early interventions in severe sepsis and septic shock: a ... · pdf fileearly interventions in...

712 MINERVAANESTESIOLOGICA June2012

E X P E R T O P I N I O N

Anno: 2012Mese: JuneVolume: 78No: 6Rivista: MINERVA ANESTESIOLOGICACod Rivista: Minerva Anestesiol

Lavoro: titolo breve: Early interventions in severe sepsis and septic shockprimo autore: RIVERSpagine: 712-24

Sepsisrepresentsacontinuumbeginningwitha host-pathogen interaction that triggers a

complex interplay between pro-inflammatory,anti-inflammatory and apoptotic mediators.1Asthediseaseprogresses,organdysfunctioncanresultfromcirculatoryinsufficiencyfromhypo-volemia,myocardialdepression,increasedmeta-bolicdemandsandvasoregulatoryperfusionab-normalities.Thesehemodynamicperturbationslead to an imbalancebetween systemicoxygensupplyanddemand,leadingtoglobaltissuehy-poxiaandshock.Thesepathogeniceventssignif-icantlycontributetothemorbidityandmortal-ityinearlysepsis.2,3

Acriticaldecreaseinsystemicoxygendelivery(DO2)isfollowedbyanincreaseinthesystemicoxygen extraction ratio (O2ER) and adecreaseincentralvenousoxygensaturation(ScvO2)ormixedvenousoxygensaturation(SvO2).Thisin-creaseinOERisacompensatorymechanismtomatchsystemicoxygendemands.Whenthelim-itofthiscompensatorymechanism(OER>50to60%)isreached,anaerobicmetabolismensuresleadingtolactateproduction.4Inthiscriticalde-liverydependentorhypodynamicphase,lactateconcentrationsareinverselyrelatedtoDO2andScvO2/SvO2 (Figure 1).5 This phase can occurwithnormalvitalsignsandiscommonlyreferred

Earlyinterventionsinseveresepsisandsepticshock:areviewoftheevidenceonedecadelater

E.P.RIVERS1,M.KATRANJI2,K.A.JAEHNE1,S.BROWN1

G.ABOUDAGHER1,C.CANNON3,V.COBA1

1DepartmentofEmergencyMedicineandSurgery,HenryFordHospital,WayneStateUniversity,Detroit,MI,USA;2DepartmentofMedicine,PulmonaryandCriticalCareMedicine,PontiacOsteopathicHospital,Pontiac,MI,USA;3DepartmentofEmergencyMedicine,UniversityofKansas,MedicalCenter,KansasCity,KS,USA

A B S T R A C TTheoutcomes of acutemyocardial infarction, trauma, and strokehave improvedby implementingprocesses thatprovideearlydiagnosisandaggressiveinterventionsatthemostproximalpointofdiseasepresentation.Acommonfeatureintheseconditionsistheimplementationofearlyinterventionstrategies.Onedecadeago,asimilarapproachtosepsisbeganwhenaprospectiverandomizedtrialcomparedearlygoal-directedtherapy(EGDT)tostandardcareusingspecificcriteriafortheearlyidentificationofhighriskpatientswithinfection.ThecomponentsofEGDTwerederivedfromexpertconsensusopiniontoproduceaprotocoltoreversethehemodynamicperturbationsofhypovo-lemia,vasodysregulation,myocardialsuppressionandincreasedmetabolicdemandsforpatientswithseveresepsisintheintensivecareunit(ICU).However,EGDTwasprovidedatthemostproximalphaseofdiseasepresentationintheEmergencyDepartment(ED).WithEGDT,areductioninmortalityofover16%wasshownoverstandardcare.SincetheEGDTstudywaspublishedadecadeago,significantemphasisworldwidehasbeenplacedonacomprehensiveapproachtothefirst6hoursofsepsismanagementwhichiscommonlyreferredtoastheresuscitationbundle(RB).TheRBconsistsofearlydiagnosis,riskstratificationusinglactatelevels,hemodynamicresponseafterafluidchallenge,antibiotics,sourcecontrolandhemodynamicoptimizationorEGDT.ThisreviewwillexamineonedecadeofevidenceforthecomponentsoftheRBexaminingitsimpactonsystemicinflammation,theprogressionoforganfailure,healthcareresourceconsumptionandmortalityinseveresepsisandsepticshock.(Minerva Anestesiol 2012;78:712-24)Key words: Sepsis-Shock,septic-Lactaticacid-Resuscitation.

