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• Rapiddeteriora9onwith
markedincreaseinabdsizeandtension
• Intubatedformixedrespfailure
• Volumeresuscita9onandvasopressor
• Emergentex-lap
Progression
Lac9cacidlevelsrangingfrom6-15last10hours;pH7.17-7.28BPhoveringat90/50(MAP60)Hasreceived13Lcrystalloid,nocolloid
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
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.
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.