9/21/2016 Sepsissyndromesinadults:Epidemiology,definitions,clinicalpresentation,diagnosis,andprognosis

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Sepsissyndromesinadults:Epidemiology,definitions,clinicalpresentation,diagnosis,andprognosis

Author SectionEditor DeputyEditor

RemiNeviere,MD PollyEParsons,MD GeraldineFinlay,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Aug2016.|Thistopiclastupdated:Sep19,2016.
INTRODUCTIONSepsisisaclinicalsyndromethathasphysiologic,biologic,andbiochemicalabnormalities
causedbyadysregulatedinflammatoryresponsetoinfection.Sepsisandtheinflammatoryresponsethatensuescan
leadtomultipleorgandysfunctionsyndromeanddeath.

Theepidemiology,definitions,riskfactors,clinicalpresentation,diagnosis,andoutcomesofsepsisarereviewedhere.
Thepathophysiologyandtreatmentofsepsisarediscussedseparately.(See"Pathophysiologyofsepsis"and
"Evaluationandmanagementofsuspectedsepsisandsepticshockinadults".)

EPIDEMIOLOGY

IncidenceInthelate1970s,itwasestimatedthat164,000casesofsepsisoccurredintheUnitedStates(US)each
year[1].Sincethen,ratesofsepsisintheUSandelsewherehavedramaticallyincreasedassupportedbythe
followingstudies[25]:

OnenationaldatabaseanalysisofdischargerecordsfromhospitalsintheUSestimatedanannualrateofmore
than1,665,000casesofsepsisbetween1979and2000[2].

Anotherretrospectivepopulationbasedanalysisreportedincreasedratesofsepsisandsepticshockfrom13to
78casesper100,000between1998and2009[3].

Aretrospectiveanalysisofaninternationaldatabasereportedaglobalincidenceof437per100,000personyears
forsepsisand270per100,000personyearsforseveresepsisbetweentheyears1995and2015,althoughthis
ratewasnotreflectiveofcontributionsfromlowandmiddleincomecountries[6].

Theincreasedrateofsepsisisthoughttobeaconsequenceofadvancingage,immunosuppression,andmultidrug
resistantinfection[4,710].Itisalsolikelytobeduetotheincreaseddetectionofearlysepsisfromaggressivesepsis
educationandawarenesscampaigns,althoughthishypothesisisunproven.

Theincidenceofsepsisvariesamongthedifferentracialandethnicgroups,butappearstobehighestamongAfrican
Americanmales(figure1)[1].

Theincidenceisalsogreatestduringthewinter,probablyduetotheincreasedprevalenceofrespiratoryinfections[11].

Olderpatients65yearsofageaccountforthemajority(60to85percent)ofallepisodesofsepsiswithanincreasing
agingpopulation,itislikelythattheincidenceofsepsiswillcontinuetoincreaseinthefuture[1,4,12,13].

PathogensThecontributionofvariousinfectiousorganismstotheburdenofsepsishaschangedovertime[1417].
GrampositivebacteriaaremostfrequentlyidentifiedinpatientswithsepsisintheUnitedStates,althoughthenumber
ofcasesofGramnegativesepsisremainssubstantial.Theincidenceoffungalsepsishasincreasedoverthepast
decade,butremainslowerthanbacterialsepsis[1,14].

DiseaseseverityTheseverityofdiseaseappearstobeincreasing[18].Inoneretrospectiveanalysis,the
proportionofpatientswithsepsiswhoalsohadatleastonedysfunctionalorganincreasedfrom26to44percent
between1993and2003[19,20].Themostcommonmanifestationsofsevereorgandysfunctionwereacuterespiratory
distresssyndrome,acuterenalfailure,anddisseminatedintravascularcoagulation[21].However,itisunclearasto
whethertherisingincidenceofseveresepsisandsepticshockreflectstheoverallincreasedincidenceofsepsisor
altereddefinitionsofsepsisovertime.

DEFINITIONSSepsisexistsonacontinuumofseverityrangingfrominfectionandbacteremiatosepsisandseptic
shock,whichcanleadtomultipleorgandysfunctionsyndrome(MODS)anddeath.Thedefinitionsofsepsisandseptic
shockhaverapidlyevolvedsincetheearly1990s[14,2227].Thesystemicinflammatoryresponsesyndrome(SIRS)is
nolongerincludedinthedefinitionsinceitisnotalwayscausedbyinfection.Thedefinitionsforsepsisthatweprovide
belowreflectexpertopinionfromtaskforcesgeneratedbynationalsocietiesincludingtheSocietyofCriticalCare
Medicine(SCCM)andtheEuropeanSocietyofIntensiveCareMedicine(ESICM).Importantly,suchdefinitionsarenot

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diagnosticofsepsissincetheydonotcomprehensivelyincludespecificcriteriafortheidentificationofinfection.(See
'Diagnosis'below.)

