Septic Shock Treatment & Management

24/12/2015
SepticShockTreatment&Management:ApproachConsiderations,GeneralTreatmentGuidelines,GoalsofHemodynamicSupport
SepticShockTreatment&Management
Author:AndreKalil,MD,MPHChiefEditor:MichaelRPinsky,MD,CM,Dr(HC),FCCP,MCCMmore...
Updated:Apr17,2015
ApproachConsiderations
Patientswithsepsis,severesepsis,andsepticshockrequirehospitaladmission.Patientswithsepsiswhorespond
toearlyresuscitationtherapyintheemergencydepartment(ED)andshownoevidenceofendorganhypoperfusion
maybeadmittedtoageneralhospitalunit,optimallyonethathasclosenursingobservationandmonitoring.Such
patientsdonotrequireinvasivehemodynamicmonitoringandusuallydonotrequireadmissiontoanintensivecare
unit(ICU).
PatientswhodonotrespondtoinitialEDtreatment(ie,whohaverecurrenthypotensiondespiteadequatefluid
challenges)andthosewhoareinsepticshockrequireadmissiontoanICUforcontinuousmonitoringandcontinued
goaldirectedtherapy.IfanappropriateICUbedorphysicianisnotavailable,thepatientshouldbetransferredwith
advancedlifesupportmonitoringtoanotherhospitalwiththeavailableresources.
Thereissignificantcontroversysurroundinggoaldirectedtherapy(EGDT)inthemanagementofseveresepsisand
septicshock.EGDTwaspreviouslyevaluatedinasmall,single,randomizedtrialatasingleinstitution. [69]
Subsequently,threenewer,large,multicenterrandomizedtrialswereperformedintheUnitedStates(ProCESS
[ProtocolizedCareforEarlySepticShock]), [58]Australia(ARISE[AustralasianResuscitationInSepsisEvaluation]),
[59]andtheUnitedKingdom(ProMISe[ProtocolisedManagementInSepsis]). [60]
IntheProCESStrial,1341patientswithsepticshockin31academichospitalEDsreceivedtreatmentbasedonone
ofthreeapproaches:protocolbasedEGDTprotocolbasedstandardtherapythatdidnotrequiretheplacementofa
centralvenouscatheter,administrationofinotropes,orbloodtransfusionsorstandardcare. [70,71]Nosignificant
differencesbetweengroupswerefoundfor90daymortality,1yearmortality,ortheneedfororgansupport.
SimilarfindingswerereportedfromboththeARISEandtheProMISetrials.Importanttonote,measuringlactate,
targetingScvO2values,andinsertionofacentralvenouscatheterwerenotassociatedwithimprovedoutcomes.
Whatwasimportantwasthedirectandaggressiveindividualizedcareeachpatientreceived,includingearly
bacteriologicculturesofappropriatesites(eg,blood,urine,sputum),earlyandcorrectinstitutionofbroadspectrum
antibiotics,restorationofbloodpressure,andreversalofevidenceofendorganperfusion.Thesefindingsare
reasonablewhenconsideredwithinthecontextofacutecaremedicineresuscitationprinciples.Namely,stabilizethe
patient,reversethecauseofshock,anddonoadditionalharm.
Goalsandprinciplesoftreatment
Thetreatmentofpatientswithsepticshockhasthefollowingmajorgoals:
Startadequateantibiotictherapy(properdosageandspectrum)asearlyaspossible
Resuscitatethepatient,usingsupportivemeasurestocorrecthypoxia,hypotension,andimpairedtissue
oxygenation(hypoperfusion)
Identifythesourceofinfection,andtreatwithantimicrobialtherapy,surgery,orboth(sourcecontrol)
Maintainadequateorgansystemfunction,guidedbycardiovascularmonitoring,andinterrupttheprogression
tomultipleorgandysfunctionsyndrome(MODS)
Managementprinciples,basedonthecurrentliterature,includethefollowing:
Earlyrecognition
Earlyandadequateantibiotictherapy
Sourcecontrol
Earlyhemodynamicresuscitationandcontinuedsupport
Properventilatormanagementwithlowtidalvolumeinpatientswithacuterespiratorydistresssyndrome
(ARDS)
Initialtreatmentincludessupportofrespiratoryandcirculatoryfunction,supplementaloxygen,mechanical
ventilation,andvolumeinfusion.Treatmentbeyondthesesupportivemeasuresincludesantimicrobialtherapy
targetingthemostlikelypathogen,removalordrainageoftheinfectedfoci,treatmentofcomplications,and
interventionstopreventandtreateffectsofharmfulhostresponses.Sourcecontrolisanessentialcomponentof
sepsismanagement.
Venousaccess
Inallcasesofsepticshock,adequatevenousaccessmustbeensuredforvolumeresuscitation.Whensepsisis
suspected,2largebore(16gauge)intravenous(IV)linesshouldbeplacedifpossibletoallowadministrationof
aggressivefluidresuscitationandbroadspectrumantibiotics.Centralvenousaccessisusefulwhenadministering
vasopressoragentsandinestablishingastablevenousinfusionsitebutisnotmandatory.
Ifthehypotensiondoesnotrespondtoacrystalloidfluidbolusof30mL/kg(12L)over3060minutesoriffluids
cannotbeinfusedrapidlyenough,acentralvenouscathetershouldbeplacedintheinternaljugularorsubclavian
vein.Thiscatheterallowsadministrationofmedicationcentrallyandprovidesmultipleportsforrapidfluid
administration,antibiotics,andvasopressorsifneeded.Italsoallowsmeasurementofcentralvenouspressure
(CVP),asurrogateforvolumestatus,ifCVPmeasurementcapabilityisavailable.
Ifanintravascularaccessdeviceissuspectedasthesourceofseveresepsisorsepticshock,alternativevascular
accessmustbeobtained,andthesuspectdevicemustthenberemoved.
Urinarycatheterization
http://emedicine.medscape.com/article/168402treatment#showall
1/18
24/12/2015
Anindwellingurinarycathetershouldbeplaced.Inallpatientswithsepsis,urineoutput(UOP),amarkerfor
adequaterenalperfusionandcardiacoutput,shouldbecloselymonitored,asshouldrenalfunctionmortalityis
greatlyincreasedinpatientswithurosepsisandseveresepsisorsepticshock.NormalUOPinanadultis0.5
mL/kg/hrormore, [12,61]equivalenttoabout3050mL/hrformostadults.
AnyabnormalitiesinUOPshouldpromptassessmentoftheadequacyofcirculatingbloodvolume,cardiacoutput,
andbloodpressuretheseshouldbecorrectedifinadequate.Aswithsepsisinothersites,earlyandappropriate
initiationofantimicrobialtherapyaswellasidentificationandmanagementofanyurinarytractdisordersis
essential. [55]
Intubationandmechanicalventilation
Mostpatientswithsepsisdeveloprespiratorydistressasamanifestationofseveresepsisorsepticshock.Thelung
injuryischaracterizedpathologicallyasdiffusealveolardamage(DAD)andrangesfromacutelunginjury(ALI)or
mildARDS,bytheBerlinDefinition[11]tomoderateorsevereARDS(seeBackground).Thesepatientsneed
intubationandmechanicalventilationforoptimalrespiratorysupport.Intubationshouldbeconsideredearlyinthe
courseofprogressingseveresepsisandsepticshock.
Directdeliveryofoxygenintothetracheaatafractionofinspiredoxygen(FIO2)of1isfarsuperiortodeliveryviaa
nonrebreatheroxygenmask.Mechanicalventilation,withappropriatesedation,alsoeliminatestheworkofbreathing
aswellasdecreasesthemetabolicdemandsofbreathing,whichaccountsforabout30%oftotalmetabolicdemand
atbaseline.
Alveolaroverdistentionandrepetitiveopeningandclosingofalveoliduringmechanicalventilationhavebeen
associatedwithanincreasedincidenceofARDS.Lowtidalvolumeventilatorystrategieshavebeenusedto
minimizethistypeofalveolarinjury.Therecommendedtidalvolumeis6mL/kg,withplateaupressureskeptator
below30mLH2O. [12,61]Positiveendexpiratorypressure(PEEP)isrequiredtopreventalveolarcollapseatend
expiration. [72]
GeneralTreatmentGuidelines
Themajorfocusofresuscitationfromsepticshockisonsupportingcardiacandrespiratoryfunctions.Theother
organsystemsmayalsorequireattentionandsupportduringthiscriticalperiod.Patientsinsepticshockgenerally
requireintubationandassistedventilationbecauserespiratoryfailureeitherispresentattheonsetofillnessormay
developduringitscourse.Correctionoftheshockstateandabnormaltissueperfusionisthenextstepinthe
treatmentofpatientswithsepticshock.
In2004,thefirstsetofformaltreatmentguidelinesforsepticshockwerepublished. [73]Theseguidelines,knownas
theSurvivingSepsisCampaign,wereformulatedbyaninternationalconsensusgroupthatwascomposedofexperts
from11organizations,includingtheSocietyofCriticalCareMedicine(SCCM),theAmericanCollegeofChest
Physicians(ACCP),theEuropeanSocietyofIntensiveCareMedicine(ESICM),andtheAmericanCollegeof
EmergencyPhysicians(ACEP).Theseguidelinesarereviewedandupdatedperiodically.
TheSurvivingSepsisCampaignguidelineswerelastupdatedin2012,andthecurrentversionsreflecttheopinionof
areasonableapproachtothetreatmentofsepticshock. [12]ThereaderisencouragedtochecktheSepsis
CampaignsWebsiteperiodicallyfornewinformation.Specifically,withtherecentlylargeclinicaltrialsinthe
managementofsepticshockcompleted,specificrecommendationsmaybedegraded.Thosearehighlightedbelow.
Thefirst6hoursofresuscitationofacriticallyillpatientwithsepsisorsepticshockarecritical. [12]Thefollowing
shouldbecompletedwithin3hours:
Obtainthelactatelevel(Althoughrecommended,thethreerecenttrialsshowedthatlactateguidedtherapy
hadnoimpactonsurvival.Still,lactatelevelsparallelsepticshockseverityandhaveprognosticimplication.)
Obtainbloodculturesbeforeadministeringantibiotics
Administerbroadspectrumantibiotics
Administer30mL/kgofcrystalloidsolutionforhypotensionorforlactatelevelsof4mmol/Lorhigher(Again,
althoughmostpatientspresentingwithseveresepsisareinafunctionalhypovolemicstate,requiringfluid
resuscitation,carefulmonitoringofrightventricularvolumeoverloadisessentialiflargequantilesoffluidare
tobegivenquickly,toavoidinducingacutecorpulmonale.)
Thefollowingshouldbecompletedwithin6hours:
Administervasopressorsforhypotensionthatdoesnotrespondtoinitialfluidresuscitationtomaintaina
meanarterialpressure(MAP)of65mmHgorhigher(Recentstudiesshowedthevalidityofthe7075mm
Hglowermeanarterialpressuretargetor8085mmHginthosepatientswithpreexistinghypertension.)
Ifhypotensionpersistsdespitevolumeresuscitationortheinitiallactatelevelis4mmol/Lorhigher,then
measurecentralvenouspressure(CVP)(aimingfor8mmHg),measurecentralvenousoxygensaturation
(ScvO 2)(aimingfor70%),andnormalizelactatelevels(Theserecommendationswillprobablybemodified
inlieuofthefindingsthatCVPdoesnotrepresentaneffectivetarget.Seebelowaboutthevenoarterial
PCO 2gradientanalysisasbeingamorespecificmeasureoftissuehypoperfusion.)
TheRoyalCollegeofObstetriciansandGynaecologists(RCOG)recommendsfollowingtheSurvivingSepsis
Campaignguidelinesformanagingpregnantwomenwithsepsisorsepticshock. [74]Treatmentstrategiesinclude
earlyrecognitionandresuscitationmeasures,supportivecare,removalofthesepticfocus,administrationofblood
productsasneeded,andthromboprophylaxis,aswellastheinvolvementofamultidisciplinaryteam. [12,74](See
ShockandPregnancy.)
Althoughnotpartoftheguidelines,muchattentiontomeasuringnotonlyeffectiveoxygendeliverybutalsoorgan
bloodflowhasemergedasreasonableparameterstogradeshockseverity.Clearly,alowScvO2canoccurfrom
reducedcardiacoutput,butitcanalsooccurfromsevereanemia(orhemoglobinopathies)andhypoxemia.Similarly,
anormalorhighScvO2mayreflectmetabolicblock,shunt,orsamplingerrors.
ToaddressmanyoftheseerrorsoneshouldcalculatethearterialtocentralvenousPO2gradient(PavO2).Since
viabletissuesproducecarbondioxideasanendpointofmetabolism,endcapillaryPCO2increasesastissueblood
flowdecreases.ThecentralvenoustoarterialPCO2gap(PvaCO2)assessesbloodflow.Finally,lactate,although
insensitiveasamarkerofischemia,isstillanexcellentmeasureoftissueinjuryandtheinflammatorystate.Thus,
thePvaCO2/PavO2ratiocanbeusedtoassesstheseverityofcirculatoryshockinsepsis. [75,76]
Respiratorysupport
Aninitialassessmentofairwayandbreathingisvitalinapatientwithsepticshock.Supplementaloxygenshouldbe
administeredtoallpatientswithsuspectedsepsis.Earlyintubationandmechanicalventilationshouldbestrongly
consideredforpatientswithanyofthefollowing:
2/18
24/12/2015
Oxygenrequirement
Dyspneaortachypnea
Persistenthypotension
Evidenceofpoorperipheralperfusion
Circulatorysupport
Patientswithsuspectedsepticshockrequireaninitialcrystalloidfluidchallengeof30mL/kg(12L)over3060
minutes,withadditionalfluidchallenges.(Afluidchallengeconsistsofrapidadministrationofvolumeovera
particularperiod,followedbyassessmentoftheresponse.)(SeeFluidResuscitation.)
Administrationofcrystalloidsolutionistitratedtoagoalofadequatetissueperfusion.IfCVPisusedtotarget
