Intensive Care Unit Delirium | Anesthesiology - ASA Publications

A large portion of ICU patients develop delirium, especially those who are mechanically ventilated or who have other risk factors on admission. While many of ... SkiptoMainContent Advertisement Close AnesthesiologyASAMonitorMoreASAPublicationsAnesthesiologyTodayeNewsletterASAPWeeklyeNewsletterACE(AnesthesiologyContinuingEducation)SEE(SummariesofEmergingEvidence)MACRAMemoeNewsletterASAPodcastsASACommunity Search navsearch searchinput Searchinputautosuggest searchfilter AllContentAllPublicationsAnesthesiology Search AdvancedSearch Cart UserTools Cart Register SignIn ToggleMenuMenu ArticlesandIssues OnlineFirst Issues Topics Multimedia Podcasts Videos ForAuthors AuthorResourceCenter SubmissionAdvice CallforPapers CME JournalInformation AbouttheJournal EditorialBoard JournalStaff SocialMedia Awards AdvertisingInfo Reprints AccessOptions Rights&Permissions EnhancementsIndex SkipNavDestination ArticleNavigation Closemobilesearchnavigation Articlenavigation Volume125,Issue6 December2016 PreviousArticle NextArticle CharacterizingDelirium DeliriumPrevention DeliriumTreatment Conclusions ResearchSupport CompetingInterests References ArticleNavigation Education| December2016 IntensiveCareUnitDelirium:AReviewofDiagnosis,Prevention,andTreatment ChristinaJ.Hayhurst,M.D.; ChristinaJ.Hayhurst,M.D. FromtheDivisionofAnesthesiologyCriticalCareMedicine,DepartmentofAnesthesiology,VanderbiltUniversitySchoolofMedicine,Nashville,Tennessee. Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar PratikP.Pandharipande,M.D.; PratikP.Pandharipande,M.D. FromtheDivisionofAnesthesiologyCriticalCareMedicine,DepartmentofAnesthesiology,VanderbiltUniversitySchoolofMedicine,Nashville,Tennessee. Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar ChristopherG.Hughes,M.D. ChristopherG.Hughes,M.D. FromtheDivisionofAnesthesiologyCriticalCareMedicine,DepartmentofAnesthesiology,VanderbiltUniversitySchoolofMedicine,Nashville,Tennessee. AddresscorrespondencetoDr.Hughes:DivisionofAnesthesiologyCriticalCareMedicine,DepartmentofAnesthesiology,VanderbiltUniversitySchoolofMedicine,121121stAvenueSouth,MedicalArtsBuilding526,Nashville,Tennessee37212.christopher.hughes@vanderbilt.edu.Informationonpurchasingreprintsmaybefoundatwww.anesthesiology.orgoronthemastheadpageatthebeginningofthisissue.Anesthesiology’sarticlesaremadefreelyaccessibletoallreaders,forpersonaluseonly,6monthsfromthecoverdateoftheissue. Searchforotherworksbythisauthoron: ThisSite PubMed GoogleScholar AuthorandArticleInformation ThisarticlehasbeenselectedfortheAnesthesiologyCMEProgram.LearningobjectivesanddisclosureandorderinginformationcanbefoundintheCMEsectionatthefrontofthisissue. SubmittedforpublicationApril27,2016.AcceptedforpublicationAugust24,2016. Thisarticleisfeaturedin“ThisMonthinAnesthesiology,”page1A. Figures1and2wereenhancedbyAnnemarieB.Johnson,C.M.I.,MedicalIllustrator,VivoVisuals,Winston-Salem,NorthCarolina. AddresscorrespondencetoDr.Hughes:DivisionofAnesthesiologyCriticalCareMedicine,DepartmentofAnesthesiology,VanderbiltUniversitySchoolofMedicine,121121stAvenueSouth,MedicalArtsBuilding526,Nashville,Tennessee37212.christopher.hughes@vanderbilt.edu.Informationonpurchasingreprintsmaybefoundatwww.anesthesiology.orgoronthemastheadpageatthebeginningofthisissue.Anesthesiology’sarticlesaremadefreelyaccessibletoallreaders,forpersonaluseonly,6monthsfromthecoverdateoftheissue. AnesthesiologyDecember2016,Vol.125,1229–1241. https://doi.org/10.1097/ALN.0000000000001378 Split-Screen ViewsIcon Views Articlecontents Figures&tables Video Audio SupplementaryData PDFLinkPDF ShareIcon Share Twitter LinkedIn CiteIcon Cite GetPermissions SearchSite Citation ChristinaJ.Hayhurst,PratikP.Pandharipande,ChristopherG.Hughes;IntensiveCareUnitDelirium:AReviewofDiagnosis,Prevention,andTreatment.Anesthesiology2016;125:1229–1241doi:https://doi.org/10.1097/ALN.0000000000001378 Downloadcitationfile: Ris(Zotero) ReferenceManager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbarsearch Search navsearch searchinput Searchinputautosuggest searchfilter AllContentAllPublicationsAnesthesiology Search AdvancedSearch A77-YR-OLDmanisadmittedtothehospitalaftersustainingahipfracture.Hehasamedicalhistoryofchronicobstructivepulmonarydisease,hypertension,hyperlipidemia,chronicbackpain,andhearingloss.Beforesurgery,hereceivesmidazolamforagitationandmorphineforpaincontrol.Heundergoesageneralanestheticforhisfracturerepair,requiringhighdosesoffentanylforpaincontrol.Postoperatively,hehaspoorpulmonarymechanicsandistakentotheintensivecareunit(ICU)intubatedandmechanicallyventilated.Onpostoperativeday1,hissedationisweanedandheisputonaspontaneousbreathingtrial.Whileheappearsintermittentlyawake,hewillnotfollowcommandsandonlyintermittentlymakeseyecontact.Thepatientisleftintubatedduetohisalteredmentalstatus. Deliriumisacommonproblemincriticallyillpatientsbuthasonlyrecentlybeenrecognizedasaseriousentityassociatedwithimportantclinicaloutcomes,includingincreaseddaysonmechanicalventilation,lengthofhospitalstay,costofcare,long-termcognitiveimpairment,requirementforpostdischargeinstitutionalization,andmortality.1–3 ValidateddeliriumscreeningtoolsforICUpatients,whichcanbeusedbyawiderangeofpersonnel,haveimproveddiagnosis,androutinedeliriumassessmentisnowrecommendedasthestandardofcareintheICU.Furthermore,potentialpharmacologic(e.g.,antipsychoticsanddexmedetomidine)andnonpharmacologic(e.g.,earlyphysicaltherapyandsleephygiene)preventionandtreatmentstrategieshavebeenstudiedtoreducedeliriumandimproveitsassociatedoutcomeswithvaryingresults.ThisreviewwillexploretheriskfactorsforICUdelirium,toolsforitsdiagnosis,preventativestrategies,anditspotentialtreatments.Thisinformationcanbeutilizedthroughoutthepatient’shospitalization,includingintheperioperativeenvironment,andcanbepracticedbyanesthesiologistsandintensiviststoimprovepatientcare. CharacterizingDelirium Theterm“delirium”isfrequentlyusedacrossclinicalsettingstodescribepatientswithalteredmentalstatus,butitsproperdiagnosisrequiresspecificmanifestationstobepresent.DeliriumisdefinedinTheDiagnosticandStatisticalManualofMentalDisorders,FifthEdition(DSM-5)4 asareducedabilitytodirect,focus,sustain,andshiftattention.Thisiscoupledwithachangeincognition,intheformofmemorydeficit,disorientation,orperceptualdisturbances.Importantly,theinattentionandchangeincognitioncannotbeaccountedforbyabaselineneurocognitivedisorder(e.g.,dementia)oraseverelyreducedlevelofarousal(e.g.,sedativeadministrationandcoma).Thedisturbanceinmentalstatusmustbeanacutechangefrombaselineandfluctuatethroughoutthedaybutmayoccurinadditiontobaselinedisease(e.g.,deliriumsuperimposedondementiaanddeliriumafterstroke).Deliriumdiagnosisidentifiestheconstellationofalteredbrainfunctionsignsbutdoesnotidentifytheetiology.Itshould,therefore,promptfurtherinvestigationintopotentialpatientvulnerabilityfactorsandprecipitatingfactorsassociatedwiththecurrentillnessorhospitalcourse. Incidence Theincidenceofdeliriumvarieswidelydependingonthepatientpopulationexaminedandthemethodofdiagnosis(e.g.,psychiatricevaluationvs.nursescreeningtool).Ithasbeenreportedtooccurin16to89%ofhospitalizedpatients,includingupto45%ofpostanesthesiacareunitpatientsand50%ofpostoperativepatientsontheward.5,6 Theincidence,however,seemstobethehighestintheICU,withupto80%ofmechanicallyventilatedpatientshavingdelirium.7,8 Deliriumcanpresentwiththreemotorsubtypes—hyperactive,hypoactive,andmixed—thatmaycarrydifferentprognoses.9,10 Thetwomostcommontypesofdelirium,asstudiedinamedicalICU,weremixedat54.9%andhypoactiveat43.5%ofdeliriouspatients.11 Hypoactivedeliriumischaracterizedbyslowedmentation,lethargy,anddecreasedmovement.Itisfoundmorecommonlyintheelderly,withagemorethan65yrbeinganindependentriskfactor.11 Ittypicallyrequiresactivescreeningwithdeliriumassessmenttoolstodiagnosesinceitisoftenlessclinicallyapparentthantherestlessnessandagitatedbehaviorofhyperactivedelirium.InastudyofpatientsadmittedtotheICUpostoperativelyafterelectiveprocedures,patientswhosufferedfromhypoactivedeliriumhadincreased6-monthmortalitycomparedtothepatientswhosufferedfromothersubtypesofdelirium(32.0vs.8.7%;P=0.04).12  RiskFactors