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ARationalApproachtoFluidTherapyinSepsis
P.MarikR.Bellomo
BrJAnaesth.2016116(3):339349.

AbstractandIntroduction
Abstract

Aggressivefluidresuscitationtoachieveacentralvenouspressure(CVP)greaterthan8mmHghasbeenpromotedasthe
standardofcare,inthemanagementofpatientswithseveresepsisandsepticshock.Howeverrecentclinicaltrialshave
demonstratedthatthisapproachdoesnotimprovetheoutcomeofpatientswithseveresepsisandsepticshock.
Pathophysiologically,sepsisischaracterizedbyvasoplegiawithlossofarterialtone,venodilationwithsequestrationofbloodin
theunstressedbloodcompartmentandchangesinventricularfunctionwithreducedcomplianceandreducedpreload
responsiveness.Thesedatasuggestthatsepsisisprimarilynotavolumedepletedstateandrecentevidencedemonstratesthat
mostsepticpatientsarepoorlyresponsivetofluids.Furthermore,almostalloftheadministeredfluidissequesteredinthe
tissues,resultinginsevereoedemainvitalorgansand,thereby,increasingtheriskoforgandysfunction.Thesedatasuggestthat
aphysiologic,haemodynamicallyguidedconservativeapproachtofluidtherapyinpatientswithsepsiswouldbeprudentand
wouldlikelyreducethemorbidityandimprovetheoutcomeofthisdisease.

Introduction

Inthe19thcentury,patientswithcholeradyingfromhypovolaemicshockweretreatedbyvenesectionorbloodletting. [1,2]This
treatmentwasconsideredthestandardofcareforthisdisorder.Inthefirstpartofthe21stcenturypatientswithsepticshock
weretreatedwithmassiveamountsofcrystalloids,approaching17litresinthefirst72hofhospitalization. [3,4]Thisapproachwas
consideredthestandardofcareandendorsedbyInternationalGuidelines. [57]Clearly,thesetreatmentapproachesfailedto
appreciatethepathophysiologicalchangesofbothdisordersandthattheprescribedtreatmentswereharmful.Choleraisa
diseaseassociatedwithprofoundvolumedepletionthroughdiarrhoeathatrequiresreplacementwithi.v.fluids. [1,2]Severesepsis
andsepticshockhowever,arenotassociatedwithvolumeloss.Sepsisischaracterizedbyarterioandvenodilationtogetherwith
microcirculatoryandmyocardialdysfunction,withsepticpatientsbeingpoorlyresponsivetofluidadministration.Nevertheless,
aggressivefluidresuscitationtoachieveacentralvenouspressure(CVP)greaterthan8mmHg('EarlyGoalDirectedTherapy'
EGDT),hasbeenconsideredthestandardofcareinthemanagementofpatientswithseveresepsisandsepticshock. [57]
However,recentmulticentreclinicaltrials(ProCESS,ARISEandPROMISE)andametaanalysisofEGDThavedemonstrated
thatthisapproachdoesnotimprovetheoutcomeofpatientswithseveresepsisandsepticshock. [811]Thisarticlereviewsthe
haemodynamicchangesassociatedwithsepsisandprovidesarationalapproachtofluidmanagementinthiscomplexdisorder.

PertinentNormalCardiovascularPhysiology
Theamountofbloodpumpedoutoftheheart(cardiacoutput)isequivalenttovenousreturn(volumeenteringtherightatrium).
[12]AccordingtoGuyton,venousreturnisdeterminedbythepressuregradientbetweentheperipheralveinsandtherightatrium

(CVP). [13]Thevenoussystemcanbedividedintotwotheoreticalcompartments,theunstressedandstressedvolume. [14]The

intravascularvolumethatfillsthevenoussystemtothepointwhereintravascularpressurestartstoincreaseiscalledunstressed
volume,whereasthevolumethatstretchestheveinsandcausesintravascularpressuretoincreaseiscalledthestressedvolume.
Themeancirculatoryfillingpressure(MCFP)isconceptualizedasthepressuredistendingthevasculature,whentheheartis
stopped(zeroflow)andthepressuresinallsegmentsofthecirculatorysystemhaveequalized. [14,15]Thestressedvenous
systemisthemajorcontributortotheMCFP. [14,15]TheMCFPinhumansisnormallyintherangeof8l0mmHg. [14,15]The
MCFPisthemajordeterminantofvenousreturn.

