Revista: Terapia de fluidos para adultos en estado crítico con sepsis

FluidTherapyforCriticallyIllAdultsWithSepsis AReview

FernandoG.Zampieri,MD,PhD;SeanM.Bagshaw,MD,MSc;MatthewW.Semler,MD,MSc

IMPORTANCE Approximately20%to30%ofpatientsadmittedtoanintensivecare unithavesepsis.Whilefluidtherapytypicallybeginsintheemergencydepartment, intravenousfluidsintheintensivecareunitareanessentialcomponentof therapyforsepsis.

OBSERVATIONS Forpatientswithsepsis,intravenousfluidcanincreasecardiacoutput andbloodpressure,maintainorincreaseintravascularfluidvolume,anddeliver medications.Fluidtherapycanbeconceptualizedas4overlappingphasesfromearly illnessthroughresolutionofsepsis:resuscitation(rapidfluidadministeredtorestore perfusion);optimization(therisksandbenefitsofadditionalfluidstotreatshock andensureorganperfusionareevaluated);stabilization(fluidtherapyisusedonly whenthereisasignaloffluidresponsiveness);andevacuation(excessfluid accumulatedduringtreatmentofcriticalillnessiseliminated).Among3723patients withsepsiswhoreceived1to2Loffluid,3randomizedclinicaltrials(RCTs) reportedthatgoal-directedtherapyadministeringfluidbolusestoattainacentral venouspressureof8to12mmHg,vasopressorstoattainameanarterialbloodpressure of65to90mmHg,andredbloodcelltransfusionsorinotropestoattainacentral venousoxygensaturationofatleast70%didnotdecreasemortalitycompared withunstructuredclinicalcare(24.9%vs25.4%; P =.68).Among1563patientswith sepsisandhypotensionwhoreceived1Loffluid,anRCTreportedthatfavoring vasopressortreatmentdidnotimprovemortalitycomparedwithfurtherfluid administration(14.0%vs14.9%; P =.61).AnotherRCTreportedthatamong1554 patientsintheintensivecareunitwithsepticshocktreatedwithatleast1Loffluid comparedwithmoreliberalfluidadministration,restrictingfluidadministration intheabsenceofseverehypoperfusiondidnotreducemortality(42.3%vs42.1%; P =.96).AnRCTof1000patientswithacuterespiratorydistressduringtheevacuation phasereportedthatlimitingfluidadministrationandadministeringdiureticsimproved thenumberofdaysalivewithoutmechanicalventilationcomparedwithfluidtreatment toattainhigherintracardiacpressure(14.6vs12.1days; P <.001),anditreportedthat hydroxyethylstarchsignificantlyincreasedtheincidenceofkidneyreplacementtherapy comparedwithsaline(7.0%vs 5.8%; P =.04),Ringerlactate,orRingeracetate.

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AuthorAffiliations: Departmentof CriticalCareMedicine,Facultyof MedicineandDentistry,Universityof AlbertaandAlbertaHealthServices, Edmonton,Alberta,Canada (Zampieri,Bagshaw);Departmentof Medicine,DivisionofAllergy, Pulmonary,andCriticalCare Medicine,VanderbiltUniversity MedicalCenter,Nashville,Tennessee (Semler);CenterforLearning Healthcare,VanderbiltInstitutefor ClinicalandTranslationalResearch, VanderbiltUniversityMedicalCenter, Nashville,Tennessee(Semler).

CONCLUSIONSANDRELEVANCE

Fluidsareanimportantcomponentoftreatingpatients whoarecriticallyillwithsepsis.Althoughoptimalfluidmanagementinpatientswith sepsisremainsuncertain,cliniciansshouldconsidertherisksandbenefitsoffluid administrationineachphaseofcriticalillness,avoiduseofhydroxyethylstarch, andfacilitatefluidremovalforpatientsrecoveringfromacuterespiratory distresssyndrome.

JAMA.2023;329(22):1967-1980.doi:10.1001/jama.2023.7560

Approximately20%to30%ofpatientsadmittedtoan intensivecareunit(ICU)havesepsis.1 Ofthese,approximately25%to40%diepriortohospitaldischarge. 2,3 Fluidtherapyisanimportantcomponentoftreatmentforpatients withsepsis.4,5 Fluidtherapymaybeadministeredduringanyphase ofcriticalillnesswithsepsis,includingbefore,during,andafterICU admission.ThisreviewsummarizesfluidtherapyintheICUfor patientscriticallyillwithsepsis.

CorrespondingAuthor: FernandoG. Zampieri,MD,PhD,Departmentof CriticalCareMedicine,Facultyof MedicineandDentistry,Universityof AlbertaandAlbertaHealthServices, 8440-112StNW,2-124,Edmonton, ABT6G2B7,Canada(fzampier@ ualberta.ca).

SectionEditor: MaryMcGrae McDermott,MD,DeputyEditor.

Methods

WesearchedPubMedfortheterms earlygoal-directedtherapy [and] sepsis, fluidresuscitation [and] sepsis, fluidtherapy [and] sepsis [and] criticalillness , fluidresponsiveness [and] sepsis ,and POCUS (point-of-careultrasonography)[and] criticalcare forrelevantreferences.Of5585manuscriptsidentified,76articleswere

A Fluid infusion and the 3-compartment model of fluid distribution

Intravenous fluid infusion

INTRAVASCULAR COMPARTMENT

Inflammation causes damage to endothelium and endothelial glycocalyx, leading to increased fluid extravasation, interstitial edema, and decreased volume of venous return.

Volume ofvenousreturn

B Effect of fluid infusion on volume of venous return, right atrial pressure, and cardiac output

1 Increased right atrial pressure may increase cardiac output.

2 Fluid infusion increases venous return volume and right atrial pressure and may lead to increased cardiac output.

3 Further infusion will not increase cardiac output despite increased right atrial pressure and may lead to tissue edema.

INTERSTITIAL COMPARTMENT

Factors affecting fluid distribution

Sepsis and anesthesia:

• Decreased diuresis

• Increased fluid extravasation

Low endothelial integrity:

• Increased fluid extravasation

Low infusion volume:

• Decreased fluid extravasation

High infusion rate:

• Decreased fluid reabsorption into circulation

Low serum osmotic pressure:

• Increased fluid extravasation

Low capillary hydrostatic pressure:

• Decreased fluid extravasation

INTRACELLULAR COMPARTMENT

INTERSTITIAL COMPARTMENT

Interstitial fluid is primarily reabsorbed into the circulation via the lymphatic system. Fluid is removed from the circulation through diuresis or dialysis.

A,Intheclassic3-compartmentmodel,fluidadministeredintravenously distributesfromtheplasmatotheinterstitiumandfromtheinterstitiumto cells.Filteredfluidreturnstotheplasmamostlythroughthelymphsystemand iseliminatedbyurine.8,9 Thecompositionofthefluid(ie,colloidvscrystalloid) andthecharacteristicsofitsadministration(eg,volumeandrate)influenceits movementfromtheplasmaintotheinterstitiumandcells.8 B,Intheclassic Frank-Starlingmodelofcardiacphysiology,whenintravenousfluid

included,consistingof28randomizedclinicaltrials(RCTs),7secondaryanalysesofRCTs,20observationalstudies,5systematic reviews/meta-analyses,1scopingreview,and1practiceguideline. Theremaining14referenceswereaddedfromreferencereview. RCTs,includingrelevantsecondaryanalysesofclinicaltrialdata, wereprioritizedforinclusion.

PathophysiologyofFluidTherapy

Multiplephysiologicalpathwaysresponsibleformaintainingintravascularvolume,venousreturn,cardiacoutput,andtissueperfusionaredisruptedbysepsis.Fluidlosses,combinedwithincreased venouscapacitanceanddecreasedvenousresistance,reducethe effectiveintravascularvolumeinsepsis,whichmaydecreasevenousreturn,cardiacoutput,andtissueperfusion.6,7 Intravenous(IV) fluidtherapycanincreasebloodvolumeinthevasculature,thevolumeofvenousbloodreturningtotheheart,thecardiacoutput,and thevolumeofoxygendeliveredtotissues(Figure1).8,10 Changesin arterialpressureafterfluidadministrationdependonarterialelastance.Afluidbolusincreasesbloodpressurebyagreateramount

As cardiac output increases,

blood pressure (pulse pressure) will increase if arterial elastance is high but may not increase if arterial elastance is low.

administrationincreasesintravascularvolume,thevolumeofbloodintheright ventricleincreases.Iftheheartisintheascendingpartofthecurve,the increasedventricularfillingincreasescardiacoutput.Iftheheartisfurtherto therightonthecurve,furtherfluidadministrationmaynotincreasecardiac output.Whetheranincreaseincardiacoutputincreasesarterialbloodpressure dependsoncardiacelastance.

whenthearteriesarestiffandnoncompliant(highelastance)comparedwithwhenthearteriesareflexibleandcompliant.11 Therefore,fluidadministrationmayincreaseapatient’scardiacoutput withoutincreasingbloodpressure.

