REVIEW Open Access Delirium in the ICU an overview Rod - PDF document

REVIEWOpenAccess DeliriumintheICU:anoverview RodrigoCavallazzi 1 ,MohamedSaad 1 andPaulEMarik 2,3* Abstract Deliriumischaracterizedbyadisturbanceofconsciousnesswithaccompanyingchangeincognition.Delirium typicallymanifestsasaconstellationofsymptomswithanacuteonsetandafluctuatingcourse.Deliriumis extremelycommonintheintensivecareunit(ICU)especiallyamongstmechanicallyventilatedpatients.Three subtypeshavebeenrecognized:hyperactive,hypoactive,andmixed.Deliriumisfrequentlyundiagnosedunless specificdiagnosticinstrumentsareused.TheCAM-ICUisthemostwidelystudiedandvalidateddiagnostic instrument.However,theaccuracyofthistoolmaybelessthanidealwithoutadequatetrainingoftheproviders applyingit.Thepresenceofdeliriumhasimportantprognosticimplications;inmechanicallyventilatedpatientsitis associatedwitha2.5-foldincreaseinshort-termmortalityanda3.2-foldincreasein6-monthmortality. Nonpharmacologicalapproaches,suchasphysicalandoccupationaltherapy,decreasethedurationofdeliriumand shouldbeencouraged.Pharmacologicaltreatmentfordeliriumtraditionallyincludeshaloperidol;however,more dataforhaloperidolareneededgiventhepaucityofplacebo-controlledtrialstestingitsefficacytotreatdeliriumin theICU.Second-generationantipsychoticshaveemergedasanalternativeforthetreatmentofdelirium,andthey mayhaveabettersafetyprofile.Dexmedetomidinemayprovetobeavaluableadjunctiveagentforpatientswith deliriumintheICU. Keywords: Delirium,Criticalillness,Coma,Sedatives,Antipsychotics Definition Deliriumisasyndromeofseveraldifferentetiologieschar- acterizedbyadisturbanceof consciousnesswithaccom- panyingchangeincognition.C haracteristicfeaturesofthe hort-termmemory,impaired attention,disorientation,developmentoverashortperiod oftime,andafluctuatingcourse[1].Notalldescribed featuresneedtobepresentforthediagnosisofdelirium, andtheintensityofthesymptomsrangeswidelyamong patients.Oneofseveralapproachestoclassifydeliriumisto divideitintomotoricsubtypes.Threesubtypesofdelirium arerecognizedbasedonthepatternofsymptoms:hyper- active,hypoactive,andmixed[2].Physiologically,delirium ischaracterizedbyaderangementofcerebralmetabolism withcerebraldysfunctionandisusuallycausedbya generalmedicalillness,intoxication,orsubstancewith- drawal[1,3].Thesyndromeofdeliriumencompassesafew distinctentitieswithuniquepathophysiologyandclinical manifestations.Theseincludesepsis-associatedenceph- alopathy,alcoholwithdrawalsyndrome,andhepatic encephalopathy. Epidemiology Inamulticenterstudy,theprevalenceofdeliriuminICU patientswas32.3%[4].InspecializedICUs,theprevalence ofdeliriummaybehigher.Forinstance,astudyshoweda prevalenceofdeliriumashighas77%inventilatedburn patients[5].TheincidenceofdeliriumintheICUranges from45%to87%[6-8].Theincidenceappearstovary accordingtowhetherthestudiedpopulationiscomposed exclusivelyofmechanicallyventilatedpatients.Asan 20%innonintubatedICUpatients[9],whereasanother studyfoundanincidenceof83%inmechanicallyventilated patients[10]. ThetwomostcommontypesofdeliriumintheICUare mixedandhypoactive[11].Hypoactivedeliriumtendsto occurmorefrequentlyinold erpatientscomparedwith othertypesofdeliriumandhasaworseprognosis.Ina studyofpatientswhounderwen telectivesurgerywithpost- operativeICUadmission,th e6-monthmortalitywas32% *Correspondence: marikpe@evms.edu 2 DivisionofPulmonaryandCriticalCare,EasternVirginiaMedicalSchool, NorfolkVA,USA 3 DepartmentofMedicine,EasternVirginiaMedicalSchool,825Fairfax Avenue,Suite410,Norfolk,VA23507,USA Fulllistofauthorinformationisavailableattheendofthearticle ©2012Cavallazzietal.;licenseeSpringer.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommons AttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproduction inanymedium,providedtheoriginalworkisproperlycited. Cavallazzi etal.AnnalsofIntensiveCare 2012, 2 :49 http://www.annalsofintensivecare.com/content/2/1/49 inpatientswithhypoactivedeliriumcomparedwith8.7%in thosewithothertypesofdelirium[12]. Pathophysiology Differentmechanismshavebeenproposedtoexplainthe pathophysiologyofdelirium.However,thesemechanisms arenotmutuallyexclusiveanditislikelythattheyoftenact inconcert(Figure1).Onehypothesispostulatesthat decreasedcholinergicactivitymayleadtodelirium[13]. Thishypothesisissupportedby theobservationthatanti- cholinergicmedicationuseisassociatedwithincreasein deliriumsymptoms[14]andthatpatientswithdelirium havehigherserumanticholinergicactivitycomparedwith thosewithoutdelirium[15]. Acetylcholinedownregulatesinflammation.Thus,itis