Thevenoussystemhasalargevascularcapacitanceandaconstantcomplianceinwhichanincreasedbloodvolumeis
associatedwitharelativelysmallchangeintheMCFP. [14]However,becauseoftherestrainingeffectsofthepericardiumand
cardiaccytoskeleton,thediastoliccomplianceofthenormalheart(bothleftandrightventricles)reducesasdistendingvolume
increasesconsequently,withlargevolumefluidresuscitation,thecardiacfillingpressures(particularlyontherightside,i.e.CVP)
increasefasterthantheMCFP,decreasingthegradientforvenousreturn. [1618]Organbloodflowisdeterminedbythe
differenceinthepressurebetweenthearterialandvenoussidesofthecirculation.Themeanarterialpressure(MAP)minusthe
CVPisthereforetheoveralldrivingforcefororganbloodflow.AhighCVPthereforedecreasesthegradientforvenousreturn,
whileatthesametimedecreasingorgandrivingpressureandthereforebloodflow.Venouspressurehasamuchgreatereffect
onmicrocirculatoryflowthantheMAPprovidedthattheMAPiswithinanorgan'sautoregulatoryrange,theCVPbecomesthe
majordeterminantofcapillarybloodflow. [19,20]

AccordingtotheFrankStarlingprinciple,asleftventricular(LV)enddiastolicvolume(i.e.preload)increases,LVstrokevolume
(SV)increasesuntiltheoptimalpreloadisachieved,atwhichpointtheSVremainsrelativelyconstant. [21]Thisoptimalpreloadis
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relatedtothemaximaloverlapoftheactinmyosinmyofibrils.FluidadministrationwillonlyincreaseSViftwoconditionsaremet,
namely:i)thatthefluidbolusincreasestheMCFPmorethanitincreasestheCVP,therebyincreasingthegradientforvenous
return,andii)thatbothventriclesarefunctioningonthe'ascendinglimb'oftheFrankStarlingcurve. [22,23]

Thevascularendotheliumiscoatedontheluminalsidebyawebofmembraneboundglycoproteinsandproteoglycansknownas
theendothelialglycocalyx. [2426]Theglycocalyxplaysamajorroleasavascularbarrier,preventinglargemacromolecules
movingacrosstheendothelium,preventingleucocyteandplateletaggregationandlimitingtissueoedema.Anintactendothelial
glycocalyxisaprerequisiteofafunctioningvascularbarrier. [27]Increasedcardiacfillingpressuresafteraggressivefluid
resuscitationincreasethereleaseofnatriureticpeptides. [28,29]Natriureticpeptidescleavemembraneboundproteoglycansand
glycoproteins(mostnotablysyndecan1andhyaluronicacid)offtheendothelialglycocalyx. [3032]Damagetotheglycocalyx
profoundlyincreasesendothelialpermeability.Inaddition,increasednatriureticpeptidesinhibitthelymphaticpropulsivemotor
activityreducinglymphaticdrainage. [3335]

VascularDysfunctionWithSepsis
Septicshockisprimarilyavasoplegicstatewitharterialandvenousdilatation,asaresultoffailureofthevascularsmooth
muscletoconstrict. [36]Vasoplegicshockisbelievedtobebecauseofincreasedexpressionofinduciblenitricoxidesynthetase
withincreasedproductionofnitricoxide(NO),activationofK ATPchannelsresultinginhyperpolarisationofthemusclecell
membrane,increasedproductionofnatriureticpeptides(whichactsynergisticallywithNO)andarelativevasopressindeficiency.
[36]Arterialdilatationresultsinsystemichypotension.However,moreimportantly,profoundvenodilationoccursinthesplanchnic

andcutaneousvascularbedsincreasingtheunstressedbloodvolume,decreasingvenousreturnandcardiacoutput. [14,15]As
approximately70%ofthebloodvolumeiswithinthevenoussystem,changesinvenousbloodvolumeplayamajorrolein
determiningvenousreturn. [15]

Sepsisischaracterizedbyincreasedexpressionandactivationofendothelialadhesionmoleculeswithadhesionandactivationof
platelets,leucocytesandmononuclearcellsandactivationofthecoagulationcascade. [37]Thisresultsinadiffuseendothelial
injury,microvascularthrombosis,gapsbetweentheendothelialcells(paracellularleak)andsheddingoftheendothelial
glycocalyx. [38,39]Thecombinationofthesemechanismscontributestoareductioninfunctionalcapillarydensity,heterogeneous
abnormalitiesinmicrocirculatorybloodflowandincreasedcapillarypermeability. [40,41]

