Sedation in the Intensive Care Unit | SpringerLink

All evidence-based international guidelines regarding sedation for mechanically ventilated patients in intensive care are consistent in ... Skiptomaincontent Advertisement SearchSpringerLink Search SedationintheIntensiveCareUnit DownloadPDF DownloadPDF AssociatedContent Partofacollection: TopicalCollectiononCriticalCareAnesthesia AbstractPurposeofReviewThisnarrativereviewillustratesliteratureoverthelast5yearsrelatingtosedationdeliverytomechanicallyventilatedadultpatientsinintensivecareunits.RecentFindingsTherehasbeenanincreaseindexmedetomidine-relatedpublicationsbutalthoughsystematicreviewssuggestdexmedetomidinereducesdelirium,agitation,andlengthofstay,clinicaltrialshavenotsupportedthesefindings.Itislikelytobeusefulforthemanagingpatientswithpersistingagitation.Guidelinescontinuetorecommendlightlysedatingpatientsbutconsiderablevariationremainsinclinicalpracticeandinresearchtrials.Protocolswithnosedativeinfusionsandmorphinebolusesasneededarefeasibleandsafe,whileeducationalinterventionscandecreasesedation-relatedadverseevents.SummaryResearchtrialshavemainlyfocusedonindividualdrugsratherthanpractice.Givenevidenceisslowtotranslateintopractice;workisneededtounderstandandrespondtotheconcernsofcliniciansregardingdeepsedationandagitation. IntroductionAllevidence-basedinternationalguidelinesregardingsedationformechanicallyventilatedpatientsinintensivecareareconsistentintheirrecommendations.TheUS,SouthAmericanandIberian,German,andUKguidanceallrecommendminimalsedation[1,2,3,4].Thegoalisapatienteasilyroused,comfortablewithgoodpaincontrol,unlessdeepsedationisclinicallyrequired.Since2016,sedation-relatedpublicationshavebeenfocusedondeterminingthesafetyandefficacyofthesedativedrugsincommonusewithanemphasisondexmedetomidine,aswellastheeffectivenessofprotocolsorbundles.Thisnarrativereviewwilloutlinesomeofthefindingsoverthelastfiveyearsrelatingtocommonsedativedrugsandsedationdeliveryprotocols.SearchStrategyPubMedsearch22ndDecfortheterms“sedationandintensivecare”,“sedation&criticalcare”,“sedationandmechanicalventilation”,“sedationanddelirium”,“sedationandagitation”,peerreviewedarticlesonhumansinEnglishpublishedinlast5yearsandseparatesearchon25thJanfor“sedationandCOVID-19”.GuidelinesAnumberofguidelinesorbundlesofcareweredesignedorupdatedtoguidecliniciansinconsistentdeliveryofoptimalsedationtomechanicallyventilatedcriticallyillpatients.TheSocietyofCriticalCareMedicineaddedImmobility(mobilization/rehabilitation)andSleep(disruption)totheir2018updateofthe2013Pain,Agitation,andDeliriumguidelinesincludingpublicationsuptoOctober2015[1•].Rehabilitation/mobilizationinterventionswererecommendedtoreduceICU-acquiredmuscleweaknessduetoimmobilitywithstartingandstoppingcriteriaforrehabilitation/mobility.Multicomponentprotocolswererecommendedtopromotesleep,includingvolumecontrolventilatorymodesandnocturnalstrategiestoreducenoiseandlight,butnorecommendationsmaderegardingmedications.Theseguidelinesincluded37actionablerecommendationsand2bestpracticestatements.Onlytwooftherecommendationswerestrong,(i)usinganeuropathicpainmedication(e.g.gabapentin,carbamazepine,andpregabalin)withopioidsforneuropathicpainmanagementincriticallyillpatientsand(ii)advisingagainstvolatileanaestheticagentsforproceduralpainmanagement.DrsPisani,Devlin,andSkrobikpublishedacomprehensiveexplorationoftheevidencegapsidentifiedbytheSCCMguidelinepanel[5••].Theyreflectedthattheassumptionsoftheguidelinecommitteeregardingtheirrecommendationsarenotconsistentwithclinicalpractice.Aclinician’sbeliefintheirabilitytoassessandeffectivelymanagepainincriticalillnessoftenoverrideswrittenevidence-basedguidance.Questionsremainregardingtheeffectivenessofopioidstocontrolpainwheninfusedcontinuously,andtheidentificationandpreventionofwithdrawalofopioidsarenotconsideredinthecriticallyilladultsyetwidelypracticedinpaediatricintensivecare.High-qualitytrialsinvestigatingtheeffectofdeliriumassessmentandtherelationshipbetweenassessmentandpatient-centredoutcomes,treatmentdecisions,andpatient,family,andstaffsatisfactionarelacking.Evidencegapsneedtobeconsideredalongsideimprovedmethodsforguidelineimplementation.SedationPracticeThe2018Cochranereviewupdateof“Protocol-directedsedationversusnon-protocol-directedsedationinmechanicallyventilatedintensivecareadultsandchildren”includedfourstudieswithatotalof3323participants(864adultsand2459paediatrics)[6•].Threestudiesweresingle-centre,randomizedcontroltrials(RCTs)andonestudywasamulticentrecluster-RCT(seeDESISTtriallater).Therewasnoclearevidenceofbenefitindurationofmechanicalventilation,mortality,orICUlengthofstayusingprotocol-directedsedation.Therewasevidenceofareductioninhospitallengthofstaymeandifference−3.09days,95%CI−5.08to−1.10;moderate-qualityevidence.Inconclusion,futurestudiesshouldaccountfordifferingcontextualcharacteristics,withmethodologicalstrategiestoreducetheriskofbias.TheABCDEFbundle(assess,prevent,andmanagepain;bothspontaneousawakeningandbreathingtrials:choiceofanalgesiaandsedation;deliriumassess,prevent,andmanage;earlymobilityandexercise;familyengagement/empowerment)aimstopromotepracticewherepatientsaremoreawake,cognitivelyengaged,andphysicallyactive.TheICULiberationCollaborativefundedbytheGordonandBettyMooreFoundationundertookaUSqualityimprovementprojecttoimplementthisbundle[7].Theyincluded15,000patientsfrom68ICUscovering29statesandPuertoRico,andthebundlewasimplementedwithinconsistentandvariablesuccess.PatientswhodidreceivemoreoftheABCDEFbundleelementseachdayhadimprovedlikelihoodofsurviving,lesscoma,delirium,andphysicalrestraint,shorterventilatortime,fewerICUreadmissions,andweremorelikelytobedischargedhome.Thelowoverall8%totalbundleperformancemeantthatallsevencomponentsofABCDEFonlyoccurred1in10patientdays.TheDESISTtrialwasundertakenineightadultICUsinScotlandandaimedtoassesstheeffectivenessofthreeinterventionstoimprovesedationpractice[8].Thesewereeducation,regularfeedbackofongoingsedation-analgesiaqualitydataandanovelsedation-monitoringtechnology(theResponsivenessIndex,Ri)basedonfacialelectromyography,providinganalertforpossibledeepsedation.ThisclusterRCTusedfourcombinationsoftheinterventionfromonlineeducationpackageintwounits,uptothelasttwounitsimplementingallthreeinterventions.Theysubsequentlypublishedtheresultsofaqualitativestudytoidentifythechallengesandbarrierstoimplementationandengagement[9•].Animpressive74to100%ofnursescompletedtheonlineeducation.Whileeducationalonedidnotimprovesedation-analgesiaquality,itwasassociatedwithanalmost50%reductioninsedation-relatedadverseeventrates(mostcommonlynasogastrictuberemoval).TheRimonitorattachedtothepatientalertedtheteamtothepossibilityofdeepsedationwithagreen,amber,orrednumber(Ri)displayed.TheRiwasredin59%patientswhenattachedandremainedredforamedianof35%(IQR18–65%)monitoredtime.NursesreportedtheRiasausefulprompttoreviewsedation,butviewsweremixedaboutitsusefulness,validity,impactonpracticeandintrusiveness.Useofthemonitorincreasedoptimalsedation-analgesiaqualityby7%.Regularfeedbackofunitsedationqualitydeliveredmadenodifferenceduetolackofintra-unitdissemination,itwasthoughttolackrelevancetodailybedsidepractice,andoftendisbelieved.Predictivemodellingconcludedthatacombinationofeducationandresponsivenessmonitoringwouldresultina10–11%improvementinproportionofshiftswithoptimalsedationwithoutanincreaseinsedation-relatedadverseevents.ThequalitativedatasuggestedthateffectsarepartlyexplainedbydifferencesinengagementwithinterventionsbetweenICUs.Thetakeawaymessagesarethatapromptisusefultoreviewdeepsedation,educationisgood,andreportsabouthowwellorbadlyanICUperformsdoesnotleadtochange.BISBispectralindex(BIS)monitors,basedontheprocessingofelectroencephalographicsignals,havereportedbenefitsintheoperatingtheatreandmayovercometherestraintsofsedationscalesduringdeepsedationorduringparalysis.ACochranereviewbyShettyandcolleaguesin2018concludedthattherewasinsufficientevidenceofbenefitofBISforICUsedation,becauseoflimitednumberofstudieswithevidencelowtoverylowcertainty[10].Moreresearchisneededtomonitorthebraininpatientsparalysedanddeeplysedated,toideallyavoidburstsuppression[11].NoSedationGiventhatsedationmayworsenoutcomes,amulti-nationalRCT(NONSEDA)wasundertakentodetermineifaplanofnosedationinpatientsrequiringmechanicalventilationwouldresultinanimprovedsurvivaloutcomeoverlightsedationwithdailysedationinterruption[12••].Thiswasafollowontrialtoa2010singlecentrestudythatshowedbenefit[13].EightcentresacrossDenmark(5),Norway(2),andSweden(1)randomized710patientstoeithernosedativeinfusionswithmorphinebolusesasrequiredorsedativeinfusionstomaintainalevelofRASS−2to−3(Fig.1)[14].Propofolwasusedinfusedfor48handthenreplacedbymidazolamwithdailysedationinterruptions. Fig.1RichmondAgitationSedationScale.TheRichmondAgitation-SedationScale,RASS,differentiatesresponsetoverbalstimulusfromthattoaphysicalstimulus,unlikeothersedationscoressuchastheRamsay.*Physicalstimulation:shakingand/orrubbingsternum.AdaptedfromSesslerCNetal.TheRichmondAgitation-SedationScale:validityandreliabilityinadultintensivecareunitpatients.AmericanJournalofRespiratoryandCriticalCareMedicine2002;166:1338–44FullsizeimageInthesedationgroup,themeanRASSscorewas−2.3onday1increasingto−1.8byday7,andinthenon-sedationgroupthemeanRASSscorewas−1.3onday1and−0.8onday7.Inthenosedationgroup,38%ofpatientsreceivedrescuesedationatsometimeduringtheirstay.Therewasnodifferencein90-daymortalitybetweenthetwogroups.Therewas1moredayfreefromcomaordeliriumwithnosedationversuslightsedationandfewerthromboemboliceventsinthenosedationgroupatonepatient0.3%vsten(2.8%).Thisstudyisimpressiveinthemaintenanceoflightsedationinthecontrol(sedation)group.ComparethistoSPICE3trial(discussedbelow)reportingRASSscores−3to−5in45.6%ofthecontrolgroupthroughoutthefirst2days[15].InNONSEDA,afollow-upsurveyofrelative’ssatisfactionwith39(73%)responsesreportednodifferencesbetweenthegroupswithregardtorelative’spersonalreactionsorsatisfactionwithcare,treatmentorcommunication.PatientExperienceAmeta-synthesisandmeta-summarytounderstandpatients’experiencesreportedinqualitativestudiesofadultICUpatientsreceivingmechanicalventilationincludedninestudiespublishedbetween2015and2019,predominantlyfromScandinaviancountries,and175patientsreportedtheirexperiences[16•].Thestudiesweremostlybasedonphenomenological–hermeneuticalapproaches,andtwoweremixed-methodstudies.Criticallyillpatientsoverallexperienceasenseofvulnerabilitydescribing(a)intensestressonbodysystems,(b)negativeemotionalsituations,(c)feelingsofbeingcaredforinanICU,and(d)supportfromfamilyandlovedones.Theconclusionwas“Attheunitandatthepolicylevels,strategiesaimedatpromotingfamilyaccesstopatients,maximizingthetimeavailableforfamiliestobewithpatientandencouraginginteractionsarerecommended(e.g.,holdingthepatient'shand).Moreoveranappropriatenurse-to-patient-ratiocapableofensuringpresenceatthebedsideisstronglysuggested”.AlphaAgonistsClonidineThereisapaucityofevidencetosupporttheuseofclonidinebecauseofalackofcontrolledtrialsincriticallyilladults.ItisincommonuseintheUK;a2014surveypublishedin2016(91%responserate)reportedveryfrequent/frequentuseofclonidinein32.7%ofunits[17].InSweden,asurveyreportedthatcliniciansregularlyprescribeclonidine,theindicationsbeinglightsedation(32%),non-invasiveventilation(23%),andnightlysedation(18%)[18].AsystematicreviewofstudiesuntilMarch2016inmechanicallyventilatedpatientsincludedeightRCTs,fourinadults[19].Sixtrialsusedintravenousclonidinewithvariationindosingfrom0.88to3μg/kg/h.Onetrialreportedclonidineassolesedative,andtwowerepostoperativepatientswithshortperiodsofventilation.Theauthorsfoundnodifferenceindurationofmechanicalventilation,mortality,orlengthofICUstayandahighdegreeofclinicalheterogeneity.Theyconfirmedthatclonidinereducesthetotaldoseofopioids,whileassociatedwithincreasedincidenceofclinicallysignificanthypotension(RR3.11,95%CI=1.64to5.87,I2=0%,moderatecertainty).Therewerethreetrialsongoingatthetimeofwhichtwowereterminatedearlyduetodifficultyrecruitingpatients,NCT01139996andNCT02509273.CloesmeijerandcolleaguesdevelopedthefirstpopulationpharmacokineticmodelforclonidinedosinginanadultICU[20•].TheydefinedanoptimalplasmaconcentrationforICUsedationasrangingfrom1.5to4.0μg/L.Usingdifferentdailydosesofintravenousclonidineinadditiontostandardsedation,theydetermined1200μgperdaywhichprovidedatargetsedationconcentrationofmorethan1.5μg/L.Ratherthanaloadingdose,theyrecommendadoublingoftheinfusionratefor6hasmoreeffective,reducingtimetoachievesteady-stateto5hwithoutpeaksinplasmaconcentration.DexmedetomidineAdisproportionatenumberofdexmedetomidine-relatedsystematicreviewsandmeta-analysesincriticallyillventilatedpatientsofvariablequalitywerepublishedcoveringdifferentpatientpopulationsandoutcomes.Twosystematicreviewsfocusedonpatientsdifficulttoweanfrommechanicalventilationusedthesamesixtrials[21,22].Onedescribedtheevidencetosuggesttheuseofdexmedetomidinebeingoflowquality,whereastheotherconfidentlyconcludedthatdexmedetomidinewasassociatedwithasignificantreductioninthetimetoextubationandshorterICUstays.Twomorereviewsinpatientswithsepsisagreedthatdexmedetomidineimprovedtheshort-termmortalityofpatients,afindingnotupheldbysubsequentclinicaltrials[23,24].Fourreviewsincardiacsurgicalpatientsgenerallyagreedthatdexmedetomidineuseislikelytoreducedeliriumandlengthsofstay,butwithincreasedratesofbradycardia[25,26,27,28].Thetworeviewsintheneuro-criticalcarepopulationconcludeddexmedetomidineuseappearedtobesafereviewinglimiteddata[29,30].Bothreviewsincludedcohortstudies,generallythoughtnottoberobustmethodology.Ngandcolleagues’2019systematicreviewandmeta-analysisoftheeffectofdexmedetomidineinICUonagitationanddeliriumwasinresponsetothepublicationofnewstudies[31].Twentyofthe25RCTsincludedwereinpatientsadmittedtosurgicalICUs.IneightRCTs,sixinpostoperativepatients,deliriumincidencewasreducedwithanoddsratio0.36(0.26–0.51),bradycardiawasmorethantwiceaslikelywithdexmedetomidine,andhypotensionwasincreased(oddsratio1.89).TheUKNationalInstituteforHealthCareResearchfundedacomprehensivesystematicreviewintotheuseofalphaagonistsforsedation[32].Theauthorsusedeighteentrialswithatotalof2489adultpatients.Theyassessedthatoverallriskofbiasashighorunclearparticularlywithrelationtoblindedoutcomeassessors.ThelengthofICUstay(meandifference–1.26days,95%CI–1.96to–0.55days,I2=31%)andtimetoextubation(meandifference–1.85days,95%CI–2.61to–1.09days,I2=0%)weresignificantlyshorteramongpatientswhoreceiveddexmedetomidine.Dexmedetomidineusewasassociatedwithahigherriskofbradycardia(RR1.88,95%CI1.28to2.77,I2=46%.Theuseofdexmedetomidinefornon-invasiveventilationwasstudiedinasystematicreview/meta-analysisoftrialspublishedupuntilJuly31,2020[33•].Twelvestudieswereincludedwithatotalof738participants.Comparedtoanysedationstrategyorplacebo,dexmedetomidinereducedtheriskofdelirium(absoluteriskreduction16%)andneedforintubationandmechanicalventilation(absoluteriskreduction16%).Anybenefitsofdexmedetomidineshouldbeweighedagainsttheprobableundesirableeffectsofhypotensionandbradycardiaasuseofdexmedetomidinewasassociatedwithanincreasedriskofbradycardia(RR2.80,95%CI1.92to4.07,moderatecertainty)andhypotension(RR1.98,95%CI1.32to2.98,moderatecertainty).Thisreviewwasmethodologicallyrigorous;however,duetothesmallnumberofstudiespooledforeachoutcome,theywereunabletoexaminefunnelplotstodetectpublicationbias.DexmedetomidineandLightSedationEarlydeepsedationisanindependentpredictoroftimetoextubation,hospitaldeath,and180-daymortality.TheSPICE3trialwasamultinational,open-label,randomizedtrialtoinvestigatetheeffectofusingdexmedetomidineastheprimaryand,ifpossible,soleagentforearlylightsedation[15].Theprimaryoutcomewas90-dayrateofdeathfromanycause.Seventy-fourICUsineightcountriesrandomlyassigned4000patientstoreceiveeitherdexmedetomidineorusualcare.ThesedationgoalwasaRASSscoreof−2(lightlysedated)to+1(restless),unlessthetreatingcliniciandecidedtherewasanindicationfordeepsedation.Thefinalanalysisincluded3904patientsandratesofdeathweresimilarinbothgroupsat90days.Cliniciansdeemedthatonthefirstdayaround60%ofpatientsrequiredsedationdeeperthanRASS−2,i.e.brieflyawakenstovoice.Inthefirst2daysafterrandomization,thepercentageofRASSscoresinthetargetrangeoflightsedation(−2to+1)wasonly56.6%inthedexmedetomidinegroupand51.8%intheusual-caregroup.Theeditorialnotedthatregardlessofguidelinesonthebenefitsoflightsedationandwell-conductedtrialsdemonstratingtherisksofdeepsedation,beliefsdrivepracticeandareslowtochange[34].Overallpatientsinthisstudyweremaintainedatdeeperlevelsofsedationbyclinicians.Therewasheterogeneitywithrespecttomortalityratesbelowandabovethemedianage(63.7years)withhighermortalityinyoungerpatients(riskdifference4.4(95%confidenceintervals0.8to7.9)inthedexmedetomidinearm.Thesignificanceofthedifferencecouldnotbedeterminedandfurtheranalysisisawaited.DexmedetomidineandSepsisAsubgroupanalysisofthe2010MENDStrialreportedthatpatientswithsepsistreatedwithdexmedetomidineasopposedtolorazepamhadanimprovedmortalityleadingtoaninnovativetrialundertakeninanItalianUniversityhospital[35,36•].Itaimedtodetermineifswitchingfrompropofoltodexmedetomidinereducednoradrenalinerequirementsinpatientswithsepticshock.Thirty-eightmechanicallyventilatedpatientsrequiringdeepsedationRASS−3/−4werestabilizedwithameanarterialpressure65–75usingnoradrenalinewhilesedatedwithpropofolandremifentanil.After60min,thepropofolinfusionwasreplacedbydexmedetomidine,andthenafter4h,thesedationinfusionswerereversedagain.Noradrenalinerequirementsdecreasedwithdexmedetomidinefrom0.69±0.72micrograms/kg/minto0.3±0.25micrograms/kg/min,andincreasedagainto0.42±0.36micrograms/kg/minpost-dexmedetomidine.Thissupportsexperimentalworkandmaybepartlybutnotfullyexplainedbytheavoidanceofpropofol-relatedcardiovasculareffectspronouncedinsepticshock.Themulti-centreDESIREtrialineightJapaneseICUspublishedinJAMArandomized201consecutivepatientsadmittedwithsepsisrequiringrespiratorysupporttosedationwithorwithoutopen-labeldexmedetomidine[37].(Curiously,theytargetedaRASSof0duringthedaybut−2atnight).Thecumulativeincidenceofdeathat28dayswas22.8%(n=19)inthedexmedetomidinegroupand30.8%(n=28)inthecontrolgroup(P = .20).Althoughthedifferencein28-daymortalitywas8%,itwaspoweredfora20%differencesomayhavebeenunderpowered;however,theMENDS2trialresultssuggestotherwise.MENDS2followingonfromMENDSwasamulticentretrialcomparingdexmedetomidinewithpropofolforsedationinmechanicallyventilatedpatientswithsepsis[38].Theyrecruited432patientstoblindedpropofolordexmedetomidine.Theprimaryoutcomewasnumberofdelirium-free,coma-freedaysinthe14daysfollowingrandomization,andwiththeRASStargetthatwassetbytheclinicians.Therewasnodifferencebetweengroupsintheprimaryoutcomeoranysecondaryoutcomes.Thepatientshadhighseverityofillness(APACHEIIscoremedian27)andhigh90-daymortalityrate(38–39%).Over40%ofpatientsneededsupplementarymidazolamandantipsychotics.Notablythedexmedetomidinedosegivenwasrelativelylow,median0.27μg/kg/hascomparedwithusualdose0.2–1.4μg/kg/h.DexmedetomidineandDeliriumTheDahLIAstudy,“DexmedetomidinetoLessenICUAgitation”,wasamulti-centredouble-blind,placebo-controlled,parallel-groupRCTinmechanicallyventilatedpatientswhobecamesoagitatedthatsedationcouldnotbesafelyweanedforextubation[39].Datawascollectedon71patients,39whoreceivedadexmedetomidineinfusionand32receivedasalineinfusionforasedationtargetofRASS0.Theprimaryoutcomewasnumberofventilator-freehoursupuntildayseven.Theplannedrecruitmentwas96patientstodetecta20-hdifference;however,thetrialwasterminatedearlyduetolackoftimeandfunding.Therewasasignificantdifferenceinventilator-freehoursat7days,median144.8hvs127.5h,withnodifferenceinnumberoftracheostomies.Themediantimetoextubationwas21.9hforthedexmedetomidinevs44.3hforplacebo,andmedianlengthofICUstayis2daysshorter.Deliriumresolvedmorerapidlyinpatientswhoreceiveddexmedetomidine23.3hvs.40.0h,withamedianoftwoadditionaldelirium-freedaysduringtheirICUstay.Adverseeventswererare.Theauthorsdidnotethat21500patientswerescreenedtorecruit74patients.Theseresultsregardlesssupporttheuseofdexmedetomidinetomanagesymptomsofpersistentagitation.Atwo-centredeliriumpreventionstudyaimedtodetermineifalowdosenocturnaldexmedetomidineinfusionpreventeddeliriumandimprovedsleepinICUadultpatients[40•].Thehypothesiswasthatdexmedetomidine,byactingonthelocuscoeruleus,promotesnaturalsleep.Onehundredpatientswererandomizedinthisphase2,blinded,placebo-controlledtrial.Allpatient’ssedativeinfusionswerehalvedat9.30pmanddexmedetomidineordextrose5%infusionsstartedthendiscontinuedat6.30am.Asignificantnumberofpatientswhoreceiveddexmedetomidineremaineddelirium-freeduringtheiradmission,40of50patientsversus27of50patientswhoreceivedplacebo.Thetotalnumberofnight-timehoursspentattargetgoalofRASS−1wasgreaterinthedexmedetomidinegroup,55%vs.24%.Thisstudywasunabletoundertakeapolysomographystudyrelyingonself-reportedsleepqualityassessmentsin64patients,whichshowednodifferencebetweenthetwogroups.DexmedetomidineandSleepOnestudyinvestigatedtheeffectofenteraldexmedetomidineonsleeppolysomnographyin15participants[41].Following700μgoforaldexmedetomidine,thedurationofnon-rapideyemovement(non-REM)stage2sleepwasincreasedby63(95%CI,19to107)min(P=0.010)andthedurationofrapideyemovement(REM)sleepwasdecreasedby42(5to78)min(P=0.031).Itsupportstheevidencethatdexmedetomidine,similartobenzodiazepines,increasestotalsleeptimebutnotstage3andREMsleeptime.OtherDrugsandRoutesTheN-methyl-d-aspartatereceptorantagonistketaminehasalsobeenshowntohaveanalgesicproperties,alongwithbronchodilatoryeffectsandcardiovascularstimulation.Ketaminesedationinmechanicallyventilatedpatientswasreportedinasystematicreviewandmeta-analysisthatincludedfifteenstudiestotalling892patients,non-randomizedtrials(12)included[42].Everystudywaspublishedsince2014,exceptone.Asisoftenthecase,reviewershighlightedthelackofdata,oranydemonstrationofclinicalbenefitintheincludedstudies.Oneplacebo-controlled,double-blindtrialtodetermineiflowdoseketaminedecreasedopioidconsumptionanddelirium,albeitundertakenin2011to2012,waspublishedin2018inasurprisinglylow-impactjournal[43].Onehundredsixty-twopatientswererandomizedtoacontinuousinfusionoflow-doseketamine0.2mg/kg/horequivalentvolumeofsaline.Theincidenceofdeliriumwas21%(17)intheketaminegroupand37%(30)intheplacebogroup,aposthocanalysisreportedasignificantinteractionbetweentheketaminebolususedforintubationintheketaminegrouponlywith16.6%deliriumincidenceifketamineusedforintubationasopposedto26.3%ifotherdrugswereused.Therewasnodifferenceinopioidconsumptionbetweengroups.Asystematicreviewandmeta-analysisreviewedtheliteratureonsafetyandefficacyofvolatileanaestheticagentsinmechanicallyventilatedcriticallyillpatients,ascomparedwithintravenouspropofolormidazolam[44•].Therewereeighttrialswith523patientscomparingvolatileagentswithmidazolamorpropofolreportingareductioninextubationtimesusingvolatileagents(differenceinmeans,−52.7min;95%confidenceinterval[CI],−75.1to−30.3).Unsurprisingly,thedifferencewasgreaterwhenvolatileagentswerecomparedwithmidazolamratherthanpropofolwithadifferenceinmeansof−292.2minasopposedto−29.1min.Theirfunnelplotrevealedalargepublicationbiaswithtrialsreportingpredominantlypositiveresults.Thefindingssuggestedthattheuseofvolatileagentsedationmightbeusefulinpostoperativepatientsrequiringshort-termventilation,andawell-conductedresearchtrialisrequired.Alternativemethodsofsedativedeliverymaybeneededinthenottoodistantfuture[45].Amulti-centre,randomizedcontrolledtrialcomparedenteralversusintravenoussedation[46].Threehundredandforty-eightpatientsfrom12ItalianICUswererandomizedtoreceiveeithermidazolamorpropofolinfused,orhydroxyzine,lorazepam,andmelatoninenterallyforsedation.Thiswasasuperioritytrial.TherewasnodifferenceintheprimaryoutcomeofpercentageofworkshiftsinwhichpatientsreachedatargetorRASS0±1.Halfofthepatientsintheenteralsedationgrouphadprotocolviolationssothegroupswerenotadequatelyseparated.Interestinglythereweremoreunplannedextubationsintheenteralsedationgroupbutdidnotneedreintubation,andtheenteralsedationgroupreceivedmoreenteralnutrition.COVID-19andSedationTheSARS-coronavirusorCOVID-19pandemichaspresentednewchallengestocliniciansaimingforoptimalsedationinmechanicallyventilatedpatients[47].Hospitalshavebeenoverwhelmedwithcriticallyillpatientsgenerallyresultingalowerskillednursetopatientratio.Morepatientsrequirelongerperiodsofventilation,useofneuromusculardrugs,andproningwithdeepsedation.Therearereportedshortagesofcommonlyusedsedativedrugs.Amultinational,multi-centrecohortstudyinvolving69ICUsin14countriescollecteddataon2088patients[48].ThemedianRASSscoreonventilationwas−4(−5to−3)andthemediannumberofdaysincomawasten(IQR6to16).Thiscompareswithdaysincomaof1day(IQR1–2)inthe2018deliriumtreatmentMIND-USAtrialcompletedbythesameinvestigatorgroup[49].Importantlyinthiscohortstudy,morethan50%ofpatientshadagitation.BeforetheCOVID-19pandemic,incriticallyillpatients,thereportedincidenceofnewagitateddeliriumwasupto13%,withanoverallprevalenceofupto20%[50].Similarly,Helmsandcolleaguesreviewed58consecutiveICUpatientswithCOVID-19,ofwhom40(69%)becameagitatedfollowingcessationofmusclerelaxationandsedation[51].ConclusionClinicaltrialstodatedonotfullysupporttheuseofdexmedetomidineotherthantomanageagitation.Meantime,moreattentionisbeingpaidtoolderdrugsincommon,e.g.clonidineandketamine,anddeliriumriskfactorsandmanagement.Knowledgetranslatedintoguidelinesandprotocolsareallverywell,butstudiesneedtolookattranslatingevidenceintopractice. 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DownloadreferencesAuthorinformationAffiliationsDepartmentofAnaesthesia,WatfordGeneralHospital,VicarageRoad,Watford,WD180HB,UKValeriePageDepartmentofSurgeryandCancer,ImperialCollegeLondon,London,SW72AZ,UKValeriePageFacultyofLifeSciencesandMedicine,KingsCollegeLondon,London,SE19RT,UKCathyMcKenziePharmacyandCriticalCare,KingsCollegeHospital,London,SE59RS,UKCathyMcKenzieAuthorsValeriePageViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCathyMcKenzieViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCorrespondingauthorCorrespondenceto ValeriePage.Ethicsdeclarations ConflictofInterest Neitheroftheauthorshasanypotentialconflictsofinteresttodisclose. AdditionalinformationPublisher’sNoteSpringerNatureremainsneutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations.ThisarticleispartoftheTopicalCollectiononCriticalCareAnesthesiaRightsandpermissionsReprintsandPermissionsAboutthisarticleCitethisarticlePage,V.,McKenzie,C.SedationintheIntensiveCareUnit. CurrAnesthesiolRep11,92–100(2021).https://doi.org/10.1007/s40140-021-00446-5DownloadcitationAccepted:23March2021Published:24April2021IssueDate:June2021DOI:https://doi.org/10.1007/s40140-021-00446-5SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative KeywordsSedationVentilationIntensivecareCriticalcareDexmedetomidineProtocol DownloadPDF AssociatedContent Partofacollection: TopicalCollectiononCriticalCareAnesthesia Advertisement