update in the management of sepsis - …thececonsultants.com/images/2little_sepsis.pdf · update in...

UpdateintheManagementofSepsisNATHANIELLITTLE,MD

UNIVERSITYOFCOLORADO

DIVISIONOFPULMONARYSCIENCES&CRITICALCAREMEDICINE

DisclosureIhavenoactualorpotentialconflictofinterestinrelationtothispresentation.

Objectives

Explore Explorecurrentcontroversiesinthemanagementofsepsisandsepticshock

Review Reviewemergingliteraturesurroundingsepsismanagement

Identify Identifythescientificrationalebehindcoresepsisbundlecomponentsandassesthecontributionofeachcomponenttooverallclinicaleffect

Understand Understandrecentrefinementsinthedefinitionofsepsis-relatedclinicalentitiesandprognosticationtools

ClinicalCase66year-oldLebanesewomanwithhistoryofmigraines,HTN,GERD,DM2,diastolicHF,OSApresentstotheEDwithcomplaintsofalteredmentalstatusandnausea/vomiting

-usualstateofhealthwithexceptionofsevereheadacheandsomeshakingchillslastevening

-retiredtobedfollowinguseofhertriptanandthetrustyCPAPmask

-husbandnotedabnormalsoundscomingfromherroomat10:00amthenextmorning

-findspatientobtunded,vomitingintoherCPAPmaskandshakingvigorously

-intubatedintheEDforrespiratoryextremis,uponfoley catheterplacement,notedtohaveastenchfromurinethatwould“knockyoursocksoff”

ClinicalCaseVitalsintheED:temperature38.3F,respiratoryrate22,pulse112,Osat 83%,GCS6

Intubatedforairwayprotection/hypoxemia,initialABG7.3/28/101on50%FiO2

CBC:WBC12.7Hgb11.1Plt 130

BMP:139/4.7/105/16/17/1.2

LFT’s:AST14,ALT13,TB0.9,AP71,Alb3.7

Followingintubation:developmentofnotablehypotension,MAP67requiring15ug/kg/mindopamineinED

TrendsInSepsisIncidence&Mortality

Rheeetal.IncidenceandtrendsofsepsisinUShospitalsusingclinicalvsclaimsdata,2009-2014.JAMA.2017;318(13):1241.

WhatIsSepsis?ClinicalSyndromeà

ResultinginPathologic/BiochemicalDerangementsà

DuetoDysregulatedInflammatoryProgrammingà

InResponsetoInfection

NetSum:OrganDysfunctionàIncreaseRiskofDeath

Rhodesetal.Survivingsepsiscampaign:internationalguidelinesformanagementofsepsisandsepticshock:2016.IntensiveCareMed2017;43:304.

SepsisDefinitions(1991)

Sepsis:

-Systemicinflammatoryresponseinthecontextofproven/suspectedinfection

SevereSepsis:

-Sepsiscomplicatedbyorgandysfunction

SepticShock:

-Sepsisrelatedacutecirculatoryfailurecharacterizedbypersistentarterialhypotensionunexplainedbyothercauses

Boneetal.Consensusconference:Definitionsforsepsisandorganfailureandguidelinesfortheuseofinnovativetherapiesinsepsis.Crit CareMed.1992;20(6):864.

SepsisDefinitionin2016Sepsis:Life-threateningorgandysfunctioncausedbydysregulatedhostresponsetoinfection

SepticShock:Subsetofsepsiswithcirculatoryandcellular/metabolicdysfunctionassociatedwithhigherriskofmortality

Singeretal.Thethirdinternationalconsensusdefinitionsforsepsisandsepticshock(sepsis-3).JAMA.2016;315(8):801.

SuspectedInfection

SOFAScore> 2(AboveBaseline)

SEPSIS

Sepsis

VasopressorsNeedor

Lacatate >2

SEPTICSHOCK

WhatIsSOFA?