COPYRIGHT© 2012 EDIZIONI MINERVA MEDICA

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EARLyINTERVENTIONSINSEVERESEPSISANDSEPTICSHOCK RIVERS

Vol.78-No.6 MINERVAANESTESIOLOGICA 713

toas“occultshock”,wherethepatientoutwardlyappearslessill.Asaresultorgandysfunctionandsuddencardiopulmonarycollapsearecomplica-tionsassociatedwiththisphaseifunrecognizedor leftuntreated.2,6,7Thisstatepredominantlycharacterizestheearlysepsispresentation(Figure2)andisanimportantdistinctionfrompreviousunsuccessfulsepsisresuscitationtrialsperformedintheICUsetting.8-11

Afteradequateresuscitation,ahyperdynamicphase follows the hypodynamic phase. Com-pensated sepsis is characterized by an elevatedScvO2/SvO2 and normal lactate. Later an el-evated lactateandelevatedScvO2/SvO2denotepathologicdeliverydependenceordeliveryinde-pendenceandisassociatedwithincreasedmor-tality.12ThefailuretoincreaseOERandthusin-creasesystemicoxygenconsymption(VO2)maybe secondary to impairment of microvascularoxygenperfusionormitochondrialdysfunction.

Origin of the resuscitation bundle (RB) components

The RB and its components are not novelstrategies.Wilsonet al.wroteaseriesofexpertopinionsbeginningin1976thatcomprisedthetenetsofearly sepsismanagement (Figure2).13Theserecommendationsincludedthefollowing:earlyidentificationofhighriskpatients,appro-priatecultures, sourcecontrol,andappropriateantibioticadministration.Thiswasfollowedbystrategies aimed at early hemodynamic opti-mizationofoxygendelivery guidedbypreload(central venous pressure or surrogate, fluids),afterload (mean arterial pressure, vasopressors),

arterialoxygencontent(packedredbloodcells,oxygen), and contractility (inotropes) if ScvO2remainedlow(Figure2).

In the 2001 publication, these componentswhichwerealso recommendedbyaconsensusofexpertopinion14wereappliedatthemostproximalsiteofhospitalpresentationmirroringtheapproachtotrauma,strokeandacutemyocardialinfarction.14This approach called early good-directed therapy(EGDT)wastestedagainststandardcareinaran-domizedcontroltrialresultinginamortalityben-efitofover16%.Inordertoavoidtheethicalissues(withholding life saving therapy), the control orstandardcarearmalsoreceivedcontinuouscentralvenouspressure(CVP),arterialbloodpressureandurineoutputmonitoring.Thiswasnotastandardofcareinemergencydepartment(ED)throughouttheUnitedStatesatthetimewherebaselinemortal-itywasestimatedtobeover50%.InregardstothesuccessoftheEGDTgroup,itmustbeemphasizedthatcontrolgrouptherapyalsoreducedmortality(46.5%)comparedtothehistoricalcaremortalitywhich was over 50%.15 Over the last decade thevariouscomponentsofEGDTortheresuscitationbundlehavebeenexamined,validatedandincorpo-ratedintoevidencebasedguidelines.16,17

Early risk stratification using blood pressure and lactate levels

EGDTbeginswithearlyidentificationofhighriskpatientsbasedonhypotension(systolicbloodpressure<90mmHg)andalactatelevel>4mmol/L(Figure2).Althoughit is intuitive,ahypotensiveepisodeisassociatedwithanincreaseriskforsud-denandunexpecteddeath.18AfterAduenet al.es-tablishedthegeneralprognosticvalueofalactateof4mM/Lonhospitaladmission;multiplestudieshaveconfirmedtheriskstratificationofthis levelfor illnessseverityandmortality inboththepre-hospitalandin-hospitalsetting.19-23

Antibiotic therapy

Once patients are identified, source controland appropriate cultures should be obtained.24While there are no prospective outcome trialsto support early administration of antibiotics,the animal and retrospective human literature

Figure1.—Oxygendeliveryandconsumption.


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RIVERS EARLyINTERVENTIONSINSEVERESEPSISANDSEPTICSHOCK


otics and earlyhemodynamicoptimizationhasbeen shown to be approximately 3-6 hours toarchivethebestoutcomesinhumanstudies.26,29Hutchinson et al. showed that early antibiotic

regarding the benefits of early and appropriateantibioticadministrationispresentinbothani-mal and multiple human studies of sepsis.25-28Thetimeperiodforthecombinationofantibi-

Figure2.—Theearlygoaldirectedtherapyalgorithm.


