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SimplifiedSevereSepsisProtocol
ARandomizedControlledTrialofModifiedEarlyGoalDirectedTherapyin
Zambia
BenAndrews,MD,LevyMuchemwa,MBChB,PaulKelly,MD,FRCP,ShabirLakhi,MBChB,MMed,MPH,
DouglasC.Heimburger,MD,MS,FACP,GordonR.Bernard,MD
CritCareMed.201442(11):23152324.

AbstractandIntroduction
Abstract

ObjectiveToassesstheefficacyofasimple,goaldirectedsepsistreatmentprotocolforreducingmortalityinpatientswith
severesepsisinZambia.

DesignSinglecenternonblindedrandomizedcontrolledtrial.

SettingEmergencydepartment,ICU,andmedicalwardsofthenationalreferralhospitalinLusaka,Zambia.

PatientsOnehundredtwelvepatientsenrolledwithin24hoursofadmissionwithseveresepsis,definedassystemic
inflammatoryresponsesyndromewithsuspectedinfectionandorgandysfunction

InterventionsSimplifiedSevereSepsisProtocolconsistingofupto4LofIVfluidswithin6hours,guidedbyjugularvenous
pressureassessment,anddopamineand/orbloodtransfusioninselectedpatients.Controlgroupwasmanagedasusualcare.
Bloodcultureswerecollectedandearlyantibioticsadministeredforbotharms.

MeasurementsandMainResultsPrimaryoutcomewasinhospitalallcausemortality.Onehundredninepatientswere
includedinthefinalanalysisand88patients(80.7%)wereHIVpositive.Pulmonaryinfectionswerethemostcommonsourceof
sepsis.Inhospitalmortalityratewas64.2%intheinterventiongroupand60.7%inthecontrolgroup(relativerisk,1.0595%
CI,0.791.41).Mycobacteriumtuberculosiscomplexwasisolatedfrom31of82HIVpositivepatients(37.8%)withavailable
mycobacterialbloodcultureresults.PatientsinSimplifiedSevereSepsisProtocolreceivedsignificantlymoreIVfluidsinthe
first6hours(2.7Lvs1.7L,p=0.002).Thestudywasstoppedearlybecauseofhighmortalityrateamongpatientswith
hypoxemicrespiratoryfailureintheinterventionarm(8/8,100%)comparedwiththecontrolarm(7/10,70%relativerisk,1.43
95%CI,0.952.14).

ConclusionFactorsotherthantissuehypoperfusionprobablyaccountformuchoftheendorgandysfunctioninAfrican
patientswithseveresepsis.Studiesoffluidbasedinterventionsshouldutilizeinclusioncriteriatoaccuratelycapturepatients
withhypovolemiaandtissuehypoperfusionwhoaremostlikelytobenefitfromfluids.Exclusionofpatientswithsevere
respiratorydistressshouldbeconsideredwhenventilatorysupportisnotreadilyavailable.

Introduction

IntheUnitedStates,750,000peopledieeachyearfromsepsis. [1]Althoughavailabledataarelimited,thenumberofsepsis
relateddeathsislikelymuchhigherinsubSaharanAfrica,wheremorethanhalfofalldeathsareattributedtoinfections. [2]
CohortstudiesfromtheregionhavefoundsepsistobethethirdleadingcauseofdeathamongHIVinfectedadults,after
tuberculosis(TB)andcryptococcalmeningitis, [3]andanunpublishedauditattheUniversityTeachingHospital(UTH)inZambia
showedsepsistobetheleadingcauseofdeathamonghospitalizedmedicalpatients.However,optimalmanagement
strategiesforpatientswithsepsisinAfricaremaincontroversial. [47]

ProtocolbasedmanagementofsepsishashadwideuptakeinNorthAmericaandEurope. [8,9]Studiesofearlygoaldirected
therapyhavedemonstratedthataggressiveIVfluidadministration,hemodynamicsupport,andbloodtransfusioncan
significantlyreducemortalityduetosepsis.Centralvenouspressureorserumlactateguidedapproacheshavegenerally
resultedinpatientsreceivingbetween4and5Loffluidinthefirst6hoursofadmission. [10,11]InsubSaharanAfrica,however,
uptakehasbeengenerallynonexistentduetoresourcelimitations. [12]Centralvenouscathetersandlacticacidtestsarenot
widelyavailable,andtheuseofIVfluidsforvolumeresuscitationhasbeenmuchmoreconservativethanguidelines

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recommend. [13,14]TherearealsoquestionsregardingthegeneralizabilityofexistingevidencetothesubSaharanAfrican
setting,consideringtheunderrepresentationofresourcelimitedstudysitesandpatientswithHIV/AIDSinmostsepsistrials.
[15]Furthermore,thelimitedexistingevidencefromtheregionisconflictingregardingthepotentialbenefitsandharmsof

aggressivefluidresuscitation. [4,6]

Wehypothesizedthatanovelsimplifiedtreatmentprotocol,basedonexistingearlygoaldirectedtherapyprotocols,would
reducemortalitycomparedwithusualcareinAfricanpatientswithseveresepsis.TheSimplifiedSevereSepsisProtocol
(SSSP)interventionconsistedofearlygoaldirectedfluidadministration,plusdopamineand/orbloodtransfusionwhen
indicated.Patientsinbotharmsreceivedclosenursemonitoringwithearlybloodculturesandantibiotics.