HowDoWeUseSOFA?-Attemptstodoabetterjobofconnectingevidenceoforgandysfunctionwithsepsis

-OrgandysfunctionisidentifiedasacutechangeintotalSOFAScore> 2(fromknownbaseline)or> 2(ifunknownbaseline)

-SOFAscore>2predictsanoverallmoralityriskof~10%ingeneralinpatientpopulationwithsuspectedinfection


BackToOurPatientNotedintheEDtohavetemp38.3F,respiratoryrate22,pulse112,Osat 83%,GCS6

Intubatedforairwayprotection,initialABG7.3/28/101on50%FiO2


BMP:139/4.7/105/16/17/1.2


Followingintubation:notablehypotension,MAP67with15ug/kg/mindopamine

BackToOurPatientNotedintheEDtohavetemp38.3F,respiratoryrate22,pulse112,Osat 83%,GCS6

Intubatedforairwayprotection,initialABG7.3/28/101on50%FiO2


BMP:139/4.7/105/16/17/1.2


Followingintubation:notablehypotension,MAP67with15ug/kg/mindopamine

SOFAScore11

ButIWasUndertheImpressionThereWouldBeNoMath?WhatisthisqSOFA?

-PatientsmeetingcriteriaofqSOFA are:-morelikelyeithertohaveprolongedICUstayorlikelytodieduringthecurrenthospitalization


Finkelsztein etal.ComparisonofqSOFA andSIRSforpredictingadverseoutcomesofpatientswithsuspicionofsepsisoutsidetheintensivecareunit.CriticalCare201721:73.

CorePrinciplesofSepsisManagement1.InfectionContainment

2.HemodynamicAssessment/Resuscitation

3.AddressingMetabolicDerangements

4.SupportingVentilation/Oxygenation

5.AdjuvantTherapies

EarlyGoalDirectedTherapyComparingEGDTvsUsualCare(at7-72hours)

InHospitalMortality:30.5%vs46.5%(p=0.009)

CVO2:70.4%vs65.3%(p<0.02)

Lactate:3.0vs3.9(p<0.02)

APACHEII13vs15.9(p<0.02)

Riversetal.Earlygoal-directedtherapyinthetreatmentofseveresepsisandsepticshock.NEngl JMed2001;345:1368.

ChallengingTheEGDTParadigmARISETrial:2014

ProMISe Trial:2015

ProCESS Trial:2014

Mouncey etal.TrialofEarly,Goal-DirectedResuscitationforSepticShock.NEngl JMed.2015;372:1301.

Peakeetal.Goaldirectedresuscitationforpatientswithearlysepticshock.NEngl JMed.2014;371:1496.

Yealy etal.Arandomizedtrialofprotocol-basedcareforearlysepticshock.NEngl JMed.2014;370:1683.

HowDidTheyDiffer?OriginalEGDT(Rivers2001) EGDTTrio(Arise,process,Promise2014)

StudyCenters 1(US) 31-56(US,Australia,Europe)

EnrolledPatients(#) 263 1260-1600

ExistingSepsisProtocol No Yes(SSC,NationalStandards)

Pre-randomizationVol(ml/kg) 20-30ml/kg ~14ml/kg

LocationofIntervention ED ED->>>ICU

StudyBlinded Yes No

TimeinED ~8hours 1.2-1.4hours

Vitals:HR(BPM),RR(BPM) 117,31.8 104-113,24.5-25.4

Lactate(mM/L) 7.7 4.4-4.8

TotalVol6-72H(L) 8.6 4.2-4.5

Vasopressoruse(29.1) 29.1 46.6-57.9

MechVentUseat0-6H(%) 53 20.2-34.8

Nguyenetal.Earlygoaldirectedtherapyinseveresepsisandsepticshock:insightsandcomparisonstoProCESS,ProMISe,andARISE.CriticalCare2016;20:160.

Levyetal.Thesurvivingsepsiscampaign:resultsofaninternationalguidelinebasedperformanceimprovementprogramtargetingseveresepsis.Crit CareMed2010;38:367.