FluidDistribution

Administeredfluiddistributesinitiallytotheintravascularcompartmentandthendistributestotheinterstitialandintracellular compartments.8 Fluidinfluxintotheinterstitialcompartmentisprimarilyreabsorbedintothecirculationthroughthelymphatic system.9 Serumoncoticpressure,endothelialintegrity,capillary hydrostaticpressure,fluidinfusionrateandvolume,andotherfactorsaffectfluiddistribution.8 Whilehemodynamicimprovements (eg,augmentedcardiacoutput,increasedarterialbloodpressure, andimprovedtissueperfusion)canoccurduringinitialfluid therapy,excessivefluidadministrationcancausefluidextravasationandinterstitialedema,especiallyinsepsis.Damagetothevascularendotheliumandtheendothelialglycocalyxinsepsismayincreasefluidextravasation(Figure1).Tissueedemaduetoincreased venouspressurehasbeenassociatedwithorgandysfunctionand potentialcomplications12 suchasintra-abdominalhypertension

Figure1.FluidInfusioninSepsis

Movement of fluid between compartments

return

Cardiacoutput

andcompartmentsyndrome.13 Fluidtherapyshouldbetailoredto maximizeearlybenefitswhileminimizingadverseeffects.

FourFormsofFluidUse

CriticallyillpatientsprimarilyreceiveIVfluidsin4forms:fluidchallenge,fluidbolus,maintenanceorreplacementfluidoraspartofparenteralnutrition,andmedicationdiluentorcarrier.AfluidchallengeistheadministrationofasmallvolumeofIVfluid(eg,250mL) overashortperiod(eg,10minutes)withthegoalofassessingapatient’sphysiologicalresponsetothefluidsuchaschangesincardiacoutput,heartrate,arterialbloodpressure,orurinaryoutput.14 AfluidbolusistheadministrationofalargervolumeofIVfluid(eg, 500mLor1000mL)overarelativelyshortperiod(eg,15minutes),withthegoalofincreasingintravascularvolume.MaintenanceorreplacementfluidistheadministrationofIVfluidatlower ratesoverlongerdurations(eg,hourstodays)withtheaimofprovidingdailyneedsforwater,electrolytes,nutrition,andreplacementofmeasuredlosses(eg,urine,gastrointestinal,drains).CriticallyillpatientsalsoreceivesubstantialvolumesofIVfluidas medicationdiluentorcarrier,forwhichthegoalistofacilitatethe administrationofmedication.Accumulationoffluidadministered isoftenanunintendedadverseeffect.15

AssessmentforFluidTherapy

Overview

AssessingwhetherIVfluidadministrationisindicatedrequiresassessmentofthepatient’smedicalhistory,physicalexamination,laboratoryevaluation,anddiagnosticimaging(ie,chestradiographtoassesspulmonaryedemaorpoint-of-careultrasoundtoassessthe etiologyofshock.Assessmentofintravascularvolumestatusand theexpectedresponsetoIVfluidadministrationcanbechallenging.4 Becausemarkersofhypoperfusion(eg,alteredmentalstatus,low arterialpressure,cutaneousmottling,slowcapillaryrefilltime,low urineoutput,increasedlactate)arenotspecifictohypovolemia,they mustbeconsideredintheclinicalcontextofthepatientandnotas stand-aloneindicationsforfluidtherapy.

AssessmentofFluidResponsiveness

Scientificinvestigationhasdevelopedandvalidatedobjectivemeasurestoanticipateapatient’sphysiologicalresponsetoanIVfluidboluspriortofluidadministration.16-28

Eachmeasureassessescardiac preloadtodistinguishbetweenpatientsforwhomanIVfluidbolus wouldbeanticipatedtoincreasestrokevolume(andcardiacoutput [termed fluidresponsive])frompatientsforwhomanIVfluidbolus wouldnotbeanticipatedtoincreasestrokevolume(andcardiacoutput[termed fluidnonresponsive])beforefluidisadministeredtobe patient.Approximately57%ofpatientswithsepsisarefluidresponsiveatpresentation.29

Patientswithlowvariationinpulsepressure orstrokevolumewhilereceivingcontrolledmechanicalventilationor thosewhodonotincreasecardiacoutputafterapassivelegraising maneuver(Table1)16-26 maybeconsideredasfluidnonresponsive. Thesepatientswouldnotbeexpectedtoincreasecardiacoutputin responsetoafluidbolus.Dynamicmeasurementssuchaspassiveleg raisingorpulsepressurevariation,mayidentifypatientswhoarefluid responsivemoreaccuratelythanstaticmeasurements,suchasmeasurementofcentralvenouspressure.27 Anincreaseincardiacout-

putwithpassivelegraisingidentifiedpatientswhosecardiacoutput wouldincreasewithafluidbolus(positivelikelihoodratio,11[95%CI, 7.6-17];specificity,92%).28 Lackofincreaseincardiacoutputwithpassivelegraisingidentifiedpatientswhosecardiacoutputwouldnotincreasewithafluidbolus(negativelikelihoodratio,0.13[95%CI,0.070.22];sensitivityof88%).28

Foreachmeasureoffluidresponsiveness,therearecircumstancesinwhichthemeasureisnotvalidorreliable(Table1).Technicalandoperator-dependentfactorsmayalsoaffectaccuracyand interpretation.Cliniciansmayselectthemostsuitablemethodto evaluatefluidresponsivenessaccordingtopatientcharacteristics andresourceavailability.Althoughwithholdingfluidtherapyfrom patientsexpectedtobefluidnonresponsiveandadministeringfluid topatientswhoareexpectedtobefluidresponsiveislogical,28 few dataareavailabletoinformwhetherthisapproachimprovespatientoutcomes.Fluidresponsivenessisnot,whenconsideredasan independentfactor,amarkerofneedforfluidtherapyintheabsenceofhypoperfusion.30

RoleofPoint-of-CareUltrasonography

Point-of-careultrasoundreferstoadirectedultrasoundexaminationbythebedsidecliniciantoevaluateforspecificlifethreateningabnormalitiesordiagnosticinformation.Point-of-care ultrasoundcanevaluatetheetiologyofshockandpredictfluidresponsiveness;itfacilitatesiterativeassessmentofcardiacfunction,characterizespreloadresponsiveness(eg,assessmentofstroke volumechangesduringpassivelegraising),andevaluatespatients forcomplicationsoffluidaccumulation(eg,assessingforlung edema31 beforeadministeringfluid).

Evaluatinginferiorvenacavadiametercombinedwithpatternsofvenousflowinliverandkidneysmayidentifytissueedema andinformthedecisiontocontinueortowithholdfluidtherapy.26 Abnormalitiesinflowpatternmaydifferentiatesimplefluidaccumulationfromorgandysfunctioninducedbyincreasedsystemicvenouspressure.Point-of-careultrasoundmaybelimitedbyinteroperatorexperienceandvariability,changesinassessmentbetween spontaneousbreathingandpositivepressureventilation,andother technicallimitations.26

FluidTherapyGoals

Inadditiontofluidtherapydirectedbyfluidresponsiveness,other endpointsforfluidtherapyoverthecourseofcriticalillnesshave beenproposedsuchaslactate,capillaryrefilltime,andcentral venoussaturation( Table2 ). 32-43 Despitesignificantresearch, optimaloutcomesinresponsetofluidtherapyforcriticallyill patientsremainuncertain.Normalizingbloodpressureisnolonger consideredasufficientgoalforresuscitation.Cliniciansshould selectmultipletherapeuticgoalsforeachpatientsuchasnormalizationofcapillaryrefilltime,lactateclearance,andnormalization ofurinaryoutput.27

AdministrationofFluidTherapy

TimingofFluidAdministrationandRemoval

Fluidtherapyforsepsisoccursin4phasesofcriticalillness:resuscitation,optimization,stabilization,andevacuation.10 Eachphase oftherapyisassociatedwithaseparateclinicalstateofthepatient,

