Hargrove 1

BlameitontheAlcohol:ComparisonofPropofolvsDexmedetomidineforRefractoryAlcoholWithdrawal

KristiHargrove,PharmDPGY1PharmacyResident

DepartmentofPharmacotherapyandPharmacyServices,UniversityHealthSystemPharmacotherapyDivision,TheUniversityofTexasatAustinCollegeofPharmacy

PharmacotherapyEducationandResearchCenter,UTHealthSanAntonioJanuary12,2018

LearningObjectives:1. Describemechanismsofalcoholwithdrawalandpotentialdrugtargetsfortreatment2. Identifysignsandsymptomsofwithdrawal,appropriateassessmentof,andriskfactorsfor

complicationsassociatedwithalcoholwithdrawal3. Summarizeevidenceforuseofpropofolanddexmedetomidineasadjunctagentsinrefractory

alcoholwithdrawal4. Applyevidencetoapatientcasetoprovideappropriaterecommendationsbasedonclinical

presentationandcharacteristics

Hargrove 2

AssessmentQuestions

1. T/F:Aftercessationofchronicalcoholuse,thereisanincreasedexcitatorysignalduetoanincreaseofNMDAreceptors.

a. Trueb. False

2. Allthefollowingarecommonsymptomsofalcoholwithdrawalexcept:a. Tremorsb. Palpitationsc. Reducedbodytemperatured. Hypertension

3. Whatisthefirstlinetreatmentforalcoholwithdrawalsymptoms?a. Ketamineb. Benzodiazepinesc. Metronidazole

4. T/F:Dexmedetomidinecanbeusedaloneasalcoholwithdrawaltreatmentbecauseitprovidesbothsympatholyticandanticonvulsantproperties.

a. Trueb. False

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Faculty (Speaker) Disclosure: Kristi L. Hargrove has indicated she has no relevant financial relationships to disclose relative to the content of her presentation

Hargrove 3

AlcoholWithdrawalSyndrome

I. Backgroundandepidemiology1-4a. Approximately20%ofmenand10%ofwomenwillexperiencealcoholusedisorder

i. 50%ofthesewillexperiencewithdrawalsymptomsfollowingcessationordecreasedconsumption

b. Morbidityandmortalityi. Excessivealcoholconsumptioncanleadtodevelopmentofacutecomplicationsand

chronicdiseasesincluding:1. Cirrhosis2. Cardiovasculardiseaseincludinghypertension,heartdisease,andstroke3. Cancerincludinghepatocellular,colon,breast,mouth,andesophageal4. MemoryandlearningdifficultiesincludingWernicke’sencephalopathyand

dementia5. Depressionandanxiety6. Alcoholdependence

ii. AsreportedbytheNationalInstituteofHealth(NIH),alcoholrelatedmortalityisthethirdleadingcauseofpreventabledeathintheUnitedStatesaccountingforapproximately88,000deathsannually

1. Deathsareattributedtobothacuteandchroniccauses2. Acutecausesincludemotorvehiclecrashes,poisoning,suicidesecondaryto

alcoholuse,fallinjuries,homicideandfireinjuries3. Majorityofchroniccausesareattributedtoabuse/dependence,liver

disease/cirrhosis,andhemorrhagicstrokec. Economicandsocietalconsequences

i. In2010,alcoholmisusecost$249billionintheUnitedStates1. 75%ofthiscostrelatedtobingedrinking

ii. Excessiveconsumptioncanleadtolossofproductivity/unemployment,familystrain,andsocialstigma

II. Definitionsa. Alcoholusedisorder5

i. Chronic,relapsingdiseasecharacterizedbycompulsivealcoholuse,lackofcontroloveralcoholintake,andnegativeemotionalstatewhennotusingalcohol

ii. Classifiedasmild,moderate,orseverebasedonDiagnosticandStatisticalManualofMentalDisorders,5thedition(DSM-5)criteria

iii. SeeAppendixAforcriteriab. Alcoholwithdrawal1,2,5-7

i. PerDSM-5mustmeetthefollowingtwocriteriatobeconsideredalcoholwithdrawal:1. Cessationorreductioninalcoholusethathasbeenheavyandprolonged2. Twoormoreofthefollowingsymptomsdevelopedwithinseveralhourstoafew

daysafteralcoholcessation

Table1.AdditionalDiagnosticCriteriaAutonomichyperactivity PsychomotoragitationIncreasedhandtremor AnxietyInsomnia Transientvisual/auditory/tactilehallucinationNauseaorvomiting Generalizedtonic-clonicseizures

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c. Refractoryalcoholwithdrawal1,2,8,9i. Currentliteraturelacksastandardizeddefinitionii. Definedasfailuretocontrolsymptomswithhighdosesofbenzodiazepines

1. Doses>40mgofdiazepam(orequivalentbenzodiazepine)inonehour2. Doses>50mgdiazepamor10mglorazepamwithinfirsthour3. Doses>200mgdiazepamor40mglorazepamwithinthreehours

iii. Associatedwithlongerintensivecareunit(ICU)stay,increasedincidenceofmechanicalventilationandincreasedriskofnosocomialpneumonia

d. ClinicalInstituteWithdrawalAssessmentforAlcoholScalerevised(CIWA-Ar)8,9i. Toolusedfortheassessmentofseverityofalcoholwithdrawalandriskforseizuresii. Includes10commonsignsandsymptoms

1. Patientmustbeabletoverbalizeandendorsesignsandsymptoms2. UseinICUislimited

iii. ScoreAssessment:1. Mild:CIWA-Ar=0-92. Moderate:CIWA-Ar=10-193. Severe:CIWA-Ar>20

iv. SeeAppendixBforassessmentscaleIII. Pathophysiology2,6,7,12,13

a. AlcoholcausescentralnervoussystemdepressionviastimulationofGamma-AminobutyricAcid(GABA)receptorsandantagonismofN-methyl-D-aspartate(NMDA)receptors

b. ChronicalcoholconsumptioncausesanimbalanceinwhichthebodytriestorestorehomeostasisbyalteringthenumberofGABAandNMDAreceptors

c. Cessationofalcoholreturnstoanunbalancedstatesecondarytothesechangesinreceptors

Figure1.ProgressionofneurologicchangesinalcoholuseFigure2.Homeostasisinchronicalcoholuse6