Knownriskfactorsfordevelopingdeliriumarenumerousandcommonlyseparatedintofactorsthatpredisposeapatienttodeliriumandotherfactorsthatprecipitatethedevelopmentofdelirium(table1).Advancedageandbaselinecognitiveimpairmenthavebeenconsistentlyfoundtoincreasedeliriumriskacrossavarietyofhospitalsettings.5 Similarly,patientswithincreasedcomorbiddiseaseburden(especiallyrespiratorydisease)13 andfrailty14 appeartobeathigherrisk.Thus,patientswithlowercognitiveandphysicalreservelikelypossessdecreasedcapacitytomaintainnormalbrainfunctioninginresponsetostress(e.g.,surgeryandcriticalillness)andare,therefore,athigherriskfordelirium.15,16 Similarly,amoresignificantsystemicinsult,suchassepsis,prolongedmechanicalventilation,ormajorsurgery(inparticularcomplexabdominal,hipfracture,andcardiacsurgery),willincreasetheriskofdeliriumcomparedtoalesserphysiologicinsult.5 Increasedpainlevelshaverepeatedlybeenshowntoincreasedelirium,especiallyinthepostoperativesetting,potentiallyduetoheightenedstressresponseandalteredneurotransmission.17,18  Table1.DeliriumRiskFactorsViewlargeViewLarge Severalmedicationshavebeenassociatedwithdelirium.Withregardtosedativeandanalgesicmedications,useoflorazepam,midazolam,meperidine,andmorphineismoststronglyassociatedwithahigherriskofdelirium,likelyduetotheirlongerdurationofactionsandincreasedriskofdrugaccumulationwithalteredorganfunction(e.g.,renalandhepaticinsufficiency),comparedtoagentssuchaspropofol,dexmedetomidine,andfentanyl.5,13 Sedationwithbenzodiazepineinfusionsformechanicalventilation,inparticular,carriesahigherriskofdeliriumcomparedtoothersedativeregimens,19–21 asdoesdeeplevelsofsedationwhencomparedtolightsedation.19 Additionally,medicationswithanticholinergicproperties(e.g.,diphenhydramine,promethazine,andcyclobenzaprine)canprecipitatedelirium,potentiallythroughalteredneurotransmissionorreducedneuronalcontrolofinflammation.22,23 Steroidadministrationduringcriticalillness,eitherasamarkerofshockseverityorduetotheirknownpsychologicsideeffects,hasbeenassociatedwithtransitiontodelirium.24 Dopamineisaneurotransmitter,andmedicationsthatpotentiateitseffectscancausepsychosiswhereasthosethatblockitseffectsareusedasantipsychotics.Dopamineadministrationforshockgreatlyincreasestheoddsofrequiringtreatmentfordeliriumafteradjustmentforseverityofillnessfactorsalthoughdirectcomparisontoothervasoactivemedicationswasnotperformed.25  IdentifyingDeliriumintheICUSetting ThedefinitivestandardfordeliriumdiagnosisisevaluationbyapsychiatristusingDSM-5criteria,whichisnotfeasibleonaroutinebasis.Anumberofscreeningtools,therefore,havebeendevelopedandvalidatedforclinicalusebyawiderangeofpersonnel.Importantly,ithasbeendemonstratedthatmostdeliriumintheICUgoesundiagnosedwithoutusingaregularscreeningtool,26 andcurrentguidelinesrecommendtheroutinescreeningfordeliriuminallICUpatients.27 Importantly,apatientmustbearousabletovoicetoassessfordelirium.Thus,anarousal/sedationtoolsuchastheRichmondAgitation-SedationScale(RASS)28 mustbeutilizedalongwithadeliriumassessmenttool.Therearesevenvalidatedinstrumentstoassessdeliriumincriticallyillpatients(table2).7,29 Ofthese,theConfusionAssessmentMethodfortheIntensiveCareUnit(CAM-ICU)8 andtheIntensiveCareDeliriumScreeningChecklist(ICDSC)30 arethemostwidelystudied.Additionally,basedontheassessmentofpsychometricproperties,theCAM-ICUandICDSCaretherecommendedinstrumentsbytheSocietyofCriticalCareMedicine’sPain,Agitation,andDeliriumguidelinesformonitoringdeliriuminICUpatients.27  Table2.ValidatedInstrumentstoAssessDeliriuminCriticallyIllPatientsViewlargeViewLarge TheCAM-ICUisanabbreviatedversionoftheConfusionAssessmentMethod31 designedtofittheneedsofnonverbalandverbalICUpatients.OriginallydescribedbyElyetal.8 in2001,theCAM-ICUtoolassessesthesamefourcardinalfeaturesastheConfusionAssessmentMethod—acutechanges/fluctuationsinmentalstatus,inattention,disorganizedthinking,andanalteredlevelofconsciousness—butinacondensedmanneridealfortheICUsetting.TovalidatetheCAM-ICU,assessmentswereperformedin111patients(471totalevaluations)bytwoindependentnursesandcomparedtoexpertpsychiatricassessmentusingtheDSM-IVcriteria.Thestudyfoundsensitivitiesof100and93%andspecificitiesof98and100%,respectively.8 ThemomentintimedeliriumassessmentwiththeCAM-ICUrequireslessthan2 mintocomplete,whichhasprompteditsuseinhospitalsettingsoutsidetheICU.WhilethemajorityofsubsequentstudieshaveshownhighsensitivityandspecificityfortheCAM-ICUacrossavarietyofpatients(e.g.,medicalandsurgical)andseveritiesofillness,29,32,33 somestudieshavefoundlowersensitivityoftheCAM-ICUwhenusedinlessseverelyillpatientsoutsideoftheICU,suchasthepostanesthesiacareunit(althoughthesestudieshaveshownspecificitynearorabove90%).34 ArecentsystematicreviewofstudiesinICUpatientsdemonstratedpooledsensitivityof80%andspecificityof96%fortheCAM-ICU.35 TheICDSCassesseseightdiagnosticfeaturesofdeliriumoveranentirenursingshift(alteredlevelofconsciousness,inattention,disorientation,psychosis,alteredpsychomotoractivity,inappropriatespeech/mood,sleepdisturbance,andsymptomfluctuation).30 Initsvalidation,theICDSCwasperformedin93patientsandcomparedtopsychiatricevaluation.Thepresenceoffourormoreofthelistedfeatureshad99%sensitivityand64%specificityfordelirium.30 ArecentsystematicreviewofstudiesinICUpatientsdemonstratedpooledsensitivityof74%andspecificityof82%fortheICDSC.35  DeliriumassessmenttoolssuchastheCAM-ICUandICDSCshouldnotbeviewedsolelyastoolsforresearchbutratheraspivotalcomponentsinthecareofpatients.CurrentclinicalguidelinesrecommendusingeithertheCAM-ICUorICDSCforroutinedeliriumassessmentinthecriticallyill.27 Theseassessmentscanbeeffectivelyperformedoutsideoftheresearchsettingbyclinicalnursingstaffifappropriateeducationandtrainingisprovided(resourcesavailableonline).36 SuccessfulimplementationofroutinedeliriumscreeningintheICUrequiresinstitutionalacknowledgmentofthenecessityfordeliriumscreening,physicianandnurseleaderstoserveasdeliriumexpertsandresources,didacticinstruction,case-basedscenarios,bedsidedemonstrations,adjustmentoftechniquestofitpatientpopulation(e.g.,language,questions,andvisualsusedduringassessment),follow-upteaching,androutinepresentationofresultsoninterdisciplinaryrounds(e.g.,theBrainRoadmap).37 Large-scaleimplementationtrialshaveshownthatnursescanusetheCAM-ICUroutinelywithhighlevelsofcomplianceandreliability38,39 andthatcomplianceandreliabilityofmeasurementsatthebedsidecanbesustainedmultipleyearsafterimplementation.40 Giventhefluctuatingcourseofdelirium,itisimportantthattheseassessmentsareperformedinaserialnature(foranassessmentatanygivenpointintimemaynotcapturecompletesymptomatology)andcombinedwithchartreviewanddiscussionwithfamilyandcaregivers. DeliriumPrevention AlargeportionofICUpatientsdevelopdelirium,especiallythosewhoaremechanicallyventilatedorwhohaveotherriskfactorsonadmission.Whilemanyoftheseriskfactorsareoftennonmodifiablebyclinicians,severalpreventativestrategieshavebeendemonstratedtoreducetheincidenceofICUdelirium. PharmacologicProphylaxis Multiplepathophysiologicprocesseslikelycontributetodelirium,andanumberofpharmacologicprophylaxisagentshavesubsequentlybeenstudiedtodecreasedeliriumincidence(fig.1).41,42 Thisincludesagentstoreducedopamineactivityandimproveneurotransmitterimbalances(e.g.,antipsychotics)andagentsthatincreasecholinergicactivityaslowcholinergicactivityandanticholinergicmedicationshavebeenlinkedtodelirium(e.g.,acetylcholinesteraseinhibitors).Themajorityofrecentanimalandhumanresearchstudieshavefocusedonsystemicinsults(e.g.,surgeryandsepsis)leadingtoinflammatorysignalingthroughtheblood–brainbarrier,resultinginneuroinflammationandneuronalinjury.43–48 Thus,agentstoreducesystemicinflammationanddecreasetheneuroinflammatorycascade(e.g.,steroidsandstatins)arealsobeingexamined. Fig.1.ViewlargeDownloadslidePotentialmechanismsandtherapiesforintensivecareunit(ICU)delirium.HypothesizedmechanismsforICUdeliriumincludesystemicinflammation,endothelialdysfunction,increasedblood–brainbarrier(BBB)permeability,andreducedcholinergiccontroloftheinflammatoryresponsethat,alongwithbaselinepatientvulnerabilityfactors,predisposepatientstoneuroinflammationandsubsequentneuronalinjury.Primedandoveractivatedmicrogliafromtheseprocessesmayalsoexacerbatethepathophysiologicchanges.TherapeuticagentsstudiedforthepreventionortreatmentofICUdeliriumhavetargetedthesepathways.Fig.1.ViewlargeDownloadslidePotentialmechanismsandtherapiesforintensivecareunit(ICU)delirium.HypothesizedmechanismsforICUdeliriumincludesystemicinflammation,endothelialdysfunction,increasedblood–brainbarrier(BBB)permeability,andreducedcholinergiccontroloftheinflammatoryresponsethat,alongwithbaselinepatientvulnerabilityfactors,predisposepatientstoneuroinflammationandsubsequentneuronalinjury.Primedandoveractivatedmicrogliafromtheseprocessesmayalsoexacerbatethepathophysiologicchanges.TherapeuticagentsstudiedforthepreventionortreatmentofICUdeliriumhavetargetedthesepathways. Studiesinvestigatingwhetherprophylacticantipsychoticadministrationreducestheincidenceordurationofdeliriumhavehadmixedresults.Perioperativehaloperidol(1.5 