EarlysepsisInfectionandbacteremiamaybeearlyformsofinfectionthatcanprogresstosepsis.However,there
isnoformaldefinitionofearlysepsis.Nonetheless,despitethelackofdefinition,monitoringthosesuspectedofhaving
sepsisiscriticalforitsprevention.

InfectionandbacteremiaAllpatientswithinfectionorbacteremiaareatriskofdevelopingsepsisandrepresent
earlyphasesinthecontinuumofsepsisseverity:

Infectionisdefinedastheinvasionofnormallysteriletissuebyorganismsresultingininfectiouspathology.

Bacteremiaisthepresenceofviablebacteriaintheblood.

IdentificationofearlysepsisSocietalguidelinesplaceemphasisontheearlyidentificationofinfectedpatients
whomaygoontodevelopsepsisasawaytodecreasesepsisassociatedmortality.The2016SCCM/ESICMtask
forcehavedescribedanassessmentscoreforpatientsoutsidetheintensivecareunitasawaytofacilitatethe
identificationofpatientspotentiallyatriskofdyingfromsepsis[2527].Thisscoreisamodifiedversionofthe
Sequential(Sepsisrelated)OrganFailureAssessmentscore(SOFA)calledthequickSOFA(qSOFA).TheqSOFAonly
hasthreecomponentsthatareeachallocatedonepoint:respiratoryrate22/minute,alteredmentation,andsystolic
bloodpressure100mmHg.Ascore2isassociatedwithpooroutcomesduetosepsis.However,theabilityof
qSOFAtopredictdeathfromsepsisrequiresprospectiveevaluationbeforeitcanberoutinelyusedforthispurpose.
Importantly,thisqSOFAscoreisdifferentfromthefullSOFAscorewhichispartofthe2016SCCM/ESICMdefinition
ofsepsis,thedetailsofwhicharedescribedseparately.(See"Predictivescoringsystemsintheintensivecareunit",
sectionon'Sequential(sepsisrelated)OrganFailureAssessment(SOFA)'and'Sepsis'below.)

SepsisA2016SCCM/EISCMtaskforcehasdefinedsepsisaslifethreateningorgandysfunctioncausedbya
dysregulatedhostresponsetoinfection:

OrgandysfunctionOrgandysfunctionisdefinedbythe2016SCCM/ESICMtaskforceasanincreaseoftwo
ormorepointsintheSOFAscore.Thevalidityofthisscorewasderivedfromcriticallyillpatientswithsuspected
sepsisbyinterrogatingoveramillionintensivecareunit(ICU)electronichealthrecordencountersfromICUsboth
insideandoutsidetheUnitedStates[2527].ICUpatientsweresuspectedashavinginfectionifbodyfluidswere
culturedandtheyreceivedantibiotics.Predictivescores(SOFA,systemicinflammatoryresponsesyndrome
[SIRS],andlogisticOrganDysfunctionSystem[LODS])werecomparedfortheirabilitytopredictmortality.
Amongcriticallyillpatientswithsuspectedsepsis,thepredictivevalidityoftheSOFAscoreforinhospital
mortalitywassuperiortothatfortheSIRScriteria(areaunderthereceiveroperatingcharacteristiccurve0.74
versus0.64).Patientswhofulfillthesecriteriahaveapredictedmortalityof10percent.Althoughthepredictive
capacityofSOFAandLODSweresimilar,SOFAisconsideredeasiertocalculate,andwastherefore
recommendedbythetaskforce.

Importantly,theSOFAscoreisanorgandysfunctionscore.Itisnotdiagnosticofsepsisnordoesitidentify
thosewhoseorgandysfunctionistrulyduetoinfectionbutratherhelpsidentifypatientswhopotentiallyhavea
highriskofdyingfrominfection.Inaddition,itdoesnotdetermineindividualtreatmentstrategiesnordoesit
predictmortalitybasedupondemographics(eg,age)orunderlyingcondition(eg,stemcelltransplantrecipient
versuspostoperativepatient).SOFAandotherpredictivescoresarediscussedseparately.(See"Predictive
scoringsystemsintheintensivecareunit",sectionon'Sequential(sepsisrelated)OrganFailureAssessment
(SOFA)'.)

InfectionTherearenoclearguidelinestohelptheclinicianidentifythepresenceofinfectionortocausallylink
anidentifiedorganismwithsepsis.Inourexperience,forthiscomponentofthediagnosis,theclinicianisreliant
uponclinicalsuspicionderivedfromthesignsandsymptomsofinfectionaswellassupportingradiologicand
microbiologicdataandresponsetotherapy.(See'Clinicalpresentation'belowand'Diagnosis'below.)

Thetermseveresepsis,whichoriginallyreferredtosepsisthatwasassociatedwithtissuehypoperfusion(eg,elevated
lactate,oliguria)ororgandysfunction(eg,elevatedcreatinine,coagulopathy)[14,23],isnolongerusedsincethe2016
sepsisandsepticshockdefinitionsincludepatientswithevidenceoftissuehypoperfusionandorgandysfunction.

