Shankar Hari2016

8/18/2019 Shankar Hari2016

1/13

Copyright 2016 American Medical Association. All rig hts reserved.

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

Editorial page757

Author AudioInterview at

jama.com

Related articles pages762 and

801

Supplementalcontent at

jama.com

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

([email protected]).

Research

Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT

(Reprinted) 775


wnloaded From: http://jama.jamanetwork.com/ by a La Trobe University User on 02/22/2016

http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0290&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www./http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0287&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0288&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289mailto:[email protected]:[email protected]:[email protected]:[email protected]://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0288&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0287&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www./http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0290&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289


2/13


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

776 JAMA February23,2016 Volume315,Number 8 (Reprinted) jama.com



http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289


3/13


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


4/13


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


5/13


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

jama.com (Reprinted) JAMA February23,2016 Volume 315, Number8 779



http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289


6/13


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


7/13


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




http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289


8/13


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



Serum lactate ≤2 mmol/L

Group 5

2696 Patients

Not hypotensive beforefluids



Group 4

2696 Patients

Not hypotensive afterfluids

Requires no vasopressors


Group 3

223 Patients




Group 6

150 Patients



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.





http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289


9/13


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




http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0289&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289


10/13


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.





http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289


11/13


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.

REFERENCES

1. Bone RC,Balk RA,CerraFB, et al.Definitionsfor

sepsisand organ failureand guidelines forthe use

of innovativetherapiesin sepsis. Chest . 1992;101

(6):1644-1655.

2. Levy MM,FinkMP, Marshall JC,et al.

2001 SCCM/ESICM/ACCP/ATS/SIS International

Sepsis DefinitionsConference. Crit Care Med . 2003;

31(4):1250-1256.

3. RheeC, Gohil S,Klompas M. Regulatory

mandates for sepsiscare—reasons for caution.

N EnglJ Med . 2014;370(18):1673-1676.

4. Iwashyna TJ, AngusDC. Decliningcase fatality

rates forseveresepsis. JAMA. 2014;311(13):1295-1297.

5. Leligdowicz A, DodekPM, NorenaM, etal.

Association between sourceof infection and

hospital mortality in patients who haveseptic

shock. Am J Respir Crit Care Med . 2014;189(10):

1204-1213.

6. Levy MM,Dellinger RP, Townsend SR,et al.

TheSurviving SepsisCampaign:results of an

international guideline-based performance

improvementprogram targeting severe sepsis.

IntensiveCare Med . 2010;36(2):222-231.

7. Klein Klouwenberg PM,OngDS, BontenMJ,

CremerOL. Classificationof sepsis, severe sepsis

andseptic shock:theimpactof minor variations in

data capture anddefinition of SIRS criteria.


8. Shankar-Hari M, Bertolini G, Brunkhorst FM,

et al.Judgingquality of current septicshock

definitions and criteria. CritCare . 2015;19(1):445.

9. Iwashyna TJ,GovindanS. Didtheyjustprove

that a diagnosisof “septic shock”is meaningless?

Am J Respir Crit Care Med . 2014;189(10):1156-1157.

10. SingerM. The roleof mitochondrialdysfunction

in sepsis-induced multi-organfailure. Virulence .

2014;5(1):66-72.

11. HotchkissRS, MonneretG, PayenD.

Sepsis-induced immunosuppression. NatRev

Immunol . 2013;13(12):862-874.

12. Takasu O,GautJP, WatanabeE, et al.

Mechanismsof cardiac and renaldysfunction in

patients dyingof sepsis. Am J Respir Crit Care Med .2013;187(5):509-517.

13. Rudiger A, Dyson A, FelsmannK, etal.

Earlyfunctional and transcriptomic changes in the

myocardium predict outcome in a long-termrat

modelof sepsis. ClinSci (Lond). 2013;124(6):391-401.

14. SingerM, Deutschman C, Seymour CW, etal.

TheThird International Consensus Definitionsfor

Sepsisand Septic Shock(Sepsis-3). JAMA.

doi:10.1001/jama.2016.0287 .