resuscitation,itshouldbeusedasastoppingrule.If,duringfluidresuscitation,CVPrapidlyincreasesbymorethan
2mmHg,absoluteCVPgreaterthan812mmHg,orsignsofvolumeoverload(dyspnea,pulmonaryrales,or
pulmonaryedemaonthechestradiograph)occur,fluidinfusionasprimarytherapyneedstobestopped.Patients
withsepticshockoftenrequireatotalof46Lormoreofcrystalloidsolution.However,CVPmeasurementshould
notbeentirelyreliedupon,becauseitdoesnotcorrelatewithintravascularvolumestatusorcardiacvolume
responsiveness. [77]
SomestudieshaveusednoninvasivemeansofestimatingCVPforexample,ultrasonographytomeasureinferior
venacavadiameterasasurrogateforvolumestatus.Nagdevetalusedthedifferencebetweeninspiratoryand
expiratorycavaldiameter(thecavalindex)topredictCVPandfoundthata50%differencepredictedaCVPlower
than8mmHgwithbothasensitivityandaspecificitygreaterthan90%. [78]Similarly,variationsinthisdiameter
changewithrespirationcorrelatedwithvolumeresponsiveness.
UOPshouldalsobemonitoredasameasureofdehydration.UOPlowerthan3050mL/hshouldpromptfurther
fluidresuscitationorothermeasurestoincreasecardiacoutputinanonfluidresponsivepatient.Importanttonote,
duringfluidresuscitationforseveresepsis,increasedintraabdominalfluidaccumulationandileusoftenoccurand
caninduceincreasesinintraabdominalpressure.Ifintraabdominalpressureisgreaterthan12mmHg,intra
abdominalhypertensionexists.Sincerenalperfusionpressurecanbeapproximatedasmeanarterialpressureminus
CVPorintraabdominalpressure(whicheverishigher),lowUOPmayreflectlowrenalperfusionpressure.In
general,targetingarenalperfusionpressureof7075mmHgsustainsadequaterenalbloodflowinseveresepsis
unlesspreexistinghypertensionispresent,inwhichcasetargetingahigherrenalperfusionpressureof8085mm
Hgisindicated. [79]
Giventhatthirdspacingofintravascularfluidisahallmarkofsepticshock,itmakessensethatadministrationof
colloidsolutionmightbebeneficial.However,althoughcolloidresuscitationwithalbuminhasnotbeenshownin
manymetaanalysestohaveanyadvantageoverisotoniccrystalloidresuscitation(isotonicsodiumchloridesolution
orlactatedRingersolution)inthissetting, [80]Delaneyetalfoundadjunctivealbuminresuscitationtoprovidea
statisticallysignificantmortalitybenefitinrelationtootherregimens. [81]
IntheSalineversusAlbuminFluidEvaluation(SAFE)trial,inwhichabout1200of7000ICUpatientswhorequired
fluidresuscitationhadseveresepsis,nooveralldifferencebetweenthe2treatmentgroupswasseen. [82]However,
theinvestigatorsnotedatrendtowardimprovedoutcomeinpatientswithseveresepsiswhoreceived4%albumin
ratherthannormalsaline.Thedataareinconclusive,especiallywithregardtotheinitialresuscitationphasefor
septicshockintheEDtherefore,crystalloidfluidresuscitationisrecommended.
ThecurrentSurvivingSepsisguidelinesrecommendrapidadministrationofaninitialfluidchallengewith30mL/kg
ofcrystalloidsolution. [12]Albuminshouldbeusedonlywhensubstantialamountsofcrystalloidsolutionarerequired.
Hydroxyethylstarchsolutionsarenotrecommended. [12](SeeGoalsofHemodynamicSupport.)Severalrecent
retrospectiveandsmallerprospectiveclinicaltrialshaveunderscoredtheriskthat0.9NNaClhasasaprimary
resuscitationfluid.Itcauseshyperchloremicmetabolicacidosisandisassociatedwithanincreasedmortalityrelative
tobalancedsaltsolutions(eg,plasmalyte). [83]
Correctionofanemiaandcoagulopathy
Hemoglobinlevelsaslowas7g/dLarewelltoleratedbypatients,andtransfusionisnotrequiredunlessthepatient
haspoorcardiacreserveordemonstratesevidenceofmyocardialischemia.Thrombocytopeniaandcoagulopathy
arecommoninpatientswithsepsisthesepatientsdonotrequirereplacementwithplateletsorfreshfrozenplasma
(FFP)unlesstheydevelopactiveclinicalbleeding.
Ifhemoglobinlevelsfallbelow7g/dL,redbloodcell(RBC)transfusionisrecommendedtoatargethemoglobin
rangeof79g/dL. [12]Evenintheabsenceofapparentbleeding,patientswithseveresepsisshouldreceiveplatelet
transfusionifplateletcountsfallbelow10109/L(10,000/L).Platelettransfusionmayalsobeconsideredwhen
bleedingriskisincreasedandplateletcountsarebelow20109/L(20,000/L). [12]Patientswhoaretoundergo
surgeryorotherinvasiveproceduresmayrequirehigherplateletcounts(eg,50109/L[50,000/L]).
Otherpointstoconsiderwithrespecttotheadministrationofbloodproductsincludethefollowing[12,61]:
Erythropoietinisnotrecommendedforspecifictreatmentofanemiaassociatedwithseveresepsisrather,it
shouldbegiventosuchpatientsforotheracceptableindications(eg,anemiaassociatedwithrenalfailure)
FFPisnotrecommendedforthecorrectionoflaboratoryclottingabnormalitiesunlessbleedingispresentor
invasiveproceduresareplanned
Antithrombinagentsarenotrecommendedfortreatmentofseveresepsisandsepticshock
RecombinantactivatedproteinC(rhAPC)isnolongeravailablefortreatingpatientswithseveresepsisor
septicshock
Antimicrobialtherapy
IVantibiotictherapyshouldbeinitiatedwithinthefirsthouraftertherecognitionofsepticshockorseveresepsis
delaysinadministrationareassociatedwithincreasedmortality. [4,12,61]Selectionofantibioticagentsisempiric,
basedonanassessmentofthepatientsunderlyinghostdefenses,thepotentialsourceofinfection,andthemost
likelyresponsibleorganisms.(SeeEmpiricAntimicrobialTherapy.)
Whenthesourceisunknown,theantibioticchosenmustbeabroadspectrumagentthatcoversgrampositive,
gramnegative,andanaerobicbacteria.Inaddition,considerationmustbegiventopathogenswithantibiotic
resistance,suchasmethicillinresistantStaphylococcusaureus(MRSA),Pseudomonasspecies,andgramnegative
organismswithextendedspectrumbetalactamase(ESBL)activity.
Patientswhoareatriskforthesetypesofinfectionarethosewithrecent,prolonged,ormultiplehospitalizations.
The2012SurvivingSepsisCampaignguidelinesrecommendcombinationempirictherapyforneutropenicpatients
aswellasforthosewithdifficulttotreat,multidrugresistantmicroorganisms,suchasAcinetobacterand
Pseudomonas. [12]
3/18
24/12/2015
Temperaturecontrol
Fevergenerallyrequiresnotreatment,exceptinpatientswhohavelimitedcardiovascularreserveasaconsequence
ofincreasedmetabolicrequirements.Antipyreticdrugsandphysicalcoolingmethods,suchasspongingorcooling
blankets,maybeusedtolowerthepatientstemperature.
Externalcoolingisanothermethodoffevercontrolthathasbeenreportedtobesafeandtodecreasevasopressor
requirementsandearlymortalityinpatientswithsepticshock.Inamulticenter,randomized,controlledstudy
comprisingfebrilepatientswithsepticshockwhorequiredvasopressors,mechanicalventilation,andsedation,the
groupthatreceivedexternalcooling,ascomparedwiththegroupthatdidnot,exhibitedthefollowing[84]:
Significantlylowerbodytemperatureafter2hours
SignificantlymorecommonoccurrencesofshockreversalintheICU
Significantlylowerday14mortality
Althougha50%decreaseinthevasopressordosewassignificantlymorecommonafter12hoursofexternalcooling
treatment,thesameresultwasnotfoundafter48hoursofthistherapy. [84]
Metabolicandnutritionalsupport
Patientswithsepticshockdevelopelectrolyteabnormalities.Potassium,magnesium,andphosphatelevelsshould
bemeasuredandcorrectedifdeficient.
Patientswithsepticshockgenerallyhavehighproteinandenergyrequirements.Althoughabriefperiod(several
days)withoutnutritiondoesnotcausedeleteriouseffects,prolongedstarvationmustbeavoided.
Earlynutritionalsupportisofcriticalimportanceinpatientswithsepticshock.Theoralorenteralrouteispreferred,
unlessthepatienthasanileusorotherintestinalabnormality.Gastroparesisiscommonlyobservedandcanbe
treatedbyadministeringmotilityagentsorplacingasmallbowelfeedingtube.
Diminishedbowelsoundsarenotacontraindicationtoatrialofenteralnutrition,thoughmotilityagentsorasmall
bowelfeedingtubemaybenecessary.Thebenefitsofenteralnutritionareasfollows:
Protectionofgutmucosa
Preventionoftranslocationoforganismsfromthegastrointestinal(GI)tract
Reductionofthecomplicationrate
Lowercost
The2012SurvivingSepsisCampaignguidelinesrecommendusingnutritionalsupportwithoutspecific
immunomodulatingsupplementation. [12]
GoalsofHemodynamicSupport
Shockreferstoastateofinabilitytomaintainadequatetissueperfusionandoxygenation,whichultimatelycauses
cellular,andthenorgansystem,dysfunction.Therefore,thegoalsofhemodynamictherapyarerestorationand
maintenanceofadequatetissueperfusionsoastopreventmultipleorgandysfunction.
Carefulclinicalandinvasivemonitoringisrequiredforassessmentofglobalandregionalperfusion.Shockatthe
bedsideisdefinedbyanMAPlowerthan60mmHgoradecreaseinMAPof40mmHgfrombaseline.
Elevationofthebloodlactatelevelonserialmeasurementsoflactatecanindicateinadequatetissueperfusion.In
addition,mixedvenousoxyhemoglobinsaturationservesasanindicatorofthebalancebetweenoxygendeliveryand
consumption.Adecreaseinmaximalvenousoxygen(MVO2)canbesecondarytodecreasedcardiacoutput
however,maldistributionofbloodflowinpatientsexperiencingsepticshockmayartificiallyelevatetheMVO2levels.
AnMVO2oflessthan65%generallyindicatesdecreasedtissueperfusion.
Regionalperfusioninpatientswithsepticshockisevaluatedbyassessingtheadequacyoforganfunction.
Indicationsofinadequateperfusionmayincludeanyofthefollowing:
Evidenceofmyocardialischemia
Renaldysfunction,manifestedbydecreasedUOPorincreasedcreatininelevels
Centralnervoussystem(CNS)dysfunction,indicatedbyadecreasedlevelofconsciousness
Hepaticinjury,shownbyincreasedlevelsoftransaminases
Splanchnichypoperfusion,manifestedbystressulceration,ileus,ormalabsorption
Hemodynamicsupportinsepticshockisprovidedbyrestoringtheadequatecirculatingbloodvolume,and,if
necessary,optimizingperfusionpressureandcardiacfunctionwithvasoactiveandinotropicsupporttoimprove
tissueoxygenation.
FluidResuscitation
Hypovolemiaisanimportantfactorcontributingtoshockandtissuehypoxiatherefore,allpatientswithsepsis
requiresupplementalfluids.Theamountandrateofinfusionareguidedbyanassessmentofthepatientsvolume
andcardiovascularstatus.
Monitorpatientsforsignsofvolumeoverload,suchasdyspnea,elevatedjugularvenouspressure,crackleson
auscultation,andpulmonaryedemaonthechestradiograph.Improvementsinmentalstatus,heartrate,MAP,
capillaryrefill,andUOPindicateadequatevolumeresuscitation.
Volumeresuscitationcanbeachievedwitheithercrystalloidorcolloidsolutions.Thecrystalloidsolutionsare0.9%
sodiumchlorideandlactatedRingersolutionthecolloidsolutionsarealbumin,dextrans,andpentastarch.Although
mostclinicaltrialshavenotshowneithertypeofresuscitationfluidtobesuperiorinsepticshock,ametaanalysisby
Delaneyetalfoundasignificantreductioninmortalityassociatedwithalbumincontainingsolutionsascompared
withotherfluidresuscitationregimens. [81]
Itshouldbekeptinmind,however,thatcrystalloidfluidsnotonlymustbegiveninconsiderably(24times)greater
volumesthancolloidfluidsbutalsotakelongertoachievethesameendpoints.Ontheotherhand,colloidsolutions
aremuchmoreexpensivethancrystalloidsolutions.
The2012SurvivingSepsisCampaignguidelinesrecommendrapidadministrationofaninitialfluidchallengewith30
mL/kgofcrystalloidsolution. [12]Albumininfusionshouldbeusedonlywhensubstantialamountsofcrystalloid
solutionarerequired.Hydroxyethylstarchsolutionsarenotrecommended.
Insomepatients,clinicalassessmentoftheresponsetovolumeinfusionmaybedifficult.Insuchcases,itmaybe
facilitatedbymonitoringtheresponseofCVPorpulmonaryarteryocclusionpressure(PAOP)tofluidboluses.Fluid
4/18
24/12/2015
administrationshouldbecontinuedaslongashemodynamicimprovementcontinues. [12,61]Hemodynamic
improvementisdefinedasincreasedorganperfusion,decreasingserumlactateandmetabolicacidosis,and
improvedendorganfunction.
Asustainedriseofmorethan5mmHgincardiacfillingpressureafterafluidvolumeisinfusedindicatesthatthe
complianceofthevascularsystemisdecreasingasfurtherfluidisbeinginfused.Suchpatientsaresusceptibleto
volumeoverload,andfurtherfluidshouldbeadministeredwithcare.
Datafromseveralstudiessuggestthattheincidenceofpulmonaryedemaisessentiallythesamewithcrystalloid