IV. Clinicalmanifestations1,2,7,10,14-17

a. AlcoholundergoessaturablemetabolismbytheliverviaalcoholdehydrogenaseandCYP2E1i. Asthebodymetabolizesalcoholthereisareductioninbloodalcohollevelleadingto

withdrawalii. Chronicalcoholusemayleadtoacceleratedmetabolismiii. Symptomsstartwithin6-8hours,peakat72hours,andgenerallyreducebyday7

ChronicAlcoholUse

Increasedinhibitorytone

DownregulationGABAreceptor

Reducedinhibitorysignal

Reducedexcitatorytone

UpregulationNMDAreceptor

Increasedexcitatorysignal

Hargrove 5

b. Initialphase:6-12hours

c. Latephase:12-48hoursi. Hallucinationsii. Seizures

d. Deliriumtremens(DT)>3daysi. Definition:Themostseriousmanifestationofalcoholwithdrawalpresentingwith

autonomicinstabilityplushyperactivedeliriumii. Occursinabout3-5%ofpatientshospitalizedforalcoholwithdrawalandhasamortalityof

upto4-8%iii. Symptoms

Table3.SymptomsofDTEarly Progression

Changesinlevelofconsciousness MalignantarrhythmiasInattention/cognitivedeficits SevereelectrolyteabnormalitiesHallucinations DehydrationConfusion ProlongedseizuresHypertension Multiorgandysfunction Death

iv. DTriskfactors1.HistoryofpreviousDT 6.Lastalcoholintake>2days2.Recentuntreatedwithdrawalseizures 7.Age>30years3.Systolicbloodpressure>150mmHgorheartrate>100beats/minute

8.Recentmisuseofotherdepressantssuchasbenzodiazepines

4.Historyofsustaineddrinking 9.Concurrentmedicalillness5.CIWA-Ar³15

Table2.SymptomsofearlyalcoholwithdrawalTremors DiaphoresisAnxiety/insomnia TachycardiaNausea/vomiting HypertensionDiarrhea HeadachePalpitations Increasebodytemperature

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CurrentManagement

I. Supportivetherapy1,2,6,18a. Fluidrepletioninpatientswhoappearhypovolemic

i. Alcoholleadstoimpairedsaltandwaterabsorptionalongwithadiureticeffect(inhibitionofantidiuretichormonerelease)leadingtoareductionintotalwatervolume

ii. Patientsmaynothavebaselineadequatefluidintakeiii. Insensiblelossesthroughvomiting,diarrhea,feverandsweating

b. Vitaminandelectrolyterepletioni. Patientswithchronicalcoholuseareoftenmalnourished

1. Poornutrientintake2. Increasedmetabolicrate

ii. Increasedgutmotilityandmucosalpermeabilityleadstoreducedabsorptioncompoundedbynutrientleakage

iii. Decreasedvitaminabsorptionduetochangesinactivetransport1. Macrocyticanemia(folate)2. RiskofWernicke’sencephalopathy(thiamine)

iv. Intakeofsolutefreefluidandinabilitytohandlefluidappropriatelyleadstorelativesodiumdeficiency

v. Structuralchangesinthekidney,includingthickenedmembranesandalteredcellstructure,alongwithimpairedregulationresultsinelectrolytedisturbances

1. Lossofpotassiumcanleadtodeadlyarrhythmiasvi. Repletethefollowing:

1. Thiamine2. Folate3. Multivitamin4. Electrolytesasindicated:potassium,sodium,phosphate,andmagnesium

II. Benzodiazepinetherapy2,6,19,20

a. Firststudiedin1969,leadingtotheestablishmentofbenzodiazepinetherapyasfirstlinetreatment

b. Followinstitutionspecificguidelinesforpreferredbenzodiazepineanddosing

Figure3.Strategiesforbenzodiazepineuse

FixedDose

•Dailydosecalculatedaccordingtoaveragedailyalcoholintake•Onestandarddrink=~5mgdiazepam•Totaldosedividedevery6hours•Dailymaximumnottoexceeddiazepam60mg•Benzodiazepinetaperedafterapproximately2-3daysofstabilization

•Morereasonableforoutpatientuseifinpatientadmissionnotanoption

SymptomDirected

•Standardofcareasfirstlinealcoholwithdrawaltreatment•CIWA-Arusedtoassesswithdrawalandadministerpre-specifieddosesofbenzodiazepine•Comparedtofixeddose,overallreductioninbenzodiazepineuseandlessunwantedsedationobservedinsymptomdirected•CautioninpatientswithahistoryofalcoholwithdrawalseizuresasseizuresmayprecipitateevenwhenCIWA-Arappearscontrolled

Hargrove 7

III. Benzodiazepinerefractoryalcoholwithdrawal1,8,13,21,22a. Benzodiazepinemonotherapyisnotalwayssufficienttocontrolsymptomsandescalatingdoses

mayleadtoadverseeffectsi. BenzodiazepinesmaysaturatebindingsitethereforetargetingsecondGABAbindingsite

mayimproveefficacyoftherapyii. Glutaminergicactivityisfundamentaltoalcoholwithdrawalsymptomsandisnottargeted

bybenzodiazepinetherapyiii. Benzodiazepinesmayleadtooversedationduetosequestrationintissuefollowinghigh

doseregimensiv. Highcumulativedosescanleadtoadverseoutcomesincludingrespiratorydepression,

increasedaspiration/intubationrisk,increaseddeliriumriskandincreasedhospitallengthofstay

b. Adjunctagentsi. Variousadjunctiveagentshavebeenemployedforuseinpatientswithoutadequate

symptomcontrolfrominitialbenzodiazepinesii. Idealmanagementofbenzodiazepinerefractoryalcoholwithdrawalremainsunclear

Figure4.Mechanismofactionandpharmacologicpropertiesofadjunctagents

Phenobarbital

BindsGABAA receptoratseparatesitefromGABAtoenhance

bindingandpotentiateinhibitorytone

Synergisticeffectswithbenzodiazepinesinpatientsconsidered

refractory

Propofol

BlockNMDAreceptorstoreduceexcitatory

tone

BindsGABA,glycine,nicotinicandM1

muscarinicreceptorstoreduceoveralneural

transmission

Providessedative,anxiolytic,

anticonvulsant,amnesticand

antiemeticproperties

Adverseeffects:hypotensionand

respiratorydepression

Dexmedetomidine

Centralactinga2adrenergicagonistà reductionin

norepinephrinereleaseandsympathetic

outflow

NOTE:DoesNOTprovideanticonvulsant

properties

Providesanxiolytic,sedative,analgesicand

sympatholyticproperties

Adverseeffects:bradycardiaandhypotension

Ketamine

NMDAreceptorantagonist

Opposeoverexpressedexcitatorysignalleading

toreducedbenzodiazepinerequirement

Hargrove 8

LiteratureFocus:UseofPropofolorDexmedetomidine

Propofol7,9

I. Datatosupportusea. CasereportshavedescribedsuccessfuluseofpropofolinpatientswithrefractoryDTb. Useinpatientswithrefractoryalcoholwithdrawalorrequiringmechanicalventilationhasbeen

studiedretrospectivelyTable4.Studiesevaluatingtheuseofpropofolinbenzodiazepinerefractoryalcoholwithdrawal

