Shock

FellowCoreCurriculum2018

CasePresenta9on

•  42yofemaletransferredtoICUwithshockfollowingprimaryadmissionforcatatonia

•  BP71/42,HR83,RR32,SaO298%2LNC,38.8

CasePresenta9on

•  Quicklyapparentthatsheismostlikelyinsep9cshock

•  C.difresultedposi9vedayoftransfertoICU

CasePresenta9on

•  Stabilizesfollowingvolumeresuscita9on•  StartedonIVflagyl,enteralvanc

•  Low-doseNE(0.08-0.15mcg/kg/min)

•  BedsideUS-OKcardiacindices

CasePresenta9on

•  Stabilizesfollowingvolumeresuscita9on•  C.difresultedposi9vedayoftransfertoICU

•  Startedonlow-doseNE

•  BedsideUSOKcardiacindices

Progression

Progression•  Rapiddeteriora9onwith

markedincreaseinabdsizeandtension

•  Intubatedformixedrespfailure

•  Volumeresuscita9onandvasopressor

•  Emergentex-lap

Progression

Lac9cacidlevelsrangingfrom6-15last10hours;pH7.17-7.28BPhoveringat90/50(MAP60)Hasreceived13Lcrystalloid,nocolloid

ThingsIMeantoKnow…AboutShock

•  Whatdowedowithalactate?

•  Whataboutbicarb?

Lactate–anaerobicmetabolism

GlucosetoCO2andH2OviaTCAcyclegets38ATPsfromeachglucose.Anaerobicpathwaygets2ATPWhenlimitedO2tosupportaerobicglycolysis,pyruvatemetabolismshifstoanaerobicpathway(thuslactateproduced)Typicallactate:pyruvatera9ois10:1

Lac9cAcidosis

ATPhydrolyzedtoADP–HisbyproductWhenTCAcyclerunning,Hionsareusedduringoxphos.Themilieuthatpredisposedtoanaerobicglycolysisintheshockstateusuallyassociatedwithmitochondrialdysfunc9on(nooxphos),andHionsabound.Thusacidosis.

LactateConsump9on

•  Primarilymetabolizedinliver(60%)andkidney(30%)

•  Majoruseisgluconeogenesis(Coricycle)

LactateConsump9on

•  Therela9onshipbetweenlactateandpyruvateisbidirec9onal(lactatecanbeoxidizedbacktopyruvate)

LactateTransport(Shujle)

•  Allowconsump9onoflactateinmitochondriaoftargetorgansatadistantsite

•  MCTsmovelactate(andprotons)acrossmembranes–MCTsaremostprevalentinskeletalmuscle,cardiacmyocytes,andliver,alsobrain.LDHalsopresentinthesesites.

•  Cardiacmyocytesandliverimportlactate,convertbacktopyruvate,whichmaythenbeconsumedbymitochondria(orgluconeogenesisinliver)

•  Suggestslactateproduc9onisimportantadap9veresponse–i.ealterna9vefuel

Sepsisandglycolysis

•  Sepsisincreasesbasalmetabolicrate,andincreasesglycolysis“glycoly9cflux”

•  IfenzymescatalyzingTCAcycleareoverwhelmed(rate-limi9ng),pyruvatewillbeshuntedtolactate(i.e.maynotalwaysrepresentanaerobicenvironment)

Glycoly9cFluxinskeletalmusclemarkedlyincreasedbycatecholamines

KushimotoetalAcuteMedicineandSurgery2016;3:293-297

Glycoly9cFluxinskeletalmusclemarkedlyincreasedbycatecholamines

•  Sugges9onthatincreasedlactateinsemngofofstress(orcatecholinfusion)mayrepresentintactcytosolfunc9onandadap9vemechanism

•  Lactaterisewithepi(orsepsis)maynotrepresent9ssueischemia

Lactateresponsetoepinephrine

Retrospec9vestudyof100pa9entswithshockonepi–analyzedchangeinlactatebeforeand4hoursaferini9a9onofepiinfusion.InMVanalysis,pa9entswhoselactateswentUPhadalowerriskofdeath(52%versus85%)

WutrichY,BarraudD,ConradMetal.Earlyincreaseinarteriallactateconcentra9onunderepinephrineinfusionsisassociatedwithabejerprognosisduringshock.Shock2010.

LactateClearance

•  SEP-1requiresmeasurementofseriallactateinsep9cshock(notwithstandingevidencefromPROCESS,PROMISE,andARISE)aspartof3hourbundle

•  ThismeasurewaslargelybasedonSurvivingSepsisGuidelinestargemngbundletreatmentforsep9cshock,includingthosedefinedbylactate>4.0

Whatwastheevidencebase?•  IndexStudy:Nguyen2004•  Prospec9veobs•  enrolledseveresepsis&

sep9cshock•  n=111,overallhosp

mortality42%•  Lactatemeasuredat

indexandhour6

•  Manycaveats

Nguyenetal.Earlylactateclearanceisassociatedwithimprovedoutcomeinseveresepsisandsep9cshock.CCM2004;32(8):1637-42.

