Dexmedetomidine • LITFL • CCC Pharmacology

Dexmedetomidine · loading dose 1mcg/kg over 10 minutes (optional) · 0.2-0.7mcg/kg/hr infusion. Skiptocontent Reviewedandrevised 25August2016 CLASS alpha2agonist MECHANISMOFACTION selectivealpha2agonistinCNS8timesmoreselectivethanclonidine)bindsall3subtypesofalpha2receptor(A,B,C)Sedationreducessympatheticactivityandagitation,causingastateresemblingthenon-REMphaseofsleepwithoutimpairingcognitivefunctionsedationisinducedbyinhibitionofnoradrenergicactivity viaactivationofalpha-2receptorsatthelocuscoeruleusproducesapatientwhoissedatedbutcanbeeasilyrousedwithminimalstimulationminimal respiratorydepression(RR,PaCO2,SpO2,andhigherPFratios)Analgesiaposteriorhornsofthespinalcordwherethemodulationofpainimpulsesismediatedbythenoradrenergicbulbar/spinalpathwayperipheralnervemechanismsalsoimplicatedreduceneedforopioidanalgesiaNeuroprotectiveeffectsdecreasescirculatingandcerebralcatecholaminesandCNSglutamateOthereffectsdecreasesCBF,CNSVO2,andmilddecreaseinICPdecreasesshiveringsuppressionofstressresponsetosurgeryandothernoxiousstimuli DOSE loadingdose1mcg/kgover10minutes(optional)0.2-0.7mcg/kg/hrinfusion INDICATIONS sedoanalgesiaanalgesiasparingpostoperationdeliriumpreventionandmanagementventilatordysynchronyduetodiscomfortwithdrawalsyndromesawakeintubationperi-operativesympatholysisneuraxialandregionalanesthesiaSVT(usedescribedinchildren) DISADVANTAGES onlylicensedforuseinmechanicallyventilatedpatientsfor<24hrs(dataemergingofsafetyinusingpostthisperiod)decreasedoseinliverdysfunction Adverseeffects bradycardiaandhypotensionnauseadrymouthinitialtransienthypertensionwithreflexbradycardia(stimulationofα2Bsubtypesofreceptorspresentinvascularsmoothmuscles)discontinuationsyndrome: tachycardia, nervousness,agitation,headaches,andhypertensivecrisis(e.g.ifprolongeduseduetoupregulationofalpha2receptors) PHARMACOKINETICS Absorption–IVDistribution–t1/2alpha=6minutes;VD=118L;94%proteinboundMetabolism–hepatic: completebiotransformationbyglucuronidationandbycytochromeP-450mediatedaliphatichydroxylationtoinactivemetabolitesElimination–metabolitesexcretedrenally(95%)andinfaeces(4%); context-sensitivehalf-lifevariesfrom4minfora10mininfusionto250minforan8hinfusion EVIDENCE PandharipandePP,etal.Effectofsedationwithdexmedetomidinevslorazepamonacutebraindysfunctioninmechanicallyventilatedpatients:theMENDSrandomizedcontrolledtrial.JAMA.2007Dec12;298(22):2644-53.PubMedPMID:18073360. DBRCTn=103DexmedetomidinecomparedwithlorazepamIVinfusionImprovedcoma-freedaysandtimeattarget levelofsedationinmechanicallyventilated patientsrequiredmoreopen-labelfentanyl,higherincidenceofbradycardia PandharipandePP,etal;MENDSinvestigators.Effectofdexmedetomidineversuslorazepamonoutcomeinpatientswithsepsis:anapriori-designedanalysisoftheMENDSrandomizedcontrolledtrial.CritCare.2010;14(2):R38.PMC2887145. re-analysiswithregardtosepsisofMENDStrialgiventhedifferenteffectsofdexandlorazepamonimmunefunctionpatientswithsepsisanddexmedetomidinedidbetter:lessdelirum,morecomafreedays,highersurvival