Methods
WeconductedapilotnonblindedrandomizedcontrolledtrialofpatientspresentingtotheUTHinLusaka,Zambia,withsevere
sepsisbetweenFebruaryandJuly2012.UTHisthenationalreferralhospitalforZambiaandisalsoamajorprimarycare
hospitalforthecityofLusaka.EthicalapprovalwasobtainedfromtheUniversityofZambiaBiomedicalResearchEthics
Committee(UNZABREC)andtheVanderbiltUniversityInstitutionalReviewBoard(IRB),andthestudywasregisteredwith
ClinicalTrials.gov(NCT01449916).

Patients

Allpatientspresentingtotheemergencydepartmentwerescreenedforeligibility.Enrollmentoccurred24hr/dfromMonday
7:30AMtoFriday1:00PM.Patientswereeligibleiftheywere18yearsoldorolderandmetcriteriaforseveresepsisupon
presentationtotheemergencydepartment.Additionally,patientswhomanifestedseveresepsisafterarrivaltothehospitalwere
eligibleiftheywerestillintheemergencydepartmentlessthan24hoursafterpresentationandwerewithin6hoursoffirst
meetingseveresepsiscriteria.Severesepsiswasdefinedasthepresenceofallthreeofthefollowing:1)infectionsuspected
bytreatingdoctor,2)systemicinflammatoryresponsesyndrome(SIRS),definedastwoormoreofthefollowing:heartrate>
90/min,respiratoryrate>20/min,temperature38Cor36C,orWBC>12,000/mm3or<4,000/mm3,and3)oneormore
signsoforgandysfunction.Organdysfunctioncriteriaweresystolicbloodpressure<90mmHgormeanarterialblood
pressure(MAP)<65mmHg,alteredmentation,creatinine>1.85mg/dL,plateletcount<100109/L,respiratoryrate>
40/min,orjaundice.Patientswereexcludediftheyhadagastrointestinalbleed,requiredimmediatesurgery,orhadsuspected
congestiveheartfailureexacerbationorendstagerenaldisease.Patientswithraisedjugularvenouspressure(JVP)morethan
3cmabovethesternalangle,asmeasuredwithalevelandaruler,werealsoexcluded.JVPwasmeasuredverticallyfromthe
sternalanglewiththepatientpositionedbetween0and45inclinesothatthewaveformwasvisible.ThenormalrangeforJVP
is13cmabovethesternalangle,andJVPover3cmisareliablemeasureofvolumeoverloadbyphysicalexamination. [16,17]
StudydoctorsandnursesunderwenttwohalfdaytrainingsessionsinassessingJVP,followedbyregularperiodicbedside
assessmentsbytheprincipalinvestigatoruntilstaffmembersfeltconfidentwiththetechnique.

Randomization

Patientswererandomlyassignedina1:1ratiotoeitherusualcareortheSSSP.Assignmentswerebasedoncomputer
generatedpermutedblocksof2,4,and6.Randomizationassignmentswereplacedinnumbered,sealedopaqueenvelopes,
whichwereopenedafterwritteninformedconsentwasobtained.Studystaffwerenotblindedtopatientassignments.
Emergencydepartmentandinternalmedicinedoctorswerenotinformedofpatientassignment,althoughprotocolorderswere
readilyvisibleinthepatients'files.

Interventions

Patientsintheusualcaregroupreceivedcareasperorderswrittenbytheemergencydepartmentphysicians.Usualcare
consistedofIVfluids,antibiotics,andoccasionaluseofnontitrateddopamine.Adedicatedstudynursemonitoredallpatients
inbothgroups,ensuredallorderswerecarriedout,andnotifiedemergencydepartmentphysiciansofcriticalvitalsignsor
changesincondition.Vitalsignsweremonitoredeveryhourfor6hours.TheSSSP(intervention)groupreceivedprotocolbased
careforthefirst6hoursfollowingenrollment.PatientsintheSSSPgroupreceivedaninitial2Lbolusofnormalsalineor
lactatedRinger'swithin1hourofassessment.Aftertheinitialbolus,aninvestigatororstudynursereevaluatedthepatient's
JVP.IfJVPwaslessthan3cmabovethesternalangle,patientsreceivedanadditional2Loffluidover4hours,foratotalof4
Linthefirst56hoursofenrollment.Thetargetof4Lwasdeterminedbasedonpreviousgoaldirectedtherapystudies. [10,11]
Fluidswerestoppedforanypatientwhodevelopedworseningrespiratorysignsorsymptomsasdeterminedbythestudy
physicianornonstudydoctors.IfMAPwasbelow65mmHgafter2Lfluidbolus,thenadopamineinfusionwasstartedata
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rateof10g/kg/min,tobetitratedtomaintainaMAPgreaterthanorequalto65mmHg.Patientswithhemoglobinlessthan7
g/dLinSSSPwereofferedwholebloodtransfusion.Inbothgroups,bloodculturesweredrawnandantibioticswerecommenced
assoonaspossible,preferablywithin1hourofrecognitionofsepsis.Oneaerobicbloodculturewasdrawnfromeachpatient
andincubatedinaBactecFX(BDDiagnostics,Sparks,MD).InHIVpositivepatients,anadditionalmycobacterialbloodculture
wascollectedandincubated.PositivemycobacterialcultureswerespeciatedasMycobacteriumtuberculosiscomplexor
nontuberculosiscomplexbasedonMPT64rapidantigentest(StandardDiagnostics,Seoul,SouthKorea). [18]Selectionof
antibiotics,antimalarials,andtuberculosistherapywaslefttotheadmittingnonstudyphysicians,aswasthedeterminationof
additionalinvestigations,suchasmalariabloodslidesandcerebralspinalfluidstudies.DecisionsregardingtransfertoICUand
initiationofmechanicalventilationorhemodialysiswerelikewiselefttononstudyphysicians.Patientsinbotharmscould
receiveempiricwholebloodtransfusioniforderedbytheadmittingdoctors.

