D.C.AngusA.E.BarnatoD.BellR.BellomoC.-R.ChongT.J.CoatsA.DaviesA.DelaneyD.A.HarrisonA.HoldgateB.HoweD.T.HuangT.IwashynaJ.A.KellumS.L.PeakeF.PikeM.C.ReadeK.M.RowanM.SingerS.A.R.WebbL.A.WeissfeldD.M.YealyJ.D.YoungA systematic review and meta-analysis of earlygoal-directedtherapyforsepticshock:the ARISE, ProCESS and ProMISe InvestigatorsReceived:25March2015Accepted:10April2015Springer-VerlagBerlinHeidelbergandESICM2015FortheARISE,ProCESS, ProMISeandPRISMInvestigators.Take-homemessage:EGDTforpatientspresenting to the ED with early septic shockdoesnotdecreasemortalitybutdoesincreaseICUresourceutilisation.ElectronicsupplementarymaterialTheonlineversionofthisarticle(doi:10.1007/s00134-015-3822-1)containssupplementarymaterial, whichisavailabletoauthorizedusers.D. C. Angus D. T. Huang J. A. Kellum F. PikeDepartmentofCriticalCareMedicine,UniversityofPittsburghSchoolofMedicine, Pittsburgh, USAD. M.YealyDepartmentofEmergencyMedicine,UniversityofPittsburghSchoolofMedicine, Pittsburgh, USAA. E.BarnatoDepartmentofMedicine, UniversityofPittsburghSchoolofMedicine, Pittsburgh,USAD. BellFacultyofMedicine, ImperialCollegeLondon,London, UKD. BellDepartment of Acute Medicine, Chelsea andWestminsterHospitalNHSFoundationTrust,London, UKR.Bellomo A. Davies A. Delaney B.Howe T.Iwashyna S.L. Peake S.A. R. WebbAustralianandNewZealandIntensiveCareResearchCentre,SchoolofPublicHealthandPreventiveMedicine,MonashUniversity, Melbourne, VIC, AustraliaR.BellomoAustinHospital,Melbourne,VIC,AustraliaC.-R.ChongPharmacyDepartment,TheQueenElizabethHospital,Adelaide,SA,AustraliaC.-R.Chong S.L. PeakeSchool of Medicine, University of Adelaide,Adelaide, SA,AustraliaT. J.CoatsDepartmentofCardiovascularSciences,UniversityofLeicester, Leicester, UKA. DaviesFrankstonHospital, Frankston, VIC,AustraliaA. DelaneyRoyalNorthShoreHospitalandUniversityofSydney, Sydney,NSW, AustraliaA. DelaneyNorthernClinicalSchool, SydneyMedicalSchool, UniversityofSydney, Sydney,NSW, AustraliaD. A. Harrison K. M.RowanClinicalTrialsUnit, IntensiveCareNationalAuditandResearchCentre,London, UkD. A. Harrison K. M.RowanLondonSchoolofHygieneandTropicalMedicine, London, UKA. HoldgateLiverpoolHospitalandUniversityofNSW,Sydney, NSW, AustraliaIntensiveCareMedDOI10.1007/s00134-015-3822-1SEVEN-DAYPROFILEPUBLICATIONT.IwashynaUniversityofMichiganandVACentreforClinical Management Research, Ann Arbor,MI, USAM.C. ReadeBurns,traumaandcriticalcareresearchcentre,UniversityofQueensland,Brisbane,QLD, AustraliaM.C. ReadeJointHealthCommand, AustralianDefenceForce, Canberra,ACT,AustraliaK. M.RowanDepartmentofHealthServicesResearchandPolicy,LondonSchoolofHygieneandTropicalMedicine,London, UKK. M.RowanDivisionofResearchStrategy, UniversityCollegeLondon, London,UKM.SingerBloomsburyInstituteofIntensiveCareMedicine, UniversityCollegeLondon,London, UKS. A.R. WebbRoyalPerthHospitalandUniversityofWesternAustralia,Perth, WA,AustraliaL.A. WeissfeldStatisticsCollaborative, Washington, DC,USAJ.D. YoungNufeldDivisionofAnaesthetics,UniversityofOxford,Oxford, UKS.L. Peake())DepartmentofIntensiveCareMedicine,TheQueenElizabethHospital, 28WoodvilleRoad,Woodville, SA5011,Australiae-mail:sandra.peake@health.sa.gov.auAbstract Purpose: Todeterminewhetherearlygoal-directedtherapy(EGDT)reducesmortalitycomparedwithotherresuscitationstrategiesforpatientspresentingtotheemergencydepartment(ED)withsepticshock.Methods: Using a search strategy ofPubMed,EmBaseandCENTRAL,weselectedallrelevantrandomisedclinicaltrialspublishedfromJanuary2000toJanuary2015.Wetranslatednon-Englishpapersandcontactedauthorsasnecessary.Ourprimaryanalysis generated a pooled odds ratio(OR)fromaxed-effectmodel.Sensitivityanalysesexploredtheef-fectofincludingnon-EDstudies,adjustingforstudyquality,andcon-ductingarandom-effectsmodel.SecondaryoutcomesincludedorgansupportandhospitalandICUlengthof stay. Results: From 2395 initiallyeligibleabstracts, verandomisedclinicaltrials(n=4735patients)metallcriteriaandgenerallyscoredhighforqualityexceptforlackofblinding.Therewasnoeffectontheprimarymortalityoutcome(EGDT:23.2%[495/2134]versuscontrol:22.4%[582/2601];pooledOR1.01[95%CI0.881.16],P=0.9,withheterogeneity[I2=57%;P=0.055]). Thepooledestimateof90-daymortalityfromthethreere-centmulticentrestudies(n=4063)alsoshowednodifference[pooledOR0.99(95%CI0.861.15),P=0.93]withnoheterogeneity(I2=0.0%;P=0.97). EGDTin-creasedvasopressoruse(OR1.25[95%CI1.101.41];P\0.001)andICUadmission[OR2.19(95%CI1.822.65); P\0.001]. Includingsixnon-EDrandomisedtrialsincreasedheterogeneity(I2=71%;P\0.001) but did not change