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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;MitchellL. Levy, MD;Christopher W. Seymour, MD, MSc; Vincent X. Liu, MD, MSc;
Clifford S. Deutschman, MD; DerekC. Angus, MD,MPh; Gordon D. Rubenfeld, MD,MSc; Mervyn Singer, MD,FRCP; forthe Sepsis Definitions Task Force
IMPORTANCE Septicshockcurrently refers to a stateof acute circulatory failure associated
with infection. Emerging biological insights and reported variation in epidemiology challenge
the validity of this definition.
OBJECTIVE To develop a newdefinitionand clinical criteria foridentifying septic shock in adults.
DESIGN, SETTING, ANDPARTICIPANTS The Society of Critical Care Medicine andthe European
Society of IntensiveCare Medicine convened a task force (19 participants) to revise currentsepsis/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 currentlyreported to identify septicshock
and informthe Delphiprocess;(2) a Delphistudyamong the task force comprising 3 surveys
and discussions of results from thesystematicreview, surveys, andcohort studies to achieve
consensus on a newseptic shock definitionand clinical criteria;and (3)cohort studies to test
variablesidentified 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 847165) electronic healthrecord (EHR) data sets.
MAINOUTCOMES AND MEASURES Evidence for and agreementon septic shock definitions
and criteria.
RESULTS Thesystematic reviewidentified 44 studies reporting septic shock outcomes(total of
166 479patients)from a total of 92 sepsis epidemiology studies reporting differentcutoffs
andcombinationsfor bloodpressure(BP),fluid resuscitation, vasopressors, serumlactatelevel,
andbasedeficit to identify septic shock. Theseptic shock–associatedcrude mortalitywas 46.5%
(95%CI, 42.7%-50.3%), withsignificant between-study statisticalheterogeneity(I2 = 99.5%;
τ 2 = 182.5; P < .001).The Delphi process identifiedhypotension,serum lactate level,
andvasopressor therapy as variables to testusing cohort studies. Basedon these3 variables
alone or in combination, 6 patient groups weregenerated.Examination of theSSC database
demonstratedthatthe patient grouprequiringvasopressorsto maintain meanBP 65 mm Hg
orgreater andhavinga serum lactate level greater than 2 mmol/L(18 mg/dL)afterfluid
resuscitation hada significantly higher mortality(42.3%[95% CI, 41.2%-43.3%]) in risk-adjusted
comparisons withthe other5 groups derived using either serumlactatelevel greater than
2 mmol/L alone or combinations of hypotension,vasopressors,and serumlactatelevel 2 mmol/L
orlower. Thesefindingswerevalidated inthe UPMC andKPNCdatasets.
CONCLUSIONS AND RELEVANCE Basedon a consensusprocessusing results froma systematic
review, surveys,and cohortstudies, septicshock is definedas a subsetof sepsisin which
underlyingcirculatory, cellular, andmetabolicabnormalitiesare associated witha greater riskof
mortalitythan sepsis alone. Adultpatientswith septicshockcan be identifiedusing theclinical
criteria of hypotension requiring vasopressor therapy to maintain meanBP 65 mm Hg or greater
andhaving a serumlactatelevel greater than2 mmol/L afteradequatefluid resuscitation.
JAMA. 2016;315(8):775-787.doi:10.1001/jama.2016.0289
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Author Affiliations: Author
affiliationsare listed atthe endof this
article.
Group Information: Members of the
SepsisDefinitions Task Forceare
listed atthe endof this article.
Corresponding Author: Manu
Shankar-Hari, MD,MSc, Department
of CriticalCareMedicine, Guy’sand St
Thomas’ NHS FoundationTrust,
LondonSE1 7EH,United Kingdom
Research
Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT
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Consensusdefinitions, generatedin andrevisitedin
, describe septic shock as a state of cardiovascu-
lar dysfunction associated with infection and unex-
plainedby other causes.The increasingavailabilityof large elec-
tronic healthrecord(EHR)datasets,registries, national casemix
programs, trial data sets, and claims databases using Interna-
tional Classificationof Diseasescodeshavesincegenerated mul-
tiple observational studies reporting septic shock epidemiol-
ogy. However, variable interpretation and application of the
consensus definitions, have contributed to variable esti-
mates of both incidence and outcomes.- Itis unclear towhat
extent thesevariationsrepresenttrue differences or an artifact
attributableto inconsistent use of definitions.,Furthermore,
emerginginsights intosepsispathophysiology-warrant a re-
viewof thecurrentseptic shockdefinition andthecriteria used
to identify it clinically.
Against thisbackground, theSocietyof CriticalCare Medi-
cine (SCCM) and the European Society of Intensive Care Med
(ESICM) convened an international task force to review defini-
tionsof sepsisand septicshock inJanuary . Tosupportthe
task force deliberations on redefining septic shock, a series of
activities was performed: a systematic review and meta-
analysis of criteriausedin observational studiesreporting sep-
sis epidemiology in adults; a Delphi study to achieve consen-
sus; cohort studiesusing the Surviving Sepsis Campaign(SSC)
registry; andsubsequenttesting of theapplicability of thenew
criteriain patients with suspected infection from large EHR-
derived data sets.The aims of this study were todevelop anup-
dated septic shock definition and to derive clinical criteria for
identifying patients withsepticshock meetingthis updated defi-
nition.Specifically, thisupdateddefinitionand these criteriaare
intended to provide a standard classificationto facilitate clini-
cal care, future clinical research, and reporting.