RikerRR,ShehabiY,BokeschPM,CerasoD,WisemandleW,KouraF,WhittenP,MargolisBD,ByrneDW,ElyEW,RochaMG;SEDCOM(SafetyandEfficacyofDexmedetomidineComparedWithMidazolam)StudyGroup.Dexmedetomidinevsmidazolamforsedationofcriticallyillpatients:arandomizedtrial.JAMA.2009Feb4;301(5):489-99.PMID:19188334. DBRCT, 68centersin5countries 375medical/surgicalICUpatientswithexpectedmechanicalventilationfor>24hoursDexmedetomidine comparedwithmidazolamComparableinachievingsedationtargets inMVpatientsReducedICUdeliriumand MVdurationinthedexmedetomidinegroup JakobSM,etal;DexmedetomidineforLong-TermSedationInvestigators.Dexmedetomidinevsmidazolamorpropofolforsedationduringprolongedmechanicalventilation:tworandomizedcontrolledtrials.JAMA.2012Mar21;307(11):1151-60.PMID:22436955. DBMCRCT;mixednon-inferiorityandsuperioritytrialn=1000,mechanicallyventilatedDexmedetomidine(0.2–1.4mcg/kg/hr)versus propofol(PRODEX)ormidazolam(MIDEX)Exclusioncriteria:narrow,reasonable(pregnancy,shock,pre-existingbradycardiaetc)Dexmedvspropofol–NOdifferencein:TimewithingoalofsedationDurationofMV:extubatedsoonerwithdexmedhoweverrequiredNIVpostICUorhospitalLOSIncidenceofhypotension/bradycardia(13%each)Dexmedcomparedwithmidazolam:NodifferenceICUorhospitalLOSShorterMVduration:extubated2dayssoonerPatientsmorealertandcommunicativeBetterabletocommunicatepainSignificantlymorehypotensionSignificantlymorebradycardia(14%vs5%)CommentaryNon-inferioritytrialpowered(90%)totestthehypothesisthatdexmedetomideisnomorethan15%worsethanpropofol(PRODEX)ormidazolam(MIDEX)fortimetoreachsedationtargetusingper-protocolanalysisOtherendpoints(e.g.MVduration)testedaspartofasuperioritytrialusingintention-to-treatanalysisTrialdesignedandcontrolledbyOrionPharma(patentholdersofdexmedetomidine),includingstatisticalanalysesandmanuscriptpreparation(listedasco-author)Oneauthor(notalead)disclosedpersonalpaymentfromOrionDoseutiliseduptotwicethemaximum0.7mcg/kg/hrdosingapprovedbyFDAinUS DahLIAtrial,2016 MCRCT(15AustralasianICUs)n=71adultICUpatientswhoneededtoremainmechanicallyventilatedbecausetheirdegreeofagitationwasconsideredsosevereastomakelesseningtheirsedationandextubationunsafeIntervention: Dexmedetomidinestartedat0.5mcg/kg/hrandthentitratedtoratesbetween0and1.5mcg/kg/hrtoachieveRASS0or aphysician-prescribedgoal; clinical-directedoptionforbolusof1.0mcg/kgover20minutesControl:placeboOutcomesPrimaryoutcomeincreaseinmedianventilatorfreehoursat7daysinthedexmedetomidinegroup:144.8vs.127.5hours,P=0.01Multiplesecondaryoutcomes,somefavoureddexmedetomidineandnonefavouredthecontrolarmCommentaryunderpowered(didnotreachthecalculatedn=96samplesize),yetstillfoundadifferencePatientsinthedexmedetomidinegroupwereventilatedforlongerpriortoenrolmentinthestudy(mediantimeswere63hoursvs43.5hours)SedationreceivedpriortorandomisationwasnotwellcharacterisedClinicianscouldusedexmedetomidineasarescueagentinthecontrolarmfewpatientsenrolleddespitescreening>20,000patients,whichmaylimitexternalvalidityConclusionAmongpatientswithagitateddeliriumreceivingmechanicalventilationintheIntensiveCareUnit,theadditionofdexmedetomidinetostandardcarecomparedwithstandardcarealoneresultedinmoreventilator-freehoursat7days. ReferencesandLinks FOAMandwebresources TheBottomLine—DahLIA Journalarticles