the marik protocol final 2017 -...

Metabolicresuscitationinsepsis

KElfituriNov2017

Declaration

• FinancialsupportandsponsorshipNil

• ConflictsofinterestTherearenoconflictsofinterest

Outlines

• Verybriefoverviewofthescientificrationale• WhydoesVitaminC help?• WhydoesThiamine help?• VitaminCdeficiencycausesclinicaldisease• Thiaminedeficiencycausesclinicaldisease• ClinicalstudiesofIVVitaminC:• ClinicalstudiesofThiamine:• Marikprotocol• Takehomemessage

Verybriefoverviewofthescientificrationale• SepticpatientsareinvariablydeficientinVitaminC,andfrequentlydeficientinthiamine.

• DeficienciesinVitaminCandthiaminemightexplainmanyoftheabnormalitiesseeninsepsis.

• VitaminCandthiaminehaveanoutstandingtrackrecordofsafety,provenoverdecadesofexperimentationandclinicalexperience.

Verybriefoverviewofthescientificrationale

• ManyRCTshavesuggestedbenefitfromVitaminCorthiamineincriticallyillpatients,withnoevidenceoftoxicity.

• Arecentbefore-afterstudyfoundasubstantialmortalitybenefitfromthecombinationofstress-dosesteroid,IVvitaminC,andIVthiamine.Althoughthisisn'tanRCT,theresultsarequitestriking.

• Furtherresearchisrequired,butintheinterimthisisareasonableinterventiongiventheexcellentsafetyprofileoftheseagents.

VitaminC

Why does VitaminC help?


• Antioxidant:qScavengesROSandRNS,qpreventsendothelialdamageqmaintainingmicrovascularintegrity


• SynthesisofcatecholaminesActsascofactorinsynthesisofepinephrine,dopamine,andvasopressinallowingformaintenanceofvasculartoneandcardiacoutputqdopaminebeta-hydroxylase ,Thisenzymeconvertsdopamineintoepinephrine

qRate-limitingstepofsynthesising L-DOPA,theprecursorofdopamine


• ImmunefunctionqSupportslymphocyticproliferation,qassistsinneutrophilickillingofbacteria,qimproveschemotaxisqInhibitsNF-KBactivation

Journal Name: BiofactorsReview Article Title :Mechanism of action of vitamin C in sepsis: Ascorbate modulates redox signaling in endotheliumAuthors: Wilson et al 2009• Conclusion/Recommendation:• VitaminCdeficiencycorrelateswithmultiorgan failureanddeath

• microvascularfunctionmaybeimprovedinsepsisbyparenteraladministrationofascorbateasanadjuvanttherapy

Why does Thiamine help?

Why does Thiamine help? • Thiamine deficiencyiscommoninsepsis,occurringinperhapsone-thirdofpatients.Thisisassociatedwithincreasedmortality(Manganese2011).

• isacriticalco-factorintheglyocolysis andoxidativedecarboxylationofcarbohydratesforenergyproduction.

• ShuntsmetabolismofvitaminCawayfromoxalate(potentialforrenalcrystallisation)

Journal Name: Curr Opin Clin Nutr Metab CareReview Article title :Thiamine supplementation in the critically illAuthors: Manganese 2011

• depletionisfrequentlyunrecognisedandunderdiagnosedbyclinicians.

• Potentiallydeleteriousconsequencesofthiaminedepletionshouldbeavoidedbyearlyandappropriatesupplementation


• ShuntsmetabolismofvitaminCawayfromoxalate(potentialforrenalcrystallisation)

VitaminCdeficiencycausesclinicaldisease

Vitamindeficiencycausesclinicaldisease• VitaminCdeficiencycausesscurvy.• VitaminCisimportantforthemaintenanceofendothelialboundaries,withedemanotedinscurvy.

• VitaminCisalsorequiredforthesynthesisofcatecholamines andcortisol,sodeficiencycausesfailureofthesympatheticnervoussystem.

scurvy

Thiaminedeficiencycausesclinicaldisease

Vitamindeficiencycausesclinicaldisease

• ThiaminedeficiencymaycauseqDelirium

(Wernicke'sencephalopathy)and

qcardiacdysfunction(Beriberi).Beriberiinparticularcanmimicsepsis,bycausingdistributiveshockandlacticacidosis.