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laterstageofdiseasepresentation.Itmaybebe-causeofthisthatadministrationanddurationofvasopressorsalsocorrelateswithworseoutcome.Levyet al.hasshownthatthedelayeduseofva-sopressor therapy for cardiovascular support isincrementally associated with a significantlyhigher mortality than any other organ failurebeyondthefirst24hoursofsepsis.3Oneoftheattributesofearlyvolumetherapyisasignificantreduction invasopressor therapywhich furtherreducedneedforvasopressinandcorticosteroidtherapy.3,14, 39-41 De Backer et al. showed thattherewasnosignificantdifferenceintherateofdeath between patients treated with dopamineasthefirst-linevasopressoragentandthosewhoweretreatedwithnorepinephrine,however,theuse of dopamine was associated with a greaternumberofadverseevents.42

Central venous and tissue oxygen saturation

ManyofthesalutaryeffectsofScvO2moni-toring are based on its ability to detect imbal-ances of DO2 toVO2 in the delivery depend-entphaseevenwithnormalvitalssigns.6Inthepresenceofa lowvalue, therapeuticmaneuverstoincreaseDO2ordecreaseVO2arerequiredtonormalizethisnumber.Thus,ScvO2becomesatriggerforincreasinginspiredoxygenconcentra-tion(arterialhypoxia),redbloodcelltransfusion(decreased arterial oxygen content), inotropetherapy(myocardialsuppression),andmechani-calventilation(increasedoxygendemands).43-46Multiple studies have compared ScvO2 withSvO2showingthatthereisanabsolutedifference(5%)betweenthetwosites.47,48Whilethereisa difference, the clinical utility of both sites iscomparableandvalidatedbyoutcomestudies.48Inamulticenterstudy,Popeet al.foundthatthefailuretoreachaScvO2greaterthan70%withinthefirstsixhoursisassociatedwithsignificantlyincreased(14%)mortality.12Castellanos-Ortegaet al.examinedallofthesepsisbundleelementsat6and24hoursofsepsisandfoundthattheattainmentof anScvO2>70%had the statisti-cally most significant impact on survival thanall other bundle elements.49 In a meta-analysisexamining five studies comprising over 11000patients,itwasshownthatpatientsreachingthis

administrationwasassociatedwithasignificant-ly reducedhospital lengthof stay andhospitalcosts.30

Central venous pressure and fluid therapy

While some question the accuracy of CVPinassessingvolumestatus;equivalentoutcomeshave been shown when compared to the pul-monary artery catheter for assessment of fluidstatusinacutelunginjury.31CVPmeasurementis indicative of fluid responsiveness in the low-errangesandaCVP>10istheupperlimitforalgorithms of fluid challenges.32 CVP has beenshowntohaveasignificantassociationwith30-day mortality.33 Ferrer et al.34 and Boyd et al.concluded a negative impact on survival whenCVPwasusedasaguidetofluidmanagement.35The use of CVP appears to be time sensitive.Early,aggressivefluidtherapywhichisassociatedwithimprovedoutcomesmustbedistinguishedfromlateaggressivefluidtherapy.36Theadminis-teredvolumeintheEGDTgroupwithinthefirst6 hours was significantly greater compared tostandardtherapygroup,butover72hourstherewere no differences in the amount of fluid be-tweenthetwogroups.Inameta-analysis,theuseofalbuminisassociatedwithlowermortality.37

Mean arterial pressure and vasopressor use

The mean arterial blood pressure target inEGDTis supportedbyVarpulaandDunser et al.33, 38They examinedhemodynamic variablesin septic shock patients during the first 24-48hoftreatmentandfoundaMAPbelow60-65mmHgtobemostpredictiveof28-30-daymor-tality and organ function. It is preferable thatthisendpointbemetwithfluidversusvasopres-sortherapy.EGDTisassociatedwithgreatervol-umeadministrationanddiminishedvasopressoruseoverfirst6hoursofresuscitation.However,an equal amountoffluid is usedover thefirst72hoursofhospitalization.Intheabsenceofdi-minishedearlyvolumetherapy,therewasanin-creaseintheincidenceofsuddenhemodynamicdeteriorationandvasopressoruse.