Outcomes

Theprimaryoutcomewasinhospitalallcausemortality.Secondarymortalityoutcomesincluded28dayallcausemortality,in
hospitaland28daymortalitiesadjustedfortheSimplifiedAcutePhysiologyScore3(SAPS3),andtimetodeath. [19]Process
measuresincludedvolumeofIVfluidsadministeredinthefirst6,24,and72hours,proportionofpatientsreceivingantibiotics
within1hour,andproportionofpatientsreceivingbloodtransfusion.Patientsweremonitoredforchangesinrespiratorystatus,
includingriseinrespiratoryrateof5ormoreanddecreaseinoxyhemoglobinsaturation(SpO2)of3%ormore.Reasonsfor
stoppingIVfluidswerealsorecorded.

StatisticalAnalysis

Ourpreviousdatafounda54.9%inpatientmortalityrateinpatientsadmittedtoourhospitalwithseveresepsis. [14]Weused
thisfigureastheexpectedmortalityinthecontrolgroup.Assuminga5%twosidedtypeIerrorrateand80%power,we
estimatedthatasamplesizeof342patientswouldberequiredtodetecta15%absolutereductionininhospitalmortality.

Baselinecharacteristicsofpatientswithseveresepsiswerecomparedbyinterventionusingttestforcontinuousvariablesand
chisquareorFisherexacttestsforcategoricalvariables.KaplanMeierestimatesandlogranktestwereusedtocompare
survivalbyinterventionupto28daysfollowingadmission.Allhypothesistestingwastwosidedwithalevelofsignificanceset
at0.05.Weassessedinhospitalmortalityforthefollowingprespecifiedsubgroups:HIVpositiveversusnegative,MAP65
versus>65mmHg,respiratoryrate40versus<40,hemoglobin7versus<7g/dL,andaboveversusbelowmedianscore
forSAPS3.Posthocsubgroupanalysesincludedpatientswithhypoxemicrespiratorydistress,definedasbaselinerespiratory
ratemorethan40/minandSpO2lessthan90%,andpatientswithtuberculosis.Multivariableloglinearregressionwasusedfor
subgroupanalysestoestimateriskratiosadjustedforbaselineSAPS3score.Wetestedforinteractioneffectbetween
subgroupandinterventiongroupontheriskofinhospitalmortalityusingBreslowDaytestofhomogeneity.Linearregression
wasusedtoassesschangesinfluidadministrationintheusualcaregroupasafunctionofdateofstudyinitiation.Allanalyses
wereintentiontotreat,usingStataversion12.1(StataCorp,CollegeStation,TX)andOpenEpi(http://www.openepi.com)for
BreslowDaycalculations.

Results
Weenrolled112patientsinthestudy(Fig.1).Twopatientsnotmeetingtheeligibilitycriteriawereexcludedwithinhoursof
enrollment.Onepatientwasexcludedwithin1hourofrandomizationbecauseinformedconsentwasverbalandnotwritten.The
remaining109patientswereincludedinintentiontotreatanalysis.Inhospitalsurvivalwasavailableforallpatients.The28day
survivaloutcomewasnotascertainedinsixpatientswhowerelosttofollowupafterdischarge.

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Figure1.

Selectionandfollowupofstudypatients.Duringthestudyperiod,382patientspresentingtotheemergencydepartmentwere
screenedforeligibility.Ofthose,112patientswithseveresepsiswereenrolledandrandomizedtoeitherSimplifiedSevere
SepsisProtocol(SSSP)orusualcare.Threepatientswereexcludedwithinhoursofrandomizationduetonotmeetingall
elibilitycriteria(2)orimproperconsent(1)andwerenotincludedinthefinalanalysis.

Eightyeightpatients(80.7%)wereHIVpositive,withmedianCD4countof49cells/mm3.Mediantimefromadmissionto
enrollmentwas2.5hours(interquartilerange[IQR],0.96.4hr).In100patientsforwhomJVPwasassessable,88(88%)had
belownormalJVP,including28withexpiratoryJVPatthelevelofthesternalangle(0cm)and60withaJVPthatwasbelow
thesternalangleandonlyvisibleinthesupineposition.Meanrespiratoryratewasveryhighinboththeinterventionandcontrol
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groups,38.2and37.7breaths/min,respectively.Pulmonaryinfectionwasthemostcommonlysuspectedsourceofsepsis,
occurringin63of109participants(57.8%).Eightyonepatients(74.3%)werenonambulatoryatthetimeofadmissionwitha
mediantimeof5days(IQR,37)sincelastwalking.Baselinecharacteristicsaresummarizedin.