Studydesign Patientpopulation Intervention BZDdoses ResultsSohrabyetal.(2014)7

Retrospectivecohortanalysis

AdmittedwithalcoholwithdrawalbasedonDSMIVcriteriarequiringMVandreceivingBZDorPROPcontainingregimens

PROP+/-BZDvsBZDinfusionmonotherapy

MedianBZDdosepriortointubation:-PROP=56mgLORequivalents-BZD=15mgLORequivalentsp=0.03

MedianBZDdoseafterintervention:-PROP=10mgLORequivalents-BZD=36mgLORequivalentsp=0.06

n=64

-PROPpatientshadsimilartimetoresolution(PROP8daysvsBZD7days)despitehigherBZDrequirementspriortointubationandPROPinitiation-Adverseeventratessimilarbetweengroupsandincludedhypotensionandbradycardiainbothgroups;pancreatitisandAKIalsoobservedinthePROPgroup(singleepisodeofeach)-PROPprovidesalternativetreatmentinpatientswithalcoholwithdrawaluncontrolledbyBZDrequiringMV

Wongetal.(2015)9

Retrospectivecohortreview

Patientsmeetingrefractoryalcoholwithdrawalcriteria:Useof³40mgdiazepam(orequivalent)within1hour

BZD+PROPvsBZDalone-Patientsexcludedifotheradjunctagentswereused

MedianBZDforrefractorydesignation:-BZD+PROP=54mgDIAequivalents-BZDonly=50mgDIAequivalents

TotalBZDrequirementin7-dayperiodafterrefractorydesignation:-BZD+PROP=743mgDIAequivalents-BZDonly=576mgDIAequivalents

n=66

-LongertimetoresolutionofsymptomsinPROPcontaininggroup(PROP7daysvsBZD5days)-TheadditionofPROPtoBZDforrefractoryalcoholwithdrawalwasassociatedwithmoreclinicalcareincludinglongerICU/hospitallengthofstay,increasednosocomialpneumoniaandhigheralcoholwithdrawalrelatedcomplicationssuchashallucinationandDTs

Abbreviations:AKI=AcuteKidneyInjury,BZD=benzodiazepine,DIA=diazepam,DSMIV=DiagnosticandStatisticalManualofMentalDisorders,DT=deliriumtremens,LOR=lorazepam,MV=mechanicalventilation,PROP=propofol

Hargrove 9

Dexmedetomidine23-26

I. Datatosupportusea. Multipleretrospectivecaseseriesandstudieshaveinvestigateduseofdexmedetomidine

Table5.Studiesevaluatingtheuseofdexmedetomidineinbenzodiazepinerefractoryalcoholwithdrawal22-25

Studydesign Patientpopulation Intervention BZDdose ResultsRayneretal.(2012)23

Singlecenterretrospectiveobservational

Patientsadmittedtomedical,surgical,neuroscienceICU-Predominatelymalesubjectswithaverageage44.9years-ExcludedforseverecomorbiddiseaseincludingCNStraumaandCVA

AdditionofDEXfordocumentedmanagementofalcoholwithdrawalsymptoms

AverageBZDdosepriortoDEX:-52.7mg/24hours

AverageBZDinfirst24hoursafterDEXinitiation:-20.3mg/24hours

p<0.001

n=20

-DEXtherapyassociatedwithreducedBZDdosingandbluntedhyperadrenergicresponsedefinedasareductioninHRandSBP-Onepatientrequireddiscontinuationduetobriefasystolicpauses.-Bradycardiaandhypotensionwerenotsignificantlydifferent

Frazeeetal.(2014)24

Retrospectivecaseseries

CriticallyilladultswithICUadmissiondiagnosisofalcoholwithdrawaltreatedwithDEX-PredominantlywhitemalepatientsinthemedicalICU

ProviderdrivenadditionofDEXtoinstitutionalstandardsymptomdrivenBZDprotocol

CumulativemedianBZDdose-PriortoDEX:30mg-AfterDEX:8mg

n=33

-ReductioninBZDdose,SBPandHRafterinitiationofDEX-EarlyintroductionofDEXforseverealcoholwithdrawaldecreasedBZDrequirementsandautonomichyperreactivity-Threepatientsexperiencedseizuresecondarytowithdrawal-Multimodalmanagementmayimprovecontrolofwithdrawalincriticallyillpatients

Crispoetal.(2014)25

Multicenter,retrospectivecohortstudy

Non-intubatedadultsage18-89withalcoholwithdrawalwhoreceivedcontinuousinfusionBZD

BaselineCharacteristics:DEXgroupincludedsignificantlyolder(p=0.03),white(p<0.01)malesBZDgroupincludedyounger,Hispanicmales-Greaterolanzapineandpre-studyBZDusep<0.01

DEXinfusionvsBZDinfusion(lorazepamormidazolam)

CumulativemeanBZDpriortostudydrug:-DEX=8.4mgLORequivalents-BZD=19.6LORequivalents

CumulativemeanBZDdoseduringstudy-DEX=10.8mgLORequivalents-BZD=160.4mgLORequivalentsa

n=61

-Nodifferenceincompositeefficacyendpointofrespiratorydistressorseizure-OnepatientintheDEXgroupdevelopedaseizureafternotreceivinganyBZD-Bradycardia(46.5%vs15.2%)andhypotension(42.9%vs12.1%)werebothsignificantlyhigherinDEXgroupoverBZDgroup(p<0.01)-DEXdemonstratedaBZDsparingeffect-Protectiveeffecttopreventintubationcouldnotbeproven

Hargrove 10

Studydesign Patientpopulation Intervention BZDdose ResultsVanderWeideetal.(2016)26