mg/day)prophylaxisinelderlyhipsurgerypatientsdidnotaffecttheincidenceofdeliriumbutdiddecreasetheduration(5.4vs.11.8days;P<0.001)comparedtoplacebo.49 Alow-dosehaloperidolbolus(0.5 mgintravenously)followedbyaninfusion(0.1 mg/hfor12 hr)inelderlypatientsadmittedtotheICUafternoncardiacsurgerydecreasedtheincidenceofdeliriumonlyafterintraabdominalsurgeries(14.5vs.24.7%;P=0.018).50 Abefore–afterstudyofintravenoushaloperidol(1 mgevery8 h)asprophylaxisinICUpatientsdeemedhighriskfordeliriumshowedsignificantlylessincidence(P=0.01)andduration(P=0.003)ofdelirium.51 Amorerecentrandomizedcontrolledtrial—TheHaloperidolEffectivenessinIntensiveCareUnitDelirium(HOPE-ICU)study—however,showednodifferenceindaysaliveandfreeofdeliriumorcomabetweenpatientsprophylacticallytreatedwithintravenoushaloperidol(2.5 mgevery8 h)andthosetreatedwithplacebo.52 Oversedationwasthemostcommonadverseeventinthetrial(15%inthehaloperidolgroup);thosetreatedwithhaloperidol,however,werelesslikelytodevelopagitationwithanRASSscoregreaterthanorequalto+2(13vs.20%;P=0.0075). Numerousstudieshaveexaminedagentstopreventdeliriumaftercardiacsurgery.Inablinded,placebo-controlledtrialof126patientsundergoingelectivecardiacsurgerywithcardiopulmonarybypass,asingledoseofsublingualrisperidone(1 mg)uponregainingconsciousnessreducedtheincidenceofdeliriumcomparedtothatofplacebo(11vs.32%;P=0.009).53 Anotherstudyofrisperidoneinelderlypatientsrequiringcardiacsurgerywithcardiopulmonarybypassexaminedwhetherrepeateddoses(0.5 mgevery12 h)couldpreventthedevelopmentofdeliriuminpatientsexhibitingsignsofacutebraindysfunctionbutwhodidnotyetmeetdeliriumcriteria(referredtoassubsyndromaldelirium).54 Theyfoundalowerincidenceofdeliriumdevelopmentintherisperidonegroupcomparedtotheplacebogroup(13.7vs.34%;P=0.031).Thesestudiesutilizedvalidateddeliriumassessments,andtheincidenceofdeliriumintheplacebogroupswassimilartothatinotherpublishedcohorts.55 Thepositiveresultsseenwithrisperidoneneedtobeconfirmedinadditionallargercohortsbeforeroutineadministrationcanberecommended.Prophylacticadministrationofdexamethasoneuponinductionofanesthesiatoreducethesubsequentsystemicandneurologicinflammatorycascadeofsurgeryandcardiopulmonarybypassdidnotreducetheincidenceordurationofdeliriuminthefirst4daysaftersurgerycomparedtoplaceboinastudyofpatientsundergoingcardiacsurgerywithcardiopulmonarybypass.56 Gamberinietal.57 performedarandomizedcontrolledtrialofa7-daycourseoftheacetylcholinesteraseinhibitorrivastigmineversusplaceboinpatientsundergoingelectivecardiacsurgerywithcardiopulmonarybypassbutfoundnodifferenceintheincidenceofpostoperativedelirium. Donepezil,anacetylcholinesteraseinhibitorusedcommonlyindementiapatients,hasbeenstudiedwithregardtodeliriumprophylaxisbutwithnegativeresults.Inastudyof80elderlypatientsundergoingelectivetotaljointreplacementsurgery,patientswererandomizedtodonepezilorplacebofor14daysbeforesurgeryand14daysafterward.58 Nosignificantdifferenceindeliriumincidencewasfoundbetweenthegroups.Similarresultswereseeninapilottrialof16elderlypatientsundergoinghipfracturerepairrandomizedtodonepezilorplacebowithin24 hofsurgery.59 Thedonepeziltreatmentgroupexperiencedmoreadverseeffectsandhadnosignificantimprovementsindeliriumpresenceorseverity.Arandomized,double-blind,placebo-controlledtrialof33patientsundergoingelectivetotalhipreplacementalsofoundnosignificantdifferenceintheincidenceofdelirium.60  Thereisinterestinthepleiotropicantiinflammatoryeffectsofstatinmedicationswithregardtodelirium.61 OngoingstatintherapywhileintheICUhasbeenshowntobeassociatedwithloweroverallriskofdeliriumintwostudies,62,63 andincreasingdurationofstatinwithholdinginchronicstatinusersincreasestheoddsofdevelopingdelirium.63Furtherrandomizedcontrolledtrialsareneededtoprovideevidenceoftheabilityofstatinstopreventdelirium. Despitethemultipleagentsevaluatedcoveringavarietyofpathophysiologicpathways,thereremainsalackofprovenprophylacticagentstoreducedelirium.Inaddition,manyoftheseagentshavesignificantsideeffects,inparticulartheantipsychotics,whichmayprolongtheQTinterval,leadtooversedation,orcauseneurolepticmalignantsyndrome.Thisemphasizesthenecessityofnonpharmacologicpreventativemeasurestoimprovedeliriumoutcomes. ChoiceofSedationforMechanicalVentilation ThetypeofsedationusedinmechanicallyventilatedpatientsintheICUcanaffectratesofdelirium.Currently,itisrecommendedbythePain,Agitation,andDeliriumguidelinestoperformanalgesia-firstsedationfollowedbynonbenzodiazepinemedicationsifneededforsedationinmechanicallyventilatedpatientsintheICU.27 Thisispartlybaseduponevidencedemonstratingincreasedriskofdeliriumwithtraditionalsedationregimensinvolvingcontinuousbenzodiazepineinfusionsanddeeperlevelsofsedation.Pandharipandeetal.19 comparedsedationwithdexmedetomidineversuslorazepaminfusioninintubatedpatients,assessingratesofdelirium(asdefinedbyCAM-ICU),coma,ICUlengthofstay,andmortality.Thisstudyof106criticallyillpatientsfoundthatthepatientsreceivingdexmedetomidinehadmoredelirium/coma-freedaysthanthosereceivinglorazepam(7vs.3;P=0.01)andlesscoma(63vs.92%;P<0.001).Therewasnodifferenceinantipsychoticusebetweenthegroups.ThesefindingsweresubsequentlyconfirmedwithamulticentertrialbyRikeretal.,20 inwhichdexmedetomidinewascomparedtomidazolamfortargetedsedation.Theyfoundsimilarresults,with54%ofthedexmedetomidine-treatedpatientsdevelopingdelirium,while76.6%ofthemidazolam-treatedpatientsdevelopeddelirium(P≤0.001).20 Incomparingsedationwithpropofolversusdexmedetomidine,astudyfoundfewerneurocognitivedisordersandimprovedarousal,cooperation,andcommunicationwithdexmedetomidine.64 However,theyonlyassessedtheCAM-ICUonce,48 haftertheinfusionshadbeendiscontinued,andfoundnodifferenceindelirium.ArecentCochranemetaanalysispooledsevenrandomizedcontrolledtrialscomparingsedationwithdexmedetomidinetosedationwithbenzodiazepines,propofol,or“standardcare”thatincludedpropofolormidazolam.65 Theriskofdeliriumwasnumericallylowerwithdexmedetomidinebutnotstatisticallysignificant(riskratio[RR],0.85;95%CI,0.63to1.14).Subgroupanalysesshowedthattheriskofdeliriumwaslowerinpatientsreceivingdexmedetomidinethaninthosereceivingbenzodiazepines(RR,0.81;95%CI,0.59to1.09;1,007participants)orpropofol(RR,0.37;95%CI,0.16to0.87;495participants).65 Overall,theauthorsfoundhighratesofheterogeneitybetweenthestudies,includingthebaselineriskfordelirium,timeinICUbeforeenrollmentandassessment,frequencyanddurationofdeliriumassessments,andlevelsofsedationtargeted,allofwhichwouldbiasdeliriumoutcomes.Theyrecommendedthatfurtherstudiesstratifyrandomizedpatientsbasedondeliriumrisk.Dexmedetomidinehasadditionallybeenfoundtoreducedeliriumrateswhenusedaftercardiacsurgery.66 Mostrecently,arandomizedcontrolledtrialofdexmedetomidineversuspropofolforICUsedationin183patientsaftercardiacsurgeryfoundadecreasedincidence(17.5vs.31.5%;P=0.028)andreduceddurationofdelirium(2vs.3days;P=0.04)inthedexmedetomidinegroup,leadingtoareductioninICUtimeandcostrelatedtodelirium.67  Inthesedationstudiesoutlined,analgesia(andlikelysupplementalsedation)wasprovidedwithfentanylinadditiontothesedativemedicationsadministered.Similarfentanylrequirementswerefoundbetweendexmedetomidine,midazolam,andpropofolregimens20,64 withtheexceptionofaftercardiacsurgery,inwhichdexmedetomidinepatientsrequiredlessanalgesicmedications.67 Therearenowdataexamininganalgesia-basedsedationregimensandtheireffectondelirium.Onetrialshowedthatpatientstreatedonlywithintermittentmorphinehadhigherratesofagitateddelirium(20vs.7%;P=0.04)comparedtopatientssedatedwithpropofolormidazolam(hypoactivedeliriumwasnotassessedinthisstudy)althoughpatientsreceivinganalgosedationhadshorterICUlengthsofstay.68 