notsurprisingthatthereisanimbalancebetweenin- flammatoryandanti-inflammatorymediatorsindelir- ium,withincreasedlevelsofinflammatorymediators andabluntedanti-inflammatoryresponse[16].Inthis light,theroleofinflammationanditsconsequent derangedcoagulationhasbeenexploredinarecentco- hortstudyofmechanicallyventilatedICUpatients.In thisstudy,fivemarkersofinflammationandfourmar- kersofcoagulationweremeasuredintheplasmaof patients.Afteradjustmentforpotentialconfounders,in- cludingseverityofillness,higherplasmaconcentrations oftheinflammatorymarkersolubletumornecrosisfac- torreceptor-1,andlowerplasmaconcentrationsofthe coagulationmarkerproteinCwereassociatedwith increasedriskofdelirium.However,anunexpectedfind- ingwasthatlowerplasmaconcentrationsofmatrix metalloproteinase-9,anothe rinflammatorymarker,were associatedwithhigherriskofdelirium[17].Anothermech- anismimplicatedinthepathophysiologyofdeliriumis overactivityofthedopaminergic system.Clinically,evidence forthiscomesfromcasereportsassociatingbupropion,an antidepressantwithdopamine andnorepinephr ineactivity, withdevelopmentofdelirium[18].Furthermore,agenetic basisforincreaseddopaminergicsystem-induceddelirium hasbeensubstantiatedbythe demonstrationthatmutant genesleadingtolowercerebraldopamineactivityarepro- tectiveagainstdelirium[19]. Bothincreasedserotonergicactivityandarelativesero- tonindeficiencyalsohavebeenassociatedwithdelirium [20].Ahighserotonergicstateinassociationwithdelirium hasbeenclassicallydescribedinpatientswiththeserotonin syndrome,aconditionoftenem ergingfromtheinteraction ofmedicationsleadingtoincreasedserotonergiceffectsand thatinitsmostsevereformpresentswithhyperthermia, musclerigidity,andmultipleorganfailure[21].Onthe otherhand,lowlevelsoftryptophan — anaminoacidthat crossesthebloodbrainbarrierandisaprecursortoneuro- transmittersserotoninandmelatonin — havebeenasso- ciatedwithdeliriumaftersurg eryinpatientsolder50years [22].Anotherstudyfoundthateitherhighorverylow levelsoftryptophanareindependentlyassociatedwithan increasedriskofdeliriuminI CUmechanicallyventilated patients[23].Whereasdecrea sedserotoninactivitymaybe implicatedinthedevelopmentofdelirium,italsoispos- siblethattheproductionofothermetabolitesoftrypto- phan,suchaskynurenine,leadstopathwayactivitythat resultsinneurotoxinspredisposingtodelirium[24]. Patientswhoaremorepronetodelirium,suchasthe elderlyorthosewithunderlyingcentralnervoussystem disease,alsomayhaveheightenedcentralnervoussystem responsetoinflammatorymediators.Itappearsthatthese patientsmayhaveanincreasednumberofmicroglialcells, whichareprimedandcanbereadilyactivatedinresponse toamildstressor[25]. Theamino-acidneurotransmittersystemhasapromin- entroleinthepathophysiologyofalcoholwithdrawal syndrome.Inparticular,chronicalcoholexposuremaylead toadecreaseinthenumberofandfunctionofgammaami- nobutyricacidreceptorsandanincreaseinthe N -methyl- D-aspartatereceptors.Bothmechanismscouldpredispose patientstoalcoholwithdrawalsyndrome[26,27]. Clinicalmanifestations Deliriumtypicallymanifestsasaconstellationofsymp- tomswithanacuteonsetandafluctuatingcourse.These Figure1 Factorsleadingtodelirium. Cavallazzi etal.AnnalsofIntensiveCare 2012, 2 :49 Page2of11 http://www.annalsofintensivecare.com/content/2/1/49 symptomshavebeenorganizedintocognitiveandbe-havioralgroups.Commoncognitivesymptomsincludedisorientation,inabilitytosustainattention,impairedshort-termmemory,impairedvisuospatialability,reducedlevelofconsciousness,andperseveration.Commonbe-havioralsymptomsincludesleep-wakecycledisturbance,irritability,hallucinations,anddelusions[28].Themani-festationsofdeliriumcanvarywidelyamongpatients.Whereassomepatientsmaymanifestsomnolenceandevencoma,othersappearanxious,disruptive,orcombat-ive[29].Recognitionofthissymptomvariabilityhasledtotheclassificationofdeliriumintomotoricsubtypes.Onesuchsubtypeishyperactivedelirium,ofwhichthemani-festationsincludeagitation,hypervigilance,irritability,lackofconcentration,andperseveration.Hypoactivedeliriummanifestsasdiminishedalertness,absenceoforslowedspeech,hypokinesia,andlethargy.Mixeddelirium,asthenameimplies,includesmanifestationsofbothhyperactiveandhypoactivedelirium[2].Theclinicalmanifestationsalsovaryaccordingtotheprecipitatingfactors.Forinstance,patientswithbacteremiaoftenpresentwithencephalopathyanddeclinedmentalsta-tus[30].Conversely,patientswithalcoholwithdrawalsyn-dromepresentwithsymptomsofanoveractivesympatheticcentralnervoussystem[31].Asaconsequence,patientswithalcoholwithdrawalsyndromecommonlyhaveagita-tion,insomnia,tremor,tachycardia,andhypertension[32].AssessmentofdeliriumAnumberofinstrumentsareavailabletodetectdeliriumincriticallyillpatients.Theimportanceofusingtheseinstru-mentsliesinthatmostcasesofdeliriumintheICUgoundetected.Indeed,thereisevidencethatevenwhenpromptedtoreportdelirium,ICUphysiciansrecognizelessthanonethirdofdeliriouscriticallyillpatientswhentheyarenotusinganinstrumenttoaidintheirdiagnosis[33].Inasystematicreviewfrom2007,sixvalidatedinstrumentstoassessdeliriumincriticallyillpatientswereidentified.TheseincludedtheCognitiveTestforDelirium,abbre-viatedCognitiveTestforDelirium,ConfusionAssess-mentMethodfortheIntensiveCareUnit(CAM-ICU),IntensiveCareDeliriumScreeningChecklist,NeelonandChampagneConfusionScale,andtheDeliriumDetectionScore[34].Anotherinstrumenttodetectdelir-iumistheNursingDeliriumScreeningScale,ofwhichthevalidityandreliabilitywereassessedintheICU[35].Table1summarizesthesediagnosticinstruments[8,36-40].ThemostextensivelystudiedinstrumentistheCAM-ICU,whichwasvalidatedtoassessdeliriumatthebedsideinnonverbalventilatedICUpatients[41].Usingastruc-turedformat,thistoolevaluatesfourfeatures,namely,acuteonsetorfluctuatingcourse,inattention,disorganizedthinking,andalteredlevelofconsciousness.Whenadmi-nisteredbybedsidenurseswithnoformalpsychiatrictraining,theCAM-ICUdemonstratedhighaccuracy(sensi-tivityof93%to100%andspecificityof98%to100%)andinterraterreliability(K=0.96)inasingle-centerstudy[10].Inanotherstudy,theCAM-ICUwassystematicallyappliedbybedsidenursesintheICUduringanimplementationprocessthatinvolvedtrainingofthenurses.Theagreementbetweentheassessmentfrombedsidenursesandaresearchstaffraterwaslowatbaselinebutveryhighduringtheimplementationprocess[42].However,subsequentstudieshaveshownthattheCAM-ICUhasamoremodestsensi-tivityrangingfrom64%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,andDeliriumDetec-tionScore)wascomparedinaprospectivestudyof156patients.AlthoughthesensitivitiesofCAM-ICUandtheNursingDeliriumScreeningScaleweresimilar(81%forCAM-ICU;83%forNursingDeliriumScreeningScale),theCAM-ICUshowedsuperiorspecificity(96%vs.81%).TheDeliriumDetectionScoreshowedasensitivityof30%andaspecificityof91%[43].Theabove-mentionedinstrumentsareourbesttoolsfortheearlydetectionofdeliriumintheICU,buttheirwidespreadapplicationhassomelimitations.First,studiesshowquitedifferentsensitivitiesforthesameinstrument,particularlytheCAM-ICU.Thedifferenceinsensitivitiesmaybeexplainedbyheterogeneityinthepatientpopula-tionsincludedinthestudiesbutmorenotablybydifferen-tialleveloftrainingandexperienceamongtheassessorsinthestudies.Thus,itisdifficulttoestablishhowaccuratetheseinstrumentsarewithoutadequatetraining,butitisreasonabletoinferthatasubstantialproportionofcriticallyillpatientswithdeliriumwillremainundiagnosediftheseinstrumentsareappliedbyinexperiencedornontrainedhealthcareproviders.Insupportofthisnotion,tworecentsystematicreviewspooledseveralstudiesevaluatingtheaccuracyofCAM-ICU[47,48].ThemajorityofthestudiesincludedinthesystematicreviewsshowedthattheCAM-ICUisahighlyaccurateinstrumentforthediagnosisofdeliriumintheICU.However,intheonlystudythatwasperformedinanonresearchsetting,mostpatientswithdeliriumwerenotdetectedbyCAM-ICU[45,47].etal.AnnalsofIntensiveCarePage3of11http://www.annalsofintensivecare.com/content/2/1/49 WhethertheseinstrumentscanbefeasiblyimplementedinbusynonacademicICUsisanimportantissue.Further-more,itisnotwellestablishedthatthesystematicapplica-tionoftheseinstrumentsinfluencestheoutcomesofcriticallyillpatients.However,thereisevidencethatwhendeliriumscreeningisappliedaspartofabroaderprotocolinitiativethatincludesactivemanagementofsedativesandanalgesicsaswellasnonpharmacologicalmeasures,suchasmusicandreassurance,severalclinicalbenefitsmayensue,suchasshorterdurationofmechanicalventilation,lowerICUandhospitalstay,andlower30-daymortality[49].Theprotocolalsoisassociatedwithcostsavings[50]. Table1InstrumentsforthediagnosisofdeliriumintheICUInstrumentAssessmentfeaturesAssessmentmethodDiagnosisAbbreviatedCognitiveTestfordeliriumdelirium36]Totalscoreobtainedbysumminguptwocontentscores:attention(range014)andmemory(range0Memoryisassessedbyrecognitionofpicturedobjects.AttentionisassessedusingthevisualmemoryspansubtestoftheWechslerMemoryScale-Revised.MethodfortheICU[Theinstrumentassessesfourfeatures:1)acuteonsetofmentalstatuschangesorfluctuatingcourse;2)inattention;3)disorganizedthinking;4)alteredlevelofconsciousnessFeature1:assessforacutechangeinmentalstatus,fluctuatingbehaviororserialGlasgowComaScoreorsedationratingsover24hours.Feature2:assessusingpicturerecognitionorrandomlettertest.Feature3:assessbyaskingthepatienttoholdupacertainnumberoffingers.Feature4:ratelevelofconsciousnessfromalerttocoma.Features1or2arepositive,alongwitheitherFeature2orFeature4IntensiveCareChecklist[Checklistofeightitems:alteredlevelofconsciousness,inattention,disorientation,hallucinationordelusion,psychomotoragitationorretardation,inappropriatemoodorspeech,sleep/wakecycledisturbance,andsymptomfluctuation.Thepresenceofeachitemofthescaleisattributedonepoint.Thescaleiscompletedbasedoninformationcollectedfromtheentireshift.Itemsscoredinastructuredwaywithdefinitionsavailableforeveryitem.NeelonandChampagneScale[Thescaleisdividedintothreesubscales:1)informationprocessing(attention,processingandorientation);2)behavior(appearance,motorandverbalbehavior);and3)physiologicalcondition(vitalfunction,oxygensaturation,andurinaryincontinence).Thesubscalescontainatotalofnineitems.Thescorerangesfrom0through30.EachitemisscoredaccordingtotheseverityoftheInformationbasedonobservationsbynursesatbedside.Itemsscoredinastructuredwaywithdefinitionsavailableforeveryitem.Moderatetoseveredelirium(019);mildtoearlydelirium(20athighriskfordelirium(25nodelirium(27Score[Eightcriteria:agitation,anxiety,hallucination,orientation,seizures,tremor,paroxysmalsweating,andalteredsleep-wakerhythm.Eachcriterionhasfourseveritylevelsandaccountsfor0,1,4,or7pointsdependingonseverityofthesymptom.Assessmentperformedduringeachshiftbythetreatingphysicianandnursewhousedaformwiththeitemsanddefinitions.Thehighestscoreineachshiftwasrecorded.Itemsscoredinastructuredwaywithdefinitionsavailableforeveryitem.Scale[Thisscalecontainsfiveitems:disorientation(verbalorbehavioralmanifestationofnotbeingorientedtotimeorplaceormisperceivingpersonsintheenvironment);inappropriatebehavior(behaviorinappropriatetoplaceand/orfortheperson,suchaspullingattubesordressings,attemptingtogetoutofbedwhenthatiscontraindicated,andthelike);inappropriatecommunication(communicationinappropriatetoplaceand/orfortheperson,suchasincoherence,noncommunicativeness,nonsensicalorunintelligiblespeech);illusions/hallucinations(seeingorhearingthingsthatarenotthereordistortionsofvisualobjects);andpsychomotorretardation(delayedresponsivenessorfewornospontaneousactions/words).Symptomsareratedfrom0to2basedonthepresenceandintensityofeachsymptom.Totalscoreisobtainedfromtheadditionofthesymptomratings.Maximalscoreis10.Assessmentperformedpershiftbybedsideetal.AnnalsofIntensiveCarePage4of11http://www.annalsofintensivecare.com/content/2/1/49 BiomarkersSeveralbiomarkershavebeenassociatedwithdelirium.Serumanticholinergicactivityisenhancedinpatientswithdelirium,andthenumberofsymptomsofdeliriumincreaseswithhigherserumanticholinergicactivitylevel[15].TheS100Bproteinisanindicatorofglialactivationand/ordeath;thus,itisanonspecificmarkerofbraininjury[51]TheS100Bproteinhasbeenshowntobeelevatedinpatientswithdelirium[52].Recently,emphasishasbeengiventothestudyofinflammatorybiomarkersforthepre-dictionofdelirium.Forinstance,McGraneetal.evaluated87criticallyillpatientsinastudy;themajorityofthemhadsepsisuponadmissiontotheICU.TheyfoundthathigherbaselinelevelsofprocalcitoninorC-reactiveproteinwereassociatedwithmoredayswithdelirium[53].Otherinves-tigatorshavefoundthattheprofileofincreasedinflamma-torybiomarkerschangesincriticallyillpatientswithdeliriumaccordingtothepresenceorabsenceofclinicalevidenceofinflammation(infectionorsystemicinflamma-toryresponsesyndrome)[54].Additionalserumbiomar-kersshowntobeelevatedinpatientswithdeliriumincludebrain-derivedneurotrophicfactor,neuron-specificenolase,interleukins,andcortisol[55,56].Whereastheuseofbiomarkersfordeliriumispromising,becausetheycanprovidediagnosticandprognosticinformation,morevali-dationstudiesarenecessarybeforetheycanbeappliedinclinicalpractice.RiskfactorsfordeliriumInastudyofnon-ICUpatientswhounderwenthipfrac-turerepair,olderageandmalesexhavebeenassociatedwithanincreasedandindependentriskofdelirium[57].Asystematicreviewthatincludedsixobservationalstudiesevaluatedriskfactorsfordeliriumbymultivariateanalysis.Twenty-fiveriskfactorsweresignificantlyassociatedwithdelirium,andamongthosefourwererecognizedaspredis-posingtodelirium:respiratorydisease,olderage,alcoholabuse,anddementia.Twenty-oneriskfactorswereconsi-deredprecipitating,becausetheywererelatedthepatient'sunderlyingdisease;someoftheseincludedelectrolyteabnormalities,fever,pressorrequirement,increasingopiatedose,andmetabolicacidosis[58].Medicationsareanimportantriskfactorfordelirium,especiallyintheelderly.Classesofmedicationscommonlyassociatedwithdeliriumincludeanticholinergicagents,benzodiazepines,andopiates[59].IntheICU,benzodiazepinesappeartohaveamoreprominentroleinthedevelopmentofdelirium[60].Prognosisetal.evaluatedtheeffectofdeliriumon6-monthmortalityandlengthofhospitalstayamong224criticallypatientsreceivingmechanicalventilationinaprospect-ivecohortstudy.DeliriumwasassesseddailybystudynurseswiththeuseofCAM-ICU.Afteradjustingforclinicallyrelevantvariables,includingage,severityofillness,comorbidconditions,anduseofsedativesandanalgesicmedications,deliriumremainedassociatedwitha3.2-foldincreasein6-monthmortalityanda2-foldincreaseinhospitalstayduration[61].Outcomesofcriticallyillpatientsareinfluencednotonlybythepresenceofdeliriumbutalsothedurationofit.Inamul-ticenterstudy,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].Inpatientswhosesymptomsdonotful-fillcriteriaforaformaldiagnosisofdelirium,thepresenceofpsychomotoragitationanindividualmanifestationofdeliriumisassociatedwithincreasedriskfordeathafteradjustmentforAcutePhysiologyandChronicHealthEvaluationScore(APACHE),age,andthepresenceofcoma[65].Inadditiontoleadingtoanincreaseinhospitalstayandmortality,deliriumisassociatedwithlong-termcognitiveimpairment.Forinstance,inacohortstudyof77patientswhounderwentmechanicalventilation,morethan70%ofthemhadcognitiveimpairmentat1yearfollow-up.In-creasingdurationofdeliriumwasindependentlyassociatedwithcognitiveimpairmentafteradjustmentforseveralco-variates,includingeducationandpreexistingcognitivefunction[66].Inanothercohortstudyof1,292ICUsurvi-vors,qualityoflifequestionnairesweresenttopatients18monthsafterICUdischarge.Thestudyhadanoverallresponserateof71%.Althoughtherewasnostatisticallysignificantdifferenceinqualityoflifebetweenpatientswithdeliriumandthosewithoutdelirium,morepronouncedcognitivefailureasdeterminedbyself-reportedcognitivefailurequestionnairewasfoundinpatientswithdeliriumafteradjustmentforcovariates[67].NonpharmacologicaltherapyNonpharmacologicaltherapieshaveanimportantroleinboththepreventionandtreatmentofdelirium.Asanexample,astudyin852elderlypatientsadmittedtoahospitalshowedthataninterventionstrategyagainstdeliriumledtoa40%decreaseintheoddsofdevelopingetal.AnnalsofIntensiveCarePage5of11http://www.annalsofintensivecare.com/content/2/1/49 delirium.Thestrategycomprisedprotocolsthattargeted riskfactorsfordelirium,suchasdehydration,immobility, sleepdeprivation,visualimpai rment,cognitiveimpairment, andhearingimpairment[68].Althoughthisstudywas performedinnon-ICUpatients,itisreasonabletoinferthat componentsoftheinterventionalsoareeffectivein criticallyillpatients.Inthislight,otherauthorshave emphasizedtheimportanceofenvironmentalfactorsinthe riskofdevelopingdeliriumintheICU,andsomestrategies havebeenproposedtomitigatetheimpactofdelirium. Theseincludenoisereduction,naturallightexposureat daytime,minimizationofartificiallightexposureatnight- time,ambienttemperatureoptimization,andimproved communication[69]. NoiseintheICUisknowntodisturbpatients ’ sleep[70]. Furthermore,ithasbeensugge stedthatadisturbedsleep mayinfluencetheriskofdelirium.Theimpactofnoiseon thequalityofsleepandthusontheriskofdeliriumhas beenillustratedinarecentclinicaltrialthatdemonstrated thattheuseofearplugsatnighttimeleadstobettersleep andlessconfusion[71].Limit ingtheexposuretosedatives alsomayhavebeneficialeffectsontheriskofdelirium.A randomized,clinicaltrialshowedthatprotocolizeddaily interruptionofsedativesassociatedwithspontaneous breathingtrialsleadstosigni ficantlyshorterdurationof comainmechanicallyventilatedpatientsbutnosignificant changeindeliriumintheass essablepatients[72].The additionofphysicalandoccupa tionaltherapytodailyinter- ruptionofsedationleadstos horterdurationofdelirium andbetterfunctionalstatusinmechanicallyventilated patients[73].Figure2presen tsaproposedstrategyforthe initialmanagementofpatientswithdeliriumintheICU. Pharmacologicaltherapy Sedatives Sedativeshavethepotentialtopromotedelirium[74].In anobservationalstudy,lorazepamwasanindependent andstatisticallysignificantriskfactorfordevelopmentof deliriumwhereasothersedatives,suchaspropofoland opiates,hadnostatisticallysignificantassociationwith delirium[60].Inarandomized,double-blindtrial,30hos- pitalizedAIDSpatientswithdeliriumwereassignedto treatmentwithhaloperidol,chlorpromazine,orlorazepam. Treatmentwithhaloperidolorchlorpromazineresultedin significantimprovementinthesymptomsofdeliriumand lowprevalenceofextrapyramidalsideeffects.Patients Figure2 ProposedstrategyfortheinitialmanagementofpatientswithdeliriumintheICU. Cavallazzi etal.AnnalsofIntensiveCare 2012, 2 :49 Page6of11 http://www.annalsofintensivecare.com/content/2/1/49 