overallresults[pooledOR0.94(95%CI0.82to1.07);P=0.33]. Conclu-sion: EGDTisnotsuperior tousualcare for ED patients with septic shockbutisassociatedwithincreasedutilisationofICUresources.Keywords Earlygoal-directedtherapyorEGDT Resuscitation Septicshock Centralvenousoxygensaturation Meta-analysis Systematicreview RandomisedclinicaltrialsIntroductionIn2001,Riversandcolleaguespublishedasingle-centre,randomisedtrialofprotocolisedresuscitationforpatientspresentingtotheemergencydepartment(ED)withsepticshock[1]. Thetherapies prescribedinthis specic, 6-hresuscitation algorithm, termed early goal-directed therapy(EGDT), wereguidedbytheoptimisationof haemody-namic goals targeting both arterial and central venouspressure and a central venous oxygenation saturation(ScvO2)of70%orgreater. EGDTdecreasedshort-termmortality compared with non-protocolised standard resus-citation. Anumber of non-randomised, predominantlybeforeafter, studies subsequently reported a survivalbenet withEGDT, evenwhenimplementationwasin-complete [24]. Since 2004, the Surviving SepsisCampaignguidelines have endorsedEGDT[5] but theuptake of this resuscitation approach has been variable [6].Barriers to uptake include concerns regarding the general-isabilityoftheoriginal EGDTtrial ndingsoutsideofasingleUScentre,thepotentialrisksassociatedwithindi-vidual elements of the protocol and the infrastructure andresource requirements needed to implement EGDT. Threerecent large, multicentre, randomisedclinical trialscon-ducted in the USA[7, 8], Australasia [9, 10] and the UK[11,12] failed to nd that EGDT decreased mortality.We sought tosystematicallyreviewthe randomisedclinical trial evidencefor EGDTintheresuscitationofpatients presentingtotheEDwithsepticshockandtoaddress the primary question of whether EGDT, com-pared with other resuscitation strategies, is associatedwithasurvival benet. Our secondaryobjectivewastoevaluate EGDTin all patients with septic shock irre-spectiveofpresentingsourceortiming.MethodsWe prospectively registered our study protocol withPROSPERO(International prospective register of sys-tematic reviews; CRD2014015682). The researchquestion was formulated according to the Participants,Interventions, Comparisons and Outcomes (PICO) model:P, patientspresentingtotheemergencydepartment withseptic shock; I, EGDT; C, non-EGDThaemodynamicresuscitationstrategy;O,mortality[13].Themethodsforreportingthesubsequent resultshavefollowedPRISMA(PreferredReportingItems for SystematicReviews andMeta-Analyses)guidelines[14].InclusioncriteriaWe included randomised clinical trials conducted in adultor paediatric patient populations withsepticshockthatcompared EGDTwith either usual care or another re-suscitationstrategythat didnot incorporateEGDT. Thedenition of EGDT was based on the original publicationbyRiversetal. [1]astheprotocolisedadministrationofintravenous uids, vasoactiveagents andredcell trans-fusion to achieve the predetermined haemodynamic goalsof central venous pressure, mean arterial pressure andScvO2.Weonlyanalysedstudiesthatreportedmortality,excludingthosereportingonlyphysiological end-points,solely descriptive or non-randomised and any studiespublishedbefore2000.SearchstrategyTwo authors (SLP, ADe) independently conducted thesearch of PubMed, Embase and the Cochrane CentralRegisterofControlledTrials(CENTRAL)databasesforthe period 1 January 2000 to 15 January 2015 to identify allrandomised clinical trials of EGDT in human subjects withseptic shock. The search terms were sepsis, septi-caemia, shock, septic, earlygoal-directedtherapy,EGDT, sepsisprotocol, clinical protocols, cen-tralvenousoxygensaturation,ScvO2,goal-directedresuscitation, goal-directedtherapycombinedwithsen-sitivelterstoidentifyrandomisedclinical trials. Therewere no language restrictions. The detailed search strategyis reported in the Supplementary Appendix. We alsosearchedclinicaltrialsregistriesandcontactedexpertsinthe eld to identify unpublished studies.Twoauthors(SLP, ADe)independentlyreviewedthetitlesandabstractsofallarticlesgeneratedbythesearchtoidentifypotentiallyrelevantstudies.Weretrievedfull-text manuscripts of potentially relevant studies for furtherevaluationandinclusionif thepredenedinclusioncri-teriaweremet. Wealsoscreenedthereferencelists ofincludedarticlesandprevioussystematicreviewsforthesameperiod[1517]toidentifyotherpotentiallyeligiblestudies.Ifneeded,wecontactedauthorstoclarifydetailsof trials. Differences of opinionwereresolvedvia dis-cussionandconsensus.DataextractionTwo authors (SLP, ADe) independently extracted pre-dened data from included studies into standardiseddata abstraction forms except for articles written inChinese, which were translated (by C-RC) and dataextracted(C-RC, SLP) separately. Informationincluded(1) study characteristics (lead author, publication year,countryorregion, numberofparticipatingsites, numberof patients enrolled, EDand/or non-EDsource, EGDTandcontrol resuscitationgoals); (2) participant charac-teristics(age, sex, baselineAPACHEII score, presenceof hypotensionandhyperlactataemia); (3) interventionsdelivered up to 6h post-randomisation (including in-travenous uids, vasopressors, dobutamineandredcelltransfusion); (4) time to antimicrobial administration;(5) receipt and duration of organ support (invasivemechanical ventilation, vasopressors andrenal replace-ment therapy); and (6) outcome (mortality, intensivecare unit (ICU) admission and duration of ICUandhospital stay).QualityassessmentWe assessed thequality of the included studies using twoindependent assessors who had no role in the design,conduct, analysis or reporting of any of the includedstudies(TI, ADa). TheCochraneCollaborationtool wasusedtoassesstheriskof biasfor theindividual studiesacross the following domains: randomsequence gen-eration (selection bias); allocation concealment (selectionbias); blinding of participants and personnel (performancebias); blindingof outcome assessment (detectionbias);incompleteoutcomedata(attritionbias);selectivereport-ing(reportingbias); andothersourcesofbias[18]. Therisk of bias for each domain was assessed as high,low or unclear. When differences in assessmentexisted, consensuswasobtainedviadiscussionbetweentheassessors.OutcomemeasuresWe classied studies according to the patient entrysource, into those conducted among patients presenting totheED, andthoseinwhichsomeorall thepatientsen-rolled were fromthe general ward and/or ICUor thesource was unable to be determined fromeither thepublishedarticleor fromattempts tocontact thecorre-spondingauthorofthestudy.For the primary objective, the prespecied primaryoutcomewas mortalityinstudies conductedinpatientspresentingtotheEDwithsepticshock. If mortalityatmore than one time was reported for a given trial, we usedthemortalityidentiedastheprimaryoutcomefor thatstudyintheanalysisof our primaryobjective. Wealsoconductedadditional analyses for mortalityat 28days,90days andat hospital discharge for studies reportingthese mortality outcomes. Secondary outcomeswere ICUadmissionrateanddurationofstayinICUandhospital.Our secondaryobjectivewas toassessmortalityat anytime in patients with septic shock irrespective of pre-senting source. Mortality was the primary mortalityoutcomeforeachstudyincludedintheanalysis.StatisticalanalysisWe used a xed-effect model to obtain an estimate of theeffect size for the primary objective expressed as a pooledoddsratio(OR) with95%condenceinterval (CI) andpresented as a forest plot. We also conducted a sensitivityanalysis using a random-effects model. We used uni-variate meta-regression to assess the effect of eachdomainofthequalityassessmentontheoverallestimateoftreatment effect, aswell asotherpotential sourcesofheterogeneity. To assess heterogeneity in treatment effectacrossstudies, weusedtheI2statistic. Aprioriexplana-tions for heterogeneity included (1) methodologicalquality of the studies (using individual risk of biasdomains); (2)harmonisedstudies(AustralasianResusci-tationinSepsis Evaluation[ARISE], ProtocolizedCarefor Early Septic Shock [ProCESS] and ProtocolisedManagement In Sepsis [ProMISe]) versus non-har-monised studies; (3) control intervention (usual careversus another resuscitation protocol); (4) duration ofintervention; and(5)adult versuspaediatricpopulations.Examination of small study effects was conducted byconstructionandvisual examinationof funnel plotsandEggersstatistic.ToassesstheeffectofEGDTonreceiptanddurationof organ support and secondary outcomes (ICU admissionand duration of stay in ICU and hospital), we used a xed-Fig.1 StudyselectionEGDTdenotesearlygoal-directedtherapy. Identiedthroughpersonalcontactwithinvestigatorspriortopublication[12]aeffectmodelandreportedapooledORand95%CIforcategorical variables or overall mean weighted difference(WMD) with 95%CI for continuous variables. Foranalysisofoursecondaryobjective(mortalityinpatientswithsepticshockirrespectiveof presentingsource), weusedthepooledORwith95%CI usingaxed-effectmodel.We usedStata/SEversion13.1(StataCorp, CollegeStation, Texas) for