CardiacChangesWithSepsis
Myocardialdepressioninpatientswithsepticshockwasfirstdescribedin1984byParkerandcolleagues[42]usingradionuclide
cineangiography.Inaseriesof20patients,theseinvestigatorsreporteda50%incidenceofLVsystolicdysfunction.Notably,in
thisstudytheinitialejectionfractionandventricularvolumeswerenormalinnonsurvivorsandtheseindicesdidnotchange
duringserialstudiesitislikelythatthesepatientshadsignificantdiastolicdysfunction.Theinitialstudiesevaluatingcardiac
functioninsepsisfocusedonLVsystolicfunction.However,LVdiastolicdysfunctionhasemergedasacommonfindingin
patientswithseveresepsisandsepticshock. [43]Adequatefillingduringdiastoleisacrucialcomponentofeffectiveventricular
pumpfunction.DiastolicdysfunctionreferstothepresenceofanabnormalLVdiastolicdistensibility,filling,orrelaxation,
regardlessofLVejectionfraction.Predominantdiastolicdysfunctionappearstobeatleasttwiceascommonassystolic
dysfunctioninpatientswithsepsis. [43]Inthelargeststudytodate(n=262),Landesbergandcolleagues44reporteddiastolic
dysfunctionin54%ofpatientswithsepsiswhile23%ofpatientshadsystolicdysfunction.Brownandcolleagues45performed
serialechocardiogramsin78patientswithseveresepsisorsepticshock.Inthisstudy62%ofpatientshaddiastolicdysfunction
onatleastoneechocardiogram.UnlikesystolicLVdysfunction,diastolicdysfunctionisanimportantprognosticmarkerinpatients
withsepsis. [4345]Diastolicdysfunctionisbecomingincreasingrecognizedinthecommunity,particularlyinpatientswith
hypertension,diabetes,obesityandwithadvancingage. [4648]Theseconditionsareassociatedwithanincreasedriskofsepsis
andmaythereforefurtherincreasetheprevalenceandseverityofdiastolicdysfunctioninpatientswithsepsis.Patients'with
diastolicdysfunctionrespondverypoorlytofluidloading. [44]ThiswasdemonstratedinalandmarkstudypublishedbyOgnibene
andcolleagues[49]in1988,whoreportedaninsignificantincreaseLVstrokeworkindexandLVenddiastolicvolumeindexin
patientswithsepticshockwhoreceivedafluidchallenge.Inthesepatients,fluidloadingwillincreasecardiacfillingpressures,
increasevenousandpulmonaryhydrostaticpressureswiththeincreasedreleaseofnatriureticpeptideswithminimal(ifany)
increaseinSV.Furthermore,asreviewedabove,aggressivefluidresuscitationinitselfcausesdiastolicdysfunctionwhichwill
compoundthepreexistingand/orsepsisinduceddiastolicdysfunction.

FluidResponsiveness
Thewidelyacceptedrationalebehindfluidresuscitationinsepsisistoimprovecardiacoutputandorganperfusion,thereby
limitingorgandysfunction.Logically,therefore,theonlyreasontoresuscitateapatientwithfluid(giveafluidbolus)wouldbeto
causeaclinicallysignificantincreaseinSV.ApatientwhoseSVincreasesby1015%afterafluidchallenge(250500ml)is
consideredtobeafluidresponder. [50]Nonetheless,accordingtotheFrankStarlingprinciple,asthepreloadincreases,SV

increasesuntiltheoptimalpreloadisachieved,atwhichpointtheSVremainsrelativelyconstant. [50]Ifthefluidchallengedoes
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increasesuntiltheoptimalpreloadisachieved,atwhichpointtheSVremainsrelativelyconstant. [50]Ifthefluidchallengedoes
notincreaseSV,volumeloadingservesthepatientnousefulbenefitandislikelyharmful.Theadverseeffectsoffluidloading
whenapatientisontheflatportionoftheFrankStarlingcurve,isrelatedtothecurvilinearshapeoftheleftventricularpressure
volumecurve,resultingfromaltereddiastoliccomplianceathigherfilingpressures. [1618]Asthepatientreachestheplateauof
his/herFrankStarlingcurve,atrialpressuresincrease,increasingvenousandpulmonaryhydrostaticpressureswhichcombined
withtheincreasedreleaseofnatriureticpeptides,causesashiftoffluidintotheinterstitialspace,withanincreaseinpulmonary
andtissueoedema(seeFig.1).Tissueoedemaimpairsoxygenandmetabolitediffusion,distortstissuearchitecture,impedes
capillarybloodflowandlymphaticdrainageanddisturbscellcellinteractions. [52,53]Increasedrightatrialpressure(CVP)is
transmittedbackwardsincreasingvenouspressureinvitalorgans,withaprofoundeffectonmicrocirculatoryflowandorgan
function. [19]Thekidneyisparticularlyaffectedbyincreasedvenouspressure,whichleadstoincreasedrenalsubcapsularpressure
andreducedrenalbloodflowandglomerularfiltrationrate. [52]

Figure1.

SuperimpositionoftheFrankStarlingandMarikPhillipscurvesdemonstratingtheeffectsofincreasingpreloadonstrokevolume
andlungwaterinapatientwhoispreloadresponsive(a)andnonresponsive(b).WithsepsistheEVLWcurveisshiftedtothe
left. 51EVLW=extravascularlungwaterCO=cardiacoutputSV=strokevolume.MCFP=meancirculatingfillingpressure.
ReproducedwithpermissionfromtheBritishJournalAnaesthesia201412:620622.

