70,79,90 Variables highlighted in
Table 1 and in eTable 2 in the Supplement informed the Del-
phi survey questions.
The random-effects meta-analysis showed significant
heterogeneity in septic shock mortality (mean mortality,
46.5% [95% CI, 42.7%-50.3%], with a near 4-fold variation
from 23.0% to 81.8%; I2 = 99.5%; τ2 = 182.5; and P < .001)
(Figure 2). Statistically significant heterogeneity was also
observed in random-effects meta-analysis by clinical criteria
reported for septic shock case definition in studies (Table 2).
The meta-regression models described could not explain this
heterogeneity (eTable 3A and eTable 3B in the Supplement).
Delphi Study
In the first round, informed by the systematic review, 15 task
force members (88%) voted to include persistent hypoten-
sion, vasopressor therapy, and hyperlactatemia in the
updated criteria. There was no agreement on the lower cutoff
for serum lactate level in this round. Eleven members (65%)
voted that including fluid resuscitation would improve the

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New Definition and Criteria for Septic Shock Original Investigation Research

Table 3. Distribution of Septic Shock Cohorts and Crude Mortality From Surviving Sepsis Campaign Database (n = 18 840 patients)
Lactate Mortality,
Category, No. (% of total) Acute Hospital Mortality, χ2 Test Adjusted OR
a
Cohorts mmol/Lb [n = 18 840] No. (%) [95% CI] for Trend (95% CI)c P Valuec
Group 1 (hypotensive after fluids
and vasopressor therapy and serum lactate
levels >2 mmol/L) >2 to ≤3 2453 (13.0) 818 (33.3) [31.5-35.3] <.001 1 [Reference]
>3 to ≤4 1716 (9.1) 621 (36.2) [33.9-38.5]
>4 4351 (23.1) 2163 (49.7) [48.2-51.2]
All 8520 (45.2) 3602 (42.3) [41.2-43.3]
Group 2 (hypotensive after fluids ≤2 3985 (21.2) 1198 (30.1) [28.6-31.5] NAd 0.57 (0.52-0.62) <.001
and vasopressor therapy and serum lactate
levels ≤2 mmol/L)
Group 3 (hypotensive after fluids
and no vasopressors and serum lactate
levels >2 mmol/L) >2 to ≤3 69 (0.4) 15 (21.7) [12.7-33.3] .04 0.65 (0.47-0.90) .009
>3 to ≤4 57 (0.3) 14 (24.6) [14.1-37.8]
>4 97 (0.5) 35 (36.1) [26.6-46.5]
All 223 (1.2) 64 (28.7) [22.9-35.1]
Group 4 (serum lactate levels >2 mmol/L
and no hypotension after fluids
and no vasopressors) >2 to ≤3 860 (4.6) 179 (20.8) [18.1-23.7] <.001 0.71 (0.62-0.82) <.001
>3 to ≤4 550 (2.9) 105 (19.1) [15.9-22.6]
>4 1856 (9.9) 555 (29.9) [27.8-32.0]
All 3266 (17.3) 839 (25.7) [24.2-27.2]
Group 5 (serum lactate levels between
2-4 mmol/L and no hypotension before fluids
and no vasopressors) >2 to ≤3 1624 (8.6) 489 (30.1) [27.9-32.4] NAd 0.77 (0.66-0.90) .001
>3 to ≤4 1072 (5.7) 313 (29.2) [26.5-32.0]
>4 790e
All 2696 (14.3) 802 (29.7) [28.0-31.5]
Group 6 (hypotensive after fluids and no ≤2 150 (0.8) 28 (18.7) [12.8-25.8] NAd 0.32 (0.20-0.51) <.001
vasopressors and serum lactate ≤2 mmol/L)
c
Abbreviations: NA, not available; OR, odds ratio. Refers to the adjusted OR generated using generalized estimating equation
SI conversion factor: To convert serum lactate values to mg/dL, divide by 0.111. regression model (eTable7 in the Supplement).
d
a
Mean arterial pressure less than 65 mm Hg was used to define hypotension. χ2 test for trend could only be performed if there were 3 or more serum
“After fluids” was defined using the field “crystalloids” coded as a binary term lactate categories.
e
within the Surviving Sepsis Campaign database. Excluded from full case analysis.
b 2
Using χ tests, trends in mortality across serum lactate categories within
groups (>2 to ⱕ3 mmol/L; >3 to ⱕ4 mmol/L and >4 mmol/L) were assessed.

criteria. The task force determined that neither a severity
grading for septic shock nor criteria for either adequacy of
fluid resuscitation or persistent hypotension should be pro-
posed because of the nonstandardized use of hemodynamic
monitoring, resuscitation protocols, and vasopressor dosing
in clinical practice. (Other results are reported in eTable 4 in
the Supplement.)
In Delphi round 2, the task force was provided with a pre-
liminary descriptive analysis from the SSC database. With
agreement on the description of the septic shock illness con-
cept, 3 test variables (hypotension after fluid resuscitation, va-
sopressor therapy, and serum lactate level) were agreed on for
predictive validity analyses. The “after fluids” field in the SSC
database was used as a proxy for resuscitation. The need for
vasopressors was agreed as a proxy for persistent hypoten-
sion by 95% of the task force. Twelve members (71%) voted that
a minimum vasopressor dose should not be proposed in view
of the variability in blood pressure targets and resuscitation
protocols identified by the systematic review, and because of
variable sedation use. Vasopressor therapy was therefore
treated as a binary variable within the analysis. To derive an
optimal cutoff for serum lactate level, 13 task force members
(77%) agreed on acute hospital mortality as the outcome vari-
able. The test variables could be present either alone or in com-
binations, thus identifying 6 potential groups of patients with
septic shock (Table 3; eTable 5 in the Supplement).
Prior to the final round of the Delphi process, all analyses
from the SSC data set and the EHR data sets were provided.
These findings generated the new definition—“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”—and the clinical
criteria described below.
Cohort Studies
SSC Database
Patients with serum lactate levels greater than 4 mmol/L who
did not receive fluids as recommended by the SSC guidelines111
(n = 790 [2.8%]) were excluded. Patients without any serum
lactate values measured were excluded initially for full case
analysis (n = 4419 [15.7%]) but were reassessed in the miss-
ing data analysis. Of the 22 941 remaining patients, 4101 coded
as having severe sepsis were excluded from this analysis, gen-
erating the analysis set of 18 840 patients who were either hy-

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 Research Original Investigation New Definition and Criteria for Septic Shock

Figure 3. Selection of Surviving Sepsis Campaign Database Cohort

28 150 Patients identified from SSC database

4419 Excluded from full case analysis

(missing continuous serum
lactate values) a

23 731 With serum lactate values

790 Excluded (serum lactate level

>4 mmol/L and did not receive
fluids or vasopressors)

22 941 Potentially eligible for full analysis set

4101 Excluded (did not meet septic

shock definition by definition groups)

18 840 Met potential septic shock definition groups

and included in full case analysis cohort

Group 1 Group 2 Group 3 Group 4 Group 5 Group 6

8520 Patients 3985 Patients 223 Patients 2696 Patients 2696 Patients 150 Patients
Hypotensive after fluids Hypotensive after fluids Hypotensive after fluids Not hypotensive after Not hypotensive before Hypotensive after fluids
Requires vasopressors Requires vasopressors Requires no vasopressors fluids fluids Requires no vasopressors
Serum lactate >2 mmol/L Serum lactate ≤2 mmol/L Serum lactate >2 mmol/L Requires no vasopressors Requires vasopressors Serum lactate ≤2 mmol/L
Serum lactate >2 mmol/L Serum lactate >2 mmol/L

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

potensive after fluids or required vasopressors or had a se-
rum lactate level measurement (Figure 3 and Table 3).
Hypotension was reported in 83.1%, serum lactate level greater
than 2 mmol/L in 78.1%, and receipt of vasopressors in 66.4%.
Overall, crude hospital mortality was 34.7%. Cohort charac-
teristics by setting are shown in eTable 6 in the Supplement.
Predictive Validity of Potential Septic Shock Groups
Of the 6 groups of potential patients with septic shock (Table 3),
the most prevalent was group 1 (hypotension + vasopressor
therapy + serum lactate level >2 mmol/L) (n = 8520); followed
by groups 2 (n = 3985) and 4 (n = 3266). Crude hospital mor-
tality rates in these 3 groups were 42.3%, 30.1%, and 25.7%, re-
spectively. Statistically significant increasing trends in crude
mortality were observed over increasing serum lactate level cat-
egories within groups (χ2 test of trend: P < .001 for groups 1 and
4, P = .04 for group 3). The adjusted OR for hospital mortality
using group 1 for reference was significantly lower in all other
groups (P < .01 for groups 2 to 6), suggesting that group 1 rep-
resents a distinct subpopulation with a significantly greater risk
of death (eTable 7 in the Supplement). By a majority (cumula-
tive first choice, 72.2%; second choice, 55.6%) (eTable 4 in the
Supplement), the task force agreed that group 1 was most con-
sistent with the proposed septic shock definition, thus gener-
ating the new septic shock criteria.
Derivation of Serum Lactate Cutoff Value and Missing Data Analysis
In the generalized estimating equation model (shown in eTable
8 in the Supplement), serum lactate level was associated with
mortality, and the adjusted OR for hospital mortality in-
creased linearly with increasing serum lactate level. An in-
crease in serum lactate level from 2 to 10 mmol/L increased
the adjusted OR for hospital mortality from 1.4 (95% CI, 1.35-
1.45) to 3.03 (95% CI, 2.68-3.45) (referent lactate = 1; Figure 4).
A serum lactate level greater than 2 mmol/L was chosen as the
preferred cutoff value for the new septic shock criteria, the ra-
tionale being the trade-off between highest sensitivity (82.5%
when using the n = 18 840 subset, and 74.9% when using pa-
tients in groups 1 and 2 combined [n = 12 475]), and the deci-
sion from the Delphi process to identify the lowest serum lac-
tate level independently associated with a greater risk of death
(OR of 1.4 at a lactate value of 2 mmol/L) (Table 4; eTable 9,
eFigure 1, and eFigure 2 in the Supplement).
Predicated on this understanding of the SSC database struc-
ture and the regression analyses completed (eTable 6, eTable
7, and eTable 8 in the Supplement), we assumed that data were
missing at random; ie, any difference between observed val-
ues and missing values did not depend on unobserved data.
Complete case analysis was therefore performed, followed by
multiple imputation analysis to support the missing-at-
random assumption.114 The ORs for mortality per unit in-

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New Definition and Criteria for Septic Shock Original Investigation Research

crease in serum lactate level using complete case analysis
(n = 18 840) and imputed analyses (n = 22 182) were similar
(1.09 [95% CI, 1.08-1.10]; P < .001 vs 1.09 [95% CI, 1.08-1.09];
P < .001, respectively). The imputed and complete case analy-
sis probabilities of hospital mortality were also similar (36.4%
and 35.5%, respectively).
EHR Data Sets
The UPMC and KPNC EHRs included 148 907 and 321 380 adult
patients with suspected infection, respectively (eTable 10 in
the Supplement). Forty-six percent (n = 5984) of UPMC pa-
tients and 39% (n = 54 135) of KPNC patients with 1 or more
MAP of 65 mm Hg or greater and having a serum lactate level
greater than 2 mmol/L persisting after fluid resuscitation.
The proposed definition and criteria of septic shock differ
from prior definitions1,2,111 in 2 respects: (1) the need for both a
serum lactate level and vasopressor-dependent hypotension
(ie, cardiovascular SOFA score ≥2) instead of either alone
and (2) a lower serum lactate level cutoff of 2 mmol/L vs
Figure 4. Serum Lactate Level Analysis
5.0

GEE Model Adjusted Odds Ratio (95% CI)

4.0
SOFA score points and suspected infection fulfilled criteria for
1 of the 6 potential septic shock groups described. Patients 3.0

meeting group 1 criteria (hypotension + vasopressor

therapy + serum lactate level >2 mmol/L) comprised 5.3%
(UPMC) and 14.9% (KPNC) of the EHR population of patients
with suspected infection and had a mortality of 54% and 35%,
respectively. Similar to the SSC database, crude mortality rates
within each group were higher among those with higher se-
rum lactate levels (Table 5).
Discussion
The systematic review illustrated the variability in criteria cur-
rently used to identify septic shock, whereas the meta-
analysis demonstrated the heterogeneity in mortality. In-
formed by this systematic review, a Delphi process was used to
reach a consensus definition of septic shock and related clini-
cal criteria. Three large data sets were then used to determine
the predictive validity of these criteria. Septic shock was de-
fined as a subset of sepsis in which circulatory, cellular, and
metabolic abnormalities are associated with a greater risk of mor-
tality than sepsis alone. The clinical criteria representing this
definition were the need for vasopressor therapy to maintain a
2.0
1.0
0.5
1 1.5 2 3 4 5 6 7 8 9 10
Serum Lactate, mmol/L
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.

Table 4. Characteristics of Serum Lactate Level Cutoff Values for Complete Case Analysis and Imputation Analysis Using Surviving Sepsis
Campaign Database

Serum Lactate Level, mmol/L

>2 >3 >4
Characteristic Died/Total % (95% CI) Died/Total % (95% CI) Died/Total % (95% CI)
Complete Case Analysis (n = 18 795)
Hospital mortality, % 5757/18 795 30.6 (29.9-31.4) 6101/18 795 32.5 (31.8-33.2) 6456/18 975 34.3 (33.7-35.0)
Sensitivity, % 5372/6509 82.5 (81.6-83.4) 3779/6509 58.1 (56.8-59.3) 2811/6509 43.2 (42.0-44.4)
Specificity, % 2748/12 286 22.4 (21.6-23.1) 6418/12 286 52.2 (51.4-53.1) 8564/12 286 69.7 (68.9-70.5)
PPV, % 5372/14 910 36.0 (35.3-36.8) 3779/9647 39.2 (38.2-40.2) 2811/6533 43.0 (41.8-44.2)
NPV, % 2748/3885 70.7 (69.3-72.2) 6418/9148 70.1 (69.2-71.1) 8564/12 286 69.8 (69.0-70.7)
Imputed Missing Serum Lactate Level (n = 22 182)
Hospital mortality, % 6965/22 182 31.4 (30.8-32.0) 7363/22 182 33.2 (32.6-33.8) 7772/22 182 35.0 (34.4-35.7)
Sensitivity, % 6457/7748 83.3 (82.5-84.2) 4461/7748 57.6 (56.5-58.7) 2931/7748 37.8 (36.7-38.9)
Specificity, % 3341/14 434 23.1 (22.5-23.8) 7833/14 434 54.3 (53.5-55.1) 10 801/14 434 74.8 (74.1-75.5)
PPV, % 6457/17 550 36.8 (36.1-37.5) 4461/11 062 40.3 (39.4-41.2) 2931/6564 44.6 (43.4-45.8)
NPV, % 3341/4634 72.1 (70.8-73.4) 7833/11 120 70.4 (69.6-71.3) 10 801/15 618 69.2 (68.4-69.9)

Abbreviations: NPV, negative predictive value; PPV, positive predictive value.

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

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 Research Original Investigation New Definition and Criteria for Septic Shock

Table 5. Crude Mortality in Septic Shock Groups From UPMC and KPNC Data sets

Highest Serum Lactate UPMC KPNC

Levels 24 h After Acute Hospital Mortality Acute Hospital Mortality
Infection Identified, No. (%) No. (%)
Variablea mmol/L (n = 5984) No. % (95% CI) (n = 54 135) No. % (95% CI)
Group 1 >2 (all) 315 (5.3) 171 54.3 (48.6-59.9) 8051 (14.9) 2835 35.2 (34.2-36.3)
>3 246 (4.1) 147 59.8 (53.3-65.9) 6006 (11.1) 2355 39.2 (38.0-40.5
>4 189 (3.2) 120 63.5 (56.2-70.4) 4438 (8.2) 1939 43.7 (42.2-45.2)
Group 2 ≤2 147 (2.5) 37 25.2 (18.4-33.0) 3094 (5.7) 582 18.8 (17.4-20.2)
Group 3 >2 (all) 3544 (59.2) 1278 36.1 (34.5-37.7) 12 781 (23.6) 2120 16.6 (15.9-17.2)
>3 2492 (41.6) 1058 42.5 (40.5-44.4) 6417 (11.9) 1381 21.5 (20.5-22.5)
>4 1765 (29.5) 858 48.6 (46.3-51.0) 3316 (6.1) 914 27.6 (26.0-29.1)
Groups 4 >2 (all) 1978 (33.1) 355 17.9 (16.3-19.7) 30 209 (55.8) 2061 6.8 (6.5-7.1)
and 5
>3 1033 (17.3) 224 21.7 (19.2-24.3) 12 450 (23.0) 1138 9.1 (8.6-9.7)
>4 566 (9.4) 146 25.8 (22.2-29.6) 5394 (9.9) 637 11.8 (11.0-12.7)
Abbreviations: KPNC, Kaiser Permanente Northern California; SSC, Surviving to patients with hypotension and serum lactate levels greater than 2 mmol/L.
Sepsis Campaign; UPMC, University of Pittsburgh Medical Center. Groups 4 and 5 refer to isolated serum lactate level greater than 2 mmol/L.
SI conversion factor: To convert serum lactate values to mg/dL, divide by 0.111. Counts within a group are not mutually exclusive, as those with serum
a lactate levels greater than 2 mmol/L will include those in the higher serum
Group 1 refers to patients with hypotension + vasopressors + serum lactate
lactate cutoffs.
levels greater than 2 mmol/L. Group 2 refers to patients with hypotension +
vasopressors + serum lactate levels less than 2 mmol/L. Group 3 refers