Whencomparingmorphinetodexmedetomidineforsedationaftercardiacsurgery,patientsreceivingamorphine-basedregimenhadsimilaroverallincidenceofdeliriumbuthadanincreaseddurationofdeliriumby3days(P=0.03).69  Exposuretosedativemedicationsanddeeperlevelsofsedationareassociatedwithincreasedriskofdelirium,butquestionshavearisenregardingwhetherdeliriumthatabatesquicklyaftersedativediscontinuation—rapidlyreversible,sedation-relateddelirium—portendssimilaroutcomestodeliriumthatpersistsaftersedativediscontinuation—persistentdelirium.Aprospectivecohortstudyperformeddeliriumassessmentsbeforeandaftersedativediscontinuation.70 Itfounddeliriumtobeextremelyprevalent,with89%ofpatientsdevelopingdelirium,butonlyasmallgroupofpatients(12%)haddeliriumthatabatedaftersedationinterruption(rapidlyreversible,sedation-relateddelirium).70 Thisgroupwithrapidlyreversible,sedation-relateddeliriumhadfewerventilatordays(P<0.001),ICUdays(P=0.001),andhospitaldays(P<0.001),wasmorelikelytobedischargedhomeversusaninstitution(P<0.001),andhadhighersurvivalrates(P<0.001)thanthosewhosedeliriumpersisted.Persistentdelirium(77%ofthecohort)remainedassociatedwithworseoutcomes.Thisstudyhasimportantclinicalimplications:(1)recentsedativeadministrationshouldbecarefullyconsideredwhenevaluatingfordelirium;(2)theeffectofpersistentdeliriumonnegativeoutcomesislikelygreaterthanmeasuredinpreviousstudiesasthosewithrapidlyreversible,sedation-relateddeliriumwereincluded,biasingthosestudiestowardthenull,and(3)onlyasmallsubsetofpatientsonsedativemedicationsresolvetheirdeliriumrapidlyafterdiscontinuationofthosemedications,underliningtheimportanceofmonitoringfordeliriumeveninpatientsonsedativemedications. EarlyMobility Earlyphysicalandoccupationaltherapyinintubatedandmechanicallyventilatedpatientscoordinatedamongnursingstaff,physicaltherapists,andrespiratorytherapistsisfeasible,safe,andhasbeendemonstratedtoreduceICUdelirium.71 Therapycanprogressfrompassiverangeofmotiontoactiverangeofmotion,exerciseinbed,sitting,standing,walking,andactivityofdailylivingtrainingdependingonapatient’ssedationlevelandphysicalabilities.Schweickertetal.71 conductedamulticenter,randomizedcontrolledtrialof104hemodynamicallystablemedicalICUpatientstolookattheeffectofdailysedationinterruptionspairedwithphysicalandoccupationaltherapyonlong-termfunctionalindependence,withsecondaryoutcomesthatincludeddelirium.Afterpatientswererandomized,thoseintheinterventiongrouphadregularsessionswiththephysicalandoccupationaltherapistswhiletheirsedationwaspaused,progressingfromrange-of-motionexercisestowalking.Theyfoundamedianof2daysofICUdeliriumintheearlyphysicaltherapygroup,whereasthecontrolgrouphadamedianof4daysofdelirium(P=0.03).Bothgroupshadsimilarsedationandanalgesiaalthoughthephysicaltherapygrouphad,onaverage,moretimewithoutsedationthanthecontrolgroup. SleepHygiene Fragmentedsleephasbeenassociatedwithdelirium,andstudieshaveevaluatedwaystoimprovesleephygiene(i.e.,habitsandpracticesconducivetosleep)byprovidingmorefavorableenvironmentsforsleepintheICU.ProvidingearplugstopatientsintheICUhasbeenshowntoreducetheincidenceofdeliriumandimprovesleepperception.72 Aqualityimprovementprojectaimedatimprovingsleepbyminimizingsleepdisruptions,promotingnormalcircadianrhythms,usingnonpharmacologicsleepaids,andimplementingalternativesleepmedicationswhennecessary(e.g.,zolpidem,haloperidol,andatypicalantipsychotics)hasalsobeenshowntodecreasetheincidenceofICUdelirium/comaandimprovedailydelirium/coma-freestatusalthoughwithoutimprovedperceivedsleepquality.73 Theauthorssubsequentlyfoundnoassociationbetweendailyperceivedsleepqualityratingandtransitiontodelirium.21 ThesestudiessuggestthatmaintainingpracticesconducivetosleepisimportanttopreventdeliriumintheICUbuthighlightthedifficultyinmonitoringsleepanddifferentiatingbetweensleepperceptionandmeasuresofactualsleep. Whileoutwardlyappearingtoimprovesleep,sedativeadministrationintheICUhasbeenshowntodifferentiallyaltersleeppatternswhenmeasuredbypolysomnography.Inastudyof12ICUpatientsnotrequiringvasoactiveorsedativemedications,patientsweremonitoredwithpolysomnographyfortwonights,oneofwhichtheyreceivedpropofolandtheothernosedationtoserveasacontrol.74 Theyfoundthatpropofoladministrationsignificantlydecreasedthenumberofpatientsexhibitingrapideyemovement(REM)sleep(P=0.02)andthepercentageofREMsleep(P=0.04).Inasimilarstudyof13hemodynamicallystableICUpatientsnotrequiringvasoactiveorsedativemedications,patientsweremonitoredwithpolysomnographyforthreenights,receivingdexmedetomidineonthesecondnightonlyandnosedativestheothertwonightstoserveasacontrol.75 Theyfoundthatdexmedetomidineimprovedsleepefficiency(P<0.002)andstage2sleep(P=0.006)whiledecreasingnighttimesleepfragmentation(P=0.023).Theselimiteddataincriticallyillpatientsareconsistentwithadditionaldataindicatingthatsedationwithdexmedetomidinemorecloselyresemblesnaturalnon-REMsleepthansedationwithγ-aminobutyricacid–mediatedagents.76 However,clinicalstudiesinvestigatingtheinteractionsbetweensedativeagents,sleeppatterns,anddeliriumhavenotyetbeenperformed. Interestinsleepdisturbancesindeliriumhasledtostudiesinvestigatingtheroleofmelatoninindelirium.AbnormalreleaseofcircadianmelatoninhasbeenfoundinsepticICUpatients,77 andmelatoninlevelshavebeenfoundtobesignificantlylowerinpostoperativeICUpatientswithdeliriumthaninthosewithoutdelirium.78 Importantly,dataregardingwhethermelatoninormelatoninagonistsimprovesleepqualityandcircadianrhythmsinICUpatientsarelimitedandunclear.Inarandomizedcontrolledtrialof24patientsonmechanicalventilationaftertracheostomy,melatoninsupplementationincreasednocturnalsleepefficiencyasmeasuredbythebispectralindexbutnotbyothersleepmeasurements.79 Anotherstudyof32patientswithtracheostomyfoundnosignificantdifferenceinsleepdurationasmeasuredbynursingassessment.80  Oneofthefirstrandomizedcontrolledtrialsexaminingmelatoninasanagentfordeliriumpreventionfoundthatmelatonin(0.5 mgnightly)wasassociatedwithalowerriskofdeliriumcomparedtoplacebo(12.0vs.31.0%;P=0.014)in145elderlypatientsadmittedtoamedicalacutecareunit.81 Adouble-blind,randomizedcontrolledtrialofmelatonin(3 mgnightly)versusplaceboin378patientswithhipfracture,however,didnotdemonstrateadifferenceintheincidenceofdelirium.82 Ramelteon,amelatoninreceptoragonist,hasbeenshowntolowerriskofdelirium(3vs.32%;P=0.003)inarandomizedcontrolledtrialof67elderlypatientsadmittedtoamedicalICUoracutecarewardwhoreceivedramelteon(8 mgnightly)orplacebo.83 Theydidnotfindanybenefitoframelteononsleepmetrics,makingitunclearwhethertheeffectsoframelteonondeliriumarerelatedtosleep.Limitationsofstudiesexaminingmelatoninandramelteonincludethelackofsleepmeasurementviapolysomnographyorelectroencephalogramandinabilitytoadjustforactualsleepdifferencesbetweengroups.Whilegenerallywelltolerated,theseagentsarenotbenignandmaycauseheadache,daytimesleepiness,dizziness,anddepressivesymptoms.Thus,large,randomizedcontrolledtrialswithdirectsleepmeasurementarerequiredtoclarifytheroleofpharmacologicagentsinsleepanddeliriumpreventionintheICUbeforeprophylacticadministrationcanberecommended.Arecentsystemicreviewconcludedthatnonpharmacologicandpharmacologicsleepinterventionsmaybeapromisingapproachtoimprovedeliriumbutthatcurrentresearchislimitedbyvariedmethodologiesandsignificantbias,requiringasystematicapproachinfutureresearchtoevaluatethecomplexinteractionsbetweensleepinterventionsanddelirium.84  SedationBundles Whileseveralstudieshaveidentifiedspecificinterventionsthatreducedeliriumrates,othershavecombinedtheevidence-basedpreventiontechniquesintobundlestoevaluateif,whenappliedtogetherinaconsistentmanner,theycouldreducedeliriumratesevenfurther.TheAwakeningandBreathingCoordination,DeliriumMonitoring/Management,andEarlyExercise/Mobility(ABCDE)bundlewasoriginallypublishedin201185 andstudiedinabefore–aftertrialbetween2010and2012atatertiarymedicalcenter.86 CriticallyillpatientswereenrolledfromfiveseparateICUs,onestepdownunit,andahematology/oncologyspecialtyunit.Thepatientsinthe“before”groupweretreatedasperthestandardpractice,whichincludedspontaneousawakeningtrials(SAT)andspontaneousbreathingtrials(SBT)butnoconsistentdeliriumscreeningbyclinicalproviders.Inthe“after”group,theABCDEbundlewasimplementedandincludedadailySAT,whichwasthencoordinatedwithanSBT,scheduledRASSandCAM-ICUassessments,deliriumactionplandiscussionsamongproviders,andearlymobilityevaluationsandperformance.Patientsinthepostimplementationbundlegrouphadlessdelirium(48.7vs.62.3%;P=0.02)andalowerpercentofICUdaysspentdelirious(33vs.50%;P=0.002).TherewasasignificantindependenteffectoftheABCDEbundleondecreasingdelirium(P=0.03). SimilartotheABCDEbundle,anotherstudyexaminedaqualityimprovementprojectaimedatreducingbenzodiazepineexposure,lighteningsedation,andincreasingmobility.Thisstudyfoundasignificantincreaseinthedaysalivewithoutdelirium(53vs.21%;P=0.003).87 