15. USDepartment of Healthand HumanServices

(DHHS). FrequentlyAsked QuestionsAbout Human

Research.DHHS website. http://www.hhs.gov

/ohrp/policy/faq/index.html.May 10,2010.

Accessed Feburary 1, 2016.

16. Seymour CW, LiuV,IwashynaTJet al.

Assessmentof clinical criteria forsepsis: forthe

ThirdInternational Consensus Definitions for Sepsis

and Septic Shock(Sepsis-3). JAMA.doi:10.1001

/jama.2016.0288.

17. CasserlyB, Phillips GS,Schorr C,et al.

Lactate measurements in sepsis-induced tissue

hypoperfusion. Crit Care Med . 2015;43(3):567-573.

18. WorldHealth Organisation(WHO).Health

Statistics and InformationSystems: Definitionof

Region Groupings. WHOwebsite. http://www.who

.int/healthinfo/global_burden_disease/definition

_regions/en/. July 5,2015.

NewDefinitionand Criteriafor SepticShock Original Investigation Research




http://www.ncbi.nlm.nih.gov/pubmed/1303622http://www.ncbi.nlm.nih.gov/pubmed/1303622http://www.ncbi.nlm.nih.gov/pubmed/1303622http://www.ncbi.nlm.nih.gov/pubmed/1303622http://www.ncbi.nlm.nih.gov/pubmed/12682500http://www.ncbi.nlm.nih.gov/pubmed/12682500http://www.ncbi.nlm.nih.gov/pubmed/12682500http://www.ncbi.nlm.nih.gov/pubmed/12682500http://www.ncbi.nlm.nih.gov/pubmed/24738642http://www.ncbi.nlm.nih.gov/pubmed/24738642http://www.ncbi.nlm.nih.gov/pubmed/24738642http://www.ncbi.nlm.nih.gov/pubmed/24638109http://www.ncbi.nlm.nih.gov/pubmed/24638109http://www.ncbi.nlm.nih.gov/pubmed/24638109http://www.ncbi.nlm.nih.gov/pubmed/24635548http://www.ncbi.nlm.nih.gov/pubmed/24635548http://www.ncbi.nlm.nih.gov/pubmed/24635548http://www.ncbi.nlm.nih.gov/pubmed/24635548http://www.ncbi.nlm.nih.gov/pubmed/20069275http://www.ncbi.nlm.nih.gov/pubmed/20069275http://www.ncbi.nlm.nih.gov/pubmed/20069275http://www.ncbi.nlm.nih.gov/pubmed/22476449http://www.ncbi.nlm.nih.gov/pubmed/22476449http://www.ncbi.nlm.nih.gov/pubmed/22476449http://www.ncbi.nlm.nih.gov/pubmed/26702879http://www.ncbi.nlm.nih.gov/pubmed/26702879http://www.ncbi.nlm.nih.gov/pubmed/26702879http://www.ncbi.nlm.nih.gov/pubmed/24832739http://www.ncbi.nlm.nih.gov/pubmed/24832739http://www.ncbi.nlm.nih.gov/pubmed/24832739http://www.ncbi.nlm.nih.gov/pubmed/24185508http://www.ncbi.nlm.nih.gov/pubmed/24185508http://www.ncbi.nlm.nih.gov/pubmed/24185508http://www.ncbi.nlm.nih.gov/pubmed/24185508http://www.ncbi.nlm.nih.gov/pubmed/24232462http://www.ncbi.nlm.nih.gov/pubmed/24232462http://www.ncbi.nlm.nih.gov/pubmed/24232462http://www.ncbi.nlm.nih.gov/pubmed/24232462http://www.ncbi.nlm.nih.gov/pubmed/23348975http://www.ncbi.nlm.nih.gov/pubmed/23348975http://www.ncbi.nlm.nih.gov/pubmed/23348975http://www.ncbi.nlm.nih.gov/pubmed/23348975http://www.ncbi.nlm.nih.gov/pubmed/22988837http://www.ncbi.nlm.nih.gov/pubmed/22988837http://www.ncbi.nlm.nih.gov/pubmed/22988837http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0287&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0287&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0287&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.hhs.gov/ohrp/policy/faq/index.htmlhttp://www.hhs.gov/ohrp/policy/faq/index.htmlhttp://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0288&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0288&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0288&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0288&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.ncbi.nlm.nih.gov/pubmed/25479113http://www.ncbi.nlm.nih.gov/pubmed/25479113http://www.ncbi.nlm.nih.gov/pubmed/25479113http://www.who.int/healthinfo/global_burden_disease/definition_regions/en/http://www.who.int/healthinfo/global_burden_disease/definition_regions/en/http://www.who.int/healthinfo/global_burden_disease/definition_regions/en/http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.who.int/healthinfo/global_burden_disease/definition_regions/en/http://www.who.int/healthinfo/global_burden_disease/definition_regions/en/http://www.who.int/healthinfo/global_burden_disease/definition_regions/en/http://www.ncbi.nlm.nih.gov/pubmed/25479113http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0288&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0288&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.hhs.gov/ohrp/policy/faq/index.htmlhttp://www.hhs.gov/ohrp/policy/faq/index.htmlhttp://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0287&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.0289http://www.ncbi.nlm.nih.gov/pubmed/22988837http://www.ncbi.nlm.nih.gov/pubmed/23348975http://www.ncbi.nlm.nih.gov/pubmed/23348975http://www.ncbi.nlm.nih.gov/pubmed/24232462http://www.ncbi.nlm.nih.gov/pubmed/24232462http://www.ncbi.nlm.nih.gov/pubmed/24185508http://www.ncbi.nlm.nih.gov/pubmed/24185508http://www.ncbi.nlm.nih.gov/pubmed/24832739http://www.ncbi.nlm.nih.gov/pubmed/26702879http://www.ncbi.nlm.nih.gov/pubmed/22476449http://www.ncbi.nlm.nih.gov/pubmed/20069275http://www.ncbi.nlm.nih.gov/pubmed/24635548http://www.ncbi.nlm.nih.gov/pubmed/24635548http://www.ncbi.nlm.nih.gov/pubmed/24638109http://www.ncbi.nlm.nih.gov/pubmed/24738642http://www.ncbi.nlm.nih.gov/pubmed/12682500http://www.ncbi.nlm.nih.gov/pubmed/12682500http://www.ncbi.nlm.nih.gov/pubmed/1303622http://www.ncbi.nlm.nih.gov/pubmed/1303622