4 mmol/L as currently used in the SSC definitions. In the new
septic shock definition, an increase in serum lactate level is po-
sitioned as a proxy for a cellular metabolic abnormality, and as
a variable independently associated with acute mortality (pre-
dictive validity), which is consistent with the published
literature.115-118 An elevated serum lactate level is not specific
for cellular dysfunction in sepsis118,119 but has face validity given
the lack of a superior yet readily available alternative. This
present study identifies a lower serum lactate level cutoff as
an independent prognostic variable when compared with a re-
cent analysis of the entire SSC database. This disparity is ex-
plained by using a data set of 18 840 patients in the analysis in
this study rather than the total 28 150-patient SSC data set used
by Casserly et al.17 From this subpopulation 6 groups were iden-
tified and analyzed as risk strata within the generalized esti-
mating equation model and performance-tested for various se-
rum lactate level cutoffs. The group with a significantly greater
risk of death was then selected. In contrast, Casserly et al17 re-
ported the independent relationship of hypotension and se-
rum lactate levels with mortality in severe sepsis.
The 6 potential septic shock patient groups analyzed in this
study also provide an explanation for the heterogeneity in sep-
tic shock mortality highlighted by the meta-analysis. Depend-
ing on the group selected, septic shock mortality ranged from
12.8% to 51.2% within the SSC data set and from 7.0% to 64.0%
in the EHR data sets. The KPNC EHR data set corroborated the
consistent trends of higher mortality associated with a higher
serum lactate level, even in a population with a wider range
of illness severity captured by more prevalent measurement
of serum lactate levels.
The key strengths of the present study are in the method-
ology used to arrive at the new definition and clinical criteria
for septic shock, a clinical syndrome with a range of signs,
symptoms, and biochemical abnormalities that are not pathog-
nomonic. Furthermore, the supporting studies (systematic re-
view, Delphi process, and analyses of the SSC and EHR co-
horts) were iterative and concurrent with the consensus
process, a significant step forward from previous definitions.
This study also has several limitations. First, the systematic
review did not formally assess study quality and was restricted
to MEDLINE publications, adult populations, and observational
studies reporting epidemiology. Second, only the Delphi-derived
variables were tested in multiple data sets to generate the pro-
posed septic shock criteria. Other variables, including tissue per-
fusion markers (eg, base deficit, oliguria, acute alteration in men-
tation), blood pressure characteristics (eg, diastolic pressure),
resuscitation end points (eg, central venous saturation, lactate
clearance), and numerous biomarkers reported in the literature,17
could potentially improve on the proposed septic shock criteria
but were not included. However, operationalizing the definition
of septic shock with 3 commonly measured variables should in-
crease both generalizability and clinical utility. Third, the lack of
agoldstandarddiagnosticcriteriaforsepticshock8 precludescom-
parative assessment of these proposed criteria. Fourth, all data
sets had missing data that could potentially introduce a form of
selection bias.120 In the primary data set (SSC database) this is-
sue was addressed by demonstrating that full case analysis is an
appropriate method (see “Derivation of Serum Lactate Cutoff
Value and Missing Data Analysis”). Fifth, serum lactate measure-
ments are not universally available, especially outside of a criti-
cal care setting or in resource-limited environments. Although
feasibility is a quality indicator for a definition,8 identification of
a critically ill patient would generally trigger obtaining a serum
lactate measurement, both to stratify risk and to monitor the re-
sponse to treatment.17 Sixth, although the proposed new defini-
tion and clinical criteria for sepsis are arbitrary, these do have pre-
dictive validity for mortality, alongside face and content validity.8
This study represents one step in an ongoing iterative pro-
cess and provides a resourceful structure and a predictive va-
lidity standard for future investigations in this area. Prospec-
tive validation of the clinical criteria may improve on the
variables and cutoffs proposed herein, and identification and

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New Definition and Criteria for Septic Shock Original Investigation Research

validation of novel markers of organ dysfunction and shock
may replace lactate level.8
Conclusions
Based on a consensus process using results from a system-
atic review, surveys, and cohort studies, septic shock is
defined as a subset of sepsis in which underlying circula-
tory, 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 clini-
cal criteria of hypotension requiring use of vasopressors to
maintain mean blood pressure of 65 mm Hg or greater and
having a serum lactate level greater than 2 mmol/L persist-
ing after adequate fluid resuscitation.

ARTICLE INFORMATION
Author Affiliations: Division of Asthma, Allergy,
and Lung Biology, King’s College London, London,
United Kingdom (Shankar-Hari); Department of
Critical Care Medicine, Guy’s and St Thomas’ NHS
Foundation Trust, London SE17EH, United Kingdom
(Shankar-Hari); The Ohio State University College of
Medicine, Department of Biomedical Informatics,
Center for Biostatistics, Columbus (Phillips);
Rhode Island Hospital, Brown University School of
Medicine, Providence, Rhode Island (Levy); Clinical
Research, Investigation, and Systems Modeling of
Acute Illness Center, Department of Critical Care
and Emergency Medicine, University of Pittsburgh,
Pittsburgh, Pennsylvania (Seymour, Angus);
Division of Research, Kaiser Permanente, Oakland,
California (Liu); 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 York (Deutschman); Department 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 (Deutschman); Feinstein
Institute for Medical Research, Manhasset,
New York (Deutschman); Associate Editor, JAMA
(Angus); Interdepartmental Division of Critical Care
Medicine, University of Toronto, Toronto, Ontario,
Canada (Rubenfeld); Sunnybrook Health Sciences
Centre, Toronto, Ontario, Canada (Rubenfeld);
Bloomsbury Institute of Intensive Care Medicine,
University College London, London,
United Kingdom (Singer).
Author Contributions: Dr Shankar-Hari had full
access to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Shankar-Hari, Levy,
Deutschman, Angus, Rubenfeld, Singer.
Acquisition, analysis, or interpretation of data:
Shankar-Hari, Phillips, Levy, Seymour, Liu, Singer.
Drafting of the manuscript: Shankar-Hari, Phillips,
Levy, Deutschman, Angus, Singer.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Shankar-Hari, Phillips,
Seymour, Liu.
Obtained funding: Levy.
Administrative, technical, or material support:
Shankar-Hari, Levy, Deutschman, Angus.
Study supervision: Seymour, Deutschman, Singer.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Drs
Shankar-Hari and Singer reported receiving support
from the UK NIHR Biomedical Research Centre
schemes. Dr Levy reported receiving a grant from
ImmuneExpress. Dr Seymour reported receiving
personal fees from Beckman Coulter. Dr Liu
reported receiving K grant support from the
National Institutes of Health (K23GM112018). Dr
Deutschman reported holding patents on materials
not related to this work and receiving travel/
accommodations and related expenses for
participation in meetings paid by the Centers for
Disease Control and Prevention, World Federation
of Societies of Intensive and Critical Care,
Pennsylvania Assembly of Critical Care Medicine/PA
Chapter, Society of Critical Care Medicine (SCCM)/
Penn State–Hershey Medical Center, Society of
Critical Care Medicine, Northern Ireland Society of
Critical Care Medicine, International Sepsis Forum,
Department of Anesthesiology, Stanford University,
Acute Dialysis Quality Initiative, and European
Society of Intensive Care Medicine (ESICM). Dr
Singer reported serving on advisory boards for
Bayer and Biotest and that he is a recipient of a UK
NIHR Senior Investigator Fellowship (2009-2017).
No other disclosures were reported.
Members of the Sepsis Definitions Task Force
and Delphi Study: Derek Angus, Djilalli Annane,
Michael Bauer, Rinaldo Bellomo, Gordon Bernard,
Jean-Daniel Chiche, Craig Coopersmith,
Cliff Deutschman (cochair), Richard Hotchkiss,
Mitchell Levy, John Marshall, Greg Martin,
Steve Opal, Gordon Rubenfeld, Christopher
Seymour (co-opted), Manu Shankar-Hari
(co-opted), Mervyn Singer (cochair),
Tom van der Poll, Jean-Louis Vincent.
Funding/Support: The Sepsis Definitions Task
Force received unrestricted funding support from
the European Society of Intensive Care Medicine
and the Society of Critical Care Medicine
(sponsors).
Role of the Funders/Sponsors: The funders/
sponsors had no role in the design and conduct of
the study; collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Disclaimer: Dr Angus, JAMA Associate Editor, had
no role in the evaluation of or decision to publish
this article.
REFERENCES
1. Bone RC, Balk RA, Cerra FB, et al. Definitions for
sepsis and organ failure and guidelines for the use
of innovative therapies in sepsis. Chest. 1992;101
(6):1644-1655.
2. Levy MM, Fink MP, Marshall JC, et al.
2001 SCCM/ESICM/ACCP/ATS/SIS International
Sepsis Definitions Conference. Crit Care Med. 2003;
31(4):1250-1256.
3. Rhee C, Gohil S, Klompas M. Regulatory
mandates for sepsis care—reasons for caution.
N Engl J Med. 2014;370(18):1673-1676.
4. Iwashyna TJ, Angus DC. Declining case fatality
rates for severe sepsis. JAMA. 2014;311(13):1295-1297.
5. Leligdowicz A, Dodek PM, Norena M, et al.
Association between source of infection and
hospital mortality in patients who have septic
shock. Am J Respir Crit Care Med. 2014;189(10):
1204-1213.
6. Levy MM, Dellinger RP, Townsend SR, et al.
The Surviving Sepsis Campaign: results of an
international guideline-based performance
improvement program targeting severe sepsis.
Intensive Care Med. 2010;36(2):222-231.
7. Klein Klouwenberg PM, Ong DS, Bonten MJ,
Cremer OL. Classification of sepsis, severe sepsis
and septic shock: the impact of minor variations in
data capture and definition of SIRS criteria.
Intensive Care Med. 2012;38(5):811-819.
8. Shankar-Hari M, Bertolini G, Brunkhorst FM,
et al. Judging quality of current septic shock
definitions and criteria. Crit Care. 2015;19(1):445.
9. Iwashyna TJ, Govindan S. Did they just prove
that a diagnosis of “septic shock” is meaningless?
Am J Respir Crit Care Med. 2014;189(10):1156-1157.
10. Singer M. The role of mitochondrial dysfunction
in sepsis-induced multi-organ failure. Virulence.
2014;5(1):66-72.
11. Hotchkiss RS, Monneret G, Payen D.
Sepsis-induced immunosuppression. Nat Rev
Immunol. 2013;13(12):862-874.
12. Takasu O, Gaut JP, Watanabe E, et al.
Mechanisms of cardiac and renal dysfunction in
patients dying of sepsis. Am J Respir Crit Care Med.
2013;187(5):509-517.
13. Rudiger A, Dyson A, Felsmann K, et al.
Early functional and transcriptomic changes in the
myocardium predict outcome in a long-term rat
model of sepsis. Clin Sci (Lond). 2013;124(6):391-401.
14. Singer M, Deutschman C, Seymour CW, et al.
The Third International Consensus Definitions for
Sepsis and Septic Shock (Sepsis-3). JAMA.
doi:10.1001/jama.2016.0287.
15. US Department of Health and Human Services
(DHHS). Frequently Asked Questions About Human
Research. DHHS website. http://www.hhs.gov
/ohrp/policy/faq/index.html. May 10, 2010.
Accessed Feburary 1, 2016.
16. Seymour CW, Liu V, Iwashyna TJ et al.
Assessment of clinical criteria for sepsis: for the
Third International Consensus Definitions for Sepsis
and Septic Shock (Sepsis-3). JAMA. doi:10.1001
/jama.2016.0288.
17. Casserly B, Phillips GS, Schorr C, et al.
Lactate measurements in sepsis-induced tissue
hypoperfusion. Crit Care Med. 2015;43(3):567-573.
18. World Health Organisation (WHO). Health
Statistics and Information Systems: Definition of
Region Groupings. WHO website. http://www.who
.int/healthinfo/global_burden_disease/definition
_regions/en/. July 5, 2015.

jama.com (Reprinted) JAMA February 23, 2016 Volume 315, Number 8 785

Copyright 2016 American Medical Association. All rights reserved.

