Etiologies of Delirium in Consecutive COVID-19 Inpatients ...

Medications used to manage delirium in patients with COVID-19 have included haloperidol and other antipsychotics, with melatonin as prophylaxis. SignIn Username ForgotUsername? Password Forgotpassword? Keepmesignedin NewUser SigninviaOpenAthens ChangePassword OldPassword NewPassword TooShort Weak Medium Strong VeryStrong TooLong PasswordChangedSuccessfully Yourpasswordhasbeenchanged Createyouraccount Email Returninguser ForgetyoutPassword? Enteryouremailaddressbelowandwewillsendyoutheresetinstructions Email Iftheaddressmatchesanexistingaccountyouwillreceiveanemailwithinstructionstoresetyourpassword Close ForgotyourUsername? Enteryouremailaddressbelowandwewillsendyouyourusername Email Iftheaddressmatchesanexistingaccountyouwillreceiveanemailwithinstructionstoretrieveyourusername Backtotableofcontents PreviousarticleNextarticle ClinicalandResearchReportsFullAccessEtiologiesofDeliriuminConsecutiveCOVID-19InpatientsandtheRelationshipBetweenSeverityofDeliriumandCOVID-19inaProspectiveStudyWithFollow-UpJuanD.Velásquez-Tirado,M.D.,PaulaT.Trzepacz,M.D.,JoséG.Franco,M.D.,Ph.D.JuanD.Velásquez-TiradoSearchformorepapersbythisauthor,M.D.,PaulaT.TrzepaczSearchformorepapersbythisauthor,M.D.,JoséG.FrancoSearchformorepapersbythisauthor,M.D.,Ph.D.PublishedOnline:12Apr2021https://doi.org/10.1176/appi.neuropsych.20100251AboutSectionsViewarticleAbstractViewPDFViewEPUB ToolsAddtofavoritesDownloadCitationsTrackCitations ShareShareonFacebookTwitterLinkedInEmail ViewarticleAbstractObjective:Theinvestigatorsaimedtodescribedeliriumetiologiesandclinicalcharacteristics,aswellastherelationshipbetweenCOVID-19anddeliriumseverities,atbaselineandfollow-upafterdeliriumimprovementamongpatientswithSARS-CoV-2infection.Methods:Alongitudinalstudyof20consecutivecriticallyill,deliriousCOVID-19inpatients,assessedwiththeCharlsonComorbidityIndex–ShortForm(CCI-SF),COVID-19ClinicalSeverityScale(CCSS),DeliriumEtiologyChecklist,DeliriumMotorSubtypeScale–4,andDeliriumDiagnosticTool–Provisional(DDT-Pro),wasconducted.Correlationalanalysisofdeliriumseverity(DDT-Pro)witheachmeasureofclinicalseverity(CCI-SFandCCSS)andcomparisonofbaselineDDT-Proscoresbetweenpatientswhowerelivingandthosewhoweredeceasedatfollow-upwereconducted.Results:Participantswere50–90yearsold(male,75%;hypertension,60%).Theprevalenceofpreexistingmedicalcomorbidities(CCI-SF)waslowandnotcorrelatedwithdeliriumseverity(p=0.193).Eighteenpatientswereonmechanicalorhigh-flownoninvasiveventilationatbaselineintheintensivecareunit(ICU;CCSSscores2–4).Deliriumseverity(DDT-Proscores0–6)correlatedwithCOVID-19severity(0.459,p=0.021).Deliriummotorsubtypewashyperactivein75%ofpatients.Therewerethreetofouretiologiesfordeliriumineachpatient,mostcommonlyorganinsufficiency(100%),systemicinfection(100%),andmetabolicandendocrinedisturbances(95%).ThebaselineDDT-Proscorewas≤4forfive(25%)patientswhodiedbeforethefinalassessment,withatrendofbeinglowerthanthatforsurvivors(χ2=3.398,p=0.065).Conclusions:AmonginpatientswithCOVID-19,atleastthreedifferentetiologicalcategorieswereidentifiedfordelirium.ICUstafftreatingpatientswithseverecasesofCOVID-19shouldanticipateagreaterseverityofdelirium.Althoughmultivariateanalyseswithlargerstudysamplesareneeded,moreseveredeliriummayheraldgreaterriskofdeathamongCOVID-19patients.Deliriumisanacuteimpairmentofconsciousnessthataffectsallhighercerebral-corticalfunctionsandiscommoninseriouslymedicallyillpatients,withreportedincidenceratesbetween4%and55%amongpatientsinintensivecareunits(ICUs)(1).IncreasinglyrecognizedascommonlyoccurringduringtheCOVID-19pandemic(2),deliriumhasahigherprevalencethanotherconditionsaffectingthecentralnervoussystem(CNS)whencomparedwithstroke,encephalitis,convulsions,ormeningitis(3).MostpatientswithCOVID-19,causedbytheSARS-CoV-2virus,haverespiratorysymptomsandcomplications.SARS-CoV-2entersthebodyviatheangiotensin-convertingenzyme2receptorpresentinepithelialorendothelialcellsfromrespiratoryandgastrointestinalsystems,bloodvessels,kidneys,heart,liver