Wernicke'sencephalopathy

Beriberi

ClinicalstudiesofIVVitaminC:

WhyIV?

IntestinalabsorptionofvitaminCis saturable

ClinicalstudiesofIVvitaminCincardiacpatients

ClinicalstudiesofIVvitaminCincriticallyillpatients:

JournalName:JAMAsurgeryStudyTitle:ReductionofresuscitationfluidvolumesinseverelyburnedpatientsusingascorbicacidadministrationAuthors :TanakaHetal,2000• Studytype,number: N37

AprospectiveRCTinvolvingpatientswithmajorburns(>30%bodysurfacearea).

• Methodology:PatientswererandomizedregardingwhetherornottoreceiveAninfusionofIVvitaminC,66mg/kg/hrforthefirst24hoursofhospitalisation.

TanakaHetal,2000

• Results: patientsinthevitaminCgrouprequiredq lessfluidresuscitation,q hadhigherurineoutput,andq developedlesswoundedema

• Conclusion/Recommendation:• thistranslatedinto

q improvedoxygenationandq lesstimeonmechanicalventilationamongthe

VitaminCgroup(averageof12vs.21daysofventilation,p=0.03).

JournalName:AnnSurgStudyTitle :Randomized,prospectivetrialofantioxidantsupplementationincriticallyillsurgicalpatientsAuthors: Nathens ABetal.2002

• Studytype,number:595Randomized,prospectivetrial

• Methodology:TheyrandomisedpatientsshortlyafteradmissiontotheICUtonotherapyvs.acombinationofenteralvitaminEplusIVvitaminC1000mgq8hruntilICUdischarge

Nathens ABetal.2002

• Results:patientstreatedwithvitaminsEandCfaredbetteronavarietyofsecondaryendpointsincluding

qlesstimeontheventilatorandqlessmultiorganfailure

• Conclusion/Recommendation:prophylacticantioxidantsprovidedtosurgicalICUpatientscouldreducepulmonarycomplications

JournalName:JTranslMedStudyTitle :PhaseIsafetytrialofintravenousascorbicacidinpatientswithseveresepsisAuthors: FowlerAetal.2014

• Studytype,number:N24SingleCentre,PRDPCTInvolvingpatientswithseveresepsisinamedicalICU

• Methodology:patientswererandomisedtoreceive

§ placebo,§ low-dosevitaminC(12.5mg/kgIVq6hr),or§ high-dosevitaminC(50mg/kgIVq6hr).

FowlerAetal.2014

• Results:Theprimaryendpointwassafetyandtolerability,withnoadverseeventsnoted

• Conclusion/Recommendation:PatientstreatedwithvitaminCexperienceda

q dose-dependentimprovementinSOFAscoreovertime

q Improvedinflammatorymarkers

JournalName:J Pulm Respir Med,StudyTitle:Impact of intravenous ascorbic acid infusion on novel biomarkers in patients with severe sepsisAuthors :Natarajanetal2014

• Studytype,number: N24Singlecentre,retrospectiverandomized

• Methodology:50 mg/kgor200 mg/kgIVinfusionevery24 h

Natarajanetal2014

• Results:• Conclusion/Recommendation:

q Decreaseinbiomarkersofsepsis(cf-DNAandmtDNA)and

q DecreaseinRDW

JournalName:JResPharmPractStudyTitle:Effectofhigh-doseascorbicacidonvasopressorrequirementinsepticshockAuthors :Zabet MHetal2016

• Studytype,number: N28Singlecentre,DBRCT

• Methodology:AsurgicalICUwithvasopressor-dependentsepticshockwererandomizedtoreceiveplacebovs.VitaminC25mg/kgIVq6hr.

Zabet MHetal2016

• Results:• Conclusion/Recommendation:Reductionin

qvasopressordoseandqvasopressordurationqmortalityamongpatientstreatedwithVitaminC.