Methods
In thisarticle, “definition” refers toa description of septic shock
and “clinical criteria” to variables used to identify adult pa-
tients with septic shock.
Task Force
TheSCCM andESICM eachnominatedcochairsof thetask force
andprovidedunrestrictedfundingsupporttowardtheworkcon-
ducted.The cochairs then selected other task force partici-
pants based on their scientific expertise in sepsis epidemiol-
ogy, clinicaltrials,and basicor translational research.Taskforce
participants are listed at the end of the article. The task forceretainedcomplete autonomy forall decisions. ESICMandSCCM
hadno role in study design, conduct, or analysis butwere con-
sulted for peer review and endorsement of the manuscript.
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
andwhetherthesecriteriawere associatedwith differencesin
reported outcomes. MEDLINE was searched using search
terms, MeSHheadings,and combinationsof sepsis, septic shock,
and epidemiology andlimitsof humanstudies;adults years
or older;English-languagepublications;and publication dates
betweenJanuary , (definitions), andDecember,
. For full-text review, only noninterventional studies re-
porting sepsis epidemiology and all-cause mortality were in-
cluded.Randomizedclinical trials were excluded, becausethe
additionalinclusion andexclusion criteria mightconfoundthe
effect of criteria on mortality (the study objective). 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 usedto identifysepticshock,and acute
mortality. Detailed methods, includingsearch strategy, arepre-
sented in eMethods and eTable in the Supplement.
Delphi Study
Togenerate consensuson theseptic shock definition and cri-
teria, face-to-face meetings, -round sequential pretested
questionnaires,and emaildiscussions among thetask force par-
ticipants wereconducted.One taskforcemember did not par-
ticipate in these surveys becauseof lack of content expertise,
and didnotrespondto thefirst surveys.Questionnaireswere
developed, refined, and administeredconsistingof single- and
multiple-answer questions, free-text comments, and a -point
Likert agreement scale. For consensus discussions and not-
ing agreement, the -point Likert agreement scales were
grouped at the tails of the scale choices (ie, “strongly dis-
agree” grouped with“disagree”;“stronglyagree” grouped with
“agree”).All outputsfrom thesystematicreview, surveys,and
the results of cohort studies were made available to partici-
pants throughout the Delphi study.
In the first round (August ), using questions in
domains, agreement and opinions were explored on () com-
ponents of the new septic shock definition; () variables andtheir cutoffs identified by the systematic review; () defini-
tions of, and criteria for, hypotension, persistent hypoten-
sion, adequacyof resuscitation, and resuscitation end points;
and () septic shock severity scoring. In the second round
(November ), questions were used to generate state-
ments for key terms (persistent hypotension, adequacy of re-
suscitation,and septicshock) andto reach agreement on test
variablesand outcomes for subsequent analysis of predictive
validity. Theobjectives of thethird round (January ) were
to establish a consensus definition of septic shock and re-
lated clinical criteria.In thethirdsurvey, thetaskforcemem-
bers were given choices for the septic shock updated crite-
ria ([] serum lactate level alone; [] hypotension alone;[] vasopressor-dependent hypotension or serum lactate
level; []vasopressor-dependent hypotensionand serumlac-
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 %. Choices forwhichagreement wasless than %
wererediscussed to achieveconsensus or wereeliminated, as
appropriate to achievethe project aims. Thesurvey question-
naires are presented in eMethods in the Supplement.
Research Original Investigation NewDefinition andCriteriafor SepticShock
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Cohort Studies
The institutional review boards of Cooper University Hospital
(Camden,New Jersey),Universityof Piitsburgh MedicalCen-
ter (UPMC; a network of hospitals in western Pennsylvania),
and Kaiser Permanente Northern California (KPNC) pro-
vided ethicsapprovals forresearchusing theSSC andEHR data
sets, respectively.
The SSC registry includes data collected from hospi-
tals in countries on patients with suspected infec-
tion who, despite adequate fluid resuscitation as judged by
the collecting sites, still had or more systemic inflamma-
tory responsesyndromecriteriaand or moreorgan dysfunc-
tion criteria (eMethods in the Supplement). The SSC data-
base setup, inclusion, and reporting items are described in
detail elsewhere., Toselect clinical criteriafor thenew sep-
tic shock definition, an analysis data set was created that in-
cluded all patients witha serumlactatelevel measurementor
a mean arterialpressurelessthan mmHg afterfluids, or who
received vasopressors.
For external validation,mortalitywasdeterminedusingthe
same clinical criteria in patients with suspected infection
(culturestaken,antibioticscommenced) within large EHRda-
tabasesfrom UPMC (hospitals, -,n = ) and
KPNC (hospitals, -, n = ).Three variables
(hypotension, highest serum lactate level, and vasopressor
therapyas a binaryvariable [yes/no]) wereextracted fromthese
data sets during the -hour period after infection was sus-
pected. Descriptiveanalyses, similar to thoseperformedon the
SSCdata set, were then undertaken. Becauseof constraints on
data availability, hypotension was considered present if sys-
tolicblood pressurewas mm Hgor less for any single mea-
surement taken during the -hour period after infection was
suspected. Serum lactate levels were measured in % of in-
fectedpatientsat UPMC andin %of thoseat KPNC afterimple-
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 andsepsis definitions was
performed. Two meta-regression models of septic shock mor-
tality were tested with the covariates: sepsis definition, crite-
riafor shock,mid–cohort-yearof study population, singlecen-
ter or multicenter, and World Health Organization member
state regions. These models (with and without per capita
intensive care unit beds) were generatedto account forinter-
national cohorts and countries for whichper capita intensive
care unit bed data were unavailable (See eMethods in theSupplement for details).
CohortStudies
Hospital mortalitywas used as theprimary outcome forderi-
vationand descriptivevalidationanalysis.Using the dichoto-
mousvariablesidentified in round of theDelphi process,the
SSCcohort wasdivided into groupsand thevariables tested
either alone or in combination: () hypotension (mean arte-
rial pressure
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generalizedestimatingequation population-averaged logistic
regression models with exchangeable correlation structure,
where hospital site was thepanel variable.
Thefirst model used the potential septic shock groups to
derivedfromthesevariables(eTableintheSupplement),with
group as the referent group and adjusted for other covariates
toassesstruemortalitydifferencebetweenthesegroups.Thesec-
ondmodelassessedthe independent association of these po-
tentialcriterion variablesonhospitalmortalityadjustedforother
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 careunit), antibioticadministration,
steroid use, organdysfunction(pulmonary, renal,hepatic,and
acutelyaltered mental state),infectionsource(pneumonia,uri-
nary tract infection, abdominal, meningitis and other),hyper-
Table 1. Summary of Septic Shock Definitions and CriteriaReported in theStudies Identified by theSystematicReviewa
Criteria
Septic Shock Case Definitions and Corresponding Variables Reported in Literature
Other Descriptionof Criteria Variables
Consensus Definitions Other Definitions
Bone et al1 Levy et al2 SSC111 Trial-based112
Infection Suspected o rproven Suspected o rproven Suspected o rproven Suspected o rproven Bacteremia, c ulturepositive; CDC definitionsfor infection
SIRS criteria, No. 2 One or more of 24variablesb
2 3 NA
Septic shockdescription
Sepsis-inducedhypotensiondespiteadequate resuscitationOR receivingvasopressors/Inotropespluspresenceofperfusion abnormalities
State of acute circulatoryfailure characterizedby persistent arterialhypotensionafteradequate resuscitationunexplainedbyother causes
Sepsis-inducedhypotensionpersistingdespite adequatefluid resuscitation
Cardiovasculardysfunctiondefinedashypotensiondespiteadequate resuscitationor needfor vasopressors
Precoded datausingICD-9 and ICD-10 codesc
Hypotension, mm Hg
Systolic BP 4 mmol/L), or oliguria
No d escription Serum l actate>2.5 mmol/L;base deficit>5 mEq/L, alkalinereserve
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thermia (>.°C),hypothermia(/min), leukopenia ( mg/dL [. mmol/L),platelet count
2 mmol/L
3602 8520Group 1b 42.3 (41.2-43.3)
106 203Silva et al,48
2004 52.2 (45.3-59.1)28 57Laupland et al,49 2005 49.1 (36.5-61.8)
Hypotension + Perfusion Abnormalities + Vasopressor Therapy
19 41Lundberg et al,54 1998 46.3 (31.1-61.6)
3428 7436Levy et al,6 2010 46.1 (45.0-47.2)
728 1495Quenot et al,26 2013 48.7 (46.2-51.2)
250 462Vincent et al,43 2006 54.1 (49.6-58.7)
90 363Karlsson et al,40 2007 24.8 (20.4-29.2)
250 462Sakr et al,39 2007 54.1 (49.6-58.7)
185 255Kauss et al,34 2010 72.5 (67.1-78.0)
915 2494Levy et al,6 2010 36.7 (34.8-38.6)
441 939Phua et al,32 2011 47.0 (44.3-49.7)
117 282Ogura et al,20 2014 41.5 (35.7-47.2)
15 935 26 295GiViTI database, 2015a 60.6 (60.0-61.2)
Hypotension or Vasopressor Therapy14 36Dahmash et al,59 1993 38.9 (23.0-54.8)
73 101McLauchlan et al,58 1995 72.3 (63.5-81.0)
Hypotension or Serum Lactate Any Value or Vasopressor Therapy
827 2536Liu et al,21 2014 32.6 (30.8-34.4)
6556 18 840SSC database,16 2016b 34.8 (34.1-35.5)
International Classification of Diseases Codes
13 269 26 172Annane et al,51 2003 50.7 (50.1-51.3)457 1562Flaatten,50 2004 29.3 (27.1-31.6)
117 321Whittaker et al,24 2013 36.4 (31.2-41.7)
7 12Pittet et al,57 1995 58.3 (30.4-86.2)
32 80Schoenberg et al,53 1998 40.0 (29.3-50.7)
119 190Engel et al,42 2007 62.6 (55.8-69.5)
27 59Esteban et al,41 2007 45.8 (33.1-58.5)
164 303Khwannimit and Bhuayanontachai,37 2009 54.1 (48.5-59.7)
22 61Moore et al,33 2011 36.1 (24.0-48.1)
215 530Zahar et al,30 2011 (community) 40.6 (36.3-44.8)
123 232Zahar et al,30 2011 (ICU) 53.0 (47.1-59.0)
233 580Zahar et al,30 2011 (nosocomial) 40.2 (36.1-44.2)
29 47Klein Klowenberg et al,7 2012 61.7 (47.8-75.6)
228 740Park et al,28 2012 30.8 (27.5-34.1)
Hypotension ± Vasopressor Therapy or Metabolic Abnormalities
75 324Peake et al,36 2009 23.1 (18.6-27.7)
Serum Lactate Level >4 mmol/L
242 811Levy et al,6 2010 29.8 (26.7-33.0)
219 466Phua et al,32 2011 47.0 (42.0-52.0)
44 129Gaspraovic et al,45 2006 34.1 (25.9-42.3)
15 53Shapiro et al,44 2006 28.3 (16.2-40.4)
Hypotension + Perfusion Abnormalities and/or Vasopressor Therapy
51 110Rangel-Frausto et al,56 1995 46.4 (37.0-55.7)
27 33Salvo et al,55 1995 81.8 (68.7-95.0)
752 1180Alberti et al,52 2002 63.8 (60.7-67.0)
202 458Povoa et al,35 2009 44.1 (39.6-48.7)
52 98Klein Klowenberg et al,7 2012 53.1 (43.2-62.9)
14 609 51 079Kaukonen et al,22 2014 28.6 (28.2-29.0)
Overall (I2 = 99.5%; P = .000) 46.5 (42.7-50.3)
Forty-four studies reportseptic
shock–associated mortality5-7,19-59
and wereincluded in thequantitative
synthesis usingrandom-effects
meta-analysis. TheSurvivingSepsisCampaign (SSC)database
analyses with similardataare
reported in2 studies6,29; therefore,
onlyoneof these was usedin the
meta-analysis reported.6 Levyet al
report3 septicshocksubsets,6
Klein Klowenberget al report2
(restrictiveand liberal),7 Zahar etal
report3 (community-acquired,
ICU-acquired, and nosocomial
infection–associated septic shock),30
and Phuaet alreport2 groups,32
whichwere treated as separate
data pointsin themeta-analysis.