solutionsaswithcolloidsolutionswhencardiacfillingpressuresaremaintainedatalowerlevel.However,ifhigher
fillingpressuresarerequiredformaintenanceofoptimalhemodynamics,crystalloidsolutionsmayincrease
extravascularfluidfluxesthroughadecreaseinplasmaoncoticpressure.
EGDTmaybeconsideredforseveresepsisandsepticshock[69]however,thisapproachremainscontroversial,and
furtherstudiesareunderway.Oneofthesestudieswasjustcompletedandpublishedin2014,theProCESStrial,
[58]whichwasarandomizedtrialofprotocolbasedcareforearlysepticshock.Thistrialenrolled1341patientsand
comparedaprotocolbasedEGDT(N=439)totwootherarms:protocolbasedstandardtherapy(N=446)andusual
care(N=456).Theresultsshowednosignificant60daymortalitydifferencesamongthethreearms,21%,18.2%,
and18.9%,respectively.BecausethesemortalityrateswerelowerthantheoriginalEGDTstudy, [69]theauthors
performedasubgroupanalysisincludingthesickestthirdofpatientsbasedonlactatelevelsandAPACHEIIscores,
whichshowedsimilarorhighermortalitythanthatfromtheoriginalstudy, [69]butnobenefitfromEGDTwas
detectedinthishighdiseaseseveritypopulation.
FollowingProCESS,twoadditionalEGDTstudies,onefromAustraliaNewZealandcalledARISE [59]andtheother
fromtheUnitedKingdomcalledProMISe, [60]bothfoundtheexactsameresults,suggestingthatstrictprotocolized
resuscitationfromsepticshockisnotasimportantasclosebedsidetitrationofcarebasedonsoundphysiologic
principles,independentofmeasuresoflactateorScvO2.
Anotherstudyrecentlypublished,theOPTIMISEstudy, [85]wasapragmatic,randomized,observerblindedtrialthat
comparedacardiacoutputguidedhemodynamictherapyalgorithmforintravenousfluid/inotrope(dopexamine)
(N=368)withusualcarewithin6hoursfollowingmajorgastrointestinalsurgery(N=366).Theoutcomemeasuredwas
acompositeof30daymortalityplusmoderateormajorcomplicationsnocompositeoutcomedifferenceswere
observedbetweenthetwogroups.Theauthorsalsoperformedanupdatedmetaanalysiswiththeadditionoftheir
newdataandfoundapotentialreductionincomplicationrates,butnotinmortality.
However,atthesametime,aFrenchstudyshowedthatinpreviouslynonhypertensivepatients,targetingamean
arterialpressureof6575mmHgwasasgood,ifnotbetter,thantargetingameanarterialpressure8085mmHg.
[79]Inthosepatientswithpreexistinghypertension,therewaslessAKIandlessneedforhemodialysisbutalsomore
cardiovascularcompilations,presumablybecausethehighermeanarterialpressuregroupreceivedhigherdosesof
vasopressoragents.
Further,thelargeretrospectivestudyofallofAustraliaandNewZealandICUcarefrom20002012demonstrateda
clearprogressivedeclineinsepticshockmortalityratesfrom35%to18%overthisperiod,withequaltrendsacross
allagegroupsandtreatmentsettings. [48]
VasopressorTherapy
Ifthepatientdoesnotrespondtoresuscitationwithseveralliters(usually4L)ofisotoniccrystalloidsolutionorif
evidenceofvolumeoverloadispresent,thedepressedcardiovascularsystemcanbestimulatedbymeansof
vasopressortherapy.
Vasopressoradministrationisrequiredforpersistenthypotensiononceadequateintravascularvolumeexpansionhas
beenachieved.Persistenthypotensionistypicallydefinedassystolicbloodpressurelowerthan90mmHgorMAP
lowerthan65mmHgwithalteredtissueperfusion.Themeanbloodpressurerequiredforadequatesplanchnicand
renalperfusion(MAP,60or65mmHg)isbasedonclinicalindicesoforganfunction.
Thegoalofvasopressortherapyistoreversethepathologicvasodilationandalteredbloodflowdistributionthat
occurasaresultoftheactivationofadenosinetriphosphate(ATP)dependentpotassiumchannelsinvascular
smoothmusclecellsandthesynthesisofthevasodilatornitricoxide(NO).
Firstlineagents:norepinephrinevsdopamine
Therecommendedfirstlineagentforsepticshockisnorepinephrine,preferablyadministeredthroughacentral
catheter. [12,61]Norepinephrinehaspredominantalphareceptoragonisteffectsandresultsinpotentperipheral
arterialvasoconstrictionwithoutsignificantlyincreasingheartrateorcardiacoutput.Thedosagerangefor
norepinephrineis520g/min,anditisnotbasedontheweightofthepatient.
Norepinephrineispreferredtodopamineformanagingsepticshockbecausedopamineisknowntocause
unfavorableflowdistribution(morearrhythmias).Inthissetting,norepinephrinehasbeenshowntobeboth
significantlysaferandsomewhatmoreeffective.
Inasystematicreviewofrandomizedcontrolledtrials,norepinephrinewassignificantlysuperiortodopaminein
improvingbothinhospitaland28daymortalityinsepticshockpatients. [86]Inametaanalysisthatevaluatedthese
2agentsinthesettingofsepticshock,theinvestigatorsdeterminedthatincomparisonwithdopamine,epinephrine
wasassociatedwithadecreasedriskofdeathandalowerincidenceofarrhythmicevents. [87]
Intheory,norepinephrineistheidealvasopressorinthesettingofwarmshock,whereinperipheralvasodilation
existsinassociationwithnormalorincreasedcardiacoutput.Thetypicalpatientwithwarmshockhaswarm
extremitiesbutexhibitssystemichypotensionandtachycardia,theresultsofdecreasedsystemicvascular
resistance.
Dopamineshouldbeusedonlyincertainhighlyspecificsituations,suchaswhenthereisalowriskof
tachyarrhythmiasandinthepresenceofcoexistentbradycardia.Treatmentusuallybeginsat510g/kg/minIV,and
theinfusionisadjustedaccordingtothebloodpressureandotherhemodynamicparameters.Often,patientsmay
requirehighdosagesofdopamine(upto20g/kg/min).Lowdosedopamineisnotrecommendedforrenal
protection. [12,61]
Secondlineagents
Secondlinevasopressorsappropriateforpatientswhohavepersistenthypotensiondespitemaximaldosesof
norepinephrineordopamineareepinephrine,phenylephrine,andvasopressin.
EpinephrineclearlyincreasesMAPinpatientsunresponsivetoothervasopressors,mainlybyvirtueofitspotent
inotropiceffectsontheheartthus,itshouldprobablybethefirstalternativeagentconsideredinpatientswithseptic
5/18
24/12/2015
shockwhoshowapoorclinicalresponsetonorepinephrineordopamine. [12,61]Adverseeffectsinclude
tachyarrhythmias,myocardialandsplanchnicischemia,andincreasedsystemiclactateconcentrations.
Phenylephrineexertsapurealphareceptoragonisteffect,whichresultsinpotentvasoconstriction,albeitatthe
expenseofdepressedmyocardialcontractilityandheartrate.Phenylephrinemaybeconsideredafirstlineagentin
patientswithextremetachycardiaitspurealphareceptoractivitywillnotresultinincreasedchronotropy. [88]
Vasopressin,orantidiuretichormone(ADH),hasbeenproposedforuseinsepticshockbecauseitisanendogenous
peptidewithpotentvasoactiveeffectsanditscirculatinglevelsaredepressedinsepticshock.Accordingtothe2012
SurvivingSepsisCampaignguidelines,vasopressinshouldnotbethesingleinitialvasopressorbutshouldbe
reservedforsalvagetherapy. [12]Afterfirstlinetreatment,0.03U/minofvasopressinmaybeaddedto
norepinephrine,withananticipatedeffectequivalenttothatofnorepinephrinealone. [12,61]
Characteristicsofthevasopressors
Norepinephrine
Norepinephrineisapotentalphaadrenergicagonistwithminimalbetaadrenergicagonisteffects.Itcanincrease
bloodpressuresuccessfullyinpatientswithsepsiswhoremainhypotensiveafterfluidresuscitationanddopamine.
Thedosagemayrangefrom0.2to1.5g/kg/min,anddosagesashighas3.3g/kg/minhavebeenusedbecause
ofthealphareceptordownregulationinsepsis.
Inpatientswithsepsis,indicesofregionalperfusion(eg,urineflow)andlactateconcentrationhaveimprovedafter
norepinephrineinfusion.Severalstudieshavefoundthatasignificantlygreaterpercentageofpatientstreatedwith
norepinephrinewereresuscitatedsuccessfully,incomparisonwithpatientstreatedwithdopamine. [86,87]Therefore,
norepinephrineshouldbeusedearlyandshouldnotbewithheldasalastresortinpatientswithseveresepsiswho
areinshock.
Concernsaboutcompromisingsplanchnictissueoxygenationhavenotbeenborneoutbythedatathestudieshave
confirmednodeleteriouseffectsonsplanchnicoxygenconsumptionandhepaticglucoseproduction,providedthat
adequatecardiacoutputismaintained.
Dopamine
Aprecursorofnorepinephrineandepinephrine,dopaminehasvaryingeffects,accordingtothedosesinfused.At
lowerdoses,ithasamuchgreatereffectonbetareceptorsathigherdoses,ithasmorealphareceptoreffectsand
increasesperipheralvasoconstriction.
Dosagesrangefrom2to20g/kg/min.Adosagelowerthan5g/kg/minresultsinvasodilationofrenal,
mesenteric,andcoronarybeds. [12]Atadosageof510g/kg/min,beta1adrenergiceffectsinduceanincreasein
cardiaccontractilityandheartrate.Atdosagesofabout10g/kg/min,alphaadrenergiceffectsleadtoarterial
vasoconstrictionandelevationinbloodpressure. [12]
Dopamineisofteneffectiveforrestoringmeanarterialpressureinpatientswithsepticshockwhoremain
hypotensiveaftervolumeresuscitation.Thebloodpressureincreasesprimarilyasaresultofthedrugsinotropic
effect,whichisusefulinpatientswhohaveconcomitantreductionsincardiacfunction.However,asmentioned
above,inacomparisonofnorepinephrinetodopamineforthemanagementofarterialpressureinsepticshock,
failureofdopaminetoreachmeanarterialpressuretargetsoccurredin30%ofthetreatmentarm,necessitating
addingnorepinephrine.
Dopaminemaybeparticularlyusefulinthesettingofcoldshock,whereperipheralvasoconstrictionexists(cold
extremities)andcardiacoutputistoolowtomaintaintissueperfusion.Undesirableeffectsincludetachycardia,
increasedpulmonaryshunting,thepotentialtodecreasesplanchnicperfusion,andanincreaseinpulmonaryarterial
wedgepressure(PAWP).
Lowdose(renaldose)dopaminehasbeenstudied.Dopamineatadosageof23g/kg/minisknowntoinitiate
diuresisbyincreasingrenalbloodflowinhealthyanimalsandvolunteershowever,severalwelldesignedclinical
trialshavenotfoundsuchregimenstohaveanybeneficialeffectsonrenalbloodflowandfunctioninthesettingof
circulatoryshockofanyetiology.
Multiplestudiesalsohavenotshownprophylacticortherapeuticlowdosedopamineadministrationtohaveany
beneficialeffectinpatientswithsepsiswhoarecriticallyill.Inviewoftherealsideeffectsofdopamineinfusion,the
useofrenaldosedopamineshouldbeabandoned.
Epinephrine
EpinephrinecanincreaseMAPbyincreasingcardiacindexandstrokevolume,aswellasbyincreasingsystemic
vascularresistanceandheartrate.Thisagentmayincreaseoxygendeliveryandoxygenconsumption.Theuseof
epinephrineisrecommendedonlyinpatientswhoareunresponsivetotraditionalagents.Theundesirableeffectsof
epinephrineincludethefollowing:
Anincreaseinsystemicandregionallactateconcentrations
Thepotentialtoproducemyocardialischemiaandpromotedevelopmentofarrhythmias
Reducedsplanchnicflow
Phenylephrine
Phenylephrineisaselectivealpha1adrenergicreceptoragonistthatisusedprimarilyinanesthesiatoincrease
bloodpressure.Althoughthedataarelimited,studieshavefoundphenylephrinetoincreaseMAPinpatientswho
weresepticandhypotensivewithincreasedoxygenconsumption.However,concernremainsaboutthisagents
potentialtoreducecardiacoutputandlowerheartrateinpatientswithsepsis.Phenylephrinemaybeagoodchoice
whentachyarrhythmiaslimittherapywithotheragents.
Vasopressin
Vasopressinissynthesizedinthehypothalamusandexcretedbytheposteriorpituitary.Incontrasttoendogenous
catecholamines(eg,norepinephrine),whoseserumlevelsareuniversallyhighinsepticshock,vasopressinstoresare
limitedanditslevelsarelow. [89]Furthermore,catecholamineeffectivenessonvascularsmoothmusclecellsis
inhibitedbytheactivationofATPdependentpotassiumchannelsandNO.
ExogenousadministrationofvasopressinresultsinvasoconstrictionviaactivationofV1receptorsonvascular
smoothmusclecellsthathavetheeffectofinhibitingATPdependentpotassiumchannelsand,intheory,restoring
theeffectivenessofcatecholamines.VasopressinisalsothoughttoinhibitNOsynthaseandthereforecounteract
thevasodilatoryeffectofNO.Inaddition,vasopressinincreasesrenalperfusionbycausingvasodilationofafferent
renalarterioles,incontrasttotherenalvasoconstrictioncausedbycatecholamines.
SeveralsmallclinicaltrialshaveshownthatlowdosevasopressinincreasesMAPanddecreasestherequirementfor
6/18
24/12/2015
catecholamineswhilemaintainingmesentericandrenalperfusion. [89]However,alarge,randomizedtrial(the
VasopressinandSepticShockTrial[VASST])didnotfindmortalitytobesignificantlylowerinpatientswho