These observations reveal that hypotensionismorerefractorytofluidadministrationatthe


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with altered capillary perfusion at baseline.57Whiletherearemanypublicationsthatincrimi-nate RBC transfusions with worse outcome, arecentlargeobservationalstudyfoundthatRBCtransfusionwasassociatedwithdecreasedmor-talityrates.58Furtherstudiesareneededtosup-port the current recommendation for a hemo-globinof10mg/dLduringsepticshock.59

Myocardial dysfunction and inotrope therapy

Theearlyrecognitionofmyocardialdysfunc-tionrequiringinotropicusewasfoundtobeata12.9%greaterfrequencyintheEGDTversusthecontrolgroupintheoriginalEGDTstudyandthis incidence is consistentwithpreviousfind-ingsbyParrilloet al.60Grissomet al.establishedthatphysicalexaminationfindingsofinadequatecirculationarenotusefulforpredictinglowcar-diacindexorScvO2.51Afessaet al.examined962patientsusingapropensityscoreforeachbundleelementandfoundthatcompliancewithlactatemeasurement and inotrope administration wasindependentlyassociatedwithdecreasedriskofmortality.61 Shah et al. performed a retrospec-tive review of 183 sepsis episodes in patientswithpre-existingechocardiograms(priortothesepsisevent)documentingsystolicdysfunction.In the 135 patients who did not meet EGDTadherence requirements, themortality ratewas36.3%andinthe48patientswhometEGDTadherence requirements, themortality ratewas16.67%,P<0.05.44

Decreasing systemic oxygen consumption

The indications for ventilatory support in-clude hypoxia, hypercarbia, severe metabolicacidosis,alteredmental statusand“the lookofimpending demise”. A persistently low ScvO2may signal cardiopulmonary decompensationand the need for ventilator support.45, 62 Fur-thermore,theworkofbreathingcanbeeliminat-edwhichconsumes20-40%ofsystemicoxygendelivery.63-65Inpatientswithsevereadultrespi-ratorydistresssyndrome;earlyadministrationofaneuromuscularblocking agent improves out-comeanddecreasesdurationofmechanicalven-tilation.66 The outcome benefit may be related

endpointweretwiceaslikelytosurvivethanpa-tientswithout reaching this endpoint.50 ScvO2remains significantly predictive of outcome 47hours after the onset of acute lung injury andupto48hoursintheICUphaseofsepsis.33,51FurtherevidenceexistsshowingthatcontinuousScvO2 monitoring is superior to intermittentmonitoring.52 Tissue oxygenation (StO2) canbe obtained using near-infrared spectroscopyusingaprobeapplied to the thenarportionofthe hand. Napoli showed that while a statisti-cally significant relationship existed betweenStO2andScvO2,StO2appearstosystematicallyoverestimatelowerScvO2valuesandunderesti-mateathigherScvO2values.53Mesquidaet al.found that StO2 values below 75% predictedlowScvO2valueswithhighspecificity,butthispredictive value did not hold for StO2 valuesabove75%.Inexaminingthisvariable inearlyresuscitation,Colinet al. foundmassetertissueoxygen saturationpredictive of 28-daymortal-ity.54Thus, StO2might beuseful very early inresuscitation,beforeScvO2isavailable.55

Hemoglobin threshold and red blood cell transfusion

Anemiainearlyseveresepsisandsepticshockresults froma combinationofpre-existingdis-ease,acutevolumeresuscitation,impairedbonemarrowresponseandaproposeddecreaseinthesensitivityoferythropoietinreceptors.56Anemialeads to a compensatory increase in systemicoxygen extraction to systemic oxygen needs.Whenthiscompensatoryresponseisinadequate,thephysiologic rationale for transfusionof redbloodcells(RBCs)duringthisdeliverydepend-entphysiology(increasedlactateandlowScvO2)iswarranted.This concepthas been supportedbyValletet al.whofoundthatmortalityisopti-mizedwhenanScvO2of69.5%isusedasatrig-gerfortransfusion.43Becausehemoglobincon-centrations may vary in the central, peripheralandmicrovascularcirculations, theoxygencar-ryingcapacityandrheologicalcharacteristicsofa specificregion isunpredictable.For instance,findingssuggestthatthesublingualmicrocircu-lationisgloballyunalteredbyRBCtransfusionin septic patients yet can improve in patients