FluidResponsivenessandtheHaemodynamicEffectsofFluidsinPatientsWithSepsis
Studiesinheterogeneousgroupsofcriticallyillandinjuredpatientsandthoseundergoingsurgeryhavereproducibly
demonstratedthatonlyabout50%ofhaemodynamicallyunstablepatientsarefluidresponders. [50,5456]Thisisafundamental
conceptwhichisnotwidelyappreciated, [57,58]andchallengesthewidelyacceptednotionthatfluidadministrationisthe

'cornerstoneofresuscitation'. [57,59]Asaresultoftheeffectsofsepsisonthevenouscapacitancevesselsandmyocardial
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'cornerstoneofresuscitation'. [57,59]Asaresultoftheeffectsofsepsisonthevenouscapacitancevesselsandmyocardial
function,itislikelythatlessthan40%ofhypotensivepatientswithseveresepsisorsepticshockare'fluidresponders'. [6062]

ThegoaloffluidresuscitationistoincreasethestressedbloodvolumeandMCFPmorethantheCVP,andtherebyincreasethe
pressuregradientforvenousreturn.Howevertheabilityofcrystalloids(themostcommonfluidusedfortheresuscitationof
patientswithsepsis)toexpandtheintravascularvolumeispoor.Chowdhuryandcolleagues63reportedthatinhealthyvolunteers,
only15%ofacrystalloidbolusremainedintheintravascularspaceat3h,with50%oftheinfusedvolumebeinginthe
extravascularextracellularcompartment.Inpatientswithsepsisandinexperimentalmodels,lessthan5%ofacrystalloidbolus
remainsintravascularanhouraftertheendoftheinfusion. [64,65]Itisthereforelikelythatthehaemodynamiceffectsofafluid
bolus(inthefluidresponders)areshortlived,withtheneteffectbeingtheshiftoffluidintotheinterstitialcompartmentwith
tissueoedema.Nunesandcolleagues[66]demonstratedthatinfluidresponders,theSVreturnedtobaseline60minaftera
crystalloidbolus.Glassfordandcolleagues[67]performedasystematicreviewwhichexaminedthehaemodynamicresponseof
fluidbolusesinpatientswithsepsis.Theseauthorsreportedthatwhilethemeanarterialpressure(MAP)increasedby7.8(3.8)
mmHgimmediatelyafterthefluidbolus,theMAPhadreturnedclosetobaselineatonehwithnoincreaseinurineoutput.Ina
retrospectiveanalysisoftheARDSnetFluidandCatheterTreatmentTrial(FACTT), [68]Lammiandcolleagues62examinedthe
physiologicaleffectof569fluidboluses(15mlkg11025243ml)in127patients(themajorityofwhomwereseptic),
randomizedtothepulmonaryarterycatheterarmofthestudy.TheFACTTtrialrequiredreassessmentofthehaemodynamic
profileonehafterthefluidbolus,iftheindicationforfluidswasshock,ineffectivecirculation,orlowurineoutputandfourhifthe
indicationwasalowpulmonaryarteryocclusionpressure(PAOP). [68]Fiftyeightpercentoffluidbolusesweregivenforshockor
poorurineoutput/ineffectivecirculation,with42%ofbolusesgivenforalowPAOP.Inthisstudy,only23%ofpatientswerefluid
responders(increaseinCI>15%).TherewasasmallincreaseintheMAP(78.316.4to80.416.5mmHg)whiletheurine
outputdidnotchangeinthe14hafterthefluidbolus.

MongeGarciaandcolleagues[69]measuredtheeffectsofafluidbolusonarterialloadinpatientswithsepticshock.Inthisstudy
67%ofpatientswerefluidresponders,howevertheMAPincreasedinonly44%ofthesepatients(pressureresponder).Overall
therewasasignificantreductionineffectivearterialelastance(Ea)andsystemicvascularresistance(SVR),thiseffectbeing
mostmarkedinthepreloadresponderswhowerepressurenonresponders.Additionalstudieshavedemonstratedadecreasein
SVRafterfluidresuscitationinpatientswithsepsis. [70,71]Thissuggeststhatfluidbolusesshouldbeconsideredvasodilator
therapy,inpatientswithsepsisandthataggressivefluidresuscitationmaypotentiatethehyperdynamicstate.

Insummary,thesestudiesdemonstratethatthemajorityofpatientswithseveresepsisandsepticshockarenotfluidresponders.
Furthermore,thehaemodynamicchangesinthefluidrespondersaresmall,shortlivedandlikelytobeclinicallyinsignificant.
However,aggressivefluidresuscitationwilllikelyhaveadversehaemodynamicconsequencesincludinganincreaseincardiac
fillingpressures,damagetotheendothelialglycocalyx,arterialvasodilationandtissueoedema.Consequently,theconceptthat
aggressivefluidresuscitationisthe'cornerstoneofresuscitation'ofpatientswithseveresepsisandsepticshockneedstobe
reconsidered. [57,59]Indeed,itislikelythataggressivefluidresuscitationincreasesthemorbidlyandmortalityofpatientswith
sepsis(seesectionbelow).NeverthelesstheupdatedSurvivingSepsisCampaignGuidelines,publishedafterthepublicationof
theProCESS,ARISEandPROMISEstudies[810]mandatetheadministrationof'30mlkg1crystalloidforhypotensionor
lactate4mmolLitre1'within3hofpresentationtohospital. [72]Thisrecommendationisproblematicasthemajorityof
hypotensivepatientswithsepticshockwillnotrespondtofluidsthisapproachislikelytoleadto'saltwaterdrowning'withan
increaseinthemorbidityandmortalityofthesepatients. [73]Furthermore,asdiscussedbelow,anincreasedbloodlactateis
unlikelytobeassociatedwithanaerobicmetabolism,orinadequateoxygendelivery,andattemptsatincreasingoxygendelivery
donotincreaseoxygenconsumptionorlowerlactateconcentrations.Indeedsuchanapproachhasbeendemonstratedto
increasetheriskofdeathofcriticallyillpatients. [74]