receivedvasopressininadditiontonorepinephrinethaninthosewhoreceivednorepinephrinealone,eventhough
vasopressinreducedtherequirementfornorepinephrine. [90]
Overall,themajoradverseeffectsattributedtovasopressin(myocardialischemia,cardiacarrest,mesenteric,and
digitalischemia)werenotsignificantlyincreasedinthetrialhowever,patientswithknowncoronaryarterydiseaseor
congestiveheartfailurewereexcludedfromthestudy. [90]Theincidenceofdigitalischemiawashigherwith
vasopressinuse.BecausethemeantimetoreceivingthedruginVASSTwas12hours,thisstudydoesnotaddress
theuseofvasopressininearlysepsisresuscitation.
InotropicTherapyandAugmentedOxygenDelivery
Althoughmyocardialperformanceisalteredduringsepsisandsepticshock,cardiacoutputgenerallyismaintainedin
patientswithvolumeresuscitatedsepsis.Datafromthe1980sand1990ssuggestedalinearrelationbetween
oxygendeliveryandoxygenconsumption(pathologicsupplydependency),indicatingthattheoxygendeliverylikely
wasinsufficienttomeetthemetabolicneedsofthepatient.
However,subsequentinvestigationschallengedtheconceptofpathologicsupplydependency,suggestingthat
elevatingcardiacindexandoxygendelivery(hyperresuscitation)wasnotassociatedwithimprovedpatientoutcome.
Therefore,theroleofinotropictherapyisuncertain,unlessthepatienthasinadequatecardiacindex,MAP,mixed
venousoxygensaturation(SmvO2),andUOPdespiteadequatevolumeresuscitationandvasopressortherapy.
Patientswithseveresepsisorsepticshockhavehypermetabolism,maldistributionofbloodflow,and,possibly,
suboptimaloxygendeliverytherefore,attemptsatdetectingandcorrectingtissuehypoxiamustbemade.Lactic
acidosisisanindicationofeitherglobalischemia(inadequateoxygendelivery)orregional(organspecific)ischemia.
CalculationofpHinthegastricmucosaviagastrictonometrymaydetecttissuehypoxiainthesplanchniccirculation
however,thistechniquehasnotbeenvalidatedextensivelyandisnotwidelyavailable.
Dobutamineisaninotropicagentthatstimulatesbetareceptorsandresultsinincreasedcardiacoutput.Intheory,it
canenhancetissueoxygendeliveryinpatientswithsepticshockwhohavereceivedadequatefluidresuscitationand
vasopressorsupport.InEGDT,dobutamineisrecommendedifthereisevidenceoftissuehypoperfusion(central
venousoxygensaturation[ScvO2]<70mmHg)afterCVP,MAP,andhematocritgoalshavebeenmet.
The2012SurvivingSepsisCampaignguidelinesrecommendadministrationofdobutaminedosagesupto20
g/kg/minonlyinthepresenceofmyocardialdysfunctionorpersistenthypoperfusiondespiteadequatefluid
resuscitationandadequateMAP. [12]
Althoughinitialaggressiveresuscitationtomaximizeoxygendeliveryimprovesoutcome,manipulationofoxygen
deliverytodeliversupraphysiologicoxygentotissuesviabloodtransfusion,fluidboluses,orinotropictherapyonce
organdysfunctionhasdevelopedhasnotimprovedoutcomeincriticallyillpatients.Hayesetalreportedahigher
mortalityinpatientswithsepsiswhoweremaintainedonhighlevelsofoxygendelivery. [91]Thus,inotropictherapyis
notrecommendedforincreasingthecardiacindextosupranormallevels. [12,61]
Inpatientswithsepticshock,theinabilitytoincreaseoxygenconsumptionandtodecreaselactatelevelsmostlikely
isaconsequenceofimpairedoxygenextractionorinabilitytoreverseanaerobicmetabolism.Boostingoxygen
deliverytosupranormallevelsdoesnotreversethesepathophysiologicmechanismsafterthedevelopmentoforgan
injury.
EmpiricAntimicrobialTherapy
Empiricantimicrobialtherapyshouldbeinitiatedearlyinpatientsexperiencingsepticshock(within1hourof
recognitionofsepticshock)andseveresepsiswithoutsepticshock,ifpossible. [12,61]
TheSurvivingSepsisCampaignguidelinesrecommendincluding1ormoreagentsthatarenotonlyactiveagainst
thelikelyorganismsbutalsocapableofpenetratinginadequateconcentrationsintothepresumedsourceof
sepsis,withdailyreevaluationoftheantiinfectivetherapyforpotentialdeescalation. [12,61]
Generally,a7to10daytreatmentcourseisfollowed.Longertreatmentregimensmaybewarrantedinthe
presenceofaslowclinicalresponse,undrainablefociofinfection,andimmunologicdeficiencies(eg,neutropenia).
Theuseofprocalcitoninorsimilarbiomarkersmayfacilitatediscontinuanceofantibioticsinpatientswithclinical
improvementandnofurtherevidenceofinfection. [12]
Combinationempirictherapyisrecommendedforpatientswiththefollowing[12]:
Difficulttotreat,multidrugresistantmicroorganisms(eg,PseudomonasandAcinetobacterspp)
Severeinfectionsassociatedwithrespiratoryfailureandsepticshock
Septicshockandbacteremiafrompneumococci
However,combinationtherapyshouldbelimitedto35days,afterwhichperiodtreatmentshouldswitchtothemost
appropriatemonotherapyoncetheresultsofthesusceptibilityprofileareavailable. [12,61]
Thefollowingpointsmustalwaysbeconsidered:
Earlybroadspectrumempiricantibiotictherapyisessentialthecoveragespectrumwillbenarrowedlater,
whencultureresultsbecomeavailable
Waitinguntilculturesarebackisaninvalidreasontowithholdantibiotics
Only30%ofpatientswithpresumedsepticshockhavepositivebloodcultures [2,3,4,38]
About25%ofpresumedsepticshockpatientsremainculturenegativefromallsites,butmortalityissimilar
tothatforculturepositivecounterparts [2,3,4,38]
Promptlydiscontinueantimicrobialtherapyifthepatientsconditionisdeterminedtobefromanoninfectious
source [12,61]
Antibioticselection
Theselectionofappropriateagentsisbasedonthepatientsunderlyinghostdefenses,thepotentialsourcesof
infection,andthemostlikelyculpritorganisms.Antibioticsmustbebroadspectrumagentsandmustcovergram
positive,gramnegative,andanaerobicbacteriabecauseorganismsfromanyofthesedifferentclassescanproduce
thesameclinicalpictureofdistributiveshock.
Ifthepatientisantibioticexperienced,strongconsiderationshouldbegiventousinganaminoglycosideratherthan
aquinoloneorcephalosporinforgramnegativecoverage.Knowingtheantibioticresistancepatternsofboththe
hospitalitselfanditsreferralbase(ie,nursinghomes)isveryimportant.
7/18
24/12/2015
Antibioticsshouldbeadministeredparenterally,indosesadequatetoachievebactericidalserumlevels.Many
studieshavefoundthatclinicalimprovementcorrelateswiththeachievementofserumbactericidallevelsrather
thanwiththenumberofantibioticsgiven.
Intheselectionofempiricantibiotics,theincreasingprevalenceofMRSAmustbetakenintoaccount,andanagent
suchasvancomycinorlinezolidshouldbeincluded.ThisisespeciallytrueinpatientswithahistoryofIVdruguse,
thosewithindwellingvascularcathetersordevices,orthosewithrecenthospitalizations.Antianaerobiccoverageis
indicatedinpatientswithintraabdominalorperinealinfections.
Certainorganisms,chieflyEnterobacteriaceae(eg,EscherichiacoliandKlebsiellapneumoniae),containabeta
lactamaseenzymethathydrolyzesthebetalactamringofpenicillinsandcephalosporinsandthusinactivatesthese
antibiotics(ESBLproducingbacteria).Thisphenomenonhasbecomeanincreasingconcernasitsprevalencehas
increased.BetalactamantibioticsthathaveremainedeffectiveagainstESBLproducingorganismsinclude
cephamycins(eg,cefotetan)andcarbapenems(eg,imipenem,meropenem,andertapenem). [92]
Inimmunocompetentpatients,monotherapywithcarbapenems(eg,imipenemandmeropenem),thirdorfourth
generationcephalosporins(eg,cefotaxime,cefoperazone,ceftazidime,andcefepime),orextendedspectrum
penicillins(eg,ticarcillinandpiperacillin)isusuallyadequate,withouttheneedforanephrotoxicaminoglycoside. [93]
Patientswhoareimmunocompromisedorathighriskformultidrugresistantorganismstypicallyrequiredualbroad
spectrumantibioticswithoverlappingcoverage.
Withinthesegeneralguidelines,nosinglecombinationofantibioticsisclearlysuperiortoanyother.
TheFDArecentlyapproved3newantibiotics,oritavancin(Orbactiv),dalbavancin(Dalvance),andtedizolid
(Sivextro),forthetreatmentofacutebacterialskinandskinstructureinfections.Theseagentsareactiveagainst
Staphylococcusaureus(includingmethicillinsusceptibleandmethicillinresistantSaureus[MSSA,MRSA]isolates),
Streptococcuspyogenes,Streptococcusagalactiae,andStreptococcusanginosusgroup(includesStreptococcus
anginosus,Streptococcusintermedius,andStreptococcusconstellatus),amongothers.Forcompletedrug
information,includingdosing,seethefollowingmonographs:
Oritavancin
Dalbavancin
Tedizolid
Communityacquiredpneumonia
ForinpatientswithpneumoniawhoarenotadmittedtotheICU,theguidelinesformulatedbytheInfectious
DiseasesSocietyofAmerica(IDSA)andtheAmericanThoracicSociety(ATS)recommendadministeringthe
following[67]:
Arespiratoryfluoroquinolone,especiallyinpenicillinallergicpatients
Abetalactamagent(cefotaxime,ceftriaxone,orampicillin)plusamacrolideertapenemmaybeusedfor
selectedpatients,anddoxycyclinemaybeanalternativetothemacrolide
Antibiotictherapyforaminimumof5daysforcommunityacquiredpneumoniathetreatmentdurationmay
beincreasedincomplicatedcasesorincaseswheretheinitialtherapydidnotprovideaclinicalresponse
againsttheidentifiedorganism
ForinpatientswithpneumoniawhoareadmittedtotheICU,theIDSA/ATSguidelinesofferthefollowingminimal
recommendations[67]:
Administerabetalactam(eg,cefotaxime,ceftriaxone,ampicillinsulbactam)pluseitherazithromycinora
fluoroquinolonepenicillinallergicpatientsmayreceivearespiratoryfluoroquinoloneandaztreonam
Forpseudomonalinfections,administer(1)anantipneumococcal,antipseudomonalbetalactamagent(eg,
piperacillintazobactam,cefepime,imipenem,ormeropenem)plusciprofloxacinorlevofloxacin(2)thebeta
lactamaboveplusanaminoglycosideandazithromycinor(3)thebetalactamaboveplusanaminoglycoside
andanantipneumococcalfluoroquinolone(forpenicillinallergicpatients,useaztreonaminsteadoftheabove
betalactam)
AddvancomycinorlinezolidforpatientswithcommunityacquiredMRSA(CAMRSA)infection
OtherIDSA/ATSrecommendationsincludethefollowing[1]:
InfluenzaAEarlytreatment(48hraftersymptomsonset)withoseltamivirorzanamiviralthoughthese2
agentsarenotrecommendedforuseinuncomplicatedinfluenzawithsymptomslongerthan48hours,they
maybeusedforreductionofviralsheddingininpatientsorforinfluenzapneumonia
H5N1infectionInsuspectedcases,administeroseltamivirandantibacterialagentsagainstSpneumoniae
andSaureus,whichcancausesecondarybacterialpneumoniaininfluenzapatients
Intraabdominalinfections
Forcommunityacquiredabdominalinfections,theIDSAandtheSurgicalInfectionSociety(SIS)indicatethat
empiricantibiotictherapiesshouldbeactiveagainstentericgramnegativeaerobicandfacultativebacilliaswellas
entericgrampositivestreptococci. [1]
EmpiriccoverageisnotneededforEnterococcus,norisempiricantifungaltherapyneededforCandida,unless
theseinfectionsaresevere.AntibioticswithactivityagainstEfaecalisincludeampicillin,piperacillintazobactam,
andvancomycin.FluconazoleisusedforisolatedCalbicansanechinocandin(eg,caspofungin,micafungin,or
anidulafungin)isusedforfluconazoleresistantCandida. [1]Incriticallyillpatients,anechinocandinisrecommended
overatriazole(eg,fluconazoleoritraconazole). [1]
AgentsthatcausehealthcareassociatedintraabdominalinfectionsincludeCandida,Enterococcus,andMRSA.
Empiricantibiotictherapyforthoseinfectionsshouldbebasedonlocalsusceptibilityresults.
Inadultswithcommunityacquiredinfectionorhospitalassociatedintraabdominalinfectionofhighseverity(eg,
AcutePhysiologyAndChronicHealthEvaluation[APACHE]IIscore>15),broadspectrumagentsareusedagainst
gramnegativeactivity(eg,metronidazoleplusmeropenem,imipenemcilastatin,doripenem,piperacillin
tazobactam,ciprofloxacin,orlevofloxacinalternatively,metronidazoleplusceftazidimeorcefepime). [1]
Antibioticsthatarenotrecommendedfortreatingintraabdominalinfections,becauseofthegreaterprevalenceof
resistance,includeampicillinsulbactamandquinolones(highresistanceincommunityacquiredEcoli),aswellas
cefotetanandclindamycin(highresistanceinBacteroidesfragilis). [1]Inaddition,aminoglycosides,becauseoftheir
toxicityandtheavailabilityofotheragents,arenotrecommendedforroutineuseincommunityacquiredabdominal
infections.
CorticosteroidTherapy
8/18
24/12/2015