12/13


19. OrtízG, DueñasC, RodríguezF, et al.

Epidemiologyof sepsisin Colombian intensive care

units. Biomedica. 2014;34(1):40-47.

20. Ogura H,GandoS, SaitohD,et al.

Epidemiologyof severe sepsisin Japanese

intensivecare units. J Infect Chemother . 2014;20

(3):157-162.

21. Liu V, Escobar GJ, GreeneJD,et al.Hospital

deathsin patientswith sepsisfrom 2 independent

cohorts. JAMA. 2014;312(1):90-92.

22. KaukonenKM, BaileyM, SuzukiS, Pilcher D,

Bellomo R. Mortalityrelated to severesepsis and

septicshock amongcriticallyill patients in Australia

and NewZealand,2000-2012. JAMA. 2014;311

(13):1308-1316.

23. Gonçalves-Pereira J,PereiraJM, Ribeiro O,et al.

Impactof infectionon admissionand of theprocess

of care on mortality of patientsadmittedto the

intensivecare unit:the INFAUCIstudy. Clin

Microbiol Infect . 2014;20(12):1308-1315.

24. WhittakerSA, MikkelsenME, Gaieski DF, Koshy

S,KeanC, FuchsBD.Severe sepsiscohorts derived

from claims-basedstrategies appearto be biased

toward a more severely ill patient population. Crit

Care Med . 2013;41(4):945-953.

25. Sakr Y, EliaC, MasciaL, etal. Epidemiology and

outcome of sepsissyndromes inItalian ICUs.

Minerva Anestesiol . 2013;79(9):993-1002.

26. QuenotJP, Binquet C, Kara F, etal.

Theepidemiology of septicshockin French

intensivecare units.Crit Care . 2013;17(2):R65.