Inabefore–afterstudyofprotocolizeddeescalationofsedationandrequiredRASSandCAM-ICUassessments,theauthorsfoundasignificantreductionintheoddsofdevelopingdelirium(oddsratio,0.67;P=0.01)alongwithareductioninmechanicalventilationduration(P=0.04)andhospitallengthofstay(P=0.02).88 Thus,currentevidencesupportstheuseofsedationbundlestodecreasethedevelopmentofdelirium. TheAmericanAssociationofCriticalCareNurseshasdevelopedatoolkitforimplementingtheABCDEbundleatthebedside.89 Thistoolkitincludesresourcesforthespecificcomponentsofthebundleandtoolsforoverallimplementation.TheSocietyofCriticalCareMedicinehasrecentlylaunchedtheICULiberationcollaborativewithareworkingoftheABCDEbundle.90 Thenowcoined“ABCDEF”bundleinvolvesAssessmentandmanagementofPain,BothSATsandSBTs,Choiceofsedationifrequired,Deliriummonitoringandmanagement,Earlymobilityandexercise,andFamilyengagementandempowerment(fig.2). Fig.2.ViewlargeDownloadslideTheABCDEF(AssessmentandmanagementofPain,BothSATsandSBTs,Choiceofsedationifrequired,Deliriummonitoringandmanagement,Earlymobilityandexercise,andFamilyengagementandempowerment)buildingblocksofintensivecareunit(ICU)deliriummanagement.MultidisciplinaryICUcarebundlesfocusingonpainmanagement,liberationfrommechanicalventilation,lightsedationornosedation,avoidanceofbenzodiazepines,routinedeliriummonitoring,andearlymobilityhavebeenshowntoreducedeliriumandimprovepatientoutcomes.MoreinformationontheABCDEFbundlecanbefoundonline.36,90 ADLs=activitiesofdailyliving;BPS=BehavioralPainScale;CAM-ICU=ConfusionAssessmentMethodfortheIntensiveCareUnit;CPOT=Critical-CarePainObservationTool;ICDSC=IntensiveCareDeliriumScreeningChecklist;MV=mechanicalventilation;SAT=spontaneousawakeningtrial;SBT=spontaneousbreathingtrial.Fig.2.ViewlargeDownloadslideTheABCDEF(AssessmentandmanagementofPain,BothSATsandSBTs,Choiceofsedationifrequired,Deliriummonitoringandmanagement,Earlymobilityandexercise,andFamilyengagementandempowerment)buildingblocksofintensivecareunit(ICU)deliriummanagement.MultidisciplinaryICUcarebundlesfocusingonpainmanagement,liberationfrommechanicalventilation,lightsedationornosedation,avoidanceofbenzodiazepines,routinedeliriummonitoring,andearlymobilityhavebeenshowntoreducedeliriumandimprovepatientoutcomes.MoreinformationontheABCDEFbundlecanbefoundonline.36,90 ADLs=activitiesofdailyliving;BPS=BehavioralPainScale;CAM-ICU=ConfusionAssessmentMethodfortheIntensiveCareUnit;CPOT=Critical-CarePainObservationTool;ICDSC=IntensiveCareDeliriumScreeningChecklist;MV=mechanicalventilation;SAT=spontaneousawakeningtrial;SBT=spontaneousbreathingtrial. DeliriumTreatment Preventionofdeliriumisofutmostimportancebecausethenumberofevidence-basedpharmacologictreatmentoptionsisminimal,andthosethatexisthavesignificantlimitations.Therefore,thecornerstoneofdeliriumtreatmentiscorrectionofthepatient’smedicalconditionsthatmaybecontributingtodelirium. PotentialTreatmentOptions Despitetheabundanceofliteratureandresearchondelirium,thereremainsapaucityoflarge,randomizedcontrolledtrialsofpharmacologictreatmentsfordelirium.Theclinicalapproachtopharmacologictreatmentoftenincludestheuseoftypical(e.g.,haloperidol)andatypical(e.g.,olanzapine,quetiapine,andziprasidone)antipsychotics,butevidenceontheirefficacyislimitedandconflicting.Inapilotstudyof101ICUpatientsatriskfordelirium,placeboversushaloperidol(5 mg)versusziprasidone(40 mg)inrepeateddosesshowednodifferenceindelirium-freedaysamongallthreegroups.91 Anotherevaluationofhaloperidol(2.5to5 mgevery8 h)versusolanzapine(5 mgdaily)showednodifferenceinlengthofdeliriumin73ICUpatientsalthoughthepatientsreceivinghaloperidoldidhavemoreextrapyramidalsideeffects.92 Inastudyof36ICUpatientswithdeliriumrequiringintravenoushaloperidol,patientswererandomizedtoscheduledquetiapine(50 mgevery12 h)orplaceboinadditiontothe“as-needed”haloperidol.Thegroupthatreceivedquetiapinehadafasterresolutionofthefirstepisodeofdelirium(36vs.120 h;P=0.006)althoughmortalityandICUlengthofstayweresimilar.93 Basedonevidencethatimpairedcholinergicneurotransmissionmayleadtothedevelopmentofdelirium,rivastigmine(1.5to6 mgevery12 h)wasstudiedasanadjuncttohaloperidolversusacombinationofplaceboandhaloperidol.94 Thisstudyfoundnodecreaseinthedurationofdelirium,andtherewasatrendtowardincreasedmortalityintherivastigminegroup.94  Inasmallpilotstudyofpatientswithagitateddeliriumpreventingtrachealextubation,20patientswererandomizedtoadexmedetomidine(0.2to0.7μgkg−1h−1)orhaloperidol(0.5to2 mg/h)infusion.Thepatientsreceivingdexmedetomidinehadashortertimetoextubation(19.9vs.42.5 h;P=0.016),ICUlengthofstay(1.5vs.6.5days;P=0.004),andlessrequirementfortracheostomy.95 TherecentlypublishedDexmedetomidinetoLessenICUAgitation(DahLIA)trialrandomizedpatientswhosecriticalillnesshadotherwiseresolved,butforwhomweaningfrommechanicalventilationwashamperedbyhyperactiveoragitateddelirium,toreceiveupto7daysofintravenousdexmedetomidineupto1.5μgkg−1h−1(n=41)orplacebo(n=33).96 Patientstreatedwithdexmedetomidinehadincreasedventilator-freetimeat7days(144.8vs.127.5 h;P=0.01)andhadfasterresolutionoftheirdeliriumsymptoms(23.3vs.40.0 h;P=0.01).Nodifferencewasfoundinbradycardiarequiringinterruptionofstudydrugorhypotensionrequiringvasopressorsupportbetweengroups.Arecentlypublished,nonrandomizedstudyexaminedtheeffectivenessofdexmedetomidineasarescuetherapyfornonintubatedICUpatientswithhyperactivedelirium.97 Patientswhoseagitateddeliriumfailedtobecontrolledwithupto30 mgintravenoushaloperidol(n=46)receiveddexmedetomidine(0.2to0.7μgkg−1h−1).Patientswhoseagitateddeliriumimprovedafterhaloperidol(n=86)receivedahaloperidolinfusion(0.5to1 mg/h).Patientsreceivingdexmedetomidinehadahigherpercentageoftimeattargetsedation(92vs.59%;P=0.001),lessoversedation(0vs.11.6%;P=0.01),andashorterICUlengthofstay(3.1vs.6.4;P<0.001)withoutincreasedincidenceofhemodynamicsideeffects.97 Additionally,theoverallfailurerateforhaloperidolinthisstudywas43%whenincludingpatientswithdeliriumrefractorytohaloperidolandthoseinwhomhaloperidoladministrationresultedinadverseevents,demonstratingthelimitedefficacyofantipsychoticagentsinthetreatmentofICUdelirium. TreatmentAlgorithms Overall,theevidencedoesnotsupportasingleeffectivepharmacologicapproachtothetreatmentofdeliriumintheICU.Thetreatmentoptionsavailablealsohavesignificantsideeffects.Antipsychoticagentscancausesedation,respiratorydepression,andprolongedQTintervalsandmayleadtorarebutlife-threateningneurolepticmalignantsyndrome.Oneofthemostcommonclinicalconcernswithdexmedetomidineisbradycardia.Whilebradycardiawascommonlyseeninseveraltrials,therewerenosignificantdifferencesbetweenthedexmedetomidineandthecomparatorgroups(benzodiazepines,propofol,placebo,andhaloperidol)withregardstobradycardianecessitatingtreatment(e.g.,atropine,glycopyrrolate,orpacing).19,20,64,96,97 CurrentevidencesupportstheuseofdexmedetomidineforpreventionofdeliriumandfortreatmentofrefractorydeliriumacrossawidevarietyofICUpatients,includingthosenotonmechanicalventilation,butfurtherstudiesareneededondexmedetomidineasthefirst-linetherapyforthetreatmentofdeliriumonceitdevelops.Additionally,studiesexaminingtheeffectivenessofα2-agonistsadministeredorallyorbyintermittentintravenousbolus(e.g.,guanfacineandclonidine)areneededwithregardtodelirium,asoneofthelimitationsofdexmedetomidinetherapyisitsadministrationbycontinuousinfusion.Ingeneral,pharmacologicmeasuresshouldonlybeconsideredoncenonpharmacologicpreventionstrategieshavefailedandthepatientisarisktoselforothers.Synthesizingtheevidence,werecommendthealgorithminfigure2,builtupontheSocietyofCriticalCareMedicine’sABCDEFbundle,fordeliriumpreventionandtreatmentintheICU. Conclusions