Pulmonary arteryocclusion pressure16

Estimatesleft ventricular end-diastolic pressureorleftatrial pressure

5-10cmH2OEnablesmeasuringvascularsystem pressureusingcentrallyplaced venouscatheterstoestimate stressedvolume,definedasthe volumeinthevasculaturethat exertsstretchonvesselwalls Lowvaluesimplypatientsmay increasecardiacoutputandother hemodynamicparameters(eg, bloodpressure)withfluidtherapy

4-12cmH2OEnablesmeasuringvascularsystem pressureusingcentrallyplaced venouscatheterstoestimate stressedvolume,definedasthe volumeinthevasculaturethat exertsstretchonvesselwalls Lowvaluesimplypatientsmay increasecardiacoutputandother hemodynamicparameters(eg, bloodpressure)withfluidtherapy

10%-15%

Pulsepressure(systolicpressure minusdiastolicpressure)a varies normallyduringtherespiratory cycleinpatientsreceiving mechanical(positivepressure) ventilationduetodynamicchanges inintrathoracicpressure

Duringpositivepressure ventilation,alargerdifferencein pulsepressurebetweeninspiration andexpirationareassociatedwith thefollowingevents:

Adecreaseinrightventricular venousreturnleadingtoa decreaseinleftventricularfilling afteralagof2-4heartbeats

Anincreaseincardiacpreload andoutputwithlargepulse pressurevariationinresponseto afluidchallenge

Anisolatedorstaticmeasureof centralvenouspressurealonemay notreflectwhetherapatientwillbe responsivetofluidtherapy

Measuresshouldbe integratedwithadditional clinicalinformationandthe broadercontexttoinformthe valueoffluidtherapy

Anisolatedorstaticmeasureof pulmonaryarteryocclusionpressure alonemaynotreflectwhethera patientwillberesponsiveto fluidtherapy

Measuresshouldbe integratedwithadditional clinicalinformationandthe broadercontexttoinformthe valueoffluidtherapy

Conditionswithwhichpulse pressurevariationmaybealess reliablepredictoroffluid responsiveness:

Spontaneousbreathing (falsepositive)

Cardiacarrhythmias (falsepositive)

Increasedintra-abdominal pressure(falsepositive)

Rightventriculardysfunction (falsepositive)

Lowtidalvolumeorlow compliance(falsenegative)

Pulsepressurevariation

>10%-12%hasasensitivity of88%andaspecificityof 89%forpredictingfluid responsiveness

Pulsepressurevariation

>10%-12%thresholdwould discriminateagreater likelihoodoffluid responsiveness;however, differentthresholdsmaybe usedindifferentconditions

Strokevolume variation20,21b

Indicatesthe dynamicchangein leftventricular strokevolume occurringduring respirationwith mechanical ventilation

End-expiratory occlusiontest22 Indicatesan approximate15-s occlusionofthe endotrachealtubein apatientreceiving mechanical ventilationatend expiration

10%-13%Largedecreasesinstrokevolume betweenexpirationandinspiration (>25%)amongpatientsreceiving positivepressureventilation indicatesdecreasedrightventricular preloadandvenousreturnand identifiespatientswhoaremore likelytoexperienceincreased cardiacpreloadandoutputin responsetoafluidchallenge

Similartopulsepressurevariation, thereareconditionsinwhichstroke volumevariationmaybealess reliablepredictoroffluid responsiveness:

Spontaneousbreathing (falsepositive)

Cardiacarrhythmias (falsepositive)

Increasedintra-abdominal pressure(falsepositive)

Rightventriculardysfunction (falsepositive)

Lowtidalvolumeorlow compliance(falsenegative)

Avalueofstrokevolume variation>12%threshold maybeusedtopredictfluid responsiveness

Performanceissimilartothat ofpulsepressurevariation

Variable

Largeincreasesinpulsepressure (>15%)andcardiacoutput(>12%) followingtheend-expiratory occlusiontestpredictgreater likelihoodofresponsivenesstoa fluidchallenge

Temporarilyaugmentsvenous return,cardiacpreload,andstroke volumeinresponsivepatients, mimickingasafluidchallenge

Likeotherdynamicmaneuversto predictfluidresponsiveness,the end-expiratoryocclusiontest requirespatientstoreceiveinvasive mechanicalventilation

Conditionsinwhichthe end-expiratoryocclusiontestmay belimitedoralessreliable predictoroffluidresponsiveness:

Inabilitytoperforma15-s end-expiratoryocclusiontestin patientswithspontaneoushigh workofbreather

Lowtidalvolumeorlow compliance(falsenegative)

goalsoffluidtherapy,assessmentsperformed,andtheinterventionsdelivered( Figure2 and Table3 ). 32,38,39,42,44-49 These

Achangeinpulsepressure >5%duringthe end-expiratoryocclusiontest isassociatedwithanincrease incardiacoutputwithafluid challengewithasensitivity of87%andaspecificity of100%

phaseshighlightthattheapproachtofluidtherapychangesduring apatient’scriticalillnessandrecovery.Thisconceptualframework

Table1.MeasuresandTestsforIdentifyingWhetheraFluidChallengeIsLikelytoIncreaseCardiacOutput

Table1.MeasuresandTestsforIdentifyingWhetheraFluidChallengeIsLikelytoIncreaseCardiacOutput(continued)

MarkerDefinition

Passiveleg raising20,23 Indicatesadynamic maneuvertoassess forchangesin cardiacpreloadand outputinresponseto rapidrepositioning ofasemirecumbent patienttosupine withbothlegsraised to30°-45°

Normal rangeRationaleCommentsandapplicationApplication

Variable

Largeincreasesinpulsepressureor strokevolume(>10%-15%) followingapassivelegraisingtest predictgreaterlikelihoodoffluid responsiveness

Passivelegraisingcantemporarily augmentvenousreturn,cardiac preload,andstrokevolumein responsivepatients,mimickingas afluidchallenge(≈300mLof autotransfusion)

Unlikeotherdynamicmaneuversto predictfluidresponsiveness,the passivelegraisingtestdoesnot requireapatienttoreceiveinvasive mechanicalventilation

Conditionsinwhichpassiveleg raisingmaynotbefeasibleoris limitedtopredictfluid responsiveness:

Severehypovolemia (falsenegative)

Raisedintra-abdominalpressure (falsenegative)

Inabilitytomobilizeortorapidly changepositioninbed (eg,spinaltrauma)

Diminishedresponsewith concomitantuseofcompression stockings

Maybeinfluencedbyoperator, includingcorrectpassiveleg raisingtechnique,andcardiac outputassessment

Achangeinstrokevolume >9%andpulsepressure>10% duringpassivelegraisingis associatedwithanincreasein cardiacoutputwithafluid challengewithpooled sensitivityof85%anda specificityof91%

Minifluid challenge20,24

Indicatesadynamic maneuverinwhicha smallvolumeoffluid (≈100mL)isgiven rapidlyover≈1min topredictfluid responsiveness

Point-of-care ultrasound25,26 Indicatesadirected ultrasoundfor severalparameters topredictfluid responsivenessand assessfor complicationsof fluidtherapy

VariableLargeincreases(>10%)invelocity timeindex(anestimateofstroke volume)followingarapid100-mL fluidbolus(followedby400mLover 14min)ispredictiveoffluid responsiveness

Unlikeotherdynamicmaneuversto predictfluidresponsiveness,the minidoesnotrequireapatienttobe mechanicallyventilatedorto initiallyreceivealargevolume offluid

Addedconsiderationsinwhichthe minimaybelimited: Notwellvalidated Requiresadministrationof fluidbolus Requirespoint-of-care ultrasoundtomeasurereal-time changeinvelocitytimeindex

Achangeinvelocitytime index>10%inresponsetoa 100-mLfluidchallengeis associatedwithanincreasein cardiacoutputwithafluid challengewithasensitivityof 95%andaspecificityof78%

VariableEstimatesthefollowing parameters: Subaorticvelocitytimeindexas anestimateofstrokevolume Assessesleftventricular end-diastolicvolumeasan estimateofpreload Assessestheinferiorvenacava diameterandvariationin inspiratorycollapsetopredict fluidresponsiveness (orintolerance)