ClinicalstudiesofThiamine:

JournalName:Crit CareMedStudyTitleRandomized,double-blind,placebo-controlledtrialofthiamineasametabolicresuscitatorinsepticshock:ApilotstudyAuthors: DonningMW2016

• Studytype,number88patientswithsepticshockRandomised,double-blind,placebocontrolledtrial

Methodology:Investigatingtheeffectofthiamine(200mgIVq12hr)Endpoint:Lactatelevels,timetoshockreversal,SOI,mortality

DonningMW2016

• Results:– Nodifferenceinoverallgroups– Inpatientswithbaselinethiaminedeficiency(35%oftotal):

• Lowerlactate• Decreasedmortality

Conclusion/Recommendation:Withinthispre-specifiedsubgroup,thiamineadministrationdidreducelactatelevelsandmortality

Clinical studies of Thiamine:

• PaulMarik,MBBCh• ChiefofPulmonaryandCriticalCareMedicine

Marik protocol

WhatHeDid:

• ElectronicHeathRecord(EHR)Retrospectivebefore-afterclinicalstudy

• Comparedtheclinicalcourseandoutcomeofconsecutiveseveresepsis(maybeclarifythatthisisthenewdefinition?)andsepticshockpatientsandaprocalcitonin(PCT) ≥2ng/mL:

MarikProtocolcont¢d

• DesignqRetrospectiveobservationalstudyqSinglecentred

• SettingqSinglecentreinUSqJanuary– July2016


TreatmentGroup• Treatedwithstandardsepsiscare

+q IntravenousvitaminC,q Hydrocortisone andq Thiaminewithin24hoursofICUadmission

ControlGroup:• Treatedwithstandardsepsiscareonly.

StandardICUCare:

• Empiricbroadspectrumantibioticsgivinginitially,whichwerede-escalatedaccordingtomicrobiologicaldataandclinicalprogress

• Conservativephysiologic fluidbasedtherapy• Intravenoushydrocortisone 50mgq6hr• Lungprotectivestrategyandavoidanceofhyperoxia

• Limiteduseof sedativeagents(dexmedetomidinewasthepreferredagent)


• Norepinephrine wasthevasopressorofchoice(titratedtoadoseof20ug/mintargetingaMAP>65mmHg)

• Ifneeded,thenextvasopressoraddedwasvasopressin at0.04U/min,followednextwithbyphenylephrine orepinephrine

• Enteralnutritionwasinitiated24hoursafterICUadmissionandclinicalstabilityachieved

• DVTprophylaxiswithenoxaparin (orheparininpatientswithcreatinine clearance<30ml/min)andsequentialcompressiondevices

VitaminC(Marik)TreatmentProtocol:

• StandardICUcareplus:• IntravenousvitaminC1.5gq6hrx4doruntilICUdischarge

• Hydrocortisone 50mgq6hrx7doruntilICUdischargefollowedbyataperover3d

• Intravenousthiamine 200mgq12hrx4oruntilICUdischarge

Outcomes:• Primary:Hospitalsurvival• Secondary:

– Durationofvasopressortherapy– Requirementforrenalreplacementtherapy(RRT)inpatientswithAKI

– ICUlengthofstay– Changeinserumprocalcitonin(PCT)– ChangeinSOFAscoreoverthefirst72hours

Outcomes:

Figure 1

NNTfordeathwas3.1inthisstudy,roundedupto4treatedpatientstoavoidonedeath

Figure 2

CHEST 2017 151, 1229-1238DOI: (10.1016/j.chest.2016.11.036)

Figure 4

CHEST 2017 151, 1229-1238DOI: (10.1016/j.chest.2016.11.036) Copyright © 2016 American College of Chest Physicians Terms and Conditions

Figure 3

CHEST 2017 151, 1229-1238DOI: (10.1016/j.chest.2016.11.036) Copyright © 2016 American College of Chest Physicians Terms and Conditions

Strengths:

• Nodifferenceinbaselinecharacteristicsbetweengroups

• Consecutivepatientsenrolled• Thestudiedinterventionswerecheap,seeminglysafe andreadilyavailable.However,vitaminCtoxicitycancauserenalfailureandthesafetyprofilewouldbebestevaluatedinthecontextofanRCT

Strengthscont‘d

• Thiswasthefirststudytoevaluatethecombination ofintravenousvitaminC,hydrocortisone,andthiamine

• Aninterestinghypothesisgeneratingstudywhichhassomebiologicallyplausibleexplanationsforbenefitinsepsis

Limitations:

• NotaRCT• Smallsamplesize• Onlyasinglecenterstudy• Useofnon-concurrentcontrols(i.e.,patientswerenotevaluatedduringthesametimeframe)