Studies under“consensus definition”
cite theSepsis Consensus
Definitions.1,2 Thecategorizationused to assessheterogeneitydoes
notfullyaccountfor septicshock
detailsin individual studies.
SI conversionfactor: To convert
serum lactatevalues to mg/dL,divide
by 0.111.
a Dataobtained from GiViTIdatabase
provided byBertoliniet al
(published 20158).
b Themortality data of Group 1
patients (newseptic shock
population) and theoverall
potential septicshock patient
populations (n = 18840) described
in themanuscript from thecurrent
study usingthe SurvivingSSCdatabaseare alsoincludedin the
meta-analysis. Septic shock–specific
data wereobtained from Australian
& NewZealandIntensiveCare
Society AdultPatientDatabase
(ANZICS), from a previously
published report.22 This resultsin
52 datapoints for random-effects
meta-analysis.
NewDefinitionand Criteriafor SepticShock Original Investigation Research
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These models were used to estimate acute hospital mor-
tality odds ratios(ORs)and adjusted ORsfor mortality per-unit
increase in the serum lactate level using continuous natural
log–transformed serum lactatelevel. The operating character-istics (sensitivity/specificity over hospital mortality curves;
positive and negative predictive values) of different serum
lactate cutpoints (, , and mmol/L) were also tested using
the logistic regression model. Multiple imputations (n = )
were used toassess thestatistical effectof missing serum lac-
tate values.
P < .(-sided) wasconsidered statisticallysignificant. All
analyses were performed using Stata version . (StataCorp).
Results
Systematic Review and Meta-analysisThe systematic review identified studies (
patients) reporting septic shock mortality-,- from a total
of studies reporting sepsis cohorts between and
-,- (Figure ; eTable in the Supplement). Different
shock criteria were used for systolic blood pressure
(% of baseline value if hypertensive), mean arterial
pressure (, > mmol/L) and base deficit (− mmol/L) (Table ;
eTable 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 c ardiovascularSequential [Sepsis-related] Organ Failure Assessment (SOFA)
score categories. Diverse infection and organ dysfunction
codes were also used in the International Classification of
Diseases–based derivations.,,, Variables highlighted in
Table and in eTable in the Supplement informed the Del-
phi survey questions.
The random-effects meta-analysis showed significant
heterogeneity in septic shock mortality (mean mortality,
.% [% CI, .%-.%], with a near -fold variation
from .% to .%; I = .%; τ = .; and P < .)
(Figure ). Statistically significant heterogeneity was also
observed in random-effects meta-analysis by clinical criteria
reported for septic shock case definition in studies (Table ).The meta-regression models described could not explain this
heterogeneity (eTable A and eTable B in the Supplement).
Delphi Study
In the first round, informed by the systematic review, task
force members (%) 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 (%)
voted that including fluid resuscitation would improve the
Table 2. Random Effects Meta-Analysis by Septic Shock CriteriaGroups
Septic Shock Case Definition Criteriaa No.bMortality, No. of Events/No. of Patients (%) [95% CI]c
HeterogeneityStatisticd df P Value I2, %e τ2f
Consensus definitions cited (no description) 7 4954/9590(51.6) [46.3-56.9]
53.2 6
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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 in
the Supplement.)
In Delphiround , thetaskforce wasprovided with a pre-
liminary descriptive analysis from the SSC database. With
agreementon the description of the septic shock illness con-
cept, test variables (hypotensionafter fluidresuscitation, va-
sopressor therapy, andserum lactatelevel) wereagreedon forpredictive validity analyses. The“after fluids” fieldin the SSC
database was used as a proxy for resuscitation. The need for
vasopressors was agreed as a proxy for persistent hypoten-
sion by% ofthe task force.Twelvemembers(%)votedthat
a minimum vasopressordose shouldnot be proposed in view
of the variability in blood pressure targets and resuscitation
protocolsidentified 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, task force members
(%)agreed on acute hospitalmortality as the outcome vari-
able. Thetestvariablescould be present eitheraloneor in com-
binations,thus identifying potentialgroups of patientswith
septic shock (Table ; eTable inthe Supplement).