treatedwithlorazepamhadnoimprovementindeliriumanddevelopedtreatment-limitingadverseevents[75].Thus,benzodiazepinesaregenerallyavoidedforthetreatmentofdeliriuminhospitalizedpatients.Infact,becausebenzodiazepinesareanimportantriskfactorfordeliriumincriticallyillpatients,limitingtheirusemaydecreasetheoverallincidenceofdeliriumintheICU.Itshouldbenoted,however,thatinpatientswithalcoholwithdrawalsyndrome,benzodiazepinesaretherecommendedtherapy[76].Furthermore,benzodiaze-pinesshouldnotbeabruptlydiscontinuedinpatientswithbenzodiazepinedependence[27].Dexmedetomidineisahighlyselectivereceptoragonistthatprovidesanalgesiaandcooperativesedationwithoutimportanteffectsonrespiratorystatus[77,78].Itmaybeasuitablesedativeagentformechanicallyventilatedpatientswithdeliriumoragitationinwhomextu-bationisbeingconsidered,agroupforwhichthereislittledata.Ameta-analysisofclinicaltrialsthatincludednon-electivecriticallyillpatientsorpatientsafterhigh-riskelectivesurgeryshowedthatdexmedetomidineledtoamodestreductioninlengthofICUstay(0.48days;95%CI0.18to0.78days;=0.002)butnosignificantdifferenceindelirium,mortality,andlengthofhospitalstay.Thereviewwasweighedonbystudiesthatincludedpatientswhounderwenthigh-riskelectivesurgery.Inaddition,themeta-analysiswaslimitedbysignificantheterogeneityamongtheincludedstudies,butoneimportantfindingwasthattheuseofbothaloadingdoseandahighmaintenancedoseofdexmedetomidineledtoasignificantlyincreasedriskofbradycardia(5.8%vs.0.4%;=0.007)[78].Dexmedetomidineappearstobeparticularlyeffectivetodecreasetheriskofdeliriumcomparedwithbenzo-diazepinesinmechanicallyventilatedICUpatients.Comparedwithlorazepam,dexmedetomidineledtoastatisticallysignificantincreaseindaysalivewithoutdeliriumorcoma(median7vs.3;=0.1)inarando-mized,controlledtrialof106patients[79].Morerecently,Jakobetal.publishedtheresultsoftwoclinicaltrials;onecompareddexmedetomidinewithmidazolamandtheotherdexmedetomidinewithpropofol.AlthoughtherewasnochangeinlengthofICUandhospitalstay,thosewhoreceiveddexmedetomidineweremoreabletoarouse,cooperate,andcommunicatetheirpain.Dexme-detomidinealsoledtoareductionindurationofme-chanicalventilationcomparedwithmidazolambutnotcomparedwithpropofol.Importantly,dexmedetomidineledtomorebradycardiaandhypotensioncomparedwithmidazolamandmorefirst-degreeatrioventricularblockcomparedwithpropofol[80].Furthermore,therehavebeenreportsofpatientsreceivingdexmedetomidinewhodevelopedbradycardiaandsubsequentlypulselesselec-tricalactivity[81,82].Thus,cautionshouldbeexercisedintheelderly,patientswithunderlyingheartdisease,andthosewhodevelopbradycardiawhilereceivingdexmedetomidine.AntipsychoticsThefirst-generationantipsychotichaloperidolhasbeenusedtraditionallyfortreatmentofdelirium.Indeed,the2002clinicalpracticeguidelinesonsedativesrecom-mendhaloperidolastheagentofchoiceforthetreat-mentofdelirium[74].TherealsoisevidencethathaloperidolmaybebeneficialinpreventingdeliriuminaselectgroupofICUpatients[83].Patientstakinghalo-peridolshouldhaveelectrocardiographicmonitoringforQTintervalprolongationandarrhythmias.Inthecriticalcaresetting,haloperidolisusuallygivenasanintermit-tentintravenousinjection[74].Morerecently,therehavebeenstudiesthatevaluatedtheefficacyofsecond-generation(atypical)antipsychoticmedicationsinICUpatients(Table2)[84-87].HaloperidolforpreventionofdeliriumintheICUInarandomized,double-blindtrialfromtwocenters,theeffectondeliriumpreventionofintravenoushalo-peridol(0.5mgfollowedbyaninfusionat0.1mg/hover12hours)wascomparedwithplaceboin457patientsolderthan65yearswhowereadmittedtotheICUafternoncardiacsurgery.Haloperidolledtoasignificantde-creaseintheincidenceofdeliriumwithinthefirst7daysaftersurgery(15.3%vs.23.2%;=0.031)andadecreaseinlengthofICUstay(21.3hvs.23h;=0.024).Al-thoughhaloperidolwasassociatedwithlower28-daymortality,thiswasnotstatisticallysignificant(0.9%vs.=0.175)[83].Thatthepatientsincludedinthisstudywerenotsoill(asdeterminedbytheirmeanAPA-CHEIIscore9)isapotentialdrawbackofthisstudy.Anotherlimitationistheabsenceofanoutcomedeter-miningthepatientsfunctionality,suchasabilitytoreturntoindependentliving[88].Comparisonofhaloperidolwithsecond-generation(atypical)antipsychoticmedicationsInaclinicaltrialthatincluded73ICUpatients,oralhaloperidolwascomparedwitholanzapineforthetreat-mentofdelirium.Therewasnodifferenceinreductionindeliriumseveritybetweenthegroups;however,13%ofthepatientswhoreceivedhaloperidoldevelopedmildextrapyramidalsymptoms,whereasnoneofthepatientsintheolanzapinegrouphadthesesideeffects.Thestudydesignwaslimitedbyinadequaterandomizationmethod,smallsamplesize,andlackofblindingfromthetreatingphysicianandnurses.Inaddition,thestudyhadnoplacebogroup[87].Aclinicaltrial,including101patientsonmechanicalventilationwithabnormallevelofconsciousness,foundnodifferenceinnumberofdaysalivewithoutdeliriumetal.AnnalsofIntensiveCarePage7of11http://www.annalsofintensivecare.com/content/2/1/49 