Thesedatasuggestthatonlypatientswhoarefluidresponsiveshouldbetreatedwithfluidboluses.Furthermore,thepatients'
fluidresponsivenessandtherisk/benefitratiooffluidadministrationneedstobedeterminedbeforeeachfluidbolus. [75]Asthe
haemodynamicresponsetoafluidchallengeisveryshortlivedandlargefluidboluses(2030mlkg1)areassociatedwith
severevolumeoverload,theminifluidbolusapproach(200500ml)tofluidtherapyisrecommended. [76]Thepassivelegraising
manoeuvre(PLR)andthefluidbolustestcoupledwithrealtimeSVmonitoring,arecurrentlytheonlytechniqueswhichhavean
acceptabledegreeofclinicalaccuracy,whichcanbeusedfordeterminingfluidresponsiveness. [51]Becauseofitseaseofuse,
simplicity,highdiagnosticaccuracy,inherentsafetyandshortproceduretime(lessthan5mintoperform)thePLRisthe
preferredmethodtoassessfluidresponsivenessintheemergencydepartment,hospitalwardandICU. [51,75]ThePLR
manoeuvreisperformedbyliftingthelegspassivelyfromthehorizontalpositionandisassociatedwiththegravitationaltransfer
ofblood(about300ml)fromthelowerlimbsandabdomentowardtheintrathoraciccompartment. [75,77,78]ThePLRmanoeuvre
hastheadvantageofreversingitseffectsoncethelegsarereturnedtothehorizontalposition. [75,79,80]Therefore,thePLR
manoeuvreisconsideredareversibleor'virtual'fluidchallenge.TheabilityofthePLRmanoeuvretoserveasatestofpreload
responsivenesshasbeenconfirmedinmultiplestudiesperformedincriticallyillpatients.Ametaanalysis,whichpooledthe
resultsofeightstudies,confirmedtheexcellentvalueofPLRtopredictfluidresponsivenessincriticallyillpatientswithaglobal
areaundertheROCcurveof0.95(95%CI,0.920.95). [81]Inanupdatedmetaanalysiswhichevaluated21studies,wereporta
pooledROCAUCof0.930.95(MonnetX,MarikP,TeboulJLsubmittedforpublication).Asthemaximalhaemodynamic
effectsofPLRoccurwithinthefirstminoflegelevation, [75,80]itisimportanttoassesstheseeffectswithamethodabletotrack
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effectsofPLRoccurwithinthefirstminoflegelevation, [75,80]itisimportanttoassesstheseeffectswithamethodabletotrack
changesincardiacoutputorSVonarealtimebasis.ItisimportanttonotethatthechangeinbpafteraPLRorfluidchallenge
isapoorguidetofluidresponsivenessSVmayincreasewithoutasignificantchangeinbp. [70]Furthermore,unliketechniquesto
determinefluidresponsivenessbasedonheartlunginteractions,thePLRmanoeuvrecanbeperformedinspontaneously
breathingpatients,patientswithcardiacarrhythmiasandthosereceivinglowtidalvolumeventilation. [75,51]