Prior to the final round of theDelphi process, allanalyses
from the SSC data set and the EHR data sets were provided.
These findingsgenerated the new definition—“septicshockis
defined as a subset of sepsisin 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
Patientswith serumlactatelevels greater than mmol/Lwho
didnot receive fluidsas recommendedby theSSC guidelines
(n = [.%]) were excluded. Patients without any serum
lactate values measured were excluded initially for full case
analysis (n = [.%]) but were reassessed in the miss-
ingdata analysis. Of the remainingpatients, coded
as having severe sepsis wereexcluded fromthis analysis, gen-
erating theanalysis setof patients whowereeither hy-
Table 3. Distribution of Septic Shock Cohorts and Crude MortalityFrom SurvivingSepsisCampaignDatabase (n = 18 840 patients)
Cohortsa
LactateCategory,mmol/Lb
No. (% of total)[n = 18840]
Acute Hospital Mortality,No. (%) [95% CI]
χ 2 Testfor Trend
Mortality,Adjusted OR(95% CI)c P Valuec
Group1 (hypotensive afterfluidsand vasopressor therapy and serum lactatelevels >2 mmol/L)
>2 t o ≤3 2453 (13.0) 818 (33.3) [31.5-35.3] 3 t o ≤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]
Group2 (hypotensive afterfluidsand vasopressor therapy and serum lactatelevels ≤2 mmol/L)
≤2 3985 (21.2) 1198 (30.1) [28.6-31.5] NAd 0.57 (0.52-0.62) 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]
Group4 (serum lactate levels >2 mmol/Land no hypotension afterfluidsand no vasopressors)
>2 t o ≤3 860 (4.6) 179 (20.8) [18.1-23.7] 4 1856 (9.9) 555 (29.9) [27.8-32.0]
All 3266 (17.3) 839 (25.7) [24.2-27.2]
Group5 (serum lactate levels between2-4 mmol/L andno hypotension before fluidsand no vasopressors)
>2 to ≤3 1624 (8.6) 489 (30.1) [27.9-32.4] NAd 0.77 (0.66-0.90) .001
>3 t o ≤4 1072 (5.7) 313 (29.2) [26.5-32.0]
>4 790e
All 2696 (14.3) 802 (29.7) [28.0-31.5]
Group6 (hypotensive afterfluids andnovasopressors and serum lactate ≤2 mmol/L)
≤2 150 (0.8) 28 (18.7) [12.8-25.8] NAd 0.32 (0.20-0.51) 2 to3 mmol/L; >3to4 mmol/Land >4mmol/L) were assessed.
c Refers to theadjusted OR generatedusing generalized estimatingequation
regression model(eTable7 in the Supplement).
d χ 2 test fortrendcouldonly beperformedif there were 3 or moreserum
lactate categories.
e Excluded from full caseanalysis.
NewDefinition andCriteriafor SepticShock Original Investigation Research
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potensive after fluids or required vasopressors or had a se-
rum lactate level measurement (Figure and Table ).Hypotensionwas reported in .%, serumlactate levelgreater
than mmol/L in .%,and receiptof vasopressorsin .%.
Overall, crude hospital mortality was .%. Cohort charac-
teristics by setting are shown in eTable in the Supplement.
PredictiveValidity of Potential SepticShock Groups
Ofthe groupsof potentialpatients with septicshock (Table ),
the most prevalent was group (hypotension + vasopressor
therapy + serum lactate level > mmol/L)(n = );followed
by groups (n = ) and (n = ). Crude hospital mor-
talityratesin these groups were .%,.%, and.%, re-
spectively. Statistically significant increasing trends in crude
mortalitywere observedoverincreasing serum lactatelevelcat-egories withingroups(χ test oftrend: P < .for groups and
, P = . for group ). The adjusted OR for hospital mortality
using group for reference was significantly lower in all other
groups ( P < . for groups to ), suggesting that group rep-
resents a distinctsubpopulationwith a significantlygreaterrisk
of death (eTable in the Supplement). By a majority (cumula-
tive first choice,.%; second choice,.%) (eTable in the
Supplement),the taskforce agreed thatgroup 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 DataAnalysis
In thegeneralizedestimatingequationmodel(shownin eTableinthe Supplement), serumlactate levelwas 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 to mmol/L increased
the adjusted OR for hospital mortality from . (% CI, .-
.) to . (% CI,.-.)(referentlactate = ; Figure).
A serumlactatelevel greaterthan mmol/Lwaschosenas the
preferred cutoff value for thenew septic shock criteria,the ra-
tionale being thetrade-off between highestsensitivity(.%
when using the n = subset, and.% when using pa-
tients in groups and combined [n = ]), and the deci-
sion from theDelphi process toidentify the lowestserum lac-
tate level independentlyassociated witha greaterrisk of death(OR of . at a lactate value of mmol/L) ( Table ; eTable ,
eFigure , and eFigure in the Supplement).
Predicatedon thisunderstandingof theSSC databasestruc-
ture and the regression analyses completed (eTable , eTable
,andeTableintheSupplement), weassumed that data were
missing at random; ie, any difference between observed val-
ues and missing values did not depend on unobserved data.