Unbundlingthe[Sepsis]Bundles

http://www.workhouses.org.uk/tour/oakum.shtml

“PickingOakum”





5.AdjuvantTherapies

IsThereAnyNewInsightIntoInfectionContainment?

Seymouretal.Timetotreatmentandmortalityduringmandatedemergencycareforsepsis.NEngl JMed2017;376:23.

TimingtoAntibiotics-ED?

Liuetal.Thetimingofearlyantibioticsandhospitalmortalityinsepsis.AJRCC2017;196(7):856.

TimingtoAntibiotics-ED/ICU?

Ferreretal.Empiricantibiotictreatmentreducesmortalityinseveresepsisandsepticshockfromthefirsthour:resultsfromaguideline-basedperformanceimprovementprogram.Crit CareMed2014;42(8):1749.

ReasonsForDelayInEffectiveAntibioticsinSepsis1.Failuretorecognizeinfectioninatimelymanner

2.Failuretorecognizethathypotensionassepticshock

3.Effectofinappropriateantimicrobialinitiation

4.Failuretoappreciateriskofresistantorganismsincertainscenarios(eg,immunocompromisedversusimmunosuppressed;antecedentantimicrobialuse)leadingtoinappropriateinitialantimicrobials

5.Waitingforbloodculturesbeforegivingantibiotic

6.TransferfromERbeforeorderedantibioticsgiven

7.Failuretousestatorders

8.Failuretorecognizethatadministrationofinappropriateantimicrobialsisequivalenttoabsentantimicrobialtherapywhenrespondingtoclinicalfailure

9.Nospecifiedorderwithmultipledrugregimenssothatkeydrug(usuallymostexpensiveandhardesttoaccess)maybegivenlast

10.Administrative/logisticdelays

Funketal.Anti-microbialtherapyforlife-threateninginfections:speedislife.Crit CareClin 2011;27:53.

HowMuchDoesAntibioticChoiceMatter?

Kumaretal.Initiationofinappropriateantimicrobialtherapyresultsinafivefoldreductionofsurvivalinhumansepticshock.Chest2009;136(5):1237.

TimingofCultures

0

20

40

60

80

100

120

140

160

0-4h 4-8h 8-12h 12-24h 24-48h

NumberPositiveCulturesvsTimofAbxAdministration

BacTec BacT/AlertOnly

Zadroga etal.Comparisonof2bloodculturemediashowssignificantdifferencesinbacterialrecoveryforpatientsonantimicrobialtherapy.ClinicalInfectiousDiseases2013;56(6):790.

InterimSummary:InfectionContainment-Empiricantibiotics/antimicrobialsshouldbeinitiatedwithin1hourofpresentationforsepsis

-Outsideofdefinitivesourcecontrol,antibioticslikelyremainthemostessentialpillarofsepsismanagement

-Relevantmicrobialculturesshouldbeobtainedassoonaspossible(preferablypriortoantibiotics),butshouldnotdelayadministrationofantimicrobials

-Appropriatechoiceofempiricantibioticsisnecessaryforoptimaloutcomes(bettertoinitiateappropriatelybroadspectrumandnarrowasrapidlyaspossible)

-Sequenceofantibioticsmatters:(gramnegativecoverage>>>grampositivecoverage>>>doublegramnegativecoverage/anti-fungalcoverage)





5.AdjuvantTherapies

InitialResuscitation-Sepsisandsepticshockaremedicalemergencies,itisrecommendthatresuscitationbeginimmediately-Intravascularhypovolemiaandsepsis-relatedhypoperfusion andcommonlyencountered,requiringpromptrecognition/action

DefinitionsofShock:“Theclinicalresultofcirculatoryfailurethatresultsininadequatecellularoxygenutilization.”