Retrospectivecontrolledcohortstudy

PatientsadmittedtoICUwithprimarydiagnosisofalcoholwithdrawalreceiving>8mgLORwithin6-hourwindowandCIWA-Ar>8included-Predominantlymiddleage(45-50yearold)whitemales-Nosignificantdifferencesatbaseline

DEXinfusionvsmatchedcontrol

12hourpre/postdifference:-DEX=-19.9mg-Control=8.3mg-p=0.04624hourpre/postdifference:-DEX=-29.6mg-Control=-11mg-p=0.06

n=20-Median12hourBZDrequirementsignificantlydecreased-NosignificantdifferenceinBZDrequirementat24hours-PatientsreceivingDEXexperiencedsignificantlymorebradycardia(1patientHR<40)butnothypotensionreinforcingsafetyconcernwithDEXuse

Abbreviations:BZD=benzodiazepine,CIWA-Ar=ClinicalInstituteWithdrawalAssessmentScalerevised,CNS=centralnervoussystem,CVA=cerebrovascularaccident,DEX=dexmedetomidine,HR=heartrate,ICU=intensivecareunit,LOR=lorazepam,SBP=systolicbloodpressureaIncludedcontinuousinfusionBZDintotaldose

Table6.MuellerSWetal.Arandomized,double-blind,placebo-controlleddoserangestudyofdexmedetomidineasadjunctivetherapyforalcoholwithdrawal(2014)27

ObjectiveEvaluatetheefficacyofDEXasadjunctivetherapytoasymptomtriggeredalcoholwithdrawalprotocol

MethodsSinglecenter,doubleblind,placebocontrolledstudy

PatientpopulationInclusion• AdultsadmittedtomedicalICUwithseverealcohol

withdrawal• Receivingstandard,symptom-driventherapy• Severealcoholwithdrawal:

CIWA-Ar³15andLORuse³16mgina4-hourperiod

Exclusion• Age<18yearsoldor>85yearsold• AdministrationofBZDforotherindications• CurrentuseofDEX• NotadmittedtoICU• Comatoseduetometabolic/neurologiccause• ActiveMI/Heartblock• Child-PughclassCliverdisease• Pregnancy• Moribundstatewithplannedwithdrawaloflife

support• KnownhistoryofadversereactiontoDEX• Non-Englishspeaking• Abuseofmultiplesubstances

Intervention

DEXlowdose(LD)(0.4mcg/kg/hr)vsDEXhighdose(HD)(1.2mcg/kg/hr)vsplacebo• Standardtherapyincludedsymptom-drivenprotocolwithnurse-managed,slidingscaleBZDaccordingto

withdrawalseveritymeasuredbyCIWAscoreatminimumevery4hoursandafterintervention• Lorazepam2-4mgIVadministeredevery30minutesforCIWAscores>15• Providernotifiedif³8mgLOR,thenLORinfusionoradjunctivemedicationswereinitiated• Patientsreceivedadditionalagentsincludingopiates,antipsychoticsandphenobarbitalatthediscretionofthe

provider

Hargrove 11

OutcomesPrimary• DLORrequirementsover24hours• CumulativeLORrequirementover7days

OutcomesreportedasLD,HDandcombinedtreatmentgroup(LD+HD)

Secondary• Post-randomizationandtotaldailyLORrequirements• Intubation• Seizureafterstartingstudydrug• Severityofseverealcoholwithdrawal• Safetyoutcomes:bradycardia(HR<50)and

hypotension(MAP<65orSBP<90)andadjustmentofinfusionduetohemodynamiceffects

Statistics• Outcomeswerereportedasmedian+IQRorproportionsbasedonnatureoftheendpoint• Goalenrollment24patients(2:1randomizationincombinedDEXgrouptoplacebo)toachieve80%powerand5%

significancelevelbasedonadesiredmeandifferenceof80mgofLORoverthefirst7days• p<0.05consideredsignificant

Baselinecharacteristics

• Predominantlymiddleaged(47-51yo)males• BaselinemedianAPACHEIIIscoresignificantlyhigherintheLDgroupascomparedwithplacebobutnotHD(p=0.01

andp=0.066respectively)• Intubationatstudyentry:Placebo3(37.5%)vsLD5(62.5%)vsHD3(37.5%)• Trendtowardshigherpre-study24-hourrequirementoflorazepamintheLDandHDgroupvsplacebothoughp

valuesnon-significanto Placebo=39mgvsLD=94mgvsHD=75mg(combined=82mg)

• TrendtowardslongertimestudydrugadministrationinLDgroupthoughnosignificantdifference

ResultsDurationofinfusion:Placebo=70.25hrvsLD=53.13hrvsHD=78hr

Placebon=8 LDn=8 HDn=8 LD+HDn=16Primary DLORrequirements

over24hours-8mg -62.1mg

p=0.066-45mgp=0.1

-56.4mgp=0.037

CumulativeLORrequirement(7days)

180.6mg 180.5mgp=0.64

112.5mgp=0.71

159.1mgp=0.58

Secondary 24hourLORuse 77.1mg 28.5mgp=0.64

14.8mgp=0.27

22.3mgp=0.33

TotalpoststudydrugLORrequirements

109.1mg 58.5mgp=0.19

55.6mgp=0.53

58.5mgp=0.23

ICUlengthofstay 4days 5.5daysp=0.43

3.8daysp=0.64

4.7daysp=0.42

Hospitallengthofstay 7.4days 10.9daysp=0.71

8.6daysp=0.87

10daysp=0.71

Nopatientsrequiredintubationorexperiencedseizureafterstudyinitiation

Safety:#ofpatients(%) Placebo LD HD LD+HDBradycardiaa 0(0%) 1(12.5%)p=1 3(37.5%)p=0.2 4(25%)p=0.26DecreaseHRby>20bpm 2(25%) 3(37.5%)p=1 7(87.5%)p=0.04 10(62.5%)p=0.19Hypotension 0(0%) 1(12.5%)p=1 2(25%)p=0.47 3(18.75%)p=0.52Interventionforhypertension

2(25%) 3(37.5%)p=1 1(12.5%)p=1 4(25%)p=1

Temporaryd/corchangeinrateofstudydrug

0(0%) 4(50%)p=0.077 4(50%)p=0.077 8(50%)p=0.022

Onepatientrequired,discontinuationoftherapy,fluidbolusforhypotensionandthenabletoresumeinfusion.