Completecase analysiswas thereforeperformed, followed by
multiple imputation analysis to support the missing-at-
random assumption. The ORs for mortality per unit in-
Figure 3. Selectionof Surviving Sepsis Campaign DatabaseCohort
28150 Patients identified from SSC database
23731 With serum lactate values
4419 Excluded from full case analysis(missing continuous serumlactate values)a
18840 Met potential septic shock definition groupsand included in full case analysis cohort
Group 1
8520 Patients
Hypotensive after fluids
Requires vasopressors
Serum lactate >2 mmol/L
Group 2
3985 Patients
Hypotensive after fluids
Requires vasopressors
Serum lactate ≤2 mmol/L
Group 5
2696 Patients
Not hypotensive beforefluids
Requires vasopressors
Serum lactate >2 mmol/L
Group 4
2696 Patients
Not hypotensive afterfluids
Requires no vasopressors
Serum lactate >2 mmol/L
Group 3
223 Patients
Hypotensive after fluids
Requires no vasopressors
Serum lactate >2 mmol/L
Group 6
150 Patients
Hypotensive after fluids
Requires no vasopressors
Serum lactate ≤2 mmol/L
4101 Excluded (did not meet septicshock definition by definition groups)
22941 Potentially eligible for full analysis set
790 Excluded (serum lactate level>4 mmol/L and did not receivefluids or vasopressors)
Hypotensionwas defined as mean arterialpressureless than 65 mmHg.
Vasopressor therapy to maintain mean arterial pressure of 65 mmHg or higher
is treated as a binaryvariable.Serumlactatelevelgreater than 2 mmol/L(18
mg/dL)is consideredabnormal.The“after fluids”fieldin theSurviving Sepsis
Campaign (SSC)databasewas considered equivalentto adequate fluid
resuscitation. “Before fluids”refers to patients whodid notreceivefluid
resuscitation. Serumlactate levelgreater than2 mmol/Lafter fluid resuscitation
butwithout hypotension or need forvasopressor therapy (group 4)is defined
as “cryptic shock.” Missing serumlactate levelmeasurements (n = 4419 [15.7%])
andpatientswithserumlactatelevelsgreaterthan4 mmol/L(36 mg/dL)who
didnot receive fluids as perSSC guidelines (n = 790[2.8%])wereexcluded
fromfullcase analysis.Of the22 941 patients,4101who were codedas having
severesepsis were excluded. Thus, theremaining18 840patientswere
categorized withinseptic shockgroups1 to 6.aPatients with screeningserumlactatelevels coded as greater than 2 mmol/L
(n=3342)were included in the missing-data analysis.
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crease in serum lactate level using complete case analysis
(n = ) and imputed analyses (n = ) were similar
(. [%CI, .-.]; P < . vs . [%CI, .-.];
P < .,respectively). Theimputed andcomplete caseanaly-
sis probabilities of hospitalmortality werealso similar (.%
and .%, respectively).
EHR Data SetsTheUPMCand KPNC EHRs included and adult
patients with suspected infection, respectively (eTable in
the Supplement). Forty-six percent (n = ) of UPMC pa-
tients and % (n = ) of KPNC patients with or more
SOFA score points andsuspectedinfection fulfilledcriteria for
of the potential septic shock groups described. Patients
meeting group criteria (hypotension + vasopressor
therapy + serum lactate level > mmol/L) comprised .%
(UPMC) and .% (KPNC) of the EHR population of patients
with suspected infectionand had a mortalityof % and %,
respectively. Similarto theSSC database,crude mortality rates
within each group were higher among those with higher se-
rum lactate levels (Table ).
Discussion
Thesystematic review illustrated thevariability in criteriacur-
rently used to identify septic shock, whereas the meta-
analysis demonstrated the heterogeneity in mortality. In-
formed by this systematic review, a Delphi process wasused 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 areassociatedwith a greaterriskof mor-
tality than sepsis alone. The clinical criteria representing thisdefinition were theneed forvasopressor therapy to maintain a
MAP of mm Hg or greater and having a serum lactate level
greater than mmol/L persisting after fluid resuscitation.
The proposed definition and criteria of septic shock differ
from prior definitions,, in respects: () the need for both a
serum lactate level and vasopressor-dependent hypotension
(ie, cardiovascular SOFA score ≥) instead of either alone
and () a lower serum lactate level cutoff of mmol/L vs
Figure 4. Serum Lactate Level Analysis
1.0
5.0
2.0
0.5
G E E M o d e l A d j u s t e d O d d s R a t i o ( 9 5 % C
I )
Serum Lactate, mmol/L
1.51 2 3 4 5 6 7 8 9 10
3.0
4.0
Adjusted oddsratiofor actualserumlactate levelsfor theentire septicshock
cohort(N = 18840).The covariatesusedin theregression model include region
(United States and Europe), location wheresepsis was suspected (emergency
department,ward, or critical careunit), antibiotic administration, steroid use,
organfailures (pulmonary, renal,hepatic,and acutely altered mental state),
infection source(pneumonia, urinarytract infection,abdominal,meningitis,
and other), hyperthermia (>38.3°C), hypothermia(20/min), leukopenia(120 mg/dL[6.7 mmol/L]), platelet count2 >3 >4
Died/Total % (95% CI) Died/Total % (95% CI) Died/Total % (95% CI)
Complete Case Analysis (n = 18 795)
Hospital mortal ity, % 5757/18795 30.6 (29.9-31.4) 6101/18795 32.5 (31.8-33.2) 6456/18975 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)
Specificit y, % 274 8/12 2 86 22 .4 (21 .6- 23. 1) 64 18/1 2 286 5 2.2 (5 1.4 -53 .1) 8 564 /12 2 86 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 mortal ity, % 6965/22182 31.4 (30.8-32.0) 7363/22182 33.2 (32.6-33.8) 7772/22182 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)
Specificit y, % 334 1/14 4 34 23 .1 (22 .5- 23. 8) 78 33/1 4 434 5 4.3 (5 3.5 -55 .1) 1 0 801 /14 4 34 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 predictivevalue; PPV, positive predictivevalue.