Thechestradiograph,CVP,centralvenousoxygensaturation(ScvO2)andultrasonography,includingthevenacavalcollapsibility
index,havelimitedvalueinguidingfluidmanagementandshouldnotbeusedforthispurpose. [54,8286]Furthermore,ithas
beenwellestablishedthatphysicalexaminationcannotbeusedtopredictfluidresponsivenessandphysicalexaminationis
unreliableforestimatingintravascularvolumestatus. [87]ItisthereforeverytroublingthattheupdatedSurvivingSepsis
CampaignGuidelineswhicharenowfederallymandatedintheUSA(SEP1EarlyManagementBundle,#0500SevereSepsis
andSepticShock:managementBundle)requireeithera'focusedexambyalicensedindependentpractitioner',ormeasurement
oftheCVPorScvO2,orbedsidecardiovascularultrasound,toassessthevolumestatusofthepatientwithseveresepsisand
septicshock. [88]Itshouldbenotedthattheareaunderthereceiveroperatorcharacteristic(ROC)curveoftheCVP,forpredicting
fluidresponsiveisapproximately0.5,whichisconsidereda'completelyuselesstest'. [54,89,90]Furthermore,itisimportantto
emphasizethatanormalCVPisbetween02mmHgthisisnecessarytoensureadequatevenousreturnandcardiacoutput(as
discussedabove).Inaddition,whilethechangeinCVPinresponsetoafluidchallengeisstillwidelypromotedasamethodto
guidefluidtherapy, [57]thistechniquehasnophysiologicbasisandisunabletopredictfluidresponsivenesswithanydegreeof
accuracy. [54,91]Furthermore,itshouldbenotedthatwiththeexceptionofmeasuringdynamicchangesinthecarotidDoppler
peakvelocity, [86,92,93]bedsideultrasoundincludingtheinferiorvenacavaldistensibilityindexcannotaccuratelypredictfluid
responsiveness. [51,82,85,86]ItissomewhatastonishingthattheScvO2isstillbeingrecommendedtoguidetheresuscitationof
criticallyillsepticpatientsandisbeingusedasanindicatorofthequalityofcaredelivered. [72,88]MonitoringtheScvO2in
patientswithsepsishasnoscientificbasis,aspatientswithsepsisusuallyhaveanormalorincreasedScvO2, [94,95]andahigh
(ScvO2>90%)ratherthanlowScvO2hasbeendemonstratedtobeanindependentpredictorofdeath. [96]Threelarge
randomizedcontrolledtrials(ProCESS,ARISEandPROMISE)havenowdemonstratedthattitratingtherapytoaScvO2>70%
doesnotimproveoutcome, [810]butratherincreasestheriskoforgandysfunction,lengthofICUstayandincreaseduseof
resourcesandcosts. [10]TheseobservationsmustleadtotheconclusionthattheoriginalEGDTstudywasnotscientificallyvalid
andthatnoaspectofthisstudyshouldbeusedtoguidethemanagementofpatientswithseveresepsisandsepticshock.
[3,97,98]

InadditiontotargetingaCVPgreaterthan8mmHg,theSurvivingSepsisCampaignguidelinerecommends'targeting
resuscitationtonormalizelactateinpatientswithelevatedlactatelevelsasamarkeroftissuehypoperfusion'. [7]This
recommendationisbasedonthenotionthatanelevatedlactateisaconsequenceoftissuehypoxiaandinadequateoxygen
delivery. [95]However,theseassertionsarelikelywrong. [99]HotchkissandKarl[100]inaseminalreviewpublishedover20yrago,
demonstratedthatcellularhypoxiaandbioenergeticfailuredoesnotoccurinsepsis.Ithasnowbeenwellestablishedthat
epinephrinereleasedaspartofthestressresponseinpatientswithseveresepsis,stimulatesNa+K+ATPaseactivity.Increased
activityofNa+K+ATPaseleadstoincreasedlactateproductionunderwelloxygenatedconditionsinvariouscells,including
erythrocytes,vascularsmoothmuscle,neurons,glia,andskeletalmuscle. [101,102]Whilesepsisisconsideredtobea
'hypermetabolic'conditionoxygenconsumptionandenergyexpenditurearebroadlycomparablewiththatofnormalpeople,with
energyexpendituredecreasingwithincreasingsepsisseverity. [103105]Therefore,thereisnorequirementthatoxygendelivery
increasewithsepsis.Indeed,increasingoxygendeliveryinpatientswithsepsisdoesnotincreaseoxygenconsumptionnor
decreaselactateconcentrations. [106,107]Thecriticaloxygendeliverythresholdforhumans(bothsepticandnonseptic)is
approximately3.8(1.5)mlmin1kg1(270mlmin1ina70kgpatient). [108]Thesevaluestranslateintoacardiacoutputof
approximately2Litremin1itislikelythatonlypreterminalmoribundpatientswithsepticshockwouldhavesuchalowcardiac
output.

EvidenceSupportingtheDeleteriousEffectsofAggressiveFluidResuscitation
Theharmfuleffectsofaggressivefluidresuscitationontheoutcomeofsepsisaresupportedbyexperimentalstudiesanddata
accumulatedfromclinicaltrials. [109,110]Multipleclinicalstudieshavedemonstratedanindependentassociationbetweenan
increasinglypositivefluidbalanceandincreasedmortalityinpatientwithsepsis. [29,111120]Themostcompellingdatathatfluid
loadinginsepsisisharmful,comesfromthelandmark'FluidExpansionasSupportiveTherapy(FEAST)'studyperformedin
3141subSaharanchildrenwithseveresepsis. [121]Inthisrandomizedstudy,aggressivefluidloadingwasassociatedwitha
significantlyincreasedriskofdeath.AftertheRivers'EarlyGoalDirectedTherapytrial, [3]whichformedthebasisfortheconcept
ofearlyaggressivefluidresuscitation,anumberofEGDTstudieshavebeenpublished. [4,810,122]Ananalysisofthesestudies
demonstratesamarkedreductioninmortalityoverthistimeperiod(seeFig.2).Whileallthesestudiesemphasizedtheearlyuse
ofappropriateantibiotics,thedeclineintheamountoffluidsadministeredinthefirst72hisstriking.Furthermoreasillustratedin
Fig.3thereisaverystrongcorrelationbetweentheamountoffluidadministered(infirst6h)andthetargetCVP.Itshouldbe
notedthattheCVPintheusualarmofboththeARISE(TheAustralasianResuscitationinSepsisEvaluation)andProMISe
(ProtocolisedManagementinSepsis)trialswasgreaterthan10mmHg,beingalmostidenticaltotheEGDTarm,andwith
almostanidenticalamountoffluidbeingadministeredintheusualarm,asintheactiveEGDTarminbothstudies. [9,10]
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almostanidenticalamountoffluidbeingadministeredintheusualarm,asintheactiveEGDTarminbothstudies. [9,10]
CliniciansseemcompelledtogivefluidwhentheCVPislessthan8mmHgtheonlysolutiontothispervasiveproblemisto
stopmeasuringtheCVP.