Hargrove 12

Conclusion• AdjunctiveuseofDEXleadtoshortterm(first24hour)butnot7-daybenzodiazepinesparingeffect• BradycardianecessitatesneedformonitoringhoweverinthisstudyDEXdoseadjustmentleadtoresolutionofside

effectReviewer’scritique

• Firstprospective,placebocontrolledstudyànewoutlookontheuseofdexmedetomidineforadjuncttreatment• Longtermbenzodiazepinereductionwasnotseenlimitingvalueforoverallreductioninbenzodiazepineuse

o Possiblyduetoshortinfusionduration(maximum3-4days)whichmaynothaveanextendedbenefit• Inclusionofmoreclinicallysignificantoutcomes,suchasdurationofalcoholwithdrawalsymptoms,couldhelptease

outbenefitofdexmedetomidineStrengths• Prospectiveandplacebocontrolled• Providedclinicallysignificantsafetyoutcomes• ComparedefficacyandsafetyatdifferentDEXdoses• DescribedICUalcoholwithdrawalprotocol

Limitations• Smallsamplesize• Samplesizemetpowercalculationhoweverresults

didnotmeetexpecteddifference• Higherthanexpectedbaselineintubationrate

reducingoptimalassessmentofalcoholwithdrawal• Variabilityinbaselinecharacteristics

Abbreviations:APACHEIII=AcutePhysiologyandChronicHealthEvaluation,BZD=benzodiazepine,CIWA-Ar=ClinicalInstituteWithdrawalAssessmentScalerevised,DEX=dexmedetomidine,HD=highdose,HR=heartrate,ICU=intensivecareunit,IQR=interquartilerange,LD=lowdose,LOR=lorazepam,LOS=lengthofstay,MAP=meanarterialpressure,MI=myocardialinfarction,SBP=systolicbloodpressure

Table7.BielkaKetal.Additionofdexmedetomidinetobenzodiazepinesforpatientswithalcoholwithdrawalsyndromeintheintensivecareunit:arandomizedcontrolledstudy(2015)28

ObjectiveEvaluateiftheadditionofDEXtoBZDtherapyiseffectivetoreduceBZDuseforalcoholwithdrawalsyndromepatientsintheICU

MethodsSinglecenter,randomized,controlledstudyinmixedICUsetting

PatientpopulationInclusion• Age18-75yearsold• DiagnosisofalcoholwithdrawalsyndromebyDSMIV

Exclusion• Historyofothersubstanceabuse• Useofgeneralanesthesiainprior24hours• NeurologicaldisorderincludingTBI/stroke/dementia• Co-morbidconditions:heartfailure,MI,HR<50,

GFR<30mL/min,liverfailure(Child-PughclassC),acuterespiratoryfailure

InterventionDEX0.2-1.4mcg/kg/hrtitratedtotargetsedationandCIWA-Ar(GroupD)vscontrol(GroupC)• TargetRASS0to-2• TargetCIWA-Ar<15• BZDprotocol:DIA10mgevery30minutesforRASS>+2orCIWA-Ar>15• Haloperidol5mgIMpermittedasrescueforsevereagitationorhallucinations

OutcomesPrimaryEfficacy• 24-houruseofDIA• CumulativeuseofDIAintheICUSecondary• ICULOS• Rateofintubation• TimespentattargetRASS• Necessityforrescuesedation• Sedationstops• Haloperidolrequirements

Safety• Hypotension(SBP<90)orhypertension(SBP>160)• Bradycardia(HR<50)ortachycardia(HR>110)• Desaturation<90%• Hypoglycemia(<70mg/dL)orhyperglycemia

(>180mg/dL)

Hargrove 13

Statistics• Categoricaldatapresentedasproportions• ContinuousdatapresentedasmedianswithIQR• p<0.05wasconsideredsignificant

Baselinecharacteristics• Predominantlymiddle-aged(46yo)males• DIAdose:nodifferenceGroupDvsGroupC(30mgvs30mg)• MedianCIWA-AratICUadmissionDEXvsplacebo25vs26(p=1)• MedianRASSatICUadmission+2forbothgroups

ResultsDurationofDEXinfusion:36hoursMediandose:0.5mcg/kg/hr

GroupD(n=35) GroupC(n=32) pvaluePrimary 24hourDIA 20mg 40mg p<0.001

CumulativeuseofDIA 60mg 90mg p<0.001Secondary ICULOS 50hr 70hr p=0.059

Sedation:TimetargetRASSRescuesedation(#)Sedationstops(#/24h)

90% 64.5% p<0.0011.25 4 p=0.0040 2 p=0.001

Haloperidolrequirement 6% 31% p=0.02Haloperidolcumulativedose

50mg 60mg p=0.2

Safety

GroupD GroupC pvalueTachycardia 0/35(0%) 5/32(16%) p=0.02Bradycardia 10/35(31%) 2/32(6%) p=0.03Hypertension 0/35(0%) 4/32(16%) p=0.05Ratesofhypotension,desaturation,hypoglycemiaandhyperglycemiaweresimilarbetweengroups

Conclusions• DEXsignificantlyreducedDIAconsumptionofsymptomtriggeredprotocolaswellasimprovedtimeintarget

sedation• UseofDEXreducedhyperadrenergicsymptomsincludinghypertensionandtachycardia• PatientsreceivingDEXshouldbemonitoredforbradycardia• AdditionofDEXtoBZDtherapyissafeandeffectiveforpatientswithalcoholwithdrawalsyndromeintheICU

Reviewer’scritique

• AdditionalmeasureoftargetsedationwithRASSgoal-2to0wasanadequatetargettokeeppatientlightlysedatedandabletoarouse

o Frequentmonitoringforoversedationandairwayprotectionrequiredsincenotallpatientswerenotintubated

• Bradycardiaisaknownsafetyconcernwiththeuseofdexmedetomidinewhichrequirespatientstobecloselymonitoredandexpectedthatthiswouldoccurmorefrequently

• Sincealcoholwithdrawalcanpresentwithtachycardiaandhypertension,theadverseeffectsobservedinthisstudyintheplacebogroupcouldbeduetoinadequatecontrolofalcoholwithdrawalindicatingadditionalmanagementstrategiescouldbeappropriate

Hargrove 14

Abbreviations:BZD=benzodiazepine,CIWA-Ar=ClinicalInstituteWithdrawalAssessmentScalerevised,DEX=Dexmedetomidine,DIA=diazepam,DSMIV=DiagnosticandStatisticalManualofMentalDisorders,GFR=glomerularfiltrationrate,HR=heartrate,ICU=intensivecareunit,IM=intramuscular,LOS=lengthofstay,MI=myocardialinfarction,RASS=RichmondAgitation-SedationScale,SBP=systolicbloodpressure,TBI=traumaticbraininjury

ClinicalQuestion:Whichsedativeagentimprovescontrolofrefractoryalcoholwithdrawalwhilemaintainingsafetyoutcomes?