Deliriumisnowrecognizedtobeacommonandseriousclinicalmanifestationofacutebrainorgandysfunctionwithlong-termconsequences.Thisrecognitionhasledtoroutinescreeningandincreasedattentiontoprevention.Intensivistsnowroutinelyassessforit,andmanyICUsaroundthecountryareimplementingpreventativestrategies,suchastheABCDEFbundle.WhilethisisalargeproblemintheICU,itisincreasinglyrecognizedthroughoutthehospitalaspatientsageandpolypharmacyworsens.Preventingdeliriumwillbecometheresponsibilityofmanyclinicianswhowillhavetheabilitytoavoidprecipitatingfactors.Furtherstudiesareneededoneffectivetreatments,differencesbetweenthemotorsubtypes,andlong-termconsequencesofICUdelirium. ResearchSupport Supportedbygrantnos.AG035117,HL111111fromtheNationalInstitutesofHealth,Bethesda,Maryland,andaresearchgrantfromHospiraInc.,LakeForest,Illinois(toDr.Pandharipande).SupportedbytheAmericanGeriatricsSocietyJahnigenCareerDevelopmentAwardandgrantnos.HL111111,AG045085fromtheNationalInstitutesofHealth(toDr.Hughes). CompetingInterests Theauthorsdeclarenocompetinginterests. References 1.LatI,McMillianW,TaylorS,JanzenJM,PapadopoulosS,KorthL,EhtishamA,NoldJ,AgarwalS,AzocarR,BurkeP:Theimpactofdeliriumonclinicaloutcomesinmechanicallyventilatedsurgicalandtraumapatients.CritCareMed2009;37:1898–905GoogleScholarCrossrefSearchADSPubMed 2.ElyEW,ShintaniA,TrumanB,SperoffT,GordonSM,HarrellFEJr,InouyeSK,BernardGR,DittusRS:Deliriumasapredictorofmortalityinmechanicallyventilatedpatientsintheintensivecareunit.JAMA2004;291:1753–62GoogleScholarCrossrefSearchADSPubMed 3.PandharipandePP,GirardTD,JacksonJC,MorandiA,ThompsonJL,PunBT,BrummelNE,HughesCG,VasilevskisEE,ShintaniAK,MoonsKG,GeevargheseSK,CanonicoA,HopkinsRO,BernardGR,DittusRS,ElyEW;BRAIN-ICUStudyInvestigators:Long-termcognitiveimpairmentaftercriticalillness.NEnglJMed2013;369:1306–16GoogleScholarCrossrefSearchADSPubMed 4.AmericanPsychiatricAssociation:DiagnosticandStatisticalManualofMentalDisorders,5thedition.Washington,D.C.,AmericanPsychiatricAssociation,20135.VasilevskisEE,HanJH,HughesCG,ElyEW:Epidemiologyandriskfactorsfordeliriumacrosshospitalsettings.BestPractResClinAnaesthesiol2012;26:277–87GoogleScholarCrossrefSearchADSPubMed 6.CardE,PandharipandeP,TomesC,LeeC,WoodJ,NelsonD,GravesA,ShintaniA,ElyEW,HughesC:Emergencefromgeneralanaesthesiaandevolutionofdeliriumsignsinthepost-anaesthesiacareunit.BrJAnaesth2015;115:411–7GoogleScholarCrossrefSearchADSPubMed 7.DevlinJW,FongJJ,FraserGL,RikerRR:Deliriumassessmentinthecriticallyill.IntensiveCareMed2007;33:929–40GoogleScholarCrossrefSearchADSPubMed 8.ElyEW,InouyeSK,BernardGR,GordonS,FrancisJ,MayL,TrumanB,SperoffT,GautamS,MargolinR,HartRP,DittusR:Deliriuminmechanicallyventilatedpatients:Validityandreliabilityoftheconfusionassessmentmethodfortheintensivecareunit(CAM-ICU).JAMA2001;286:2703–10GoogleScholarCrossrefSearchADSPubMed 9.GroverS,SharmaA,AggarwalM,MattooSK,ChakrabartiS,MalhotraS,AvasthiA,KulharaP,BasuD:Comparisonofsymptomsofdeliriumacrossvariousmotoricsubtypes.PsychiatryClinNeurosci2014;68:283–91GoogleScholarCrossrefSearchADSPubMed 10.MeagherD:Motorsubtypesofdelirium:Past,presentandfuture.IntRevPsychiatry2009;21:59–73GoogleScholarCrossrefSearchADSPubMed 11.PetersonJF,PunBT,DittusRS,ThomasonJW,JacksonJC,ShintaniAK,ElyEW:Deliriumanditsmotoricsubtypes:Astudyof614criticallyillpatients.JAmGeriatrSoc2006;54:479–84GoogleScholarCrossrefSearchADSPubMed 12.RobinsonTN,RaeburnCD,TranZV,BrennerLA,MossM:Motorsubtypesofpostoperativedeliriuminolderadults.ArchSurg2011;146:295–300GoogleScholarCrossrefSearchADSPubMed 13.VanRompaeyB,SchuurmansMJ,Shortridge-BaggettLM,TruijenS,BossaertL:Riskfactorsforintensivecaredelirium:Asystematicreview.IntensiveCritCareNurs2008;24:98–107GoogleScholarCrossrefSearchADSPubMed 14.JungP,PereiraMA,HiebertB,SongX,RockwoodK,TangriN,AroraRC:Theimpactoffrailtyonpostoperativedeliriumincardiacsurgerypatients.JThoracCardiovascSurg2015;149:869–75.e1–2GoogleScholarCrossrefSearchADSPubMed 15.JonesRN,FongTG,MetzgerE,TulebaevS,YangFM,AlsopDC,MarcantonioER,CupplesLA,GottliebG,InouyeSK:Aging,braindisease,andreserve:Implicationsfordelirium.AmJGeriatrPsychiatry2010;18:117–27GoogleScholarCrossrefSearchADSPubMed 16.QuinlanN,MarcantonioER,InouyeSK,GillTM,KamholzB,RudolphJL:Vulnerability:Thecrossroadsoffrailtyanddelirium.JAmGeriatrSoc2011;59(suppl2):S262–8GoogleScholarCrossrefSearchADSPubMed 17.LynchEP,LazorMA,GellisJE,OravJ,GoldmanL,MarcantonioER:Theimpactofpostoperativepainonthedevelopmentofpostoperativedelirium.AnesthAnalg1998;86:781–5GoogleScholarCrossrefSearchADSPubMed 18.VaurioLE,SandsLP,WangY,MullenEA,LeungJM:Postoperativedelirium:Theimportanceofpainandpainmanagement.AnesthAnalg2006;102:1267–73GoogleScholarCrossrefSearchADSPubMed 19.PandharipandePP,PunBT,HerrDL,MazeM,GirardTD,MillerRR,ShintaniAK,ThompsonJL,JacksonJC,DeppenSA,StilesRA,DittusRS,BernardGR,ElyEW:Effectofsedationwithdexmedetomidinevslorazepamonacutebraindysfunctioninmechanicallyventilatedpatients:TheMENDSrandomizedcontrolledtrial.JAMA2007;298:2644–53GoogleScholarCrossrefSearchADSPubMed 20.RikerRR,ShehabiY,BokeschPM,CerasoD,WisemandleW,KouraF,WhittenP,MargolisBD,ByrneDW,ElyEW,RochaMG;SEDCOM(SafetyandEfficacyofDexmedetomidineComparedWithMidazolam)StudyGroup:Dexmedetomidinevsmidazolamforsedationofcriticallyillpatients:Arandomizedtrial.JAMA2009;301:489–99GoogleScholarCrossrefSearchADSPubMed 21.KamdarBB,NiessenT,ColantuoniE,KingLM,NeufeldKJ,BienvenuOJ,RowdenAM,CollopNA,NeedhamDM:DeliriumtransitionsinthemedicalICU:Exploringtheroleofsleepqualityandotherfactors.CritCareMed2015;43:135–41GoogleScholarCrossrefSearchADSPubMed 22.ZaalIJ,DevlinJW,PeelenLM,SlooterAJ:AsystematicreviewofriskfactorsfordeliriumintheICU.CritCareMed2015;43:40–7GoogleScholarCrossrefSearchADSPubMed 23.SteinbergBE,SundmanE,TerrandoN,ErikssonLI,OlofssonPS:Neuralcontrolofinflammation:Implicationsforperioperativeandcriticalcare.Anesthesiology2016;124:1174–89GoogleScholarCrossrefSearchADSPubMed 24.SchreiberMP,ColantuoniE,BienvenuOJ,NeufeldKJ,ChenKF,ShanholtzC,Mendez-TellezPA,NeedhamDM:Corticosteroidsandtransitiontodeliriuminpatientswithacutelunginjury.CritCareMed2014;42:1480–6GoogleScholarCrossrefSearchADSPubMed 25.SommerBR,WiseLC,KraemerHC:Isdopamineadministrationpossiblyariskfactorfordelirium?CritCareMed2002;30:1508–11GoogleScholarCrossrefSearchADSPubMed 26.vanEijkMM,vanMarumRJ,KlijnIA,deWitN,KeseciogluJ,SlooterAJ:Comparisonofdeliriumassessmenttoolsinamixedintensivecareunit.CritCareMed2009;37:1881–5GoogleScholarCrossrefSearchADSPubMed 27.BarrJ,FraserGL,PuntilloK,ElyEW,GélinasC,DastaJF,DavidsonJE,DevlinJW,KressJP,JoffeAM,CoursinDB,HerrDL,TungA,RobinsonBR,FontaineDK,RamsayMA,RikerRR,SesslerCN,PunB,SkrobikY,JaeschkeR;AmericanCollegeofCriticalCareMedicine:Clinicalpracticeguidelinesforthemanagementofpain,agitation,anddeliriuminadultpatientsintheintensivecareunit.CritCareMed2013;41:263–306GoogleScholarCrossrefSearchADSPubMed 28.SesslerCN,GosnellMS,GrapMJ,BrophyGM,O’NealPV,KeaneKA,TesoroEP,ElswickRK:TheRichmondAgitation-SedationScale:Validityandreliabilityinadultintensivecareunitpatients.AmJRespirCritCareMed2002;166:1338–44GoogleScholarCrossrefSearchADSPubMed 29.LuetzA,HeymannA,RadtkeFM,ChenitirC,NeuhausU,NachtigallI,vonDossowV,MarzS,EggersV,HeinzA,WerneckeKD,SpiesCD:Differentassessmenttoolsforintensivecareunitdelirium:Whichscoretouse?CritCareMed2010;38:409–18GoogleScholarCrossrefSearchADSPubMed 30.BergeronN,DuboisMJ,DumontM,DialS,SkrobikY:IntensiveCareDeliriumScreeningChecklist:Evaluationofanewscreeningtool.IntensiveCareMed2001;27:859–64GoogleScholarCrossrefSearchADSPubMed 31.InouyeSK,vanDyckCH,AlessiCA,BalkinS,SiegalAP,HorwitzRI:Clarifyingconfusion:Theconfusionassessmentmethod.Anewmethodfordetectionofdelirium.AnnInternMed1990;113:941–8GoogleScholarCrossrefSearchADSPubMed 32.LinSM,LiuCY,WangCH,LinHC,HuangCD,HuangPY,FangYF,ShiehMH,KuoHP:Theimpactofdeliriumonthesurvivalofmechanicallyventilatedpatients.CritCareMed2004;32:2254–9GoogleScholarCrossrefSearchADSPubMed 33.GuentherU,PoppJ,KoecherL,MudersT,WriggeH,ElyEW,PutensenC:ValidityandreliabilityoftheCAM-ICUFlowsheettodiagnosedeliriuminsurgicalICUpatients.JCritCare2010;25:144–51GoogleScholarCrossrefSearchADSPubMed 34.NeufeldKJ,LeoutsakosJS,SieberFE,JoshiD,WanamakerBL,Rios-RoblesJ,NeedhamDM:Evaluationoftwodeliriumscreeningtoolsfordetectingpost-operativedeliriumintheelderly.BrJAnaesth2013;111:612–8GoogleScholarCrossrefSearchADSPubMed 35.Gusmao-FloresD,SalluhJI,ChalhubRÁ,QuarantiniLC:Theconfusionassessmentmethodfortheintensivecareunit(CAM-ICU)andintensivecaredeliriumscreeningchecklist(ICDSC)forthediagnosisofdelirium:Asystematicreviewandmeta-analysisofclinicalstudies.CritCare2012;16:R115GoogleScholarCrossrefSearchADSPubMed 