Figure2.

Fluidadministeredbetweenenrolmentand72hand90daymortalityinthecontrolarmoftheEarlyGoalDirectedTherapy
(EGDT)Studiesperformedbetween2001and2015.APACHEII=APACHEIISeverityofillnessscoringsystem(071).

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Figure3.

Fluidadministeredbetweenenrolmentand6handcentralvenouspressure(CVP)athintheEarlyGoalDirectedarmofthe
EGDTstudiesperformedbetween2001and2015.

AHaemodynamicallyguidedConservativeFluidResuscitationStrategy
Thesedatastronglysupportahaemodynamicallyguidedfluidresuscitationstrategyinpatientswithseveresepsisandseptic
shock.Furthermore,fromanevolutionarypointofview,humanshaveevolvedtodealwithhypovolemiaandnothypervolemia.
Largefluidbolusesmaycounterthelifepreservinghomeostaticmechanismsinunstablecriticallyillpatients,increasingtherisk
ofdeath. [123]Insomepatients,hypotensionandtachycardiadoresolvewithlimitedfluidresuscitation.Itislikelythatmanyof
thesepatientshavesuperaddeddehydrationasaresultofpoororalintakeandadelayinseekingmedicalattention.However,
fluidsalonewillnotreversethehaemodynamicinstabilityofpatientswithmoreseveresepsisinthesepatients,fluidsaloneare
likelytoexacerbatethevasodilatoryshockandincreasethecapillaryleakandtissueoedema.Basedonthesedata,theinitial
resuscitationofpatientswithsepticshockshouldlogicallyincludeatmost500mlbolusesofcrystalloid(Ringer'slactate),toa
maximumofabout20mlkg1. [124]Ideally,fluidresuscitationshouldbeguidedbythedeterminationoffluidresponsiveness.
[50,51]Normalsalineisan'unphysiologic'solutionthatshouldbeavoided,exceptinpatientswithacuteneurologicalinjuries.

Normalsalinecausesahyperchloraemicmetabolicacidosis [125128]itdecreasesrenalbloodflow[63]increasingtheriskofrenal
failure. [129]Inpatientswithsepsis,theuseofnormalsalineascomparedwithphysiologicsaltsolutions,hasbeenassociated
withanincreasedriskofdeath. [130]Similarly,syntheticstarchsolutionsincreasetheriskofrenalfailureanddeathinpatients
withsepsisandshouldbeavoided. [131,132]

Thesepticpatientwithanintraabdominalcatastrophe,whorequiresurgentsurgicalintervention,representsasubgroupof
patientsthatmayrequiremoreaggressivefluidresuscitation.However,overlyaggressivefluidresuscitationwilllikelyresultin
intraabdominalhypertension,whichisassociatedwithahighriskofcomplicationsanddeath. [133,134]Inthesepatients
continuousSVmonitoringisessentialandongoingfluidrequirementsshouldbeguidedbythetrendintheSVandthe

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haemodynamicresponsetoaminifluidbolus.Inaddition,perioperative,intraabdominalpressuremonitoringisrequiredinthese
patients. [133]