analysesandatwo-sidedPvalueof0.05orlesstoindicatestatisticalsignicance.ResultsThepreliminarysearchidentied2598articles (Fig.1).After removal of 203duplicates, wereviewed2395ab-stracts and eliminated 2365 articles not meeting the studyinclusion criteria. Two investigators (SLP, ADe) re-viewed 30 full-text articles and subsequently excluded 19asnot meetingtheinclusioncriteria. Notrialswereex-cluded because mortality was not reported. Of the 11remainingstudies,veenrolledpatientspresentingtotheED with septic shock and were suitable for assessment oftheprimaryobjective[1,8,10,12,19].Oftheremainingsix studies fullling the inclusion criteria for our sec-ondary objective, one enrolled patients presenting toeither the EDor recruitedin-patients fromthe generalwardorICU[20]andinve(all publishedinChinese),we could not determine the patient source from either theoriginalpublicationnorfollowingattemptstocontacttheauthor usingcontact details providedinthepublication[2125].StudycharacteristicsTable1 summarises the characteristics of the includedstudies. Six were conducted in multiple sites and veweresingle-centrestudies. Thetotal number of patientsenrolledwas5407, comprising2459intheEGDTgroupand 2948 in the control group. The control was usual careinvestudies[1, 10, 12, 21, 22], analternativeresusci-tationstrategyinvestudies[19, 20, 2325]andinonestudy both usual care and protocol-based standard therapy[8]. Thegoals of thealternativeresuscitationstrategiesare described in Table1. Patient characteristics andtherapies delivered during the 6-h resuscitation period areTable1 CharacteristicsofincludedstudiesfortheprimaryandsecondaryobjectivesAuthor Region No. ofsitesPopulation Source Control(s) No.ofpatientsPrimaryoutcomePrimaryobjectiveRiversetal. [1] USA 1 Adult ED Usualcare 263 In-hospitalJonesetal.[19] USA 3 Adult ED Lactateclearancec300 In-hospitalProCESSInvestigators[8] USA 31 Adult ED Usualcareorprotocol-basedstandardtherapyd1341 In-hospitalhARISEInvestigators[10] Australasiaa51 Adult ED Usualcare 1600 90-dayProMISeInvestigators[12] England 56 Adult ED Usualcare 1260 90-daySecondaryobjectiveWangetal.[21] China 1 Adult UnknownbUsualcare 33 14-dayDeOlivieraetal.[20] Brazil 2 Paediatric ED, ward,ICU ACCM/PALSguidelinese102 28-dayEGDTCollaborative[22] China 8 Adult UnknownbUsualcare 314 28-dayTianetal. [23] China 1 Adult Unknownb10or30%lactateclearance 71 28-dayYuetal.[24] China 1 Adult UnknownbLactateclearanceC10%f50 28-dayLuetal. [25] China 1 Adult UnknownbPiCCO-guidedresuscitationg82 In-hospitalThe primary objective included only those studies in which patientspresented to the EDwith septic shock (n=5). The secondaryobjective also included those studies in which the presenting sourcewas the EDandthe wardor ICUor where the source was notknown(n=11)ProCESSProtocolizedCarefor EarlySepticShock, ARISEAus-tralasianResuscitationinSepsisEvaluation,ProMISeProtocolisedManagement In Sepsis, EGDT early goal-directed therapy, EDemergencydepartment,ICUintensivecareunit,ACCM/PALSTheAmerican College of Critical Care MedicinePaediatric AdvancesLifeSupport, PiCCOpulsecontourcontinuouscardiacoutputaARISE enrolled patients in Australia, New Zealand, Hong Kong,FinlandandRepublicofIrelandbNoresponsetoemailcommunicationcIsotoniccrystalloids, vasopressors, redcellsanddobutaminetoachievecentralvenouspressureC8mmHg,meanarterialpressureC65mmHgandlactateclearance [10%dProtocol for administration of uids and vasoactive agents toreachgoals for systolicbloodpressureandshockindex, withoutrequirementforcentralvenousmonitoringeFluids, redcellsandvasoactiveagentstomaintainnormal per-fusionpressure for age, urine output [1ml/kg/h, capillaryrell\2sandnormalpulsesfFluid resuscitation to maintain central venous pressureC8mmHg, meanarterial pressureC65mmHgandlactateclear-anceC10%gFluidsandvasoactiveagentstomaintainanintrathoracicbloodvolumeindexof 8501000ml/m2, left ventricular contractilein-dex,strokevolumeindexandmeanarterialpressureof65mmHghIn-hospitalmortalitycensoredat60daysdetailed in Tables2 and 3. TablesS1 and S2 of theSupplementaryAppendixdetail thereceipt anddurationof organsupport, ICUadmissionandlengthof stayinICUandhospital.ThequalityassessmentoftheincludedstudiesisshowninTableS3of theSupplementaryAp-pendix. Giventhenatureof theintervention, all studieswereunblindedanddeemedtobeathighriskofbiasforblindingofparticipants and personnel.Two studieshad alowriskofbiasfortheremainingdomains[10, 12]andnineothersweredeemedtohaveadditional