 Research Original Investigation
19. Ortíz G, Dueñas C, Rodríguez F, et al.
Epidemiology of sepsis in Colombian intensive care
units. Biomedica. 2014;34(1):40-47.
20. Ogura H, Gando S, Saitoh D, et al.
Epidemiology of severe sepsis in Japanese
intensive care units. J Infect Chemother. 2014;20
(3):157-162.
21. Liu V, Escobar GJ, Greene JD, et al. Hospital
deaths in patients with sepsis from 2 independent
cohorts. JAMA. 2014;312(1):90-92.
22. Kaukonen KM, Bailey M, Suzuki S, Pilcher D,
Bellomo R. Mortality related to severe sepsis and
septic shock among critically ill patients in Australia
and New Zealand, 2000-2012. JAMA. 2014;311
(13):1308-1316.
23. Gonçalves-Pereira J, Pereira JM, Ribeiro O, et al.
Impact of infection on admission and of the process
of care on mortality of patients admitted to the
intensive care unit: the INFAUCI study. Clin
Microbiol Infect. 2014;20(12):1308-1315.
24. Whittaker SA, Mikkelsen ME, Gaieski DF, Koshy
S, Kean C, Fuchs BD. Severe sepsis cohorts derived
from claims-based strategies appear to be biased
toward a more severely ill patient population. Crit
Care Med. 2013;41(4):945-953.
25. Sakr Y, Elia C, Mascia L, et al. Epidemiology and
outcome of sepsis syndromes in Italian ICUs.
Minerva Anestesiol. 2013;79(9):993-1002.
26. Quenot JP, Binquet C, Kara F, et al.
The epidemiology of septic shock in French
intensive care units. Crit Care. 2013;17(2):R65.
27. Nesseler N, Defontaine A, Launey Y, Morcet J,
Mallédant Y, Seguin P. Long-term mortality and
quality of life after septic shock. Intensive Care Med.
2013;39(5):881-888.
28. Park DW, Chun BC, Kim JM, et al.
Epidemiological and clinical characteristics of
community-acquired severe sepsis and septic
shock. J Korean Med Sci. 2012;27(11):1308-1314.
29. Levy MM, Artigas A, Phillips GS, et al.
Outcomes of the Surviving Sepsis Campaign in
intensive care units in the USA and Europe. Lancet
Infect Dis. 2012;12(12):919-924.
30. Zahar JR, Timsit JF, Garrouste-Orgeas M, et al.
Outcomes in severe sepsis and patients with septic
shock [published correction appears in Crit Care
Med. 2011;39(10):2392]. Crit Care Med. 2011;39(8):
1886-1895.
31. Rodríguez F, Barrera L, De La Rosa G, et al.
The epidemiology of sepsis in Colombia:
a prospective multicenter cohort study in ten
university hospitals. Crit Care Med. 2011;39(7):1675-
1682.
32. Phua J, Koh Y, Du B, et al. Management of
severe sepsis in patients admitted to Asian
intensive care units. BMJ. 2011;342:d3245.
33. Moore LJ, McKinley BA, Turner KL, et al.
The epidemiology of sepsis in general surgery
patients. J Trauma. 2011;70(3):672-680.
34. Kauss IA, Grion CM, Cardoso LT, et al.
The epidemiology of sepsis in a Brazilian teaching
hospital. Braz J Infect Dis. 2010;14(3):264-270.
35. Póvoa PR, Carneiro AH, Ribeiro OS, Pereira AC;
Portuguese Community-Acquired Sepsis Study
Group. Influence of vasopressor agent in septic
shock mortality. Crit Care Med. 2009;37(2):410-416.
786 JAMA February 23, 2016 Volume 315, Number 8 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
36. Peake SL, Bailey M, Bellomo R, et al.
Australasian resuscitation of sepsis evaluation
(ARISE). Resuscitation. 2009;80(7):811-818.
37. Khwannimit B, Bhurayanontachai R.
The epidemiology of, and risk factors for, mortality
from severe sepsis and septic shock in a
tertiary-care university hospital setting. Epidemiol
Infect. 2009;137(9):1333-1341.
38. Angkasekwinai N, Rattanaumpawan P,
Thamlikitkul V. Epidemiology of sepsis in Siriraj
Hospital 2007. J Med Assoc Thai. 2009;92(suppl 2):
S68-S78.
39. Sakr Y, Vincent JL, Schuerholz T, et al.
Early- versus late-onset shock in European
intensive care units. Shock. 2007;28(6):636-643.
40. Karlsson S, Varpula M, Ruokonen E, et al.
Incidence, treatment, and outcome of severe sepsis
in ICU-treated adults in Finland: the Finnsepsis
study. Intensive Care Med. 2007;33(3):435-443.
41. Esteban A, Frutos-Vivar F, Ferguson ND, et al.
Sepsis incidence and outcome: contrasting the
intensive care unit with the hospital ward. Crit Care
Med. 2007;35(5):1284-1289.
42. Engel C, Brunkhorst FM, Bone HG, et al.
Epidemiology of sepsis in Germany. Intensive Care
Med. 2007;33(4):606-618.
43. Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in
European intensive care units: results of the SOAP
study. Crit Care Med. 2006;34(2):344-353.
44. Shapiro N, Howell MD, Bates DW, Angus DC,
Ngo L, Talmor D. The association of sepsis
syndrome and organ dysfunction with mortality in
emergency department patients with suspected
infection. Ann Emerg Med. 2006;48(5):583-590.
45. Gasparović V, Gornik I, Ivanović D.
Sepsis syndrome in Croatian intensive care units:
piloting a national comparative clinical database.
Croat Med J. 2006;47(3):404-409.
46. Degoricija V, Sharma M, Legac A, et al.
Survival analysis of 314 episodes of sepsis in
medical intensive care unit in university hospital.
Croat Med J. 2006;47(3):385-397.
47. Laupland KB, Zygun DA, Doig CJ, et al.
One-year mortality of bloodstream
infection-associated sepsis and septic shock among
patients presenting to a regional critical care
system. Intensive Care Med. 2005;31(2):213-219.
48. Silva E, Pedro MdeA, Sogayar AC, et al.
Brazilian Sepsis Epidemiological Study (BASES
study). Crit Care. 2004;8(4):R251-R260.
49. Laupland KB, Davies HD, Church DL, et al.
Bloodstream infection-associated sepsis and septic
shock in critically ill adults. Infection. 2004;32(2):
59-64.
50. Flaatten H. Epidemiology of sepsis in Norway
in 1999. Crit Care. 2004;8(4):R180-R184.
51. Annane D, Aegerter P, Jars-Guincestre MC,
Guidet B; CUB-Réa Network. Current epidemiology
of septic shock: the CUB-Réa Network. Am J Respir
Crit Care Med. 2003;168(2):165-172.
52. Alberti C, Brun-Buisson C, Burchardi H, et al.
Epidemiology of sepsis and infection in ICU patients
from an international multicentre cohort study.
Intensive Care Med. 2002;28(2):108-121.
53. Schoenberg MH, Weiss M, Radermacher P.
Outcome of patients with sepsis and septic shock
after ICU treatment. Langenbecks Arch Surg. 1998;
383(1):44-48.
New Definition and Criteria for Septic Shock
54. Lundberg JS, Perl TM, Wiblin T, et al.
Septic shock: an analysis of outcomes for patients
with onset on hospital wards versus intensive care
units. Crit Care Med. 1998;26(6):1020-1024.
55. Salvo I, de Cian W, Musicco M, et al. The Italian
SEPSIS study: preliminary results on the incidence
and evolution of SIRS, sepsis, severe sepsis and
septic shock. Intensive Care Med. 1995;21(suppl 2):
S244-S249.
56. Rangel-Frausto MS, Pittet D, Costigan M,
Hwang T, Davis CS, Wenzel RP. The natural history
of the systemic inflammatory response syndrome
(SIRS). JAMA. 1995;273(2):117-123.
57. Pittet D, Rangel-Frausto S, Li N, et al.
Systemic inflammatory response syndrome, sepsis,
severe sepsis and septic shock. Intensive Care Med.
1995;21(4):302-309.
58. McLauchlan GJ, Anderson ID, Grant IS,
Fearon KC. Outcome of patients with abdominal
sepsis treated in an intensive care unit. Br J Surg.
1995;82(4):524-529.
59. Dahmash NS, Chowdhury NH, Fayed DF.
Septic shock in critically ill patients. J Infect. 1993;
26(2):159-170.
60. Whittaker SA, Fuchs BD, Gaieski DF, et al.
Epidemiology and outcomes in patients with severe
sepsis admitted to the hospital wards. J Crit Care.
2015;30(1):78-84.
61. Cross G, Bilgrami I, Eastwood G, et al.
The epidemiology of sepsis during rapid response
team reviews in a teaching hospital. Anaesth
Intensive Care. 2015;43(2):193-198.
62. Vincent JL, Marshall JC, Namendys-Silva SA,
et al; ICON Investigators. Assessment of the
worldwide burden of critical illness. Lancet Respir
Med. 2014;2(5):380-386.
63. Stevenson EK, Rubenstein AR, Radin GT,
Wiener RS, Walkey AJ. Two decades of mortality
trends among patients with severe sepsis. Crit Care
Med. 2014;42(3):625-631.
64. Koupetori M, Retsas T, Antonakos N, et al;
Hellenic Sepsis Study Group. Bloodstream
infections and sepsis in Greece. BMC Infect Dis.
2014;14:272.
65. Bouza C, López-Cuadrado T, Saz-Parkinson Z,
Amate-Blanco JM. Epidemiology and recent trends
of severe sepsis in Spain. BMC Infect Dis. 2014;14:
3863.
66. Storgaard M, Hallas J, Gahrn-Hansen B, et al.
Short- and long-term mortality in patients with
community-acquired severe sepsis and septic
shock. Scand J Infect Dis. 2013;45(8):577-583.
67. Stiermaier T, Herkner H, Tobudic S, et al.
Incidence and long-term outcome of sepsis on
general wards and in an ICU at the General Hospital
of Vienna: an observational cohort study. Wien Klin
Wochenschr. 2013;125(11-12):302-308.
68. Rohde JM, Odden AJ, Bonham C, et al.
The epidemiology of acute organ system
dysfunction from severe sepsis outside of the
intensive care unit. J Hosp Med. 2013;8(5):243-247.
69. Gray A, Ward K, Lees F, et al. The epidemiology
of adults with severe sepsis and septic shock in
Scottish emergency departments. Emerg Med J.
2013;30(5):397-401.
70. Gaieski DF, Edwards JM, Kallan MJ, Carr BG.
Benchmarking the incidence and mortality of
jama.com
New Definition and Criteria for Septic Shock
severe sepsis in the United States. Crit Care Med.
2013;41(5):1167-1174.
71. Czupryna P, Garkowski A, Moniuszko A, et al.
Patients with sepsis in infectious diseases
department in years 1997-2010—epidemiology and
clinical features. Przegl Epidemiol. 2013;67(3):429-
434.
72. Seymour CW, Rea TD, Kahn JM, Walkey AJ,
Yealy DM, Angus DC. Severe sepsis in pre-hospital
emergency care. Am J Respir Crit Care Med. 2012;
186(12):1264-1271.
73. Sancho S, Artero A, Zaragoza R, et al. Impact of
nosocomial polymicrobial bloodstream infections
on the outcome in critically ill patients. Eur J Clin
Microbiol Infect Dis. 2012;31(8):1791-1796.
74. Lagu T, Rothberg MB, Shieh MS, et al.
Hospitalizations, costs, and outcomes of severe
sepsis in the United States 2003 to 2007. Crit Care
Med. 2012;40(3):754-761.
75. Bastani A, Galens S, Rocchini A, et al.
ED identification of patients with severe
sepsis/septic shock decreases mortality in a
community hospital. Am J Emerg Med. 2012;30(8):
1561-1566.
76. Vesteinsdottir E, Karason S, Sigurdsson SE,
et al. Severe sepsis and septic shock: a prospective
population-based study in Icelandic intensive care
units. Acta Anaesthesiol Scand. 2011;55(6):722-731.
77. Rosado V, Pérez L, Guerra H, et al. Outcomes
associated with conventional management of
severe sepsis at Damas Hospital. Bol Asoc Med P R.
2011;103(2):35-38.
78. Davis JS, Cheng AC, McMillan M, Humphrey
AB, Stephens DP, Anstey NM. Sepsis in the tropical
Top End of Australia’s Northern Territory. Med J Aust.
2011;194(10):519-524.
79. Wilhelms SB, Huss FR, Granath G, Sjöberg F.
Assessment of incidence of severe sepsis in Sweden
using different ways of abstracting International
Classification of Diseases codes. Crit Care Med.
2010;38(6):1442-1449.
80. Shen HN, Lu CL, Yang HH. Epidemiologic trend
of severe sepsis in Taiwan from 1997 through 2006.
Chest. 2010;138(2):298-304.
81. Husak L, Marcuzzi A, Herring J, et al. National
analysis of sepsis hospitalizations and factors
contributing to sepsis in-hospital mortality in
Canada. Healthc Q. 2010;13(Spec No):35-41.
82. Bateman BT, Schmidt U, Berman MF,
Bittner EA. Temporal trends in the epidemiology of
severe postoperative sepsis after elective surgery.
Anesthesiology. 2010;112(4):917-925.
83. Vogel TR, Dombrovskiy VY, Lowry SF. Trends in
postoperative sepsis: are we improving outcomes?
Surg Infect (Larchmt). 2009;10(1):71-78.
84. Beale R, Reinhart K, Brunkhorst FM, et al.
Promoting Global Research Excellence in Severe
Sepsis (PROGRESS): lessons from an international
sepsis registry. Infection. 2009;37(3):222-232.
85. Baharoon S, Al-Jahdali H, Al Hashmi J, Memish
ZA, Ahmed QA. Severe sepsis and septic shock at
the Hajj. Travel Med Infect Dis. 2009;7(4):247-252.
86. Rezende E, Silva JM Jr, Isola AM, et al.
Epidemiology of severe sepsis in the emergency
department and difficulties in the initial assistance.
Clinics (Sao Paulo). 2008;63(4):457-464.
87. Blanco J, Muriel-Bombín A, Sagredo V, et al;
Grupo de Estudios y Análisis en Cuidados
jama.com
Copyright 2016 American Medical Association. All rights reserved.
Intensivos. Incidence, organ dysfunction and
mortality in severe sepsis: a Spanish multicentre
study. Crit Care. 2008;12(6):R158.
88. Beovic B, Hladnik Z, Pozenel P, Siuka D;
Slovenian Severe Sepsis Study Group.
Epidemiology of severe sepsis in Slovenian
intensive care units for adults. J Chemother. 2008;
20(1):134-136.
89. Andreu Ballester JC, Ballester F, González
Sánchez A, et al. Epidemiology of sepsis in the
Valencian Community (Spain), 1995-2004. Infect
Control Hosp Epidemiol. 2008;29(7):630-634.
90. Wang HE, Shapiro NI, Angus DC, Yealy DM.
National estimates of severe sepsis in United States
emergency departments. Crit Care Med. 2007;35
(8):1928-1936.
91. Cheng B, Xie G, Yao S, et al. Epidemiology of
severe sepsis in critically ill surgical patients in ten
university hospitals in China. Crit Care Med. 2007;
35(11):2538-2546.
92. Tanriover MD, Guven GS, Sen D, Unal S,
Uzun O. Epidemiology and outcome of sepsis in a
tertiary-care hospital in a developing country.
Epidemiol Infect. 2006;134(2):315-322.
93. Strehlow MC, Emond SD, Shapiro NI, Pelletier
AJ, Camargo CA Jr. National study of emergency
department visits for sepsis, 1992 to 2001. Ann
Emerg Med. 2006;48(3):326-331.
94. Harrison DA, Welch CA, Eddleston JM.
The epidemiology of severe sepsis in England,
Wales and Northern Ireland, 1996 to 2004. Crit Care.
2006;10(2):R42.
95. Záhorec R, Firment J, Straková J, et al.
Epidemiology of severe sepsis in intensive care
units in the Slovak Republic. Infection. 2005;33(3):
122-128.
96. Sundararajan V, Macisaac CM, Presneill JJ,
Cade JF, Visvanathan K. Epidemiology of sepsis in
Victoria, Australia. Crit Care Med. 2005;33(1):71-80.
97. Adrie C, Alberti C, Chaix-Couturier C, et al.
Epidemiology and economic evaluation of severe
sepsis in France. J Crit Care. 2005;20(1):46-58.
98. van Gestel A, Bakker J, Veraart CP,
van Hout BA. Prevalence and incidence of severe
sepsis in Dutch intensive care units. Crit Care.
2004;8(4):R153-R162.
99. Finfer S, Bellomo R, Lipman J, French C, Dobb
G, Myburgh J. Adult-population incidence of severe
sepsis in Australian and New Zealand intensive care
units. Intensive Care Med. 2004;30(4):589-596.
100. Brun-Buisson C, Meshaka P, Pinton P, Vallet B;
EPISEPSIS Study Group. EPISEPSIS: a reappraisal of
the epidemiology and outcome of severe sepsis in
French intensive care units. Intensive Care Med.
2004;30(4):580-588.
101. Padkin A, Goldfrad C, Brady AR, Young D,
Black N, Rowan K. Epidemiology of severe sepsis
occurring in the first 24 hrs in intensive care units in
England, Wales, and Northern Ireland. Crit Care Med.
2003;31(9):2332-2338.
102. Martin GS, Mannino DM, Eaton S, Moss M.
The epidemiology of sepsis in the United States
from 1979 through 2000. N Engl J Med. 2003;348
(16):1546-1554.
103. Angus DC, Linde-Zwirble WT, Lidicker J,
Clermont G, Carcillo J, Pinsky MR. Epidemiology of
(Reprinted) JAMA February 23, 2016 Volume 315, Number 8
Original Investigation Research
severe sepsis in the United States: analysis of
incidence, outcome, and associated costs of care.
Crit Care Med. 2001;29(7):1303-1310.
104. Wichmann MW, Inthorn D, Andress HJ,
Schildberg FW. Incidence and mortality of severe
sepsis in surgical intensive care patients. Intensive
Care Med. 2000;26(2):167-172.
105. Sands KE, Bates DW, Lanken PN, et al.
Epidemiology of sepsis syndrome in 8 academic
medical centers. JAMA. 1997;278(3):234-240.
106. Sasse KC, Nauenberg E, Long A, Anton B,
Tucker HJ, Hu TW. Long-term survival after
intensive care unit admission with sepsis. Crit Care
Med. 1995;23(6):1040-1047.
107. Brun-Buisson C, Doyon F, Carlet J, et al;
French ICU Group for Severe Sepsis. Incidence, risk
factors, and outcome of severe sepsis and septic
shock in adults. JAMA. 1995;274(12):968-974.
108. Mayr FB, Yende S, Angus DC. Epidemiology of
severe sepsis. Virulence. 2014;5(1):4-11.
109. Moss M, Martin GS. A global perspective on
the epidemiology of sepsis. Intensive Care Med.
2004;30(4):527-529.
110. Linde-Zwirble WT, Angus DC. Severe sepsis
epidemiology: sampling, selection, and society. Crit
Care. 2004;8(4):222-226.
111. Dellinger RP, Levy MM, Rhodes A, et al.
Surviving Sepsis Campaign: international guidelines
for management of severe sepsis and septic shock:
2012. Crit Care Med. 2013;41(2):580-637.
112. Bernard GR, Vincent JL, Laterre PF, et al;
Recombinant human protein C Worldwide
Evaluation in Severe Sepsis (PROWESS) Study
Group. Efficacy and safety of recombinant human
activated protein C for severe sepsis. N Engl J Med.
2001;344(10):699-709.
113. Vincent JL, Moreno R, Takala J, et al; Working
Group on Sepsis-Related Problems of the European
Society of Intensive Care Medicine. The SOFA
(Sepsis-related Organ Failure Assessment) score to
describe organ dysfunction/failure. Intensive Care
Med. 1996;22(7):707-710.
114. Li P, Stuart EA, Allison DB. Multiple imputation:
a flexible tool for handling missing data. JAMA.
2015;314(18):1966-1967.
115. Mikkelsen ME, Miltiades AN, Gaieski DF, et al.
Serum lactate is associated with mortality in severe
sepsis independent of organ failure and shock. Crit
Care Med. 2009;37(5):1670-1677.
116. Vincent JL, Ince C, Bakker J. Clinical review:
Circulatory shock—an update: a tribute to Professor
Max Harry Weil. Crit Care. 2012;16(6):239.
117. Nichol AD, Egi M, Pettila V, et al. Relative
hyperlactatemia and hospital mortality in critically
ill patients. Crit Care. 2010;14(1):R25.
118. Levy B, Gibot S, Franck P, Cravoisy A,
Bollaert PE. Relation between muscle Na+K+
ATPase activity and raised lactate concentrations in
septic shock. Lancet. 2005;365(9462):871-875.
119. Garcia-Alvarez M, Marik P, Bellomo R.
Sepsis-associated hyperlactatemia. Crit Care. 2014;
18(5):503.
120. Grimes DA, Schulz KF. Bias and causal
associations in observational research. Lancet.
2002;359(9302):248-252.
787
 Supplementary Online Content

Shankar-Hari M, Phillips GS, Levy ML, et al; Sepsis Definitions Task Force. 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). JAMA.
doi:10.1001/jama.2016.0289.

eMethods 1. Systematic Review, Meta-analysis, and Meta-regression

eMethods 2. Delphi Survey Questionnaires1-3
eMethods 3. The Surviving Sepsis Campaign Database
eTable1. Search Strategy for Systematic Review
eTable 2. Studies Included in the Systematic Review Arranged by Publication Date
eTable 3. Meta-regression Analysis
eTable 3A. Model Without ICU Beds/100,000 Population
eTable 3B. Model With ICU Beds/100,000 Population
eTable 4. Responses to Key Delphi Survey Questions
eTable 5. Potential Septic Shock Cohorts
eTable 6. Cohort Characteristics of Patients in SSC Database
eTable 7. Generalized Estimating Equation (GEE) Population-Averaged Logistic
Regression Model for Hospital Mortality Prediction and Risk Adjustment
eTable 8. Generalized Estimating Equation (GEE) Population-Averaged Logistic
Regression Model for Estimation of Lactate Effect on Hospital Mortality (N = 18,840)
eTable 9. Characteristics of Lactate Cut-off Values for Complete Case Analysis by
Combining Patients in Groups 1 and 2
eTable 10. Descriptive Data on UPMC and KPNC Cohorts2
eFigure1. Probability of Hospital Mortality Derived Using Regression Model for Full
Case and Imputed Analyses
eFigure 2. Sensitivity and Specificity by the Probability of Hospital Mortality
eReferences

This supplementary material was provided by the authors to give readers additional
information about their work.

© 2016 American Medical Association. All rights reserved.

eMethods 1. Systematic Review, Meta-analysis, and Meta-Regression

Background and problem definition

Currently, there are no gold standard diagnostic criteria for septic shock.4 We
hypothesised that the variation in septic shock mortality could be due to the differences in
septic shock definition and operationalization of these definitions, the case-mix, the
setting, and cohort recruitment year. We tested this hypothesis by performing a
systematic review of observational studies in adults reporting septic shock epidemiology,
followed by random effect meta-analysis of mortality by criteria and by using meta-
regression models.

Study population, Exposure and study designs

Clinical illness (exposure) reviewed was sepsis. We included only adult population,
defined as age >19years, using the Medline filter for age. Only observational (non-
interventional) studies were included in this systematic review.4 To avoid variability in
outcomes related to primary exposure, reports of specific pathogens, specific patient
groups and critical illnesses such as burns, and interventional before-after studies were
excluded. Studies that report sepsis case definition and sepsis mortality were included.

Study outcome(s)
The primary outcome was to explore the relationship between criteria and reported
mortality. The secondary outcomes were the different criteria used in septic shock case
definitions reported in the literature.

Search strategy
The search involved the Medline database, between 01/01/1992 and 12/25/2015. The first
author of the paper (MSH) conducted the literature search, with input from co-authors
and members of the Task Force. The search strategy including keywords, exploded fields
and limits are presented in eTable-1. Eligible studies were identified with title and
abstract screening. Eligibility criteria for full text review were reporting of sepsis
epidemiology. All the reference lists of studies eligible for full text review were hand
searched for additional files. In addition, the references lists of systematic review5,
editorials, and review article files identified by this search were also checked and
included for full text assessment.

Data extraction and reporting

Data extracted from the studies include sample size, recruitment period, geographic
region, number of centres, hospital settings, sepsis case definition, septic shock case
definition and acute mortality for sepsis and septic shock when reported. A formal study
quality assessment was not done for this systematic review. Sepsis definitions were coded
either as Consensus6,7 or other [Definitions are summarized in Table-1 in the main
manuscript]. Septic shock criteria were coded using hypotension, vasopressors, and
hypoperfusion variables as occurring either alone or in combinations as defined in
studies. When studies used International Classification of Diseases codes to identify
septic shock patients without description of the underlying variables, they were coded as
such. Similarly, in studies where Consensus Definitions are cited without description of

© 2016 American Medical Association. All rights reserved.

the variables, they were grouped separately. The World Health Organization [WHO]
regions were coded using the country of patient recruitment into six regions: WHO
African Region; WHO Region of the Americas; WHO South-East Asia Region; WHO
European Region; WHO Eastern Mediterranean Region and WHO Western Pacific
Region.8 In studies where patient recruitment occurred in more than one geographic
region, these studies were grouped separately. The mid cohort year was defined as cohort
recruitment year as per calendar year reported. If the study population recruitment
spanned a number of years mid period was used. If studies spanned two calendar years,
the cohort year was coded as the calendar year with more number of months from start of
recruitment. Number of sites contributing to data was coded as single center and multi
center. The intensive care unit [ICU] beds per 100,000 population910-15 was recorded from
previously published data. The ICU beds/100,000 population were Japan =4;Portugal
=4.2; Thailand =6; Finland =6.1;Norway =8; Australia and New Zealand = 8.9;
Scotland=6.1; Spain =9.7; France =11.6; Italy =12.5; Brazil =13; Canada =13.5; Croatia
=14.7; Korea =17; Germany =29.2 and United States of America =20. Per capita ICU bed
data was unavailable for Columbia and Saudi Arabia. International cohorts were coded as
bed unavailable.