Inadequateoxygendeliverywithincreasedmetabolic

need

⬆ Sympatheticdrive

⬆ Cortisolrelease

⬆ Renin-angiotensinWater/Na+conservationVasoconstriction⬆ Bloodvolume

DEFENSEMECHANISMS:

Multiorgan Dysfunction• Alteredconsciousness• Respiratoryfailure(ARDS)• Renalfailure• Liverfailure• DIC

LessonsinActingQuickly

Seymouretal.Timetotreatmentandmortalityduringmandatedemergencycareforsepsis.NEngl JMed2017;376:23.

InitialResuscitation-TheTemplateHemodynamicGoals:CVP=8-12mmHgMAP=>65mmHgUrineOutput> 0.5ml/kg/hrScvO2>70%Hct >30%

Riversetal.Earlygoal-directedtherapyinthetreatmentofseveresepsisandsepticshock.NEngl JMed2001;345:1368.

InitialResuscitation:16YearsLaterARISETrial:2014

PROMISETrial:2014

PROCESSTrial:2014

HemodynamicGoals:CVP=8-12mmHgMAP=>65mmHgUrineOutput> 0.5ml/kg/hrScvO2>70%Hct >30%

Mouncey etal.TrialofEarly,Goal-DirectedResuscitationforSepticShock.NEngl JMed.2015;372:1301.

Peakeetal.Goaldirectedresuscitationforpatientswithearlysepticshock.NEngl JMed.2014;371:1496.

Yealy etal.Arandomizedtrialofprotocol-basedcareforearlysepticshock.NEngl JMed.2014;370:1683.

InitialResuscitation:30ml/kgIVCrystalloid?

MAPGoal> 65mmHg?

Varpula etal.Hemodynamicvariablesrelatedtooutcomeinsepticshock.IntensiveCareMed2005;31:1066.

MAPGoal> 65mmHg?

Asfar etal.Highversuslowblood-pressuretargetinpatientswithsepticshock.NEngl JMed2014;370(17):1583.

Increasedincidenceofarrhythmias

***PotentialdecreasedneedforRRTinchronichypertensivepatientsinhigherMAPgroup

UseofLactateClearance?

CaveatsInUnderstandingLactateMetabolism-Lactateelevationisnotadirectmeasurementoftissueperfusion

EtiologiesofIncreasedLactate:-Tissuehypoxia-Acceleratedaerobicglycolysisfromincreasedβ-adrenergicstimuli-Impairedlactateclearance(hepaticdysfunction)

Luft etal.Lacticacidosisupdateforcriticalcareclinicians.JAmSoc Nephro 2001;12:S15.


InitialResuscitation:InterimSummary-Actquickly oncesepsissyndromerecognized/entertained-30ml/kgIVcrystalloidadministrationinthe1st 3hours-Additionalfluidshouldbeadministeredbaseduponfrequentdynamicassessment-Initialtargetmeanarterialpressure(MAP)of65mmHg-Guideresuscitationtonormalizelactate

WhatAbouttheReliabilityofCVP?

Shippy etal.Reliabilityofclinicalmonitoringtoassessbloodvolumeincriticallyillpatients.Crit CareMed.1984Feb;12(2):107.

DoesCVPPredictVolumeResponsiveness?

“TheonlystudywecouldfinddemonstratingtheutilityofCVPinpredictingvolumestatuswasperformedinsevenstanding,awake

maresundergoingcontrolledhemorrhage!”

DynamicVolumeAssessment:HowMuchIsEnough?

EchocardiographicAssessment

PulsePressureVariation(PPV)

Bioreactance

WhatFluidShouldWeGive?

WhatFluidShouldWeGive?

BottomLine:-Noheadtoheadcomparisonbetweencrystalloids-LimitedevidencemaypointtowardsCl- restrictiveoverCl-liberalcrystalloidtodecreaserenalinjury-Somestudieshavesuggestedimprovedmortalitywithuseofalbumin(colloid)particularlyinlowalbuminstates,butnotasprimaryresuscitationfluid-Evidencesuggestsincreasedmortality/increasedRRTneed

Haase etal.Hydroxyethylstarchversuscrystalloidoralbumininpatientswithsepsis:systematicreviewwithmeta-analysisandtrialsequentialanalysis.BMJ2013;346:839.