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ScvO2)wheretheproductionoflactateexceedsits clearance and the serum lactate levelsbegintorise.4Therefore,SvO2ismoresensitiveatde-tecting impending tissue hypoxia than lactate.Continuous ScvO2 monitoring provides a realtimeassessment,moreefficientattainmentofre-suscitationendpointsandgreatermortalityben-efitthanintermittentsampling.47,52InanICUbased study, Jansen et al. randomly allocatedpatientswithanelevated lactate (>3mm/L) todecreaselactateby20%ormorepertwohoursfor the initial eighthours in the lactate group.Inthecontrolgroup,thetreatmentteamhadnoknowledge of lactate levels (except for the ad-missionvalue).Thelactategroupreceivedmorefluidsandvasodilators.However,therewerenosignificant differences in lactate clearance be-tweentreatmentgroups.Hospitalmortalitywassignificantlyreducedfrom43.5%inthecontrolgroupversus33.9%inthelactategroup.Inthelactategroup,therewasadecreaseinorganfail-ure, duration of inotrope therapy, mechanicalventilationfrom7-72hoursandICUlengthofstay.70 The lactate group treatment did not re-sultinfasterreductionoflactatewhencomparedwithcontrolgrouptherapy.Thismightactuallyargueagainstlactateasatargetofhemodynamictherapy.However,giventhatScvO2monitoringwasmandatoryinthelactategroupandfaculta-tive in the control group, this study couldnotexclude thepossibility that this had an impactontheobservedoutcomedifference.Thedistur-bancesof lactatemetabolismthatoccurduringsepsis areprobablymore complex than an iso-lated defect of cellular oxygenation.71 Furthera normal lactate in isolation does not excludethepresenceoftissuehypoperfusion.Twentyto50%of septic shockpatientswillneverelevatelactatelevelsatpresentationorduringtheclini-calcourseandfrequentlydevelopmulti-systemorgan failure.72-74 These observations indicatethatusinglactateandScvO2arecomplimentaryendpointsandnotmutuallyexclusive.

Modified versions of the resuscitation bundle

Linet al.employedamodifiedEGDTproto-colinamedicalICUwithouttheuseofScvO2compared to a control group. Targeting CVP,

toearlyrestorationofthebalancebetweenDO2andVO2.

Lactate clearance

Nguyenet al.foundthattheclearanceoflac-tateoverthefirstsixhoursafterpresentationwasassociatedwithasignificantdecreaseinpro-andanti-inflammatory biomarkers, improved or-gan function and reduced mortality.42, 43 Thiswasbasedonprevious investigationsusing lac-tateclearanceover24and72hoursintheICUsetting.67 In a recent prospective multicentertrial of EGDT implementation, Nguyen et al.showedthatwhenpatientsreceivedEGDT,themortalityreductionwasfurtherenhancedwhenretrospectively grouped by improving levels oflactateclearance.68Joneset al.declaredthatlac-tate clearance is equivalent toScvO2using theEGDTalgorithminanoninferioritystudy.69Inthisstudy,patientsassignedtotheScvO2groupwere resuscitated to normalize central venouspressure, mean arterial pressure, and ScvO2of 70% while patients in the lactate clearancegroup were resuscitated to normalize centralvenous pressure, mean arterial pressure, andachievea lactateclearanceofat least10%.Thestudyprotocolwascontinueduntilallgoalswereachievedorforuptosixhours.Theyconcludedthat lactate clearance guided resuscitation wasnon-inferior or equivalent to a ScvO2 guidedresuscitationbasedonnodifference inmortal-ity.ComparedtotheEGDTstudy,thepatientsenrolled by Jones et al. were of a lower illnessseverity,inamoresupplyindependentphaseatbaseline(ScvO2andlowerlactatelevelsatstudybaseline),morefrequentlyinvasodilatoryshock(vasopressor dependent) and less mechanicallyventilated, Figure 1. More importantly, only30interventionsweremadeinonly10%ofthepatientpopulation.Itisthesepatients(deliverydependentorhypodynamicphase)thatrequireadditional interventions such as supplementaloxygen, packed red blood cells, inotropes andmechanical ventilation which are physiologi-callytriggeredbyScvO2.Theseinterventionsre-ducesuddencardiopulmonarycomplicationsby50%;anissuenotaddressedbyJoneset al.Theseevents signal reaching the critical OER (low


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inflammation.76Theobservationofa15%reduc-tioninmechanicalventilationover72hoursisanexampleofpreventingthissecondhit.73Adjunc-tivetherapiestofurthermodulatetheinflamma-toryresponsewhenusedearlymayenhancethebeneficialeffectsofEGDT.77Therapeuticeffortstargetingthemicrocirculationareinprogressbuttodatehavingnotshownoutcomebenefit.78Ki-erset al. foundthatadelayinachievinghemo-dynamicgoalsofEGDTwassignificantlyassoci-atedwiththedevelopmentofacutekidneyinjury(P=0.02)andresultedina3.4%greatercreatininelevelriseperhour(P=0.03)inpatientsadmittedfromthehospitalward.79Inasubanalysisofpa-tients enrolled in theFluidandCatheterTreat-mentTrial (FACTT) of the National InstitutesofHealth,AcuteRespiratoryDistressSyndromeNetwork,animprovedSvO2wassignificantlyas-sociatedwithimprovedmortalityanddecreaseindurationofmechanicalventilation.51Thesefind-ingssupporttheobservationsofadecreasedneedformechanicalventilationoverthefirst72hoursofpresentationintheoriginalEGDTtrial.