Statistics
For meta-analysis and meta-regression, only studies reporting septic shock mortality were
included. A random effects mata-analysis of septic shock mortality, by definitional
groups was completed. In addition, we included septic shock specific data from ANZICS
[provided by Bellomo R et al]; GiViTI [provided by Bertolini G et al]; Cub-REA
[provided by Aegerter P, Guidet B, Annane D for the Cub-REA network] databases.4 In
the meta-analysis, data from the current paper is also included - SSC refers to n=18,840
patients included in the study and SSC-group 1 refers to the group of patients meeting the
new septic shock criteria. In one study, the sepsis definition could not be ascertained16. In
studies where septic shock patients were reported using multiple criteria, this data is
presented with the criteria in parenthesis if separate outcomes could be ascertained. When
two authors had the same surname or when multiple papers from same authors are
presented, the publication year in parenthesis is reported. Details are provided in eTable2
study summaries.
From the total population of sepsis patients reported, the number of septic shock patients
and the corresponding number of deaths were calculated from the studies. This data was
then used to generate the proportion and standard error of proportions. Random effects
meta-analysis was done by grouping definitions into either ‘Consensus’ definitions6,7 or
‘other’ definitions [ICD based derivations1-3,17,18; APACHE codes19, based on previous
clinical trials20,21] and by septic shock criteria as described above. Two meta-regression
models were generated to address statistical heterogeneity in the septic shock mortality,
which involved recoding of variables as described. Statistical heterogeneity was assessed
using I2 and Tau2 statistics. Meta analysis and meta regression were done using ‘Stata
13.1 (StataCorp, College Station, Texas).

© 2016 American Medical Association. All rights reserved.

Results
Ninety-two studies met the criteria for qualitative review as they reported sepsis
outcomes. Forty-four studies met criteria for quantitative review and meta-analysis as
they reported septic shock specific mortality. The disparity within clinical definition and
criteria identified using qualitative review of studies are presented in Table1 (main
manuscript) and in eTable2.

In the original 1992 version, septic shock was explicitly considered as a subset of severe
sepsis and defined as “sepsis-induced hypotension, persisting despite adequate fluid
resuscitation, along with the presence of hypoperfusion abnormalities or organ
dysfunction” 6. Sepsis-induced hypotension was defined “by the presence of a systolic BP
<90 mm Hg or its reduction by ≥40 mmHg from the baseline, in the absence of other
causes of hypotension (e.g. cardiogenic shock).”Septic shock was re-defined by the 2001
International Sepsis Definitions Conference as “a state of acute circulatory failure
characterized by persistent arterial hypotension unexplained by other causes.” For
adults, hypotension was defined as “a systolic arterial pressure (SAP) <90 mm Hg, a
mean arterial pressure (MAP) <60, or a reduction in SAP of >40 mm Hg from baseline,
despite adequate volume resuscitation, in the absence of other causes for hypotension”.
No definition was provided to characterize ‘adequate’ fluid resuscitation. The 2012
Surviving Sepsis Campaign (SSC) 22 guidelines modified this definition so that septic
shock became “sepsis-induced hypotension persisting despite adequate fluid
resuscitation.” The SSC defined sepsis-induced hypotension as either a SAP <90 mmHg,
or MAP <70 mmHg, or a SBP decrease >40 mmHg or <2 standard deviations below
normal for age in the absence of other causes of hypotension. The SSC also separately
defined “sepsis-induced tissue hypoperfusion as infection-induced hypotension, elevated
lactate, or oliguria”.

Observational studies have used different criteria to identify sepsis and septic shock
(highlighted in Table 1 main manuscript) that, in sum, can be classified as the presence of
infection (presumed or confirmed) in conjunction with varying combinations of:
(i) hypotension (SAP <90 mmHg OR MAP <60 or <70 mmHg OR fall in SAP
pressure >40 mmHg from baseline) …
AND/OR
(ii) … that persists despite ‘adequate fluid resuscitation’ (either unspecified OR after
challenges of 20 ml/kg OR 1000 ml)
AND/OR
(iii)abnormal biochemical variables (e.g. lactate >2 or >4 mmol/L or base deficit >5
mmol/l)
AND/OR
(iv) use of inotropes and/or vasopressors [not necessarily above a pre-specified dose]
AND/OR
(v) new onset organ dysfunction (defined variably using various scoring systems such
as APACHE II, APACHE III, or the cardiovascular component of the SOFA
score).

© 2016 American Medical Association. All rights reserved.

Further complexity, often overlooked in these operationalization, include:
(i) Variable end-points of adequacy of fluid resuscitation (rarely defined or reported);
(ii) Variable durations of hypotension and/or vasopressor therapy, and
(iii)The underlying blood pressure of the patient
(iv) Formal assessment of the potential hypotensive effect of other co-morbidities, co-
interventions such as vasodilator use, prior antihypertensive, and myocardial
depression due to sedative agents are seldom reported.

Please refer to main manuscript for results from random effects meta-analyses. eTables
3a and 3b for meta-regression results and eFigures1 and eFigures2 for additional results.

© 2016 American Medical Association. All rights reserved.

eMethods 2. Delphi Survey Questionnaires
Survey of Task Force to inform Septic shock re-definition

Introduction:
The 2001 International Sepsis Definitions Conference defined septic shock as “a state of
acute circulatory failure characterized by persistent arterial hypotension unexplained by
other causes.” Within this definition [in adults], hypotension was defined as “a systolic
arterial pressure (SAP) <90 mm Hg, a mean arterial pressure (MAP) <60, or a
reduction in SAP of >40 mm Hg from baseline, despite adequate volume resuscitation, in
the absence of other causes for hypotension”. The MAP definitions in this document
differ from those used by both the Surviving Sepsis Campaign (<70mmHg) and the
SOFA score (also MAP <70mmHg).
Secondly, the utility and cut-off values for lactate may need to be clarified within a new
septic shock definition. There is an obvious disconnect between the high ED department
lactates yet relatively low mortalities recorded in ARISE and ProCESS, and the much
lower lactates and much higher mortalities seen in recent ICU patient studies (e.g. the
Scandinavian TRISS and Italian ALBIOS studies).
Thirdly, other parameters used to qualify the definition of hypotension are currently
either not considered, stated, or are somewhat variable, namely (a) adequacy of fluid
resuscitation and (b) duration of hypotension.
Fourth, the use of vasopressors, ± an accompanying (variably defined) low blood
pressure definition, are also used by some to define shock.
Aim
To assess current consensus on the following domains:
Domain 1: Components of the septic shock definition
Domain 2: Hypotension, persisting hypotension, adequacy of resuscitation
Domain 3: Use of vasopressors
Domain 4: Use of lactate
Domain 5: Severity of septic shock
Your feedback will be used to inform the variables required for analyses and to support
the new definition.

Domain 1: COMPONENTS OF SEPTIC SHOCK DEFINITION

Q1. In your opinion, which of the following variables in the current septic shock
definition are should be included in the updated definitions?
- Hypotension
- Persistent hypotension
- Adequate fluid resuscitation

© 2016 American Medical Association. All rights reserved.

Q2. In your opinion, which of the following variables could add value by improving
the current septic shock definition (please tick all you would like to see included)?
- Raised lactate
- Base deficit
- Use of vasopressor therapy
- Presence of other organ dysfunction
- Others [please specify]

© 2016 American Medical Association. All rights reserved.

Domain 2: HYPOTENSION; PERSISTING HYPOTENSION; RESUSCITATION
A. HYPOTENSION

Q3. Currently, systolic blood pressure OR mean arterial pressure OR a reduction in

systolic pressure >40mmHg from baseline are used in defining hypotension. In your
opinion, should these three different blood pressure variables be retained within the
new hypotension for septic shock?
ANSWER: Likert scale agreement 5 point: Nether agree nor disagree
Q4 If disagree/strongly disagree to Q3 above, please state which you would KEEP in
the definition
- systolic arterial pressure
- mean arterial pressure
- fall in systolic arterial pressure >40 mmHg
- Other [please specify]
Q5: Currently two different MAP values are used in defining septic shock (Sepsis
Definition = <60, SOFA and SSC <70).
If you selected MAP in Q4 above, should there be one single definition of MAP?
ANSWER: Likert scale agreement 5 point: Nether agree nor disagree
Q6: If agree/strongly agree to Q5, please state which MAP cut-off value you prefer
- <60 mmHg
- <70 mmHg
- Other [please specify]
Q7: If the patient is known to be chronically hypertensive, should a different cut-off
target be used?
ANSWER: Likert scale agreement 5 point: Nether agree nor disagree
Q8: If agree/strongly agree to Q7, please state target

B. PERSISTING HYPOTENSION

Q9: In the current definitions, persisting hypotension is not explicitly defined.

In your opinion, is there a need to define persisting hypotension?
ANSWER: Likert scale agreement 5 point: Agree
Q10: If you agree/strongly agree to Q9, do you feel ‘persisting hypotension’ should
be defined using (tick all that apply)
- Duration of hypotension
- Valid surrogate, such as need for vasopressors
- Other [please specify]
Q11: If you ticked ‘yes’ to ‘duration of hypotension’ in Q10 above, please state how
long this duration should be in the free text box below

If you would to us to consider other variables in defining persisting hypotension, please

highlight in the free text box below.

C. ADEQUACY OF RESUSCITATION

© 2016 American Medical Association. All rights reserved.

Q12: In your opinion, is there a need to define ‘adequacy of resuscitation’?
ANSWER: Likert scale agreement 5 point: Agree
Q13. If you agree/strongly agree to Q12, should ‘adequate resuscitation’ be defined
using (please tick all that apply):
- Fluid boluses to a physiological endpoint
- Biochemical end-points, e.g. lactate
- Ongoing need for vasopressors after predefined fluid bolus e.g. 1L
- Other [Please specify]
Q14: If you ticked ‘yes’ to ‘fluid boluses to a physiological endpoint’ in Q13 above,
please state in the text box below which endpoints you would use

Q15: If you ticked ‘yes’ to ‘Ongoing need for vasopressors after predefined fluid
bolus’ in Q13 above, please state what amount of fluid you would give (ml, ml/kg)

If you would to us to consider other variables in defining adequacy of resuscitation,

please highlight in the free text section.

Domain 3: USE OF VASOPRESSORS

Currently, the need for vasopressors is used as a surrogate for persisting hypotension,
although it is not explicitly stated in the definitions. Furthermore, organ dysfunction
scores used to define septic shock provide a construct including dose of the drug – e.g.
SOFA score.
(n.b. use of vasopressors to describe severity will be discussed in Domain 5)

Q16. In your opinion, should the need for vasopressor therapy be used as a variable
to define septic shock?
ANSWER: Likert scale agreement 5 point: Agree
Q17. If you agree/strongly agree to Q16, should a minimum dose of vasopressor be
stated?
ANSWER: Likert scale agreement 5 point: Disagree
Q18: If you ticked ‘agree/strongly agree’ to ‘minimum dose’ in Q17 above, please
state what dose level you would use

If you would to us to consider other aspects of vasopressor use, please highlight in the
free text section.

Domain 4: USE OF LACTATE

Q19. Should lactate be used as a biochemical definition of septic shock, even in the
absence of hypotension?
ANSWER: Likert scale agreement 5 point: Agree
Q20. If lactate is included as part of the definition, what cut-off would you like to
use to identify septic shock?
- >4 mmol/L
- >3 mmol/L
- >2 mmol/L
- Generate a new cut-off using database of ED/general ward
septic shock patients with acute hospital mortality as outcome

© 2016 American Medical Association. All rights reserved.

- Other cut offs or outcomes [please specify]
If you would to us to consider other aspects of lactate use, please highlight in the free text
section (n.b. use of lactate to describe severity will be discussed in Domain 5)

Domain 5: SEVERITY OF SEPTIC SHOCK ASSESSMENT

Q21. In your opinion, is there a need for a severity grading of septic shock?
ANSWER: Likert scale agreement 5 point: Nether agree nor disagree
Q22. If you agree/strongly agree to Q21, what variables would you like to see within
the definition of shock severity (please tick all you feel should be included)?
Vasopressor dose
Lactate level
Other [Please specify]
Q23. If you agree/strongly agree to Q21, how many points should be there on the
severity scale (assuming 0 = no septic shock)
1
2
3
4
Q24: If you answered ‘yes’ to vasopressor dose in Q22, how should dose of
vasopressor be defined?
- Spot dose of vasopressor
- Average dose of vasopressor over a defined period
o if ‘yes’ please specify how long (hours)
- Peak dose of vasopressor over a defined period
- Other [Please specify]
Q25: If you answered ‘yes’ to lactate in Q22, how should the lactate level be used as
a variable in defining the severity of septic shock?
- Spot level of lactate (when BP ± vasopressor dose recorded)
- Average level of lactate over a defined period
o if ‘yes’ please specify how long (hours)
- Peak level of lactate over a defined period
- Other way of looking at lactate [Please specify]
Q26. Should a composite score be used, taking into account both the BP target and
the vasopressor dose being given? (thus, if aiming for a MAP of 75 mmHg in a
particular patient, much more vasopressor would be needed compared to a target
MAP of 60 mmHg)
ANSWER: Likert scale agreement 5 point: Nether agree nor disagree
If you would to us to consider other variables in defining septic shock, please highlight in
the free text section below.

SURVEY 2
Conclusions from the first Septic Shock definition survey:
• 88% of taskforce (TF) members wanted persistent hypotension, requirement for
vasopressors and raised lactate to be included in the updated definition.

© 2016 American Medical Association. All rights reserved.

• Most (71%) wanted a definition for ‘persistent’ hypotension; all but one of these
voters suggested need for vasopressor therapy as a surrogate to define persistent
hypotension.
Q1. The TF voted that the new septic shock definition should use high lactate and/or
persistent hypotension. However, these could either stand-alone or be used in
combination. Which of the following choices do you prefer?
(Please tick one box only)
Persistent hypotension (as defined) AND raised lactate
Persistent hypotension (as defined) OR raised lactate
Other
Please make any comments in the free text box below

Q2. “The TF members could not agree on endpoint[s] that define adequate
resuscitation in patients with septic shock. As resuscitation is an iterative process this
should be separated from the concept of persistent hypotension.”
Would you agree with this statement regarding adequacy of resuscitation?
ANSWER: Likert scale agreement 5 point: Agree
Please make any comments in the free text box below

Q3. No consensus was achieved regarding an endpoint to mark adequacy of fluid

resuscitation. Would you agree with the following definition for ‘persistent
hypotension’ that offers a compromise solution?
“Persistent hypotension is defined as hypotension persisting despite fluid
resuscitation of at least 20 ml/kg that requires vasopressor therapy for at least 60
minutes to keep MAP >60 mmHg.”
ANSWER: Likert scale agreement 3 point: Agree
Please comment in the free text box below.
If you would prefer an alterative, please state whether you would like:
• a different duration of hypotension
• and/or a different amount of fluid (including zero)
• and/or a different wording
• and/or another definition

Q4. Approximately half the TF voted for including lactate in the definition, wanted
a cut-off value to be determined by mining ‘big data’ to determine
sensitivity/specificity of acute hospital mortality? Are you happy with this proposal?
ANSWER: Likert scale agreement 3 point: Agree
Please comment in the free text box below.

© 2016 American Medical Association. All rights reserved.

eMethods 3. The Surviving Sepsis Campaign Database

Sites and patient selection

The SSC registry is an international multi-center database drawn from 218 hospitals. The
analysis set was constructed from subjects entered into the SSC database between
January 2005 and March 2010. The process of participation in the SSC is described
elsewhere23. Eligible subjects were those having a suspected site of infection, two or
more systemic inflammatory response syndrome (SIRS) criteria, and one or more organ
dysfunction criteria7. Clinical characteristics and time of presentation with severe sepsis
were collected for longitudinal analysis. Time of presentation was determined through
chart review for the diagnosis of severe sepsis and defined in instructions to data
collectors on the SSC website and in educational materials. For patients from the
Emergency Department (ED), the time of presentation was defined as the time of triage.

Data collection
Data were entered into the SSC database locally at individual hospitals into pre-
established, non-modifiable fields. Data stripped of private health information were
submitted every 30 days to the secure master server at the Society of Critical Care
Medicine (Mount Prospect, Ill.).

Institutional Review Board (IRB) approval

The global SSC improvement initiative was approved by the Cooper University Hospital
Institutional Review Board (Camden, NJ) as meeting criteria for exempt status. The US
Department of Health and Human Services’ Office for Human Research Protections
reiterated that quality improvement activities such as SSC often qualify for IRB
exemption and do not require individual informed consent.

Analysis set construction

Inclusion in the SSC database was limited to sites with at least 20 subjects and at least 3
months of subject enrollment. The updated working definition of septic shock variables
in this analysis included all patients whose lactate > 2 mmol/L or MAP < 65 mm Hg after
fluids, or received vasopressors. The severe sepsis group included those whose lactate ≤
2 mmol/L and whose MAP ≥ 65 mm Hg either before or after fluids, and did not receive
vasopressors.

Organ dysfunction assessment

Organ dysfunction is a Boolean term in the SSC database. Cardiovascular dysfunction is
defined as systolic blood pressure <90 mmHg OR mean arterial pressure <65 mmHg OR
systolic blood pressure decrease >40 mmHg from baseline values. Respiratory
dysfunction is defined as bilateral pulmonary infiltrates with new [increased] inspired
oxygen requirement to maintain arterial saturations >90% OR Bilateral pulmonary
infiltrates with a PaO2/FiO2 ratio <300mmHg. Renal dysfunction is defined as creatinine
>2 mg/dL [178.8 mol/L] OR urine output <0.5 ml/kg/hr for >2 hours. Hepatic
dysfunction is defined as bilirubin >2 mg/dL [34.2 mol/L]. Hematological dysfunction
is defined as platelet count <100,000 OR Coagulopathy [INR>1.5 or APTTR>60

© 2016 American Medical Association. All rights reserved.

seconds]. Acutely altered metial status is defined as neurological dysfunction. Serum
lactate and glucose are recorded as continuous variable in the database.