highorun-clearriskforbiasinoneormoredomains.PatientspresentingtotheemergencydepartmentwithsepticshockMortalityA total of 4735 patients were available for analysis of ourprimaryobjective. Overallmortalitywas23.2%(495of2134patients) intheEGDTgroupand22.4%(582of2601 patients) in the control group. EGDT did not confer areductioninoverallmortality(pooledOR1.01[95%CI0.881.16]; P=0.90) (Table4; Fig.2). There wasevidence of heterogeneity (I2=57%; P=0.055).Heterogeneity between studies was not explained bymethodological quality, harmonised versus non-har-monised studies or control intervention. There was novariation across the ve studies in duration of interventionandall wereconductedinadult populations. Sensitivityanalysis using a random-effects model did not change theresults (Supplementary Appendix Fig.S1). Sensitivityanalysis using only usual care as the control and excludingalternative resuscitation strategies (protocol-based stan-dardtherapy[8]andlactateclearance[19])alsodidnotchangetheresults.Forthestudiesreporting90-daymor-tality (the three harmonised studies) [8, 10, 12], the pooledORwas 0.99(95%CI 0.861.15) (P=0.93) withnoheterogeneity(I2=0.0%;P=0.97)(Fig.2).Effectes-timatesforin-hospital and28-daymortalityalsodidnotdemonstrate a reduction in mortality associated withEGDT either using a xed-effect or random-effects model(Table4;SupplementaryAppendixFigs.S2andS3[5].OrgansupportandlengthofhospitalandICUstayThere was no difference in receipt of or duration of organsupport other thanfor receipt of vasopressorswhichin-creased with EGDT (OR 1.25 [95%CI 1.101.41];P\0.001). Post hoc analysis using random-effectsTable2 PatientcharacteristicsandprimarymortalityoutcomeoftheincludedstudiesAuthor No. ofpatients APACHEIIscore Hypotension(%)Lactate(mmol/L) Primarymortality(%)EGDT Control EGDT Control EGDT Control EGDT Control EGDT ControlPrimaryobjectiveRiversetal. [1] 130 133 21.46.9 20.47.4 54.6 51.1 7.74.7 6.94.5 29.2f44.4fJonesetal.[19] 150 150 NAbNAb82.0 80.1 4.23.1 3.93.1 22.7 16.7ProCESS Investigators [8]a439 902 20.88.1 20.77.4 55.6 53.5 4.83.1 4.93.4 21.0 18.5ARISEInvestigators[10] 796 804 15.46.5 15.86.5 70.0 69.8 4.43.3 4.22.8 18.6 18.8ProMISeInvestigators [12] 630 630 18.77.1 18.07.1 54.1 55.6 5.23.5 5.13.5 29.5 29.2SecondaryobjectiveWangetal.[21] 16 17 287 276 100 100 NA NA 25.0 41.2DeOlivieraetal.[20] 51 51 NAcNAc94.1 92.2 1.1 (0.72.5)e1.2 (0.82.3)e11.8 39.2EGDTCollaborative[22] 163 151 23.55.7 21.86.5 NA NA NA NA 25.2 42.4Tianetal. [23] 19 43 20.98.6 17.65.7d100 100 NA NA 63.2 36.4dYuetal.[24] 23 25 17.93.8 18.26.0 100 100 NA 3.41.3 28.0 20.0Luetal. [25] 40 42 27.68.9 28.910.1 100 100 7.33.1 7.53.8 17.5 16.7DatapresentedasmeanSDorpercentage(%)unlessotherwiseindicated. The primary objective included only those studies inwhichpatientspresentedtotheEDwithsepticshock(n=5).Thesecondaryobjectiveincludedthosestudiesinwhichthepresentingsource was the ED and the ward or ICU or where the source was notknown (n=11). The control for analyses was usual care or anothernon-EGDTresuscitationstrategyProCESSProtocolizedCarefor EarlySepticShock, ARISEAus-tralasianResuscitationinSepsisEvaluation,ProMISeProtocolisedManagement In Sepsis, EGDT early goal-directed therapy,APACHEAcutePhysiologyAndChronicHealthEvaluation, NAnotavailableaDatapresentedforthecontrolgroupisusualcareandprotocol-basedstandardtherapygroupscombined. For theusual careandprotocol-based standard therapy groups separately, APACHEIIscore was 20.77.5 and 20.67.4, respectively; presence ofshock, 53.3and53.4%;lactate4.93.1and5.03.6mmol/L;andprimarymortality18.6and18.2%bSimpliedAcute PhysiologyScore for the EGDTandcontrolgroupswas44.117.3and44.818.4, respectivelycPaediatric Risk of Mortality Score (PRISM) (median and in-terquartilerange)fortheEGDTandcontrolgroupswas7.0 (512)and8.0(512), respectivelydDatapresentedfor10%lactateclearancegrouponly.APACHEII score and primary mortality for the 30% lactate clearance groupwere18.06.8mmol/Land28.6%eMedianandinterquartilerangefPercentagespresentedaredifferent tothosereportedintheori-ginal publication [1] in which mortality was calculated by theKaplanMeierproduct-limitmethodmodelling did not change any results (SupplementaryAppendix Figs.S46). EGDTwas associated with in-creasedICUadmission(OR2.19[95%CI 1.822.65];P\0.001) (Table4; Fig.3). However, there was nodifference in ICU length of stay for those admitted (WMD-0.02 [95% CI -0.47 to 0.43] days;P=0.93) (Fig.3).Hospital length of stay was also not different (WMD-0.28 [95% CI -1.18 to 0.62] days; P=0.55) (Table4;SupplementaryAppendixFig.S7).PatientswithsepticshockindependentofpresentingsourceMortality for the secondary objective was 23.4% (572 of2448patients) intheEGDTgroupand23.9%(699of2930 patients) in the control group. EGDT did not reduceoverall mortality (OR 0.94 [95% CI 0.821.07];P=0.33). Heterogeneity was signicant (I2=71%;P\0.001). Post hoc analysis using a random-effectsmodel didnot changetheresultsandtherewasnoevi-dence of interaction between presenting source andEGDTin a random-effects meta-regression (P=0.51)(Supplementary Appendix Fig.S8). There was no evi-dence of small study effects either by visual assessment ofthe funnel plot or byEggers test (P=0.58) (Supple-mentaryAppendixFig.S9).DiscussionOurmeta-analysisidentied11randomisedclinicaltrialsevaluating EGDT versus usual care or an alternative non-EGDTresuscitationstrategyamongmorethan5000pa-tients withsepticshock. Wefoundthat, acrossthevestudies of patients presenting to the ED with septic shock,EGDT was not associated with decreased mortalitycomparedwithusual care; however, EGDTwasassoci-atedwithincreasedadmissiontoICU.In recent years, several meta-analyses evaluatingEGDTreportedasurvival benet inpatientswithsepticshock[1517]. Barochiaet al. [17] foundthat bundledcare incorporating EGDT was associated with an increasein survival [OR1.91 (95%CI 1.492.45)]. However,sevenoftheeightincludedstudieswerenon-randomisedbeforeafter trials, of whichfour reportedbaseline im-balances between treatment groups. In many of thesestudies, compliancewiththeEGDTalgorithmwasalsolow yet an overall mortality benet was observed,Table3 Interventionsdeliveredbetweenrandomisationand6hpost-randomisationAuthor Fluids(ml) Vasopressor(%)Dobutamine(%)Blood transfu-sion(%)Timetorst antimicrobial(min), median(IQR)EGDT Control EGDT Control EGDT Control EGDT Control EGDT ControlPrimaryobjectiveRiversetal. [1] 49812984 34992438 27.4 30.3 13.7 0.8 64.1 18.5 NA NAJonesetal.[19] 43002210 45002360 75.3 72.0 5.3 3.3 3.3 7.3 115(66170)115(62180)ProCESSInvestigators[8]28051957 27831880 54.9 48.1 5.7 1.0 14.4 7.9 NA NAARISEInvestigators[10] 19641415 17131401 66.6 57.8 15.4 2.6 13.6 7.0 70(38114) 67(39110)ProMISeInvestigators[12]22261443 20221271 53.3 46.6 18.1 3.8 8.8 3.8 NAbNAbSecondaryobjectiveWangetal.[21] 4895210 234095 100 100 NA NA NA NA NA NADeOlivieraetal.[20]. NAaNAa49.0 56.9 29.4 7.8 45.1 15.7 NA NAEGDT Collaborative [22] NA NA NA NA NA NA NA NA NA NATianetal. [23] NA NA NA NA NA NA NA NA NA NAYuetal.[24] 33001210 36001360 80.0 72.0 4.0 8.0 20.0 16.0 NA NALuetal. [25] 2809795 3608715 87.5 76.2 NA NA NA NA NA NADatapresentedasmeanSDorpercentage(%)unlessotherwiseindicated. The primary objective included only those studies inwhichpatientspresentedtotheemergencydepartmentwithsepticshock(n=5). Thesecondaryobjectiveincludedthosestudiesinwhich the presenting source was the emergency department and thewardor ICUor wherethesourcewasnot known(n=11). Thecontrol for all analyseswasusual careor another non-EGDTre-suscitationstrategy. FortheProCESStrial [8], datapresentedforthecontrolgroupareusualcareandprotocol-basedstandardther-apygroupscombinedProCESSProtocolizedCarefor EarlySepticShock, ARISEAus-tralasianResuscitationinSepsisEvaluation,ProMISeProtocolisedManagementInSepsis,EGDTearlygoal-directedtherapy,NAnotavailable, IQRinterquartilerangeaMedian(interquartilerange)forEGDTandcontrolgroupswere28(2040)and5(020)ml/kg, respectivelybAllpatientsreceivedantimicrobialspriortorandomisationTable4GRADE-styleevidenceprolefortheeffectofearlygoal-directedtherapyinpatientswithsepticshockpresentingtotheemergencydepartment[26]No.ofstudiesNo.ofparticipantsStudylimitationscQualityassessmentSummaryofndingsHeterogeneityI2(Pvalue)PrecisiondPublicationbiaseRelativeeffect(95%CI)fAssumedeventrategEGDTeventrateh(%)OverallqualityPrimarystudymortalityaPrimaryobjectiveb54735Moderate56.7%(0.055)NIIUnlikely1.01(0.881.16)22.4%22.5ModerateSecondaryobjective115378Signicant70.7%(\0.001)NIIUnlikely0.94(0.821.07)23.9%22.7Low28-daymortality44330Moderate54.7%(0.085)NIIPossible0.95(0.821.10)22.6%21.7Moderate90-daymortality34063Moderate0%(0.97)NIIPossible0.99(0.801.15)26.7%26.5ModerateIn-hospitalmortality54744Moderate59.2%(0.044)NIIUnlikely1.00(0.871.16)20.3%20.3ModerateHospitallengthofstay54740Moderate0%(0.65)NIIUnlikely0.26(-1.18to0.62)1117daysModerateICUadmission44480Moderate11.6%(0.32)NIIPossible2.19(1.822.65)82.9%91.4ModerateICUlengthofstay43876Moderate0%(0.58)NIIPossible-0.02(-0.47to0.43)56daysModerateReceiptofMV54715Moderate55.0%(0.064)NIIUnlikely0.97(0.86to1