SepticshockSepticshockisatypeofvasodilatoryordistributiveshock.Septicshockisdefinedassepsisthat
hascirculatory,cellular,andmetabolicabnormalitiesthatareassociatedwithagreaterriskofmortalitythansepsis
alone[25].Clinically,thisincludespatientswhofulfillthecriteriaforsepsis(see'Sepsis'above)who,despiteadequate
fluidresuscitation,requirevasopressorstomaintainameanarterialpressure(MAP)65mmHgandhavealactate>2

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mmol/L(>18mg/dL).PerpredictionsfromtheSOFAscore,patientswhofulfillthesecriteriaforsepticshockhavea
highermortalitythanthosewhodonot(40versus10percent).(See"Predictivescoringsystemsintheintensive
careunit",sectionon'Sequential(sepsisrelated)OrganFailureAssessment(SOFA)'.)

OthersMultipleorgandysfunctionsyndrome(MODS)andsystemicinflammatoryresponsesyndrome(SIRS)are
termsfrequentlyusedinpracticethatneedtobedistinguishedfromsepsis.

MultipleorgandysfunctionsyndromeMultipleorgandysfunctionsyndrome(MODS)referstoprogressive
organdysfunctioninanacutelyillpatient,suchthathomeostasiscannotbemaintainedwithoutintervention.Itisatthe
severeendoftheseverityofillnessspectrumofbothinfectious(sepsis,septicshock)andnoninfectiousconditions
(eg,SIRSfrompancreatitis).MODScanbeclassifiedasprimaryorsecondary:

PrimaryMODSistheresultofawelldefinedinsultinwhichorgandysfunctionoccursearlyandcanbedirectly
attributabletotheinsultitself(eg,renalfailureduetorhabdomyolysis).

SecondaryMODSisorganfailurethatisnotindirectresponsetotheinsultitself,butisaconsequenceofthe
host'sresponse(eg,acuterespiratorydistresssyndromeinpatientswithpancreatitis).

TherearenouniversallyacceptedcriteriaforindividualorgandysfunctioninMODS.However,progressive
abnormalitiesofthefollowingorganspecificparametersarecommonlyusedtodiagnoseMODSandarealsousedin
scoringsystems(eg,SOFAorLODS)topredictICUmortality[2830](see"Predictivescoringsystemsinthe
intensivecareunit"):

RespiratoryPartialpressureofarterialoxygen(PaO2)/fractionofinspiredoxygen(FiO2)ratio
HematologyPlateletcount
LiverSerumbilirubin
RenalSerumcreatinine(orurineoutput)
BrainGlasgowcomascore
CardiovascularHypotensionandvasopressorrequirement

Ingeneral,thegreaterthenumberoforganfailures,thehigherthemortality,withthegreatestriskbeingassociated
withrespiratoryfailurerequiringmechanicalventilation.(See"Acuterespiratorydistresssyndrome:Prognosisand
outcomesinadults".)

SystemicinflammatoryresponsesyndromeTheuseofsystemicinflammatoryresponsesyndrome(SIRS)
criteriatoidentifythosewithsepsishasfallenoutoffavorsinceitisconsideredbymanyexpertsthatSIRScriteriaare
presentinmanyhospitalizedpatientswhodonotdevelopinfection,andtheirabilitytopredictdeathispoorwhen
comparedwithotherscoressuchastheSOFAscore[27,31,32].SIRSisconsideredaclinicalsyndromethatisaform
ofdysregulatedinflammation.Itwaspreviouslydefinedastwoormoreabnormalitiesintemperature,heartrate,
respiration,orwhitebloodcellcount[23].SIRSmayoccurinseveralconditionsrelated,ornot,toinfection.
NoninfectiousconditionsclassicallyassociatedwithSIRSincludeautoimmunedisorders,pancreatitis,vasculitis,
thromboembolism,burns,orsurgery.

RISKFACTORSTheimportanceofidentifyingriskfactorsforsepsiswashighlightedinoneepidemiologicstudy
thatreportedthatriskfactorsforsepticshockwerethefifthleadingcauseofyearsofproductivelifelostdueto
prematuremortality[33].Riskfactorsforsepsisincludethefollowing[3443]:

IntensivecareunitadmissionApproximately50percentofintensivecareunit(ICU)patientshavea
nosocomialinfectionandare,therefore,intrinsicallyathighriskforsepsis[44].

BacteremiaPatientswithbacteremiaoftendevelopsystemicconsequencesofinfection.Inastudyof270
bloodcultures,95percentofpositivebloodcultureswereassociatedwithsepsis,severesepsis,orsepticshock
[39].

Advancedage(65years)Theincidenceofsepsisisdisproportionatelyincreasedinolderadultpatientsand
ageisanindependentpredictorofmortalityduetosepsis.Moreover,olderadultnonsurvivorstendtodieearlier
duringhospitalizationandolderadultsurvivorsmorefrequentlyrequireskillednursingorrehabilitationafter
hospitalization[40].

