delirium in the cancer patient - Department of Pain Medicine and ...

Delirium in Advanced Cancer• Delirium is under-recognized and under-treated.• One of the barriers to adequate clinical intervention indelirium is the lack of appreciation for the distressexperienced by patients with delirium , as well as theimpact of delirium on spouses/caregivers and staff.• We suspect that patients with hypoactive delirium areperceived to be in less distress than agitated patientswith hyperactive delirium.

DSM-IV Criteria for DeliriumA. Disturbance of consciousness (i.e., disturbanceof awareness of the environment) with reduced abilityto focus, sustain or shift attentionB. Change in cognition (such as memory deficit,disorientation, language disturbance, perceptualdisturbance) that is not better accounted for by a preexisting,established or evolving dementia

DSM-IV Criteria for Delirium (Con’t)C. The disturbance evolves over a short period of time(usually hours to days) and tends to fluctuate during thecourse of the dayD. There is evidence from the history, physicalexamination,or laboratory findings of a general medicalcondition judged to be etiologically related to thedisturbance

Subtypes of DeliriumDelirium is a disturbance of arousaland cognition.Subtypes of delirium are based on the type of arousaldisturbance:HyperactiveHypoactiveMixed

Hypoactive Delirium: Controversies andBarriers to Treatment• Hypoactive Delirium is thought to be very rare, but in factaccounts for an average of 50% of delirium cases• Hypoactive Delirium is thought not to cause morbidity andtherefore does not require pharmacologic intervention.• Hypoactive Delirium, because of its phenomenologicdifferences with Hyperactive Delirium, is thought not torespond to pharmacologic interventions with neuroleptics

Objectives• To describe the experience of delirium in hospitalizedcancer patients.• To examine the level of distress related to the deliriumexperience in cancer patients, their spouses/caregivers,and nurses.• To examine the relationships among delirium-relateddistress, delirium phenomenology, etiology,demographic and medical variables.

Delirium Experience Questionnaire• Do you remember being confused? Yes__ No__• If no, are you distressed that you can’t remember? Yes_ No_• How distressed? 0-4 numerical rating scale (NRS)• If yes, was the experience distressing? Yes__ No__• How distressing? 0-4 NRS• Can you describe the experience?• Spouse /Caregiver: How distressed were you during the patient’sdelirium? 0-4 NRS• Nurse: Your patient was confused. Did you find it distressing?0-4 NRS• 0-4NRS: 0: not at all, 4: extremely

Sample Characteristics (n= 101)• Mean Age: 58.36 years (SD= 16.6)• Gender: Males= 52; Females= 49• Race: White= 67%; Black= 21%; Hispanic= 9%;Other=3%• Cancer Diagnoses: Lung-21%, GI-14%,Lymphoma-13%Breast-11%, Head and Neck-6%, Ovarian-4%, Brain-3%,Other cancers- 28%• Stage: Localized=16%, Metastatic=79%, Terminal=5%• Brain Metastases: 24%; History of Dementia: 18%• Karnofsky: Mean= 35.5 (SD=7.7)

Sample Characteristics (n= 101)• Memorial Delirium Assessment Scale (MDAS):Mean MDAS = 19 (SD 3.2), range 14-30• Delirium Subtypes: Hypoactive= 53%; Hyperactive=47%• Delirium Etiologies:Multiple causes= 74%; Single cause= 26%• Delirium Etiologies encountered:Opioids-65%, infection-39% steroids-30%,hypoxia-26%, dehydration-12%, CNS-12%,Other-13%

Results• 53.5% of patients (N=54) who recovered from deliriumremember being delirious.• 93% of patients who remember being delirious report theexperience as being “distressing”.• Mean level of patient distress (0-4 NRS)= 3.22 (SD=.86)• Mean level of Spouse/Caregiver distress= 3.75 (SD=.47)• Mean level of Nurse distress= 3.09 (SD=.77)

Percentage of Patients with Delirium RecallBased Upon Delirium Severity .10090807060504030201001005516Severe Moderate Mild% of Patientswith DeliriumRecall

Logistic Regression Analysis of Predictors ofPatient, Spouse/Caregiver, and Nurse DistressVariable P ORPatient DistressDelusions .05 7.9Spouse/Caregiver DistressKarnofsky (KPS) .003 9.1Nurse DistressMDAS Total Score .01 5.2Perceptual disturbances .04 3.6OR = Odds Ratio

Distress in Hyperactive vs HypoactiveDelirium• There were no significant differences in the reportof distress for patients, or nurses based on subtypeof delirium. Spouses/caregivers were moredistressed by hypoactive delirium.• Hypoactive delirium was equally as distressing asHyperactive delirium for patients, nurses.