BajwaS,KulshresthaA.Dexmedetomidine:anadjuvantmakinglargeinroadsintoclinicalpractice.AnnMedHealthSciRes.2013Oct;3(4):475-83.doi:10.4103/2141-9248.122044.Review.PubMedPMID:24379995;PubMedCentralPMCID:PMC3868110.HeXY,CaoJP,HeQ,ShiXY.Dexmedetomidineforthemanagementofawakefibreopticintubation.CochraneDatabaseSystRev.2014Jan19;1:CD009798.doi:10.1002/14651858.CD009798.pub2.Review.PubMedPMID:24442817.KeatingGM.Dexmedetomidine:AReviewofItsUseforSedationintheIntensiveCareSetting.Drugs.75(10):1119-30.2015.[pubmed]JakobSM,etal;DexmedetomidineforLong-TermSedationInvestigators.Dexmedetomidinevsmidazolamorpropofolforsedationduringprolongedmechanicalventilation:tworandomizedcontrolledtrials.JAMA.2012Mar21;307(11):1151-60.doi:10.1001/jama.2012.304.PubMedPMID:22436955.MoY,ZimmermannAE.Roleofdexmedetomidineforthepreventionandtreatmentofdeliriuminintensivecareunitpatients.AnnPharmacother.2013Jun;47(6):869-76.doi:10.1345/aph.1AR708.Review.PubMedPMID:23719785.PandharipandePP,etal.Effectofsedationwithdexmedetomidinevslorazepamonacutebraindysfunctioninmechanicallyventilatedpatients:theMENDSrandomizedcontrolledtrial.JAMA.2007Dec12;298(22):2644-53.PubMedPMID:18073360.PandharipandePP,etal;MENDSinvestigators.Effectofdexmedetomidineversuslorazepamonoutcomeinpatientswithsepsis:anapriori-designedanalysisoftheMENDSrandomizedcontrolledtrial.CritCare.2010;14(2):R38.doi:10.1186/cc8916.Epub2010Mar16.Erratumin:CritCare.2011;15(1):402.PubMedPMID:20233428;PubMedCentralPMCID:PMC2887145.ReadeMC,EastwoodGM,BellomoR.EffectofDexmedetomidineAddedtoStandardCareonVentilator-FreeTimeinPatientsWithAgitatedDelirium:ARandomizedClinicalTrial.JAMA.315(14):1460-8.2016.[pubmed]RikerRR,ShehabiY,BokeschPM,CerasoD,WisemandleW,KouraF,WhittenP,MargolisBD,ByrneDW,ElyEW,RochaMG;SEDCOM(SafetyandEfficacyofDexmedetomidineComparedWithMidazolam)StudyGroup.Dexmedetomidinevsmidazolamforsedationofcriticallyillpatients:arandomizedtrial.JAMA.2009Feb4;301(5):489-99.doi:10.1001/jama.2009.56.Epub2009Feb2.PubMedPMID:19188334.Wujtewicz1M,etal.Useofdexmedetomidineintheadultintensivecareunit.AnaesthesiolIntensiveTher2013,vol.45,no4,235–240[FreeFullText] CriticalCareCompendium…moreCCC ChrisNickson ChrisisanIntensivistandECMOspecialistatthe AlfredICUinMelbourne.HeisalsotheInnovationLeadfortheAustralianCentreforHealthInnovationatAlfredHealthandClinicalAdjunctAssociateProfessoratMonashUniversity. Heisaco-founderofthe AustraliaandNewZealandClinicianEducatorNetwork (ANZCEN)andistheLeadforthe ANZCENClinicianEducatorIncubator programme.HeisontheBoardofDirectorsforthe IntensiveCareFoundation andisaFirstPartExaminerforthe CollegeofIntensiveCareMedicine.HeisaninternationallyrecognisedClinicianEducatorwithapassionforhelpingclinicianslearnandforimprovingtheclinicalperformanceofindividualsandcollectives. AfterfinishinghismedicaldegreeattheUniversityofAuckland,hecontinuedpost-graduatetraininginNewZealandaswellasAustralia’sNorthernTerritory,PerthandMelbourne.Hehascompletedfellowshiptraininginbothintensivecaremedicineandemergencymedicine,aswellaspost-graduatetraininginbiochemistry,clinicaltoxicology,clinicalepidemiology,andhealthprofessionaleducation. HeisactivelyinvolvedininusingtranslationalsimulationtoimprovepatientcareandthedesignofprocessesandsystemsatAlfredHealth.HecoordinatestheAlfredICU’seducationandsimulationprogrammesandrunstheunit’seducation