Table1.BaselineCharacteristicsofZambianPatientsWithSevereSepsis

SimplifiedSevereSepsisProtocol(n Control(n=
Variable p
=53) 56)

Age,yr,mean(SD) 35.2(1.3) 34.8(1.4) 0.85

Male,n(%) 28(52.8) 30(53.6) 0.94

Admissionvitalsigns,mean(SD)

Systolicbloodpressure,mmHg 102.6(21.4) 101.6(24.2) 0.83

Diastolicbloodpressure,mmHg 62.4(14.4) 65.2(17.2) 0.35

Meanarterialpressure,mmHg 75.8(15.4) 77.3(18.8) 0.64

Respiratoryrate,breaths/min 38.2(10.9) 37.7(11.2) 0.81

Heartrate,beats/min 119.2(15.8) 122.9(22.3) 0.32

Temperature,C 37.3(1.5) 37.9(1.7) 0.07

GlasgowComaScale,median(IQR) 14(1115) 14(1015) 0.76

HIVpositive,n(%) 42(79.2) 46(82.1) 0.70

CD4count,median(IQR) 40(17107) 70(24109) 0.41

Onantiretrovirals,n(%ofHIVpositive) 18(42.9) 16(35.6) 0.49

Suspectedsiteofinfection,n(%) 0.86

Pulmonary 31(58.5) 32(57.1)

CNS 19(35.8) 15(26.8)

Abdomen 3(5.7) 4(7.1)

Othera 6(11.3) 7(12.5)

Chiefcomplaint,n(%) 0.62

Dyspnea 13(24.5) 15(26.8)

Alteredmentation 9(17.0) 10(17.9)

Cough 9(17.0) 8(14.3)

Headache 7(13.2) 10(17.9)

Weakness/fatigue 10(18.9) 4(7.1)

Abdominalpain 3(5.7) 5(8.9)

Othera 2(3.8) 4(7.1)

Durationofchiefcomplaint,d,median(IQR) 7(430) 14(330) 0.81

Durationofanysymptoms,bd,median(IQR) 14(730) 30(1460) 0.26

SimplifiedAcutePhysiologyScore3,mean(SD) 59.0(1.6) 56.3(1.5) 0.23

AcutePhysiologyandChronicHealthEvaluationIIscore,
17.8(0.8) 17.9(0.9) 0.95
mean(SD)

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aOtherchiefcomplaintsincludedfever(3),diarrhea(1),vomiting(1),andseizure(1).

bSymptomsincludeinabilitytowalkoranysymptomlistedunderchiefcomplaint.

Management

Treatmentofthetwogroupsissummarizedin.Slightlyoverhalfofpatientsreceivedathirdgenerationcephalosporin,either
aloneoraspartofacombination.Antituberculoustherapywasgivento21patientsinSSSP(39.6%)and14controlpatients
(25.0%).Mediantimetofirstdoseofantibioticswas1.4hours(IQR,0.53.1)fromtimeofadmissionand0hour(IQR,1.3
2.0)fromtimeofenrolment.PatientsintheSSSPgroupreceivedsignificantlymoreIVfluidsinthefirst6hourscomparedwith
control(2.8Lvs1.6L,p<0.001).Of53patientsintheSSSPgroup,30patients(56.6%)receivedatleast3Linthefirst6
hours,and14of53(26.4%)receivedatleast4L.Themostcommonreasonsforstoppingfluidsincludedtachypneaor
decreasedSpO2(ineightpatients),raisedJVP(7),lostIVaccess(2),bloodtransfusion(5),andpoorurineoutputinsuspected
oliguricrenalfailure(1).TheSSSPgroupreceivedmorefluidinthefirst72hours(5.5Lvs4.3Lp=0.02).Regressing6hour
IVfluidadministrationondateofadmissioninthecontrolgroupresultedinnomeaningfullydifferentfluidadministrationoverthe
studyperiod(0.005/d95%CI,0.013to0.003),suggestingthatusualpracticeswerenotsubstantiallyimpactedbya
Hawthornelikeeffectduringthestudyperiod.

Table2.TreatmentsAdministeredandAdverseEvents

SimplifiedSevereSepsisProtocol Control(n=
Variable p
(n=53) 56)

Initialantibioticregimensa

3rdgenerationcephalosporinb 22(41.5) 20(35.7)

3rdgenerationcephalosporincombinationc 5(9.4) 10(17.9)

PenicillinG 4(7.5) 4(7.2)

PenicillinG+chloramphenicol 6(11.3)d 7(12.5)

OtherpenicillinGcombinationc 6(11.3) 3(5.4)

Ciprofloxacinmetronidazole 5(9.4) 3(5.4)

Othere 4(7.5) 7(12.5)

Notdocumented 1(1.9) 2(3.6)

Cotrimoxazolef 6(11.3) 8(14.3) 0.64

Antituberculoustherapy 0.087

Startedatadmissionorbefore 8(15.1) 9(16.1)

Startedafteradmission 13(24.5) 5(8.9)

Mediantimetoantibiotics,hr(IQR)g

Fromadmission 1.5(0.53.7) 1.3(0.43.0) 0.42

Fromstudyenrollment 0.7(2.5to0.5) 0(1.5to0.9) 0.19

Received3Lfluidin6hr,n(%) 30(56.6) 11(20.0) <0.001

Fluidsadministered,L,mean(SD)h

Infirst6hr 2.9(1.0) 1.6(1.1) <0.001

Infirst24hr 3.9(1.3) 3.0(2.1) 0.02

Infirst72hr 5.6(2.3) 4.3(2.9) 0.02

Receivedbloodtransfusion,n(%) 16(30.2) 11(19.6) 0.20

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Mediantimetotransfusion,hr(IQR)g 16.0(7.332.9) 5.5(013.8) 0.17

Receiveddopamine,n(%) 1(1.8) 3(5.7) 0.28

Not
StoppedIVfluidsearly,n(%) 25(49.0) Notapplicable
applicable

Reasonsforstopping

Raisedjugularvenouspressure 7(13.2)