Covariates in the GEE model

A GEE population-averaged logistic regression model included the following covariates:
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
(>101 °F), hypothermia (<96.8 °F), chills with rigor, tachypnea (>20 breaths/min),
leukopenia (<4000 cells/µL), hyperglycemia (plasma glucose >120 mg/dL), platelet
count <100,000, and coagulopathy]

© 2016 American Medical Association. All rights reserved.

eTable 1. Search Strategy for Systematic Review
“Search (((((sepsis[Title/Abstract]) OR sepsis[MeSH Major Topic])) OR ((septic
shock[MeSH Major Topic]) OR septic shock[Title/Abstract]))) AND
((epidemiology[Title/Abstract]) OR epidemiology[MeSH Major Topic]) Filters:
Publication date from 1992/01/01 to 2015/12/25; Humans; English; Adult: 19+ years”
“Search (((sepsis[Title/Abstract]) OR sepsis[MeSH Major Topic])) OR ((septic
shock[MeSH Major Topic]) OR septic shock[Title/Abstract])”
“Search (septic shock[MeSH Major Topic]) OR septic shock[Title/Abstract]”
“Search (sepsis[Title/Abstract]) OR sepsis[MeSH Major Topic]”
“Search (epidemiology[Title/Abstract]) OR epidemiology[MeSH Major Topic]”
“Search septic shock[Title/Abstract]”
“Search septic shock[MeSH Major Topic]”
“Search sepsis[MeSH Major Topic]”
“Search sepsis[Title/Abstract]”
“Search epidemiology[MeSH Major Topic]”
“Search epidemiology[Title/Abstract]”

© 2016 American Medical Association. All rights reserved.

eTable 2. Studies Included in the Systematic Review Arranged by Publication Date
First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Whittaker 1853 2005 and 2009 USA Single ICU and Bone6 and Levy7 SSC based 5.2% in non-
SA24 (2015) center non-ICU ICU and
22.5% in
ICU patients
with severe
sepsis
Cross G25 159 1st April to Australia Single Hospital Bone6 Not described 25.0% sepsis
(2015) with 30th June center cases
sepsis 2011
Vincent JL26 10,069 2012 International Multicent ICU Study specific CVS SOFA score 35·3%
(2014) [84 er [730] >2 (33·5–37·1)
countries] for sepsis

Stevenson Variabl 1993 to 2009 USA Multicent Hospital ICD-9 Severe sepsis ICD-9 septic shock Trends in
EK27 (2014) e er [NIS including case identification code 785.52 change
sample data] ICU Angus algorithm reported.
sizes patients and Martin
algorithm
Ortiz G28 826 2007 – 2008 Colombia Multi ICU CDC definitions for CVS SOFA score 45.1%
(2014) center infection and Bone6 >2
(n=10)
Ogura H29 14,417 06/2010 to Japan Multicent ICU Bone6 and Levy7 CVS SOFA score 41.5%
(2014) 05/2011 er [15] >2

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Liu V30 55,008 2012 USA Multicent Hospital ICD-9 vs. Angus ICD-9 septic shock 23.3%
(2014) to [Northern er including Algorithm code 785.52
80,678 California] [NIS ICU +
[KPNC] data] patients Hypotension and/or
& Lactate>4mmol/L
280,663
to
717,718
[NIS]

Leligdowicz 7,974 1989 to 2008 Canada, the Multicent ICU Bone6 No description 52.0%
A31 (2014) United er [N=29]
States, and
Saudi Arabia
Koupetori 754 2006-2013 Greece Multicent ICU and Levy7 No description 30.5%
M32 (2014) er (n=46) non-ICU severe sepsis
Goncalves- 1652 May 2009 to Portugal Multi ICU Levy7 No description 48.8%
Pereira J33 with December center (Bone Definitions
(2014) sepsis 2010 (n=14) cited)
Kaukonen 101,064 2000 to 2012 Australia Multicent ICU Bone6 CVS failure: lowest 40.3% in
KM19 (2014) and New er MAP <65 mmHg or 2000
Zealand [N=171] lowest systolic 22.0% in
pressure <90 mmHg 2012
APACHE III codes
for septic shock

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Bouza C34 240,939 2006 to 2011 Spain Multicent Hospital ICD-9 codes CVS: 785.5 with all 43.0% for
(2014) er using sub codes severe sepsis
National Shock without
Minimum trauma: 785.1,
Basic Data 785.52, 785.9
Set Hypotension: 458
with sub codes
(458.0, 458.8 458.9)
Nonspecific low
blood pressure
reading: 796.3
Storgaard 212 with Since 1994 Denmark National Hospital CDC definitions for CVS: Systolic blood 33.0%
M35 (2013) severe registries admission infection and Bone6 pressure <90mmHg (25.%-41%)
sepsis/sh s or fall >40mmHg for severe
ock sepsis
Whittaker 1,735 2005 to 2009 University of Single ICU ICD-9 vs. Angus ICD-9 septic shock 36.4%
SA36 (2013) Pennsylvania center admission Algorithm (785.52)
s from Shock was defined
Emergenc as systolic blood
y pressure less than 90
Departme mm Hg after fluid
nt resuscitation (1500
mL) or use of
vasoactive agents.

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Stiermaier 139 with 2007 General Single Hospital ICD-10 and Bone6 in No description 48.8 [severe
T37 (2013) sepsis Hospital of center admission ICU admissions sepsis]
Vienna s

Sakr Y38 446 with 2006 Piedmont Multi- ICU Bone6 No description 58.6 (50.5-
(2013) sepsis region, Italy center 66.3)
[N=24]
Rohde JM39 3,146 2009 to 2010 University of Single Hospital ICD-9 Levy et al cited for Not
(2013) with Michigan center admission organ dysfunction extractable
severe s definitions
sepsis

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Quenot JP20 1,495 2009 to 2011 North-East Multi ICU Only Septic shock Infection requiring 48.7%
(2013) with France center population included initiation of
septic [n=14] as described vasopressors despite
shock adequate vascular
filling, with at least
one of the following
hypoperfusion
criteria: (1)
metabolic acidosis
(base excess ≥5
mEq/L, alkaline
reserve <18 mEq/L
or lactate ≥2.5
mmol/L); (2)
oliguria/ renal
insufficiency (<0.5
mL/kg/h for 3 h or
elevation >50% of
baseline creatinine);
or (3) hepatic
dysfunction (AST or
ALT >500 IU/L or
bilirubin >34
mol/L).

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Nesseler N40 96 2008 to 2010 France Single ICU Bone6 Bone et al cited for 32.0%
(2013) center septic shock

Gray A41 626 2009 Scotland Multi Emergenc SSC No description 28.3%
(2013) center y [severe
[N=20] Departme sepsis +
nt septic shock]
Gaieski DF17 Variable 2004 to 2009 USA Multicent Hospital ICD-9 vs. Angus vs. ICD-9 septic shock 14.7% to
(2013) er admission Martin vs. Wang vs. (785.52) 29.9% for
(NIS s Dombrovskiy severe sepsis
data) Algorithms
Czupryna P42 107 1997 to 2010 Poland Single Hospital Levy7 SBP<90; MAP<60 30.9% for
(2013) center admission or Fall in SBP>40 severe sepsis
s
Seymour 13,249 2000 to 2009 USA (Pre- Multi Emergenc ICD-9 [Angus No description 19.6% for
CW43 (2012) severe hospital center y Medical Algorithm] severe sepsis
sepsis Kings Services
County) encounters

Sancho S44 371 10/1998 to Valencia, Single Hospital Bone6 + Nosocomial No description 59.3% ICU
(2012) 02/2010 Spain center admission bacteremia mortality
s severe
sepsis/shock

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Klein 1,072 01/2009 to Netherlands Single ICU Multiple algorithms Refractory 45%
Klouwenberg 10/2010 center tested hypotension 62%
PMC45 Refractory
(2012) hypotension with
other organ system
failure

Park DW46 1,192 2005 to 2009 Korea Multi ICU Bone6 Either SBP ≤ 90 30.8%
(2012) center mmHg or MAP ≤ 70
[n=12] mmHg for at least 1
hour after adequate
fluid resuscitation or
use of vasopressors
to maintain systolic
blood pressure > 90
mmHg or mean
arterial pressure >
70 mmHg.
Levy MM47 25375 2005-2010 International Multi ICU; non- Levy7 Surviving sepsis As
(2012) center ICU; campaign previously
Emergenc reported
y
departmen
t

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First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Lagu T48 4,799,56 2003 to 2007 USA Multi Hospital ICD-9-CM CVS: 785.5 with all Not
(2012) 5 sepsis center sub codes extractable
cases (NIS Shock without
database) trauma: 785.1,
785.52, 785.9
Hypotension: 458
with sub codes
(458.0, 458.8 458.9)
Nonspecific low
blood pressure
reading: 796.3
Bastani A49 267 2007 to 2010 USA Single ICU SSC No description but 33.3% for
(2012) center Early Goal Directed severe
therapy referenced sepsis/shock

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Zahar JR50 3,588 1996 to 2009 France Multi ICU Bone6 Sepsis-induced 46.0%
(2011) center hypotension
[N=12] persisting despite
adequate fluid
resuscitation
together with organ
dysfunction OR
Patients receiving
inotropic or
vasoactive agents
who had organ
dysfunction but who
were no longer
hypotensive

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Vesteinsdotti 115 2008 to 2009 Iceland Multi ICU Bone6 Sepsis-induced 29.6%
r E51 (2011) severe center hypotension severe
sepsis/ [N=20] persisting despite sepsis/septic
shock adequate fluid shock
resuscitation
together with organ
dysfunction;
Patients receiving
inotropic or
vasoactive agents to
maintain MAP>65
or SBP>90mmHg
Rosado V52 30 2007 to 2009 Peurto Rico Single ICU ICD-9 Not described 66.0%
(2011) center severe
sepsis/shock
Rodriguez 2,681 2007 to 2008 Columbia Multi Hospital CDC definitions Sepsis-induced 45.6%
F53 (2011) center cohort hypotension
[N=10] persisting despite
adequate fluid
resuscitation + need
for vasoactive
agents to maintain
MAP>65 or
SBP>90mmHg

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Phua J54 1285 2009 Asian Multi ICU Levy7 SSC Hypotension or on H+V=77.1%
(2011) countries center vasopressors [H/V] LCT=38.3%
[N=150] Hyperlactatemia
>4mmol/L [LCT]
Moore LJ55 231 2007-2009 Houston, Single ICU Bone6 SIRS + infection + 36.0%
(2011) Texas, USA center [Surgical] acute cardiac
dysfunction that is
defined by the
following (must
meet both criteria):
(1) intravenous fluid
challenge >20
mL/kg/ideal body
weight of isotonic
crystalloid infusion
or central venous
pressure >8 mm Hg
or PCWP >12 mm
Hg and (2)
requirement of
vasopressors to
increase MAP >65
mm Hg.

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Davis JS56 1191 2007 to 2008 Northern Single Hospital PROWESS Not described 17.1%
(2011) territory of center admission Definition severe
Australia s sepsis/septic
shock
Wilhems 37,990 01/1987 to Sweden Multi Hospital ICD-9 and ICD-10 Angus algorithm, 22.1 to
SB18 (2010) 12/2005 center admission codes mirroring Bone Martin algorithm 29.2% for
Swedish s includes Definition and Flatten H sepsis
Hospital ICU description of ICD depending
Discharge based data on algorithm
Register extraction
Septic shock is not
described
Shen HN57 5,258 1997 to 2006 Taiwan Multi Hospital ICD-9 + Angus No description 30.8%
(2010) center admission Algorithm severe
National s sepsis/shock
Health
Insurance
Program
Levy MM23 15,022 2005 to 2008 International Multi ICU; Bone6 Lactate>4 [LCT] LCT=29.9%
(2010) center Emergenc SSC Vasopressors [V] V=36.7%
[N=165] y Lactate>4 + LCT/V=46.1
Departme vasopressors %
nt; Ward [LCT/V] Overall
38.4%

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Kauss IA58 1,179 2004 to 2005 Brazil Single ICU Bone6 Sepsis + arterial 72.7% [68.1
(2010) center hypotension needing – 76.9%]
vasopressors,
despite initial
volume
resuscitation.
Husak L59 30,587 04/2004 to Canada Multi Hospital ICD-10 No description 45.2%
(2010) 03/2009 [excluding center and severe sepsis
Quebec] (discharg Emergenc
e abstract y
database) Departme
nt
Bateman 2,039,77 1997 to 2006 USA Multicent Post ICD-9 ICD-9 septic shock 44.4%
BT60 (2010) 6 er operative (785.52) in1997 to
(NIS sepsis 34.0% in
data) Post 2006 for
operative severe sepsis
sepsis
Vogel TR61 N=1,276 1990 to 2006 New Jersey, Multi Post ICD-9 and surgical CVS failure 45.7%
(2009) ,451 USA center operative diagnosis related (785.50, 785.51, severe sepsis
(HCUP sepsis group 785.59, 458.0,
data) 458.8, 458.9, 796.3,
427.5)
Septic shock NOT
explicitly stated

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Povoa PR62 897 2004 to 2005 Portugal Multi ICU Bone6 State of acute 44.0% [ICU
(2009) center circulatory failure mortality]
[n=17] characterized by
persistent arterial
hypotension (SBP
<90mmHg,
MAP<60mmHg,or a
reduction in SBP of
>40 mm Hg from
baseline) despite
adequate fluid
resuscitation

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Peake SL63 324 2006 to 2007 Australia Multi Emergenc Levy7 EITHER: Blood BP=23.0%
(2009) and New center y pressure (BP) criteria LCT=26.9%
Zealand [n=32] Departme (one or more of the Overall:
nt following): (i) SBP 23.1%
<90 mmHg OR >40
mmHg fall below
premorbid SBP OR
MAP<65 mmHg, after
≥500 ml intravenous
fluid challenge over
30–60min; (ii)
requirement for
vasoactive infusion for
≥30 min to maintain
BP OR: Metabolic
acidosis criteria (one
or more of the
following): arterial or
venous: (i) blood
lactate >4.0 mmol/L
[LCT]; (ii) anion gap
>20 mEq/L; (iii)
serum bicarbonate
<16.0 mmol/L.

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Khwannimit 390 2004 to 2006 Thailand Single ICU Bone6 SBP<90 mmHg or 54.1%
B64 (2009) center MAP<65 mmHg]
for at least 1 h
despite adequate
fluid resuscitation
(CVP>8 mmHg or
PAOP >12 mmHg)
or use of a
vasopressor
(dopamine >5
mg/kg per min or
norepinephrine,
epinephrine any
dose) for >1 h in an
attempt to maintain
SBP >90 mmHg or
MAP>65mmHg
Beale R65 12,570 2002 to 2005 International Multi ICU Bone6 CVS dysfunction is 49.6%
(2009) adults (13 center defined as severe sepsis
countries) [n=276) hypotension in the
absence of causes
other than sepsis.
Baharoon S66 165 2004 Makkah, Multi ICU Levy7 No description 54.7% severe
(2009) Saudi Arabia center sepsis/septic
(n=2) shock

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Angkasekwi 3541 2007 Thailand Single Hospital Bone6 No data available 52.6%
nai N16 center admission
(2009) s

Rezende E67 5,332 2004 Brazil Single Emergenc Bone6 No description 64.0%
(2008) center y CVS dysfunction severe sepsis
Departme defined as
nt hypotension or need
for vasoactive drugs

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Blanco J68 4,317 2002 Spain Multi ICU PROWESS Criteria Shock: SBP ≤90 54.3%
(2008) center mmHg or MAP ≤70 severe sepsis
(N=14) mmHg, during at least + shock
1 hour despite
adequate resuscitation
with fluids or adequate
intravascular volume;
or use of vasopressors
(dopamine ≥5
µg/Kg/minute;
noradrenalin or
adrenalin at any dose;
dobutamine was not
taken into account).
Unexplained
metabolic acidosis (pH
<7.30 or base excess
≤-5 mmol/l) associated
with an arterial lactate
concentration ≥ 2
mmol/l with no other
apparent cause.
Beovic B69 701 2004 Slovenia Multi ICU Bone6 No description 45.1%
(2008) center severe sepsis
[n=28]

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Andreu 33,767 1995 to 2004 Valencia, Multi Hospital ICD-9 CVS (785.5 with all 42.5%
BallesterJC70 Spain center admission sub codes, 427.5, severe sepsis
(2008) [n=26] s 458.0, 458.8, 458.9, and shock
and 796.3)
Septic shock is not
described
Wang HE3 331.5 2001 to 2004 USA Multi National ICD-9 and Levy CVS (785.5 with Not
(2007) million center Hospital sub codes, 458.0, extractable
ED visits Ambulator 458.8, 458.9)
y Medical
Care
Survey
Sakr Y71 3,147 2002 Europe (24 Multi ICU Bone6 Referred to Bone 54.1%
(2007) countries) center Criteria
(N=198)
Karlsson S72 4,500 11/2004 to Finland Multi ICU Bone6 Not described 24.7%
(2007) 02/2005 center [refractive
(N=24) shock]

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Esteban A73 15,852 03/2003 to Madrid, Multi Ward and Bone6 Sepsis and at least 45.7%
(2007) 06/2003 Spain center ICU one of the following
[N=3] criteria: SBP <90
mm Hg despite
adequate fluid
administration, need
for inotropes or
vasopressors
(excluding
dopamine >5
g/kg/min), or SBP
decrease of >40 mm
Hg from usual
baseline level.
Engel C74 3,877 1 day in 2003 Germany Multi ICU Bone6 Sepsis or severe 62.4% [55.2
(2007) center sepsis with – 69.2]
[n=454] persistent
hypotension despite
adequate fluid
resuscitation or the
necessity of
vasopressor
administration to
maintain a MAP>=
70 mmHg

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Cheng B75 3,6665 12/2004 to China Multi Surgical Bone6 and Levy7 No description 48.7%
(2007) 11/2005 center ICUs severe sepsis
[n=10]

Vincent JL76 3,147 2 weeks in Europe (24 Multi ICU Bone6 No description 54.1% ICU
(2006) 05/2002 countries) center mortality
(N=198)
Tanriover 69 01/2002 to Turkey Single Hospital Diagnostic code of No description Not
MD77 (2006) 06/2003 center charts sepsis/septicaemia/ba extractable
cteremia
Strehlow MC 2.8 1992 to 2001 USA Multi National ICD-9 codes Martin ICD-9 codes for Not
78
(2006) million center Hospital Algorithm organ dysfunction extractable
sepsis Ambulator & Bone6 Definitions
y Medical
Care
Survey
Shapiro N79 3,102 02/2000 to Boston, USA Single Emergenc Bone Suspected infection 27.8%
(2006) 02/2001 center y and hypotension
Departme (SBP<90) which
nt persisted after a
crystalloid fluid
challenge of 20-30
cc/kg.
Harrison 92,672 12/1995 to United Multi ICU PROWESS criteria No description. CVS 48.3 to 44.7
DA80 (2006) 01/2005 Kingdom center dysfunction is coded severe
ICNARC as severe sepsis sepsis/shock
database

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Gasparovic 456 11/2004 to Croatia Multi ICU Bone6 Hypotension of 34.1%

V81 (2006) sepsis 10/2005 center <100 mm Hg
[n=24] despite volume
replacement
Degoricija 314 01/2000 to Croatia Single ICU Bone6 and Levy7 Not described 72.1% and
V82 (2006) 12/2005 center 74.4% if
MODS
Zahorec R83 124 07/2002 to Slovakia Multi ICU Bone6 Organ dysfunction 51.2%
(2005) sepsis 12/2002 center defined as per severe
[n=12] PROWESS sepsis/shock

Sundararajan 33,741 07/1999 to Victoria, Multi Hospital ICD-10 ICD-10 codes based 29.5%
V84 (2005) 06/2003 Australia center admission Bone6 on Martin severe sepsis
Populatio s Algorithm
n 785.59
database
Laupland 251 07/1999 to Calgary, Multi ICU SIRS + bacteremia BSI-associated 51.0% [28
KB85 (2005) 03/2002 Canada center sepsis patients that day
Populatio required a mortality]
n databse vasopressor infusion
at any dose