ImmunosuppressionComorbiditiesthatdepresshostdefense(eg,neoplasms,renalfailure,hepaticfailure,
AIDS,asplenism)andimmunosuppressantmedicationsarecommonamongpatientswithsepsis,severesepsis,
orsepticshock.(See"Clinicalfeaturesandmanagementofsepsisintheasplenicpatient".)

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DiabetesandcancerDiabetesandsomecancersmayaltertheimmunesystem,resultinanelevatedriskfor
developingsepsis,andincreasetheriskofnosocomialsepsis.

CommunityacquiredpneumoniaSeveresepsisandsepticshockdevelopinapproximately48and5percent,
respectively,ofpatientshospitalizedwithcommunityacquiredpneumonia[41].

PrevioushospitalizationHospitalizationisthoughttoinduceanalteredhumanmicrobiome,particularlyin
patientswhoaretreatedwithantibiotics.Previoushospitalizationhasbeenassociatedwithathreefoldincreased
riskofdevelopingseveresepsisinthesubsequent90days[42].Patientswithhospitalizationsforinfection
relatedconditions,especiallyClostridiumdifficileinfection,areatgreatestrisk.

GeneticfactorsBothexperimentalandclinicalstudieshaveconfirmedthatgeneticfactorscanincreasethe
riskofinfection.Infewcases,monogenicdefectsunderlievulnerabilitytospecificinfection,butgeneticfactors
aretypicallygeneticpolymorphisms.Geneticstudiesofsusceptibilitytoinfectionhaveinitiallyfocusedon
defectsofantibodyproduction,oralackofTcells,phagocytes,naturalkillercells,orcomplement.Recently,
geneticdefectshavebeenidentifiedthatimpairrecognitionofpathogensbytheinnateimmunesystem,
increasingsusceptibilitytospecificclassesofmicroorganisms[43].

CLINICALPRESENTATIONPatientswithsuspectedordocumentedsepsistypicallypresentwithhypotension,
tachycardia,fever,andleukocytosis.Asseverityworsens,signsofshock(eg,coolskinandcyanosis)andorgan
dysfunctiondevelop(eg,oliguria,acutekidneyinjury,alteredmentalstatus)[14,23].Importantly,thepresentationis
nonspecificsuchthatmanyotherconditions(eg,pancreatitis,acuterespiratorydistresssyndrome)maypresent
similarly.Detaileddiscussionoftheclinicalfeaturesofshockarediscussedseparately.(See"Evaluationofandinitial
approachtotheadultpatientwithundifferentiatedhypotensionandshock",sectionon'Clinicalmanifestations'.)

SymptomsandsignsThesymptomsandsignsofsepsisarenonspecificbutmayincludethefollowing:

Symptomsandsignsspecifictoaninfectioussource(eg,coughdyspneamaysuggestpneumonia,painand
purulentexudateinasurgicalwoundmaysuggestanunderlyingabscess)

Arterialhypotension(eg,systolicbloodpressure[SBP]<90mmHg,meanarterialpressure[MAP]<70mmHg,an
SBPdecrease>40mmHg,orlessthantwostandarddeviationsbelownormalforage)

Temperature>38.3or<36C

Heartrate>90beats/minormorethantwostandarddeviationsabovethenormalvalueforage

Tachypnea,respiratoryrate>20breaths/min

Alteredmentalstatus

Ileus(absentbowelsoundsoftenanendstagesignofhypoperfusion)

Decreasedcapillaryrefill,cyanosis,ormottling(mayindicateshock)

LaboratorysignsSimilarly,laboratoryfeaturesarenonspecificandmaybeassociatedwithabnormalitiesdueto
theunderlyingcauseofsepsisortotissuehypoperfusionororgandysfunctionfromsepsis.Theyincludethefollowing:

Leukocytosis(whitebloodcell[WBC]count>12,000microL1)orleukopenia(WBCcount<4000microL1)

NormalWBCcountwithgreaterthan10percentimmatureforms

Hyperglycemia(plasmaglucose>140mg/dLor7.7mmol/L)intheabsenceofdiabetes

PlasmaCreactiveproteinmorethantwostandarddeviationsabovethenormalvalue

Plasmaprocalcitoninmorethantwostandarddeviationsabovethenormalvalue(notroutinelyperformedinmany
centers)

Arterialhypoxemia(arterialoxygentension[PaO2]/fractionofinspiredoxygen[FiO2]<300)

Acuteoliguria(urineoutput<0.5mL/kg/hourforatleasttwohoursdespiteadequatefluidresuscitation)

Creatinineincrease>0.5mg/dLor44.2micromol/L

Coagulationabnormalities(internationalnormalizedratio[INR]>1.5oractivatedpartialthromboplastintime
[aPTT]>60seconds)

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Thrombocytopenia(plateletcount<100,000microL1)

Hyperbilirubinemia(plasmatotalbilirubin>4mg/dLor70micromol/L)

Hyperlactatemia(higherthanthelaboratoryupperlimitofnormal)

Adrenalinsufficiency(eg,hyponatremia,hyperkalemia),andtheeuthyroidsicksyndromecanalsobefoundin
sepsis

ImagingTherearenoradiologicsignsthatarespecifictotheidentificationofsepsisotherthanthoseassociated
withinfectioninaspecificsite(eg,pneumoniaonchestradiography,fluidcollectiononcomputedtomographyofthe
abdomen).