Assesseslungparenchymafor pulmonaryedema(eg,B-lines)to predictfluidintolerance

Abbreviations:PPmax,maximumobserveddifferencebetweensystolicand diastolicpressure;PPmin,minimaldifferencebetweensystolicanddiastolic pressureduringventilatorycycle;SVmax,maximumobserveddifference betweensystolicanddiastolicstrokevolume;SVmin,minimalstrokevolume observedduringventilatorycycle;SVmean,averagestrokevolumeoverthe ventilatorycycle.

beginswithrapidinitialresuscitation,proceedsthroughoptimizationoforganandtissueperfusion,isfollowedbyaphaseofphysiologicstabilization,andendswithaphaseofrecoveryoforgandysfunction,oftencharacterizedbyfacilitatedfluidevacuation.10

Resuscitation

Intheresuscitationphase,thetherapeuticgoalistorapidlyreversehypoperfusion,withorwithouthypotension,administering fluidboluses(andfrequentlyadministeringvasopressors).Prior

Advantages: Noninvasive Enablesserialassessment Enablesassessmentforchanges inresponsetointerventions

Contextsinwhichpoint-of-care ultrasoundmaybelimitedorless reliable:

Operatortrainingforimage acquisitionandinterpretation

Dynamicmeasuressuchas respiratoryvariationininferior venacavadiameterislessreliable inpatientsreceivingmechanical ventilation

Point-of-careultrasoundisa versatiletoolthatcaninform bothfluidresponsivenessand fluidintolerance

a Theformulaforpulsepressurevariation:(PPmax–PPmin)/(PPmax+PPmin)/2.

b Theformulaforstrokevolumevariation(SVmax–SVmin)/(SVmean).

tofluidresuscitation,sepsisdiagnosisandevidenceofhypoperfusionshouldbeestablished.Evidenceofhypoperfusionincludesalteredlevelofconsciousness,lowarterialbloodpressure(typicallydefinedasameanarterialpressure<65mmHg), decreasedurinaryoutput(<0.5mL/kg/h),livedoreticularis,prolongedcapillaryrefilltime( 3seconds),andelevatedserum lactate(>2mmol/L)(Table2).

Assessmentsoffluidresponsivenessanddiagnosticevaluationofthecauseofthehemodynamicabnormalityoccurinthe

Cardiacoutput36 Volumeofbloodpumped bytheheart/min

Whenbloodpressureislow,heartrate increasestoincreasecardiacoutputand deliveryofoxygen

Heartratemayreturntonormalwhen hypovolemiaiscorrected

Meanarterialpressureisanassessmentof perfusionofvitalorgans

Perfusionofvitalorgansdecreaseswithmean arterialpressures<60-65mmHg

5-6L/minCardiacoutputdetermines,inpart,the volumeofoxygendeliveredtoorgansand tissues

Ifcardiacoutputisinsufficienttodeliver adequateoxygentotissues,ischemiaand anaerobicmetabolismoccur

Tachycardiamayresultfromfactorsotherthan hypovolemia(eg,fever)ormaynotoccurwhen hypovolemiaispresent(eg,afterβ-blockerreceipt)

Heartrateisnotasufficientmeasuretoguidefluid therapyformostpatients

Maintainingameanarterialbloodpressure≥65mm Hgisrecommendedformostcriticallyilladultswith sepsis

Alowmeanarterialpressuredoesnotaccurately identifypatientswhosecardiacoutputwillincrease withfluidadministration

Thebalanceofoxygensupplyanddemandismore importantthanabsolutevaluesforcardiacoutput Evenwithsufficientcardiacoutput,disordered microcirculationinsepsismayimpairperfusion RCTshavenotfoundthatincreasingcardiacoutput improvesoutcomesinsepsis

ScvO232,37-39 Hemoglobinsaturationof bloodinthesuperior venacava

70%-80%ScvO2 reflectsthebalancebetweenglobal oxygendeliveryandglobaloxygen consumption

Lowvaluessuggestthatincreasingthe deliveryofoxygentotissuesmaybe beneficial

Centralvenouspressurehasbeenusedasa surrogatemeasureforrightatrialpressure, right-ventricularend-diastolicpressure,and cardiacpreload

RCTsdidfindusingScvO2 toguidetreatmentto improveoutcomesinsepsis

MeasuringScvO2 requiresacentralvenouscatheter

LowvaluesofScvO2 mayidentifypatientswith inadequateoxygendelivery,andhighvaluesmay identifypatientswithimpairedoxygenextraction

Centralvenouspressuredoesnotaccuratelyidentify patientswhowillexperienceanincreaseincardiac outputwithfluidadministration

RCTsdidnotfindusingcentralvenouspressureto guidefluidtherapytoimproveoutcomesinsepsis

Urineoutputisinfluencedbyfactorsotherthan perfusionofthekidney,includingmicrovascular changesandthedevelopmentofacutetubular necrosis

Fluidadministrationthatincreasescardiacoutput andorganperfusionmaynotincreaseurineoutput

Increasedlactatelevelsmayindicate inadequateoxygendeliveryfrominsufficient cardiacoutputorbloodoxygencontent

≤3sCapillaryrefilltimemeasuresperipheral perfusion,reflectscouplingbetweenthe macrocirculationandmicrocirculation,and respondsrapidlytofluidresuscitation

Abbreviations:RCT,randomizedclinicaltrial;ScvO2,centralvenousoxygensaturation.

resuscitationphase.Intheresuscitationphase,fluidtherapyis typicallycontinueduntilthepatient’smeanarterialpressureno longerincreaseswithIVfluidadministration,goalsofresuscitationareattained,thepatient’sconditionisnolongerimmediately lifethreatening,orcomplicationsoffluidtherapyarise(eg,worseninghypoxemia).

EarlyFluidTherapyandEarlyGoal-DirectedTherapy

Evidenceforearlyfluidtherapyimmediatelyaftersepsisdiagnosis islimited.AnRCTof3141children(medianage,2years)presenting withacuteinfectionreportedthat,comparedwithnoIVfluidbolus,themortalitywashigheramongpatientsrandomizedtoreceiveIVfluidbolusesofeither0.9%salineoralbumin.Mortalityrates were12.0%withalbumin,12.2%with0.9%saline,and8.7%for thosewhoreceivednoIVfluid(P =.004).44 Anadministrativedata analysisreportedthatadherencetoa3-hourbundleofsepsismanagement(bloodcultures,antibiotics,andlactatemeasurement)was

Elevatedlactatelevelsinsepsisfrequentlyoccur despiteadequateoxygendeliverytotissues

Althoughdecreasinglactateidentifiespatientslikely toexperiencebetteroutcomes,RCTsdidnotfind usinglactateclearancetoguideresuscitation improvedoutcomesinsepsis

Capillaryrefilltimeisaninexpensiveanduniversally availabletestofperipheralperfusion

AnRCTfoundoutcomesofsepsistobeatleastas goodwithuseofcapillaryrefilltimecomparedwith lactateclearancetoguidefluidtherapy

associatedwithlowermortality(among49331patients,thelonger thetimetocompletethe3-hourbundle,thehigherthein-hospital mortality;oddsratio,1.04perhour[95%CI,1.02-1.05]; P <.001); however, timecompletionofinitialfluidboluswasnotassociated withlowermortality(oddsratio,1.01perhour[95%CI,0.99-1.02]; P =.21).50

OptimalfluidtherapyintheresuscitationphasehasbeeninformedbyRCTstodefineearlygoal-directedtherapy(EGDT).EGDT isdefinedbyaspecificapproachtomanagingsepsis-inducedhypoperfusion,whichincludesadministeringIVfluidbolusestoachieve acentralvenouspressureof8to12mmHg,vasopressorstoachieve ameanarterialbloodpressureof65to90mmHg,andredblood celltransfusionsand/orinotropestoachieveacentralvenousoxygensaturationofatleast70%.32,37-39

InanRCTof263patientswithsepsis-inducedhypoperfusion inanurbanemergencydepartment,26 comparedwithacontrol group,EGDTreducedhospitalmortality(30.5%vs46.5%; P =.009).