,andbrain,amongotherorgans;therefore,ithasthepotentialtodirectlyaffectallofthesetissues(4).Thevirusalsotriggersaninflammatoryresponse,humoralandcellular,withsomepatientsdevelopinganexaggeratedresponseasacytokinestormorautoimmunereaction(5).Patientswithsevereinfectiondevelopsystemiccoagulopathy,withriskofthromboembolismandD-dimerelevation(6).Hypertension,obesity,diabetes,andothercardiovascularriskfactorsareassociatedwithincreasedseverityofCOVID-19(7).DeliriuminpatientswithCOVID-19hasmanypossibleetiologies,includingmetabolic,respiratory,andcoagulationalterationsthatareconsequencesofthedirecteffectsofSARS-CoV-2onperipheralorgansandsystems.Additionally,systemicinflammationthatalterstheblood-brainbarrierleadstoaCNSimmuneresponse(8).Thevirusproducesadirecteffectinthebraininaminorityofcases(encephalitisandmeningitis),suchthatdeliriumcouldresultfromaCNSinfection(9,10)aswellasbraininflammation.TherearelimitedreportsondeliriumduringtheCOVID-19pandemic,mostlycasereports(11–13)orretrospectivestudies(3,14),althoughoneprospectivestudyoftwoICUcohortsinFrancereporteda79.5%incidencerateofdeliriumusingtheConfusionAssessmentMethod–ICU(CAM-ICU)(9).COVID-19deliriumoftenpresentsasthehyperactivemotorsubtypeinupto69%ofpatients(9,12),althoughthehypoactivesubtypemaybemorecommonintheelderly(11,14).EEGshaveshowngeneralizedslowingconsistentwithdelirium(15).Neuroimaginghasmostoftenfoundmicrohemorrhagewithapredilectionforthespleniumin60%ofpatients,acuteandsubacuteinfarctsin25%,andwatershedwhitematterhyperintensitiesin20%(3).MedicationsusedtomanagedeliriuminpatientswithCOVID-19haveincludedhaloperidolandotherantipsychotics,withmelatoninasprophylaxis.Drugsusedtomanagehyperactivityhaveincludedhaloperidol,dexmedetomidine,clonidine,trazadone,benzodiazepines,andvalproicacid(12,16,17).OpioidsareusedinICUstomanagepainandrespiratorydistress,althoughthesearealsodeliriogenic,asarebenzodiazepines.DexmedetomidinemaybeassociatedwithalowerriskofdeliriumthanothersedatingmedicationsusedintheICU,suchaspropofol(18,19).Toourknowledge,noreportshaveexaminedtherelationshipbetweenCOVID-19diseasestatusseverityanddeliriumseverityorasystematicclinicalassessmentoftherelationshipofetiologieswithdeliriuminaconsecutivecohort.Becausedeliriumalmostalwayshasmultifactorialprecipitants,weanticipatemultipleetiologiesfordeliriuminhospitalizedCOVID-19patients.Inthepresentstudy,weaimedtodescribetheetiologies,clinicalfeatures,andCOVID-19anddeliriumseveritiesinaprospectiveseriesofconsecutivedeliriousCOVID-19patientsassessedusingstandardizedtoolsbyadeliriumexpertliaisonpsychiatristworkinginanICU.AssessmenttoolsincludedtheDeliriumEtiologyChecklist(DEC),DSM-5criteria,DeliriumMotorSubtypeScale–4(DMSS-4),DeliriumDiagnosticTool–Provisional(DDT-Pro),andCOVID-19ClinicalSeverityScale(CCSS).Here,wereportetiologiesfordeliriumandtherelationshipbetweenCOVID-19anddeliriumseveritiesatbaselineandfollow-upafterdeliriumimprovement.MethodsDesign,EligibilityCriteria,Participants,andEthicsThisisaprospectivelongitudinalstudyofthefirst20consecutiveadultinpatientswithSARS-CoV-2infection(COVID-19disease)whohaddeliriumdiagnosedbytheLiaisonPsychiatryServiceatClinicaUniversitariaBolivarianainMedellín,Colombia(CUB).SARS-CoV-2infectionswerediagnosedinCUBusingtheCharité/Berlin(WorldHealthOrganization)protocolofreal-timeRNAreverse-transcriptionintoDNAwithpolymerasechainreactionofEandRdRpgenes.Accordingtothelaboratory,theprotocolsensitivityis95%whenassayedinSARScoronavirusvirions,andnofalsepositivesinclinicalsamplespretestedpositiveforotherrespiratoryviruses(20).AccordingtotheCUBprotocol,samplesfordiagnosiswereobtainedfromnasopharyngealswabinall20cases.DeliriumdiagnosiswasmadeaccordingtoDSM-5criteria(21);deliriumseveritywasassessedwiththeDDT-Pro(22,23)andetiologiestabulatedwiththeDEC(24).COVID-19severitywasmeasuredwiththeCCSS(25,26).Demographicandmedicalinformationwereobtainedfrommedicalrecords.Thestudywasapprovedbyourinstitution’sethicscommittee(ComitédeÉticadeInvestigaciónenSaluddelaUniversidadPontificiaBolivariana,Medellín,Colombia),andpermissionforgatheringinformationfromelectronicchartswasobtainedfromtheCUBresearchcommittee.InstrumentsRelevantdemographicandclinicalvariableswerecollectedusingastandardmethod.Clinicalvariablesincludedmedicaldiagnoses,medications,preexistingdementiadiagnosis,anddeathatfollow-up.CharlsonComorbidityIndex–ShortForm(CCI-SF).TheCCI-SFquantifiestheseverityofbaselinemedicalstatusonascalefrom0to1(nomedicalcomorbidity)to10(maximumcomorbidity)points,whereascoreof2indicateslowcomorbidityand≥3indicateshighcomorbidity.CCI-SFassesseseighthealthconditions;eachofthefirstsixaddsonepointandthelasttwoeachaddtwopoints.Theconditionsarestroke,diabetesmellitus,chronicobstructivepulmonarydisease,congestiveheartfailureandischemicheartdisease,dementia,peripheralarterydisease,chronickidneyfailure,andcancer(27).CCSS.TheCCSSisanordinalscaletogradeclinicalstatusofCOVID-19patientsbythefollowingsevenlevels:death;hospitalized,oninvasivemechanicalventilationorextracorporealmembraneoxygenation;hospitalized,onnoninvasiveventilationorhigh-flowoxygendevices;hospitalized,requiringlow-flowsupplementaloxygen;hospitalized,notrequiringsupplementaloxygen,requiringongoingmedicalcare(COVID-19relatedorotherwise);hospitalized,notrequiringsupplementaloxygen,nolongerrequiresongoingmedicalcare;nothospitalized(25,26).DDT-Pro.TheDDT-Proisathree-itembriefstructuredscaleforprovisionaldiagnosisandseverityofdelirium,whichcanbeadministeredbyanyhealthcareprofessional;ithasbeenvalidatedintraumaticbraininjuryandmedical-surgicalsamples(22,23).Itcontainsstructuredandquantitativelyscoreditemsforevaluatingvigilance(item1)andcomprehension(item2)adaptedfromtheCognitiveTestforDelirium(CTD)(28)thatareassesseddirectlythroughpatientperformancewithoutneedingverbalresponses(usefulinmechanicallyventilatedpatients),andsleep-wakecycledisturbance(item3),adescriptivelyanchoreditemfromtheDeliriumRatingScale–Revised–98(DRS-R-98)(29),ratedusingallsourcesofclinicalinformationforthepreceding12–24hours.Item3ratingvalueswerereversedtoalignwiththescoringfortheCTDitems.Theseitemsrepresentsymptomsfromeachofthethreecoredomainsthatarecharacteristicofdelirium(cognitive,higher-levelthinking,andcircadian)(22,23,30).TotalDDT-Proscoresrangefrom9points(best)to0(worst),whereeachitemisscored0–3.ThebestcutofffordiagnosingdeliriumisaDDT-Proscore≤6,withscoresrangingfrom7to9indicatingnondelirium(22,23).Ithastwoalternateequivalentforms,AandB,foritems1and2.Thetoolwasusedinthisstudytoquantifydeliriumseverityinpatientsdiagnosedbytheliaisonpsychiatrist.DEC.TheDECisatwo-partstructuredtooltodeterminetheattributionofetiologiestoanepisodeofdeliriumaccordingto13categories,includingmetabolic,infection,primaryCNSdisorders,systemicdisturbancesthataffectcerebralfunction,anddrugortoxinexposure(includingintoxicationandwithdrawal)(24).TheDEChasaworksheettocapturethespecificmedical,surgical,andpharmacologicalconditionsthatarepresentandaratingtabletosystematicallyrateeachetiologycategoryforitsdegreeoflikelihoodforcausingdeliriumbasedonoverallclinicalevaluationofapatientusingallsourcesoflaboratoryandmedicalinformation.Theratingsareasfollows:definitecause;likelycause;presentandpossiblycontributory;presentbutapparentlynotcontributory;andruledout,notpresent,ornotrelevant.ProceduresAliaisonpsychiatristassessed,diagnosed,andmanageddeliriumtreatmentforallSARS-CoV-2positivelytestedpatientsincludedinthisreport,usuallywithinaday(range0–48hours)afterreferralbytheprimaryattendingphysicianwhosuspecteddelirium.Theliaisonpsychiatristworkscloselyaspartoftheteamwiththeattendingphysicians,whoarealsotrainedinclinicaldeliriumdetection.DeliriumdiagnosiswasmadebythepsychiatristaccordingtoDSM-5criteria(21),andmotorsubtypesweredeterminedaccordingtotheDMSS-4ashyperactive,hypoactive,ormixed(31).Thepsychiatristhadaccesstoallavailableinformationsourcesanddiscussedpatients’clinicalstatuswiththeteam;therefore,diagnosticandtherapeuticdecisionsregardingdeliriumweretakenafterconsideringclinicalcharacteristicsofeachpatient.Preexistingdementiawasdiagnosedclinicallyusingallavailablesources(patients,caregivers,andfamiliesinterviewedbyphoneifneeded;clinicalcharts;neuroimages).TheDECwascompletedatbaselinevisit.TheDDT-ProandCCSSwereperformedatthefirstandfinalpsychiatricassessmentwhendeliriumhadbeenclinicallyimprovedforatleast1dayafterstabilizationofclinicalstatus,transfertogeneralward,ordeliriummedicationdown-titration.Patientswerefolloweddailybytheliaisonpsychiatristforroutinedeliriummanagement,includingpsychopharmacological,afterthebaselineassessmentuntilclinicalcomplicationsanddeliriumwereresolved.StatisticalAnalysisAnSPSS23.0databasewascreated.Discretevariablesarereportedbyabsoluteandrelativefrequencies(percentages).AccordingtoShapiro-Wilkstest,agewasnormallydistributedandisreportedwithmeansandstandarddeviations;theothercontinuousvariablesarereportedbymediansandinterquartileranges.Finally,weperformedsomeexploratoryanalysesusingSpearman’srhocorrelations(one-tailedpvalues)fordeliriumseveritywiththeDDT-Pro,CCI-SFforbaselinemedicalburden,andCCSSforcurrentCOVID-19status;andmeanrankscomparisonforbaselineDDT-Probetweenthosewhodiedatfollow-upandthosealiveatlastassessment.Significancevaluesweresetatp<0.05.ResultsTable1showsbaselinepatientcharacteristics;75%weremaleandagerangedfrom50to90years.Prevalenceofdementiaandpreexistingcomorbidconditionswaslow.TheCCI-SFscorewas≤2in19(95%)patients,withoutameaningfulcorrelationwiththeDDT-Pro(ρ=0.205,p=0.193)orCCSS(ρ=–0.016,p=0.474).Twelvepatients(60%)werehypertensiveandfive(25%)haddiabetes.TABLE1.Baselinedemographicandclinicalcharacteristics,includingdeliriumattributesandseverity,ofconsecutiveinpatientswithconfirmedSARS-CoV-2anddeliriumatthefirstliaisonpsychiatryassessment(N=20)aCharacteristicN%Age(years)(mean±SD)67.810.5CharlsonComorbidityIndex–ShortForm(medianandinterquartilerange)11Frequency Facility  Intensivecareunit1890  Internalmedicineward210 Male1575 Mainadmissiondiagnosis  SARS-CoV-2pneumonia1050  SARS-CoV-2plusbacterialpneumonia630  SARS-CoV-2infection315  Urinarytractinfection,bacterial15 Secondmainadmissiondiagnosis  Acuterespiratorydistresssyndrome945  Acuterespiratoryfailure525  SARS-CoV-2pneumonia15  Bacterialpneumonia15  Decompensatedchronicobstructivepulmonarydisease15  Pneumothorax15  Sepsis,bacterial15  Urinarytractinfection,bacterial15 Thirdmainadmissiondiagnosis  Acutekidneyfailure630  None630  Bacterialsepsis210  Othersdiagnoseswithfrequency630 StatusaccordingtoCOVID-19ClinicalSeverityScalescoreb  2=Hospitalized,oninvasivemechanicalventilationorextracorporealmembraneoxygenation1155  3=Hospitalized,onnoninvasiveventilationorhigh-flowoxygendevices630  4=Hospitalized,requiringlow-flowsupplementaloxygen315 D-dimerelevation(normal<500ng/mL)1365 TreatmentrelatedtoSARS-CoV-2infection  Anycorticosteroid1890  Anyantiviral00 Hypertension1260 Diabetes525 Cancer00 Dementia210 Medication  Anyanticholinergic1890  Midazolamoranyotherbenzodiazepine1680  Anyantipsychotic20100  Dexmedetomidine1050  Fentanyloranyotheropiate1785  AnyNSAID1260  Anyantibiotic1890  Anyotherpsychoactive1365 Deliriumcharacteristic Deliriummotorsubtype  Hyperactive1575  Hypoactive315  Mixed15  Nosubtype15 Presenceofhallucinations/hallucinatorybehavior315 Presenceofdelusionsorsuspiciousness15 Psychoticsymptomsnotassessable1890 DDT-Proscore(range0–9;medianandinterquartilerange)2.55aDDT-Pro=DeliriumDiagnosticTool–Provisional;NSAID=nonsteroidalanti-inflammatorydrugs.bCOVID-19ClinicalSeverityScalescores:1=death;2=hospitalized,oninvasivemechanicalventilationorextracorporealmembraneoxygenation;3=hospitalized,onnoninvasiveventilationorhigh-flowoxygendevices;4=hospitalized,requiringlow-flowsupplementaloxygen;5=hospitalized,notrequiringsupplementaloxygen,requiringongoingmedicalcare(COVID-19-relatedorotherwise);6=hospitalized,notrequiringsupplementaloxygen,nolongerrequiresongoingmedicalcare;and7=nothospitalized.TABLE1.Baselinedemographicandclinicalcharacteristics,includingdeliriumattributesandseverity,ofconsecutiveinpatientswithconfirmedSARS-CoV-2anddeliriumatthefirstliaisonpsychiatryassessment(N=20)aEnlargetableAllornearlyallpatientsweretreatedwithcorticosteroids,anticholinergics,benzodiazepines,andopiates(includingfentanyl);halfreceiveddexmedetomidineaspartoftheirmedicalmanagementintheICU.Nonereceivedantivirals.AllexcepttwopatientswereintheICUduringthebaselineassessmentandoninvasivemechanicalorhigh-flownoninvasiveventilation(CCSSscoresof2–4).Atbaseline,DDT-ProdeliriumseveritycorrelatedsignificantlywiththeseverityofCOVID-19ontheCCSS(ρ=0.459,p=0.021).Nearlyallpatientshadadefinitelikelihoodfordeliriumetiology.Themostcommondefiniteorlikelycausesorpossiblycontributoryetiologieswereorganinsufficiency(100%),systemicinfection(100%),andmetabolicandendocrinedisturbances(95%)(Table2).Allhadbetweenthreeandfourdeliriumetiologies(fromdefinitetopossiblecontributors);themostcommoncombinationsweremetabolicandendocrineplussystemicinfectionplusorganinsufficiency(85%)andmetabolicandendocrineplussystemicinfectionplusorganinsufficiencyplusanyotherCNSdisorderoranyotherdiversecause(10%).The“anyother”CNSetiologieswereallpreexistingchronicconditionsrelatedtocognitiveormotorimpairment.TABLE2.CategoriesofetiologiesfordeliriumasassessedwiththeDeliriumEtiologyChecklistamongpatientswithconfirmedSARS-CoV-2(N=20)PresentandpossiblycontributoryPresentbutapparentlynotcontributoryRuledout,notpresent,ornotrelevantDefinitecauseLikelycauseCategoryN%N%N%N%N%Drugintoxication0000000020100Drugwithdrawal0000000020100Metabolicandendocrinedisturbance31513653150015Traumaticbraininjury0000000020100Seizures0000000020100Infection Intracranial0000000020100 Systemic1890210000000Neoplasm Intracranial0000000020100 Systemic0000000020100Cerebrovascular0000000020100Organinsufficiency199500150000Othercentralnervoussystemdisordera0021000151785Othercausesb001500001995aTraumaticbraininjuryantecedentwithcognitiveormotorimpairment(N=1),schizophreniaanddegenerativedementia(N=1),anddegenerativedementia(N=1).bPostoperative(tracheostomy).TABLE2.CategoriesofetiologiesfordeliriumasassessedwiththeDeliriumEtiologyChecklistamongpatientswithconfirmedSARS-CoV-2(N=20)EnlargetableAccordingtotheDECworksheet(couldhave>1specificconditionpresentinagivencategory),organinsufficienciesrelatedtodeliriumwerepulmonary(95%),renal(35%),cardiac(10%),andhepatic(5%).Systemicinfectionsrelatedtodeliriumwereviral(85%),followedbyavarietyofbacterialcausesandcomplications(75%).Metabolicandendocrineetiologieswereavarietyofacid-baseandelectrolytedisorders(100%),anemia(60%),hyperglycemia(40%),andhypoalbuminemia(30%).Deliriumcharacteristicsandseverity,where75%ofpatientshadhyperactivemotorsubtype,arepresentedinTable1.Three(15%)patientshadhallucinations;althoughitwasdifficulttoassessthoughtcontentbecauseoforalcommunicationrestrictions,one(5%)whodidnothavehallucinationsdidhavedelusionsorsuspiciousness.TheDDT-Proscorerangeatbaselineassessmentwas0–6,witheight(40%)patientsscoring0or1.Nonpharmacologicaltherapeuticmeasuresfordeliriumwereappliedforallpatients,althoughtheirisolationneedsandbiosecuritymeasuresprecludeddirectfamilyinvolvementintheircareandconstrictedtheinteractionbetweenpatientsandstaff.Nonetheless,standardofcareincludedthefollowing:restrictionofinvasiveprocedures(centralandperipherallines),hydrationassessment,noisecontrol,useofglassesandhearingaidswhenpossible,preservationofenvironmentalcuesofdayandnightasmuchaspossible,reorientation,explanationofprocedures,picturesandrecordedmessagesfromthefamilywhenavailable,andcommunicationbetweenthestaffandthefamilymembersandhomecaregivers.Allpatientsreceivedantipsychoticsasfirstoptionsfordeliriumtreatment(haloperidol5–20mg/day[except1mgforpatientswithhypoactivesubtypeornomotorsubtype],N=16[80%];quetiapine50–600mg/day,N=4[20%]).Quetiapinewaschoseniftherewasahistoryofextrapyramidaladverseeventswhenusingtypicalantipsychoticsorforitshypnoticeffectadministeredatnight.Threepatientshadaninadequateresponsetohaloperidol;itwaschangedtoquetiapineintwo(12.5%)andlevomepromazine25mg/dayinone(6.2%).Adjunctivetrazodone50–100mgq.h.s.wasaddedineightoutof20(40%)patientsforsleepandnocturnalactivityregulation.Medianpsychiatryfollow-uptimewas9days(interquartilerange=22)witharangeof3–49.Figure1showsratinglevelsforCCSSandDDT-Proatbaseline(N=20),whereCCSSscoresareseverestagesandDDT-Proscoresindicateseveredelirium.Atthefinalassessment(N=15)scoreswereimprovedforbothscales.Fivepatients(25%)diedbeforethefinalDDT-Proassessment,representingCCSS=1.FinalDDT-Proscoresrangedfrom6to9,and46.7%ofpatientsreceivedascoreof8.FinalCCSSscorescorrelatedsignificantlywithDDT-Proforsurvivors(0.567,p=0.028).FIGURE1.RatinglevelsforCOVID-19ClinicalSeverityScale(CCSS)andDeliriumDiagnosticTool–Provisional(DDT-Pro)scoresatbaselineandthefinalliaisonpsychiatryassessmentamongconsecutiveinpatientswithconfirmedSARS-CoV-2anddelirium(N=20)a ThegraphsshowthefrequencyofspecificscoresfortheCCSS(rangefrom1=deathto7=nothospitalized)andDDT-Pro(deliriumwithdecreasingseverityasscoresgofrom0to6andnodeliriumfrom7to9)atthebaselinepsychiatricassessmentandthefinalpsychiatricassessment(twobarsattheright)for20patients(living,N=15;deceased,N=5[denotedinblack]).RatingsforthefivedeceasedpatientswerenotassessableontheDDT-Pro.ScoreswereworseontheCCSSandDDT-Pro(inthedeliriumrange)atbaseline,whilescoresonbothmeasureswereimprovedatthefinalassessment.Foracolorversionofthefigure,seetheonlineeditionofthisarticle.ThebaselinemedianDDT-Proscoreinthe5patientswhodiedwas1(interquartilerange=4),versus3(interquartilerange=6)inthe15survivors(p=0.266).BecausethebaselineDDT-Proscoreinthosewhodiedrangedbetween0and4,weperformedaposteriorlikelihoodratiochi-squaretesttoexplorewhethertheDDT-Proscore≤4atbaselinewasrelatedtomortality(likelihoodratioχ2=3.398;df=1,p=0.065).Becauseapvalueof0.065isclosetothesignificancethresholdanddeathisacriticallyimportantoutcome,wecalculatedsignificancevaluesforthefirst10andthenfirst15patientsofthestudy(p=0.201andp=0.095respectively),findingatrendtowardsignificanceforarelationshipwithmortalityamongpatientsscoring≤4ontheDDT-Proasthesamplesizeincreased.Nosurvivoratfinalassessmentrequiredmechanicalventilationorhigh-flowoxygensupport;rather,mostwereonsupplementarylow-flowoxygenandhospitalmedicalcare(CCSSlevels4and5),andallhadDDT-Proscoresbetween6and9.FourofthefivepatientswhodiedhadbaselineCCSS=2(onmechanicalventilation)scores.DiscussionGiventhepaucityofprospectivedeliriumstudiesduringtheCOVID-19pandemicusingstandardizedtoolsdesignedfordeliriumandadministeredbydeliriumexpertpsychiatrists,weconductedalongitudinalstudyof20inpatientswithCOVID-19whometDSM-5diagnosticcriteriafordeliriuminanacademichospitalinMedellín,Colombia,18ofwhomwereinanICUatbaseline.Thesepatientswereassessedbyaliaisonpsychiatristexpertinbothclinicalandresearchdeliriumevaluationandmedicationtreatment,whomanagedthepatientsclinicallyduringthestudyperioduntileitherdeathorthefinalevaluationforimproveddelirium.Mostpatientsweremale,andmorethanhalfhadchronichypertension,bothrecognizedriskfactorsforsevereCOVID-19(7).Surprisingly,baselinepreexistingmedicalproblemsratedusingtheCCI-SFdidnotcorrelatewithdeliriumorCOVID-19severity.However,therewasacorrelationbetweengreaterseveritiesofCOVID-19(CCSS)anddelirium(DDT-Pro)atbaseline(p=0.021)andfinalassessment(p=0.028).AlthoughtheCAM-ICUdoesnotmeasureseverity,CAM-ICUdeliriuminCOVID-19patientswithacuterespiratorydistresssyndromewasassociatedwithlongermechanicalventilationtimeandICUlengthofstay(9).Thus,thereappearstobearelationshipbetweendeliriumandCOVID-19diseaseburden.DeliriumiscommoninCOVID-19;however,ourobjectivewasnottodetermineincidencebutrathertodescribetheclinicalcharacteristicsofdeliriumandtheirrelationshiptoetiologiesandmedicalseverity.ThedeliriumincidencerateamongICUpatientswithCOVID-19wasreportedat79.5%,basedontheCAM-ICUbeingpositiveatanytimeduringthehospitalstay,and18%onadmission(9).Kotfisetal.