Corticosteroidinsufficiencyhasbeenassociatedwithsevereillness. [94]TheAmericanCollegeofCriticalCare
Medicine(ACCCM)usesthetermcriticalillnessrelatedcorticosteroidinsufficiency(CIRCI)todescribe
hypothalamicpituitaryadrenal(HPA)axisdysfunctionincriticallyillpatientsandrecommendsavoidinguseofthe
termsabsoluteorrelativeadrenalinsufficiencyinsuchpatients. [66]
Althoughthereistheoreticalandexperimentalanimalevidencefavoringtheuseoflargedosesofcorticosteroids
(eg,methylprednisolone,hydrocortisone,anddexamethasone)inpatientswithseveresepsisandsepticshock,the
clinicalmedicalliteraturedoesnotsupporttheroutineuseofsuchdosesinthesepatients.
Highdosecorticosteroidsshouldnotbeusedinpatientswithseveresepsisorsepticshock.Ametaanalysisof
prospective,randomized,controlledtrialsofglucocorticoidusedidnotfindanybenefitfromcorticosteroidsand
suggestedthattheirusecouldbeharmful. [95]Areviewof3metaanalysesfoundthatuseoflowdose
corticosteroidsdidnotimprovesurvivalinsepticshockandseveresepsisandthattheywereassociatedwithside
effectsthatincludedsuperinfections,bleeding,andhyperglycemia. [96]
Sometrialshavedocumentedpositiveresultsfromstressdoseadministrationofcorticosteroidsinpatientswith
severeandrefractoryshock. [97]Althoughfurtherconfirmatorystudiesareawaited,stressdosesteroidcoverage
shouldbeprovidedtopatientswhohavethepossibilityofadrenalsuppression.
Otherstudieshaveshownthatlowerdosesteroidsmaybebeneficialforpatientswithrelativeadrenalinsufficiency.
InastudybyAnnaneetalthatincluded299patientswithsepticshockwhowererandomlyassignedtoreceivelow
dosesteroids(hydrocortisone,50mgq6hr,andfludrocortisone,50g/day)orplacebo,77%werenonrespondersfor
nonresponderswhoreceivedsteroids,therewasa10%absolutebenefitwithrespecttomortality(63%vs53%). [98]
Inthisstudy,allpatientshadbeenintubated,hadbeenpersistentlyhypotensivedespitecrystalloidresuscitationand
vasopressoradministration,andhadhadevidenceofendorganfailure. [98]Nonrespondersweredefinedasthose
whosecortisollevelincreasedbylessthan10g/dLinacortisolstimulationtestandthuswereconsideredadrenally
insufficient.Thistestinvolvesmeasuringcortisollevelsbeforeand30minutesafterIVadministrationof0.25mgof
cosyntropin(ie,adrenocorticotropichormone[ACTH]).
AlthoughperformingthecortisolstimulationtestintheEDsettingmaynotbepractical,giventimeandresource
constraints,itisworthnotingthatmorethan75%ofpatientswithvasopressorrefractoryhypotensionwereadrenally
insufficient. [98]Thisfindingsuggestedthatthemajorityofpatientswithvasopressorrefractoryshockwouldbenefit
fromsteroidadministration,regardlessoftheresultsofthecortisolstimulationtest.Acommonchoiceis
hydrocortisone100mgIVagoodalternativeisdexamethasone10mgIV.
Inasubsequentstudy,Annaneetalpublishedasystematicreviewofcorticosteroiduseforseveresepsisandseptic
shock,thepooledresultsofwhichshowedthatthesubgroupofstudiesusingprolonged,lowdosecorticosteroid
therapydemonstratedabeneficialeffectonshorttermmortality. [99]However,noclearbenefitwasshownwiththe
useofhighdosecorticosteroidsforseveresepsisorsepticshock. [99]
IntheCORTICUS(CorticosteroidTherapyofSepticShock)study,alargerandomizedtrialofhydrocortisoneversus
placeboinpatientswithsepticshock,nodifferenceinmortalitywasnotedbetweenthegroups,eventhoughthe
patientswhoreceivedsteroidshadamorerapidresolutionofshock,asmeasuredbyashorterdurationof
vasopressortherapy[100]andafasterimprovementinSequentialOrganFailureAssessment(SOFA)scores. [101]
However,theincidenceofsuperinfectionandrecurrentsepsiswashigherinthosewhoreceivedsteroids.
Additionally,theresultofthecortisolstimulationtesthadnobearingonoutcomeintheCORTICUStrial, [100]which
raisesquestionsaboutthevalueofthistestindeterminingwhowillbenefitfromsteroidtreatment.However,the
CORTICUSstudyenrolledallpatientswithsepticshock,regardlessofvasopressorresponse.Consequently,
patientsinthisstudyhadalowermortalitythanthoseintheAnnanestudy.
Guidelinesrecommendationsandsummaryofkeypointsregardingsteroids
The2012SurvivingSepsisCampaignguidelinesemphasizethatsteroidsshouldnotbeadministeredtopatients
withsepticshockunlesshemodynamicstabilitycannotbeachievedwithfluidresuscitationandvasopressoragents.
[12]Inaddition,theseguidelines[12,61]andthoseoftheACCCM [66]recommendthefollowing:
DonotusetheACTHstimulationtesttoidentifythesubsetofadultpatientswithsepticshock(orARDS)
whoshouldreceivehydrocortisone [12,61,66]
Donotadministerdexamethasonewhenhydrocortisoneisavailablefludrocortisoneisoptionalif
hydrocortisoneisused,butwhenhydrocortisoneisnotavailableandthesubstitutedsteroiddoesnothave
significantmineralocorticoidactivity,considerdailyadministrationoforalfludrocortisone(50goncedaily)
[12,61]
TheACCCMalsohasthefollowingtreatmentrecommendations[66]:
Forpatientswithsepticshock,administerhydrocortisone200mg/dayIVin4divideddosesorasa100mg
bolusfollowedbycontinuousinfusionat10mg/hr(240mg/d)inpatientswithearlysevereARDS,the
optimalinitialtreatmentregimeniscontinuousinfusionofmethylprednisolone1mg/kg/day
AlthoughtheoptimaltreatmentperiodforcorticosteroidsinpatientswithsepticshockandearlyARDS
remainstobedetermined,aregimenof7daysorlongershouldbeusedinpatientswithsepticshock
providedthatsignsofsepsisorshockdonotrecurbeforetapering,andaregimenof14daysorlonger
shouldbeusedinpatientswithearlyARDSbeforetapering
DonotusedexamethasonetherapyforsepticshockorARDS
Thefollowingkeypointssummarizeuseofcorticosteroidsinsepticshock:
Older,traditionaltrialsofcorticosteroidsinsepsiswereunsuccessful,probablybecauseofhighdosagesand
poorpatientselection
Morerecenttrialswithlowdose(physiologic)dosagesinselectpatientpopulations(thosewithvasopressor
dependenceand,possibly,relativeadrenalinsufficiency)haveresultedinimprovedoutcome
Corticosteroids(hydrocortisone)shouldbeinitiatedforpatientswithvasopressordependentsepticshock [66]
weansteroidtherapywhenvasopressortherapyisnolongerneeded [12,61]
ConsidermoderatedosecorticosteroidsinthemanagementofpatientswithearlysevereARDS(arterial
oxygentension[PaO 2]/fractionofinspiredoxygen[FIO 2]<200),aswellasbeforeday14inpatientswith
unresolvingARDS [66]investigatorsstillneedtodeterminewhatrolecorticosteroidtreatmentmayhavein
lesssevereARDS(PaO 2/FIO 2>200) [66]
Acortisolstimulationtestmaybeperformedtoidentifypatientswithrelativeadrenalinsufficiency,definedas
failuretoincreaselevelsbymorethan9g/dL
Donotadministercorticosteroidstotreatsepsiswhenshockisnotpresent [12,61]
Maintenancesteroidtherapyorstressdosesteroidsmaybecontinuedasneededonthebasisofthe
patientsendocrineorcorticosteroidadministrationhistory [12,61]
9/18
24/12/2015
GlycemicControl
ABelgianstudyofcriticallyillsurgicalICU(SICU)patientsfounda10%mortalitybenefitinthosewithtighter
glycemiccontrolwhentheglucoselevelsweremaintainedbetween80and110mg/dLthroughintensiveinsulin
therapy. [102]However,subsequentlarge,randomizedstudiesdidnotreplicatetheresultsfromtheBelgianstudy[103,
104,105]Infact,intensiveinsulintreatmenthasbeenshowntoleadtoincreasedepisodesofhypoglycemiaand
increasedmortalityinICUpatients. [105,106,107,108]
Onthebasisofthecurrentevidence,theSurvivingSepsisCampaignguidelinesrecommendmaintainingaglucose
levelbelow180mg/dL. [12]
DVTProphylaxisandManagementofDIC
Deepveinthrombosis
TheSevereSepsisCampaignguidelineshavethefollowingrecommendationsorsuggestionsregardingprophylaxis
ofdeepveinthrombosis(DVT)inpatientswithseveresepsis[12,61]:
Intheabsenceofcontraindications(eg,activebleedingorthrombocytopenia),administereitherlowdose
unfractionatedheparin(UFH2or3timesdaily)orlowmolecularweightheparin(LMWH)LMWHmaybe
preferredinveryhighriskpatients(eg,patientswithseveresepsisandpreviousDVT,trauma,ororthopedic
surgery)
Ifthepatientscreatinineclearanceislessthan30mL/min,dalteparinmaybeused
Inthepresenceofcontraindicationsforheparinuseandintheabsenceofothercontraindications,use
mechanicalDVTpreventiondevices(eg,graduatedcompressionstockings[GCS]orintermittentcompression
devices[ICDs])
Inveryhighriskpatients,considercombiningpharmacologicandmechanicalprophylactictherapyunless
contraindicationsexistorsuchtherapywouldbeimpractical
(SeeDeepVenousThrombosis,Thromboembolism,andGeneralPrinciplesofAnticoagulationinDeepVenous
Thrombosis.)
Disseminatedintravascularcoagulation
DIC,aconditioninwhichbleedingandthrombosisoccur,cancontributetomultiorgansystemfailureandcarriesa
highmortality.AlthoughcontroversyexistsregardingDICtreatment,theoverallmanagementstrategyistotreatthe
underlyingcauseandprovidesupportivecare(seeCorrectionofanemiaandcoagulopathyunderGeneralTreatment
Guidelines).
In2009,theBritishCommitteeforStandardsinHaematology(BCSH)publishedtheirguidelinesrecommendations,
inwhichtheystatethattreatingtheunderlyingetiologyisthecornerstoneofDICtherapy. [109]TheBSCH
guidelinesregardingadjunctivetreatment(eg,plasmaandplatelettransfusion,anticoagulation,useofanticoagulant
factorconcentrates,andantifibrinolytictherapy)arediscussedbelow.
Plasmaandplatelettransfusion
Ingeneral,theBSCHrecommendsreservingtransfusionofplateletsorplasma(components)forpatientswithDIC
whoarebleeding(ratherthanadministeringthistherapyonthebasisoflaboratoryfindings).Thus,platelet
transfusionshouldbeconsideredinpatientswithDICandbleeding(orahighriskofbleeding)whohaveaplatelet
countbelow50109/L(50,000/L). [109]TheSurvivingSepsisCampaignsuggestsconsideringplatelettransfusion
insuchpatientswhenplateletcountsarebelow20109/L(20,000/L). [12]
OtherBSCHplasma/platelettransfusionguidelinesincludethefollowing[109]:
Donotadministerprophylacticplatelettransfusionsinnonbleedingpatientsunlesstheyareathighriskof
bleeding
ConsideradministeringFFPinpatientswithDICandactivebleedingwhohaveprolongedprothrombintime
(PT)andactivatedpartialthromboplastintime(aPTT),aswellasthosewhomayundergoaninvasive
proceduredonotadministerFFPsolelyonthebasisoflaboratoryfindings
Consideradministeringfactorconcentrates(eg,prothrombincomplexconcentrate)ifFFPcannotbe
transfusednotethattheseagentscontainonlyselectedfactorsandwillnotcompletelycorrecttheDIC
Consideradministeringfibrinogenconcentrateorcryoprecipitateincasesofpersistentsevere
hypofibrinogenemia(<1g/L)despiteFFPtherapy
Anticoagulation
TherapeuticdosesofheparinshouldbeconsideredinthefollowingclinicalsituationsofDIC[109]:
Whenthrombosispredominates(eg,arterialorvenousthromboembolism)
Inthepresenceofseverepurpurafulminanswithassociatedinadequateperfusiontotheextremities
Inthepresenceofvascularskininfarction
ContinuousinfusionofUFHshouldbeconsideredinpatientswithDICwhoareathighriskofbleedingforexample,
weightadjusteddoses(eg,10U/kg/hr)maybeusedwithouttheintentiontoprolongtheaPTTratioto1.52.5
timesthecontrol.[109]ClosemonitoringofthesepatientsisrequiredforsignsofbleedingandfortheiraPTT
measurements.
DVTprophylaxiswithprophylacticdosesofheparinorLMWHisrecommendedforcriticallyillpatientswithDICwho
arenotactivelybleeding. [109]
Antifibrinolytictherapy
Ingeneral,theBSCHdoesnotrecommendadministeringantifibrinolyticagentstopatientswithDIC. [109]Inpatients
whohaveDICthatischaracterizedbyaprimaryhyperfibrinolyticstateandwhopresentwithseverebleeding,
administrationoflysineanalogues(eg,tranexamicacid1gq8hr)maybeconsidered.
ManagementofAcuteRespiratoryDistressSyndrome
ARDSandALI(nowoftenreferredtoasmildARDS,inaccordancewiththeBerlinDefinition[11])aremajor
complicationsofsepsisandsepticshock.TheincidenceofARDSinsepticshockrangesfrom20%to40%andis
higherwhenapulmonarysourceofinfectionexists.(SeeAcuteRespiratoryDistressSyndromeandPediatricAcute
RespiratoryDistressSyndrome.)
ARDScanbeassociatedwithclinicaldisorderscausingdirectlunginjury,suchasgastricacidaspiration,thoracic
10/18
24/12/2015
trauma,pneumonia,andneardrowningorindirectlunginjury,includingseveresepsis,acutepancreatitis,drug