SI conversionfactor:To convert serumlactate valuesto mg/dL,divideby 0.111.
NewDefinition andCriteriafor SepticShock Original Investigation Research
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mmol/L as currently used in the SSC definitions. In the new
septicshockdefinition,an increase in serum lactate level ispo-
sitioned as a proxy for a cellular metabolic abnormality, andas
a variable independently associatedwith acute mortality (pre-
dictive validity), which is consistent with the published
literature.- An elevated serum lactate level is not specific
forcellulardysfunctionin sepsis, buthas facevalidity 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 witha re-
cent analysis of the entire SSC database. This disparity is ex-
plained by using a data set of patients in the analysis in
this study ratherthanthe total -patient SSCdataset used by Casserlyet al.Fromthis subpopulation groups wereiden-
tified and analyzed as risk strata within the generalized esti-
mating equationmodelandperformance-testedfor various se-
rumlactatelevelcutoffs.The groupwith a significantlygreater
risk of death was then selected.In contrast, Casserly et al re-
ported the independent relationship of hypotension and se-
rum lactate levels with mortality in severe sepsis.
The potentialseptic shockpatient groups analyzedin this
study also providean explanation forthe heterogeneity in sep-
ticshock mortality highlightedby themeta-analysis.Depend-
ing on the group selected,septic shock mortality ranged from
.%to .% within theSSC data setand from.%to .%
in the EHRdata sets.The KPNCEHR dataset corroboratedtheconsistent trends of higher mortalityassociated witha higher
serum lactate level, even in a population with a wider range
of illness severity c aptured by more prevalent measurement
of serum lactate levels.
Thekey strengths of thepresent study arein themethod-
ology used to arrive at the newdefinition and clinical criteria
for septic shock, a clinical syndrome with a range of signs,
symptoms,and biochemicalabnormalitiesthat arenot pathog-
nomonic.Furthermore,the supportingstudies(systematicre-
view, Delphi process, and analyses of the SSC and EHR co-
horts) were iterative and concurrent with the consensus
process,a significant stepforward from previous definitions.
Thisstudyalsohas severallimitations.First,the systematic
reviewdid notformallyassess study quality andwas restricted
toMEDLINEpublications, adult populations,and observational
studies reportingepidemiology. Second,only theDelphi-derived
variables were tested in multiple data sets to generate the pro-
posed septicshockcriteria.Othervariables,including tissueper-
fusionmarkers(eg, basedeficit, oliguria, acutealterationin men-
tation), blood pressure characteristics (eg, diastolic pressure),
resuscitation end points (eg, central venous saturation, lactate
clearance), andnumerousbiomarkers reportedintheliterature,
couldpotentiallyimproveon theproposedseptic shock criteria butwere notincluded. However, operationalizing thedefinition
of septic shock with commonlymeasuredvariablesshouldin-
crease bothgeneralizability andclinicalutility. Third, thelack of
agoldstandarddiagnosticcriteriaforsepticshockprecludescom-
parativeassessment of theseproposed criteria. Fourth, all data
sets hadmissingdatathatcould potentially introducea form of
selection bias. In the primary data set(SSC database) this is-
suewas addressed bydemonstratingthatfull caseanalysisis an
appropriate method (see “Derivation of Serum Lactate Cutoff
ValueandMissing DataAnalysis”).Fifth,serumlactatemeasure-
ments arenotuniversally available,especially outside of a criti-
cal care setting or in resource-limited environments. Although
feasibilityis a qualityindicatorfora definition,
identification of a critically ill patient would generally trigger obtaininga serum
lactate measurement,both to stratifyrisk andto monitorthe re-
sponseto treatment.Sixth, althoughthe proposednew defini-
tion andclinicalcriteriaforsepsisarearbitrary, thesedo havepre-
dictive validityformortality, alongsideface andcontentvalidity.
Thisstudyrepresents onestep in an ongoingiterative pro-
cess andprovides a resourceful structureand a predictive va-
lidity standard for future investigationsin this area. Prospec-
tive validation of the clinical criteria may improve on the
variablesand cutoffs proposed herein, and identification and
Table 5.CrudeMortalityin Septic ShockGroups FromUPMC andKPNCDatasets
Variablea
Highest Serum LactateLevels 24 h AfterInfection Identified,mmol/L
UPMC KPNC
No. (%)(n = 5984)
Acute Hospital MortalityNo. (%)(n = 54135)
Acute Hospital Mortality
No. % (95% CI) 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 4and 5
>2 (all) 1978 (33.1) 355 17.9 (16.3-19.7) 30 209 (55.8) 2061 6.8 (6.5-7.1)
>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
SepsisCampaign;UPMC, Universityof PittsburghMedical Center.
SI conversion factor: To convert serum lactatevalues to mg/dL,divideby 0.111.
a Group1 refersto patients withhypotension + vasopressors + serum lactate
levelsgreater than 2 mmol/L. Group 2 refersto patients with hypotension +
vasopressors + serum lactatelevels less than 2 mmol/L.Group3 refers
to patients with hypotension andserumlactatelevelsgreater than 2 mmol/L.
