Delirium in the ICU: an overview | Annals of Intensive Care

Delirium is characterized by a disturbance of consciousness with accompanying change in cognition. Delirium typically manifests as a ... Skiptomaincontent Advertisement SearchallSpringerOpenarticles Search DownloadPDF Review OpenAccess Published:27December2012 DeliriumintheICU:anoverview RodrigoCavallazzi1,MohamedSaad1&PaulEMarik2,3  AnnalsofIntensiveCare volume 2,Article number: 49(2012) Citethisarticle 84kAccesses 124Citations 90Altmetric Metricsdetails AbstractDeliriumischaracterizedbyadisturbanceofconsciousnesswithaccompanyingchangeincognition.Deliriumtypicallymanifestsasaconstellationofsymptomswithanacuteonsetandafluctuatingcourse.Deliriumisextremelycommonintheintensivecareunit(ICU)especiallyamongstmechanicallyventilatedpatients.Threesubtypeshavebeenrecognized:hyperactive,hypoactive,andmixed.Deliriumisfrequentlyundiagnosedunlessspecificdiagnosticinstrumentsareused.TheCAM-ICUisthemostwidelystudiedandvalidateddiagnosticinstrument.However,theaccuracyofthistoolmaybelessthanidealwithoutadequatetrainingoftheprovidersapplyingit.Thepresenceofdeliriumhasimportantprognosticimplications;inmechanicallyventilatedpatientsitisassociatedwitha2.5-foldincreaseinshort-termmortalityanda3.2-foldincreasein6-monthmortality.Nonpharmacologicalapproaches,suchasphysicalandoccupationaltherapy,decreasethedurationofdeliriumandshouldbeencouraged.Pharmacologicaltreatmentfordeliriumtraditionallyincludeshaloperidol;however,moredataforhaloperidolareneededgiventhepaucityofplacebo-controlledtrialstestingitsefficacytotreatdeliriumintheICU.Second-generationantipsychoticshaveemergedasanalternativeforthetreatmentofdelirium,andtheymayhaveabettersafetyprofile.DexmedetomidinemayprovetobeavaluableadjunctiveagentforpatientswithdeliriumintheICU. DefinitionDeliriumisasyndromeofseveraldifferentetiologiescharacterizedbyadisturbanceofconsciousnesswithaccompanyingchangeincognition.Characteristicfeaturesofthesyndromeincludeimpairedshort-termmemory,impairedattention,disorientation,developmentoverashortperiodoftime,andafluctuatingcourse[1].Notalldescribedfeaturesneedtobepresentforthediagnosisofdelirium,andtheintensityofthesymptomsrangeswidelyamongpatients.Oneofseveralapproachestoclassifydeliriumistodivideitintomotoricsubtypes.Threesubtypesofdeliriumarerecognizedbasedonthepatternofsymptoms:hyperactive,hypoactive,andmixed[2].Physiologically,deliriumischaracterizedbyaderangementofcerebralmetabolismwithcerebraldysfunctionandisusuallycausedbyageneralmedicalillness,intoxication,orsubstancewithdrawal[1,3].Thesyndromeofdeliriumencompassesafewdistinctentitieswithuniquepathophysiologyandclinicalmanifestations.Theseincludesepsis-associatedencephalopathy,alcoholwithdrawalsyndrome,andhepaticencephalopathy.EpidemiologyInamulticenterstudy,theprevalenceofdeliriuminICUpatientswas32.3%[4].InspecializedICUs,theprevalenceofdeliriummaybehigher.Forinstance,astudyshowedaprevalenceofdeliriumashighas77%inventilatedburnpatients[5].TheincidenceofdeliriumintheICUrangesfrom45%to87%[6–8].Theincidenceappearstovaryaccordingtowhetherthestudiedpopulationiscomposedexclusivelyofmechanicallyventilatedpatients.Asanexample,astudyfoundanincidenceofdeliriumofonly20%innonintubatedICUpatients[9],whereasanotherstudyfoundanincidenceof83%inmechanicallyventilatedpatients[10].ThetwomostcommontypesofdeliriumintheICUaremixedandhypoactive[11].Hypoactivedeliriumtendstooccurmorefrequentlyinolderpatientscomparedwithothertypesofdeliriumandhasaworseprognosis.InastudyofpatientswhounderwentelectivesurgerywithpostoperativeICUadmission,the6-monthmortalitywas32%inpatientswithhypoactivedeliriumcomparedwith8.7%inthosewithothertypesofdelirium[12].PathophysiologyDifferentmechanismshavebeenproposedtoexplainthepathophysiologyofdelirium.However,thesemechanismsarenotmutuallyexclusiveanditislikelythattheyoftenactinconcert(Figure1).Onehypothesispostulatesthatdecreasedcholinergicactivitymayleadtodelirium[13].Thishypothesisissupportedbytheobservationthatanticholinergicmedicationuseisassociatedwithincreaseindeliriumsymptoms[14]andthatpatientswithdeliriumhavehigherserumanticholinergicactivitycomparedwiththosewithoutdelirium[15].Figure1 