website, INTENSIVE. Hecreatedthe‘CriticallyIllAirway’courseandteachesonnumerouscoursesaroundtheworld.Heisoneofthefoundersofthe FOAM movement(FreeOpen-AccessMedicaleducation)andisco-creatorof litfl.com, the RAGEpodcast,the Resuscitology course,andthe SMACC conference. Hisonegreatachievementisbeingthefatheroftwoamazingchildren. On Twitter,heis @precordialthump. |INTENSIVE|RAGE|Resuscitology|SMACC Related LeaveaReplyCancelreply ThissiteusesAkismettoreducespam.Learnhowyourcommentdataisprocessed. SubscribetoLITFLviaEmail Blog ECGlibrary CCC Eponyms PartONE Top100 Podcasts FullMenu Weusecookiesonourwebsitetogiveyouthemostrelevantexperiencebyrememberingyourpreferencesandrepeatvisits.Byclicking“Accept”,youconsenttotheuseofALLthecookies.Incaseofsaleofyourpersonalinformation,youmayoptoutbyusingthelinkDonotsellmypersonalinformation.CookiesettingsACCEPTCookiesPolicy Close PrivacyOverview Thiswebsiteusescookiestoimproveyourexperiencewhileyounavigatethroughthewebsite.Outofthesecookies,thecookiesthatarecategorizedasnecessaryarestoredonyourbrowserastheyareessentialfortheworkingofbasicfunctionalitiesofthewebsite.Wealsousethird-partycookiesthathelpusanalyzeandunderstandhowyouusethiswebsite.Thesecookieswillbestoredinyourbrowseronlywithyourconsent.Youalsohavetheoptiontoopt-outofthesecookies.Butoptingoutofsomeofthesecookiesmayhaveaneffectonyourbrowsingexperience. Necessary Necessary AlwaysEnabled Necessarycookiesareabsolutelyessentialforthewebsitetofunctionproperly.Thiscategoryonlyincludescookiesthatensuresbasicfunctionalitiesandsecurityfeaturesofthewebsite.Thesecookiesdonotstoreanypersonalinformation. NonNecessary non-necessary Anycookiesthatmaynotbeparticularlynecessaryforthewebsitetofunctionandisusedspecificallytocollectuserpersonaldataviaanalytics,ads,otherembeddedcontentsaretermedasnon-necessarycookies.Itismandatorytoprocureuserconsentpriortorunningthesecookiesonyourwebsite. Uncategorized uncategorized Undefinedcookiesarethosethatarebeinganalyzedandhavenotbeenclassifiedintoacategoryasyet. Analytics analytics Analyticalcookiesareusedtounderstandhowvisitorsinteractwiththewebsite.Thesecookieshelpprovideinformationonmetricsthenumberofvisitors,bouncerate,trafficsource,etc. Advertisement advertisement Advertisementcookiesareusedtoprovidevisitorswithrelevantadsandmarketingcampaigns.Thesecookiestrackvisitorsacrosswebsitesandcollectinformationtoprovidecustomizedads. Performance performance Performancecookiesareusedtounderstandandanalyzethekeyperformanceindexesofthewebsitewhichhelpsindeliveringabetteruserexperienceforthevisitors. Preferences preferences Preferencecookiesareusedtostoreuserpreferencestoprovidecontentthatiscustomizedandconvenientfortheusers,likethelanguageofthewebsiteorthelocationofthevisitor. Functional functional Functionalcookieshelptoperformcertainfunctionalitieslikesharingthecontentofthewebsiteonsocialmediaplatforms,collectfeedbacks,andotherthird-partyfeatures. Save&Accept