Respiratorychanges 8(15.1)

LostIVaccess 2(3.8)

Transfuseblood 5(9.4)

Oliguria 1(1.9)

Other 2(3.8)

IncreaseinrespiratoryrateordecreaseinSpO2first6
18(34.0) 16(28.6) 0.54
hr,n(%)i

IQR=interquartilerange.

aExcludesantituberculoustherapyorcotrimoxazoletherapy,listedseparately.

bIncludesthreepatientswhoreceived3rdgenerationcephalosporinpluscrystallinepenicillin.

c Includescombinationswithciprofloxacin,erythromycin,metronidazole,and/orcloxacillin.

dIncludestwopatientswhoreceivedcrystallinepenicillin+chloramphenicol+metronidazole.

eCloxacillin+metronidazole(1),chloramphenicol(1),erythromycin(3),cotrimoxazolemonotherapy(2),andantituberculous

therapyonly(4).

f Includesprophylaxisortreatmentdoses,usedwithoneoftheabovecombinationsin12patientstwopatientsreceivedonly

cotrimoxazole.

gMissingdataontimetobloodtransfusionintwotransfusedpatientsandantibioticsstarttimein12patients.

hMissingdataforfluidsinfirst6hr(onepatient),24hr(eightpatients),and72hr(15patients).

iRespiratorychangesincludedrespiratoryrateincreaseof5breaths/minormoreordecreaseinoxyhemoglobinsaturationof

3%ormore.

Dashsignifiesintentionalomission(pvaluewasnotcalculatedtocomparetheinitialantibioticregimens).

OnlythreepatientsintheSSSPgroupandonepatientinthecontrolgroupreceiveddopamine.Sixteenpatients(30.2%)inthe
interventiongroupand11controlpatients(19.6%)receivedbloodtransfusion(p=0.20).Mediannumberofunitstransfusedwas
identicalbetweenthetwogroups(twounits).Themajorityofpatientsreceivedantibioticswithin1hourofenrollment,although
antibioticsstarttimewasmissingfor12patients.Onlytwopatients,oneineachgroup,weretreatedintheICU.Forboth
patients,theindicationforICUtransferwasmechanicalventilation.ThelocalconventionsforICUusearedescribedin
Discussionsection.

ClinicalOutcomes

Overall,68patients(62.4%)diedpriortodischarge.Inhospitalmortalitywasnotsignificantlydifferentbetweenthetwogroups.
Of53patientsintheinterventiongroup,34patients(64.2%)diedinhospitalcomparedwith34of56(60.7%)incontrols(relative

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risk,1.0595%CI,0.791.41SAPS3adjustedriskratio,1.0195%CI,0.761.33).The28daymortalitywas71.4%inthe
interventiongroupcomparedwith66.7%forcontrols(relativerisk,1.07[0.831.39]adjustedrelativerisk,1.03[0.811.32]).We
failedtodetectdifferencesbetweeninterventionandcontrolfortheprespecifiedsubgroups().Becausecategorizingcontinuous
predictorsintointervalsmayleadtolossofpower,modelswerererunwithcontinuousexposures(i.e.,notcategorizedintoa
priorisubgroups)withsimilarresults(notshown).Mediansurvivalwas4daysintheSSSPgroupversus9daysinthecontrol
group,buttheIQRwas228daysinbothgroupsandKaplanMeierestimatesshowedlittledifference(logrankp=0.57)(Fig.
2).

Table3.RelativeRiskofInHospitalDeathinPatientsManagedWithSimplifiedSevereSepsisProtocolVersusUsualCare:
SubgroupAnalysisa

Subgroups SimplifiedSevereSepsisProtocol b Control b RelativeRisk(95%CI) p c

HIVpositive 29/42(69.0) 29/46(63.0) 1.10(0.811.48) 0.70

HIVnegative 5/11(45.5) 5/10(50.0) 0.91(0.372.22)

MAP65mmHg 26/39(66.7) 28/46(60.9) 1.10(0.791.51) 0.72

MAP<65mmHg 8/14(57.1) 6/10(60.0) 0.95(0.481.88)

Respiratoryrate>40d 16/20(80.0) 15/23(65.2) 1.23(0.851.78) 0.37

Respiratoryrate40 18/33(54.5) 18/32(56.3) 0.97(0.631.50)

Hemoglobin<7e 8/13(61.5) 5/8(62.5) 0.98(0.501.96) 0.83

Hemoglobin7 20/33(60.6) 22/39(56.4) 1.07(0.731.59)

SAPS3median 22/28(78.6) 20/29(69.0) 1.14(0.831.56) 0.52

SAPS3<median 12/25(48.0) 14/27(51.9) 0.93(0.541.60)

ConfirmedTB 10/15(66.7) 12/16(75.0) 0.89(0.561.40) 0.39

NoconfirmedTB 24/38(63.2) 22/40(55.0) 1.15(0.791.66)

Hypoxemicrespiratorydistressf 8/8(100.0) 7/10(70.0) 1.43(0.952.14) 0.17

Nohypoxemicrespiratorydistress 26/45(57.8) 27/46(58.7) 0.98(0.701.39)

Overall 34/53(64.2) 34/56(60.7) 1.06(0.791.41)

MAP=meanarterialpressure,SAPS3=SimplifiedAcutePhysiologyScore3,TB=tuberculosis.

aAllsubgroupswereprespecified,excepttuberculosisandhypoxemicrespiratorydistress.

bPercentmortalityinparentheses.

c Testforinteractionofriskratiooversubgroups.

dMissingrespiratoryrateinoneparticipant.

eMissinghemoglobinin18participants.

f Hypoxemicrespiratorydistressdefinedasrespiratoryrate>40andoxyhemoglobinsaturation<90%.