27. NesselerN, Defontaine A, LauneyY,Morcet J,

Mallédant Y, Seguin P. Long-termmortalityand

quality of lifeafter septicshock. IntensiveCare Med .

2013;39(5):881-888.

28. ParkDW, ChunBC,Kim JM, etal.

Epidemiological and clinical characteristics of

community-acquired severe sepsisand septic

shock. J Korean Med Sci . 2012;27(11):1308-1314.

29. LevyMM, ArtigasA, Phillips GS,et al.

Outcomes of theSurviving SepsisCampaigninintensivecareunitsin theUSA andEurope. Lancet

Infect Dis. 2012;12(12):919-924.

30. Zahar JR,Timsit JF, Garrouste-OrgeasM, etal.

Outcomes insevere sepsisand patients with septic

shock[publishedcorrectionappears in Crit Care

Med . 2011;39(10):2392]. Crit Care Med . 2011;39(8):

1886-1895.

31. RodríguezF,Barrera L,De LaRosa G,et al.

Theepidemiology of sepsisin Colombia:

a prospectivemulticenter cohortstudy in ten

university hospitals. Crit Care Med . 2011;39(7):1675-

1682.

32. PhuaJ, Koh Y, DuB, etal.Managementof

severesepsis in patients admittedto Asian

intensivecare units.BMJ . 2011;342:d3245.

33. Moore LJ, McKinleyBA, Turner KL,et al.Theepidemiology of sepsisin general surgery

patients. J Trauma. 2011;70(3):672-680.

34. KaussIA, Grion CM,Cardoso LT, etal.

Theepidemiology of sepsisin a Brazilian teaching

hospital. Braz J InfectDis. 2010;14(3):264-270.

35. PóvoaPR, Carneiro AH,Ribeiro OS, Pereira AC;

PortugueseCommunity-AcquiredSepsis Study

Group.Influenceof vasopressor agentin septic

shock mortality. Crit Care Med . 2009;37(2):410-416.

36. PeakeSL, BaileyM, BellomoR, etal.

Australasianresuscitation of sepsisevaluation

(ARISE). Resuscitation. 2009;80(7):811-818.

37. Khwannimit B, BhurayanontachaiR.

Theepidemiologyof, and risk factors for, mortality

fromsevere sepsisand septicshockin a

tertiary-care universityhospital setting. Epidemiol

Infect . 2009;137(9):1333-1341.

38. Angkasekwinai N, RattanaumpawanP,

Thamlikitkul V. Epidemiologyof sepsisin SirirajHospital 2007. J Med Assoc Thai . 2009;92(suppl 2):

S68-S78.

39. Sakr Y, Vincent JL,Schuerholz T, etal.

Early- versuslate-onset shockin European

intensive careunits. Shock . 2007;28(6):636-643.

40. KarlssonS, Varpula M,RuokonenE, etal.

Incidence, treatment,and outcome of severe sepsis

in ICU-treatedadults in Finland: the Finnsepsis

study. IntensiveCare Med . 2007;33(3):435-443.

41. Esteban A, Frutos-Vivar F,Ferguson ND, etal.

Sepsis incidenceand outcome: contrasting the

intensivecareunit with thehospital ward. Crit Care

Med . 2007;35(5):1284-1289.

42. Engel C, BrunkhorstFM, Bone HG,et al.

Epidemiology of sepsisin Germany. IntensiveCare

Med . 2007;33(4):606-618.

43. Vincent JL,Sakr Y, SprungCL, etal. Sepsisin

Europeanintensivecareunits: results of theSOAP

study. Crit Care Med . 2006;34(2):344-353.

44. Shapiro N,Howell MD, Bates DW, Angus DC,

Ngo L, Talmor D.Theassociation of sepsis

syndrome and organdysfunctionwith mortality in

emergencydepartment patients withsuspected

infection. Ann Emerg Med . 2006;48(5):583-590.

45. GasparovićV,GornikI, Ivanović D.

Sepsis syndrome in Croatian intensive careunits:

piloting a national comparativeclinical database.