Table2.SummaryofMeasurestoGuideFluidTherapyinPatientsWithSepsis

However,inan individualpatient-levelmeta-analysisthatcombinedresultsfrom3subsequentinternationalRCTs(3723patients in138hospitals)ofpatientswhoalreadyreceivedinitialfluids,EGDT wasnotassociatedwithimproved90-daymortalitycomparedwith usualcare(EGDT,24.9%vsusualcare,25.4%; P =.68).51 Itremains unclearwhethercarebundlesthatincludefluidtherapyandother sepsisinterventionsimproveoutcomes.33,50,52,53

Anopen-labelRCTcomparedrestrictivevsliberalfluidtherapy among1563patientswithsepsis-inducedhypotensionwhohadreceivedanaverageof2Loffluidpriortoenrollment.47 Intherestrictivegroup,hypotensionwastreatedwithvasopressors,andadditionalfluidwasadministeredonlyforselectindications.Intheliberal group,hypotensionwastreatedwithfluidadministration,andvasopressorswereadministeredonlyforselectindications.ThemedianvolumeofIVfluidreceivedinthefirst24hourswas1.2Linthe restrictivegroupand3.4Lintheliberalgroup.All-causemortality beforedischargehomebyday90didnotsignificantlydifferbetweentherestrictivefluidgroup(14.0%)andtheliberalfluidgroup (14.9%)(P =.61).47

RCTsinlow-andmiddle-incomecountriescomparedadministrationofIVfluidvsnofluidforacutelyillchildrenandadultspresentingwithhypoperfusionfrominfection.AnRCTof209adults withsepsisinZambiareportedsignificantlyhighermortalityin patientsrandomizedtoreceiveIVfluidvsvasopressorsaspartof anEGDTprotocolcomparedwithusualcare(48.1%vs33.0%) (P =.03).45

AnRCTof424patientswithearlysepticshockin5 countries(Argentina,Chile,Colombia,Ecuador,andUruguay)that compareduseoflactatelevelsvscapillaryrefilltimetoguidefluid therapyfoundnostatisticallysignificantdifferenceinmortalityby day28betweenthe2groups(34.9%inthecapillaryrefilltime groupvs43.4%inthelactateclearancegroup(P =.06).42 However,asecondarybayesiananalysissuggestedprobablebenefitfor capillaryrefilltime–guidedresuscitation(oddsratiofor28-daymortality,0.65[95%credibleinterval,0.43-0.96];98%probabilityof benefit).43

Together,theseresultssuggestthat,forpatientswithsepsiswho havereceived1to3Loffluid,earlygoal-directedtherapytargeting centralvenouspressure,meanarterialpressure,andcentralvenous oxygensaturationmaynotimproveoutcomesandthatoutcomesmay besimilarbetweenanapproachthatprioritizesadditionalfluidadministrationandonethatprioritizesuseofvasopressors.

OptimizationandStabilizationPhases

Theoptimizationphasehasthegoalofattainingperfusionto organsandtissues,andthestabilizationphasehasthegoalof maintaininghomeostasisandfacilitatingorgandysfunctionresolution.FewRCTshavestudiedfluidtherapyduringthesephases.The CLASSICtrial46 comparedrestrictivevsstandardfluidmanagement followinginitialresuscitationin1554criticallyilladults.Investigatorshypothesizedthatamorerestrictiveapproach,withfluid boluseslimitedtopatientswithmarkersofseverehypoperfusion, wouldimprove90-daymortalitybyavoidingunnecessaryfluid accumulation.Therestrictivestrategy,inwhichfluidboluseswere allowedonlyforlactatelevelabove4mmol/L,meanarterialpressurebelow50mmHg,mottlingbeyondtheedgeofthekneecap, ordiuresisoflessthan0.1mL/kg/hourduringfirst2hoursafterrandomization,resultedin1627mLlessIVfluidadministrationthrough day5ofICUadmissioncomparedwiththeliberalgroup,inwhich

Figure2.TimingofFluidAdministrationandRemoval

Critically ill with sepsis

1

Resuscitation - Administer fluids to reverse hypoperfusion

Establish diagnosis of sepsis and hypoperfusion. Administer initial fluid boluses. Administer vasopressors if necessary (eg, norepinephrine, vasopressin). Assess responsivenss to fluids and treat infection.

Optimization - Establish perfusion to organs and tissues

2 Consider risks and benefits of additional fluid administration based on responsiveness to fluids and signs of hypoperfusion. Titrate vasopressors and inotropes for specific hemodynamic targets (eg, lactate, capillary refill time).

3

Stabilization - Maintain perfusion

Monitor for fluid overload and associated organ dysfunction. Assess and treat any organ dysfunction. Consider a restrictive approach that limits additional fluids. Monitor capillary refill time, lactate, and other perfusion markers.

4 Consider removal of excess fluid accumulated during critical illness using diuresis or kidney replacement therapy if indicated. Initiate early rehabilitation, mobilization, and nutrition plans.

Evacuation - Facilitate recovery and removal of excess fluid

Discharge from hospital

Stepsindicatefluidtherapyacrosstheconceptualphasesofcriticalillness. Patientsmayprogresslinearlythroughthe4phasesormaymovebackand forthbetweenphases.

fluidwasadministeredaslongaspatientsexperiencedhemodynamicimprovement.At90-dayfollow-up,mortalitydidnotdiffer betweengroups(restrictive[42.3%]vsstandard[42.1%]; P =.96). Secondaryoutcomes,includingkidneyinjury;cerebral,myocardial, intestinal,orlimbischemia;andnumberofdaysaliveandoutofthe hospitalweresimilarbetweengroups.Variabilitybetweenthetrials inthedefinitionsofrestrictiveorliberalfluidmanagement,markers ofhypoperfusion,andtheindicationsforfluidtherapymadeitdifficulttodevelopasinglebestapproachtofluidtherapyamong patientswithcriticalillness.Areasonableapproachistolimitfluid administrationtopatients’objectivemarkersofhypoperfusionand fluidresponsiveness.27

Evacuation

Evacuationisthelastphaseoffluidtherapy.Criticallyilladultswith sepsismayexperienceedemaandorganfailureduetoexcessaccumulationoffluidsadministeredduringcriticalillness15 andreduced capacityforfluidelimination(eg,duetoacutekidneyinjury).Daily documentationoffluidintake,output,balance,andweights,andsettingspecificgoalsforfluidmanagementmayhelpcliniciansprevent adverseoutcomesduetofluidaccumulationsuchasacutekidneyinjury,abdominalcompartmentsyndrome,andmortality.12,13 Duringrecoveryfromcriticalillness,patientsmayspontaneouslyexcreteexcessaccumulatedfluid.Forsomepatients,facilitatingfluidremoval

POTENTIAL REGRESSION THROUGH PHASES

Trialsourceby phaseoftherapy considered Population andlocationSettingHypothesisFluidmanagementResultsImplications Resuscitationphase

FEAST Maitlandetal,44 2011

3141Children withsevere febrileillness

6Centers:Kenya (1),Tanzania(1), Uganda(4)

Fluidbolus wouldimprove 48-hmortality

Intervention1

Administering 20mL/kgof0.9% salinein1h

Intervention2

Administering 20mL/kgof5% albuminin1h

Control

Nobolus

Additionalbolusallowed ininterventiongroups

Higher48-hmortality withanyfluidbolus (relativerisk,1.45 [95%CI,1.13-1.86]; P =.003)

Cardiovascularcollapse wasthemostcommon mortalitycause

Inaspecificpopulation, fluidbolusincreasedshort termmortality

ProCESS

Yealyetal,32 2014

1351Patients withsepsisand hypotension refractoryto ≥1000mLof initialbolus

31Hospitalsin theUnitedStates

EGDTwould improve in-hospital mortality truncatedat60d

Intervention1

TraditionalEGDT(asin Bentzeretal28);fluid givenin500-mLbolus untilcentralvenous pressureis>8mmHg

Intervention2

500-to1000-mLfluid bolusuntilsystolic bloodpressureis >100mmHg,orshock indexis<0.8orsignsof fluidoverload

Control

Fluidtherapyasper clinician’sdiscretion untilsignsoffluid overload

Medianfluiduseof2.8L inEGDTgroup,3.3Lin modified(protocol-based) group,and2.3Lincontrol groupinthefirst6h Mortalitywassimilarin protocolizedgroupswhen comparedwithstandard ofcare(relativerisk,1.04 [95%CI,0.82-1.31]; P =.83)

PatientsintheEGDT groupweremore frequentlyadmittedto theICU

Thistrialdidnotsupport EGDToramodifiedEGDT approachinsepsispatients andcouldnotconfirm previousresults

ProMISe

Mounceyetal,38

2015

1260Patients withsepsis,signs ofsystemic inflammatory response syndrome,and refractory hypotensionto initial1000-mL fluidboluses

56Hospitalsin England

EGDTwould reduce90-d mortality

Intervention

TraditionalEGDT(asin Bentzeretal28);fluid givenin500mLover 20-minbolusuntil centralvenouspressure is>8mmHg Control

Fluidtherapyasper clinician’sdiscretion untilsignsoffluid overload

Medianfluiduseof1750 mLinEGDTgroup,1500 mLincontrolgroupinthe first6h

Nofounddifferencesin outcomewithEGDT (relativerisk,1.01 [95%CI,0.85-1.20]; P =.90)

Thistrialcouldnotfinda benefitofEGDTtherapy

ARISE Peakeetal,39 2014

1600Patients withsepsis definedas ProCESS

51Hospitals: Australia(42), Finland(2), HongKong(3), Ireland(1), NewZealand(3)

EGDTwould reduce90-d mortality

Intervention

TraditionalEGDT(asin Bentzeretal28);fluid givenin500-mLbolus untilcentralvenous pressureis>8mmHgor >12mmHgifpatientis onnoninvasiveor invasiveventilation Control

Fluidtherapyasper clinician’sdiscretion

throughpharmacologic(eg,diuretics)ormechanical(eg,kidneyreplacementtherapy)approachesmaybenecessary.