Outcome evidence in adult patients

Over the last decade, the external validityandgeneralizabilityoftheRBcontainingvary-ing versions of EGDT has been established inmultiplestudies.Thesestudiescompriseover50publications containing over 18000 adult pa-tients(TableI).8,41,49,68,80-128Theoutcomeben-efit of these studies combined equal or exceedthereductioninmortalityfoundintheoriginal

MAP, hemoglobin and urine output, not onlyledtoasignificantdecreaseofthemortalityrate,but also to shortening the length of ICU stay,duration of mechanical ventilator support anddurationofantibioticadministration.Therewasmore rapid reversal of shock and less delayedvasopressor administration. For medical ICUswithout facility to monitor ScvO2, this modi-fied therapeutic protocol provides an alterna-tivethatreducesmortality,ICUstay,ventilatorsupportduration, and tissuehypoperfusionas-sociatedmajor organdysfunction.The authorsaddedthatwithScvO2measurementtherewasachanceofimprovingclinicaloutcomesfurther.

Impact on inflammation, the microcirculation and organ failure

Theassociationbetweenglobaltissuehypoxiaandinflammationhasbeenwelldescribedinvivomodels. Boulos et al. have shown that SvO2 issignificantlyassociatedwithmitochondrialfunc-tion and that inflammatorymediators in septicpatients can significantly alter mitochondrialfunction.75 In a further analysis of EGDT pa-tients,Riversalsoshowedthatthepersistenceofglobal tissuehypoxia (increased lactate and lowScvO2)correlatessignificantlywiththeactivityofinflammatorymediators.InpatientstreatedwithEGDT, alteration of the inflammatory cascadeis evidenced by significantly lower IL-8 levels.Whenuntreated,thispathogenicmechanismofinflammation can lead to a “second hit” phe-nomenonofmulti-organ failure andworsening

Table I.—Comparison of sepsis intervention studies using the resuscitation bundle compared to the original EGDT study.8, 41, 49, 68, 80-128

Summaryofimplementationstudy Riverset al.

Beforeorcontrol After Control EGDT

Numberofpatients 9527 9884 133 130APACHEIIscore 24.24 24.2 20.4 21.4Sex,%Males 58.15 57.3 50.4 50.8Age(years) 63.84 62.9 64.4 67.1Mortalitybefore(SD)** 46.8(26)% 29.1(12)% 46.5% 30.5%Relativeriskreduction 0.37 0.34Absoluteriskreduction 18.3% 16.0%NNT 5.45 6.25

*Includesbeforeandafterandconcurrentimplementationstudies.**Theaveragemortalityofeachstudy.NNT=numberneededtotreat.


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plyingwiththegoalsofEGDTonpatientout-comeswhencompletedbeyondthesix-hourrec-ommendationperiod.Compliancewasassessedat6,18and24hoursafterdiagnosisof severesepsisorsepticshock.Thecompliersat18hhadanabsolute10.2%significantlylowerin-hospi-talmortalitycomparedtothenon-compliersat18h(37.1%vs.47.3%).Whenadjustedfordif-ferencesinbaselineillnessseverity,thecompliersat18hhadagreaterreductioninpredictedmor-talityof26.8%versus9.4%(P<0.01).Thisstudyuniquelyshowsthatwhenbundlecompletionisextended to 18 hours, the mortality reductionremainssignificant.SimilarfindingswerenotedbyCastellanos-Ortegaet al.119

Challenges of implementation

Significantreductionsinmortalityhavebeenshown even with suboptimal compliance ratesapproaching51%.87Withoutacontinuousqual-ityinitiative(CQI),eventhesecompliancerateswillnotimproveandwilldecreaseovertime.142Multiple studies have shown that standardizedorder sets, enhanced bedside monitor display,

trial.IthasbeenstatedthattheoriginalEGDTstudyenrolledpatientsofhigherillnessseveritythan that observed in other studies. However,themeanage,baselineAPACHEII scoresandmortalityrateofthesepreviousadultstudiesaresimilartotheoriginalEGDTstudy.129-131Theseoutcomes results have been observed in com-munityandtertiarycarehospitals,EDandICUsettings,medicalandsurgicalpatients.98Studiesthatareintheprocessofexaminingthecompo-nentsofEGDTcanbefoundatwww.clinicaltri-als.gov.