orcomainpatientstreatedwithhaloperidol,ziprasi-done,orplacebo.Therewasnostatisticallysignificantdifferenceinextrapyramidalsymptomsamongthethreegroupsofpatients.Limitationsofthisstudyincludedasmallsamplesizeandthelargeproportionofpatients(42%)intheplacebogroupwhoreceivedopen-labelhalo-peridol[85].ComparisonofhaloperidolwithdexmedetomidineArandomized,open-labeltrialcomparedhaloperidolwithdexmedetomidinein20patientswithagitateddelir-iumintheICU.TheICUlengthofstaywassignificantlydecreasedby5daysinthosewhoreceiveddexmedeto-midine.Limitationsofthisstudyincludedlackofblind-ingandthesmallsamplesize[84].Comparisonofsecond-generation(atypical)antipsychoticmedicationswithplaceboArandomized,double-blindtrialcomparedquetiapinewithplaceboin36criticallyillpatientswithdelirium.Allpatientswereallowedtoreceiveintravenoushalo-peridol.Thetimetoresolutionofdeliriumwassignifi-cantlyshorterwithquetiapinetherapythanwithplacebo;thedecreasewasby3.5days(=0.001).Thisstudywaslimitedbysmallsamplesize,performanceofmultiplestatisticalanalyses(whichincreasestheoddsoftype1error),andthelowenrollmentrate,whichistheresultofstringentinclusioncriteria[86].FinalconsiderationsontheuseofantipsychoticsfortreatingandpreventingdeliriumintheICUInsummary,theevidenceforuseofantipsychoticsfortreatingdeliriumintheICUisweak.ThestudiesassessingantipsychoticsintheICUhaveseverallimitationsaspointedoutabove.Thescarcityofdatacallsforwell-designedandpoweredclinicaltrials.Whilewewaitforthose,andintheabsenceofothereffectivepharmacologicaloptionsforthetreatmentofdeliriumintheICU,itisouropinionthatantipsychoticscanbejudiciouslyusedinICUpatientswithdelirium,particularlyinthosewithagitation.ThedataonhaloperidolasaprophylacticagentagainstdeliriumintheelderlyadmittedtotheICUaftersurgeryappearspromising.However,morestudiesareneededbeforehaloperidolcanbeusedroutinelyasaprophylacticagentinthispatientpopulation.ConclusionsDeliriumiscommoninICUpatientsbutoftengoesundetected.Differentinstrumentshavebeendesignedtohelpintheidentificationofpatientswithdelirium.Whethertheimplementationoftheseinstrumentsleadstobetteroutcomesisnotfullyestablished.Nonpharma-cologicalapproaches,suchasphysicalandoccupationaltherapy,decreasethedurationofdeliriumandshouldbeencouraged.Pharmacologicaltreatmentfordeliriumtraditionallyincludeshaloperidol.Second-generationantipsychoticshaveemergedasanalternativeforthetreatmentofdelirium,andtheymayhaveabettersafety Table2Clinicaltrialsevaluatingantipsychoticsincriticallyillpatientswithdelirium.No.ofInclusioncriteriaInterventionsBlindingRandomizationPrimaryendpointnt84],200920Mechanicalventilation,inabilitytoextubatebecauseofDexmedetomidine0.2-0.7mcg/kg/h(loadingdosewasoptional)Haloperidol0.5-2mg/h(loadingdosewasoptional)NoComputer-TimefromcommencementofstudydrugtoextubationPatientsondexmedetomidinewereextubatedsoonerthanthoseonhaloperidol:9.9(IQR7.3-24)vs.42.5(IQR23.2-117.8)=0.016.0.016.85],2010101Mechanicalventilation,abnormallevelofconsciousness,receiptofsedativeoranalgesicmedicationsHaloperidol5mgZiprasidone40mgplacebo.Seconddoseadministered12hoursafterthefirstifQT500msec;thenevery6hours.YesComputer-permuted-blockNumberofdaysalivewithoutdeliriumorcomaNosignificantdifferenceinnumberofdaysalivewithoutdeliriumorcoma.=0.66.Haloperidol:14(IQR6daysZiprasidone:15(IQR9.1-18)daysPlacebo:12.5(IQR1.2-17.2)daysdays86],201036ICUpatientswithdeliriumandanorderforas-neededQuetiapine50mgevery12hourstitratedupwardsonadailybasisifhaloperidolwasneeded.YesComputer-TimetofirstresolutionofTimetofirstresolutionwasshorterwithQuetiapinetherapythanwithplacebo,=0.001.Quetiapine:1(IQR0.5-3)daysPlacebo:4.5(IQR7)daysdays87],200473ICUpatientswithHaloperidol2.5-5mgevery8hoursOlanzapine5mgdailyoutcomesEven/oddsdayNotspecifiedNodifferenceindeliriumindexscores,=0.83.Nodifferenceinbenzodiazepine=0.9.IQR,interquartilerange.etal.AnnalsofIntensiveCarePage8of11http://www.annalsofintensivecare.com/content/2/1/49 