MicrobiologyTheidentificationofanorganismincultureinapatientwhofulfillsthedefinitionofsepsis(see
'Sepsis'above)ishighlysupportiveofthediagnosisofsepsisbutisnotnecessary.Therationalebehinditslackof
inclusioninthediagnosticcriteriaforsepsisisthataculpritorganismisfrequentlynotidentifiedinupto50percentof
patientswhopresentwithsepsisnorisapositiveculturerequiredtomakeadecisionregardingtreatmentwithempiric
antibiotics[45].

DIAGNOSISAlimitationofthedefinitionsabove(see'Definitions'above)isthattheycannotidentifypatients
whoseorgandysfunctionistrulysecondarytoanunderlyinginfection.Thus,aconstellationofclinical,laboratory,
radiologic,physiologic,andmicrobiologicdataistypicallyrequiredforthediagnosisofsepsisandsepticshock.The
diagnosisisoftenmadeempiricallyatthebedsideuponpresentation,orretrospectivelywhenfollowupdatareturns(eg,
positivebloodculturesinapatientwithendocarditis)oraresponsetoantibioticsisevident.Importantly,the
identificationofaculpritorganism,althoughpreferred,isnotalwaysfeasiblesinceinmanypatientsnoorganismis
everidentified.Insomepatientsthismaybebecausetheyhavebeenpartiallytreatedwithantibioticsbeforecultures
areobtained.

Althoughsepticshockhasaspecifichemodynamicprofileonpulmonaryarterycatheterization(PAC)(table1),PACs
aredifficulttointerpretandrarelyplacedinpatientswithsuspectedsepsis.(See"Pulmonaryarterycatheterization:
Interpretationofhemodynamicvaluesandwaveformsinadults"and"Evaluationofandinitialapproachtotheadult
patientwithundifferentiatedhypotensionandshock",sectionon'Pulmonaryarterycatheterization'.)

Theevaluationanddiagnosisofshockisdiscussedseparately.(See"Evaluationofandinitialapproachtotheadult
patientwithundifferentiatedhypotensionandshock".)

PROGNOSIS

InhospitalmorbidityandmortalitySepsishasahighmortalityrate.Ratesdependuponhowthedataare
collectedbutestimatesrangefrom10to52percent[1,4,19,31,4655].Dataderivedfromdeathcertificatesreportthat
sepsisisresponsiblefor6percentofalldeathswhileadministrativeclaimsdatasuggesthigherrates[55].Mortality
ratesincreaselinearlyaccordingtothediseaseseverityofsepsis[31].Inonestudy,themortalityratesofSIRS,
sepsis,severesepsis,andsepticshockwere7,16,20,and46percent,respectively[21].Inanotherstudy,the
mortalityassociatedwithsepsiswas10percentwhilethatassociatedwithsepticshockwas40percent[25].
Mortalityappearstobelowerinyoungerpatients(<44years)withoutcomorbidities(<10percent)[4].

Severalstudieshavereporteddecreasingmortalityratesovertime[1,4,19,50,56,57].Asanexample,a12yearstudy
of101,064patientswithseveresepsisandsepticshockfrom171intensivecareunits(ICUs)inAustraliaandNew
Zealandreporteda50percentriskreduction(from35to18percent)ininhospitalmortalityfrom2000to2012[4].This
persistedafteradjustingformultiplevariablesincludingunderlyingdiseaseseverity,comorbidities,age,andtherisein
incidenceofsepsisovertime.Thissuggestedthatthereductioninmortalityobservedinthisstudywaslesslikelydue
totheincreaseddetectionofearlysepsisandpossiblyduetoimprovedtherapeuticstrategiesforsepsis.However,
despiteimprovedcompliancewithpracticeguidelinesforthetreatmentofsepsis(alsoknownassepsisbundles),
complianceratesvaryandthereisconflictingevidenceastowhethersepsisbundlestrulyimprovemortality
[3,50,52,5862].