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Adrie C86 1698 04/1997 to France Multi ICU Bone6 CVS failure = need 39% severe
(2005) 12/2000 center for vasopressors sepsis/shock
[n=6] and/or inotropic
drugs, and/or SBP
of <90 mm Hg, and/
or drop in SBP >40
mm Hg from
baseline

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Van Gestel 151 One day Netherlands Multi ICU Bone6 Septic shock = Not
A87 (2004) [11/12/2001] center Sepsis + CVS organ extractable
[N=47] failure + metabolic
dysfunction during
the first 24 hours of
ICU admission.
CVS failure: SBP ≤
90 mmHg or MAP≤
70 mmHg for 1
hour, despite
adequate fluid
resuscitation, or the
need to administer
vasopressors in
order to maintain
SBP≥ 90 mmHg or
MAP≥ 70 mmHg.
Metabolic
dysfunction:
metabolic acidosis
(pH ≤ 7.30 or base
deficit ≥ 5.0 mmol/l)
in association with a
plasma lactate level
> 3.0 mmol/l

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Silva E88 1383 05/2001 to Brazil Multi ICU Bone6 Septic shock was 52.2%
(2004) 01/2002 center defined as severe
[n=5] sepsis and
vasoactive drug
requirement (SOFA
3–4).
Laupland 1,981 05/1999 to Calgary, Multi ICU SIRS + bacteremia BSI-associated 49.0%
KB89 (2004) 04/2000 Canada center septic shock was the
Populatio subset of BSI-
n associated sepsis
database patients that
presented with
hypotension
[MAP<60mmHg].
Flaatten H90 6665 1999 Norway Multi Hospital ICD-10 A41.9 – septic 29.3%
(2004) center data shock
Norwegia I50.9 – Unspecified
n patient heart failure
registry

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Finfer S91 5878 05/1999 to Australia/ Multi ICU Bone6 PROWESS SBP<90 mmHg or a 32.4%
(2004) 07/1999 New center MAP<70 mmHg for severe
Zealand [N=21] at least 1 h despite sepsis/ shock
adequate fluid
resuscitation,
adequate
intravascular
volume status,
and/or need for
vasopressors to
maintain systolic
blood pressure >90
mmHg or MAP >70
mmHg for >1 h
Brun- 3738 2 weeks in France Multi ICU Bone6 No description 35.0%
Buisson 92 11/2001 center severe
(2004) [n=206] sepsis/shock
Padkin A93 56,673 1995 to 2000 England/Wal Multi ICU PROWESS trial No description 47.3%
(2003) es and center severe
Northern [n=91] sepsis/shock
Ireland

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Martin GS2 10,319,4 1979 to 2000 USA Multi Hospital ICD-9 ICD-9 CVS codes 70.0%
(2003) 18 sepsis center admission 458.0 - severe
Hospital s Hypotension, sepsis/shock
discharge postural; 785.5
data Shock; 785.51
cardiogenic shock
and 785.59 septic;
796.3 Transient
hypotension
Annane D94 100,554 1993 to 2000 France Multi ICU Bone6 Not described 60.1%
(2003) center
[n=22]

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Alberti C95 14,364 05/1997 to International Multi ICU Bone6 Sepsis-induced 47.2% to
(2002) 05/1998 – Europe, center hypotension 63.8%
Canada and (n=28) persisting despite
Israel adequate fluid
resuscitation along
with the presence of
hypoperfusion
abnormalities or
organ dysfunction
(patients receiving
inotropic or
vasopressor agents
may no longer be
hypotensive by the
time they manifest
hypoperfusion
abnormalities or
organ dysfunction
but would be
considered to have
septic shock).
Angus DC1 192,980 1995 USA Multi Hospital ICD-9 CVS organ Sepsis
(2001) center discharge Angus derivation dysfunction 28.6%
[n=847] records Shock without trauma
ICD codes (785.5 and
458)

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Wichmann 48,136 02/1991 to Germany Single Surgical Bone6 Need for 65.7%
MW96 06/1998 center ICU catecholamine severe
(2000) therapy despite sepsis/shock
adequate fluid
support
Schoenberg 664 1997 Germany Single Surgical Bone6 Severe sepsis 40.0%
MH97 (1998) center ICU concomitant with
arterial hypotension
with a SBP<90
mmHg and/or the
need for vasopressor
treatment with
noradrenaline and/or
adrenaline (infusion
rate >0.1 g/kg/min)
and/or dopamine
(infusion rate >5
g/kg/min) despite
adequate volume
resuscitation

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Lundberg 41 08/1992 to USA Single ICU Bacteremia + Bone6 Septic shock = a) at 46.0%
JS98 (1998) 04/1993 center least two criteria
SIRS; b) positive
blood
culture(s); c)
systematic
manifestation of
peripheral
hypoperfusion,
defined as lactic
acidosis, oliguria, or
acute alteration of
mental status; and d)
hypotension, defined
as systolic blood
pressure (BP) <90 mm
Hg unresponsive to a
500-mL fluid bolus or
requiring use of
vasopressors to keep
the systolic BP of >90
mm Hg. If the patient
had been hypertensive,
a decrease of 40 mm
Hg systolic BP was
considered the
criterion for
hypotension.

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Sands KE99 1342 01/1993 to USA Multi Hospital Bone6 Presence of sepsis 34.0% 28
(1997) 04/1994 center admission syndrome plus a day
[n=8] s >40mmHg drop in mortality
SBP unresponsive to sepsis
a fluid challenge, syndrome
occurring within 24
hours before or
6hours after the
onset of sepsis
syndrome.
Sasse KC100 153 01/1987 to USA Single ICU Bone6 Not described 51.0%
(1995) 03/1991 center severe sepsis

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First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Salvo I101 1101 04/1993 to Italy Multi ICU Bone6 Sepsis with 81.8%
(1995) 03/1994 center hypotension, despite
[n=99] adequate fluid
resuscitation, along
with the presence of
perfusion
abnormalities that may
include, but are not
limited to lactic
acidosis, oliguria, or
an acute alteration in
mental status. Patients
who are on inotropic
or vasopressor agents
may not be
hypotensive at the
time that per- fusion
abnormalities are
measured
Hypotension: A
systolic BP of <90
mmHg or a reduction
of >40mmHg from
baseline in the absence
of other causes for
Hypotension.

© 2016 American Medical Association. All rights reserved.

First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

Rangel- 3708 08/1992 to USA Multi ICU Bone6 Septic shock was 46.0%
Frausto 04/1993 center defined as a patient
MS102 (1995) [n=3] with hypotension
not responsive to a
500-mL intravenous
fluid challenge plus
manifestations of
peripheral
hypoperfusion.
Patients without
hypotension but
receiving more than
5mcg/kg/minute of
dopamine or any
other vasopressor
Pittet D103 170 04/1992 USA Single Surgical Bone6 Shock was defined 58%
(1995) center ICU as SBP<90 mmHg
OR a fall in SBP
equal to or greater
than 50 percent for
hypertensive
patients; or blood
pressure requiring a
continuous infusion
of vasopressors.

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First author No. Recruitment Geographic Single Hospital Sepsis case Septic shock Acute
Reference period Region center setting definition cited definition and Mortality
number (S) criteria % (95% CI)
(publication /multi-
year) center
(M) [N]

McLauchlan 125 01/1990 to Edinburgh, Single ICU Study specific Not described 72.0%
GJ21 (1995) 06/1993 Scotland center

Brun- 11,828 01/1993 to France Multi ICU Bone6 Shock was defined 59.0%
Buisson104 02/1993 center as hypotension severe
(1995) [n=170] persisting at least 1 sepsis/shock
hour despite
administration of
fluids, associated
with signs of organ
dysfunction or
hypoperfusion.
Hypotension =
SBP<90 or drop
>40mmHg from
baseline
Dahmash NS 45 02/1989 to Saudi Arabia Single ICU Study specific Not described 40.0%
105
(1993) 05/1991 center

The study specific checklist included: cohort recruitment period, cohort size, cohort location [geographic; Emergency department [ED]; Ward;
Intensive Care unit [ICU]], sepsis and septic shock definitions and acute mortality as reported in the document. Angus algorithm1 = ICD-9-CM
code for infection + Organ Dysfunction code; Martin algorithm2 = ICD-9-CM codes for septicaemia, bacteraemia, or fungaemia + Organ
Dysfunction code. Wang3 and Dombrovskiy algorithms use ICD-9 infection along with ICD-9 severe sepsis codes; PROWESS criteria are the trial
based criteria, which uses 3 systemic inflammatory response syndrome and one or more organ dysfunction to define severe sepsis. USA – United

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States of America; ICU – Intensive Care unit; Bone – refers to Bone R et al Consensus definitions; Levy – refers to Levy MM et al Consensus
Definitions; CDC – Centre for Disease Control and Prevention; ICD – International Classification of Diseases; SOFA score – refers to Sepsis
(Sequential) Organ Failure Score; NIS data = The National (Nationwide) Inpatient Sample data; CVS – Cardiovascular system; APACHE score –
Acute Physiology and Chronic Health Evaluation Scores; SSC – Surviving Sepsis Campaign; SIRS – systemic inflammatory response syndrome;
BSI – blood stream infection; SBP = systolic blood pressure; MAP – Mean arterial pressure; CVP – central venous pressure; PAWP – Pulmonary
artery wedge pressure.

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eTable 3. Meta-regression Analysis

eTable 3A. Model Without ICU Beds/100,000 Population

Variable Coefficient Standard t p>|t| 95%CI of
error coefficient
-0.018 0.048 -0.38 0.709 -0.114 – 0.079
Sepsis Case
Definition
-0.008 0.009 -0.86 0.396 -0.027 – 0.011
Septic Shock Criteria
-0.007 0.004 -1.75 0.087 -0.016 – 0.011
Mid cohort year
-0.0311 0.050 -0.62 0.540 -0.013 – 0.071
Single vs Multicenter
-0.002 0.009 -0.24 0.808 -0.021 – 0.017
WHO regions
15.47 8.500 1.82 0.076 -1.664 – 32.605
Constant
The table shows the summary of the random effects meta-regression model described in
eMethods1. The number of observations in this model was 49. The estimate of between
study variance (tau2) was 0.019 and the proportion of residual variation due to
heterogeneity (I2_res) was 99.54%. The proportion of between-study variance explained
by covariates included in this model was 0.69%. The joint test for all covariates in the
model was not significant (p=0.44).

eTable 3B. Model With ICU Beds/100,000 Population

Variable Coefficien Standard t p>|t| 95%CI of
t error coefficient
Sepsis Case -0.058 0.062 -0.93 0.360 -0.186 – 0.070
Definition
Septic Shock Criteria -0.004 0.011 -0.33 0.743 -0.025 – 0.018
Mid cohort year -0.009 0.005 -1.80 0.082 -0.019 – 0.001
Single vs Multicenter -0.053 0.055 -0.95 0.348 -0.166 – 0.060
WHO regions -0.019 0.027 -0.69 0.498 -0.075 – 0.037
Per capital ICU beds -0.004 0.005 -0.87 0.392 -0.014 – 0.006
Constant 18.81 10.03 1.88 0.071 -1.698 – 39.313

The table shows the summary of the random effects meta-regression model described in
eMethods1, where per-capita ICU beds data was available to be included as a covariate.
The number of observations in this model was 36, due to either lack of per capita bed
data or international cohorts. The estimate of between study variance (tau2) was 0.02 and
the proportion of residual variation due to heterogeneity (I2_res) was 98.54%. The
proportion of between-study variance explained by covariates included in this model was
2.11%. The joint test for all covariates in the model was not significant (p=0.39)

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eTable 4. Responses to Key Delphi Survey Questions
Phase 1 (N=17 responses) Response N (%)
A N D
1. Currently, systolic blood pressure OR mean arterial 7 1 9
pressure OR a reduction in systolic pressure (41.2%) (5.9%) (52.9%)
>40mmHg from baseline are used in defining
hypotension. In your opinion, should these three
different blood pressure variables be retained within
the new hypotension for septic shock?
2. Currently two different MAP values are used in 14 1 2
defining septic shock (Sepsis Definition = <60, SOFA (82.4%) (5.9%) (11.8%)
and SSC <70). Should there be one single definition
of MAP?
3. If the patient is known to be chronically hypertensive, 6 2 9
should a different cut-off target be used? (35.3%) (11.8%) (52.9%)
4. In the current definitions, persisting hypotension is 12 1 4
not explicitly defined. In your opinion, is there a need (70.6%) (5.9%) (23.5%)
to define persisting hypotension?
5. In your opinion, is there a need to define ‘adequacy of 13 1 3
resuscitation’? (76.5% (5.9%) (17.6%)
6. In your opinion, should the need for vasopressor 15 1 1
therapy be used as a variable to define septic shock? (88.2%) (5.9%) (5.9%)
7. Should lactate be used as a biochemical definition of 11 4 2
septic shock, even in the absence of hypotension? (64.7%) (23.5%) (11.8%)
8. In your opinion, is there a need for a severity grading 8 4 5
of septic shock? (47.1%) (23.5%) (29.4%)
Phase 2 (N=17 responses)
1. “The TF members could not agree on endpoint[s] that 9 0 8
define adequate resuscitation in patients with septic (52.9)% (47.1%)
shock. As resuscitation is an iterative process this
should be separated from the concept of persistent
hypotension.” Would you agree with this statement
regarding adequacy of resuscitation?
2. No consensus was achieved regarding an endpoint to 11 0 7
mark adequacy of fluid resuscitation. Would you (64.7%) (41.2)%
agree with the following definition for ‘persistent
hypotension’ that offers a compromise solution?
“Persistent hypotension is defined as hypotension
persisting despite fluid resuscitation of at least 20 ml/kg
that requires vasopressor therapy for at least 60 minutes
to keep MAP >60 mmHg.”
3. Approximately half the TF voted for including lactate 13 0 4
in the definition, wanted a cut-off value to be (76.9%) (23.1%)
determined by mining ‘big data’ to determine
sensitivity/specificity of acute hospital mortality? Are
you happy with this proposal?

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Phase 3 (N=18 responses)
1. The TF members were given four choices for the
septic shock updated criteria and were asked to
provide their first and second choice independently.
The reported proportions represent cumulative first or 2 (11.1%)
second choices. 5 (27.8%)
a. Lactate alone 10 (55.6%)
b. Hypotension alone 13 (72.2%)
c. Vasopressor dependent hypotension OR
lactate
d. Vasopressor dependent hypotension AND
lactate
A,N,D
Response A= Agree or strongly agree; N= Neither agree nor disagree; D= Disagree
or strongly disagree

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eTable 5. Potential Septic Shock Cohorts
Variable Hypotension after fluids Vasopressor Raised Lactate
>2 mmol/L
Group 1 Yes Yes Yes
Group 2 Yes Yes No
Group 3 Yes No Yes
Group 4 No No Yes
Group 5 No hypotension before fluids No Yes
Group 6 Yes No No

The three variables proposed from the Delphi process could be present as single
variables, simultaneously, or in pairs i.e. hypotension AND/OR need for vasopressor
therapy AND/OR abnormal lactate. Abnormal lactate refers to concentrations greater
than 2mmol/L. Hypotension refers to mean arterial pressure less than 65mmHg in SSC
database and systolic blood pressure less than 100mmHg in HER datasets. The field
‘crystalloids’ coded as a binary variable within the SSC database defined the ‘after fluids’
term, which refers to resuscitation. We defined cryptic shock as persistently elevated
lactate ‘after fluids’. Hypotension and Vasopressor therapy are related variables.
Hypotension was assumed when vasopressor therapy was administered. Therefore, the
groups were collapsed down to six.
Group 1: Hypotensive after fluids requiring vasopressor therapy with lactate >2
mmol/L
Group 2: Hypotensive after fluids requiring vasopressor therapy with lactate <2
mmol/L
Group 3: Hypotensive after fluids with lactate >2 mmol/L
Group 4: Raised lactate after fluids = ‘cryptic’ shock
Group 5: Isolated lactate >2 mmol/L without hypotension or need for vasopressor,
thus doesn’t mandate resuscitation coding within the SSC database and therefore does
not meet ‘cryptic shock’ definition
Group 6: Hypotension after fluids and lactate<2mmol/L and no use of vasopressor

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eTable 6. Cohort Characteristics of Patients in SSC Database
Patient characteristics Total = 18,840 N [%] ED = 10,843 Ward = 5934 ICU = 2063
N[%] N [%] N [%]
Site of infection
Pneumonia 8,286 [44.0] 5,026 [46.4] 2,256 [38.0] 1,004 [48.7]
Urinary Infection 4,258 [22.6] 3,172 [29.3] 875 [14.8] 211 [10.2]
Abdominal 4,384 [23.3] 1,801 [16.6] 2,019 [34.0] 564 [27.3]
Meningitis 248 [1.3] 171 [1.6] 51 [0.9] 26 [1.3]
Skin/bone 1,302 [6.9] 822 [7.6] 372 [6.3] 108 [5.2]
Wound 803 [4.3] 468 [4.3] 262 [4.4] 73 [3.5]
Catheter 695 [3.7] 309 [2.9] 279 [4.7] 107 [5.2]
Endocarditis 185 [1.0] 113 [1.0] 61 [1.0] 11 [0.5]
Device 203 [1.1] 120 [1.1] 68 [1.2] 15 [0.7]
Other infection 2,345 [12.5] 1,466 [13.5] 637 [10.7] 242 [11.7]
Hypotension mmHg
• MAP<65 13,678 [72.6] 7,639 [70.5] 4,448 [75.0] 1,591 [77.1]
• SBP<90 14,609 [77.5] 8,294 [76.5] 4,663 [78.6] 1,652 [80.1]
• Fall in SBP>40 8,333 [44.2] 4,660 [43.0] 2,711 [45.7] 962 [46.6]
• MAP<65 & SBP<90 12,626 [67.0] 7,189 [66.3] 4,003 [67.5] 1,434 [69.5]
Lactate mmol/L
• ≤2 4,135 [22.0] 1,924 [17.7] 1,538 [25.9] 673 [32.6]
• >2 to ≤ 3 5,006 [26.6] 2,807 [25.9] 1,618 [27.3] 581 [28.2]
• >3 to ≤ 4 3,395 [18.0] 2,113 [19.5] 973 [16.4] 309 [15.0]
• >4 6,304 [33.5] 3,999 [36.9] 1,805 [30.4] 500 [24.2]
ScvO2
• No (>70%>24 hrs) 537 [3.0] 264 [2.5] 202 [3.5] 71 [3.5]
• Yes (>70% <24 hrs) 6,940 [38.1] 3,464 [33.1] 2,500 [43.5] 976 [48.3]
• Not obtained 6,179 [33.9] 3,877 [37.0] 1,741 [30.3] 561 [27.8]
• N/A 4,576 [25.1] 2,864 [27.4] 1,301 [22.7] 411 [20.4]

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 Patient characteristics Total = 18,840 N [%] ED = Ward = 5934 ICU = 2063
10,843 N [%] N [%]
N[%]
Vasopressors
• No 374 [2.0] 257 [2.4] 92 [1.6] 25 [1.2]
• Yes 12,505 [66.4] 6,619 [61.0] 4,314 [72.7] 1,572 [76.2]
• N/A 5,961 [31.6] 3,967 [36.6] 1,528 [25.8] 466 [22.6]
Baseline non-CVS OD
• Pulmonary 4,588 [24.4] 2,246 [20.7] 1,679 [28.3] 663 [32.1]
• Renal 3,879 [36.5] 3,946 [36.4] 2,189 [36.9] 744 [36.1]
• Hepatic 1,879 [10.0] 995 [9.2] 659 [11.1] 225 [10.9]
• Hematologic 4,588 [24.4] 2,484 [22.9] 1,606 [27.1] 498 [24.1]
• Acute altered mental status 5,806 [30.8] 3,577 [33.0] 1,698 [28.6] 531 [25.7]
Septic shock
+ 0 non-CVS OD 5,418 [28.8] 3,190 [29.4] 1,599 [26.9] 629 [30.5]
+ 1 non-CVS OD 6,365 [33.8] 3,789 [34.9] 1,953 [32.9] 623 [30.2]
+ 2 non-CVS OD 4,487 [23.8] 2,473 [22.8] 1,520 [25.6] 494 [23.9]
+ 3 non-CVS OD 1,951 [10.4] 1,086 [10.0] 637 [10.7] 228 [11.1]
+ 4 non-CVS OD 547 [2.9] 270 [2.5] 198 [3.3] 79 [3.8]
+ 5 non-CVS OD 72 [0.4] 35 [0.3] 27 [0.5] 10 [0.5]
Mortality
Septic shock overall 6,533 [34.7] 3,014 [27.8] 2,559 [43.1] 960 [46.5]
+ 0 non-CVS OD 1,444 [26.7] 636 [19.9] 562 [35.2] 298 [37.7]
+ 1 non-CVS OD 2,037 [32.0] 953 [25.2] 798 [40.9] 421 [43.9]
+ 2 non-CVS OD 1,756 [39.1] 793 [32.1] 721 [47.4] 348 [50.0]
+ 3 non-CVS OD 931 [47.7] 462 [42.5] 341 [53.5] 172 [57.0]
+ 4 non-CVS OD 323 [59.1] 152 [56.3] 120 [60.6] 71 [68.3]
+ 5 non-CVS OD 42 [58.3] 18 [51.4] 17 [63.0] 9 [64.3]
ED: Emergency department; ICU: Intensive Care Unit; MAP: Mean arterial pressure in mmHg; SBP: systolic blood pressure in
mmHg; ScvO2: Central venous saturations; N/A: Not applicable; Non-CVS OD: non-cardiovascular organ dysfunction.