Norepinephrineshouldbeinitiatedinthosepatientswhoremainhypotensive(MAP<65mmHg)despitethisinitial,limitedfluid
strategy. [124,135]Norepinephrineincreasesarterialvasculartoneincreasingbpandorganbloodflow.Venouscapacitancevessels
aremuchmoresensitivetosympatheticstimulationthanarearterialresistancevessels,consequentlylowdose1agonists
causegreatervenothanarterioconstriction. [136]Insepticpatients,1agonistsmobilizebloodfromtheunstressedreservoirsin
thesplanchniccirculationandskin,therebyincreasingvenousreturnandcardiacoutput.Inaporcineendotoxicshockmodel,
DattaandMagder[137]demonstratedthatnorepinephrineincreasedtheMCFP,leadingtoanincreaseinvenousreturn.Similarly
inpatientswithsepticshock,Persichiniandcolleagues[138]demonstratedthatdeceasingthedoseofnorepinephrine,decreased
theMCFPwithadecreaseinvenousreturnandcardiacoutput.InacohortofpatientswithsepticshockKozierasand
colleagues[139]demonstratedthatnorepinephrineincreasedcardiacindex,systemicvascularresistanceandcentralblood
volumes(intrathoracicbloodvolume,globalenddiastolicvolume),asmeasuredbytranspulmonarythermodilution.Inthisstudy
extravascularlungwater(EVLW)remainedunchanged.Hamzaouiandcolleagues[140]demonstratedthattheearly
administrationofnorepinephrineincreasedpreload,cardiacoutputandMAPlargelyreversingthehaemodynamicabnormalities
ofseverevasodilatoryshock.Abidandcolleagues[141]demonstratedthattheearlyuseofnorepinephrineinpatientswithseptic
shockwasastrongpredictorofsurvival.Thesestudiesdemonstratethatinpatientswithsepticshock,theearlyuseof
norepinephrinerestoresthestressedbloodvolume,increasingtheMCFP,venousreturnandcardiacoutput.Theincreaseinthe
stressedbloodvolumeisasaresultofthemobilisationofblood,ratherthantheshortlivedeffectofavolumeexpander.
Thereforeunlikefluids,theeffectof1agonistsonvenousreturnisenduringandnotassociatedwithtissueoedema.1
agonistsshouldnotbeusedinpatientswithhypovolaemicshock(e.g.cholera)whoarealreadyvenoconstrictedinthissetting,
1agonistswillcauseseverevasoconstriction,impairingorganbloodflow.However,insepticvenoandarteriodilatedpatients,
1agonistsincreasevenousreturn,increasestrokevolumeandincreasearterialtone,therebyincreasingorganbloodflow. [142
144]Digitalandlimbischaemiaandischaemicskinlesionsareextremelyrarewiththeuseofnorepinephrine, [145]occurring

usuallywithhighdosagesandusuallywhenusedtogetherwithvasopressin. [146,147]Furthermore,uncontrolleddisseminated
intravascularcoagulation(DIC)playsacontributingroleinthesepatients. [148]Weareunawareofanyreportedpatientswith
digitalorlimbischaemiaassociatedwiththeearlyuseofnorepinephrine.Inourexperiencetheearlyuseofnorepinephrine
appearstoreducethepeakandtotaldoseofvasopressorsadministered.Itisnoteworthythatnorepinephrinemaybesafely
giventhroughawellfunctioningperipheralvenouscatheter, [149]precludingtherequirementforemergentcentralvenous
catheterization,whichisgenerallyregardedasanobstacletotheearlyuseofnorepinephrine.Inexperimentalsepsismodels,
norepinephrineappearspreferabletoepinephrineandphenylephrineasafirstlinetherapyinrestoringhaemodynamicstability.
[150,151]Dopamineasopposedtonorepinephrineisassociatedwithanincreasedriskofarrhythmiasanddeathinpatientswith

sepsisandshouldbeavoided. [152154]

Conclusions
Anemergingbodyofbasicscienceandclinicalstudiessupportstheconceptofahaemodynamicallyguided,restrictedfluid
resuscitationstrategyinpatientswithseveresepsisandsepticshock.Initialfluidresuscitationshouldbelimitedandguidedbyan
assessmentoffluidresponsiveness.Norepinephrineincreasespreload,systemicvascularresistanceandcardiacoutputandits
useinpatientswithpersistenthypotensionisrecommendedearlyinthecourseofsepticshock.Earlybedsideechocardiographic
assessmentofcardiacfunctionisrecommendedtoguidefurtherhaemodynamicmanagement.Adequatelypowered,
randomized,controlledtrials,areurgentlyrequiredtodemonstratethebenefitsoftheearlyuseofnorepinephrineanda
conservative,haemodynamicallyguidedfluidresuscitationstrategy.

Sidebar
Editor'sKeyPoints

Theauthorsreview,indetail,thephysiologyofhypoandhypervolaemia,andtheeffectsofvenodilationand
arteriodilation.

Theycontendthatuniversal,aggressivefluidadministrationinsepticshockcarriesconsiderablerisk,andthata
haemodynamicallyguided,conservativeapproachislikelytoproducebetteroutcome.

Theyalsoarguethatearlynorepinephrinetherapyislikelytoimproveoutcome.

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Authors'contributions
Writingpaper:P.M.,R.B.
Revisingpaper:bothauthors

Declarationofinterest
Inthelast5yrP.M.hasreceivedanhonorariumfromPulsionMedical,manufactureofthePiCCOhaemodynamicdevicefora
lecturedeliveredataninternationalCriticalCareSymposium(about1000GBP)andanhonorariumfromCheetahMedical,
manufactureroftheNiCOMhaemodynamicdeviceforalecturedeliveredatmedicalgrandrounds(about1500GBP).R.B.has
noconflictsofinteresttodeclare.

Acknowledgements
Weacknowledgeourmentorsandstudentswhohavetaughtuseverythingweknowandinspiredustolearnevenmore.

BrJAnaesth.2016116(3):339349.2016OxfordUniversityPress
Copyright2007TheBoardofManagementandTrusteesoftheBritishJournalofAnaesthesia.PublishedbyOxfordUniversity
Press.Allrightsreserved.

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