Table8.LudtkeKAetal.Retrospectivereviewofcriticallyillpatientsexperiencingalcoholwithdrawal:dexmedetomidineversuspropofoland/orlorazepamcontinuousinfusions(2015)29

Objective

EvaluatetheincidenceanddurationofmechanicalventilationandICUlengthofstayinalcoholwithdrawalpatientstreatedwithDEXvsPROPand/orLORcontinuousinfusions

MethodsSinglecenterretrospectivechartreviewstudyofpatientsdiagnosedwithtreatedforalcoholwithdrawalduringtheirICUadmission

PatientPopulationInclusion• Adultcriticalcarepatients• Diagnosisofalcoholwithdrawal• Treatedwithcontinuousinfusionoftargetedagents

Exclusion• TreatmentwithcontinuousinfusionofDEX+either

PROPorLOR

InterventionDEXcontinuousinfusionvsPROP/LORinfusionsrepresentingstandardofcare• LowdoseintermittentBZDavailableasscheduledorasneededrescuemedicationduetolackofanticonvulsant

effectofDEXOutcomes

Primary• Mechanicalventilation(MV)• LengthofMV• ICU/hospitalLOS

Statistics• ContinuousvariablesusedttestandMann-Whitney-Utest• CategoricaldatawereanalyzedwithFisher’sexacttest• LinearregressiontodeterminepredictorsofICULOSandhospitalLOS• p<0.05consideredsignificant

BaselineCharacteristics• Nosignificantdifferencesinageandsex• ICUadmitmeanCIWAsignificantlyhigherinpatientstreatedwithDEX(23.1DEXvs15PROP/LORp=0.039)

ResultsPrimary:DEX(n=15)vsPROP/LOR(n=17)• MV(days):2vs10(p=0.006)• Meanlengthofintubation(days):0.95vs4.1(p=0.264)• MeanICULOS(days):2.2vs4.8(p=0.016)• MeanhospitalLOS(days):5.7vs10(p=0.008)

ConclusionDuetoreducedintubationandshorterLOS,DEXisanattractivealternativetoPROPandBZDinfusionsinthemanagementofalcoholwithdrawalsyndrome

Strengths• Prospective• Similarbaselinecharacteristics• Clinicallysignificantoutcomesmeasuredandwide

varietyofsafetyendpoints

Limitations• Noplacebocomparator• Smallsamplesize• Additionaladjunctmedicationused

Hargrove 15

Reviewer’sCritique• ComparedDEXtothestandardofcareatthetimeincludingLORand/orPROPinfusioninseverealcoholwithdrawal• LOSandMVwerestatisticallygreaterinthePROP/LORgroupvsDEX

o Therewasnobreakdownofthe17patientsinthePROP/LORgroupmakingitdifficulttodrawconclusionsofDEXvsPROPasadjunctagents

• FurthersubgroupanalysiswouldhelpdistinguishbenefitsofDEXandPROPseparatelythoughauthorscommentedthatthegoalwastocomparestandardofcaretoDEX

• Additionally,thestudydidnotcommentonobservedadverseeffectswhichareclinicallyimportantwithuseofthesemedications

Strengths• Directcomparisonofstudydrugs• Assessedappropriateclinicaloutcomesthatmayshow

benefitforuseofoneagentovertheotherbasedonpatientcharacteristicsandriskforcomplication

Limitations:• Retrospectiveleadingtopotentialformissingdata• Baselinedifferencesinstudygroupsandnocontrol

forco-morbiditiesthatmayaffectintubationorlengthofstay

• NosubgroupanalysisofPROPandLORgroupseparately

Abbreviations:CIWA-Ar=ClinicalInstituteWithdrawalAssessmentScale,DEX=dexmedetomidine,ICU=intensivecareunit,LOR=lorazepam,LOS=lengthofstay,MV=mechanicalventilation,PROP=propofol

Table9.LizotteRJetal.Evaluatingtheeffectsofdexmedetomidinecomparedtopropofolasadjunctivetherapyinpatientswithalcoholwithdrawal(2014)230

ObjectiveCompareeffectsofDEXvsPROPonBZDandhaloperidolrequirementsinpatientswithalcoholwithdrawal

MethodsSinglecenter,retrospectivestudyofpatientsadmittedtothemedical,cardiac,surgicalortransitionalICUwiththealcoholwithdrawalordersetpluseitherDEXorPROPforsedationfromNovember2010toOctober2013

PatientpopulationInclusion• Age>18yearsold• Diagnosisofalcoholwithdrawal• ReceivedsedationwithDEXorPROP• Activelyreceivingtheinstitution’salcoholwithdrawal

orderset

Exclusion• Alcoholwithdrawalordersdiscontinuedbeforestart

ofsedation• ScheduledBZDorantipsychoticfromhome• ConcomitantadministrationCIBZD• ContraindicationstoBZDorantipsychoticuse• Receivedsedationwithin4hoursofadmission• CombinationDEX+PROP

Intervention

DEXvsPROPaddedtoalcoholwithdrawalprotocolbasedonproviderpreference• AlcoholWithdrawalAssessmentScale(AWAS):measurestremor,tachycardia,bloodpressure,diaphoresis,

fever,nausea/vomiting,agitation/confusion,sleeplessnessandhallucinationsformaxscore=29• LorazepamgivenbasedoncurrentAWASscore>11assessedevery30minutes• Haloperidolpermittedevery30minutesforsevereagitation• AlcoholwithdrawalprotocolincludesIVfluids,thiamine,vitamins,haloperidolandlorazepam

Outcomes

Primary• BZDandhaloperidolutilizationbeforeandafter

additionofDEXorpropofol

Secondary• ICULOS• Rateandtimeofintubation• Analgesicuse• AWASscore/RASS/CAM-ICU• Adverseeffects:bradycardia(HR<60)and

hypotension(SBP<90mmHg)