Croat MedJ . 2006;47(3):404-409.

46. DegoricijaV,SharmaM, LegacA, etal.

Survival analysis of 314episodesof sepsisin

medical intensivecare unitin universityhospital.Croat MedJ . 2006;47(3):385-397.

47. Laupland KB,Zygun DA,DoigCJ, etal.

One-yearmortality of bloodstream

infection-associated sepsisand septic shockamong

patients presentingto a regional critical care

system. IntensiveCare Med . 2005;31(2):213-219.

48. Silva E, PedroMdeA,Sogayar AC,et al.

Brazilian SepsisEpidemiological Study(BASES

study). Crit Care . 2004;8(4):R251-R260.

49. Laupland KB,Davies HD, ChurchDL, etal.

Bloodstreaminfection-associated sepsisand septic

shock in critically ill adults. Infection. 2004;32(2):

59-64.

50. FlaattenH. Epidemiology of sepsisin Norway

in 1999. Crit Care . 2004;8(4):R180-R184.

51. Annane D, Aegerter P, Jars-GuincestreMC,

GuidetB; CUB-Réa Network. Current epidemiology

of septicshock: theCUB-Réa Network. Am J Respir

Crit Care Med . 2003;168(2):165-172.

52. Alberti C, Brun-Buisson C,BurchardiH, etal.

Epidemiology of sepsisand infectionin ICUpatients

from an international multicentrecohort study.


53. Schoenberg MH, Weiss M, RadermacherP.

Outcome of patients with sepsisand septicshock

afterICU treatment.LangenbecksArch Surg. 1998;

383(1):44-48.

54. Lundberg JS,PerlTM, WiblinT,et al.

Septicshock: ananalysis of outcomes forpatients

with onseton hospital wards versusintensive care

units. Crit Care Med . 1998;26(6):1020-1024.

55. Salvo I,de CianW,MusiccoM, etal.TheItalian

SEPSISstudy:preliminaryresults on theincidence

andevolutionof SIRS,sepsis, severesepsis and

septicshock. Intensive CareMed . 1995;21(suppl 2):

S244-S249.

56. Rangel-Frausto MS,Pittet D, Costigan M,Hwang T, DavisCS, Wenzel RP. Thenatural history

of thesystemicinflammatoryresponsesyndrome

(SIRS). JAMA. 1995;273(2):117-123.

57. Pittet D,Rangel-Frausto S,Li N,et al.

Systemicinflammatoryresponse syndrome,sepsis,

severe sepsisand septicshock. IntensiveCare Med .

1995;21(4):302-309.

58. McLauchlan GJ,AndersonID, GrantIS,

Fearon KC.Outcome of patients withabdominal

sepsistreated inan intensivecare unit. BrJ Surg.

1995;82(4):524-529.

59. Dahmash NS,ChowdhuryNH, Fayed DF.

Septic shockin critically ill patients. J Infect . 1993;

26(2):159-170.

60. Whittaker SA,Fuchs BD, Gaieski DF, etal.

Epidemiologyand outcomes in patients with severe

sepsisadmittedto the hospital wards. J Crit Care .

2015;30(1):78-84.

61. Cross G,Bilgrami I, Eastwood G,et al.

Theepidemiologyof sepsisduring rapidresponse

team reviews in a teachinghospital. Anaesth

IntensiveCare . 2015;43(2):193-198.

62. Vincent JL, Marshall JC, Namendys-SilvaSA,

et al; ICONInvestigators.Assessmentof the

worldwide burdenof critical illness. LancetRespir

Med . 2014;2(5):380-386.

63. StevensonEK, RubensteinAR, RadinGT,

WienerRS, Walkey AJ. Two decades of mortality

trends amongpatientswith severe sepsis. Crit Care

Med . 2014;42(3):625-631.

64. KoupetoriM, RetsasT,Antonakos N,et al;Hellenic Sepsis StudyGroup. Bloodstream

infections and sepsisin Greece. BMCInfect 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. StorgaardM, HallasJ, Gahrn-HansenB, etal.