overdose,reperfusioninjury,andseverenonthoracictrauma.SepsisassociatedARDScarriesanabysmalprognosis
andcarriesthehighestmortality.
ManagementofARDSisprimarilysupportivepharmacologicandotherinnovativetherapieshavenotproved
especiallybeneficial.Generalsupportivecareincludesadequatetreatmentofunderlyingsepsiswithappropriate
antibioticsandsurgicalmanagementifindicated.Appropriatefluidmanagementtolowerintravascularvolume
withoutaffectingcardiacoutputandorganperfusionmaybebeneficial.Thefluidmanipulationoftenrequires
invasivehemodynamicmonitoring.
Thegoalsofmechanicalventilationincludethefollowing:
Improvinggasexchange
Reducingworkofbreathing
Avoidingoxygentoxicity
Minimizinghighairwaypressures
Avoidingfurtherlungdamage
Allowingtheinjuredlungtoheal
Alungprotectiveandpressurelimitedventilatorystrategyhasbeenshowntoimprovesurvivalratesandlowerrates
ofbarotrauma.Currentrecommendationsaretouseatidalvolumeof58mL/kg,toemployalongerinspiratory
time,andnottoexceedatranspulmonarypressureof30cmH2O.Permissivehypercapniamayensuemayoccur
withtheuseoflessertidalvolumes,butitistolerated.
TheuseofPEEPmayreduceorpreventventilatorinducedlunginjury.SufficientPEEPtorecruitatelectatic
alveolarunitsandtoincreaselungvolumessothatrespirationhappensonthemostcompliantpartofthepressure
volumecurveisrecommended.Inclinicalpractice,thiscanbeachievedbymeasuringplateaupressuresand
calculatinglungcomplianceatdifferentlevelsofPEEP.TheuseofpronepositioningandNOmayprovetobe
beneficialintheshorttermtheseinterventionshavenotbeenshowntoimprovesurvivalrates.
Highdosecorticosteroids,thoughnotusefulinearlymanagement,canimprovesurvivalinpatientswhoseARDSis
notresolving.InastudybyMedurietal,prolongedadministrationofmethylprednisoloneinpatientswith
nonresolvingARDSwasassociatedwithimprovementandreducedmortality. [110]Mortalitywas0/16(0%)forthe
treatmentgroupand5/8(62%)fortheplacebogroupintheICU.Therateofinfections,includingpneumonia,was
similarinthe2groups.MoreevidenceisneededregardingsteroiduseandARDS.
SurgicalTreatment
Patientswithfocalinfectionsshouldbesentfordefinitivesurgicaltreatmentafterinitialresuscitationandantibiotic
therapy. [1]Littleisgainedbyspendinghoursstabilizingthepatientwhileaninfectedfocuspersists.However,even
thoughurgentmanagementiswarrantedforhemodynamicallystablepatientswithoutevidenceofacuteorgan
failure,itmaybepossibletodelayinvasiveproceduresupto24hoursprovidedthatverycloseclinicalmonitoring
isinstitutedandappropriateantimicrobialtherapyadministered. [1]
Anysofttissueabscessshouldbedrainedpromptly.Certainconditionswillnotrespondtostandardtreatmentfor
septicshockuntilthesourceofinfectionissurgicallyremoved.Someofthesecommonfociofinfectioninclude
intraabdominalsepsis(perforationorabscess),empyema,mediastinitis,cholangitis,pancreaticabscess,
pyelonephritisorrenalabscessfromuretericobstruction,infectiveendocarditis,septicarthritis,infectedprosthetic
devices,deepcutaneousorperirectalabscess,andnecrotizingfasciitis.
Wheneverpossible,percutaneousdrainageofabscessesandotherwelllocalizedfluidcollectionsispreferredto
surgicaldrainage. [1]Forexample,asuperficialabscesscanbedrainedintheED.However,anydeepabscessor
suspectednecrotizingfasciitisshouldbedrainedinthesurgicalsuite.Otherexamplesofemergencyconditionsthat
callforrapidmanagementarediffuseperitonitis,cholangitis,andintestinalinfarction. [12,61]
Incasesofsepsisofunclearetiology,athoroughsearchforabscessesshouldbeperformed,withparticular
attentionpaidtotherectalandperianalarea.
Prevention
Patientswithimpairedhostdefensemechanismsareatgreatlyincreasedriskforsepsis.Themaincausesof
impairedhostdefenseareasfollows:
Chemotherapeuticdrugs
Malignancy
Severetrauma
Burns
Diabetesmellitus
Renalorhepaticfailure
Advancedage
Ventilatorysupportandinvasivecathetersfurtherincreasetheriskofinfection.Avoidingtheuseofcathetersor
removingthemassoonaspossiblemaypreventseveresepsis.
Prophylacticantibioticsintheperioperativephase,particularlyafterGIsurgery,maybebeneficial.Theuseof
topicalantibioticsaroundinvasivecathetersandaspartofdressingsforpatientswithburnsishelpful.Other
preventivemeasuresincludemaintenanceofadequatenutrition,administrationofpneumococcalvaccineinpatients
whohaveundergonesplenectomy,andearlyenteralfeeding.
Preventionofsepsiswithtopicalorsystemicantibioticsissuggestedforhighriskpatients.Useofnonabsorbable
antibioticsinthestomachtopreventtranslocationofbacteriaandoccurrenceofbacteremiaisacontroversialissue.
Numeroustrialshavebeenperformed,usingeithertopicalantibioticsaloneoracombinationoftopicalandsystemic
antibiotics.AsystemicreviewbyNathensfoundnobenefitinmedicalpatientsbutdocumentedareducedmortality
insurgicaltraumapatients. [111]Thebeneficialeffectwasachievedwithacombinationofsystemicandtopical
antibiotics,predominantlybyreducinglowerrespiratorytractinfectionsintreatedpatients.
Progressionfrominfectionwithsystemicinflammatoryresponsesyndrome(ie,sepsis)toseveresepsiswithorgan
dysfunctiontosepticshockwithrefractoryhypotensioncanoftenbereversedwithearlyidentification,aggressive
crystalloidfluidresuscitation,broadspectrumantibioticadministration,andremovaloftheinfectioussourceif
possible.
Basicmeasurestopreventnosocomialinfectionsincludethefollowing[55]:
Shorteningthehospitalstay
Removingindwellingcathetersasearlyaspossible
11/18
24/12/2015
Avoidingunnecessaryinvasiveprocedures
Usingaseptictechniques
Medication
ContributorInformationandDisclosures
Author
AndreKalil,MD,MPHProfessorofMedicine,DepartmentofMedicine,SectionofInfectiousDiseasesDirector,
TransplantIDProgram,UniversityofNebraskaMedicalCenter
Disclosure:Receivedgrant/researchfundsfromSpectralDiagnosticsfornoneReceivedgrant/researchfunds
fromAsahiKaseiforother.
Coauthor(s)
KristinaLBailey,MDAssistantProfessor,DepartmentofMedicine,SectionofPulmonary,CriticalCare,Sleep
andAllergy,UniversityofNebraskaMedicalCenter
KristinaLBailey,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofChestPhysicians,
AmericanThoracicSociety,ResearchSocietyonAlcoholism
Disclosure:Nothingtodisclose.
ChiefEditor
MichaelRPinsky,MD,CM,Dr(HC),FCCP,MCCMProfessorofCriticalCareMedicine,Bioengineering,
CardiovascularDisease,ClinicalandTranslationalScienceandAnesthesiology,ViceChairofAcademicAffairs,
DepartmentofCriticalCareMedicine,UniversityofPittsburghMedicalCenter,UniversityofPittsburghSchoolof
Medicine
MichaelRPinsky,MD,CM,Dr(HC),FCCP,MCCMisamemberofthefollowingmedicalsocieties:American
CollegeofChestPhysicians,AssociationofUniversityAnesthetists,EuropeanSocietyofIntensiveCare
Medicine,AmericanCollegeofCriticalCareMedicine,AmericanHeartAssociation,AmericanThoracicSociety,
ShockSociety,SocietyofCriticalCareMedicine
Disclosure:Receivedincomeinanamountequaltoorgreaterthan$250from:Masimo<br/>Receivedhonoraria
fromLiDCOLtdforconsultingReceivedintellectualpropertyrightsfromiNTELOMEDforboardmembership
ReceivedhonorariafromEdwardsLifesciencesforconsultingReceivedhonorariafromMasimo,Incforboard
membership.
Acknowledgements
FatimaAlFaresi,MDDermatologist,TawamHospital,AlAin,UAE
BarryEBrenner,MD,PhD,FACEPProfessorofEmergencyMedicine,ProfessorofInternalMedicine,
ProgramDirector,EmergencyMedicine,CaseMedicalCenter,UniversityHospitals,CaseWesternReserve
UniversitySchoolofMedicine
BarryEBrenner,MD,PhD,FACEPisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha,
AmericanAcademyofEmergencyMedicine,AmericanCollegeofChestPhysicians,AmericanCollegeof
EmergencyPhysicians,AmericanCollegeofPhysicians,AmericanHeartAssociation,AmericanThoracic
Society,ArkansasMedicalSociety,NewYorkAcademyofMedicine,NewYorkAcademyofSciences,andSociety
forAcademicEmergencyMedicine
JohnLBrusch,MD,FACPAssistantProfessorofMedicine,HarvardMedicalSchoolConsultingStaff,
DepartmentofMedicineandInfectiousDiseaseService,CambridgeHealthAlliance
JohnLBrusch,MD,FACPisamemberofthefollowingmedicalsocieties:AmericanCollegeofPhysiciansand
InfectiousDiseasesSocietyofAmerica
IsmailCinel,MD,PhDVisitingAssociateProfessor,DivisionofCriticalCareMedicine,RobertWoodJohnson
MedicalSchool,UniversityofMedicineandDentistryofNewJersey
ClaraDinaCokonis,MDStaffPhysician,DepartmentofMedicine,DivisionofDermatology,CooperHospital
UniversityMedicalCenter
RPhillipDellinger,MDProfessorofMedicine,ProgramDirector,CriticalCareMedicineFellowshipProgram,
RobertWoodJohnsonSchoolofMedicine,UniversityofMedicineandDentistryofNewJerseyHead,Divisionof
CriticalCareMedicine,MedicalDirector,Medical/Surgical/CardiovascularSurgicalIntensiveCareUnit,Cooper
UniversityHospital
Disclosure:WyethConsultingfeeConsultingBRAHMSGrant/researchfundsOtherClinicalTrialArtisan
Grant/researchfundsOtherClinicalTrialAgenixGrant/researchfundsOtherClinicalTrial
DanielJDire,MD,FACEP,FAAP,FAAEMClinicalProfessor,DepartmentofEmergencyMedicine,University
ofTexasMedicalSchoolatHoustonClinicalProfessor,DepartmentofPediatrics,UniversityofTexasHealth
SciencesCenterSanAntonio
DanielJDire,MD,FACEP,FAAP,FAAEMisamemberofthefollowingmedicalsocieties:AmericanAcademy
ofClinicalToxicology,AmericanAcademyofEmergencyMedicine,AmericanAcademyofPediatrics,American
CollegeofEmergencyPhysicians,andAssociationofMilitarySurgeonsoftheUS
DirkMElston,MDDirector,AckermanAcademyofDermatopathology,NewYork
DirkMElston,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofDermatology
MichaelRFilbin,MDClinicalInstructor,DepartmentofEmergencyMedicine,MassachusettsGeneralHospital
12/18
24/12/2015
MichaelRFilbin,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofEmergency
Physicians,MassachusettsMedicalSociety,andSocietyforAcademicEmergencyMedicine
FranklinFlowers,MDChief,DivisionofDermatology,Professor,DepartmentofMedicineandOtolaryngology,
AffiliateAssociateProfessorofPediatricsandPathology,UniversityofFloridaCollegeofMedicine
FranklinFlowers,MD,isamemberofthefollowingmedicalsocieties:AmericanCollegeofMohsMicrographic
SurgeryandCutaneousOncology
CoryFranklin,MDProfessor,DepartmentofMedicine,RosalindFranklinUniversityofMedicineandScience
Director,DivisionofCriticalCareMedicine,CookCountyHospital
CoryFranklin,MDisamemberofthefollowingmedicalsocieties:NewYorkAcademyofSciencesandSociety
ofCriticalCareMedicine
TheodoreJGaeta,DO,MPH,FACEPClinicalAssociateProfessor,DepartmentofEmergencyMedicine,Weill
CornellMedicalCollegeViceChairmanandProgramDirectorofEmergencyMedicineResidencyProgram,
DepartmentofEmergencyMedicine,NewYorkMethodistHospitalAcademicChair,AdjunctProfessor,
DepartmentofEmergencyMedicine,StGeorge'sUniversitySchoolofMedicine
TheodoreJGaeta,DO,MPH,FACEPisamemberofthefollowingmedicalsocieties:AllianceforClinical
Education,AmericanCollegeofEmergencyPhysicians,ClerkshipDirectorsinEmergencyMedicine,Councilof
EmergencyMedicineResidencyDirectors,NewYorkAcademyofMedicine,andSocietyforAcademic
EmergencyMedicine
HassanIGaladari,MDAssistantProfessorofDermatology,FacultyofMedicineandHealthSciences,United
ArabEmiratesUniversity
HassanIGaladari,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofDermatology,
AmericanMedicalAssociation,AmericanMedicalStudentAssociation/Foundation,andAmericanSocietyfor
DermatologicSurgery
WilliamDJames,MDPaulRGrossProfessorofDermatology,ViceChairman,ResidencyProgramDirector,
DepartmentofDermatology,UniversityofPennsylvaniaSchoolofMedicine
WilliamDJames,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofDermatologyand
SocietyforInvestigativeDermatology
Disclosure:ElsevierRoyaltyOther
PaulKrusinski,MDDirectorofDermatology,FletcherAllenHealthCareProfessor,DepartmentofInternal
Medicine,UniversityofVermontCollegeofMedicine
PaulKrusinski,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofDermatology,
AmericanCollegeofPhysicians,andSocietyforInvestigativeDermatology