Hargrove 16

Statistics• Primaryoutcomereportedasameanandanalyzedusingtwo-tailedWilcoxonsigned-ranktests• SecondaryoutcomesreportedasmeansandpercentagesandanalyzedusingtwotailedMann-WhitneyUtests• p<0.05consideredsignificant

BaselineCharacteristics

CAM-ICU:6patientsassessedatbaselineandpositiveforCAM-ICU

BaselineAWASscorepriortoinitiation:• DEX=11.4(n=24)• PROP=12.8(n=2)• AWASscoreswerenotavailablefor15patients

BaselineRASS:• DEX=0.11• PROP=0.87• RASSnotcollectedon12patients

Results

DEX(n=34) PROP(n=7) pvaluePrimary BZDusebeforeandafter

intervention20.9mgvs4.4mgp£0.0001

17.4mgvs3.9mgp=0.043

p=0.933

Haloperidolusebeforeandafterintervention

8.5mgvs0.9mgp£0.0001

8.7mgvs0.7mgp=0.026

p=0.465

Secondary ICUlengthofstay(hrs) 123.6 156.5 p=0.125Intubationrate 5(14.7%) 7(100%) Durationofintubation(hrs) 19.9 97.6 p=0.002Analgesicuse NodifferencereportedMeanAWASn=24 7.5 Notcollected MeanRASSn=29 -0.7 -2.5

Safety Bradycardia 6(17.6%) 0 Hypotension 6(17.6%) 2(28.5%)

Conclusions• Thisanalysissupportstheuseofadjunctivetherapyinseverealcoholwithdrawal• DEXandPROPsignificantlyreducealcoholwithdrawalrelatedsymptomsandBZD/haloperidolrequirements

Reviewer’sCritique• Bothagentssignificantlyreducedbenzodiazepineandhaloperidolusewithnodifferencebetweenthetwoagents• Patientspecificcharacteristicsandotherdrugconsiderationscanbedrawnfromthisstudy• Rateanddurationofintubationwerelongerinthepropofolgroupaccompaniedbydeepersedation(meanRASS-

2.5)whichmayleadtoventilationandICUrelatedcomplicationsincludinginfectionanddeliriumo Notallpatientsinthedexmedetomidinegroupwereintubated.However,thosethatwerehadshortertime

toextubationo Includingnon-intubatedpatientsreinforcesadvantageofdexmedetomidineuseinsparingneedfor

intubation• Asexpected,higherratesofbradycardiaandhypotensionwereseenwithdexmedetomidine• OpposingsafetyoutcomesaddtothelackofdistinctionbetweenaclearlyfavorablechoiceStrengths• Firstdirectcomparisonofdrugspreviouslystudiedvs

placebo• Assessedclinicallyappropriateadverseeffects• Compareddifferenceswithinthedrugaswellas

betweenthetwodrugs

Limitations• Didnotdefinebaselinecharacteristicsorcomment

onpotentialdifferences• UsedinstitutionalAWASscoreratherthanCIWA-Ar

forassessmentofwithdrawalsymptomsreducingoutsideapplicability

• Incompletedataduetoretrospectivestudy• Smallsamplesizewithmismatchednumberof

patientsineachgroupAbbreviations:AWAS=Acutewithdrawalassessmentscale,BZD=benzodiazepine,CAM-ICU=confusionassessmentmethodintheICU,CI=continuousinfusion,CIWA-Ar=ClinicalInstituteWithdrawalAssessmentScaleRevised,DEX=dexmedetomidine,HR=heartrateICU=intensivecareunit,LOS=lengthofstay,PROP=propofol,RASS=RichmondAgitation-SedationScale,SBP=systolicbloodpressure

Hargrove 17

Conclusion

I. Overalla. Alcoholwithdrawalisaseriouscomplicationofalcoholabusewhichcanleadtoseizures,

arrhythmias,delirium,organfailureandevendeathb. Initialtreatmentwithasymptomdirectedbenzodiazepineprotocolisthestandardofcarefor

alcoholwithdrawalc. Patientswhorequireescalatingdosesofbenzodiazepinewithoutadditionalbenefitorsymptom

improvementareconsideredrefractorytofirstlinetreatmentd. Dexmedetomidineandpropofolarealternativeadjunctagentsusedinrefractoryalcohol

withdrawale. Dexmedetomidineprovidesaviableadditionaloptionforsedationinbenzodiazepinerefractory

alcoholwithdrawalanddoesnotrequireintubation.i. ICUlevelcareisstillrequiredformonitoringofdose-relatedbradycardiaand

hypotension.f. Adjunctdexmedetomidineandpropofolhavebeenseentoreducesymptomtriggered

benzodiazepinerequirementandshortenICUlengthofstayreducingriskofdeliriumwithfavorablesafetyprofile

II. FutureDirectionsa. Prospectiveheadtoheadevaluationofdexmedetomidinevspropofolb. Studyinfluenceoftimetoinitiationofsedativeagent(earliervslateraddition)c. Furtherexplorationofketamineuseandadditiontodexmedetomidine(currentstudyinprogress)

III. TreatmentRecommendations

a. Non-intubatedpatients:Recommenddexmedetomidinei. Reducebenzodiazepinerequirementsandhyperadrenergicrelatedsymptomsii. Doesnotroutinelyrequirepatientbeintubatedforinitiation

b. Inintubatedpatients:Recommenddexmedetomidinei. Facilitateshorterintubationtimeii. Potentialreductioninintubationrelatedcomplication

c. Wouldnotrecommenddexmedetomidineinthefollowingpatientpopulationsi. Patientswithcardiachistory(suchasheartblock)inwhichbradycardiacouldbeharmfulii. Patientswithactivealcoholwithdrawalseizuresorrecenthistoryofalcoholwithdrawal