36.ICUDeliriumandCognitiveImpairmentStudyGroup:Deliriumpreventionandsafety:StartingwiththeABCDEF's.Availableat:http://www.icudelirium.org.AccessedAugust24,201637.BrummelNE,VasilevskisEE,HanJH,BoehmL,PunBT,ElyEW:ImplementingdeliriumscreeningintheICU:Secretstosuccess.CritCareMed2013;41:2196–208GoogleScholarCrossrefSearchADSPubMed 38.PunBT,GordonSM,PetersonJF,ShintaniAK,JacksonJC,FossJ,HardingSD,BernardGR,DittusRS,ElyEW:Large-scaleimplementationofsedationanddeliriummonitoringintheintensivecareunit:Areportfromtwomedicalcenters.CritCareMed2005;33:1199–205GoogleScholarCrossrefSearchADSPubMed 39.SojaSL,PandharipandePP,FlemingSB,CottonBA,MillerLR,WeaverSG,LeeBT,ElyEW:Implementation,reliabilitytesting,andcompliancemonitoringoftheConfusionAssessmentMethodfortheIntensiveCareUnitintraumapatients.IntensiveCareMed2008;34:1263–8GoogleScholarCrossrefSearchADSPubMed 40.VasilevskisEE,MorandiA,BoehmL,PandharipandePP,GirardTD,JacksonJC,ThompsonJL,ShintaniA,GordonSM,PunBT,WesleyEE:Deliriumandsedationrecognitionusingvalidatedinstruments:Reliabilityofbedsideintensivecareunitnursingassessmentsfrom2007to2010.JAmGeriatrSoc2011;59(suppl2):S249–S255GoogleScholarCrossrefSearchADSPubMed 41.vanGoolWA,vandeBeekD,EikelenboomP:Systemicinfectionanddelirium:Whencytokinesandacetylcholinecollide.Lancet2010;375:773–5GoogleScholarCrossrefSearchADSPubMed 42.HughesCG,PatelMB,PandharipandePP:Pathophysiologyofacutebraindysfunction:What’sthecauseofallthisconfusion?CurrOpinCritCare2012;18:518–26GoogleScholarCrossrefSearchADSPubMed 43.CerejeiraJ,FirminoH,Vaz-SerraA,Mukaetova-LadinskaEB:Theneuroinflammatoryhypothesisofdelirium.ActaNeuropathol2010;119:737–54GoogleScholarCrossrefSearchADSPubMed 44.TerrandoN,ErikssonLI,RyuJK,YangT,MonacoC,FeldmannM,JonssonFagerlundM,CharoIF,AkassoglouK,MazeM:Resolvingpostoperativeneuroinflammationandcognitivedecline.AnnNeurol2011;70:986–95GoogleScholarCrossrefSearchADSPubMed 45.HughesCG,PandharipandePP,ThompsonJL,ChandrasekharR,WareLB,ElyEW,GirardTD:Endothelialactivationandblood-brainbarrierinjuryasriskfactorsfordeliriumincriticallyillpatients.CritCareMed2016;44:e809–17GoogleScholarCrossrefSearchADSPubMed 46.CunninghamC,WilcocksonDC,CampionS,LunnonK,PerryVH:Centralandsystemicendotoxinchallengesexacerbatethelocalinflammatoryresponseandincreaseneuronaldeathduringchronicneurodegeneration.JNeurosci2005;25:9275–84GoogleScholarCrossrefSearchADSPubMed 47.TerrandoN,YangT,RyuJK,NewtonPT,MonacoC,FeldmannM,MaD,AkassoglouK,MazeM:Stimulationoftheα7nicotinicacetylcholinereceptorprotectsagainstneuroinflammationaftertibiafractureandendotoxemiainmice.MolMed2014;20:667–75GoogleScholarCrossrefSearchADS 48.VacasS,DegosV,TraceyKJ,MazeM:High-mobilitygroupbox1proteininitiatespostoperativecognitivedeclinebyengagingbonemarrow-derivedmacrophages.Anesthesiology2014;120:1160–7GoogleScholarCrossrefSearchADSPubMed 49.KalisvaartKJ,deJongheJF,BogaardsMJ,VreeswijkR,EgbertsTC,BurgerBJ,EikelenboomP,vanGoolWA:Haloperidolprophylaxisforelderlyhip-surgerypatientsatriskfordelirium:Arandomizedplacebo-controlledstudy.JAmGeriatrSoc2005;53:1658–66GoogleScholarCrossrefSearchADSPubMed 50.WangW,LiHL,WangDX,ZhuX,LiSL,YaoGQ,ChenKS,GuXE,ZhuSN:Haloperidolprophylaxisdecreasesdeliriumincidenceinelderlypatientsafternoncardiacsurgery:Arandomizedcontrolledtrial.CritCareMed2012;40:731–9GoogleScholarCrossrefSearchADSPubMed 51.vandenBoogaardM,SchoonhovenL,vanAchterbergT,vanderHoevenJG,PickkersP:Haloperidolprophylaxisincriticallyillpatientswithahighriskfordelirium.CritCare2013;17:R9GoogleScholarCrossrefSearchADSPubMed 52.PageVJ,ElyEW,GatesS,ZhaoXB,AlceT,ShintaniA,JacksonJ,PerkinsGD,McAuleyDF:Effectofintravenoushaloperidolonthedurationofdeliriumandcomaincriticallyillpatients(Hope-ICU):Arandomised,double-blind,placebo-controlledtrial.LancetRespirMed2013;1:515–23GoogleScholarCrossrefSearchADSPubMed 53.PrakanrattanaU,PrapaitrakoolS:Efficacyofrisperidoneforpreventionofpostoperativedeliriumincardiacsurgery.AnaesthIntensiveCare2007;35:714–9GoogleScholarCrossrefSearchADSPubMed 54.HakimSM,OthmanAI,NaoumDO:Earlytreatmentwithrisperidoneforsubsyndromaldeliriumafteron-pumpcardiacsurgeryintheelderly:Arandomizedtrial.Anesthesiology2012;116:987–97GoogleScholarCrossrefSearchADSPubMed 55.McPhersonJA,WagnerCE,BoehmLM,HallJD,JohnsonDC,MillerLR,BurnsKM,ThompsonJL,ShintaniAK,ElyEW,PandharipandePP,PandhvaripandePP:DeliriuminthecardiovascularICU:Exploringmodifiableriskfactors.CritCareMed2013;41:405–13GoogleScholarCrossrefSearchADSPubMed 56.SauërAM,SlooterAJ,VeldhuijzenDS,vanEijkMM,DevlinJW,vanDijkD:Intraoperativedexamethasoneanddeliriumaftercardiacsurgery:Arandomizedclinicaltrial.AnesthAnalg2014;119:1046–52GoogleScholarCrossrefSearchADSPubMed 57.GamberiniM,BolligerD,LuratiBuseGA,BurkhartCS,GrapowM,GagneuxA,FilipovicM,SeebergerMD,ParggerH,SiegemundM,CarrelT,SeilerWO,BerresM,StrebelSP,MonschAU,SteinerLA:Rivastigmineforthepreventionofpostoperativedeliriuminelderlypatientsundergoingelectivecardiacsurgery–arandomizedcontrolledtrial.CritCareMed2009;37:1762–8GoogleScholarCrossrefSearchADSPubMed 58.LiptzinB,LakiA,GarbJL,FingerothR,KrushellR:Donepezilinthepreventionandtreatmentofpost-surgicaldelirium.AmJGeriatrPsychiatry2005;13:1100–6GoogleScholarCrossrefSearchADSPubMed 59.MarcantonioER,PalihnichK,AppletonP,DavisRB:Pilotrandomizedtrialofdonepezilhydrochloridefordeliriumafterhipfracture.JAmGeriatrSoc2011;59(suppl2):S282–8GoogleScholarCrossrefSearchADSPubMed 60.SampsonEL,RavenPR,NdhlovuPN,VallanceA,GarlickN,WattsJ,BlanchardMR,BruceA,BlizardR,RitchieCW:Arandomized,double-blind,placebo-controlledtrialofdonepezilhydrochloride(Aricept)forreducingtheincidenceofpostoperativedeliriumafterelectivetotalhipreplacement.IntJGeriatrPsychiatry2007;22:343–9GoogleScholarCrossrefSearchADSPubMed 61.MorandiA,HughesCG,GirardTD,McAuleyDF,ElyEW,PandharipandePP:Statinsandbraindysfunction:Ahypothesistoreducetheburdenofcognitiveimpairmentinpatientswhoarecriticallyill.Chest2011;140:580–5GoogleScholarCrossrefSearchADSPubMed 62.PageVJ,DavisD,ZhaoXB,NortonS,CasarinA,BrownT,ElyEW,McAuleyDF:Statinuseandriskofdeliriuminthecriticallyill.AmJRespirCritCareMed2014;189:666–73GoogleScholarCrossrefSearchADSPubMed 63.MorandiA,HughesCG,ThompsonJL,PandharipandePP,ShintaniAK,VasilevskisEE,HanJH,JacksonJC,LaskowitzDT,BernardGR,ElyEW,GirardTD:Statinsanddeliriumduringcriticalillness:Amulticenter,prospectivecohortstudy.CritCareMed2014;42:1899–909GoogleScholarCrossrefSearchADSPubMed 64.JakobSM,RuokonenE,GroundsRM,SarapohjaT,GarrattC,PocockSJ,BrattyJR,TakalaJ;DexmedetomidineforLong-TermSedationInvestigators:Dexmedetomidinevsmidazolamorpropofolforsedationduringprolongedmechanicalventilation:Tworandomizedcontrolledtrials.JAMA2012;307:1151–60GoogleScholarCrossrefSearchADSPubMed 65.ChenK,LuZ,XinYC,CaiY,ChenY,PanSM:Alpha-2agonistsforlong-termsedationduringmechanicalventilationincriticallyillpatients.CochraneDatabaseSystRev2015;1:CD010269GoogleScholarPubMed 66.JiF,LiZ,NguyenH,YoungN,ShiP,FlemingN,LiuH:Perioperativedexmedetomidineimprovesoutcomesofcardiacsurgery.Circulation2013;127:1576–84GoogleScholarCrossrefSearchADSPubMed 67.DjaianiG,SilvertonN,FedorkoL,CarrollJ,StyraR,RaoV,KatznelsonR:Dexmedetomidineversuspropofolsedationreducesdeliriumaftercardiacsurgery:Arandomizedcontrolledtrial.Anesthesiology2016;124:362–8GoogleScholarCrossrefSearchADSPubMed 68.StrømT,MartinussenT,ToftP:Aprotocolofnosedationforcriticallyillpatientsreceivingmechanicalventilation:Arandomisedtrial.Lancet2010;375:475–80GoogleScholarCrossrefSearchADSPubMed 69.ShehabiY,GrantP,WolfendenH,HammondN,BassF,CampbellM,ChenJ:Prevalenceofdeliriumwithdexmedetomidinecomparedwithmorphinebasedtherapyaftercardiacsurgery:Arandomizedcontrolledtrial(DEXmedetomidineCOmparedtoMorphine-DEXCOMStudy).Anesthesiology2009;111:1075–84GoogleScholarCrossrefSearchADSPubMed 70.PatelSB,PostonJT,PohlmanA,HallJB,KressJP:Rapidlyreversible,sedation-relateddeliriumversuspersistentdeliriumintheintensivecareunit.AmJRespirCritCareMed2014;189:658–65GoogleScholarCrossrefSearchADSPubMed 71.SchweickertWD,PohlmanMC,PohlmanAS,NigosC,PawlikAJ,EsbrookCL,SpearsL,MillerM,FranczykM,DeprizioD,SchmidtGA,BowmanA,BarrR,McCallisterKE,HallJB,KressJP:Earlyphysicalandoccupationaltherapyinmechanicallyventilated,criticallyillpatients:Arandomisedcontrolledtrial.Lancet2009;373:1874–82GoogleScholarCrossrefSearchADSPubMed 