StevenMManders,MDClinicalAssistantProfessor,DepartmentofDermatology,UniversityofPennsylvania
AssociateProfessor,DepartmentofInternalMedicine,DivisionofDermatology,UniversityofMedicineand
DentistryofNewJersey
StevenMink,MDHead,SectionofPulmonaryMedicine,DepartmentofInternalMedicine,StBoniface
HospitalProfessorofMedicine,UniversityofManitoba,Canada
StevenMink,MDisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha
MarkLPlaster,MD,JDExecutiveEditor,EmergencyPhysiciansMonthly
MarkLPlaster,MD,JDisamemberofthefollowingmedicalsocieties:AmericanAcademyofEmergency
MedicineandAmericanCollegeofEmergencyPhysicians
Disclosure:MLPlasterPublishingCoLLCOwnershipinterestManagementposition
SatSharma,MD,FRCPCProfessorandHead,DivisionofPulmonaryMedicine,DepartmentofInternal
Medicine,UniversityofManitobaSiteDirector,RespiratoryMedicine,StBonifaceGeneralHospital
SatSharma,MD,FRCPCisamemberofthefollowingmedicalsocieties:AmericanAcademyofSleep
Medicine,AmericanCollegeofChestPhysicians,AmericanCollegeofPhysiciansAmericanSocietyofInternal
Medicine,AmericanThoracicSociety,CanadianMedicalAssociation,RoyalCollegeofPhysiciansandSurgeons
ofCanada,RoyalSocietyofMedicine,SocietyofCriticalCareMedicine,andWorldMedicalAssociation
FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedicalCenterCollege
ofPharmacyEditorinChief,MedscapeDrugReference
Disclosure:MedscapeSalaryEmployment
VickenYTotten,MD,MS,FACEP,FAAFPAssistantProfessor,CaseWesternReserveUniversitySchoolof
MedicineDirectorofResearch,DepartmentofEmergencyMedicine,UniversityHospitals,CaseMedicalCenter
VickenYTotten,MD,MS,FACEP,FAAFPisamemberofthefollowingmedicalsocieties:AmericanCollegeof
EmergencyPhysiciansandSocietyforAcademicEmergencyMedicine
RichardPVinson,MDAssistantClinicalProfessor,DepartmentofDermatology,TexasTechUniversityHealth
13/18
24/12/2015
SciencesCenter,PaulLFosterSchoolofMedicineConsultingStaff,MountainViewDermatology,PA
RichardPVinson,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofDermatology,
AssociationofMilitaryDermatologists,TexasDermatologicalSociety,andTexasMedicalAssociation
EricLWeiss,MD,DTM&HMedicalDirector,OfficeofServiceContinuityandDisasterPlanning,Fellowship
Director,StanfordUniversityMedicalCenterDisasterMedicineFellowship,Chairman,SUMCandLPCH
BioterrorismandEmergencyPreparednessTaskForce,ClinicalAssociateProgressor,DepartmentofSurgery
(EmergencyMedicine),StanfordUniversityMedicalCenter
EricLWeiss,MD,DTM&Hisamemberofthefollowingmedicalsocieties:AmericanCollegeofEmergency
Physicians,AmericanCollegeofOccupationalandEnvironmentalMedicine,AmericanMedicalAssociation,
AmericanSocietyofTropicalMedicineandHygiene,PhysiciansforSocialResponsibility,SoutheasternSurgical
Congress,SouthernAssociationforOncology,SouthernClinicalNeurologicalSociety,andWildernessMedical
Society
References
1. SolomkinJS,MazuskiJE,BradleyJS,RodvoldKA,GoldsteinEJ,BaronEJ,etal.Diagnosisand
managementofcomplicatedintraabdominalinfectioninadultsandchildren:guidelinesbytheSurgical
InfectionSocietyandtheInfectiousDiseasesSocietyofAmerica.ClinInfectDis.2010Jan15.50(2):133
64.[Medline].
2. BrunBuissonC,DoyonF,CarletJ,etal.Incidence,riskfactors,andoutcomeofseveresepsisandseptic
shockinadults.Amulticenterprospectivestudyinintensivecareunits.FrenchICUGroupforSevere
Sepsis.JAMA.1995Sep27.274(12):96874.[Medline].
3. SandsKE,BatesDW,LankenPN,GramanPS,HibberdPL,KahnKL,etal.Epidemiologyofsepsis
syndromein8academicmedicalcenters.JAMA.1997Jul16.278(3):23440.[Medline].
4. KumarA,RobertsD,WoodKE,LightB,ParrilloJE,SharmaS,etal.Durationofhypotensionbefore
initiationofeffectiveantimicrobialtherapyisthecriticaldeterminantofsurvivalinhumansepticshock.Crit
CareMed.2006Jun.34(6):158996.[Medline].
5. BoneRC,BalkRA,CerraFB,etal.Definitionsforsepsisandorganfailureandguidelinesfortheuseof
innovativetherapiesinsepsis.TheACCP/SCCMConsensusConferenceCommittee.AmericanCollegeof
ChestPhysicians/SocietyofCriticalCareMedicine.Chest.1992Jun.101(6):164455.[Medline].
6. AmericanCollegeofChestPhysicians/SocietyofCriticalCareMedicineConsensusConference:definitions
forsepsisandorganfailureandguidelinesfortheuseofinnovativetherapiesinsepsis.CritCareMed.
1992Jun.20(6):86474.[Medline].
7. LevyMM,FinkMP,MarshallJC,AbrahamE,AngusD,CookD,etal.2001
SCCM/ESICM/ACCP/ATS/SISInternationalSepsisDefinitionsConference.CritCareMed.2003Apr.
31(4):12506.[Medline].
8. CreaF,BiasucciLM.Innateimmuneinflammatoryresponsetodanger:when,how,andwhydoesafriend
becomeafoe?.EurHeartJ.2012Jun.33(12):14347.[Medline].
9. MooreDJ,GreystokeA,ButtF,WurthnerJ,GrowcottJ,HughesA,etal.Apilotstudyassessingthe
prognosticvalueofCK18andnDNAbiomarkersinseveresepsispatients.ClinDrugInvestig.2012Mar1.
32(3):17987.[Medline].
10. BernardGR,ArtigasA,BrighamKL,CarletJ,FalkeK,HudsonL,etal.TheAmericanEuropean
ConsensusConferenceonARDS.Definitions,mechanisms,relevantoutcomes,andclinicaltrial
coordination.AmJRespirCritCareMed.1994Mar.149(3Pt1):81824.[Medline].
11. RanieriVM,RubenfeldGD,ThompsonBT,FergusonND,CaldwellE,FanE,etal.Acuterespiratory
distresssyndrome:theBerlinDefinition.JAMA.2012Jun20.307(23):252633.[Medline].
12. DellingerRP,LevyMM,RhodesA,AnnaneD,GerlachH,OpalSM,etal.Survivingsepsiscampaign:
internationalguidelinesformanagementofseveresepsisandsepticshock:2012.CritCareMed.2013
Feb.41(2):580637.[Medline].
13. SallisalmiM,TenhunenJ,YangR,OksalaN,PettilV.Vascularadhesionprotein1andsyndecan1in
septicshock.ActaAnaesthesiolScand.2012Mar.56(3):31622.[Medline].
14. CinelI,OpalSM.Molecularbiologyofinflammationandsepsis:aprimer.CritCareMed.2009Jan.
37(1):291304.[Medline].
15. WheelerAP,BernardGR.Treatingpatientswithseveresepsis.NEnglJMed.1999Jan21.340(3):207
14.[Medline].
16. HotchkissRS,KarlIE.Thepathophysiologyandtreatmentofsepsis.NEnglJMed.2003Jan9.
348(2):13850.[Medline].
17. NguyenHB,RiversEP,AbrahamianFM,MoranGJ,AbrahamE,TrzeciakS,etal.Severesepsisand
septicshock:reviewoftheliteratureandemergencydepartmentmanagementguidelines.AnnEmergMed.
2006Jul.48(1):2854.[Medline].
18. KothariN,BograJ,KohliM,MalikA,KothariD,SrivastavaS,etal.Roleofactivenitrogenmoleculesin
progressionofsepticshock.ActaAnaesthesiolScand.2012Mar.56(3):30715.[Medline].
19. CrouserED.Mitochondrialdysfunctioninsepticshockandmultipleorgandysfunctionsyndrome.
Mitochondrion.2004Sep.4(56):72941.[Medline].
20. HotchkissRS,MonneretG,PayenD.Immunosuppressioninsepsis:anovelunderstandingofthedisorder
andanewtherapeuticapproach.LancetInfectDis.2013Mar.13(3):2608.[Medline].[FullText].
21. KalilAC,FlorescuDF.Prevalenceandmortalityassociatedwithcytomegalovirusinfectionin
nonimmunosuppressedpatientsintheintensivecareunit.CritCareMed.2009Aug.37(8):23508.
[Medline].
22. LorenteJA,LandnL,DePabloR,RenesE,RodrguezDazR,ListeD.Effectsofbloodtransfusionon
14/18
24/12/2015
oxygentransportvariablesinseveresepsis.CritCareMed.1993Sep.21(9):13128.[Medline].
23. SchuetzP,JonesAE,AirdWC,ShapiroNI.Endothelialcellactivationinemergencydepartmentpatients
withsepsisrelatedandnonsepsisrelatedhypotension.Shock.2011Aug.36(2):1048.[Medline].[Full
Text].
24. LeviM,tenCateH,vanderPollT,vanDeventerSJ.Pathogenesisofdisseminatedintravascular
coagulationinsepsis.JAMA.1993Aug25.270(8):9759.[Medline].
25. MammenEF.AntithrombinIIIandsepsis.IntensiveCareMed.1998Jul.24(7):64950.[Medline].
26. TrzeciakS,RiversEP.Clinicalmanifestationsofdisorderedmicrocirculatoryperfusioninseveresepsis.Crit
Care.2005.9Suppl4:S206.[Medline].
27. LandryDW,OliverJA.Thepathogenesisofvasodilatoryshock.NEnglJMed.2001Aug23.345(8):588
95.[Medline].
28. KatzensteinAL,MyersJL,MazurMT.Acuteinterstitialpneumonia.Aclinicopathologic,ultrastructural,and
cellkineticstudy.AmJSurgPathol.1986Apr.10(4):25667.[Medline].
29. CetinbasF,YelkenB,GulbasZ.Roleofglutamineadministrationoncellularimmunityaftertotal
parenteralnutritionenrichedwithglutamineinpatientswithsystemicinflammatoryresponsesyndrome.J
CritCare.2010Dec.25(4):661.e16.[Medline].
30. HamzaouiO,CarletJ.Organdysfunctionsduringseveresepsisandsepticlikesyndromes:epidemiology,
classification,andmechanism.CavaillonJM,AdrieC,eds.SepsisandNoninfectiousSystemic
Inflammation:FromBiologytoCriticalCare..Weinheim,Germany:WileyVCHVerlagGmbH2009.5777.
31. BaluchA,JanooA,LamK,HooverJ,KayeA.Septicshock:reviewandanestheticconsiderations.Middle
EastJAnesthesiol.2007Feb.19(1):7186.[Medline].
32. KotbM.Diseasesduetoencapsulatedbacteria.KaslowRA,McNichollJM,HillAVS,KotbM,eds.
GeneticSusceptibilitytoInfectiousDiseases.NewYork,NY:OxfordUniversityPress2008.35171.
33. KramnikI.GeneticdissectionofhostresistancetoMycobacteriumtuberculosis:thesst1locusandtheIpr1
gene.CurrTopMicrobiolImmunol.2008.321:12348.[Medline].
34. BlackwellJM,JamiesonSE,BurgnerD.HLAandinfectiousdiseases.ClinMicrobiolRev.2009Apr.
22(2):37085,TableofContents.[Medline].[FullText].
35. KotbM,NorrbyTeglundA,McGeerA,ElSherbiniH,DorakMT,KhurshidA,etal.Animmunogeneticand
molecularbasisfordifferencesinoutcomesofinvasivegroupAstreptococcalinfections.NatMed.2002
Dec.8(12):1398404.[Medline].
36. NoohMM,NookalaS,KansalR,KotbM.Individualgeneticvariationsdirectlyeffectpolarizationof
cytokineresponsestosuperantigensassociatedwithstreptococcalsepsis:implicationsforcustomized
patientcare.JImmunol.2011Mar1.186(5):315663.[Medline].
37. SprungCL,AnnaneD,KehD,MorenoR,SingerM,FreivogelK,etal.Hydrocortisonetherapyforpatients
withsepticshock.NEnglJMed.2008Jan10.358(2):11124.[Medline].
38. RanieriVM,ThompsonBT,BariePS,DhainautJF,DouglasIS,FinferS,etal.Drotrecoginalfa(activated)
inadultswithsepticshock.NEnglJMed.2012May31.366(22):205564.[Medline].
39. LevyMM,ArtigasA,PhillipsGS,RhodesA,BealeR,OsbornT,etal.OutcomesoftheSurvivingSepsis
CampaigninintensivecareunitsintheUSAandEurope:aprospectivecohortstudy.LancetInfectDis.
2012Dec.12(12):91924.[Medline].
40. OpalSM,LaterrePF,FrancoisB,LaRosaSP,AngusDC,MiraJP,etal.Effectoferitoran,anantagonist
ofMD2TLR4,onmortalityinpatientswithseveresepsis:theACCESSrandomizedtrial.JAMA.2013Mar
20.309(11):115462.[Medline].
41. AngusDC,LindeZwirbleWT,LidickerJ,ClermontG,CarcilloJ,PinskyMR.Epidemiologyofseveresepsis
intheUnitedStates:analysisofincidence,outcome,andassociatedcostsofcare.CritCareMed.2001
Jul.29(7):130310.[Medline].
42. MartinGS,ManninoDM,EatonS,MossM.TheepidemiologyofsepsisintheUnitedStatesfrom1979
through2000.NEnglJMed.2003Apr17.348(16):154654.[Medline].
43. WangHE,ShapiroNI,AngusDC,YealyDM.NationalestimatesofseveresepsisinUnitedStates
emergencydepartments.CritCareMed.2007Aug.35(8):192836.[Medline].
44. HallMJ,WilliamsSN,DeFrancesCJ,GolosinskiyA.Inpatientcareforsepticemiaorsepsis:achallengefor
patientsandhospitals.NCHSDataBrief.2011Jun.18.[Medline].
45. GaieskiDF,EdwardsJM,KallanMJ,CarrBG.Benchmarkingtheincidenceandmortalityofseveresepsis
intheUnitedStates.CritCareMed.2013May.41(5):116774.[Medline].
46. ShapiroN,HowellMD,BatesDW,AngusDC,NgoL,TalmorD.Theassociationofsepsissyndromeand
organdysfunctionwithmortalityinemergencydepartmentpatientswithsuspectedinfection.AnnEmerg
Med.2006Nov.48(5):58390,590.e1.[Medline].
47. MayrFB,YendeS,LindeZwirbleWT,PeckPalmerOM,BarnatoAE,WeissfeldLA,etal.InfectionRate
andAcuteOrganDysfunctionRiskasExplanationsforRacialDifferencesinSevereSepsis.JAMA.Jun
2010.303(24):24952503.
48. KaukonenKM,BaileyM,SuzukiS,PilcherD,BellomoR.Mortalityrelatedtoseveresepsisandseptic
shockamongcriticallyillpatientsinAustraliaandNewZealand,20002012.JAMA.2014Apr2.
311(13):130816.[Medline].
49. RangelFraustoMS,PittetD,CostiganM,HwangT,DavisCS,WenzelRP.Thenaturalhistoryofthe
systemicinflammatoryresponsesyndrome(SIRS).Aprospectivestudy.JAMA.1995Jan11.273(2):117
23.[Medline].
50. BrunBuissonC.Theepidemiologyofthesystemicinflammatoryresponse.IntensiveCareMed.2000.26