profile.However,todatethestudiesevaluatingthesemedicationshavebeenlimitedbysmallsamplesize.Morepoweredclinicaltrialsareneededtoestablishthefirst-linepharmacologicaltreatmentfordelirium.ICU:IntensiveCareUnit;CAM-ICU:ConfusionAssessmentMethodfortheIntensiveCareUnit.CompetinginterestTheauthorshavenoconflictofinterestnoranyrealorperceivedfinancialinterestinanyproductmentionedinthispaper.Allthreeauthorscontributedtowritingthismanuscriptandhavereviewedandapprovedthefinalversionforpublication.AuthordetailsDivisionofPulmonary,CriticalCare,SleepDisordersUniversityofLouisville,LouisvilleKY,USA.DivisionofPulmonaryandCriticalCare,EasternVirginiaMedicalSchool,NorfolkVA,USA.DepartmentofMedicine,EasternVirginiaMedicalSchool,825FairfaxAvenue,Suite410,Norfolk,VA23507,USA.Received:21June2012Accepted:6November2012Published:27December2012AnonymousDiagnosticandStatisticalManualofMentalDisorders.4thedition.Washington,DC:AmericanPsychiatricAssociation;2000.2.LiptzinB,LevkoffSE:Anempiricalstudyofdeliriumsubtypes.BrJPsychiatry3.EngelGL,RomanoJ:Delirium,asyndromeofcerebralinsufficiency.1959.JNeuropsychiatryClinNeurosci4.SalluhJI,SoaresM,TelesJM,CerasoD,RaimondiN,NavaVS,BlasquezP,UgarteS,Ibanez-GuzmanC,CentenoJV,LacaM,GreccoG,JimenezE,Arias-RiveraS,DuenasC,RochaMG,DeliriumEpidemiologyinCriticalCareStudyDeliriumepidemiologyincriticalcare(DECCA):aninternationalCritCare5.AgarwalV,O'NeillPJ,CottonBA,PunBT,HaneyS,ThompsonJ,KassebaumN,ShintaniA,GuyJ,ElyEW,PandharipandeP:Prevalenceandriskfactorsfordevelopmentofdeliriuminburnintensivecareunitpatients.JBurnCareRes6.RobertsB,RickardCM,RajbhandariD,TurnerG,ClarkeJ,HillD,TauschkeC,ChaboyerW,ParsonsR:MulticentrestudyofdeliriuminICUpatientsusingasimplescreeningtool.AustCritCare2005,(1):6.89,1114passim.7.ThomasonJW,ShintaniA,PetersonJF,PunBT,JacksonJC,ElyEW:careunitdeliriumisanindependentpredictoroflongerhospitalstay:aprospectiveanalysisof261non-ventilatedpatients.CritCare8.ElyEW,MargolinR,FrancisJ,MayL,TrumanB,DittusR,SperoffT,GautamS,BernardGR,InouyeSK:Evaluationofdeliriumincriticallyillpatients:validationoftheConfusionAssessmentMethodfortheIntensiveCareUnit(CAM-ICU).CritCareMed9.VanRompaeyB,SchuurmansMJ,Shortridge-BaggettLM,TruijenS,ElseviersM,BossaertL:AcomparisonoftheCAM-ICUandtheNEECHAMConfusionScaleinintensivecaredeliriumassessment:anobservationalstudyinnon-intubatedpatients.CritCare10.ElyEW,InouyeSK,BernardGR,GordonS,FrancisJ,MayL,TrumanB,SperoffT,GautamS,MargolinR,HartRP,DittusR:Deliriuminmechanicallyventilatedpatients:validityandreliabilityoftheconfusionassessmentmethodfortheintensivecareunit(CAM-ICU).11.PetersonJF,PunBT,DittusRS,ThomasonJW,JacksonJC,ShintaniAK,ElyEW:Deliriumanditsmotoricsubtypes:astudyof614criticallyillJAmGeriatrSoc12.RobinsonTN,RaeburnCD,TranZV,BrennerLA,MossM:Motorsubtypesofpostoperativedeliriuminolderadults.ArchSurg13.HshiehTT,FongTG,MarcantonioER,InouyeSK:Cholinergicdeficiencyhypothesisindelirium:asynthesisofcurrentevidence.JGerontolABiolSciMedSci14.HanL,McCuskerJ,ColeM,AbrahamowiczM,PrimeauF,ElieM:Useofmedicationswithanticholinergiceffectpredictsclinicalseverityofdeliriumsymptomsinoldermedicalinpatients.ArchInternMed2001,161(8):10991105.15.FlackerJM,CummingsV,MachJRJr,BettinK,KielyDK,WeiJ:associationofserumanticholinergicactivitywithdeliriuminelderlymedicalpatients.AmJGeriatrPsychiatry16.CerejeiraJ,NogueiraV,LuisP,Vaz-SerraA,Mukaetova-LadinskaEB:cholinergicsystemandinflammation:commonpathwaysindeliriumJAmGeriatrSoc17.GirardTD,WareLB,BernardGR,PandharipandePP,ThompsonJL,ShintaniAK,JacksonJC,DittusRS,ElyEW:Associationsofmarkersofinflammationandcoagulationwithdeliriumduringcriticalillness.IntensiveCareMed18.ChanCH,LiuHC,HuangMC:Deliriumassociatedwithconcomitantuseoflow-dosebupropionsustainedreleaseandfluoxetine.JClinPsychopharmacol19.vanMunsterBC,deRooijSE,YazdanpanahM,TienariPJ,PitkalaKH,OsseRJ,AdamisD,SmitO,vanderSteenMS,vanHoutenM,RahkonenT,SulkavaR,LaurilaJV,StrandbergTE,TulenJH,ZwangL,MacDonaldAJ,TreloarA,SijbrandsEJ,ZwindermanAH,KorevaarJC:Theassociationofthedopaminetransportergeneandthedopaminereceptor2genewithdelirium,ameta-analysis.AmJMedGenetBNeuropsychiatrGenet20.FlackerJM,LipsitzLA:Neuralmechanismsofdelirium:currenthypothesesandevolvingconcepts.JGerontolABiolSciMedSci21.ChoudhuryM,HoteMP,VermaY:SerotoninsyndromeinapostoperativeJAnaesthesiolClinPharmacol22.RobinsonTN,RaeburnCD,AnglesEM,MossM:Lowtryptophanlevelsareassociatedwithpostoperativedeliriumintheelderly.AmJSurg23.PandharipandePP,MorandiA,AdamsJR,GirardTD,ThompsonJL,ShintaniAK,ElyEW:Plasmatryptophanandtyrosinelevelsareindependentriskfactorsfordeliriumincriticallyillpatients.IntensiveCareMed24.AdamsWilsonJR,MorandiA,GirardTD,ThompsonJL,BoomershineCS,ShintaniAK,ElyEW,PandharipandePP:Theassociationofthekynureninepathwayoftryptophanmetabolismwithacutebraindysfunctionduringcriticalillness*.CritCareMed25.MaclullichAM,FergusonKJ,MillerT,deRooijSE,CunninghamC:Unravellingthepathophysiologyofdelirium:afocusontheroleofaberrantstressresponses.JPsychosomRes26.DavisKM,WuJY:RoleofglutamatergicandGABAergicsystemsinJBi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