Outcome evidence in pediatric patients

EGDThas shown tobebeneficial in apro-spective randomized pediatric trial.129, 132 Arecent study in children showed that fluid bo-lusessignificantlyincreased48-hourmortalityincriticallyillchildrenwithimpairedperfusionintheseresource-limitedsettingsinAfrica.133Thesefindings are a departure from previous trialsfindingthataggressivefluidtherapyandEGDTimprovesmortalityinpediatricsepsis.134,135Thedifferencebetweenthese studiesmaybemulti-factorial includingtheetiologyofthe infectionwhichwasprimarilymalarianotbacterial.Peerreviewedevidencebasedguidelinescurrentlyex-istforthemanagementofsepsisinthepediatricpatient.136Itisimportanttonotethattherapiesconfirmedinadultsarenotnecessarilytranslatedtopediatricpatients.137

Health care resource consumption

The associated cost for sepsis in the UnitedStatesapproachesover$50billionperyearor2.5% of the health care expenditure, makingit the most expensive disease treated in hospi-tal since 1997.138 EGDT has been shown todecrease hospital related costs consistently by20%.139,140Thecostsavingsarelargelydrivenbya significantdecrease inhospital lengthof staybyfivedaysperpatient.141

Importance of timing

DoestheeffectivenessoftheRBattenuateovertime?Cobaet al.examinedtheimpactofcom-

TableII.—Early goal directed therapy.

Decreasesmortality(16-18%)Decreasestheprogressionoforganfailure

– Decreasestheprogressionofacutekidneyinjury– Decreasesneedformechanicalventilation

ModulatestheearlyinflammatoryresponseDecreaseshealthcarecosts(20%)

– Decreaseddurationofmechanicalventilation– Decreasedhospitallengthofstay

Iseffectiveupto18hoursafterdiseaseonset(intheEDandICU)DecreasessuddencardiopulmonarycomplicationsIseffectiveincommunityandtertiarycarehospitalsDiagnostic components (associated with increased mortality):

– Lactate>4mm/L– Systolicbloodpressure<90mmHg

Components (associated with improved outcomes):– Antibioticswithin1to3hours– CVP>8mmHg– MAP>65mmHg– Hematocrit>30%– ScvO2>70%

– Thresholdforredbloodcelltransfusion– Needforinotropictherapy– Indicationforandresponsetomechanicalventilation– Isnotequivalenttolactateclearance


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12. Pope JV, Jones AE, Gaieski DF, Arnold RC,Trzeciak S,Shapiro NI. Multicenter study of central venous oxygensaturation(ScvO2)asapredictorofmortalityinpatientswithsepsis.AnnEmergMed2010;55:40-6,e41.

13. WilsonRF,WilsonJA,GibsonD,SibbaldWJ.Shockintheemergencydepartment.JACEP1976;5:678-90.

14. TaskForceoftheAmericanCollegeofCriticalCareMedi-cine, Society of Critical Care Medicine. Practice param-etersforhemodynamicsupportofsepsisinadultpatientsinsepsis.CritCareMed1999;27:639-60.

15. AnderD,RiversEP,JaggiM,Massura.Acomparisonofstandard versus goal directed therapy in resuscitation ofcritically illemergencydepartmentpatients.AcadEmergMed1997;4:402-3.

16. DellingerRP,LevyMM,CarletJM,BionJ,ParkerMM,JaeschkeRet al.SurvivingSepsisCampaign:Internation-al guidelines for management of severe sepsis and septicshock:2008.CritCareMed2008;36:296-327.

17. FerrerR,ArtigasA.Effectivenessoftreatmentsforseveresepsis: data from the bundle implementation programs.MinervaAnestesiol2011;77:360-5.

18. JonesAE,yiannibasV,JohnsonC,KlineJA.Emergencydepartment hypotension predicts sudden unexpectedin-hospital mortality: a prospective cohort study. Chest2006;130:941-6.

19. AduenJ,BernsteinWK,KhastgirT,MillerJ,KerznerR,BhatianiAet al.Th euseandclinicalimportanceofasub-Theuseandclinicalimportanceofasub-strate-specific electrode for rapiddeterminationofbloodlactateconcentrations.JAMA1994;272:1678-85.

20. Mikkelsen ME, Miltiades AN, Gaieski DF, Goyal M,FuchsBD,ShahCVet al.Serumlactateisassociatedwithmortalityinseveresepsisindependentoforganfailureandshock.CritCareMed2009;37:1670-7.