Suppl1:S6474.[Medline].
51. JungB,NougaretS,ChanquesG,etal.TheAbsenceofAdrenalGlandEnlargementduringSepticShock
PredictsMortality:AComputedTomographyStudyof239Patients.Anesthesiology.2011Aug.
115(2):334343.[Medline].
15/18
24/12/2015
52. KumarA,RobertsD,WoodKE,LightB,ParrilloJE,SharmaS,etal.Durationofhypotensionbefore
initiationofeffectiveantimicrobialtherapyisthecriticaldeterminantofsurvivalinhumansepticshock.Crit
CareMed.2006Jun.34(6):158996.[Medline].
53. IwashynaTJ,ElyEW,SmithDM,LangaKM.Longtermcognitiveimpairmentandfunctionaldisability
amongsurvivorsofseveresepsis.JAMA.2010Oct27.304(16):178794.[Medline].
54. DennenP,DouglasIS,AndersonR.Acutekidneyinjuryintheintensivecareunit:anupdateandprimerfor
theintensivist.CritCareMed.2010Jan.38(1):26175.[Medline].
55. Sepsissyndromeinurology(urosepsis).GrabeM,BjerklundJohansenTE,etal,eds.Guidelineson
urologicalinfections.Arnhem,TheNetherlands:EuropeanAssociationofUrology(EAU)2011.339.[Full
Text].
56. RangelFraustoMS,PittetD,HwangT,WoolsonRF,WenzelRP.Thedynamicsofdiseaseprogressionin
sepsis:Markovmodelingdescribingthenaturalhistoryandthelikelyimpactofeffectiveantisepsisagents.
ClinInfectDis.1998Jul.27(1):18590.[Medline].
57. AnnaneD,AegerterP,JarsGuincestreMC,GuidetB.Currentepidemiologyofsepticshock:theCUBRa
Network.AmJRespirCritCareMed.2003Jul15.168(2):16572.[Medline].
58. YealyDM,KellumJA,HuangDT,etal.Arandomizedtrialofprotocolbasedcareforearlysepticshock.N
EnglJMed.2014May1.370(18):168393.[Medline].[FullText].
59. PeakeSL,DelaneyA,BaileyM,BellomoR,CameronPA,CooperDJ,etal.Goaldirectedresuscitationfor
patientswithearlysepticshock.NEnglJMed.2014Oct16.371(16):1496506.[Medline].
60. MounceyPR,OsbornTM,PowerGS,HarrisonDA,SadiqueMZ,GrieveRD,etal.Trialofearly,goal
directedresuscitationforsepticshock.NEnglJMed.2015Apr2.372(14):130111.[Medline].
61. [Guideline]DellingerRP,LevyMM,CarletJM,etal.SurvivingSepsisCampaign:internationalguidelines
formanagementofseveresepsisandsepticshock:2008.CritCareMed.2008Jan.36(1):296327.
[Medline].
62. LevyB,GibotS,FranckP,CravoisyA,BollaertPE.RelationbetweenmuscleNa+K+ATPaseactivityand
raisedlactateconcentrationsinsepticshock:aprospectivestudy.Lancet.2005Mar511.365(9462):8715.
[Medline].
63. ShapiroNI,HowellMD,TalmorD,NathansonLA,LisbonA,WolfeRE,etal.Serumlactateasapredictor
ofmortalityinemergencydepartmentpatientswithinfection.AnnEmergMed.2005May.45(5):5248.
[Medline].
64. NguyenHB,RiversEP,KnoblichBP,JacobsenG,MuzzinA,ResslerJA,etal.Earlylactateclearanceis
associatedwithimprovedoutcomeinseveresepsisandsepticshock.CritCareMed.2004Aug.
32(8):163742.[Medline].
65. JonesAE,ShapiroNI,TrzeciakS,ArnoldRC,ClaremontHA,KlineJA.Lactateclearancevscentral
venousoxygensaturationasgoalsofearlysepsistherapy:arandomizedclinicaltrial.JAMA.2010Feb24.
303(8):73946.[Medline].[FullText].
66. MarikPE,PastoresSM,AnnaneD,MeduriGU,SprungCL,ArltW,etal.Recommendationsforthe
diagnosisandmanagementofcorticosteroidinsufficiencyincriticallyilladultpatients:consensus
statementsfromaninternationaltaskforcebytheAmericanCollegeofCriticalCareMedicine.CritCare
Med.2008Jun.36(6):193749.[Medline].
67. MandellLA,WunderinkRG,AnzuetoA,BartlettJG,CampbellGD,DeanNC,etal.InfectiousDiseases
SocietyofAmerica/AmericanThoracicSocietyconsensusguidelinesonthemanagementofcommunity
acquiredpneumoniainadults.ClinInfectDis.2007Mar1.44Suppl2:S2772.[Medline].
68. GriffeeMJ,MerkelMJ,WeiKS.Theroleofechocardiographyinhemodynamicassessmentofseptic
shock.CritCareClin.2010Apr.26(2):36582,tableofcontents.[Medline].
69. KalilAC.Wanted:earlygoaldirectedtherapyforsepticshockdeadoralive,butnotcriticallyill!.Intensive
CareMed.2010Jan.36(1):13.[Medline].
70. NIHPressRelease.Sepsisstudycomparingthreetreatmentmethodsshowssamesurvivalrate.National
InstitutesofHealth.Availableathttp://www.nih.gov/news/health/mar2014/nigms18.htm.Accessed:March
24,2014.
71. ARandomizedTrialofProtocolBasedCareforEarlySepticShock.NEnglJMed.2014Mar18.
[Medline].
72. SevranskyJE,LevyMM,MariniJJ.Mechanicalventilationinsepsisinducedacutelunginjury/acute
respiratorydistresssyndrome:anevidencebasedreview.CritCareMed.2004Nov.32(11Suppl):S54853.
[Medline].
73. DellingerRP,CarletJM,MasurH.SurvivingSepsisCampaignguidelinesformanagementofseveresepsis
andsepticshock.CritCareMed.2004Mar.32(3):85873.[Medline].
74. RoyalCollegeofObstetriciansandGynaecologists(RCOG).Maternalcollapseinpregnancyandthe
puerperium.2011.
75. ValletB,PinskyMR,CecconiM.Resuscitationofpatientswithsepticshock:please"mindthegap"!.
IntensiveCareMed.2013Sep.39(9):16535.[Medline].[FullText].
76. MonnetX,JulienF,AitHamouN,LequoyM,GossetC,JozwiakM,etal.Lactateandvenoarterialcarbon
dioxidedifference/arterialvenousoxygendifferenceratio,butnotcentralvenousoxygensaturation,predict
increaseinoxygenconsumptioninfluidresponders.CritCareMed.2013Jun.41(6):141220.[Medline].
77. MarikPE,BaramM,VahidB.Doescentralvenouspressurepredictfluidresponsiveness?Asystematic
reviewoftheliteratureandthetaleofsevenmares.Chest.2008Jul.134(1):1728.[Medline].
78. NagdevAD,MerchantRC,TiradoGonzalezA,SissonCA,MurphyMC.Emergencydepartmentbedside
ultrasonographicmeasurementofthecavalindexfornoninvasivedeterminationoflowcentralvenous
pressure.AnnEmergMed.2010Mar.55(3):2905.[Medline].
79. AsfarP,MezianiF,HamelJF,etal.Highversuslowbloodpressuretargetinpatientswithsepticshock.N
EnglJMed.2014Apr24.370(17):158393.[Medline].
80. VincentJL,GerlachH.Fluidresuscitationinseveresepsisandsepticshock:anevidencebasedreview.Crit
16/18
24/12/2015
CareMed.2004Nov.32(11Suppl):S4514.[Medline].
81. DelaneyAP,DanA,McCaffreyJ,FinferS.Theroleofalbuminasaresuscitationfluidforpatientswith
sepsis:asystematicreviewandmetaanalysis.CritCareMed.2011Feb.39(2):38691.[Medline].
82. FinferS,BellomoR,BoyceN,FrenchJ,MyburghJ,NortonR.Acomparisonofalbuminandsalinefor
fluidresuscitationintheintensivecareunit.NEnglJMed.2004May27.350(22):224756.[Medline].
83. LiraA,PinskyMR.Choicesinfluidtypeandvolumeduringresuscitation:impactonpatientoutcomes.Ann
IntensiveCare.2014.4:38.[Medline].[FullText].
84. SchortgenF,ClabaultK,KatsahianS,DevaquetJ,MercatA,DeyeN,etal.Fevercontrolusingexternal
coolinginsepticshock:arandomizedcontrolledtrial.AmJRespirCritCareMed.2012May15.
185(10):108895.[Medline].
85. PearseRM,HarrisonDA,MacDonaldN,etal.Effectofaperioperative,cardiacoutputguided
hemodynamictherapyalgorithmonoutcomesfollowingmajorgastrointestinalsurgery:arandomized
clinicaltrialandsystematicreview.JAMA.2014Jun4.311(21):218190.[Medline].
86. VasuTS,CavallazziR,HiraniA,etal.NorephinephrineorDopamineforSepticShock:ASystematic
ReviewofRandomizedClinicalTrials.JIntensiveCareMed.2011Mar24.[Medline].
87. DeBackerD,AldecoaC,NjimiH,VincentJL.Dopamineversusnorepinephrineinthetreatmentofseptic
shock:ametaanalysis*.CritCareMed.2012Mar.40(3):72530.[Medline].
88. BealeRJ,HollenbergSM,VincentJL,ParrilloJE.Vasopressorandinotropicsupportinsepticshock:an
evidencebasedreview.CritCareMed.2004Nov.32(11Suppl):S45565.[Medline].
89. RussellJA.Vasopressininsepticshock.CritCareMed.2007Sep.35(9Suppl):S60915.[Medline].
90. RussellJA,WalleyKR,SingerJ,GordonAC,HbertPC,CooperDJ,etal.Vasopressinversus
norepinephrineinfusioninpatientswithsepticshock.NEnglJMed.2008Feb28.358(9):87787.
[Medline].
91. HayesMA,TimminsAC,YauEH,etal.Elevationofsystemicoxygendeliveryinthetreatmentofcritically
illpatients.NEnglJMed.1994Jun16.330(24):171722.[Medline].
92. PitoutJD,LauplandKB.ExtendedspectrumbetalactamaseproducingEnterobacteriaceae:anemerging
publichealthconcern.LancetInfectDis.2008Mar.8(3):15966.[Medline].
93. BochudPY,BontenM,MarchettiO,CalandraT.Antimicrobialtherapyforpatientswithseveresepsisand
septicshock:anevidencebasedreview.CritCareMed.2004Nov.32(11Suppl):S495512.[Medline].
94. CooperMS,StewartPM.Corticosteroidinsufficiencyinacutelyillpatients.NEnglJMed.2003Feb20.
348(8):72734.[Medline].
95. CroninL,CookDJ,CarletJ,HeylandDK,KingD,LansangMA,etal.Corticosteroidtreatmentforsepsis:a
criticalappraisalandmetaanalysisoftheliterature.CritCareMed.1995Aug.23(8):14309.[Medline].
96. KalilAC,SunJ.Lowdosesteroidsforsepticshockandseveresepsis:theuseofBayesianstatisticsto
resolveclinicaltrialcontroversies.IntensiveCareMed.2011Mar.37(3):4209.[Medline].
97. BriegelJ,ForstH,HallerM.Stressdosesofhydrocortisonereversehyperdynamicsepticshock:a
prospective,randomized,doubleblind,singlecenterstudy.CritCareMed.1999Apr.27(4):72332.
[Medline].
98. AnnaneD,SbilleV,CharpentierC,BollaertPE,FranoisB,KorachJM,etal.Effectoftreatmentwith
lowdosesofhydrocortisoneandfludrocortisoneonmortalityinpatientswithsepticshock.JAMA.2002Aug
21.288(7):86271.[Medline].
99. AnnaneD,BellissantE,BollaertPE,BriegelJ,ConfalonieriM,DeGaudioR,etal.Corticosteroidsinthe
treatmentofseveresepsisandsepticshockinadults:asystematicreview.JAMA.2009Jun10.
301(22):236275.[Medline].
100. SprungCL,AnnaneD,KehD,MorenoR,SingerM,FreivogelK,etal.Hydrocortisonetherapyforpatients
withsepticshock.NEnglJMed.2008Jan10.358(2):11124.[Medline].
101. MorenoR,SprungCL,AnnaneD,ChevretS,BriegelJ,KehD,etal.Timecourseoforganfailurein
patientswithsepticshocktreatedwithhydrocortisone:resultsoftheCorticusstudy.IntensiveCareMed.
2011Nov.37(11):176572.[Medline].
102. vandenBergheG,WoutersP,WeekersF,VerwaestC,BruyninckxF,SchetzM,etal.Intensiveinsulin
therapyincriticallyillpatients.NEnglJMed.2001Nov8.345(19):135967.[Medline].
103. ArabiYM,DabbaghOC,TamimHM,AlShimemeriAA,MemishZA,HaddadSH,etal.Intensiveversus
conventionalinsulintherapy:arandomizedcontrolledtrialinmedicalandsurgicalcriticallyillpatients.Crit
CareMed.2008Dec.36(12):31907.[Medline].
104. PreiserJC,DevosP,RuizSantanaS,MlotC,AnnaneD,GroeneveldJ,etal.Aprospectiverandomised
multicentrecontrolledtrialontightglucosecontrolbyintensiveinsulintherapyinadultintensivecareunits:
theGlucontrolstudy.IntensiveCareMed.2009Oct.35(10):173848.[Medline].
105. FinferS,ChittockDR,SuSY,BlairD,FosterD,DhingraV,etal.Intensiveversusconventionalglucose
controlincriticallyillpatients.NEnglJMed.2009Mar26.360(13):128397.[Medline].
106. FinferS,LiuB,ChittockDR,NortonR,MyburghJA,McArthurC,etal.Hypoglycemiaandriskofdeathin
criticallyillpatients.NEnglJMed.2012Sep20.367(12):110818.[Medline].
107. BrunkhorstFM,EngelC,BloosF,MeierHellmannA,RagallerM,WeilerN,etal.Intensiveinsulintherapy
andpentastarchresuscitationinseveresepsis.NEnglJMed.2008Jan10.358(2):12539.[Medline].
108. KalfonP,GiraudeauB,IchaiC,GuerriniA,BrechotN,CinottiR,etal.Tightcomputerizedversus
conventionalglucosecontrolintheICU:arandomizedcontrolledtrial.IntensiveCareMed.2014Feb.
40(2):17181.[Medline].
109. LeviM,TohCH,ThachilJ,WatsonHG.Guidelinesforthediagnosisandmanagementofdisseminated
intravascularcoagulation.BritishCommitteeforStandardsinHaematology.BrJHaematol.2009Apr.
145(1):2433.[Medline].
110. MeduriGU,HeadleyAS,GoldenE,etal.Effectofprolongedmethylprednisolonetherapyinunresolving
acuterespiratorydistresssyndrome:arandomizedcontrolledtrial.JAMA.1998Jul8.280(2):15965.
17/18
24/12/2015
[Medline].
111. NathensAB,RotsteinOD.Selectivedecontaminationofthedigestivetractinacuteseverepancreatitisan
indicationwhosetimehascome.ClinInfectDis.1997Oct.25(4):8178.[Medline].
MedscapeReference2011WebMD,LLC
18/18

Septic Shock Treatment & Management

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Septic Shock Treatment & Management

Uploaded by

Copyright:

Available Formats

24/12/2015

You might also like

Septic Shock Treatment &amp; Management

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Septic Shock Treatment &amp; Management

Uploaded by

Copyright:

Available Formats

24/12/2015

You might also like

Septic Shock Treatment & Management

Septic Shock Treatment & Management