Aclinicaltrialof1000mechanicallyventilatedpatientswith acutelunginjuryfollowinginitialresuscitation48 reportedthatwhen comparedwithconservativefluidmanagement,liberalfluidmanagementincreasedfluidaccumulationbyapproximately7Lover7 days(P <.001),buttherewasnosignificantdifferenceinmortality betweenthe2groups(conservative[25.5%]vsliberal[28.4%]; P =.30).Patientsintheconservativefluidmanagementgrouphad

Meanfluiduseinthefirst6 hwasslightlyhigherin EGDTthancontrolgroups (1964vs1713mL)

Thistrialdidnotfindaclear benefitofEGDT,butall patientsusedfluidsbefore enrollment

moredaysalive(mean[SD]14.6[0.5]daysvs12.1[0.5]daysforthe liberalgroup; P <.001)andwerefreeofmechanicalventilationat 60days,andtheyhadmoredaysnotspentintheICUat60days (13.4[0.4]daysvs11.2[0.4]daysfortheliberalgroup; P <.001).The GODIFtrialcomparedfurosemidetitrationtoattainanetnegative fluidbalancewithstandardofcare.49 Theclinicaltrialwasstopped earlyduetoimprecisefluidbalanceassessment,underscoringchallengesintestingthisscientificquestion.Theprotocolwasaltered, andasecondphaseofthetrialwascontinued.

Table3.SummaryofRandomizedClinicalTrialsofFluidTherapyinCriticalIllnessAccordingtoResuscitationPhases andTheirImplicationsforPractice

Trialsourceby phaseoftherapy considered Population

Simplified SevereSepsis Protocol2 Andrewsetal,45 2017

209Adult patientswith sepsisand hypotension

Resuscitation+optimizationphases

ANDROMEDASHOCK

Hernández etal,42 2019

424Patients withearlyseptic shock Septicshockwas definedas suspectedor confirmed infection,plus hyperlactatemia (≥2.0mmol/L) and requirementsof vasopressorsto maintainamean arterialpressure of65mmHg afteran intravenous fluidloadof ≥20mL/kgover 60min

1Centerin Zambia AnEGDTina resourceconstrained scenariowould improve outcomes

Intervention 2.0LBolusin1h followedbyadditional ≤2.0Lover4h;fluids withheldifarterial oxygensaturation decreasedby3%or respiratoryrate increasedby5or jugularvenouspressure reached3cmorabove thesternalangle

Control

Usualcare

Interventiongroup received3.5L (IQR,2.7-4.0L)vs2.0L (IQR,1.0-2.5L)inthe controlgroup

Hospitalmortalitywas higherinintervention group(relativerisk,1.46 [95%CI,1.04-2.05]; P =.03)

Amoreaggressivefluid resuscitationstrategywith bluntlimitsforfluidloading resultsinworseoutcomes inthispopulation

26ICUsin

Argentina,Chile, Colombia, Ecuador, Uruguay

Capillaryrefill time–guided therapywould improve outcomesin patientswith septicshock (28-dmortality)

Forbothgroups,fluid boluseswereonlyusedif signsofpreload responsivenessusing dynamicparameters suggestedpatientswere fluidresponsive Atleast57%ofall patientswerefluid responsiveatenrollment; theprotocolalsoincluded vasopressorandinodilator testuseforsome scenarios31

Thecapillaryrefill-guided groupreceived2359mL vs2767mLinthecontrol (lactateclearance)group Survivalatday28was similarbetweengroups (hazardratio,0.75 [95%CI,0.55-1.02]; P =.06),althougha bayesianreanalysis suggestedahigh probabilityofoverall benefit43

Capillaryrefilltime–guided therapymightbesuperiorto lactate-guidedtherapyand mayresultinloweramounts offluidbeingused

Resuscitation+optimization+stabilizationphases

CLASSIC Meyhoffetal,46 2022

1554Patients withsepticshock (sepsis,lactate >2mmol/L,need forvasopressors with≥1Lof fluiduse)

31ICUsin Belgium,the CzechRepublic, Denmark,Italy, Norway,Sweden, Switzerland, UnitedKingdom

Arestrictive fluidtherapy approachwould beassociated with7%lower 90-dmortality comparedwith standardcare

Restrictivegroup

Fluidgivenonlyif severehypoperfusion (lactate>4mmol/L, meanarterialpressure <50mmHg,mottling beyondtheedgeofthe kneecap,diuresisof <0.1mL/kg/hduring first2hafter randomizationwas present(recommended bolusof250-500mL); fluidstoreplenish losseswereallowed

Standardgroup

Fluidprescribedwhile patientsimprovedwith fluidchallenges

Fluidstrategieswere appliedfor≤90dafter enrollment

ResultsofRCTshavebeenconflictingregardingkidneyreplacementtherapyforremovingexcessfluid.Ina231-patientsinglecenterRCT,mortalitywaslowerwithearlykidneyreplacement therapy(39.3%)vswithlatekidneyreplacementtherapy(54.7%) at90-dayfollow-up(P =.03).54

Inthistrial,earlykidneyreplacementtherapywasdefinedaskidneyreplacementtherapyinitiated ifurinaryoutputwaslessthan0.5mL/kg/hourforatleast12hours oriftherewasa2-foldincreaseinserumcreatininelevelcompared withbaseline.Latekidneyreplacementtherapywasdefinedasini-

Bothgroupsreceived approximately3Lof fluidsbeforeenrollment

Medianintravenousfluid useatday5after enrollmentwas1450mL intherestrictivevs3077 mLinthestandardgroup

Thetrialhadneutral resultsfor90-dmortality (relativerisk,1.00 [95%CI0.89-1.13])

Arestrictivestrategywas notsuperiortoastandard fluidregimeninthislarge multicentertrial

tiatingtherapyonlywhenurinaryoutputwaslessthan0.3mL/kg/ hourforatleast24hoursand/oragreaterthan3-foldincreaseinserumcreatininelevelcomparedwithbaselineoraserumcreatinine levelofgreaterthanorequalto4mg/dLand/orwithanacuteincreaseofatleast0.5mg/dLwithin48hoursorurgencyforkidney replacementtherapysuchasrefractoryhypervolemiaorhyperkalemiaamongothers(54.7%; P =.03at90-dayfollow-up).54

However,theseresultswerenotconfirmedin3largermulticentertrials. 55-58 IntheAKIKItrial(620patientsincluding484

Table3.SummaryofRandomizedClinicalTrialsofFluidTherapyinCriticalIllnessAccordingtoResuscitationPhases andTheirImplicationsforPractice(continued)

Trialsourceby phaseoftherapy considered Population andlocationSettingHypothesisFluidmanagementResultsImplications

CLOVERS

Shapiroetal,47 2023

1563Patients with sepsis-induced hypotension despitereceiving 1-3Lof intravenousfluid

60Centersinthe UnitedStates Arestrictivefluid therapywouldbe associatedwith lower90-d mortality

Restrictivegroup

Maintenancefluids discontinued,no furtherfluidboluses administeredexceptfor selectindications, vasopressors administeredfor hypotension

Liberalgroup

2Lofadditional boluseswere administeredwithuse ofvasopressorsonlyif selectwerecriteriamet

Medianvolumeoffluidin the24hafterenrollment was1.2Linthe conservativegroupand 3.4Lintheliberalgroup (difference,−2.1L)