Duringhospitaladmission,sepsismayincreasetheriskofacquiringasubsequenthospitalrelatedinfection.One
prospectiveobservationalstudyof3329admissionstotheICUreportedthatICUacquiredinfectionsoccurredin13.5
percentadmissionsofpatientswithsepsiscomparedwith15percentofnonsepsisICUadmissions[63].Patients
admittedwithsepsisalsodevelopedmoreICUacquiredinfectionsincludinginfectionwithopportunisticpathogens,
hintingatpossibleimmunesuppression.Inpatientswithasepsisadmissiondiagnosis,secondaryinfectionswere
mostlycatheterrelatedbloodstreaminfections(26percent),pneumonia(25percent),orabdominalinfections(16
percent),comparedwithpatientswithnonsepsisadmissionwherepneumoniawasthemostcommonICUacquired

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infection(48percent).Inbothgroups,patientswhodevelopedICUacquiredinfectionweremoreseverelyillon
admission(eg,higherAcutePhysiologicandChronicHealthEvaluation[APACHE]IVandSequentialOrganFailure
Assessmentscoresandmoreshockonadmission)andhadhighermortalityatday60.However,thecontributionof
developingasecondaryinfectionwassmall.

LongtermprognosisFollowingdischargefromthehospital,sepsiscarriesanincreasedriskofdeath(upto20
percent)aswellasanincreasedriskoffurthersepsisandrecurrenthospitaladmissions(upto10percentare
readmitted).Mostdeathsoccurwithinthefirstsixmonthsbuttheriskremainselevatedattwoyears[6472].Patients
whosurvivesepsisaremorelikelytobeadmittedtoacutecareand/orlongtermcarefacilitiesinthefirstyearafterthe
initialhospitalization,andalsoappeartohaveapersistentdecrementintheirqualityoflife[49,6668].Themost
commondiagnosesassociatedwithreadmissionat90daysinonedatabaseanalysisof3494hospitaladmissions
includedheartfailure,pneumonia,acuteexacerbationsofchronicobstructivepulmonarydisease,andurinarytract
infections[69].Higherratesofreadmissionwithsubsequentinfectionandsepsismaybeassociatedwithprevious
hospitalizationforaninfection,particularlyinfectionwithclostridiumdifficile[42,73].Sepsissurvivorsmayalsobeat
increasedriskofmajorcardiovasculareventsandstrokewhencomparedwithpatientshospitalizedwithnonsepsis
diagnosis[72].

PrognosticfactorsClinicalcharacteristicsthatimpacttheseverityofsepsisand,therefore,theoutcomeinclude
thehost'sresponsetoinfection,thesiteandtypeofinfection,andthetimingandtypeofantimicrobialtherapy.

HostrelatedAnomaliesinthehost'sinflammatoryresponsemayindicateincreasedsusceptibilitytosevere
diseaseandmortality.Asexamples,thefailuretodevelopafever(orhypothermia)andthedevelopmentofleukopenia,
thrombocytopenia,hyperchloremia,apatient'scomorbidities,age,hyperglycemia,andhypocoagulabilityhaveallbeen
associatedwithpooroutcomes[7480].

Failuretodevelopafever(definedasatemperaturebelow35.5C)wasmorecommonamongnonsurvivorsofsepsis
thansurvivors(17versus5percent)inonestudyof519patientswithsepsis[74].Leukopenia(awhitebloodcellcount
lessthan4000/mm3)wassimilarlymorefrequentamongnonsurvivorsthansurvivors(15versus7percent)inastudy
of612patientswithGramnegativesepsis[76]andaplateletcount<100,000/mm3wasfoundtobeanearlyprognostic
markerof28daymortalityinanotherstudyof1486patientswithsepticshock[79].Inanotherretrospectiveanalysisof
criticallyillsepticpatients,hyperchloremia(Cl110mEq/L)at72hoursafterICUadmissionwasindependently
associatedwithanincreaseinallcausehospitalmortality[78].

Apatient'scomorbiditiesandfunctionalhealthstatusarealsoimportantdeterminantsofoutcomeinsepsis[74].Risk
factorsformortalityincludenewonsetatrialfibrillation[81],anageabove40years[12],andcomorbiditiessuchas
AIDS[82],liverdisease[83],cancer[84],alcoholdependence[83],and/orimmunesuppression[82,85].

Ageisprobablyariskfactorformortalitybecauseofitsassociationwithcomorbidillnesses,impairedimmunologic
responses,malnutrition,increasedexposuretopotentiallyresistantpathogensinnursinghomes,andincreased
utilizationofmedicaldevices,suchasindwellingcathetersandcentralvenouslines[1,12,86].

Admissionhyperglycemia,wasfoundinoneprospectiveobservationalstudyof987patientswithsepsistobe
associatedwithanincreasedriskofdeath(hazardratio1.66)thatwasunrelatedtothepresenceofdiabetes[80].

Inabilitytoclothasalsobeenassociatedwithincreasedmortality.Inoneprospectivestudyof260patientswithsevere
sepsis,indicatorsofhypocoagulabilityusingstandardandfunctionallevelsoffibrinogen,wereassociatedwithasix
foldincreaseintheriskofdeath,particularlyinpatientstreatedwithhydroxyethylstarch[77].