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eTable 7. Generalized Estimating Equation (GEE) Population-Averaged Logistic Regression Model for Hospital Mortality
Prediction and Risk Adjustment
Variables N Hospital mortality, N (%) Coefficient Standard error Z-value p-value OR1 95% CI of OR
Group
1 (referent) 8,520 3,602 (42.3) 0.000 1.00
2 3,985 1,198 (30.1) -0.567 0.044 -12.84 < 0.001 0.57 0.52 0.62
3 223 64 (28.7) -0.431 0.165 -2.62 0.009 0.65 0.47 0.90
4 3,266 839 (25.7) -0.336 0.069 -4.85 < 0.001 0.71 0.62 0.82
5 2,696 802 (29.7) -0.265 0.079 -3.37 0.001 0.77 0.66 0.90
6 150 28 (18.7) -1.133 0.235 -4.81 < 0.001 0.32 0.20 0.51
Admit
ED (referent) 10,843 3,014 (27.8) 0.000 1.00
Ward 5,934 2,559 (43.1) 0.476 0.044 10.72 < 0.001 1.61 1.48 1.76
ICU 2,063 960 (46.5) 0.621 0.060 10.32 < 0.001 1.86 1.65 2.09
Region
Europe (referent) 4,415 1,947 (44.1) 0.000 1.00
USA 12,724 3,706 (29.1) -0.192 0.072 -2.68 0.007 0.83 0.72 0.95
South America 1,701 880 (51.7) 0.642 0.102 6.31 < 0.001 1.90 1.56 2.32
Antibiotics
No (referent) 237 120 (50.6) 0.000 1.00
Yes 13,979 4,553 (32.6) -0.366 0.146 -2.51 0.012 0.69 0.52 0.92
Started previously 4,624 1,860 (40.2) -0.286 0.149 -1.92 0.055 0.75 0.56 1.01
Steroids
No (referent) 6,619 2,272 (34.3) 0.000 1.00
Yes 6,927 2,747 (39.7) 0.148 0.040 3.69 < 0.001 1.16 1.07 1.25
Not obtained 753 364 (48.3) 0.410 0.083 4.94 < 0.001 1.51 1.28 1.77
Ln(glucose) -0.079 0.038 -2.10 0.036 0.92 0.86 1.00
Pulmonary OD 4,588 1,945 (42.4) 0.185 0.043 4.31 < 0.001 1.20 1.11 1.31
Renal OD 6,879 2,782 (40.4) 0.262 0.036 7.34 < 0.001 1.30 1.21 1.39
Hepatic OD 1,879 849 (45.2) 0.198 0.055 3.59 < 0.001 1.22 1.09 1.36

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Variables N Hospital mortality, N (%) Coefficient Standard error Z-value p-value OR1 95% CI of OR
Mental OD 5,806 2,176 (37.5) 0.258 0.037 6.89 < 0.001 1.30 1.20 1.39
Pneumonia 8,286 3,109 (37.5) 0.327 0.041 8.04 < 0.001 1.39 1.28 1.50
Urinary infection 4,258 1,074 (25.2) -0.213 0.046 -4.61 < 0.001 0.81 0.74 0.89
Abdominal 4,384 1,795 (40.9) 0.223 0.045 4.94 < 0.001 1.25 1.14 1.37
Meningitis 248 64 (25.8) -0.272 0.156 -1.75 0.080 0.76 0.56 1.03
Hyperthermia 7,817 2,179 (27.9) -0.333 0.037 -8.88 < 0.001 0.72 0.67 0.77
Hypothermia 2,842 1,349 (47.5) 0.398 0.048 8.24 < 0.001 1.49 1.36 1.64
Chills 1,297 343 (26.5) -0.387 0.073 -5.29 < 0.001 0.68 0.59 0.78
Tachypnea 11,185 3,979 (35.6) 0.102 0.035 2.88 0.004 1.11 1.03 1.19
Leukopenia 1,670 728 (43.6) 0.256 0.057 4.46 < 0.001 1.29 1.15 1.45
Hyperglycemia 4,113 1,351 (32.8) -0.172 0.043 -4.00 < 0.001 0.84 0.77 0.92
Platelet 2,293 1,080 (47.1) 0.292 0.051 5.72 < 0.001 1.34 1.21 1.48
Coagulopathy 3,076 1,468 (47.7) 0.442 0.045 9.79 < 0.001 1.56 1.42 1.70
Constant -0.921 0.248 -3.72
The risk adjusted odds ratios for the 6 groups are shown in this table. Variables used to define septic shock groups 1-6 [lactate,
vasopressor, hypotension after fluids] were not used as adjustment variables in this regression model as they were used to define the
six groups. OR: odds ratio; ED: Emergency department; ICU: Intensive Care Unit; USA: United States of America. Glucose
increments are in 1mmol/L in the model.; OD – organ dysfunction.

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eTable 8. Generalized Estimating Equation (GEE) Population-Averaged Logistic Regression Model for Estimation of Lactate
Effect on Hospital Mortality (N = 18,840)
Variables N Hospital mortality, N (%) Coefficient Standard error Z-value p-value OR 95% CI of OR
Ln(lactate) 0.483 0.028 17.42 < 0.001 1.62 1.54 1.71
Vasopressors
No (referent) 374 92 (24.6) 0.000 1.00
Yes 12,505 4,800 (38.4) 0.261 0.138 1.89 0.059 1.30 0.99 1.70
Crystalloids
No (referent) 2696 802 (29.7) 0.000 1.00
Yes 16,144 5,731 (35.5) -0.634 0.097 -6.52 < 0.001 0.53 0.44 0.64
Admit
ED (referent) 10,843 3,014 (27.8) 0.000 1.00
Ward 5,934 2,559 (43.1) 0.406 0.046 8.90 < 0.001 1.50 1.37 1.64
ICU 2,063 960 (46.5) 0.467 0.062 7.55 < 0.001 1.59 1.41 1.80
Region
Europe (referent) 4,415 1,947 (44.1) 0.000 1.00
USA 12,724 3,706 (29.1) -0.153 0.070 -2.17 0.030 0.86 0.75 0.99
South America 1,701 880 (51.7) 0.599 0.100 6.01 < 0.001 1.82 1.50 2.21
Antibiotics
No (referent) 237 120 (50.6) 0.000 1.00
Yes 13,979 4,553 (32.6) -0.375 0.149 -2.52 0.012 0.69 0.51 0.92
Started previously 4,624 1,860 (40.2) -0.280 0.153 -1.83 0.067 0.76 0.56 1.02
Steroids
No (referent) 6,619 2,272 (34.3) 0.000 1.00
Yes 6,927 2,747 (39.7) 0.086 0.041 2.10 0.036 1.09 1.01 1.18
Not obtained 753 364 (48.3) 0.395 0.085 4.66 < 0.001 1.48 1.26 1.75
Ln(glucose) -0.106 0.039 -2.74 0.006 0.90 0.83 0.97
Pulmonary OD 4,588 1,945 (42.4) 0.177 0.055 3.24 0.001 1.19 1.07 1.33
Renal OD 6,879 2,782 (40.4) 0.239 0.037 6.53 < 0.001 1.27 1.18 1.36
Hepatic OD 1,879 849 (45.2) 0.162 0.057 2.86 0.004 1.18 1.05 1.31

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Variables N Hospital mortality, N (%) Coefficient Standard error Z-value p-value OR 95% CI of OR
Mental OD 5,806 2,176 (37.5) 0.190 0.038 4.95 < 0.001 1.21 1.12 1.30
Ventilation 9,947 4,674 (47.0) 0.806 0.039 20.66 < 0.001 2.24 2.07 2.42
Pneumonia 8,286 3,109 (37.5) 0.253 0.042 6.02 < 0.001 1.29 1.19 1.40
Urinary Infection 4,258 1,074 (25.2) -0.129 0.048 -2.71 0.007 0.88 0.80 0.96
Abdominal 4,384 1,795 (40.9) 0.120 0.047 2.58 0.010 1.13 1.03 1.24
Meningitis 248 64 (25.8) -0.403 0.158 -2.55 0.011 0.67 0.49 0.91
Hyperthermia 7,817 2,179 (27.9) -0.322 0.038 -8.38 < 0.001 0.72 0.67 0.78
Hypothermia 2,842 1,349 (47.5) 0.343 0.050 6.92 < 0.001 1.41 1.28 1.55
Chills 1,297 343 (26.5) -0.299 0.075 -3.98 < 0.001 0.74 0.64 0.86
Tachypnea 11,185 3,979 (35.6) 0.118 0.036 3.25 0.001 1.13 1.05 1.21
Leukopenia 1,670 728 (43.6) 0.224 0.059 3.81 < 0.001 1.25 1.11 1.40
Hyperglycemia 4,113 1,351 (32.8) -0.202 0.044 -4.60 < 0.001 0.82 0.75 0.89
Platelet 2,293 1,080 (47.1) 0.287 0.052 5.49 < 0.001 1.33 1.20 1.48
Coagulopathy 3,076 1,468 (47.7) 0.395 0.046 8.52 < 0.001 1.49 1.36 1.63
Screen lactate 12,566 4,398 (35.0) -0.102 0.043 -2.34 0.019 0.90 0.83 0.98
Pulmonary 2,222 987 (44.2) -0.211 0.069 -3.05 0.002 0.81 0.71 0.93
Constant -0.841 0.297 -2.83 0.005
The risk adjusted odds ratios for the individual criterion variables from second stage of Delphi (lactate, vasopressor, and fluids) are
provided in this table. For the reported adjusted odds ratios the outcome is ‘acute hospital mortality’ in septic shock group. The odds
ratios in this regression model were generated by back-transforming the adjusted natural log of the serum lactate coefficient to the
original units for serum lactate in mmol/L. OR: odds ratio; ED: Emergency department; ICU: Intensive Care Unit; USA: United States
of America; Glucose and Lactate increments are in 1mmol/L. OD – organ dysfunction.

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eTable 9. Characteristics of Lactate Cut-off Values for Complete Case Analysis by
Combining Patients in Groups 1 and 2
Characteristic Lactate ≥ 2 mmol/L Lactate ≥ 3 mmol/L Lactate ≥ 4 mmol/L
Complete case analysis [N = 12,475]*
Hospital mortality, % 4165/12475=33.3 4454/12475=35.7 4752/12475=38.1
(32.4-34.3) (34.8-36.6) (37.2-39.0)
Sensitivity, % 3584/4782=74.9 2766/4782=57.8 2191/4782=45.8
(73.7-76.2) (56.4-59.2) (44.4-47.2)
Specificity, % 2787/7693=36.2 4422/7693=57.5 5434/7693=70.6
(35.2-37.3) (56.4-58.6) (69.6-71.7)
PPV, % 3584/8490=42.2 2766/6037=45.8 2191/4450=49.2
(41.2-43.3) (44.6-47.1) (47.8-50.7)
NPV, % 2787/3985=69.9 4422/6438=68.7 5434/8025=67.7
(68.5-71.4) (67.5-69.8) (66.7-68.7)
*Analysis ignored observations where serum lactate values > 100 mmol/L

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eTable 10. Descriptive Data on UPMC and KPNC Cohorts
UPMC KPNC
Variables Infection + >=1 Septic Infection + >=1 Septic Shocka
a
SOFA point Shock SOFA point
Number of 13,133 5984 (46) 139,888 54,135 (39)
patients
Age, yrs 63 [52, 75] 64 [52, 76] 72 [59 - 83] 73 [60 - 83]
[IQR]*
Male sex, 6,827 (52) 3,161 (53) 68,213 (49) 27,539 (51)
no. (%)
SOFA1 5 [3 – 9] 7 [4 – 11] 2 [1 - 4] 3 [2 - 6]
score*
SIRS1 3 [2 – 4] 3 [2 – 4] NA NA
ICU-LOS* 6 [3 – 12] 6 [3 – 12] 2 [1 - 4] 2 [1 - 5]
days
Hosp-LOS* 11 [6 – 18] 11 [6 – 19] 4 [2 - 7] 4 [3 - 7]
days
Mortality2 2,634 (20) 1,821 (30) 11,334 (8) 7,598 (14)
N (%)
*Data presented as median [IQR]; 1SIRS and SOFA data represent worst values in 24
hours after infection identified. aRepresents any of the NEW Septic Shock groups 1 to 4.
2
Refers to acute hospital mortality; LOS – length of stay; SIRS – Systemic inflammatory
response syndrome; ICU – Intensive Care Unit; SOFA- Sepsis Organ failure score

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eFigure 1. Probability of Hospital Mortality Derived Using Regression Model for
Full Case and Imputed Analyses

Black lines are based on the complete case analysis septic shock population (N = 18,840)
while red lines are based on the imputed missing serum lactate population (N = 22,182).
Probability of hospital mortality expressed as a proportion (range 0 – 1) and is based on a
logistic regression model where the dependent variable is hospital mortality and the
independent variable is continuous serum lactate (mmol/L) (eTable8). The lines
produced by the logistic regression model show the relationship between predicted
hospital mortality and serum lactate (mmol/L). The serumn lactate level is truncated at
6mmol/L since approximately 85% of the observations are ≤ 6 mmol/L

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eFigure 2. Sensitivity and Specificity by the Probability of Hospital Mortality

Probability of hospital mortality expressed as a proportion (range 0 – 1) and is based on a

logistic regression model where the dependent variable is hospital mortality and the
independent variable is continuous serum lactate (mmol/L) (eTable8). The specific values
of serum lactate the corresponding probability of hospital mortality are reported to show
the performance characteristics of serum lactate levels (Table-4 and eTable9 for Group-1
and Group-2).

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eReferences
1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR.
Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and
associated costs of care. Crit Care Med. 2001;29(7):1303-1310.
2. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United
States from 1979 through 2000. N Engl J Med. 2003;348(16):1546-1554.
3. Wang HE, Shapiro NI, Angus DC, Yealy DM. National estimates of severe sepsis in
United States emergency departments. Crit Care Med. 2007;35(8):1928-1936.
4. Shankar-Hari M, Bertolini G, Brunkhorst FM, et al. Judging quality of current septic shock
definitions and criteria. Crit Care. 2015;19(1):445.
5. Fleischmann C, Scherag A, Adhikari NK, et al. Assessment of Global Incidence and
Mortality of Hospital-treated Sepsis - Current Estimates and Limitations. Am J Respir Crit
Care Med. 2015.
6. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines
for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference
Committee. American College of Chest Physicians/Society of Critical Care Medicine.
Chest. 1992;101(6):1644-1655.
7. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International
Sepsis Definitions Conference. Crit Care Med. 2003;31(4):1250-1256.
8. http://www.who.int/healthinfo/global_burden_disease/definition_regions/en/
9. http://www.jsicm.org/en/about_jsicm.html
10. Luangasanatip N, Hongsuwan M, Lubell Y, et al. Long-term survival after intensive care
unit discharge in Thailand: a retrospective study. Critical Care. 2013;17(5):R219.
11. Wallace DJ, Angus DC, Seymour CW, Barnato AE, Kahn JM. Critical care bed growth in
the United States. A comparison of regional and national trends. Am J Respir Crit Care
Med. 2015;191(4):410-416.
12. Rhodes A, Ferdinande P, Flaatten H, Guidet B, Metnitz PG, Moreno RP. The variability of
critical care bed numbers in Europe. Intensive Care Med. 2012;38(10):1647-1653.
13. Kwak S-H, Jeong C-W, Lee S-H, Lee H-J, Koh Y. Current Status of Intensive Care Units
Registered as Critical Care Subspecialty Training Hospitals in Korea. J Korean Med Sci.
2014;29(3):431-437.
14. Wunsch H, Angus DC, Harrison DA, et al. Variation in critical care services across North
America and Western Europe. Crit Care Med. 2008;36(10):2787-2793, e2781-2789.
15. Adhikari NK, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the global
burden of critical illness in adults. Lancet. 2010;376(9749):1339-1346.
16. Angkasekwinai N, Rattanaumpawan P, Thamlikitkul V. Epidemiology of sepsis in Siriraj
Hospital 2007. J Med Assoc Thai. 2009;92 Suppl 2:S68-78.
17. Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality
of severe sepsis in the United States. Crit Care Med. 2013;41(5):1167-1174.
18. Wilhelms SB, Huss FR, Granath G, Sjoberg F. Assessment of incidence of severe sepsis
in Sweden using different ways of abstracting International Classification of Diseases
codes: difficulties with methods and interpretation of results. Crit Care Med.
2010;38(6):1442-1449.
19. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe
sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-
2012. JAMA. 2014;311(13):1308-1316.
20. Quenot JP, Binquet C, Kara F, et al. The epidemiology of septic shock in French
intensive care units: the prospective multicenter cohort EPISS study. Crit Care.
2013;17(2):R65.
21. McLauchlan GJ, Anderson ID, Grant IS, Fearon KC. Outcome of patients with abdominal
sepsis treated in an intensive care unit. Br J Surg. 1995;82(4):524-529.
22. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international
guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med.
2013;41(2):580-637.