Trialwashaltedforfutility

Deathbyday90didnot differbetweenthe restrictive(14.0%)and liberal(14.9%)groups

Nosecondaryoutcomes differedbetweengroups

Forpatientswithsepsisand continuedhypotensionafter 1-2Lofintravenousfluid, anapproachthatlimitsfluid andprioritizesvasopressors andanapproachthat prioritizesadditionalfluid administrationproduced similarpatientoutcomes

Evacuationphase

FACTT

Wiedemann etal,48 2006

1000patients receiving mechanical ventilationwith acutelunginjury

20Centersinthe UnitedStates andCanada

Aconservative fluidstrategy wouldimprove 60-dmortality

Liberal Staticpreload measurements(central venouspressureor pulmonaryartery occlusionpressure) werekeptathigher values

Conservative Lowervaluesofstatic preloadmeasurements weretriggersfor furosemideuse

Forbothgroups, furosemidewastitratedto achieveintravascular pressuregoals

Furosemidewasnotused ifpatientswerebeing treatedwithvasopressors orhadpoortissue perfusion

Patientsinthe conservativegrouphada neutralfluidbalanceat day7,whilepatientsin theliberalgroupwereon averageapproximately7L positive

Mortalityatday60was notsignificantlydifferent betweenfluid managementstrategies

Theconservativestrategy wasassociatedwithan increaseinthemean(SD) numberofventilator-free days(14.6[0.5]vs12.1 [0.5]; P <.001)and ICU-freedays(13.4[0.4] vs11.2[0.4]; P <.001)

Therewasnoincreasein receiptofkidney replacementtherapy

Thiswasthefirsttrialto showanimprovementin respiratoryorgan dysfunctionwithaclinically relevantendpoint

Aneutralfluidbalancewas achievedwithoutan increaseinotherorgan dysfunctionsincluding shockorreceiptofkidney replacementtherapy

GODIF Wichmann etal,49 2023

Second version ongoing

Recruitment followsona secondprotocol version;includes patientswith fluid accumulation assessedbynet fluidbalance accordingto weightatthe timeof enrollment

Firstprotocol versionwas haltedafter41 patientsof1000 plannedat3ICUs inDenmark

Furosemidewill increasedays aliveanddays outsidethe hospitalat90d

Placebovsfurosemide infusiontoobtain negativefluidbalance towardneutralizationof positivefluidbalance

Firstversionhaltedat41 patientsduetoprotocol violationsdueto perceivedimprecisionin recordingoffluidbalances

Updatedtrialisenrolling patients

Thesecondprotocolversion isongoing

patientswithsepsis),60-daymortalitywasnotdifferentbetweenearlyvsdelayedkidneyreplacementtreatment(48.5%vs 49.7%; P =.79).55 IntheIDEAL-ICUtrial(488patientswithsepsis)mortalitywas58%intheearly-strategygroupvs54%inthe delayed-strategygroupat90days(P =.38).56 IntheSTARRT-AKI internationalRCT(3019patientswithacutekidneyinjuryof whom57.7%hadsepsis),90-daymortalitywas43.9%inthe early(accelerated-strategy)groupand43.7%inthestandardstrategygroup( P =.92). 57 Kidneyreplacementtherapyamong survivorswashigherintheaccelerated-strategygroup(10.4% vs6.0%).

Insummary,amongpatientswithoutacuterespiratorydistresssyndrome,RCTsdidnotsupportearly(oraccelerated)kidneyreplacementtherapytoremovefluid.Furthermore,bothslow

(netultrafiltration<1mL/kg/hour)andrapid(netultrafiltration >1.75mL/kg/hour)fluidremovalwithkidneyreplacementtherapy, comparedwithmoderate-ratefluidremoval(1.01-1.75mL/kg/ hour),maybeassociatedwithhighermortalityandlongerduration ofkidneyreplacementtherapy.59 Theoptimalrateanddurationof fluidremovalbykidneyreplacementtherapyduringthelaterphases ofcriticalillnessremainsunclear.

SelectingFluidType

IVfluidsolutionsmaybeclassifiedascrystalloidsolutions(whichcontainwaterandelectrolytes)orcolloidsolutions(whichcontainwater,electrolytes,andalargercompound).Themostcommoncrystalloidsolutionsare0.9%sodiumchloride(saline)andbalancedor bufferedcrystalloidsolutions,suchasRingerlactate.

Table3.SummaryofRandomizedClinicalTrialsofFluidTherapyinCriticalIllnessAccordingtoResuscitationPhases andTheirImplicationsforPractice(continued)

Abbreviations:EGDT,earlygoal-directedtherapy;ICU,intensivecareunit.

CrystalloidSolutions

Twoclassesofisotoniccrystalloidsolutionsexist:0.9%sodiumchloride(saline)andbalancedcrystalloidsolutions,inwhichchlorideis replacedwithabuffersuchaslactate,gluconate,oracetatetopreventhyperchloremicmetabolicacidosis.Multiplelarge,internationalRCTshavecomparedbalancedsolutionsvssalineforfluidresuscitationincriticallyillpatients.60-63

Among2278ICUpatientsin theSPLITtrial(ofwhomonly77hadsepsis),acutekidneyinjuryoccurredin9.6%ofpatientsinthebalancedcrystalloidgroupand9.2% ofpatientsinthe0.9%salinegroup(P =.77).60

Among15802criticallyilladultsatasingleacademicinstitutionintheSMARTtrial,61 ratesofdeath,kidneyreplacementtherapy,orpersistentkidneydysfunctionwas14.3%inthebalancedcrystalloidgroupvs15.4%inthe 0.9%salinegroup(P =.04).InasecondaryanalysisoftheSMART trialamongthe1641patientswithsepsis,64 30-dayin-hospitalmortalitywas26.3%inthebalancedcrystalloidsgroupand31.2%inthe 0.9%salinegroup(P =.01).64

Among10520criticallyilladultsin theBaSICStrial,therewasnodifferencein90-daymortalitybetweenpatientsrandomizedtoreceivebalancedcrystalloidsolution(26.4%)andpatientsrandomizedtoreceive0.9%saline(27.2%) (adjustedhazardratio,0.97[95%CI,0.90-1.05]),and90-daymortalityamongpatientswithsepsiswas46.7%inthebalancedcrystalloidsgroupand49%inthesalinegroup.62 Among5037criticallyilladultsinthePLUStrial,therewasnodifferencein90-day mortalitybetweenpatientsinthebalancedcrystalloidsgroupand patientsinthe0.9%salinegroup(21.8%vs22.0%;difference,−0.2 percentagepoints[95%CI,−3.6to3.3]).63 Amongpatientswithsepsis,mortalityat90dayswasnotsignificantlydifferentbetweenthe balancedcrystalloidandsalinegroups.

Ameta-analysisof34450patientsin6low-riskofbiasRCTsreportedinafrequentistanalysisthattherelativeriskfor90-daymortalitywas0.96(95%CI,0.91-1.01)forbalancedsolutionscomparedwithsaline.65 Inbayesiananalysis,theprobabilitythatbalanced crystalloidsdecreasedmortalitycomparedwithsalinewas89.5%. Among6754patientswithsepsisfrom5RCTs,therewasnodifferenceinmortalitybetweenabalancedcrystalloidgroupandasaline group(31.3%vs33.9%;relativerisk,0.93[95%CI,0.86-1.01]).65 In apreplannedsubgroupanalysis(BASICStrial),balancedcrystalloidsincreasedmortalityin483patientswithtraumaticbraininjury(oddsratio,1.48;95%credibleinterval,1.04-2.09).66 Itisconceivablethatbalancedcrystalloidsolutionsattainoutcomesthatare atleastasgoodasforsalineinpatientswithsepsis.

ColloidSolutions

HumanalbuministhemostfrequentlyusedcolloidinICUsettings. AnRCTof6997criticallyillpatientsthatincluded1218patientswith sepsisreportedthatcomparedwithsaline,albumindidnotreduce mortality(20.7%foralbuminvs20.8%forsaline; P =.87).67 Resultsformortalityweresimilarinthesubgroupofpatientswithsepsis(30.7%foralbuminvs35.3%forsaline; P =.09).AnRCTof1818 ICUpatientswithsepsisfoundthatmortalityat28-dayfollow-upwas notsignificantlydifferentbetweenpatientswhoreceivedalbumin (31.8%)comparedwithpatientswhoreceivedcrystalloidsolutions (32.0%)(P =.94).68 Theroleofalbumininsepsistreatment,ifany, ispresentlyunclear.