Whatwastheevidencebase?

•  BestRCT:Jansen2010

•  EnrolledICUadmissionswithlactate>3(excludedliverfailure)

•  n=348•  Mostweresep9cshock•  Essen9allytes9ngusualcarewithonlyanindexlactate,orEGDTwithlactateQ2H,withexplicitgoalofserial20%reduc9ons

JansenTC,vanBommelJ,SchoonderbeekFJ,etal;LACTATEstudygroup:Earlylactate-guidedtherapyinintensivecareunitpa9ents:Amul9center,open-label,randomizedcontrolledtrial.AmJRespirCritCareMed2010;182:752–761

JansenAJRCCM2010:LactateClearanceRCT

JansenAJRCCM2010:LactateClearanceRCT

JansenTC,vanBommelJ,SchoonderbeekFJ,etal;LACTATEstudygroup:Earlylactate-guidedtherapyinintensivecareunitpa9ents:Amul9center,open-label,randomizedcontrolledtrial.AmJRespirCritCareMed2010;182:752–761

JansenAJRCCM2010:LactateClearanceRCT

JansenTC,vanBommelJ,SchoonderbeekFJ,etal;LACTATEstudygroup:Earlylactate-guidedtherapyinintensivecareunitpa9ents:Amul9center,open-label,randomizedcontrolledtrial.AmJRespirCritCareMed2010;182:752–761

JansenAJRCCM2010:LactateClearanceRCT

JansenTC,vanBommelJ,SchoonderbeekFJ,etal;LACTATEstudygroup:Earlylactate-guidedtherapyinintensivecareunitpa9ents:Amul9center,open-label,randomizedcontrolledtrial.AmJRespirCritCareMed2010;182:752–761

RecentData

•  Ryoo2018•  retrospec9vestudyfromprospec9veregistry•  mul9centerenrollingpa9entswithsep9cshock(lactate>2andvasopressor[NE])whoreceivedbundle-guidedresuscita9on.

•  1060pa9ents,28Dmortality25%.

Ryoo2018RegistryDataSoit’samarker,maynotbeanybejerthansinglemeasureoflactateat6hours(infact6hourlactatelookedbejeronROCthanclearance–neitherwasgreat).Notclearwhichinterven9onstowardthismarkeractuallyimpactoutcome.

ThingsIMeantoKnow…AboutShock

•  Whatdowedowithalactate?

•  Whataboutbicarb?

Theproblemwithbicarb…

•  Adequateven9la9oncanblowofftheCO2,butsomeCO2willdiffuseacrossmembranesandworsenintracellularpH

•  Really?

2humanstudiesusuallycitedtosupportintracellularacidosistheory

Goldsmith1997•  MeasuredintracellularpH

inleukocytesfromhealthyvolunteers

•  Worseningintracellularmilleuaferalkalina9onofECFwithNaHCO3

Levraut2001•  Invitrohumanhepatocytes

•  BicarbdecreasesintracellularpHinconcertwithincreaseinpCO2inECF

2physioRCTs-bicarbvsaline

Cooper1990•  14ICUpa9entswithlac9c

acidosis•  Received2mmol/kgbicarb

over15minutes,orequivvolumesaline

•  ArterialpHroseaferbicarb(asdidpCO2)

•  EachincreasedPCWPandCOequally

•  NeitherchangedMAP

Mathieu1991•  10ICUpa9entswithlac9c

acidosis•  1mmol/kgbicarbasbolus,

orequivvolumesaline•  ArterialpHroseafer

bicarb,but9ssueoxygena9ondidn’tchange

•  NoimpactofeitherbicarborNaClonhemodynamics

BicarbClinicalTrials•  Fang2008:RCT5mL/kgofNSversushypertonicsalinev

bicarb.94pa9entwithseveresepsis.MAPandCOimprovedfasterinbicarbgj,butnodifferencesinmortality.Thesepa9entsallhadmeannormalpHatstudyentry

•  Jung2011:prospec9vemul9centerobs-pH<7.20,bicarb(5-55%)dependedoncenter,notmechanismofacidemia.noassocia9onbetweenbicarbandmortality

•  Chen2013:prospec9veRCT–sep9cshockandlac9cacidosis(pH<7.15atstudyentry),n=65.bicarbimprovedCI,O2delivery,andSVO2andresultedinlowermortality–Chineselanguageonly,nottranslated

BicarbClinicalTrials•  Kim2013:singlecenter

retrospec9vestudy2011-2012(Korea)

•  Lactate>3.3withAGMA.102pa9ents.splitintogroupsdependingonwhethertheyreceived>20mEqNaHCO3.MeanpHwas7.3(?).67%ofpa9ents(69)receivedbicarb.Bivariateanalysisbicarbassociatedwithmortality(p=0.006).ThosereceivingbicarbhadlowerpH(mean7.24),higherSOIscores,vent.BicarbstayedsignificantinMVmodel.