SiteofinfectionThesiteofinfectioninpatientswithsepsismaybeanimportantdeterminantofoutcome,with
sepsisfromaurinarytractinfectiongenerallybeingassociatedwiththelowestmortalityrates[74,87].Onestudyfound
thatmortalityfromsepsiswas50to55percentwhenthesourceofinfectionwasunknown,gastrointestinal,or
pulmonary,comparedwithonly30percentwhenthesourceofinfectionwastheurinarytract[87].Another
retrospective,multicentercohortstudyofnearly8000patientswithsepticshockreportedsimilarresultswiththe
highestmortalityinthosewithsepsisfromischemicbowel(78percent)andthelowestratesinthosewithobstructive
uropathyassociatedurinarytractinfection(26percent)[54].

Approximately50percentofpatientswithseveresepsisarebacteremicatthetimeofdiagnosisaccordingtoone
study[88].Thisisconsistentwithastudyof85,750hospitaladmissions,whichfoundthattheincidenceofpositive
bloodculturesincreasedalongacontinuum,rangingfrom17percentofpatientswithsepsisto69percentwithseptic
shock[89].However,thepresenceorabsenceofapositivebloodculturedoesnotappeartoinfluencetheoutcome,
suggestingthatprognosisismorecloselyrelatedtotheseverityofsepsisthantheseverityoftheunderlyinginfection
[89,90].

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TypeofinfectionSepsisduetonosocomialpathogenshasahighermortalitythansepsisduetocommunity
acquiredpathogens[91,92].Increasedmortalityisassociatedwithbloodstreaminfectionsduetomethicillinresistant
staphylococcusaureus(oddsratio2.70,95%CI2.033.58),noncandidalfungus(oddsratio2.66,95%CI1.275.58),
candida(oddsratio2.3295%CI1.214.45),methicillinsensitivestaphylococcusaureus(oddsratio1.9,95%CI1.53
2.36),andpseudomonas(oddsratio1.6,95%CI1.042.47),aswellaspolymicrobialinfections(oddsratio1.69,95%
CI1.242.30)[91,93].Whenbloodstreaminfectionsbecomesevere(ie,severesepsisorsepticshock),theoutcomeis
similarregardlessofwhetherthepathogensareGramnegativeorGrampositivebacteria[35,94].

AntimicrobialtherapyStudieshaveshownthattheearlyadministrationofappropriateantibiotictherapy(ie,
antibioticstowhichthepathogenissensitive)hasabeneficialimpactonbacteremicsepsis[76,90].Inonereport,
earlyinstitutionofadequateantibiotictherapywasassociatedwitha50percentreductioninthemortalityrate
comparedtoantibiotictherapytowhichtheinfectingorganismswereresistant[76].Incontrast,priorantibiotictherapy
(ie,antibioticswithinthepast90days)maybeassociatedwithincreasedmortality,atleastamongpatientswithGram
negativesepsis[95].Thisisprobablybecausepatientswhohavereceivedpriorantibiotictherapyaremorelikelyto
havehigherratesofantibioticresistance,makingitlesslikelythatappropriateantibiotictherapywillbechosen
empirically.Empiricantibioticregimensforpatientswithsuspectedsepsisarediscussedseparately.(See"Evaluation
andmanagementofsuspectedsepsisandsepticshockinadults",sectionon'Controlofthesepticfocus'.)

RestorationofperfusionFailuretoaggressivelytrytorestoreperfusionearly(ie,failuretoinitiateearlygoal
directedtherapy)mayalsobeassociatedwithmortality[96].Aseverelyelevatedlactate(>4mmol/L)isassociated
withapoorprognosisinpatientswithsepsiswithonestudyreportingamortalityof78percentinapopulationof
criticallyillpatients,athirdofwhomhadsepsis[97].Restorationofperfusionisdiscussedindetailseparately.(See
"Evaluationandmanagementofsuspectedsepsisandsepticshockinadults",sectionon'Interventionstorestore
perfusion'.)

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsand
BeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgradereading
level,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesare
bestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatient
educationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgrade
readinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopics
toyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingonpatientinfo
andthekeyword(s)ofinterest.)

Basicstopic(see"Patienteducation:Sepsisinadults(TheBasics)")

SUMMARYANDRECOMMENDATIONS

Sepsisistheconsequenceofadysregulatedinflammatoryresponsetoaninfectiousinsult.Theseverityand
ratesofsepsishavedramaticallyincreasedwithreportssuggestingratesashighas437and270per100,000
personyearsforsepsisandseveresepsis,respectively.Grampositivebacteriaarethepathogensthataremost
commonlyisolatedfrompatientswithsepsis.(See'Introduction'aboveand'Epidemiology'above.)