Factorsleadingtodelirium. Fullsizeimage Acetylcholinedownregulatesinflammation.Thus,itisnotsurprisingthatthereisanimbalancebetweeninflammatoryandanti-inflammatorymediatorsindelirium,withincreasedlevelsofinflammatorymediatorsandabluntedanti-inflammatoryresponse[16].Inthislight,theroleofinflammationanditsconsequentderangedcoagulationhasbeenexploredinarecentcohortstudyofmechanicallyventilatedICUpatients.Inthisstudy,fivemarkersofinflammationandfourmarkersofcoagulationweremeasuredintheplasmaofpatients.Afteradjustmentforpotentialconfounders,includingseverityofillness,higherplasmaconcentrationsoftheinflammatorymarkersolubletumornecrosisfactorreceptor-1,andlowerplasmaconcentrationsofthecoagulationmarkerproteinCwereassociatedwithincreasedriskofdelirium.However,anunexpectedfindingwasthatlowerplasmaconcentrationsofmatrixmetalloproteinase-9,anotherinflammatorymarker,wereassociatedwithhigherriskofdelirium[17].Anothermechanismimplicatedinthepathophysiologyofdeliriumisoveractivityofthedopaminergicsystem.Clinically,evidenceforthiscomesfromcasereportsassociatingbupropion,anantidepressantwithdopamineandnorepinephrineactivity,withdevelopmentofdelirium[18].Furthermore,ageneticbasisforincreaseddopaminergicsystem-induceddeliriumhasbeensubstantiatedbythedemonstrationthatmutantgenesleadingtolowercerebraldopamineactivityareprotectiveagainstdelirium[19].Bothincreasedserotonergicactivityandarelativeserotonindeficiencyalsohavebeenassociatedwithdelirium[20].Ahighserotonergicstateinassociationwithdeliriumhasbeenclassicallydescribedinpatientswiththeserotoninsyndrome,aconditionoftenemergingfromtheinteractionofmedicationsleadingtoincreasedserotonergiceffectsandthatinitsmostsevereformpresentswithhyperthermia,musclerigidity,andmultipleorganfailure[21].Ontheotherhand,lowlevelsoftryptophan—anaminoacidthatcrossesthebloodbrainbarrierandisaprecursortoneurotransmittersserotoninandmelatonin—havebeenassociatedwithdeliriumaftersurgeryinpatientsolder50years[22].AnotherstudyfoundthateitherhighorverylowlevelsoftryptophanareindependentlyassociatedwithanincreasedriskofdeliriuminICUmechanicallyventilatedpatients[23].Whereasdecreasedserotoninactivitymaybeimplicatedinthedevelopmentofdelirium,italsoispossiblethattheproductionofothermetabolitesoftryptophan,suchaskynurenine,leadstopathwayactivitythatresultsinneurotoxinspredisposingtodelirium[24].Patientswhoaremorepronetodelirium,suchastheelderlyorthosewithunderlyingcentralnervoussystemdisease,alsomayhaveheightenedcentralnervoussystemresponsetoinflammatorymediators.Itappearsthatthesepatientsmayhaveanincreasednumberofmicroglialcells,whichareprimedandcanbereadilyactivatedinresponsetoamildstressor[25].Theamino-acidneurotransmittersystemhasaprominentroleinthepathophysiologyofalcoholwithdrawalsyndrome.Inparticular,chronicalcoholexposuremayleadtoadecreaseinthenumberofandfunctionofgammaaminobutyricacidreceptorsandanincreaseintheN-methyl-D-aspartatereceptors.Bothmechanismscouldpredisposepatientstoalcoholwithdrawalsyndrome[26,27].ClinicalmanifestationsDeliriumtypicallymanifestsasaconstellationofsymptomswithanacuteonsetandafluctuatingcourse.Thesesymptomshavebeenorganizedintocognitiveandbehavioralgroups.Commoncognitivesymptomsincludedisorientation,inabilitytosustainattention,impairedshort-termmemory,impairedvisuospatialability,reducedlevelofconsciousness,andperseveration.Commonbehavioralsymptomsincludesleep-wakecycledisturbance,irritability,hallucinations,anddelusions[28].Themanifestationsofdeliriumcanvarywidelyamongpatients.Whereassomepatientsmaymanifestsomnolenceandevencoma,othersappearanxious,disruptive,orcombative[29].Recognitionofthissymptomvariabilityhasledtotheclassificationofdeliriumintomotoricsubtypes.Onesuchsubtypeishyperactivedelirium,ofwhichthemanifestationsincludeagitation,hypervigilance,irritability,lackofconcentration,andperseveration.Hypoactivedeliriummanifestsasdiminishedalertness,absenceoforslowedspeech,hypokinesia,andlethargy.Mixeddelirium,asthenameimplies,includesmanifestationsofbothhyperactiveandhypoactivedelirium[2].Theclinicalmanifestationsalsovaryaccordingtotheprecipitatingfactors.Forinstance,patientswithbacteremiaoftenpresentwithencephalopathyanddeclinedmentalstatus[30].Conversely,patientswithalcoholwithdrawalsyndromepresentwithsymptomsofanoveractivesympatheticcentralnervoussystem[31].Asaconsequence,patientswithalcoholwithdrawalsyndromecommonlyhaveagitation,insomnia,tremor,tachycardia,andhypertension[32].AssessmentofdeliriumAnumberofinstrumentsareavailabletodetectdeliriumincriticallyillpatients.TheimportanceofusingtheseinstrumentsliesinthatmostcasesofdeliriumintheICUgoundetected.Indeed,thereisevidencethatevenwhenpromptedtoreportdelirium,ICUphysiciansrecognizelessthanonethirdofdeliriouscriticallyillpatientswhentheyarenotusinganinstrumenttoaidintheirdiagnosis[33].Inasystematicreviewfrom2007,sixvalidatedinstrumentstoassessdeliriumincriticallyillpatientswereidentified.TheseincludedtheCognitiveTestforDelirium,abbreviatedCognitiveTestforDelirium,ConfusionAssessmentMethodfortheIntensiveCareUnit(CAM-ICU),IntensiveCareDeliriumScreeningChecklist,NeelonandChampagneConfusionScale,andtheDeliriumDetectionScore[34].AnotherinstrumenttodetectdeliriumistheNursingDeliriumScreeningScale,ofwhichthevalidityandreliabilitywereassessedintheICU[35].Table1summarizesthesediagnosticinstruments[8,36–40].Table1 InstrumentsforthediagnosisofdeliriumintheICU Fullsizetable ThemostextensivelystudiedinstrumentistheCAM-ICU,whichwasvalidatedtoassessdeliriumatthebedsideinnonverbalventilatedICUpatients[41].Usingastructuredformat,thistoolevaluatesfourfeatures,namely,acuteonsetorfluctuatingcourse,inattention,disorganizedthinking,andalteredlevelofconsciousness.Whenadministeredbybedsidenurseswithnoformalpsychiatrictraining,theCAM-ICUdemonstratedhighaccuracy(sensitivityof93%to100%andspecificityof98%to100%)andinterraterreliability(K=0.96)inasingle-centerstudy[10].Inanotherstudy,theCAM-ICUwassystematicallyappliedbybedsidenursesintheICUduringanimplementationprocessthatinvolvedtrainingofthenurses.Theagreementbetweentheassessmentfrombedsidenursesandaresearchstaffraterwaslowatbaselinebutveryhighduringtheimplementationprocess[42].However,subsequentstudieshaveshownthattheCAM-ICUhasamoremodestsensitivityrangingfrom64%to81%,whereasthespecificityremainshighrangingfrom88%to98%[33,43,44].Inamorerecentstudy,CAM-ICUhadahighspecificity(98%)butaratherlowsensitivity(47%)[45].Thecontrastbetweenthelatterstudyandothers[42,46]maystemfromdifferentimplementationprocesses,thatis,differentapproachestotrainingandeducationofprovidersapplyingthetool.Twostudieshavecompareddifferentinstrumentsfordetectionofdeliriumincriticallyillpatients[33,43].Inonestudy,CAM-ICUwasprospectivelycomparedwiththeIntensiveCareDeliriumScreeningChecklistin126patients.CAM-ICUshowedsuperiorsensitivity(64%vs.43%)butlowerspecificity(88%vs.95%)[33].Inanotherstudy,theaccuracyofthreeinstruments(CAM-ICU,NursingDeliriumScreeningScale,andDeliriumDetectionScore)wascomparedinaprospectivestudyof156patients.AlthoughthesensitivitiesofCAM-ICUandtheNursingDeliriumScreeningScaleweresimilar(81%forCAM-ICU;83%forNursingDeliriumScreeningScale),theCAM-ICUshowedsuperiorspecificity(96%vs.81%).TheDeliriumDetectionScoreshowedasensitivityof30%andaspecificityof91%[43].Theabove-mentionedinstrumentsareourbesttoolsfortheearlydetectionofdeliriumintheICU,buttheirwidespreadapplicationhassomelimitations.First,studiesshowquitedifferentsensitivitiesforthesameinstrument,particularlytheCAM-ICU.Thedifferenceinsensitivitiesmaybeexplainedbyheterogeneityinthepatientpopulationsincludedinthestudiesbutmorenotablybydifferentialleveloftrainingandexperienceamongtheassessorsinthestudies.Thus,itisdifficulttoestablishhowaccuratetheseinstrumentsarewithoutadequatetraining,butitisreasonabletoinferthatasubstantialproportionofcriticallyillpatientswithdeliriumwillremainundiagnosediftheseinstrumentsareappliedbyinexperiencedornontrainedhealthcareproviders.Insupportofthisnotion,tworecentsystematicreviewspooledseveralstudiesevaluatingtheaccuracyofCAM-ICU[47,48].ThemajorityofthestudiesincludedinthesystematicreviewsshowedthattheCAM-ICUisahighlyaccurateinstrumentforthediagnosisofdeliriumintheICU.However,intheonlystudythatwasperformedinanonresearchsetting,mostpatientswithdeliriumwerenotdetectedbyCAM-ICU[45,47].WhethertheseinstrumentscanbefeasiblyimplementedinbusynonacademicICUsisanimportantissue.Furthermore,itisnotwellestablishedthatthesystematicapplicationoftheseinstrumentsinfluencestheoutcomesofcriticallyillpatients.However,thereisevidencethatwhendeliriumscreeningisappliedaspartofabroaderprotocolinitiativethatincludesactivemanagementofsedativesandanalgesicsaswellasnonpharmacologicalmeasures,suchasmusicandreassurance,severalclinicalbenefitsmayensue,suchasshorterdurationofmechanicalventilation,lowerICUandhospitalstay,andlower30-daymortality[49].Theprotocolalsoisassociatedwithcostsavings[50].BiomarkersSeveralbiomarkershavebeenassociatedwithdelirium.Serumanticholinergicactivityisenhancedinpatientswithdelirium,andthenumberofsymptomsofdeliriumincreaseswithhigherserumanticholinergicactivitylevel[15].TheS100Bproteinisanindicatorofglialactivationand/ordeath;thus,itisanonspecificmarkerofbraininjury[51]TheS100Bproteinhasbeenshowntobeelevatedinpatientswithdelirium[52].Recently,emphasishasbeengiventothestudyofinflammatorybiomarkersforthepredictionofdelirium.Forinstance,McGraneetal.evaluated87criticallyillpatientsinastudy;themajorityofthemhadsepsisuponadmissiontotheICU.TheyfoundthathigherbaselinelevelsofprocalcitoninorC-reactiveproteinwereassociatedwithmoredayswithdelirium[53].Otherinvestigatorshavefoundthattheprofileofincreasedinflammatorybiomarkerschangesincriticallyillpatientswithdeliriumaccordingtothepresenceorabsenceofclinicalevidenceofinflammation(infectionorsystemicinflammatoryresponsesyndrome)[54].Additionalserumbiomarkersshowntobeelevatedinpatientswithdeliriumincludebrain-derivedneurotrophicfactor,neuron-specificenolase,interleukins,andcortisol[55,56].Whereastheuseofbiomarkersfordeliriumispromising,becausetheycanprovidediagnosticandprognosticinformation,morevalidationstudiesarenecessarybeforetheycanbeappliedinclinicalpractice.RiskfactorsfordeliriumInastudyofnon-ICUpatientswhounderwenthipfracturerepair,olderageandmalesexhavebeenassociatedwithanincreasedandindependentriskofdelirium[57].Asystematicreviewthatincludedsixobservationalstudiesevaluatedriskfactorsfordeliriumbymultivariateanalysis.Twenty-fiveriskfactorsweresignificantlyassociatedwithdelirium,andamongthosefourwererecognizedaspredisposingtodelirium:respiratorydisease,olderage,alcoholabuse,anddementia.Twenty-oneriskfactorswereconsideredprecipitating,becausetheywererelatedthepatient'sunderlyingdisease;someoftheseincludedelectrolyteabnormalities,fever,pressorrequirement,increasingopiatedose,andmetabolicacidosis[58].Medicationsareanimportantriskfactorfordelirium,especiallyintheelderly.Classesofmedicationscommonlyassociatedwithdeliriumincludeanticholinergicagents,benzodiazepines,andopiates[59].IntheICU,benzodiazepinesappeartohaveamoreprominentroleinthedevelopmentofdelirium[60].PrognosisElyetal.evaluatedtheeffectofdeliriumon6-monthmortalityandlengthofhospitalstayamong224criticallypatientsreceivingmechanicalventilationinaprospectivecohortstudy.DeliriumwasassesseddailybystudynurseswiththeuseofCAM-ICU.Afteradjustingforclinicallyrelevantvariables,includingage,severityofillness,comorbidconditions,anduseofsedativesandanalgesicmedications,deliriumremainedassociatedwitha3.2-foldincreasein6-monthmortalityanda2-foldincreaseinhospitalstayduration[61].Outcomesofcriticallyillpatientsareinfluencednotonlybythepresenceofdeliriumbutalsothedurationofit.Inamulticenterstudy,354mechanicallyventilatedpatientshaddailyassessmentfordeliriumwiththeuseofCAM-ICU.Afteradjustmentforage,severityofdiseaseandothercovariates,deliriumwasassociatedwitha2.5-foldincreaseinshort-termmortality,andtherewasadose-responseincreaseinmortalitywithincreasingdurationofdelirium.Patientswhohaddeliriumfor1dayhad14.5%all-cause30-daymortality,whereasthefigurewas39%forthosewith3daysormoreofdelirium[62].Inanothercohortstudy,304patientsadmittedtoasingleICUwereevaluateddailywithuseofCAM-ICU.Afteradjustmentforage,severityofillness,andothercovariates,everyadditionaldayofdeliriumintheICUwasassociatedwitha10%increaseinthehazardofdeathwithin1yearpostICUadmission[63].DeliriumintheICUalsoisassociatedwithmoremechanicalventilationdays,longerICUstay,andlongerhospitalstay[64].Inpatientswhosesymptomsdonotfulfillcriteriaforaformaldiagnosisofdelirium,thepresenceofpsychomotoragitation—anindividualmanifestationofdelirium—isassociatedwithincreasedriskfordeathafteradjustmentforAcutePhysiologyandChronicHealthEvaluationScore(APACHE),age,andthepresenceofcoma[65].Inadditiontoleadingtoanincreaseinhospitalstayandmortality,deliriumisassociatedwithlong-termcognitiveimpairment.Forinstance,inacohortstudyof77patientswhounderwentmechanicalventilation,morethan70%ofthemhadcognitiveimpairmentat1yearfollow-up.Increasingdurationofdeliriumwasindependentlyassociatedwithcognitiveimpairmentafteradjustmentforseveralcovariates,includingeducationandpreexistingcognitivefunction[66].Inanothercohortstudyof1,292ICUsurvivors,qualityoflifequestionnairesweresenttopatients18monthsafterICUdischarge.Thestudyhadanoverallresponserateof71%.Althoughtherewasnostatisticallysignificantdifferenceinqualityoflifebetweenpatientswithdeliriumandthosewithoutdelirium,morepronouncedcognitivefailureasdeterminedbyself-reportedcognitivefailurequestionnairewasfoundinpatientswithdeliriumafteradjustmentforcovariates[67].NonpharmacologicaltherapyNonpharmacologicaltherapieshaveanimportantroleinboththepreventionandtreatmentofdelirium.Asanexample,astudyin852elderlypatientsadmittedtoahospitalshowedthataninterventionstrategyagainstdeliriumledtoa40%decreaseintheoddsofdevelopingdelirium.Thestrategycomprisedprotocolsthattargetedriskfactorsfordelirium,suchasdehydration,immobility,sleepdeprivation,visualimpairment,cognitiveimpairment,andhearingimpairment[68].Althoughthisstudywasperformedinnon-ICUpatients,itisreasonabletoinferthatcomponentsoftheinterventionalsoareeffectiveincriticallyillpatients.Inthislight,otherauthorshaveemphasizedtheimportanceofenvironmentalfactorsintheriskofdevelopingdeliriumintheICU,andsomestrategieshavebeenproposedtomitigatetheimpactofdelirium.Theseincludenoisereduction,naturallightexposureatdaytime,minimizationofartificiallightexposureatnighttime,ambienttemperatureoptimization,andimprovedcommunication[69].NoiseintheICUisknowntodisturbpatients’sleep[70].Furthermore,ithasbeensuggestedthatadisturbedsleepmayinfluencetheriskofdelirium.Theimpactofnoiseonthequalityofsleepandthusontheriskofdeliriumhasbeenillustratedinarecentclinicaltrialthatdemonstratedthattheuseofearplugsatnighttimeleadstobettersleepandlessconfusion[71].Limitingtheexposuretosedativesalsomayhavebeneficialeffectsontheriskofdelirium.Arandomized,clinicaltrialshowedthatprotocolizeddailyinterruptionofsedativesassociatedwithspontaneousbreathingtrialsleadstosignificantlyshorterdurationofcomainmechanicallyventilatedpatientsbutnosignificantchangeindeliriumintheassessablepatients[72].Theadditionofphysicalandoccupationaltherapytodailyinterruptionofsedationleadstoshorterdurationofdeliriumandbetterfunctionalstatusinmechanicallyventilatedpatients[73].Figure2presentsaproposedstrategyfortheinitialmanagementofpatientswithdeliriumintheICU.Figure2 ProposedstrategyfortheinitialmanagementofpatientswithdeliriumintheICU. Fullsizeimage PharmacologicaltherapySedativesSedativeshavethepotentialtopromotedelirium[74].Inanobservationalstudy,lorazepamwasanindependentandstatisticallysignificantriskfactorfordevelopmentofdeliriumwhereasothersedatives,suchaspropofolandopiates,hadnostatisticallysignificantassociationwithdelirium[60].Inarandomized,double-blindtrial,30hospitalizedAIDSpatientswithdeliriumwereassignedtotreatmentwithhaloperidol,chlorpromazine,orlorazepam.Treatmentwithhaloperidolorchlorpromazineresultedinsignificantimprovementinthesymptomsofdeliriumandlowprevalenceofextrapyramidalsideeffects.Patientstreatedwithlorazepamhadnoimprovementindeliriumanddevelopedtreatment-limitingadverseevents[75].Thus,benzodiazepinesaregenerallyavoidedforthetreatmentofdeliriuminhospitalizedpatients.Infact,becausebenzodiazepinesareanimportantriskfactorfordeliriumincriticallyillpatients,limitingtheirusemaydecreasetheoverallincidenceofdeliriumintheICU.Itshouldbenoted,however,thatinpatientswithalcoholwithdrawalsyndrome,benzodiazepinesaretherecommendedtherapy[76].Furthermore,benzodiazepinesshouldnotbeabruptlydiscontinuedinpatientswithbenzodiazepinedependence[27].Dexmedetomidineisahighlyselectiveα2-adrenergicreceptoragonistthatprovidesanalgesiaand“cooperativesedation”withoutimportanteffectsonrespiratorystatus[77,78].Itmaybeasuitablesedativeagentformechanicallyventilatedpatientswithdeliriumoragitationinwhomextubationisbeingconsidered,agroupforwhichthereislittledata.Ameta-analysisofclinicaltrialsthatincludednonelectivecriticallyillpatientsorpatientsafterhigh-riskelectivesurgeryshowedthatdexmedetomidineledtoamodestreductioninlengthofICUstay(−0.48days;95%CI−0.18to−0.78days;P=0.002)butnosignificantdifferenceindelirium,mortality,andlengthofhospitalstay.Thereviewwasweighedonbystudiesthatincludedpatientswhounderwenthigh-riskelectivesurgery.Inaddition,themeta-analysiswaslimitedbysignificantheterogeneityamongtheincludedstudies,butoneimportantfindingwasthattheuseofbothaloadingdoseandahighmaintenancedoseofdexmedetomidineledtoasignificantlyincreasedriskofbradycardia(5.8%vs.0.4%;P=0.007)[78].DexmedetomidineappearstobeparticularlyeffectivetodecreasetheriskofdeliriumcomparedwithbenzodiazepinesinmechanicallyventilatedICUpatients.Comparedwithlorazepam,dexmedetomidineledtoastatisticallysignificantincreaseindaysalivewithoutdeliriumorcoma(median7vs.3;P=0.1)inarandomized,controlledtrialof106patients[79].Morerecently,Jakobetal.publishedtheresultsoftwoclinicaltrials;onecompareddexmedetomidinewithmidazolamandtheotherdexmedetomidinewithpropofol.AlthoughtherewasnochangeinlengthofICUandhospitalstay,thosewhoreceiveddexmedetomidineweremoreabletoarouse,cooperate,andcommunicatetheirpain.Dexmedetomidinealsoledtoareductionindurationofmechanicalventilationcomparedwithmidazolambutnotcomparedwithpropofol.Importantly,dexmedetomidineledtomorebradycardiaandhypotensioncomparedwithmidazolamandmorefirst-degreeatrioventricularblockcomparedwithpropofol[80].Furthermore,therehavebeenreportsofpatientsreceivingdexmedetomidinewhodevelopedbradycardiaandsubsequentlypulselesselectricalactivity[81,82].Thus,cautionshouldbeexercisedintheelderly,patientswithunderlyingheartdisease,andthosewhodevelopbradycardiawhilereceivingdexmedetomidine.AntipsychoticsThefirst-generationantipsychotichaloperidolhasbeenusedtraditionallyfortreatmentofdelirium.Indeed,the2002clinicalpracticeguidelinesonsedativesrecommendhaloperidolastheagentofchoiceforthetreatmentofdelirium[74].TherealsoisevidencethathaloperidolmaybebeneficialinpreventingdeliriuminaselectgroupofICUpatients[83].PatientstakinghaloperidolshouldhaveelectrocardiographicmonitoringforQTintervalprolongationandarrhythmias.Inthecriticalcaresetting,haloperidolisusuallygivenasanintermittentintravenousinjection[74].Morerecently,therehavebeenstudiesthatevaluatedtheefficacyofsecond-generation(atypical)antipsychoticmedicationsinICUpatients(Table2)[84–87].Table2 Clinicaltrialsevaluatingantipsychoticsincriticallyillpatientswithdelirium. Fullsizetable HaloperidolforpreventionofdeliriumintheICUInarandomized,double-blindtrialfromtwocenters,theeffectondeliriumpreventionofintravenoushaloperidol(0.5mgfollowedbyaninfusionat0.1mg/hover12hours)wascomparedwithplaceboin457patientsolderthan65yearswhowereadmittedtotheICUafternoncardiacsurgery.Haloperidolledtoasignificantdecreaseintheincidenceofdeliriumwithinthefirst7daysaftersurgery(15.3%vs.23.2%;P=0.031)andadecreaseinlengthofICUstay(21.3hvs.23h;P=0.024).Althoughhaloperidolwasassociatedwithlower28-daymortality,thiswasnotstatisticallysignificant(0.9%vs.2.6%;P=0.175)[83].Thatthepatientsincludedinthisstudywerenotsoill(asdeterminedbytheirmeanAPACHEIIscore<9)isapotentialdrawbackofthisstudy.Anotherlimitationistheabsenceofanoutcomedeterminingthepatients’functionality,suchasabilitytoreturntoindependentliving[88].Comparisonofhaloperidolwithsecond-generation(atypical)antipsychoticmedicationsInaclinicaltrialthatincluded73ICUpatients,oralhaloperidolwascomparedwitholanzapineforthetreatmentofdelirium.Therewasnodifferenceinreductionindeliriumseveritybetweenthegroups;however,13%ofthepatientswhoreceivedhaloperidoldevelopedmildextrapyramidalsymptoms,whereasnoneofthepatientsintheolanzapinegrouphadthesesideeffects.Thestudydesignwaslimitedbyinadequaterandomizationmethod,smallsamplesize,andlackofblindingfromthetreatingphysicianandnurses.Inaddition,thestudyhadnoplacebogroup[87].Aclinicaltrial,including101patientsonmechanicalventilationwithabnormallevelofconsciousness,foundnodifferenceinnumberofdaysalivewithoutdeliriumorcomainpatientstreatedwithhaloperidol,ziprasidone,orplacebo.Therewasnostatisticallysignificantdifferenceinextrapyramidalsymptomsamongthethreegroupsofpatients.Limitationsofthisstudyincludedasmallsamplesizeandthelargeproportionofpatients(42%)intheplacebogroupwhoreceivedopen-labelhaloperidol[85].ComparisonofhaloperidolwithdexmedetomidineArandomized,open-labeltrialcomparedhaloperidolwithdexmedetomidinein20patientswithagitateddeliriumintheICU.TheICUlengthofstaywassignificantlydecreasedby5daysinthosewhoreceiveddexmedetomidine.Limitationsofthisstudyincludedlackofblindingandthesmallsamplesize[84].Comparisonofsecond-generation(atypical)antipsychoticmedicationswithplaceboArandomized,double-blindtrialcomparedquetiapinewithplaceboin36criticallyillpatientswithdelirium.Allpatientswereallowedtoreceiveintravenoushaloperidol.Thetimetoresolutionofdeliriumwassignificantlyshorterwithquetiapinetherapythanwithplacebo;thedecreasewasby3.5days(P=0.001).Thisstudywaslimitedbysmallsamplesize,performanceofmultiplestatisticalanalyses(whichincreasestheoddsoftype1error),andthelowenrollmentrate,whichistheresultofstringentinclusioncriteria[86].FinalconsiderationsontheuseofantipsychoticsfortreatingandpreventingdeliriumintheICUInsummary,theevidenceforuseofantipsychoticsfortreatingdeliriumintheICUisweak.ThestudiesassessingantipsychoticsintheICUhaveseverallimitationsaspointedoutabove.Thescarcityofdatacallsforwell-designedandpoweredclinicaltrials.Whilewewaitforthose,andintheabsenceofothereffectivepharmacologicaloptionsforthetreatmentofdeliriumintheICU,itisouropinionthatantipsychoticscanbejudiciouslyusedinICUpatientswithdelirium,particularlyinthosewithagitation.ThedataonhaloperidolasaprophylacticagentagainstdeliriumintheelderlyadmittedtotheICUaftersurgeryappearspromising.However,morestudiesareneededbeforehaloperidolcanbeusedroutinelyasaprophylacticagentinthispatientpopulation.ConclusionsDeliriumiscommoninICUpatientsbutoftengoesundetected.Differentinstrumentshavebeendesignedtohelpintheidentificationofpatientswithdelirium.Whethertheimplementationoftheseinstrumentsleadstobetteroutcomesisnotfullyestablished.Nonpharmacologicalapproaches,suchasphysicalandoccupationaltherapy,decreasethedurationofdeliriumandshouldbeencouraged.Pharmacologicaltreatmentfordeliriumtraditionallyincludeshaloperidol.Second-generationantipsychoticshaveemergedasanalternativeforthetreatmentofdelirium,andtheymayhaveabettersafetyprofile.However,todatethestudiesevaluatingthesemedicationshavebeenlimitedbysmallsamplesize.Morepoweredclinicaltrialsareneededtoestablishthefirst-linepharmacologicaltreatmentfordelirium. AbbreviationsICU: IntensiveCareUnit CAM-ICU: ConfusionAssessmentMethodfortheIntensiveCareUnit. References1. 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DownloadreferencesAuthorinformationAffiliationsDivisionofPulmonary,CriticalCare,SleepDisordersUniversityofLouisville,Louisville,KY,USARodrigoCavallazzi & MohamedSaadDivisionofPulmonaryandCriticalCare,EasternVirginiaMedicalSchool,Norfolk,VA,USAPaulEMarikDepartmentofMedicine,EasternVirginiaMedicalSchool,825FairfaxAvenue,Suite410,Norfolk,VA,23507,USAPaulEMarikAuthorsRodrigoCavallazziViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMohamedSaadViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarPaulEMarikViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCorrespondingauthorCorrespondenceto PaulEMarik.AdditionalinformationCompetinginterestTheauthorshavenoconflictofinterestnoranyrealorperceivedfinancialinterestinanyproductmentionedinthispaper.Authors’contributionsAllthreeauthorscontributedtowritingthismanuscriptandhavereviewedandapprovedthefinalversionforpublication.Authors’originalsubmittedfilesforimagesBelowarethelinkstotheauthors’originalsubmittedfilesforimages. Authors’originalfileforfigure1Authors’originalfileforfigure2Rightsandpermissions OpenAccess ThisarticleisdistributedunderthetermsoftheCreativeCommonsAttribution2.0InternationalLicense( https://creativecommons.org/licenses/by/2.0 ),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited. ReprintsandPermissionsAboutthisarticleCitethisarticleCavallazzi,R.,Saad,M.&Marik,P.E.DeliriumintheICU:anoverview. Ann.IntensiveCare2,49(2012).https://doi.org/10.1186/2110-5820-2-49DownloadcitationReceived:21June2012Accepted:06November2012Published:27December2012DOI:https://doi.org/10.1186/2110-5820-2-49SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative KeywordsDeliriumCriticalillnessComaSedativesAntipsychotics DownloadPDF Advertisement