Short- and long-termmortality in patients with

community-acquired severe sepsisand septic

shock. Scand J Infect Dis. 2013;45(8):577-583.

67. Stiermaier T, Herkner H,TobudicS, et al.

Incidence and long-termoutcome of sepsison

general wards andin anICU atthe General Hospital

of Vienna: an observationalcohort study. WienKlin

Wochenschr . 2013;125(11-12):302-308.68. RohdeJM, OddenAJ, BonhamC, et al.

Theepidemiologyof acuteorgan system

dysfunction fromseveresepsisoutsideof the

intensivecare unit. J Hosp Med . 2013;8(5):243-247.

69. Gray A, Ward K, Lees F, etal. Theepidemiology

of adultswithsevere sepsisand septicshockin

Scottish emergencydepartments. EmergMed J .

2013;30(5):397-401.

70. Gaieski DF, EdwardsJM, KallanMJ,Carr BG.

Benchmarking theincidenceand mortality of





http://www.ncbi.nlm.nih.gov/pubmed/24967858http://www.ncbi.nlm.nih.gov/pubmed/24967858http://www.ncbi.nlm.nih.gov/pubmed/24967858http://www.ncbi.nlm.nih.gov/pubmed/24530102http://www.ncbi.nlm.nih.gov/pubmed/24530102http://www.ncbi.nlm.nih.gov/pubmed/24530102http://www.ncbi.nlm.nih.gov/pubmed/24530102http://www.ncbi.nlm.nih.gov/pubmed/24838355http://www.ncbi.nlm.nih.gov/pubmed/24838355http://www.ncbi.nlm.nih.gov/pubmed/24838355http://www.ncbi.nlm.nih.gov/pubmed/24638143http://www.ncbi.nlm.nih.gov/pubmed/24638143http://www.ncbi.nlm.nih.gov/pubmed/24638143http://www.ncbi.nlm.nih.gov/pubmed/24638143http://www.ncbi.nlm.nih.gov/pubmed/24975209http://www.ncbi.nlm.nih.gov/pubmed/24975209http://www.ncbi.nlm.nih.gov/pubmed/24975209http://www.ncbi.nlm.nih.gov/pubmed/24975209http://www.ncbi.nlm.nih.gov/pubmed/23385099http://www.ncbi.nlm.nih.gov/pubmed/23385099http://www.ncbi.nlm.nih.gov/pubmed/23385099http://www.ncbi.nlm.nih.gov/pubmed/23385099http://www.ncbi.nlm.nih.gov/pubmed/23811620http://www.ncbi.nlm.nih.gov/pubmed/23811620http://www.ncbi.nlm.nih.gov/pubmed/23811620http://www.ncbi.nlm.nih.gov/pubmed/23561510http://www.ncbi.nlm.nih.gov/pubmed/23561510http://www.ncbi.nlm.nih.gov/pubmed/23561510http://www.ncbi.nlm.nih.gov/pubmed/23358541http://www.ncbi.nlm.nih.gov/pubmed/23358541http://www.ncbi.nlm.nih.gov/pubmed/23358541http://www.ncbi.nlm.nih.gov/pubmed/23358541http://www.ncbi.nlm.nih.gov/pubmed/23166410http://www.ncbi.nlm.nih.gov/pubmed/23166410http://www.ncbi.nlm.nih.gov/pubmed/23166410http://www.ncbi.nlm.nih.gov/pubmed/23103175http://www.ncbi.nlm.nih.gov/pubmed/23103175http://www.ncbi.nlm.nih.gov/pubmed/23103175http://www.ncbi.nlm.nih.gov/pubmed/23103175http://www.ncbi.nlm.nih.gov/pubmed/21516036http://www.ncbi.nlm.nih.gov/pubmed/21516036http://www.ncbi.nlm.nih.gov/pubmed/21516036http://www.ncbi.nlm.nih.gov/pubmed/21516036http://www.ncbi.nlm.nih.gov/pubmed/21685740http://www.ncbi.nlm.nih.gov/pubmed/21685740http://www.ncbi.nlm.nih.gov/pubmed/21685740http://www.ncbi.nlm.nih.gov/pubmed/21685740http://www.ncbi.nlm.nih.gov/pubmed/21669950http://www.ncbi.nlm.nih.gov/pubmed/21669950http://www.ncbi.nlm.nih.gov/pubmed/21669950http://www.ncbi.nlm.nih.gov/pubmed/21610358http://www.ncbi.nlm.nih.gov/pubmed/21610358http://www.ncbi.nlm.nih.gov/pubmed/21610358http://www.ncbi.nlm.nih.gov/pubmed/20835510http://www.ncbi.nlm.nih.gov/pubmed/20835510http://www.ncbi.nlm.nih.gov/pubmed/20835510http://www.ncbi.nlm.nih.gov/pubmed/19114885http://www.ncbi.nlm.nih.gov/pubmed/19114885http://www.ncbi.nlm.nih.gov/pubmed/19114885http://www.ncbi.nlm.nih.gov/pubmed/19467755http://www.ncbi.nlm.nih.gov/pubmed/19467755http://www.ncbi.nlm.nih.gov/pubmed/19467755http://www.ncbi.nlm.nih.gov/pubmed/19192320http://www.ncbi.nlm.nih.gov/pubmed/19192320http://www.ncbi.nlm.nih.gov/pubmed/19192320http://www.ncbi.nlm.nih.gov/pubmed/19192320http://www.ncbi.nlm.nih.gov/pubmed/19562989http://www.ncbi.nlm.nih.gov/pubmed/19562989http://www.ncbi.nlm.nih.gov/pubmed/19562989http://www.ncbi.nlm.nih.gov/pubmed/19562989http://www.ncbi.nlm.nih.gov/pubmed/18092378http://www.ncbi.nlm.nih.gov/pubmed/18092378http://www.ncbi.nlm.nih.gov/pubmed/18092378http://www.ncbi.nlm.nih.gov/pubmed/17225161http://www.ncbi.nlm.nih.gov/pubmed/17225161http://www.ncbi.nlm.nih.gov/pubmed/17225161http://www.ncbi.nlm.nih.gov/pubmed/17414725http://www.ncbi.nlm.nih.gov/pubmed/17414725http://www.ncbi.nlm.nih.gov/pubmed/17414725http://www.ncbi.nlm.nih.gov/pubmed/17414725http://www.ncbi.nlm.nih.gov/pubmed/17323051http://www.ncbi.nlm.nih.gov/pubmed/17323051http://www.ncbi.nlm.nih.gov/pubmed/17323051http://www.ncbi.nlm.nih.gov/pubmed/17323051http://www.ncbi.nlm.nih.gov/pubmed/16424713http://www.ncbi.nlm.nih.gov/pubmed/16424713http://www.ncbi.nlm.nih.gov/pubmed/16424713http://www.ncbi.nlm.nih.gov/pubmed/17052559http://www.ncbi.nlm.nih.gov/pubmed/17052559http://www.ncbi.nlm.nih.gov/pubmed/17052559http://www.ncbi.nlm.nih.gov/pubmed/16758518http://www.ncbi.nlm.nih.gov/pubmed/16758518http://www.ncbi.nlm.nih.gov/pubmed/16758518http://www.ncbi.nlm.nih.gov/pubmed/16758516http://www.ncbi.nlm.nih.gov/pubmed/16758516http://www.ncbi.nlm.nih.gov/pubmed/16758516http://www.ncbi.nlm.nih.gov/pubmed/15666140http://www.ncbi.nlm.nih.gov/pubmed/15666140http://www.ncbi.nlm.nih.gov/pubmed/15666140http://www.ncbi.nlm.nih.gov/pubmed/15312226http://www.ncbi.nlm.nih.gov/pubmed/15312226http://www.ncbi.nlm.nih.gov/pubmed/15312226http://www.ncbi.nlm.nih.gov/pubmed/15057568http://www.ncbi.nlm.nih.gov/pubmed/15057568http://www.ncbi.nlm.nih.gov/pubmed/15057568http://www.ncbi.nlm.nih.gov/pubmed/15057568h

Shankar Hari2016

Documents

Transcript of Shankar Hari2016