• PCTisnotreadilyavailableateveryhospital

Limitationscont‘d

• Multipleinterventionsandthereforenotpossibletodeterminewhich,ifany,areassociatedwithimprovedoutcome

• 60%ofpatientsinthecontrolgroupweretreatedwithcorticosteroids

• Details areprovidedfortheunderlyingreasonfordeath(includingadvanceddementia,severeheartfailure,advancedsarcoidosis andsevereCOPD)butnotforthecontrolgroup

Discussion:

• SepsisrelateddeathNopatientsinthetreatmentgroupdiedfromcomplicationsrelatedtosepsis,rathertheirmortalitywassecondarytocomplicationsoftheirunderlyingdisease

Discussioncont’d

• PCTPCT typicallydecreasesinalinearfashioninpatientswithseveresepsis(sepsis?)_andsepticshock,reachingabout30%oftheirbaselinevaluewithin72hours.

• Afallgreaterthan30%over72hoursusuallyindicatesimprovedsurvival

Discussioncont’d

• Synergisticeffects:•Combinationof

qVitaminCqThiamineandqHydrocortisone

↓ Vaso-plegic shock↓ Vasopressorduration

Discussioncont’d

• Vit CdoseTheexactdosingstrategyforVitaminCisunknown,asitisnotbeenwellstudied.Theauthorsconcludethatupto6gramsdailyshouldbeenoughwithoutrunningtheriskofconversiontooxalateandpotentiallycausingworseningrenalimpairmentfromoxalatecrystalformationandrenaldeposition.

TheBottomLine

• Thisstudyishypothesisgenerating.• AnRCTisrequiredtodeterminetheefficacyofvitaminC,steroidsandthiamineinseveresepsisandsepticshock.

Aretherepotentialharms?VitaminCqVitaminCqcalciumoxalatenephropathyqpro-oxidanteffect

Aretherepotentialharms?

qCalciumoxalatenephropathyqDose-dependenttoxicityqHigherdoses>40grams/day;(Buehner 2016)

qConcurrentuseofthiamineshouldreducetheconversionofvitaminCintooxalate


• pro-oxidanteffect.qThiswasshownnottooccurevenatadoseof7.5gramsIVdaily(Muhlhofer 2004).

Aretherepotentialharms?Thiamine• Thiamine:Rarereportsof

q hypersensitivityorq anaphylaxis,especiallywithrepeatedinjections

Aretherepotentialharms?Steroids• Steroids

qHYPRESSTrialqCORTICUSTrialqAnnaneTrialqTheVANISHtrialqTheADRENALtrial

JournalName: JournaloftheAmericanMedicalAssociation.StudyTitle :"Effectofhydrocortisoneondevelopmentofshockamongpatientswithseveresepsis"Authors: Keh D,etal, 2016HYPRESS• Studytype:number: N=380• Multicenter,placebo-controlled,double-blindRCT• Setting:34sitesinGermany• Enrollment:January13,2009toAugust27,2013• Methodology:

• IVhydrocortisone(n=190)• Placebo(n=190)

HYPRESS

• Results:Conclusion/Recommendation:• SubgroupAnalysis

Therewasnosignificantdifferenceregardingtheprimaryandsecondaryendpointsbetweenthosewithandwithoutrelativeadrenalinsufficiencywhoreceivedhydrocortisoneversusplacebo

• AdverseEvents– Secondaryinfection40(21.5%)vs.32(16.9%)(P=0.26)– Hyperglycaemia 169(90.9%)vs.154(81.5%)(P=0.009)

JournalName:New EnglandJournalofMedicine.2008StudyTitle :"Hydrocortisonetherapyforpatientswithsepticshock"Authors:SprungCL,etal CORTICUS

• Studytype:number:N=499Multicenter,double-blind,parallel-group,randomized,placebo-controlledtrial

• Methodology:N=499

• Hydrocortisone(n=251)• Placebo(n=248)

Meanfollow-up:28days

CORTICUS

• AdverseEvents• NewsepsisorsepticshockOR1.37;95%CI1.05-1.79;NNH26

• Newshock6%vs.2%(OR2.78;95%CI1.02-7.58;NNH25)

• Hyperglycemia 85%vs.72%(OR1.18;95%CI1.07-1.31;NNH8)

• Hypernatremia29%vs.18%(OR1.59;95%CI1.13-2.22;NNH9)