21. Trzeciak S, Dellinger RP, Chansky ME, Arnold RC,SchorrC,MilcarekBet al.Serumlactateasapredictorofmortality inpatientswith infection. IntensiveCareMed2007;33:970-7.

22. ShapiroNI,HowellMD,TalmorD,NathansonLA,Lis-bonA,WolfeREet al.Serumlactateasapredictorofmor-tality in emergency department patients with infection.AnnEmergMed2005;45:524-8.

23. PearseRM.Extendingtheroleoflactatemeasurementintotheprehospitalenvironment.CritCare2009;13:115.

24. MarshallJC,alNaqbiA.Principlesofsourcecontrolinthemanagementof sepsis.CritCareClin2009;25:753-768,viii-ix.

25. SiddiquiS,RazzakJ.Earlyversuslatepre-intensivecareunitadmissionbroad spectrumantibiotics for severe sepsis inadults.CochraneDatabaseSystRev2010;10:CD007081.

26. GaieskiDF,MikkelsenME,BandRA,PinesJM,MassoneR,FuriaFFet al.Impactoftimetoantibioticsonsurvivalinpatientswithseveresepsisorsepticshockinwhomearlygoal-directed therapywas initiated in the emergencyde-partment.CritCareMed2010;38:1045-53.

27. NatansonC,DannerRL,ReillyJM,DoerflerML,Hoff-manWD,AkinGLet al.Antibioticsversuscardiovascularsupport inacaninemodelofhumansepticshock.AmJPhysiol1990;259(5Pt2):H1440-7.

28. KumarA,EllisP,Arabiy,RobertsD,LightB,ParrilloJEet al.Initiationofinappropriateantimicrobialtherapyresultsinafivefoldreductionofsurvivalinhumansepticshock.Chest2009;136:1237-48.

29. PuskarichMA,TrzeciakS,ShapiroNI,ArnoldRC,Hor-tonJM,StudnekJRet al.Associationbetweentimingofantibioticadministrationandmortalityfromsepticshockinpatientstreatedwithaquantitativeresuscitationproto-col.CritCareMed2011;39:2066-71.

30. HutchisonRW,GovathotiDA,FehlisK,ZhengQ,Cot-trell JH, Franklin N et al. Improving severe sepsis out-comes:costandtimetofirstantibioticdose.DimensCritCareNurs2011;30:277-82.

telemedicineandcomprehensiveCQIfeedbackisfeasible,modifiesclinicianbehaviorandisas-sociatedwithdecreasedhospitalmortality.41,87,

103,122,126,143

Conclusions

Onedecade later,multiplestudies (TableII)havenotonlyvalidatedtheRBanditselementsbut also provide evidence that this therapymodulatesinflammation,decreasesorganfailureprogression and conserves health care resourceconsumption.Thisapproachconsistentlysaves1outofevery6livesforpatientspresentingwithseveresepsisandsepticshock.Whileimplemen-tationremainschallenging,theRBremainsoneof themosteffective interventions intheman-agementofseveresepsisandsepticshock.

References 1. RackowEC,AstizME.Pathophysiologyandtreatmentof

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tomeetingearlygoal-directedtherapyusingtelemedicine.CritCareNursQ2011;34:187-99.

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Conflicts of interest.—Nonerelatedtothispublication.Dr.RiversreceivesresearchsupportfromtheNationalInstituteofHealth,AggennixandAlereCorporation.Inthepastfouryears,hehasbeenaonetimeconsultantforAggennix,EsaiPharmaceuticalsIdahoTechnologies,AstraZeneca,MassimoandSangard.Dr.RivershasneverpersonallyownedanypatentsorEarlyInterventionsinSevereSepsisandSepticShock:TheEvidenceOneDecadeLaterreceivedroyalties,stockorresearchsupportassociatedwiththeEGDTstudy.Dr.CannonhasreceivedconsultingfeesfromEisaiPharmaceuticals.ReceivedonMay3,2011-AcceptedforpublicationonMarch21,2012.Correspondingauthor:E.P.Rivers,MD,MPH,ViceChairmanandResearchDirector,DepartmentofEmergencyMedicine,SeniorStaffAttendinginSurgicalCriticalCareandEmergencyMedicine,ClinicalProfessor,WayneStateUniversity,270-ClaraFordPavilion,HenryFordHospital,2799WestGrandBoulevard,Detroit,MI48202,USA.E-mail:erivers1@hfhs.orgThisarticleisfreelyavailableatwww.minervamedica.it


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