.10)34.9%34.2ModerateDurationofMV41625Moderate40.2%(0.17)NIIPossible0.48(-0.34to1.30)59daysModerateReceiptofvasopressors54743Moderate78.9%(0.001)NIIUnlikely1.25(1.101.40)60.5%65.6ModerateDurationofvasopressors32984Moderate0%(0.68)NIIPossible0.09(-1.12to0.29)2.42.5daysModerateReceiptofRRT34003Moderate0%(0.52)SIPossible0.99(0.811.22)10.1%10.1ModerateDurationofRRT3430Moderate0%(0.95)NIIPossible-0.36(-1.75to1.03)59daysModerateAnalysisfortheprimaryobjectiveincludedonlythosestudiesinwhichpatientspresentedtotheemergencydepartmentwithsepticshock.AnalysisforthesecondaryobjectiveincludedthosestudiesinwhichthepresentingsourcewastheemergencydepartmentandthewardorICUorwherethesourcewasnotknown.Thecontrolforallanalyseswasusualcareoranothernon-EGDTresuscitationstrategy;fortheProCESStrialthecontrolgroupwasusualcareandprotocol-basedstandardtherapygroupscombined[8].SecondaryoutcomeswereevaluatedfortheprimaryobjectiveonlyICUintensivecareunit,MVmechanicalventilation,RRTrenalreplacementtherapy,NIInoimportantimprecision,SIsomeimprecision,CIcondenceintervals,EGDTearlygoal-directedtherapyaIfmortalityatmorethanonetimewasreported,weusedtheprimarymortalityoutcomeofeachincludedstudybEffectestimatedeterminedusingusualcareandprotocol-basedstandardtherapygroupscombinedfortheProCESStrial[8].TheeffectestimatewasnotdifferentusingtheusualcaregrouponlyandexcludingtheJonestrial(controlgrouplactateclearance)[19](OR0.97[95%CI0.841.12])cStudylimitationsweredeterminedusingtheresultsoftheindependentriskofbiasassessment(Table4).AllstudieswereadjudgedashavingatleastmoderatelimitationsduetothelackofblindingdSomeimprecisiondeterminedtobepresentwhenthe95%CIdidnotexcludea20%relativedifferenceintheeffectestimateeFormalassessmentofpublicationbiaswasunabletobeperformed(otherthanforthesecondaryobjective)duetothesmallnumberofincludedstudies.However,giventheextensivesearchstrategy,wasadjudgedtobeunlikely,otherthanforoutcomesofinterestforwhichtherewasincompletereportingandselectivereportingwasconsideredtobepossiblefEffectestimatesformortalityandreceiptoforgansupportarereportedasoddsratioandforlengthofstayanddurationoforgansupportweightedmeandifference(days)gAssumedeventratesformortalityandreceiptoforgansupportaretheeventratesfromthecontrolgroupsofallincludedstudiesandforlengthofstayanddurationoforgansupporttherangesofthemeanvaluesfromthecontrolgroupsacrosstheincludedstudieshEGDTeventratesformortalityandreceiptoforgansupportarecalculatedbyapplyingtheestimatedoddsratiostotheassumedeventratessuggesting that factors other than the specic resuscitationprotocolinuencedoutcomes. Similarly,Wiraetal. [16]reportedimprovedsurvival across 15studies; although,again, the risk of bias was high with only one randomisedtrialincluded.Finally, Guet al. [15] foundadecreaseinmortalitywith the early institution of goal-directed therapy [relativerisk0.83(95%CI 0.710.96)] acrosssevenstudies, ofwhichtwoevaluatedaresuscitationstrategythatdidnotincorporate ScvO2monitoring (including one study ofsupra-normal haemodynamic optimisation conductedover 20years ago), one included a different targetpopulation (patients with multiple organ dysfunction) andanother was not a randomised trial. When the two studiesof EGDT conducted in patients presenting to the ED withsepticshockwereanalysed[1, 8]mortalitywasnot de-creased [relative risk 0.86 (95%CI 0.521.44)]. Theresults of our meta-analysis, which focuses exclusively onrandomised clinical trials and which includes twoadditional, pivotal, multicentrerandomisedclinical trials[10,12],conrmthelackofasurvivalbenetassociatedwiththeimplementationofEGDTinpatientspresentingto the ED with septic shock compared to either usual careoranalternativeresuscitationstrategy. However, EGDTwas associated with an increased intensive care admissionrate. This increased utilisation of healthcare resources wasconsistent across a varietyof hospital settings (tertiaryreferral, metropolitan, rural) and geographical regions,despite substantial variation in hospital and intensive careresources[27]StrengthsandlimitationsWeincludedtherecent ProCESS[8], ARISE[10] andProMISe[12] harmonised, multicentrerandomisedclin-ical trials to better assess the evidence of EGDT inpatientswithsepticshock. InadditiontoincludingtheseA Primary mortality outcome of each study B 90-day mortalityOverall(I-squared = 56.7%, p = 0.055)Jones et al. (2010)ProMISe Investigators (2015)StudyProCESS Investigators (2014)Rivers et al. (2001)ARISE Investigators (2014)ID582/260125/150181/620Events,167/90259/133150/796control100.004.8732.23%21.7810.4030.71Weight1.01 (0.88, 1.16)1.47 (0.82, 2.60)1.02 (0.80, 1.30)1.17 (0.88, 1.55)0.52 (0.31, 0.86)0.98 (0.76, 1.26)OR (95% CI)495/213434/150184/623Events,92/43938/130147/792EGDTFavours EGDT Favours control.3 1 3Overall(I-squared = 0.0%, p = 0.974)ProMISe Investigators (2015)StudyARISE Investigators (2014)ProCESS Investigators (2014)ID598/2243181/620Events,150/796267/827control100.0034.62%32.9932.39Weight0.99 (0.86, 1.15)1.02 (0.80, 1.30)0.98 (0.76, 1.26)0.98 (0.76, 1.26)OR (95% CI)460/1820184/623Events,147/792129/405EGDTFavours EGDT Favours control .5 1 2Fig.2 EffectofEGDTonmortalityinpatientspresentingtotheemergencydepartmentwithsepticshock.aPrimarymortalityoutcomeofeachstudy.b90-daymortality.EGDTearlygoal-directedtherapy, ORoddsratio,CIcondenceinterval.Thecontrolwasusualcareoranothernon-EGDTresuscitationstrategy.Fixed-effectmodel:theindividual points denote the ORofeachstudyandthelineseithersidethe95%condenceintervals. Theverticallinesdenotethenulleffect. ThecontrolfortheProCESStrial[8] includes both usual care andprotocol-basedstandardtherapygroupscombined. AnalysiscomparingEGDTwiththeProCESSusualcaregrouponlyandexcludingtheJonestrial(controlgrouplactateclearance)[19]didnotchangetheresult(OR0.97[95%CI0.841.12;I256.5, P=0.08]threestudies,oursearchstrategywasbroadandincludedall studiesof EGDTirrespectiveof language; however,we couldnot conrmseveral keydesignfeatures withsomenon-English manuscripts. Althoughinvestigatorsofthethreemost recent trialsofEGDTareauthorsofourreport, we used a structured and accepted assessmentapproach, the Cochrane Collaboration tool, with inde-pendent assessors of the risk of bias. This approach,coupled with excluding observational studies, reduced theriskofbiasinourestimateofthetreatmenteffect.Our studyhasseveral limitations. Reportingof mor-tality outcomes across the included studies was notuniform. Ninety-day mortality was the primary studyoutcome in only two studies (and reported as a secondaryoutcomeinanadditionalonestudy)andonlytwoofthe11studies were assessedas havinga lowriskof bias(other thanfor blindingof participants andpersonnel).Theeffect of individual patient confounders, aswell asinternational and local variation in healthcare services(e.g. number of ED presentations and threshold forhospital andICUadmission), howEGDTwasdeliveredacrossthesitesandthenatureofusualcarecanalsonotbeestablishedinourtrial-level meta-analysis. However,weplananindividual patient datameta-analysis of thethreelargeharmonisedtrialstoallowmoredetailedandspecicquestionsincludingtheoverall effect of EGDTcomparedwithother forms of resuscitation, theroleofindividual elements of the EGDT algorithm and the effectofEGDTacrosscountriesandhospitalsettings. Wewillalsoexplorethepotentiallydifferential effect of EGDTacross clinicallyimportant subgroups (ProtocolisedRe-suscitation In Sepsis individual patient data Meta-analysis[PRISM];ClinicalTrials.gov.NCT02030158).ConclusionsOur meta-analysis of all publishedrandomisedclinicaltrials of EGDTdoes not showimproved survival forA ICU admissionaB ICU length of stay forpatients admitted to ICU (days)Overall(I-squared = 11.6%, p = 0.323)IDARISE Investigators (2014)StudyProCESS Investigators (2014)Jones et al. (2010)ProMISe Investigators (2015)2052/2474control661/796Events,774/902150/150467/626100.00Weight36.01%28.320.0035.672.19 (1.82, 2.65)OR (95% CI)2.21 (1.62, 3.02)1.75 (1.19, 2.56)(Excluded)2.54 (1.87, 3.43)1827/2006EGDT725/792Events,401/439150/150551/625Favours EGDT Favours control .5 1 4Overall(I-squared = 0.0%, p = 0.584)ProCESS Investigators (2014)IDARISE Investigators (2014)ProMISe Investigators (2015)Jones et al. (2010)Study2051774, 4.9 (6.5)(SD); control661, 4.8 (5.9)466, 6.4 (9.8)150, 5.9 (8.46)N, mean100.0034.59Weight42.7816.316.31%-0.02 (-0.47, 0.43)0.20 (-0.57, 0.97)WMD (95% CI)0.10 (-0.59, 0.79)-0.70 (-1.82, 0.42)-0.30 (-2.10, 1.50)1825401, 5.1 (6.3)(SD); EGDT725, 4.9 (7.2)549, 5.7 (8.1)150, 5.6 (7.39)N, meanFavours EGDT Favours control-3 0 3Fig.3 EffectofEGDTonICUutilisation in patients presentingtotheemergencydepartmentwithsepticshock.aICUadmissiona.bICUlengthofstayforpatientsadmittedtoICU(days). ICUintensivecareunit,EGDTearlygoal-directedtherapy, ORoddsratio,CIcondenceinterval, WMDweightedmeandifference, SDstandarddeviation.Thecontrolwasusualcareoranothernon-EGDTresuscitationstrategy.Fixed-effectmodel:theindividual points denote the ORorWMDofeachstudyandthelineseithersidethe95%condenceintervals. 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