Groups 4 and5 refer to isolated serum lactatelevel greater than 2 mmol/L.
Counts withina group arenot mutually exclusive, as those with serum
lactatelevels greater than 2 mmol/Lwill include those inthe higherserum
lactate cutoffs.
Research Original Investigation NewDefinition andCriteriafor SepticShock
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validation of novel markers of organ dysfunction and shock
may replace lactate level.
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 mm Hg or greater and
having a serum lactate level greater than mmol/L persist-
ing after adequate fluid resuscitation.
ARTICLE INFORMATION
Author Affiliations: Division of Asthma, Allergy,
and LungBiology,King’sCollege London, London,
United Kingdom (Shankar-Hari);Department of
Critical CareMedicine,Guy’sand StThomas’NHS
FoundationTrust,London SE17EH, United Kingdom
(Shankar-Hari);The OhioState UniversityCollege of
Medicine,Departmentof Biomedical Informatics,
Center for Biostatistics, Columbus (Phillips);
RhodeIsland Hospital, BrownUniversitySchool of
Medicine,Providence, RhodeIsland (Levy); Clinical
Research,Investigation, and Systems Modeling of
AcuteIllness Center,Department of Critical Care
and Emergency Medicine,Universityof Pittsburgh,
Pittsburgh,Pennsylvania(Seymour, Angus);Divisionof Research,Kaiser Permanente, Oakland,
California (Liu);Department of Pediatrics,
Hofstra-North Shore-Long IslandJewish-Hofstra
Schoolof Medicine, Steven and Alexandra Cohen
Children’s Medical Center,New HydePark,
New York (Deutschman); Departmentof Molecular
Medicine,Hofstra-North Shore-Long Island
Jewish-Hofstra Schoolof Medicine,Steven and
Alexandra CohenChildren’s Medical Center,
New HydePark, New York (Deutschman);Feinstein
Institutefor Medical Research,Manhasset,
New York (Deutschman); Associate Editor, JAMA
(Angus); Interdepartmental Division of Critical Care
Medicine,Universityof Toronto,Toronto, Ontario,
Canada(Rubenfeld); SunnybrookHealth Sciences
Centre, Toronto, Ontario, Canada(Rubenfeld);
Bloomsbury Instituteof Intensive Care Medicine,UniversityCollege London, London,
United Kingdom (Singer).
Author Contributions: Dr Shankar-Hari had full
accessto all ofthedatain the study and takes
responsibility forthe integrityof thedataand the
accuracy of thedataanalysis.
Study concept and design: Shankar-Hari, Levy,
Deutschman, Angus, Rubenfeld,Singer.
Acquisition, analysis, or interpretation of data:
Shankar-Hari, Phillips, Levy, Seymour,Liu, Singer.
Draftingof the manuscript: Shankar-Hari, Phillips,
Levy, Deutschman, Angus, Singer.
Critical revision of the manuscript for important
intellectualcontent: 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
completedand submittedthe ICMJE Form for
Disclosure of Potential Conflicts of Interest.Drs
Shankar-Hari and Singer reported receiving support
fromtheUK NIHR Biomedical ResearchCentre
schemes. DrLevy reported receivinga grantfrom
ImmuneExpress. Dr Seymour reported receiving
personal fees fromBeckmanCoulter. Dr Liu
reported receivingK grantsupportfromthe
National Institutesof Health (K23GM112018). Dr
Deutschmanreportedholding patents on materials
notrelated tothis work andreceiving travel/
accommodations and related expenses for
participationin meetings paid bythe Centers for
Disease Control and Prevention,World Federation
of Societiesof Intensiveand Critical Care,
Pennsylvania Assembly of Critical Care Medicine/PA
Chapter,Societyof Critical Care Medicine (SCCM)/
PennState–Hershey Medical Center,Society of
Critical Care Medicine,Northern Ireland Society of
Critical Care Medicine,International Sepsis Forum,
Departmentof Anesthesiology, Stanford University,
AcuteDialysis Quality Initiative,and EuropeanSociety of Intensive Care Medicine (ESICM). Dr
Singerreportedserving on advisory boards for
Bayer and Biotestandthat heis a recipient ofa UK
NIHRSenior Investigator Fellowship(2009-2017).
No otherdisclosureswere reported.
Members of the Sepsis DefinitionsTaskForce
and Delphi Study: DerekAngus, DjilalliAnnane,
Michael Bauer, Rinaldo Bellomo, GordonBernard,
Jean-Daniel Chiche, CraigCoopersmith,
Cliff Deutschman(cochair), Richard Hotchkiss,
Mitchell Levy, JohnMarshall, GregMartin,
Steve Opal,Gordon Rubenfeld,Christopher
Seymour (co-opted),Manu Shankar-Hari
(co-opted),Mervyn Singer (cochair),
Tom vander Poll,Jean-Louis Vincent.
Funding/Support: TheSepsis DefinitionsTask
Forcereceivedunrestricted funding supportfrom
theEuropean Society of IntensiveCare Medicine
andthe Society of CriticalCareMedicine
(sponsors).
Roleof the Funders/Sponsors: Thefunders/
sponsors hadno rolein thedesign andconduct of
thestudy; collection, management, analysis, and
interpretation of the data;preparation, review,or
approval of themanuscript;and decision to submit
themanuscriptfor publication.
Disclaimer: Dr Angus, JAMA Associate Editor, had
no rolein theevaluationof or decision to publish
thisarticle.
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