© 2016 American Medical Association. All rights reserved.

23. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of
an international guideline-based performance improvement program targeting severe
sepsis. Intensive Care Med. 2010;36(2):222-231.
24. Whittaker SA, Fuchs BD, Gaieski DF, et al. Epidemiology and outcomes in patients with
severe sepsis admitted to the hospital wards. J Crit Care. 2015;30(1):78-84.
25. Cross G, Bilgrami I, Eastwood G, et al. The epidemiology of sepsis during rapid response
team reviews in a teaching hospital. Anaesth Intensive Care. 2015;43(2):193-198.
26. Vincent JL, Marshall JC, Namendys-Silva SA, et al. Assessment of the worldwide burden
of critical illness: the intensive care over nations (ICON) audit. Lancet Respir Med.
2014;2(5):380-386.
27. Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ. Two decades of
mortality trends among patients with severe sepsis: a comparative meta-analysis*. Crit
Care Med. 2014;42(3):625-631.
28. Ortiz G, Duenas C, Rodriguez F, et al. Epidemiology of sepsis in Colombian intensive
care units. Biomedica. 2014;34(1):40-47.
29. Ogura H, Gando S, Saitoh D, et al. Epidemiology of severe sepsis in Japanese intensive
care units: a prospective multicenter study. J Infect Chemother. 2014;20(3):157-162.
30. Liu V, Escobar GJ, Greene JD, et al. Hospital deaths in patients with sepsis from 2
independent cohorts. JAMA. 2014;312(1):90-92.
31. Leligdowicz A, Dodek PM, Norena M, et al. Association between source of infection and
hospital mortality in patients who have septic shock. Am J Respir Crit Care Med.
2014;189(10):1204-1213.
32. Koupetori M, Retsas T, Antonakos N, et al. Bloodstream infections and sepsis in Greece:
over-time change of epidemiology and impact of de-escalation on final outcome. BMC
Infect Dis. 2014;14:272.
33. Goncalves-Pereira J, Pereira JM, Ribeiro O, Baptista JP, Froes F, Paiva JA. Impact of
infection on admission and of the process of care on mortality of patients admitted to the
Intensive Care Unit: the INFAUCI study. Clin Microbiol Infect. 2014;20(12):1308-1315.
34. Bouza C, Lopez-Cuadrado T, Saz-Parkinson Z, Amate-Blanco JM. Epidemiology and
recent trends of severe sepsis in Spain: a nationwide population-based analysis (2006-
2011). BMC Infect Dis. 2014;14:3863.
35. Storgaard M, Hallas J, Gahrn-Hansen B, Pedersen SS, Pedersen C, Lassen AT. Short-
and long-term mortality in patients with community-acquired severe sepsis and septic
shock. Scand J Infect Dis. 2013;45(8):577-583.
36. Whittaker SA, Mikkelsen ME, Gaieski DF, Koshy S, Kean C, Fuchs BD. Severe sepsis
cohorts derived from claims-based strategies appear to be biased toward a more
severely ill patient population. Crit Care Med. 2013;41(4):945-953.
37. Stiermaier T, Herkner H, Tobudic S, et al. Incidence and long-term outcome of sepsis on
general wards and in an ICU at the General Hospital of Vienna: an observational cohort
study. Wien Klin Wochenschr. 2013;125(11-12):302-308.
38. Sakr Y, Elia C, Mascia L, et al. Epidemiology and outcome of sepsis syndromes in Italian
ICUs: a muticentre, observational cohort study in the region of Piedmont. Minerva
Anestesiol. 2013;79(9):993-1002.
39. Rohde JM, Odden AJ, Bonham C, et al. The epidemiology of acute organ system
dysfunction from severe sepsis outside of the intensive care unit. J Hosp Med.
2013;8(5):243-247.
40. Nesseler N, Defontaine A, Launey Y, Morcet J, Malledant Y, Seguin P. Long-term
mortality and quality of life after septic shock: a follow-up observational study. Intensive
Care Med. 2013;39(5):881-888.
41. Gray A, Ward K, Lees F, et al. The epidemiology of adults with severe sepsis and septic
shock in Scottish emergency departments. Emerg Med J. 2013;30(5):397-401.
42. Czupryna P, Garkowski A, Moniuszko A, Pancewicz S, Ciemerych A, Zajkowska J.
Patients with sepsis in infectious diseases department in years 1997-2010 - epidemiology
and clinical features. Przegl Epidemiol. 2013;67(3):429-434, 535-428.

© 2016 American Medical Association. All rights reserved.

43. Seymour CW, Rea TD, Kahn JM, Walkey AJ, Yealy DM, Angus DC. Severe sepsis in
pre-hospital emergency care: analysis of incidence, care, and outcome. Am J Respir Crit
Care Med. 2012;186(12):1264-1271.
44. Sancho S, Artero A, Zaragoza R, Camarena JJ, Gonzalez R, Nogueira JM. Impact of
nosocomial polymicrobial bloodstream infections on the outcome in critically ill patients.
Eur J Clin Microbiol Infect Dis. 2012;31(8):1791-1796.
45. Klein Klouwenberg PM, Ong DS, Bonten MJ, Cremer OL. Classification of sepsis, severe
sepsis and septic shock: the impact of minor variations in data capture and definition of
SIRS criteria. Intensive Care Med. 2012;38(5):811-819.
46. Park DW, Chun BC, Kim JM, et al. Epidemiological and clinical characteristics of
community-acquired severe sepsis and septic shock: a prospective observational study in
12 university hospitals in Korea. J Korean Med Sci. 2012;27(11):1308-1314.
47. Levy MM, Artigas A, Phillips GS, et al. Outcomes of the Surviving Sepsis Campaign in
intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis.
2012;12(12):919-924.
48. Lagu T, Rothberg MB, Shieh MS, Pekow PS, Steingrub JS, Lindenauer PK.
Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to
2007. Crit Care Med. 2012;40(3):754-761.
49. Bastani A, Galens S, Rocchini A, et al. ED identification of patients with severe
sepsis/septic shock decreases mortality in a community hospital. Am J Emerg Med.
2012;30(8):1561-1566.
50. Zahar JR, Timsit JF, Garrouste-Orgeas M, et al. Outcomes in severe sepsis and patients
with septic shock: pathogen species and infection sites are not associated with mortality.
Crit Care Med. 2011;39(8):1886-1895.
51. Vesteinsdottir E, Karason S, Sigurdsson SE, Gottfredsson M, Sigurdsson GH. Severe
sepsis and septic shock: a prospective population-based study in Icelandic intensive care
units. Acta Anaesthesiol Scand. 2011;55(6):722-731.
52. Rosado V, Perez L, Guerra H, Hernandez R, Magraner M, Bredy R. Outcomes
associated with conventional management of severe sepsis at Damas Hospital. Bol Asoc
Med P R. 2011;103(2):35-38.
53. Rodriguez F, Barrera L, De La Rosa G, et al. The epidemiology of sepsis in Colombia: a
prospective multicenter cohort study in ten university hospitals. Crit Care Med.
2011;39(7):1675-1682.
54. Phua J, Koh Y, Du B, et al. Management of severe sepsis in patients admitted to Asian
intensive care units: prospective cohort study. BMJ. 2011;342:d3245.
55. Moore LJ, McKinley BA, Turner KL, et al. The epidemiology of sepsis in general surgery
patients. J Trauma. 2011;70(3):672-680.
56. Davis JS, Cheng AC, McMillan M, Humphrey AB, Stephens DP, Anstey NM. Sepsis in
the tropical Top End of Australia's Northern Territory: disease burden and impact on
Indigenous Australians. Med J Aust. 2011;194(10):519-524.
57. Shen HN, Lu CL, Yang HH. Epidemiologic trend of severe sepsis in Taiwan from 1997
through 2006. Chest. 2010;138(2):298-304.
58. Kauss IA, Grion CM, Cardoso LT, et al. The epidemiology of sepsis in a Brazilian
teaching hospital. Braz J Infect Dis. 2010;14(3):264-270.
59. Husak L, Marcuzzi A, Herring J, et al. National analysis of sepsis hospitalizations and
factors contributing to sepsis in-hospital mortality in Canada. Healthc Q. 2010;13 Spec
No:35-41.
60. Bateman BT, Schmidt U, Berman MF, Bittner EA. Temporal trends in the epidemiology of
severe postoperative sepsis after elective surgery: a large, nationwide sample.
Anesthesiology. 2010;112(4):917-925.
61. Vogel TR, Dombrovskiy VY, Lowry SF. Trends in postoperative sepsis: are we improving
outcomes? Surg Infect (Larchmt). 2009;10(1):71-78.
62. Povoa PR, Carneiro AH, Ribeiro OS, Pereira AC. Influence of vasopressor agent in
septic shock mortality. Results from the Portuguese Community-Acquired Sepsis Study
(SACiUCI study). Crit Care Med. 2009;37(2):410-416.

© 2016 American Medical Association. All rights reserved.

63. Peake SL, Bailey M, Bellomo R, et al. Australasian resuscitation of sepsis evaluation
(ARISE): A multi-centre, prospective, inception cohort study. Resuscitation.
2009;80(7):811-818.
64. Khwannimit B, Bhurayanontachai R. The epidemiology of, and risk factors for, mortality
from severe sepsis and septic shock in a tertiary-care university hospital setting.
Epidemiol Infect. 2009;137(9):1333-1341.
65. Beale R, Reinhart K, Brunkhorst FM, et al. Promoting Global Research Excellence in
Severe Sepsis (PROGRESS): lessons from an international sepsis registry. Infection.
2009;37(3):222-232.
66. Baharoon S, Al-Jahdali H, Al Hashmi J, Memish ZA, Ahmed QA. Severe sepsis and
septic shock at the Hajj: etiologies and outcomes. Travel Med Infect Dis. 2009;7(4):247-
252.
67. Rezende E, Silva JM, Jr., Isola AM, Campos EV, Amendola CP, Almeida SL.
Epidemiology of severe sepsis in the emergency department and difficulties in the initial
assistance. Clinics (Sao Paulo). 2008;63(4):457-464.
68. Blanco J, Muriel-Bombin A, Sagredo V, et al. Incidence, organ dysfunction and mortality
in severe sepsis: a Spanish multicentre study. Crit Care. 2008;12(6):R158.
69. Beovic B, Hladnik Z, Pozenel P, Siuka D, Slovenian Severe Sepsis Study G.
Epidemiology of severe sepsis in Slovenian intensive care units for adults. J Chemother.
2008;20(1):134-136.
70. Andreu Ballester JC, Ballester F, Gonzalez Sanchez A, Almela Quilis A, Colomer Rubio
E, Penarroja Otero C. Epidemiology of sepsis in the Valencian Community (Spain), 1995-
2004. Infect Control Hosp Epidemiol. 2008;29(7):630-634.
71. Sakr Y, Vincent JL, Schuerholz T, et al. Early- versus late-onset shock in European
intensive care units. Shock. 2007;28(6):636-643.
72. Karlsson S, Varpula M, Ruokonen E, et al. Incidence, treatment, and outcome of severe
sepsis in ICU-treated adults in Finland: the Finnsepsis study. Intensive Care Med.
2007;33(3):435-443.
73. Esteban A, Frutos-Vivar F, Ferguson ND, et al. Sepsis incidence and outcome:
contrasting the intensive care unit with the hospital ward. Crit Care Med.
2007;35(5):1284-1289.
74. Engel C, Brunkhorst FM, Bone HG, et al. Epidemiology of sepsis in Germany: results
from a national prospective multicenter study. Intensive Care Med. 2007;33(4):606-618.
75. Cheng B, Xie G, Yao S, et al. Epidemiology of severe sepsis in critically ill surgical
patients in ten university hospitals in China. Crit Care Med. 2007;35(11):2538-2546.
76. Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of
the SOAP study. Crit Care Med. 2006;34(2):344-353.
77. Tanriover MD, Guven GS, Sen D, Unal S, Uzun O. Epidemiology and outcome of sepsis
in a tertiary-care hospital in a developing country. Epidemiol Infect. 2006;134(2):315-322.
78. Strehlow MC, Emond SD, Shapiro NI, Pelletier AJ, Camargo CA, Jr. National study of
emergency department visits for sepsis, 1992 to 2001. Ann Emerg Med. 2006;48(3):326-
331, 331 e321-323.
79. Shapiro N, Howell MD, Bates DW, Angus DC, Ngo L, Talmor D. The association of
sepsis syndrome and organ dysfunction with mortality in emergency department patients
with suspected infection. Ann Emerg Med. 2006;48(5):583-590, 590 e581.
80. Harrison DA, Welch CA, Eddleston JM. The epidemiology of severe sepsis in England,
Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical
database, the ICNARC Case Mix Programme Database. Crit Care. 2006;10(2):R42.
81. Gasparovic V, Gornik I, Ivanovic D. Sepsis syndrome in Croatian intensive care units:
piloting a national comparative clinical database. Croat Med J. 2006;47(3):404-409.
82. Degoricija V, Sharma M, Legac A, Gradiser M, Sefer S, Vucicevic Z. Survival analysis of
314 episodes of sepsis in medical intensive care unit in university hospital: impact of
intensive care unit performance and antimicrobial therapy. Croat Med J. 2006;47(3):385-
397.
83. Zahorec R, Firment J, Strakova J, et al. Epidemiology of severe sepsis in intensive care
units in the Slovak Republic. Infection. 2005;33(3):122-128.

© 2016 American Medical Association. All rights reserved.

84. Sundararajan V, Macisaac CM, Presneill JJ, Cade JF, Visvanathan K. Epidemiology of
sepsis in Victoria, Australia. Crit Care Med. 2005;33(1):71-80.
85. Laupland KB, Zygun DA, Doig CJ, Bagshaw SM, Svenson LW, Fick GH. One-year
mortality of bloodstream infection-associated sepsis and septic shock among patients
presenting to a regional critical care system. Intensive Care Med. 2005;31(2):213-219.
86. Adrie C, Alberti C, Chaix-Couturier C, et al. Epidemiology and economic evaluation of
severe sepsis in France: age, severity, infection site, and place of acquisition
(community, hospital, or intensive care unit) as determinants of workload and cost. J Crit
Care. 2005;20(1):46-58.
87. van Gestel A, Bakker J, Veraart C, van Hout B. Prevalence and incidence of severe
sepsis in Dutch intensive care units. Crit Care. 2004;8(4):62.
88. Silva E, Pedro M, Sogayar A, et al. Brazilian Sepsis Epidemiological Study (BASES
study). Crit Care. 2004;8(4):60.
89. Laupland KB, Davies HD, Church DL, et al. Bloodstream infection-associated sepsis and
septic shock in critically ill adults: a population-based study. Infection. 2004;32(2):59-64.
90. Flaatten H. Epidemiology of sepsis in Norway in 1999. Crit Care. 2004;8(4):R180-184.
91. Finfer S, Bellomo R, Lipman J, French C, Dobb G, Myburgh J. Adult-population incidence
of severe sepsis in Australian and New Zealand intensive care units. Intensive Care Med.
2004;30(4):589-596.
92. Brun-Buisson C, Meshaka P, Pinton P, Vallet B, Group ES. EPISEPSIS: a reappraisal of
the epidemiology and outcome of severe sepsis in French intensive care units. Intensive
Care Med. 2004;30(4):580-588.
93. Padkin A, Goldfrad C, Brady AR, Young D, Black N, Rowan K. Epidemiology of severe
sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern
Ireland. Crit Care Med. 2003;31(9):2332-2338.
94. Annane D, Aegerter P, Jars-Guincestre MC, Guidet B, Network CU-R. Current
epidemiology of septic shock: the CUB-Rea Network. Am J Respir Crit Care Med.
2003;168(2):165-172.
95. Alberti C, Brun-Buisson C, Burchardi H, et al. Epidemiology of sepsis and infection in ICU
patients from an international multicentre cohort study. Intensive Care Med.
2002;28(2):108-121.
96. Wichmann MW, Inthorn D, Andress HJ, Schildberg FW. Incidence and mortality of severe
sepsis in surgical intensive care patients: the influence of patient gender on disease
process and outcome. Intensive Care Med. 2000;26(2):167-172.
97. Schoenberg MH, Weiss M, Radermacher P. Outcome of patients with sepsis and septic
shock after ICU treatment. Langenbecks Arch Surg. 1998;383(1):44-48.
98. Lundberg JS, Perl TM, Wiblin T, et al. Septic shock: an analysis of outcomes for patients
with onset on hospital wards versus intensive care units. Crit Care Med.
1998;26(6):1020-1024.
99. Sands KE, Bates DW, Lanken PN, et al. Epidemiology of sepsis syndrome in 8 academic
medical centers. JAMA. 1997;278(3):234-240.
100. Sasse KC, Nauenberg E, Long A, Anton B, Tucker HJ, Hu TW. Long-term survival after
intensive care unit admission with sepsis. Crit Care Med. 1995;23(6):1040-1047.
101. Salvo I, de Cian W, Musicco M, et al. The Italian SEPSIS study: preliminary results on the
incidence and evolution of SIRS, sepsis, severe sepsis and septic shock. Intensive Care
Med. 1995;21 Suppl 2:S244-249.
102. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural
history of the systemic inflammatory response syndrome (SIRS). A prospective study.
JAMA. 1995;273(2):117-123.
103. Pittet D, Rangel-Frausto S, Li N, et al. Systemic inflammatory response syndrome,
sepsis, severe sepsis and septic shock: incidence, morbidities and outcomes in surgical
ICU patients. Intensive Care Med. 1995;21(4):302-309.
104. Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors, and outcome of severe
sepsis and septic shock in adults. A multicenter prospective study in intensive care units.
French ICU Group for Severe Sepsis. JAMA. 1995;274(12):968-974.

© 2016 American Medical Association. All rights reserved.

105. Dahmash NS, Chowdhury NH, Fayed DF. Septic shock in critically ill patients: aetiology,
management and outcome. J Infect. 1993;26(2):159-170.

© 2016 American Medical Association. All rights reserved.