InmultipleRCTs,semisyntheticcolloidsolutionssuchashydroxyethylstarchwereassociatedwithincreasedratesofacutekidneyinjury,kidneyreplacementtherapy,anddeathinpatientswith

Box.CommonQuestionsRegardingFluidTherapy forCriticallyIllPatientsWithSepsis

WhenShouldFluidTherapyBeConsideredforPatientsWithSepsis? Fluidtherapyshouldbeinitiatedforpatientswithevidenceof sepsis-inducedhypoperfusion(alteredmentalstatus,lowarterial bloodpressure,reducedurinaryoutput,abnormalcapillaryrefill time)whoarelikelytohaveincreasedcardiacoutputwithfluid administration.Fluidadministrationshouldbediscontinuedwhen evidenceofhypoperfusionresolves,thepatientnolonger respondstofluid,orthepatientshowsevidenceoffluidoverload.

WhatTypeofFluidShouldBeUsed?

Balancedsolutions(eg,Ringerlactate,Ringeracetate,Plasma Lyte)shouldbeselectedover0.9%salineforfluidtherapyin patientswithsepsis.Hydroxyethylstarchesshouldnotbeusedfor patientswithsepsis.

WhenShouldFluidRemovalBeConsidered,andHowShouldFluid BeRemoved?

Fluidremovalshouldbeconsideredaftertheresuscitationand optimizationphasesandwhenapatienthasstabilized (eg,decreasingvasopressordoses,adequateperipheral perfusion).Diureticsarefirst-linetherapytofacilitateelimination offluid.Kidneyreplacementtherapymaybeconsideredfor patientswithsevereacutekidneyinjurywhohavecomplications fromfluidoverloadareunresponsivetodiuretictherapy.

sepsis.69-71 InanRCTof537patientswithsepsis,comparedwithcrystalloidtherapy(lactatedRinger),hydroxyethylstarchincreasedthe incidenceofacutekidneyinjury(22.8%vs34.9%; P =.002).69 In anRCTof804patientswithsepsisorsepticshock,comparedwith Ringeracetate,hydroxyethylstarchincreasedmortalityat90days (51%vs43%; P =.03).70 InanRCTof7000ICUpatients,comparedwithsaline,hydroxyethylstarchsignificantlyincreasedneed forkidneyreplacementtherapy(7.0%vs 5.8%; P =.04)71;inthesubgroupof1921patientswithsepsisinthistrial,comparedwithsaline,hydroxyethylstarchdidnotincreasemortality(25.4%mortalityforhydroxyethylstarchand23.7%forsaline;riskratio,1.07 [95%CI,0.92-1.25]; P =.38).71 Insummary,hydroxyethylstarch shouldnotbeadministeredtopatientswithsepsis.

InfusionRate

Asystematicreviewthatincluded3601patientsin85studiesreportedthatarapidinfusionrate(<30minutes)wasassociatedwith higherprobabilityofincreasingstrokevolumeorcardiacoutputinresponsetofluidadministration,likelybymoreeffectivelyincreasing venousreturnandpreload.72 Thevolumeoffluidusewaslessthan 500mLin12.7%ofthetrials,500mLin79.4%ofthestudies,and morethan500mLin7.9%ofthereports.AnRCTinvolving10520 criticallyillpatientsrequiringIVfluidtherapycomparedinfusionata slowerrate(333mL/hour)vsafasterrate(999mL/hour).73 Mortalityrateswere26.6%inthegroupthatreceivedaslowerinfusionand 27.0%inthefasterinfusiongroup(P =.46).Inaposthocanalysis, fasterinfusionrateswereassociatedwithbenefitinasubgroupthat includedpatientswithsepsis(oddsratioformortality,0.72[95%credibleinterval,0.54-0.91];probabilityofbenefit>0.99).74 Theeffects ofdifferentinfusionratesonoutcomesincriticallyillpatientswithsepsisremainunclear.75

ApplyingEvidence,Uncertainties, andFutureDirections

Whentreatingapatientwithsepsis,cliniciansmustevaluatebenefitsandrisksoffluidtherapyineachphaseofcriticalillness(Box). Decisionsregardingfluidmanagementrequireconsiderationofthe patient’sacuteconditionsandchroniccomorbiditiesthatmayinfluencemeasuresoffluidresponsiveness(eg,rightventricularfailure)orthepatient’sabilitytoreceivefluidwithoutdevelopingcomplicationsfromfluidtherapy(eg,end-stagekidneydisease) 76 (Table1).Informationaboutthepatient’sconditionshouldbeintegratedwithevidencethatinformswhichfluidtherapiesimprovepatientoutcomes.

Basedoncurrentevidence,criticallyillpatientswithsepsisshould typicallyreceivefluidastherapyforexpansion,maintenance,ormedicationadministration.AdministrationofadditionalIVfluidandthe amountoffluidtoadministershouldbebasedonmedicalhistory, physicalexamination,laboratorystudies,andimagingalongwiththe patient’sphaseofillnessandmeasuresoffluidresponsiveness.Effects offluidrestrictionhaverangedfrombenefit(eg,shorterduration ofventilationinacuterespiratorydistresssyndrome),tonoeffect (eg,noevidenceofeffectonmortalityinsepsis-inducedhypoten-

ARTICLEINFORMATION

AcceptedforPublication: May7,2023.

ConflictofInterestDisclosures: DrZampieri reportedotherfromBaxterHospitalar(provisionof fluidsandlogisticsfortheBaSICStrial)duringthe conductofthestudy;personalfeesfrom Bactiguard(statisticalconsulting)andBaxter (advisoryboard);grantsfromIonisPharmaceuticals (tohisinstitutionforinvestigatorinitiatedtrials) outsidethesubmittedwork;andservingaslead investigatoroftheBaSICStrial.DrBagshaw reportedpersonalfees(advisoryboard)from Baxterduringtheconductofthestudy;personal feesfromBioPorto(fundingforclinical adjudication)andNovartis(advisoryboard)outside thesubmittedwork;andservingaslead investigatoroftheSTARRT-AKItrial.DrSemler reportedgrantsfromtheNationalHeartLungand BloodInstitute(K23HL143053)andpersonalfees fromBaxterInternational(advisoryboard)during theconductofthestudy;personalfeesfromAerpio Pharmaceuticals(datasafetymonitoringboard member)outsidethesubmittedwork;andserving asleadinvestigatoroftheSMARTtrialandas co-investigatoroftheCLOVERStrial.

Submissions: Weencourageauthorstosubmit papersforconsiderationasaReview.Please contactMaryMcGraeMcDermott,MD,at mdm608@northwestern.edu

REFERENCES

1.VincentJL,MarshallJC,Namendys-SilvaSA, etal;ICONInvestigators.Assessmentofthe worldwideburdenofcriticalillness:theintensive careovernations(ICON)audit. LancetRespirMed 2014;2(5):380-386.doi:10.1016/S2213-2600(14) 70061-X

2.MachadoFR,CavalcantiAB,BozzaFA,etal; SPREADInvestigators;LatinAmericanSepsis InstituteNetwork.Theepidemiologyofsepsisin Brazilianintensivecareunits(theSepsis

sion),toharm(eg,abdominalcompartmentsyndrome).BalancedcrystalloidsareareasonableinitialIVfluidforpatientswithsepsis,butbalancedcrystalloidsshouldbeavoidedinpatientswithtraumaticbrain injury.Hydroxyethylstarch,asemisyntheticcolloidsolution,should beavoidedinpatientswithsepsis.

Limitations

Thisreviewhasseverallimitations.First,theliteraturesearchmay havemissedsomerelevantresearcharticles.Second,qualityofincludedarticleswasnotformallyevaluated.Third,thetrialsreviewedwereheterogeneousandseveraldefinitionssuchas restrictive, liberal,and early mayimpairinterpretationoftheresults.

Conclusion

Fluidtherapyisanimportantcomponentoftreatingpatientswho arecriticallyillwithsepsis.Althoughoptimalfluidmanagementin patientswithsepsisremainsuncertain,cliniciansshouldconsiderthe risksandbenefitsoffluidadministrationineachphaseofcriticalillness,avoiduseofhydroxyethylstarch,andfacilitatefluidremoval forpatientsrecoveringfromacuterespiratorydistresssyndrome.

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