AndWhenShouldWeStop?

Acheampong etal.Apositivefluidbalanceisanindependentprognosticfactorinpatientswithsepsis.Crit Care2015;19:251.

DeOliveiraetal.Positivefluidbalanceasaprognosticfactorformortalityandacutekidneyinjuryinseveresepsisandsepticshock.JCrit Care2015;30(1):97.





5.AdjuvantTherapies

WhichVasopressorShouldWeUse?

CurrentControversiesinSepsisManagement

RoleofVitaminS?

Marik etal.Hydrocortisone,vitaminc,andthiamineforthetreatmentofseveresepsisandsepticshock.Chest2017;151(6):1229.

RoleofVitaminS?

Marik etal.Hydrocortisone,vitaminC,andthiamineforthetreatmentofseveresepsisandsepticshock.Chest2017;151(6):1229.

RoleofBeta-BlockadeandSepsis?

Morellietal.EffectofHeartRateControlWithEsmolol onHemodynamicandClinicalOutcomesinPatientsWithSepticShock.JAMA2013;310(16):1683.

RoleofBeta-BlockadeandSepsis?

Morellietal.EffectofHeartRateControlWithEsmolol onHemodynamicandClinicalOutcomesinPatientsWithSepticShock.JAMA2013;310(16):1683.

Questions?

ReviewQuestionsQ1.Promptvolumeresuscitation/volumestatusassessmentiscriticaltotheearlystagesofsepsismanagement.However,increasedevidencesuggeststhatfluidbalanceinthelatestagesofsepsistreatmentisalsolikelytobeimportant.WhichofthefollowinghasNOT beenassociatedwithpositivefluidbalanceinthepost-resuscitativesepticpatient.A)Ongoingpersistenceofapositivedailyfluidbalanceoverhospitalizationdemonstratesanassociationwithahighermortalityrateinsepticpatients.B)Volumeoverloadisindependentlyassociatedwithimpairedmobilityanddischargetoahealthcarefacility.

C)Positivefluidbalanceinpost-resuscitationsepticpatientsisassociatedwithprotectionagainstthedevelopmentofacutekidneyinjury.D)Positivefluidbalanceinpost-resuscitationsepticpatientsconstitutesariskfactorforneworgansystemdysfunctionathospitaldischarge.

ReviewQuestionsQ1.Promptvolumeresuscitation/volumestatusassessmentiscriticaltotheearlystagesofsepsismanagement.However,increasedevidencesuggeststhatfluidbalanceinthelatestagesofsepsistreatmentisalsolikelytobeimportant.WhichofthefollowinghasNOT beenassociatedwithpositivefluidbalanceinthepost-resuscitativesepticpatient.A)Ongoingpersistenceofapositivedailyfluidbalanceoverhospitalizationdemonstratesanassociationwithahighermortalityrateinsepticpatients.B)Volumeoverloadisindependentlyassociatedwithimpairedmobilityanddischargetoahealthcarefacility.

C)Positivefluidbalanceinpost-resuscitationsepticpatientsisassociatedwithprotectionagainstthedevelopmentofacutekidneyinjury.D)Positivefluidbalanceinpost-resuscitationsepticpatientsconstitutesariskfactorforneworgansystemdysfunctionathospitaldischarge.