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Figure2.

KaplanMeiersurvivalestimatesforSimplifiedSevereSepsisProtocol(SSSP)interventionversususualcareinpatientswith
severesepsis.

BacteriologicFindings

Twentysixpatients(23.9%)hadpositiveaerobicbloodcultures.ThemostcommonorganismswereStaphylococcusaureus
(seven)andStreptococcuspneumoniaeandSalmonellatyphi(threeeach).Mycobacterialbloodcultureswerecollectedfrom
HIVpositivepatientsonly31of82patientshadtuberculosismycobacteria(37.8%).TwopatientshadcoinfectionwithTBand
S.aureus.Theother29patientswithTBbacteremiahadnootheridentifiableetiologyfortheirsepsis.Among46patientswith
CD4countlessthan75cells/mm3,22patients(47.8%)hadpositiveTBbloodcultures.Fourpatients,allinthecontrolgroup,
hadevidenceofCryptococcusneoformansinthecerebrospinalfluid.Twopatients,oneineachgroup,hadbloodslidepositive
malaria.

DecisiontoStopStudy

Thestudywasstoppedearlybytheinvestigatorspriortothescheduledinterimanalysis,incommunicationwithUNZABREC
andVanderbiltIRB,duetotheobservationthatpatientswithhypoxemicrespiratorydistressatbaselinemightbeatincreased
riskfromtheintervention.Becauseonlytwoof109patientsweretransferredtoICUformechanicalventilation,theinvestigators
initiatedanunscheduledanalysisofparticipantswithbaselinerespiratoryrateabove40/minandoxygensaturationlessthan
90%.Inthisgroup,15of18patients(83.3%)diedduringhospitalization,includingeightofeightintheinterventiongroup
(100%)andsevenof10inthecontrolgroup(70%,p=0.09).Basedonthesefindings,thedecisionwasmadetostopthe
study.

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Discussion
InthispilotrandomizedcontrolledtrialinLusaka,Zambia,anovelgoaldirectedtherapyprotocolconsistingofearlyaggressive
IVfluids,withdopamineandbloodtransfusioninselectedpatients,wasnoteffectiveinreducinginhospitalmortalitycompared
withusualcare.Thestudywasstoppedearlyduetoobservationsthatpatientswithsevererespiratorydistresswereunlikelyto
benefitfromtheinterventionandwereatpotentialriskofharm.Thestudyintentionallyusedbroadinclusioncriteria,defining
severesepsisasprobableinfectionwithSIRSandorgandysfunction.Endorgandysfunctionwaslikelyunrelatedtotissue
hypoperfusioninasignificantproportionofpatients.Patientswithconfusionduetomeningitisorrespiratorydistressdueto
pulmonaryinflammationhaveothermechanismsoforgandamagethatmightbeworsenedwithaggressivefluidadministration.

PreviousstudiesfromsubSaharanAfricahaveshownbothharmandbenefitwithfluidbasedinterventions.TheFluidExpansion
AsSupportiveTherapy(FEAST)trialinKenya,Uganda,andTanzaniafoundincreasedmortalityfromfluidbolusesinchildren
withseverefebrileillness. [4]Ontheotherhand,abeforeafterstudyinUgandanadults,bythePromotingResourcelimited
InterventionsforSepsisManagementinUganda(PRISMU)groupdemonstrateda12.7%absolutereductionin30day
mortality. [6]TherewereseveralkeydifferencesbetweenourstudyandPRISMU.Theirstudyenrolledonlypatientswithlowor
lownormalbloodpressures.Ourmediansystolicbloodpressureof100mmHgwasconsiderablyhigherthanthemedianof
8185mmHginPRISMU.ThecontrolgroupinthePRISMUstudyreceivedamedianofonly500mLoffluidsinthefirst6
hoursand1Linthefirst24hours.Incontrast,medianfluidadministrationinthecontrolarmoftheSSSPstudywas1.6Lin6
hoursand3.0Linthefirst24hours.Itislikelythattheobservational"before"armofPRISMUreceivedlessnursingattention
thanthe"after"interventionarm.Inresourcelimitedsettings,lowvolumesoffluidadministrationmaybetheresultofdoctors'
ordersorinadequatenursestaffing.IntheSSSPstudy,boththeinterventionandcontrolgroupreceivedonetoonecareinthe
first6hoursfromadedicatedstudynurse.Furthermore,thetwogroupsreceivedequalcareandattentionexceptfortheuseof
theSSSPprotocoltodirectfluid,dopamine,andtransfusionadministration.

OurinterventionwassimilarinmanyrespectstotheprotocolbasedstandardtherapyarmintherecentlyreportedProtocol
BasedCareforEarlySepticShock(PROCESS)study,basedintheUnitedStates. [20]Theirprotocolbasedstandardtherapy
alsocalledfor2Linitialfluidboluswithin1hour,noninvasivemonitoring,jugularvenousdistensionandrespiratorymonitoring
forfluidoverload,bloodpressuretriggersforvasopressorinitiation,andbloodtransfusionforsevereanemia(<7.5g/dLin
PROCESS<7.0g/dLinSSSP).Neitherstudydemonstratedasignificantmortalitydifferencebetweentheprotocolizedgroups
andusualcare.