(8)describedthepossiblecausesfordeliriuminsevencategories:directCNSinvasion,inductionofCNSinflammatorymediators,secondaryeffectofotherorgansystemfailure,effectofsedativestrategies,prolongedmechanicalventilationtime,immobilization,andotherneededbutunfortunateenvironmentalfactors,includingsocialisolationandquarantinewithoutfamily.WeascertainedetiologiesofdeliriumusingtheDEC,whichattributesthelikelihoodofpathophysiologicalcausesofdeliriumusingallsourcesofinformationfromlaboratoryandmedicalrecords,andfoundthatinalmostallpatientsorganinsufficiencies(notonlypulmonary)andsystemicinfectionweredefinitecausesofdelirium;allhadatleastthreeotherseriousmedicalproblemsimplicatedforcausingdelirium,includingmetabolicandendocrinedisturbances.PathophysiologicalmechanismsfordeliriuminCOVID-19aremany.Inflammatoryresponsetosystemicinfectionsalterstheblood-brainbarrier,allowingacentralinflammatoryresponseleadingtoneuronaldysfunctionofcholinergiccircuits,amongotheralterations(32).Pulmonary,cardiac,andrenalinsufficiencyreduceCNSmitochondrialoxidation,increaseCNSdopamine,anddecreaseacetylcholineproduction(33).Hepaticinsufficiencyincreasestyrosine,phenylalanine,andtryptophanlevels,leadingtoincreaseofCNSdopamineandserotonin(34).Amongmetabolicandendocrineperturbations,electrolytedisturbanceandanemiaalterCNSoxidativemetabolism(35,36),andhyperglycemiacausesdirectbraininsultandincreasesneuronaldepolarization(37).Theneuralcircuitsalteredasaresultoftheseetiologiesarerelatedtodeliriumandinvolvethereticularactivatingsystemandthalamusandtheirconnectionstotheneocortex,includingparietalandfrontallobes(38,39).Therewerenocasesofdeliriumattributabletodirectbrainpathology,suchasstroke,encephalitis,ormeningitis.TheseseemlesscommoninCOVID-19patientswhencomparedwithperipheralpathologies(3,9,10).Kotfisetal.(8)recommendedthatdeliriumpresenceshouldbeactivelyscreenedforduringCOVID-19usingdedicatedpsychometrictools.TheseincludethebriefscreeningtoolsCAM-ICUandICSDCusedbynurses;deliriumseverityshouldbecheckedusingthewell-validatedDeliriumRatingScale-Revised-98(DRS-R98)(8).WeusedtheDDT-Pro,asimple,highlystructuredthree-itemtoolderivedfromtheDRS-R98andCTDtoassessseverityofsymptomsrepresentativeofthethreecoredomainsofdelirium.Circadiancoredomain(sleep-wakecycle)isnotassessedbytheCAM-ICU.TheDDT-ProishighlycorrelatedwiththeDRS-R98score(r=0.913)(22)andissensitivetochangeindeliriumseverityatfollow-up(23).TheDDT-Promaybeadministeredbyanyclinicalstaffmemberfordeliriumdiagnosisandseverity;itscutoffscore≤6has88%–90%sensitivityand85%–87%specificityforanindependentDSM-5deliriumdiagnosiswhenadministeredbyaphysicianornursetogeriatricinpatients(23).DDT-Proscoredidnotcorrelatewithbaselinemedicalburden(CCI-SF)inoursample,wherealmostallpatientshad≤2premorbidconditionsandlowdementiaprevalence.However,accordingtoourexploratoryanalysis,stafftreatingmoresevereCOVID-19patientsshouldanticipatemoreseveredelirium(Figure1),eveninpatientswithalownumberofpreexistingmedicalcomorbidities.Althoughnonsignificant,theDDT-Proscoreatbaselineamongthefive(25%)patientswhodiedwaslowerthanthatofthe15(75%)whosurvived,andtherewasatrendforthosescoring≤4tohaveincreasedfrequencyofdeathduringthefollow-up,suggestingapredictiverelationshipformortalitywithmoreseveredeliriuminCOVID-19.AccordingtotheDMSS-4,80%ofourpatientshadhyperactivesubtypeormixedmotorsubtypedelirium,whichisconsistentwiththereportedhighprevalenceoftheRichmondAgitation–SedationScale+3and+4scores(veryagitatedandcombative)(9).Wefoundthatatleast20%ofthesamplehadhallucinationsordelusionsandsuspiciousness.ThesefindingsindicatethatpatientswithCOVID-19aremoredisruptive,causemorestressamongstaffmembers,andneedmorepharmacologicalinterventions.Theuseofnonpharmacologicalmeasuresfordeliriummanagementispossiblebutrestrictedduetopatientbiosafetyisolationneedsandlimitationsonstaffavailability.Well-designedclinicaltrialsofdeliriumtreatmentforCOVID-19patientsarelacking,andourstudyisnotaclinicaltrial;rather,itisadescriptivestudyofroutineclinicalcare.Theuseofantipsychoticsforreducingdeliriumseverityorincidenceiscommoninclinicalpracticebypsychiatrists,andtheyaregenerallywelltolerated,assupportedbyclinicaltrials(40–42).Additionally,metanalysissupportstheefficacyandsafetyofhaloperidol(asthefirstpharmacologicaloption)andquetiapine,thetwoagentsmostfrequentlyusedinoursample(43).DecadesofexperiencealsosupportthesafeuseofantipsychoticsintheICU,andtheirsafetywascorroboratedbyarecentsystematicreview(44).RecommendationsbasedoncasereportsofCOVID-19patientsindicatetheuseofantipsychoticsfordeliriumtreatmentasaresultoftheirblockingeffectofdopamineexcessandrebalancingofthecholinergicdeficiencyindelirium,suchasforthalamicsensorimotorgating(12,24,33,38).Althoughallpatientsinourcohortreceivedantipsychoticsfordelirium,almosthalfrequiredtheadditionoftrazodoneforsedation;15%neededanantipsychoticchangetoamoresedatingoptionduetoinsufficientresponsetohaloperidol.DeliriumpharmacologicalmanagementintheICUiscomplicatedbythedeliriogeniceffectsofintoxicationoremergencewithdrawalfromsedationandpainmedicationscommonlyusedintheICUsetting(45,46).NearlyallofourpatientsreceiveddrugsknowntobedeliriogenicaspartoftheirICUtreatmentregimen–corticosteroids,anticholinergics,benzodiazepinesandopiates–suggestingthatCOVID-19conditionswerenottheonlyetiologiesfordelirium.Interestingly,noneofthesedrugswasconsideredamaincauseofdeliriumontheDEC,perhapsbecausetheywereastandardofcareandovershadowedbymajorphysiologicalimpairments.Onlyhalfreceiveddexmedetomidineforsedation,reportedtosedatewithlessdeliriumrisk(18,19,47).Melatoninhasbeenreportedtohelpmaintainanormalsleep-wakerhythminCOVID-19deliriumandhaspossibleanti-inflammatoryandimmune-enhancingfeatures(48).Aclinicaltrialusingramelteon,amelatoninreceptoragonist,supportedapharmacologicalinterventioninthecircadiansystemfordeliriumprophylaxis(49).Circadianabnormalitiesareoneofthethreecoresymptomdomainsofdelirium.Unfortunately,neitherofthesetwomedicationsareavailableforroutinehospitaluseinColombia.Ourstudyislimitedbyasmallnumberofconsecutivecases,butitsstrengthsweretheuseofvaliddelirium-specifictoolsbyanexpertliaisonpsychiatristandlongitudinalfollow-up.TheDDT-ProscorescorrelatedtoCOVIDseverityatbothbaselineandfinalassessments.Althoughstudiesinlargersamplesareneeded,moreseveredeliriumonadmissiontoICUforCOVID-19maybeaharbingerofmortalityeveninpatientswhodidnothavemuchpreexistingmedicalcomorbidityontheCCI-SF.FutureresearchwithlargersamplesusingmultivariateanalysesisneededtostudyrelationshipsofconcomitantdeliriogenicmedicationsandkeymedicaletiologiesfordeliriumsuchasorganinsufficiencywithseverityofdeliriuminCOVID-19patients.PatientswithCOVID-19shouldbeassessedfordeliriumseverity.GrupodeInvestigaciónenPsiquiatríadeEnlace,FacultaddeMedicina,UniversidadPontificiaBolivariana,Medellín,Colombia(Velásquez-Tirado,Franco);ClinicaUniversitariaBolivariana,Medellín,Colombia(Velásquez-Tirado);andtheDepartmentofPsychiatry,IndianaUniversitySchoolofMedicine,Indianapolis(Trzepacz)SendcorrespondencetoDr.Franco([email protected]).Dr.TrzepaczholdsthecopyrightfortheDeliriumEtiologyChecklist,andDrs.TrzepaczandFrancoareco-ownersofthecopyrightfortheDeliriumDiagnosticTool–Provisional.Dr.Velásquez-Tiradoreportsnofinancialrelationshipswithcommercialinterests.References1.RoodP,Huisman-deWaalG,VermeulenH,etal.:Effectoforganisationalfactorsonthevariationinincidenceofdeliriuminintensivecareunitpatients:Asystematicreviewandmeta-regressionanalysis.AustCritCare2018;31:180–187Crossref,Medline, GoogleScholar2.DugganMC,VanJ,ElyEW:Deliriumassessmentincriticallyillolderadults:considerationsduringtheCOVID-19pandemic.CritCareClin2021;37:175–190Crossref,Medline, GoogleScholar3.SawlaniV,ScottonS,NaderK,etal.:COVID-19-relatedintracranialimagingfindings:alargesingle-centreexperience.ClinRadiol2020;S0009-9260(20)30392-5(inpress)doi:10.1016/j.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FiguresReferencesCitedbyDetailsCitedByDeliriumSeverelyWorsensOutcomeinPatientswithCOVID-19—ARetrospectiveCohortStudyfromTemporaryCriticalCareHospitals2July2021|JournalofClinicalMedicine,Vol.10,No.13 Volume33Issue3 Summer2021Pages210-218 Metrics KeywordsDeliriumCOVID-19PsychiatricStatusRatingScalesSeverityofIllnessIndex History Received7October2020 Revised9December2020 Accepted11December2020 Publishedonline12April2021 Publishedinprint1July2021 CloseFigureViewerBrowseAllFiguresReturntoFigureChangezoomlevelZoominZoomoutPreviousFigureNextFigureCaption