Sepsisexistsonacontinuumofseverityrangingfrominfection(invasionofsteriletissuebyorganisms)and
bacteremia(bacteriaintheblood)tosepsisandsepticshock,whichcanleadtomultipleorgandysfunction
syndrome(MODS)anddeath.A2016taskforcefromtheSocietyofCriticalCareMedicineandEuropean
SocietyofIntensiveCareMedicine(SCCM/EISCM)definesepsisandsepticshockasthefollowing(see
'Definitions'above):

Sepsisisdefinedaslifethreateningorgandysfunctioncausedbyadysregulatedhostresponsetoinfection
organdysfunctionisdefinedasanincreaseoftwoormorepointsinthesequential(sepsisrelated)organ
failureassessment(SOFA)score.Thesystemicinflammatoryresponsesyndrome(SIRS)criteriaareno
longerusedtoidentifythosewithsepsis.

Septicshockisdefinedassepsisthathascirculatory,cellular,andmetabolicabnormalitiesthatare
associatedwithagreaterriskofmortalitythansepsisalonetheseabnormalitiescanbeclinicallyidentified
aspatientswhofulfillthecriteriaforsepsiswho,despiteadequatefluidresuscitation,requirevasopressors
tomaintainameanarterialpressure(MAP)65mmHgandhavealactate>2mmol/L(>18mg/dL).

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Riskfactorsforsepsisincludeintensivecareunit(ICU)admission,anosocomialinfection,bacteremia,
advancedage,immunosuppression,previoushospitalization(inparticularhospitalizationassociatedwith
infection),andcommunityacquiredpneumonia.Geneticdefectshavealsobeenidentifiedthatmayincrease
susceptibilitytospecificclassesofmicroorganisms.(See'Riskfactors'above.)

Patientswithsuspectedordocumentedsepsistypicallypresentwithhypotension,tachycardia,fever,and
leukocytosis.Asseverityworsens,signsofshock(eg,coolskinandcyanosis)andorgandysfunctiondevelop
(eg,oliguria,acutekidneyinjury,alteredmentalstatus)[14,23].Importantly,thepresentationisnonspecificsuch
thatmanyotherconditions(eg,pancreatitis,acuterespiratorydistresssyndrome)maypresentsimilarly.(See
'Clinicalpresentation'above.)

Aconstellationofclinical,laboratory,radiologic,physiologic,andmicrobiologicdataistypicallyrequiredforthe
diagnosisofsepsisandsepticshock.Thediagnosisisoftenmadeempiricallyatthebedsideuponpresentation,
orretrospectivelywhenfollowupdatareturnoraresponsetoantibioticsisevident.Importantly,theidentification
ofaculpritorganism,althoughpreferred,isnotalwaysfeasiblesincemanypatientshavebeenpartiallytreated
withantibioticsbeforeculturesareobtained.(See'Diagnosis'above.)

Sepsishasahighmortalityratethatappearstobedecreasing.Estimatesrangefrom10to52percentwithrates
increasinglinearlyaccordingtothediseaseseverityofsepsis.Followingdischargefromthehospital,sepsis
carriesanincreasedriskofdeathaswellasanincreasedriskoffurthersepsisandrecurrenthospital
admissions.Poorprognosticfactorsincludetheinabilitytomountafever,leukopenia,age>40years,certain
comorbidities(eg,AIDS,hepaticfailure,cirrhosis,cancer,alcoholdependence,immunosuppression),anon
urinarysourceofinfection,anosocomialsourceofinfection,andinappropriateorlateantibioticcoverage.(See
'Prognosis'above.)

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GRAPHICS

Populationadjustedincidenceofsepsis,accordingto
race,19792000

Pointsrepresenttheannualincidencerate,andIbarsthestandarderror.

Datafrom:Martin,GS,Mannino,DM,Eaton,S,Moss,M.Theepidemiologyofsepsisin
theUnitedStatesfrom1979through2000.NEnglMed2003348:1546.

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Hemodynamicprofilesofshockonpulmonaryarterycatheterinadults

Physiologic Pump Tissue

Preload Afterload
variable function perfusion

Pulmonary
Systemic Mixedvenous
Clinical capillary Cardiac
vascular oxyhemoglobin
measurement wedge output*
resistance saturation
pressure

Hypovolemic (early)or (early)or >65%(early)or

(late) (late) <65%(late)

Cardiogenic <65%

Distributive (early)or or >65%

(late) (occasionally)

Obstructive

PE,PH, (early)or (early)or >65%

tension (late) (late)
pneumothorax

Pericardial <65%
tamponade

PE:pulmonaryembolusPH:pulmonaryhypertensionPAC:pulmonaryarterycatheter.
*Cardiacoutputisgenerallymeasuredusingthecardiacindex.
MixedvenousoxyhemoglobinsaturationcutoffmeasuredonPACis65%,butontriplelumencatheteris
70%.
Equalizationofrightatrial,rightventricularenddiastolicandpulmonaryarterywedgepressuresisclassicin
pericardialtamponadeanddistinguishesitfromprimarycardiogenicshock.

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