ReviewQuestionsAnswerQ1.Emergingdataappearstosuggestthatpersistentpositivefluidbalanceinthepost-resuscitativesepticpatientisanindependentriskfactorassociatedwithhighermortality,increasedlikelihoodofimpairedimmobility/readinessforpost-hospitaldischarge,increasedlikelihoodofdevelopingacutekidneydisease,aswellasincreasedriskfordevelopinganeworgandysfunctionbythetimeofhospitaldischarge.Whiledatacontinuestogrow,suchfindingsunderscoretheimportanceofprompt,aggressivevolumeresuscitationintheearlystagesofsepsis/septicshock.However,thepost-resuscitationperiodrequirescarefulattentiontoongoingvolumestatusassessment,avoidanceofexcessiveIVF,andpotentialneedforinterventionstonormalizevolumestatus(i.e.diuretics,mobilization).

References:Acheampong etal.Apositivefluidbalanceisanindependentprognosticfactorinpatientswithsepsis.Crit Care2015;19:251.Brotfain etal.Positivefluidbalanceasamajorpredictorofclinicaloutcomeofpatientswithsepsis/septicshockafterICUdischarge.AmJEmerg Med2016;34(11):2122.Mitchelletal.Volumeoverload:prevalence,riskfactors,andfunctionaloutcomeinsurvivorsofsepticshock.AnnAmThorac Soc.2015;12(12):1837.DeOliveiraetal.Positivefluidbalanceasaprognosticfactorformortalityandacutekidneyinjuryinseveresepsisandsepticshock.JCrit Care2015;30(1):97.Malbrain MLetal.Fluidoverload,de-resuscitation,andoutcomesincriticallyillorinjuredpatients:asystematicreviewwithsuggestionsforclinicalpractice.AnaesthesiolIntensiveTher.2015;46(5):361.

ReviewQuestionsQ2.Whilelactateisnotadirectmeasureoftissueperfusion,increasedlactatelevelsareassociatedwithunfavorableclinicaloutcomes.Thuslactateitisoftenutilizedasanindirectmarkertoassistintheguidanceofresuscitationinsepsis/septicshock.Whichofthefollowingisnotapredominantlycontributingsourceofincreasedserumlactate?

A)Acceleratedaerobicglycolysisfromincreasedβ-adrenergicstimuli

B)Impairedlactateclearanceviahepaticdysfunction

C)Tissuehypoxia

D)Impairedlactateclearanceviarenaldysfunction

ReviewQuestionsQ2.Whilelactateisnotadirectmeasureoftissueperfusion,increasedlactatelevelsareassociatedwithunfavorableclinicaloutcomes.Thuslactateitisoftenutilizedasanindirectmarkertoassistintheguidanceofresuscitationinsepsis/septicshock.Whichofthefollowingisnotapredominantlycontributingsourceofincreasedserumlactate?

A)Acceleratedaerobicglycolysisfromincreasedβ-adrenergicstimuli

B)Impairedlactateclearanceviahepaticdysfunction

C)Tissuehypoxia

D)Impairedlactateclearanceviarenaldysfunction

ReviewQuestionsAnswerQ2.

Aslactateisincreasinglyusedasasurrogatefortissueperfusion/tissuehypoxia,itisimportanttounderstandthevariousphysiologicandpathophysiologicstatesthatcanresultinitsaccumulation.Lactateelevationhasbeenlinkedtoincreasedtissuehypoxia,increasedproductioninthecontextofincreasedaerobicglycolysisfromexcessiveβ-adrenergicstimuli,andimpairedclearanceinthecontexthepaticdysfunction.Whilethekidneysdoindeedparticipateinlactatemetabolism(viaexcretion,gluconeogenesis,andoxidation),itisonlyestimatedtoberesponsiblefor~10-20%oftotallactatemetabolism.Theliver,however,isestimatedtoberesponsiblefor~70-75%oftotallactatemetabolism.

References:Rhodesetal.Survivingsepsiscampaign:internationalguidelinesformanagementofsepsisandsepticshock:2016.IntensiveCareMed2017;43:304.Luft etal.Lacticacidosisupdateforcriticalcareclinicians.JAmSoc Nephro 2001;12:S15.

update in the management of sepsis - …thececonsultants.com/images/2little_sepsis.pdf · update in...

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