JournalName:Journal oftheAmericanMedicalAssociation.StudyTitle :"Effectoftreatmentwithlowdosesofhydrocortisoneandfludrocortisoneonmortalityinpatientswithsepticshock“Authors:AnnaneD,etal, 2010AnnaneTrial

• Studytype:number: N=300• Randomized,prospective,double-blind,parallel-group,placebo-controlled

trial• Sites:19FrenchICUs• Timeline:1995-1999• Methodology:• N=300patientswithsepticshock

– Corticosteroids(n=151)– Placebo(n=149)

AnnaneTrial

• AdverseEventsTherewasnodifferenceintherateofadverseeventsbetweentheplaceboandsteroidgroupsexceptforahigherrateofsurgicalwoundinfectionintheplacebogroup.

JournalName: JAMA.2016.StudyTitle :EffectofEarlyVasopressinvsNorepinephrineonKidneyFailureinPatientsWithSepticShockTheVANISHRandomizedClinicalTrialAuthors:Gordonetal.2016 VANISH

• Studytype:number: N=400• Factorial(2×2)multicentre,doubleblind,RCT• 18adultgeneralICU’s• February2013– May2015

• Methodology:Patientswererandomlyallocatedtoq vasopressin(titratedupto0.06U/min)andhydrocortisone(n = 101),q vasopressinandplacebo(n = 104),q norepinephrineandhydrocortisone(n = 101),orq norepinephrineandplacebo(n = 103).

VANISH

• Seriousadverseevents(includingdigitalormesentericischaemia,life-threateningarrhythmiaandacutecoronarysyndrome)10.7%inthevasopressingroupvs8.3%inthenorepinephrinegroup;difference,2.5%[95%CI,−3.3%to8.2%]

• Nodifferenceinrenalfailure–freedays• Nodifferenceinmortality


All3studies,plusVANISHTrial,showednomortalityincreasewithsteroids

JournalName: EstimatedStudyCompletionDate:December30,2017

StudyTitle :ADjunctive coRticosteroid trEatment iN criticAlly ilLPatientsWithSepticShock(ADRENAL)Authors:Balasubramanian Venkatesh (ADRENAL)

• Studytype:number: 3800patients• amulti-centre,randomised,blinded,placebocontrolledtrial• 70IntensiveCareUnitsrecruitmentcompleted.• Followupofpatientscontinue.• Methodology:• Eligiblepatientswillberandomisedtoreceiveeither

intravenoushydrocortisone200mgorplaceboperdayforsevendays

ANAPPROACHTOSTEROIDSINSEPTICSHOCK• don’tuseinlowriskpatients• considerinhighriskpatients(multi-organfailure)acknowledgingthatsepticshockmayreversemorequicklybutwillnotchangemortality

• uselowdose• vigilanceforsuperinfection• don’tuseashortsynACTHen test• eagerlyawaittheADRENALstudy

Costs

• IVVitaminC:~£66- 196for4-daycoursedrugonly)

• IVThiamine:~£35for4-daycourse(drugonly)

• Hydrocortisone:~£60(drugonly)

ImplementationOptions:AProposal• PatientswithRefractorySepticShock

• Alreadyreceivingsteroids

• NopredictedharmfromaddingVitaminCandthiamineReasonabletoendorseuseinthisgroup

• SepsisandNonRefractorySepticShock

• ThesepatientswouldnototherwisereceivesteroidsperSSCGuidelines

• InadequateEvidence-Basedliteraturetojustifyendorsement

• Therefore,leavetoindividualpractitionerstochoose

AuthorConclusion:

• “OurresultssuggestthattheearlyuseofintravenousvitaminC,togetherwithcorticosteroidsandthiaminemayprovetobeeffectiveinpreventingprogressiveorgandysfunctionincludingAKIandreducingthemortalityofpatientswithseveresepsisandsepticshock.

• Additionalstudiesarerequiredtoconfirmthesepreliminaryfindings.”

ClinicalTakeHomePoint:

• Althoughtheresultsofthisstudyareverypromising,itisimportanttorememberthatthiswasonlyahypothesisgeneratingstudy.Westillneedanexternalvalidationbeforeimplementation(Howmanyothertreatmentsinsepsishavebeentoutedasa“cure”andnotpannedoutinsubsequentstudies?).

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