relatedseizure

Hargrove 18

References1.LongD,LongB,KoyfmanA.Theemergencymedicinemanagementofseverealcoholwithdrawal.AmJEmergMed.2017;35:1005-1011.2.SchmidtKJ,DoshiMR,HolzhausenJM,etal.Treatmentofseverealcoholwithdrawal.AnnPharmacother.2016;50(5):389-401.3.NationalInstituteonAlcoholAbuseandAlcoholism.Alcoholfactsandstatistics.https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/alcohol-use-disorders.AccessedNovember10,2017.4.CentersforDiseaseControl.FactSheets–Alcoholuseandyourhealth.https://www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm.AccessedNovember10,2017.5.NationalInstituteonAlcoholAbuseandAlcoholism.Alcoholusedisorder.https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/alcohol-use-disorders.AccessedNovember10,2017.6.KattimaniS,BharadwajB.Clinicalmanagementofalcoholwithdrawal:asystematicreview.IndPsychiatryJ.2013;22(2):100-108.7.SohrabyR,AttridgeRL,HughesDW.Useofpropofol-containingversusbenzodiazepineregimensforalcoholwithdrawalrequiringmechanicalventilation.AnnPharmacother.2014;48(4)456-461.8.HackJB,HoffmanRS,NelsonLS.Resistantalcoholwithdrawal:Doesanunexpectedlylargesedativerequirementidentifythesepatientsearly?JMedToxicol.2006;2(2):55-60.9.WongA,BenedictNJ,LohrBR,etal.Managementofbenzodiazepine-resistantalcoholwithdrawalacrossahealthcaresystem:benzodiazepinedose-escalationwithorwithoutpropofol.DrugAlcoholDepend.2015;154:296-297.10.SchuckitMA.Recognitionandmanagementofwithdrawaldelirium(deliriumtremens).NEnglJMed.2014;371(22):2109-2113.11.SullivanJT,SykoraK,SchneidermanJ,etal.Assessmentofalcoholwithdrawal:therevisedclinicalinstitutewithdrawalassessmentforalcoholscale(CIWA-Ar).BrJAddict.1989;84:1353-1357.12.LorentzenK,LauritsenAO,BendtsenAO.Useofpropofolinfusioninalcoholwithdrawal-inducedrefractorydeliriumtremens.DanMedJ.2014;61(5):1-5.13.WongA,BenedictNJ,Kane-GillSL.Multicenterevaluationofpharmacologicmanagementandoutcomesassociatedwithsevereresistantalcoholwithdrawal.JCritCare.2015;30(2):405-409.14.JawaRS,StothertJC,ShostromVK,etal.Alcoholwithdrawalsyndromeinadmittedtraumapatients.AmJSurg.2014;208(5):781-787.15.MakicMBF.Alcoholwithdrawalsyndrome.JPerianesthNurs.2017;32(2):140-141.16.Mayo-SmithMF,BeecherLH,FischerTL,etal.Managementofalcoholwithdrawaldelirium.ArchInternMed.2004;164(13):1405-1412.17.CederbaumAI.Alcoholmetabolism.ClinLiverDis.2012;16(4):667-685.18.EpsteinM.Alcohol’simpactonkidneyfunction.AlcoholHealthResWorld.1997;21(1):84-92.19.WongA,SmithburgerPL,Kane-GillSL.Reviewofadjunctivedexmedetomidineinthemanagementofsevereacutealcoholwithdrawalsyndrome.AmJDrugAlcoholAbuse.2015;41(5):382-391.20.WorldHealthOrganization.Managementofalcoholwithdrawal.http://www.who.int/mental_health/mhgap/evidence/alcohol/q2/en/.AccessedNovember10,2017.21.BarrJ,FraserGL,PuntilloK,etal.Clinicalpracticeguidelinesforthemanagementofpain,agitationanddeliriuminadultpatientsintheintensivecareunit.CritCareMed.2013;41(1):263-306.22.WongA,BenedictNJ,ArmahizerMJ,etal.Evaluationofadjunctiveketaminetobenzodiazepineformanagementofalcoholwithdrawalsyndrome.AnnPharmacother.2015;49(1):14-19.23.RaynerSG,WeinertCR,PengH,etal.DexmedetomidineasadjuncttreatmentforseverealcoholwithdrawalintheICU.AnnIntensiveCare.2012;2(12)1-6.24.FrazeeEN,PersonettHA,LeungJG,etal.Influenceofdexmedetomidinetherapyonthemanagementofseverealcoholwithdrawalsyndromeincriticallyillpatients.JCritCare.2014;29(2):298-302.25.CrispoAL,DaleyMJ,PepinJL,etal.Comparisonofclinicaloutcomesinnonintubatedpatientswithseverealcoholwithdrawalsyndrometreatedwithcontinuous-infusionsedatives:dexmedetomidineversusbenzodiazepines.Pharmacotherapy.2014;34(9):910-917.26.VanderWeideLA,FosterCJ,MacLarenR,etal.EvaluationofearlydexmedetomidineadditiontothestandardofcareforseverealcoholwithdrawalintheICU:Aretrospectivecontrolledcohortstudy.JIntensiveCareMed.2016;31(3):198-204.27.MuellerSW,PreslaskiCR,KiserTH,etal.Arandomized,double-blind,placebo-controlleddoserangestudyofdexmedetomidineasadjunctivetherapyforalcoholwithdrawal.CritCareMed.2014;42:1131-1139.28.BielkaK,KuchynI,GlumcherF.Additionofdexmedetomidinetobenzodiazepinesforpatientswithalcoholwithdrawalsyndromeintheintensivecareunit:arandomizedcontrolledstudy.AnnIntensiveCare.2015;5(33):1-7.29.LudtkeKA,StanleyKS,YountNL,etal.Retrospectivereviewofcriticallyillpatientsexperiencingalcoholwithdrawal:dexmedetomidineversuspropofoland/orlorazepamcontinuousinfusions.HospPharm.2015;50:208-213.30.LizotteRJ,KappesJA,BartelBJ,etal.Evaluatingtheeffectsofdexmedetomidinecomparedtopropofolasadjunctivetherapyinpatientswithalcoholwithdrawal.ClinPharmacol.2014;6:171-177.31.NationalInstituteonAlcoholAbuseandAlcoholism.Alcoholusedisorder:AcomparisonbetweenDSM-IVandDSM-5.https://pubs.niaaa.nih.gov/publications/dsmfactsheet/dsmfact.htm.AccessedNovember10,2017.32.UniversityHealthSystem.STICUnonweightbasedanalgesia&sedationprotocolforthemechanicallyintubatedpatient.http://phome/Protocols/docs/TraumaCriticalCare/Protocol%20Analgesia%20and%20Sedation%20for%20Mechanically%20Ventilated%20Patient%209%209%202015.pdf.AccessedJanuary10,2018.

Hargrove 19

Appendices

I. AppendixA.DSM-5criteriaforalcoholusedisorder31

Hargrove 20

II. AppendixB.ClinicalInstituteWithdrawalAssessmentforalcoholscale(CIWA-Ar)10

III. AppendixC.RichmondAgitation-SedationScale(RASS)32