72.VanRompaeyB,ElseviersMM,VanDromW,FromontV,JorensPG:Theeffectofearplugsduringthenightontheonsetofdeliriumandsleepperception:Arandomizedcontrolledtrialinintensivecarepatients.CritCare2012;16:R73GoogleScholarCrossrefSearchADSPubMed 73.KamdarBB,KingLM,CollopNA,SakamuriS,ColantuoniE,NeufeldKJ,BienvenuOJ,RowdenAM,TouradjiP,BrowerRG,NeedhamDM:TheeffectofaqualityimprovementinterventiononperceivedsleepqualityandcognitioninamedicalICU.CritCareMed2013;41:800–9GoogleScholarCrossrefSearchADSPubMed 74.KondiliE,AlexopoulouC,XirouchakiN,GeorgopoulosD:Effectsofpropofolonsleepqualityinmechanicallyventilatedcriticallyillpatients:Aphysiologicalstudy.IntensiveCareMed2012;38:1640–6GoogleScholarCrossrefSearchADSPubMed 75.AlexopoulouC,KondiliE,DiamantakiE,PsarologakisC,KokkiniS,BolakiM,GeorgopoulosD:Effectsofdexmedetomidineonsleepqualityincriticallyillpatients:Apilotstudy.Anesthesiology2014;121:801–7GoogleScholarCrossrefSearchADSPubMed 76.SandersRD,MazeM:Contributionofsedative-hypnoticagentstodeliriumviamodulationofthesleeppathway.CanJAnaesth2011;58:149–56GoogleScholarCrossrefSearchADSPubMed 77.MundiglerG,Delle-KarthG,KorenyM,ZehetgruberM,Steindl-MundaP,MarktlW,FertiL,SiostrzonekP:Impairedcircadianrhythmofmelatoninsecretioninsedatedcriticallyillpatientswithseveresepsis.CritCareMed2002;30:536–40GoogleScholarCrossrefSearchADSPubMed 78.YoshitakaS,EgiM,MorimatsuH,KanazawaT,TodaY,MoritaK:Perioperativeplasmamelatoninconcentrationinpostoperativecriticallyillpatients:Itsassociationwithdelirium.JCritCare2013;28:236–42GoogleScholarCrossrefSearchADSPubMed 79.BourneRS,MillsGH,MinelliC:Melatonintherapytoimprovenocturnalsleepincriticallyillpatients:Encouragingresultsfromasmallrandomisedcontrolledtrial.CritCare2008;12:R52GoogleScholarCrossrefSearchADSPubMed 80.IbrahimMG,BellomoR,HartGK,NormanTR,GoldsmithD,BatesS,EgiM:Adouble-blindplacebo-controlledrandomisedpilotstudyofnocturnalmelatoninintracheostomisedpatients.CritCareResusc2006;8:187–91GoogleScholarPubMed 81.Al-AamaT,BrymerC,GutmanisI,Woolmore-GoodwinSM,EsbaughJ,DasguptaM:Melatonindecreasesdeliriuminelderlypatients:Arandomized,placebo-controlledtrial.IntJGeriatrPsychiatry2011;26:687–94GoogleScholarCrossrefSearchADSPubMed 82.deJongheA,vanMunsterBC,GoslingsJC,KloenP,vanReesC,WolviusR,vanVeldeR,LeviM,deHaanRJ,deRooijSE;AmsterdamDeliriumStudyGroup:Effectofmelatoninonincidenceofdeliriumamongpatientswithhipfracture:Amulticentre,double-blindrandomizedcontrolledtrial.CMAJ2014;186:E547–56GoogleScholarCrossrefSearchADSPubMed 83.HattaK,KishiY,WadaK,TakeuchiT,OdawaraT,UsuiC,NakamuraH;DELIRIA-JGroup:Preventiveeffectsoframelteonondelirium:Arandomizedplacebo-controlledtrial.JAMAPsychiatry2014;71:397–403GoogleScholarCrossrefSearchADSPubMed 84.FlanneryAH,OylerDR,WeinhouseGL:TheimpactofinterventionstoimprovesleepondeliriumintheICU:Asystematicreviewandresearchframework.CritCareMed2016Aug9[Epubaheadofprint]GoogleScholar 85.MorandiA,BrummelNE,ElyEW:Sedation,deliriumandmechanicalventilation:The‘ABCDE’approach.CurrOpinCritCare2011;17:43–9GoogleScholarCrossrefSearchADSPubMed 86.BalasMC,VasilevskisEE,OlsenKM,SchmidKK,ShostromV,CohenMZ,PeitzG,GannonDE,SissonJ,SullivanJ,StothertJC,LazureJ,NussSL,JawaRS,FreihautF,ElyEW,BurkeWJ:Effectivenessandsafetyoftheawakeningandbreathingcoordination,deliriummonitoring/management,andearlyexercise/mobilitybundle.CritCareMed2014;42:1024–36GoogleScholarCrossrefSearchADSPubMed 87.NeedhamDM,KorupoluR,ZanniJM,PradhanP,ColantuoniE,PalmerJB,BrowerRG,FanE:Earlyphysicalmedicineandrehabilitationforpatientswithacuterespiratoryfailure:Aqualityimprovementproject.ArchPhysMedRehabil2010;91:536–42GoogleScholarCrossrefSearchADSPubMed 88.DaleCR,KannasDA,FanVS,DanielSL,DeemS,YanezND3rd,HoughCL,DellitTH,TreggiariMM:Improvedanalgesia,sedation,anddeliriumprotocolassociatedwithdecreaseddurationofdeliriumandmechanicalventilation.AnnAmThoracSoc2014;11:367–74GoogleScholarCrossrefSearchADSPubMed 89.AmericanAssociationofCritical-CareNurses:ImplementingtheABCDEbundleatthebedside.Availableat:http://www.aacn.org/wd/practice/content/actionpak/withlinks-ABCDE-ToolKit.content.AccessedAugust24,201690.ICULiberation:ABCDEFbundle.Availableat:http://www.iculiberation.org.AccessedAugust24,201691.GirardTD,PandharipandePP,CarsonSS,SchmidtGA,WrightPE,CanonicoAE,PunBT,ThompsonJL,ShintaniAK,MeltzerHY,BernardGR,DittusRS,ElyEW;MINDTrialInvestigators:Feasibility,efficacy,andsafetyofantipsychoticsforintensivecareunitdelirium:TheMINDrandomized,placebo-controlledtrial.CritCareMed2010;38:428–37GoogleScholarCrossrefSearchADSPubMed 92.SkrobikYK,BergeronN,DumontM,GottfriedSB:Olanzapinevshaloperidol:Treatingdeliriuminacriticalcaresetting.IntensiveCareMed2004;30:444–9GoogleScholarCrossrefSearchADSPubMed 93.DevlinJW,RobertsRJ,FongJJ,SkrobikY,RikerRR,HillNS,RobbinsT,GarpestadE:Efficacyandsafetyofquetiapineincriticallyillpatientswithdelirium:Aprospective,multicenter,randomized,double-blind,placebo-controlledpilotstudy.CritCareMed2010;38:419–27GoogleScholarCrossrefSearchADSPubMed 94.vanEijkMM,RoesKC,HoningML,KuiperMA,KarakusA,vanderJagtM,SpronkPE,vanGoolWA,vanderMastRC,KeseciogluJ,SlooterAJ:Effectofrivastigmineasanadjuncttousualcarewithhaloperidolondurationofdeliriumandmortalityincriticallyillpatients:Amulticentre,double-blind,placebo-controlledrandomisedtrial.Lancet2010;376:1829–37GoogleScholarCrossrefSearchADSPubMed 95.ReadeMC,O’SullivanK,BatesS,GoldsmithD,AinslieWR,BellomoR:Dexmedetomidinevs.haloperidolindelirious,agitated,intubatedpatients:Arandomisedopen-labeltrial.CritCare2009;13:R75GoogleScholarCrossrefSearchADSPubMed 96.ReadeMC,EastwoodGM,BellomoR,BaileyM,BerstenA,CheungB,DaviesA,DelaneyA,GhoshA,vanHarenF,HarleyN,KnightD,McGuinessS,MulderJ,O’DonoghueS,SimpsonN,YoungP;DahLIAInvestigators;AustralianandNewZealandIntensiveCareSocietyClinicalTrialsGroup:Effectofdexmedetomidineaddedtostandardcareonventilator-freetimeinpatientswithagitateddelirium:Arandomizedclinicaltrial.JAMA2016;315:1460–8GoogleScholarCrossrefSearchADSPubMed 97.CarrascoG,BaezaN,CabréL,PortilloE,GimenoG,ManzanedoD,CalizayaM:DexmedetomidineforthetreatmentofhyperactivedeliriumrefractorytohaloperidolinnonintubatedICUpatients:Anonrandomizedcontrolledtrial.CritCareMed2016;44:1295–306GoogleScholarCrossrefSearchADSPubMed  Copyright©2016,theAmericanSocietyofAnesthesiologists,Inc.WoltersKluwerHealth,Inc.AllRightsReserved.2016 10,946 Views 50 Citations ViewMetrics × Citingarticlesvia WebOfScience(51) GoogleScholar MostViewed ALettertoMedicalStudentsfromanAnesthesiologist PracticeGuidelinesforModerateProceduralSedationandAnalgesia2018:AReportbytheAmericanSocietyofAnesthesiologistsTaskForceonModerateProceduralSedationandAnalgesia,theAmericanAssociationofOralandMaxillofacialSurgeons,AmericanCollegeofRadiology,AmericanDentalAssociation,AmericanSocietyofDentistAnesthesiologists,andSocietyofInterventionalRadiology CalculatingIdealBodyWeight:KeepItSimple MostCited ASAPhysicalStatusClassifications:AStudyofConsistencyofRatings UptakeofHalothanebytheHumanBody PostoperativeNauseaandVomiting:ItsEtiology,Treatment,andPrevention Emailalerts ArticleActivityAlert OnlineFirstAlert AnesthesiologyFeaturedArticlesAlert CloseModal RelatedArticles EarlyTreatmentwithRisperidoneforSubsyndromalDeliriumafterOn-pumpCardiacSurgeryintheElderly:ARandomizedTrial Anesthesiology(May2012) DexmedetomidineversusPropofolSedationReducesDeliriumafterCardiacSurgery:ARandomizedControlledTrial Anesthesiology(February2016) ProphylacticHaloperidolEffectsonLong-termQualityofLifeinCriticallyIllPatientsatHighRiskforDelirium:ResultsoftheREDUCEStudy Anesthesiology(August2019) ElectroencephalogramBurst-suppressionduringCardiopulmonaryBypassinElderlyPatientsMediatesPostoperativeDelirium Anesthesiology(August2020) AcquiredMuscleWeaknessintheSurgicalIntensiveCareUnit:Nosology,Epidemiology,Diagnosis,andPrevention Anesthesiology(January2016) SocialMedia Twitter LinkedIn Facebook Instagram   Issues ASAPracticeParameters OnlineFirst Topics Podcasts Videos AuthorResourceCenter AbouttheJournal EditorialBoard Rights&Permissions ContactUs OnlineISSN1528-1175 PrintISSN0003-3022 Anesthesiology ASAMonitor Terms&Conditions PrivacyPolicy ©Copyright2021AmericanSocietyofAnesthesiologists CloseModal CloseModal ThisFeatureIsAvailableToSubscribersOnly SignInorCreateanAccount CloseModal CloseModal Thissiteusescookies.Bycontinuingtouseourwebsite,youareagreeingtoourprivacypolicy. Accept