At62%,ourmortalityratewashigherthanmortalityratesseeninPRISMUandPROCESS.ICUutilizationinourstudywas
extremelylow.ThedecisiontotransferpatientstotheICUwaslefttononstudyphysiciansinordertolimitbiasinthis
nonblindedstudy.Thestudyhospital,UTH,hasonly10ICUbedsfora1,500bedhospitalwithcatchmentpopulationof13
million,andthemajorityofICUbedsareusuallyoccupiedbysurgicalpatients.ThebiasofmedicalstafftotransfertoICUis
generallyinfavorofpatientswitheasilyreversibleconditions,suchashydrostaticpulmonaryedema,statusepilepticus,and
severemalaria,andagainstpatientswithchronicwastingfromHIVand/orTB.ThelowrateofICUtransferwasanimportant
factorinthedecisiontostopthisstudyearly,asappropriateventilatorysupportcouldnotbeguaranteedinpatientswith
preexistingorfluidinducedsevererespiratorydistress.

Comparedwithapreviousobservationalstudyofsepticpatientswithandwithoutorgandysfunctionatourhospital,ourstudy
patientshadhighermortalityrates(62%vs40%)andbaselinerespiratoryrates(meanrespiratoryrate,38/minvs28/min),and
pulmonarysourceofinfectionwasmorecommon(58%vs25%). [14]Thesedifferencescouldbeattributabletomethodologic
differences,particularlytheSSSPorganfailureinclusioncriteria,whichincludedrespiratoryratemorethan40/min,andtoa
highproportionofunspecified(32.3%)infectionsintheobservationalstudy.Ofnote,theusualcarearmofSSSPreceivedmore
fluidsat6hours(median,1.6Lvs1L)and24hours(median,3.0Lvs1L)thanpreviouslyobserved.Althoughusualcaredid
notchangeappreciablyfromthebeginningtotheendofthisstudy,wecannotruleoutthepossibilitythattheprestudytraining
mayhaveimpactedusualprescribingpractices.Wethinkitismorelikely,though,thatdedicatedstudynursesledtomore
consistentimplementationofdoctors'orderscomparedwithprestudyperiods.However,anystudysuchasoursthatcompares
anewinterventiontousualcarerunstheriskofinfluencingtheusualcarecontrolarmtowardimitationofanasyetunproven
intervention.

Therewereseveralimportantlessonslearnedinconductingthisstudy.Firstandforemost,theuseofsimplifiedinclusion
criteriathatonlylooselyreflectthepathophysiologyofinterestshouldbeavoided.AswiththeFEASTstudy,SSSPsoughtto
identifyhypoperfusedseverelysepticpatientswithoututilizingcostlytestingsuchaslacticacidmeasurement.Theintention
wastouseinclusioncriteriathatcouldbegeneralizabletoclinicaluseinthemostresourcelimitedsettings.InFEAST,the
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majorityofpatients(70%)qualifiedashypoperfusedbasedonseveretachycardia,anonspecificmeasurethatcouldreflect
hypovolemia,hypoxemia,anemia,highfever,orotherdistress.Ourstudymadeafaultyassumptionthatorgandysfunction
alonewasindicativeoftissuehypoperfusioninasepticpopulationwithahighprevalenceofvolumedepletion.Inretrospect,our
criteriafailedtoadequatelyconsiderthedirecttissuedamageattributabletoinflammationofthelungsand/orbrain.Designof
futuresepsisstudiesinvolvingIVfluidsshouldconsidermorereliablemeasuresofhypoperfusionorfluidresponsiveness.

Anotherimportantlessonlearnedregardedthemanagementofpatientswithrespiratorydistress.Intheabsenceofavailable
ventilatorysupport,cautionmustbeexercisedwhenadministeringIVfluidbolusestosuchpatients.Whereventilatorysupport
isunavailable,thedecisiontoincludepatientswithmoderatetosevererespiratorydistressshouldbescrutinizedpriortoany
studyofIVfluidintervention.FEASTandSSSPincludedsevererespiratorydistressandseveretachypnea,respectively,as
organdysfunctioninclusioncriteria,soitshouldnothavebeensurprisingthat83%ofparticipantsinFEASThadrespiratory
distressand39%ofSSSPparticipantshadrespiratoryrateabove40.Interestingly,themedianrespiratoryratesinSSSP
(38/min)werenearlyidenticaltothoseseeninPRISMU(3638/min).However,despitesimilarvolumesoffluid,morepatients
inSSSPdevelopedworseningrespiratorysigns.Adjunctivetherapies,suchasnoninvasivepositivepressureventilation(NIV),
mightbeconsideredforpatientswithrespiratorydistress,andstudiesintotheefficacyofNIVarewarrantedinthissetting.

Ourstudyraisesthequestionoftheroleofhyperacuteinterventionsinthemanagementofchronicorsubacuteprocesses.
UnlikeinNorthAmericaandEurope,wheresepsisistypicallyanacuteprocess,sepsisinsubSaharanAfricafrequently
resultsfromsubacuteorchronicinfection.Over80%ofpatientswereHIVinfected,andthemajorityhadsymptomsforatleast
2weeksprecedingadmission.Theleadingetiologyofsepsisinourstudywastuberculosis,withotherconcomitantpathogens
veryrarelyisolated.SimilarprevalenceoftuberculousbloodstreaminfectionshasbeenshowninMalawi,Tanzania,and
Uganda. [13,2124]Thisvariesgreatlyfromtheliteratureinhighresourcesettings,whereGrampositiveandGramnegative
bacteriatypicallyaccountforover60%ofconfirmedetiologies. [25,26]Ourfindingssuggestthatdisseminatedtuberculosis
infectionshouldbestronglysuspectedinpatientspresentingwithseveresepsisinsubSaharanAfrica,especiallyinpersons
infectedwithHIV.Becausethesepticprocessinthesepatientsmaybesubacuteorchronic,itisreasonabletoexpectthat
acutetimedependentinterventionslikeearlygoaldirectedtherapymayhavelimitedimpact.

ThequestionofanoptimalfluidtargetforpatientswithsepsisandtissuehypoperfusioninsubSaharanAfricaremains
unanswered.ThePRISMUstudydemonstratedthata"usualcare"consistingoflessthan1Loffluidsforsepticpatientswith
lowtolownormalbloodpressureswasnotsufficient.AposthocobservationalanalysisofPRISMUsuggestedthattheworst
prognosiswasinpatientsreceivinglessthanorequalto1Loffluidsinthefirst6hours,andthebestprognosiswasinpatients
whoreceivedmorethan12.5Loffluidinthefirst6hours,withsimilaradjustedoutcomesforthosewhoreceivedmorethan
3.5L.Themean6hourfluidintakeinourstudywas1.7Linthecontrolgroupcomparedwith2.7Lintheinterventiongroup.
Wesetacutoffof4Loffluidinthefirst6hours,andweusedJVP,ratherthanbloodpressure,astheguidetostoppingfluids.
WeintentionallyselectedJVPbecausebloodpressuremayfrequentlynormalizepriortofullvolumeresuscitation.However,we
recognizethedifficultyinstandardizingJVPmeasurements,particularlyamongnursingstaffandlessexperienceddoctors.
BeyondbloodpressureandJVP,othermethods,suchasfluidresponsivenessusingstraightlegraise,warrantinvestigationin
thissetting.

OtherquestionsremainwithregardtooptimaltreatmentofpatientswithseveresepsisinsubSaharanAfrica.Wemust
recognizethatthesepsissyndromeisaheterogeneouscollectionofinfectiousconditions,eachwithuniquephysiologic
characteristics.Althoughsomepatientswithsepsismaybenefitfromearlyfluidadministration,intheabsenceofmechanical
ventilationthosewithsevererespiratorydistressclearlydonot.Delaysinappropriateantituberculoustherapylikelycontribute
topooroutcomes, [27]magnifyingtheimportanceofclinicalalgorithmsorpointofcarediagnosticstodetectTBearlier. [28]A
studyisongoingtodeterminetheimpactofaurinelipoarabinomannanassayfordetectionofTBinHIVpositivehospitalized
patients(ClinicalTrials.govidentifier:NCT01770730).Scalableinterventions,suchasNIV,couldbestudiedaspotentialtherapy
forthosepatientswhopresentwithsepsisandsevererespiratorydistress.

Inconclusion,thisrandomizedcontrolledtrialofearlygoaldirectedfluidadministration,dopamine,andbloodtransfusionfor
Zambianpatientswithseveresepsiswasstoppedearlyduetopossibleincreasedriskamongpatientswithhypoxemic
respiratorydistress.Althoughthequestionofoptimalfluidadministrationremainsunanswered,anyfuturestudiesoffluid
interventionsshouldcarefullyconsiderinclusioncriteriatoidentifypatientsmostlikelytobenefitfromIVfluidsandshould
considerexcludingpatientswithsevererespiratorydistresswhenmechanicalventilationisnotavailable.

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ThisworkwasperformedattheUniversityTeachingHospitalandtheUniversityofZambia,SchoolofMedicineinLusaka,
Zambia.

Supported,inpart,bythegrantR24TW007988fromtheNationalInstitutesofHealthOfficeoftheDirectorandFogarty
InternationalCenterthroughtheInternationalClinicalResearchFellowsProgramatVanderbiltUniversity.

Dr.AndrewsreceivedsupportforarticleresearchfromtheNationalInstitutesofHealth(NIH).Hisinstitutionreceivedgrant
supportandsupportfortravelfromtheNIH/FogartyInternationalCenter.Dr.Muchemwareceivedgrantsupportandsupportfor
travelfromtheNIH/FogartyInternationalCenterandreceivedsupportforarticleresearchfromtheNIH.Dr.Heimburgerreceived
supportfortravelfromandservedasboardmemberforDannonResearchInstituteandreceivedbookroyaltiesfromElsevier.
HisinstitutionreceivedgrantsupportfromtheNIH/FogartyInternationalCenter.Dr.Bernardreceivedsupportforarticleresearch
fromtheNIH.Hisinstitutionreceivedgrantsupport(drugsuppliesforARDSnetSAILStrial).Theremainingauthorshave
disclosedthattheydonothaveanypotentialconflictsofinterest.

Acknowledgments

Wethankthefollowingmembers:Dr.GrantSwisher,BostonUniversityMedicalCenter(medicalofficer)BrianHeiniger,
VanderbiltUniversity(medicalstudent)EmmanuelChibwe,PeterNyauma,JoeMusonda,MaryKaonga,andJibeMilimo,
UniversityTeachingHospital(nurses)EugeneSilomba,AIDSReliefZambia(laboratorystaff).

CritCareMed.201442(11):23152324.2014LippincottWilliams&Wilkins

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