Summary: Delirium Experience• Delirium is a highly distressing experience for patients,spouses/ caregivers and nurses• Delirium is especially distressing when delirium is moresevere and is characterized by the presence of delusionsand hallucinations• Hypoactive delirium is as distressing as hyperactivedelirium• Delirium is important to treat because it is associatedwith significant suffering not only in patients, but also inspouses/caregivers and staff

Delirium Assessment MethodsDiagnostic classification systemsDSM-III, DSM-III-R, DSM-IVICD-9, ICD-10Diagnostic interview instrumentsDelirium symptom interview (DS)Confusion Assessment Method (CAM)Delirium rating scalesDelirium Rating Scale (DRS)Confusion Rating Scale (CRS)Memorial Delirium Assessment Scale (MDAS)Cognitive impairment screening scalesMini-Mental State Exam (MMSE)Short Portable Mental Status Questionnaire (SPMSQ)Cognitive Capacity Screening Examination Test (BOMC)

Memorial Delirium Assessment Scale (MDAS)• REDUCED LEVEL OF CONSCIOUSNESS (AWARENESS)• DISORIENTATION• SHORT-TERM MEMORY IMPAIRMENT• IMPAIRED DIGIT SPAN• REDUCED ABILITY TO MAINTAIN AND SHIFT ATTENTION• DISORGANIZED THINKING• PERCEPTUAL DISTURBANCE• DELUSIONS• DECREASED OR INCREASED PSYCHOMOTOR• SLEEP-WAKE CYCLE DISTURBANCE (DISORDER OF AROUSALBreitbart, et al, JPSM, 1996

Validation of the Memorial DeliriumAssessment Scale in the Terminally Ill• The MDAS is a 10 item delirium severity and diagnosticinstrument designed for repeated assessment and treatmentevaluation• Two validation studies have been conducted to date using largesamples of hospitalized cancer and AIDS patients as well as cancerpatients admitted to a palliative care unit• The MDAS is highly correlated with other diagnostic measures ofdelirium (e.g. the DRS) and cognition (e.g. the MMSE)• Diagnostic cut-off scores of 13/30 in hospitalized cancer patients,and 7/30 in PCU patients have been suggested• Prorating item scores is necessary in up to 20% of patientsBreitbart,W, et al 1996; Lawlor, P, et al 2000

Overview of Delirium ManagementDELIRIUM TREATMENT OUTCOMEPreTerminalDeliriumTerminalDeliriumAimed atreversingetiologyAimed atcontrollingsymptomatologyDelirium isreversibleDeliriumis irreversible

Assessment of Etiologies of Deliriumin Advanced Cancer Patients• Unclear or never discovered in over 50% of patients• Three or more etiologies usually present• Irreversible 30-40% of the time, especially in theterminally ill• Etiology found in 40% - 50% of cases– 30% - 70% improve with treatment of etiology

Assessment of Etiologies of Deliriumin the Advanced Cancer Patient (cont’d)• Diagnostic work-up must be consistent with the goalsof care—minimally invasive in the terminally ill—treatments are effective and/or minimallyburdensome or distressing

Causes of Delirium in Advanced CancerDirectPrimary brain tumorMetastatic spreadIndirectHypoxiaMetabolic encephalopathy due to organ failureElectrolyte imbalanceWithdrawal states

Causes of Delirium in Cancer Patients (cont’d)Indirect (cont’d)Treatment side effects fromChemotherapeutic agents, steroids,biological response modifiersRadiationOpioidsAnticholinergicsAntiemeticsInfectionHematologic abnormalitiesNutritional deficienciesParaneoplastic syndromes

Non-Pharmacological Interventions forDelirium in the Advanced Cancer Patient1. Provide safe and supportive environment for patient,staff, and family2. Reassure family of the medical nature of deliriumTheir family member is not “having a nervousbreakdown”3. Depending on stage of disease, either reassurefamily of transient nature of delirium or describe as ahallmark of approaching death

Non-Pharmacological Interventions forDelirium in Advanced Cancer (cont’d)4. Provide proper sensory environment for patient— quiet, well-lit room— visible clock, calendar— familiar people, objects5. Communicate with patient and family— goals of care and desirable outcomes, i.e.,sedation vs. awake but agitated— regarding hallucinations and their management ormeaning

Pharmacological Management of DeliriumApproximate dailyGeneric Name dosage range (mg) RouteNeurolepticsHaloperidol 0.5-5 q2-12h PO, IV, SC, IMThioridazine 10-75 q4-8h POChlorpromazine 12.5-50 q4-12h PO, IV, IMMethotrimeprazine 12.5-50 q4-8h IV, SC, PODroperidol 0.5-5 q12h IM, IVMolindone 10-50 q8-12h PO

Pharmacological Management of DeliriumApproximate dailyGeneric Name dosage range (mg) RouteAtypical AntipsychoticsRisperidone 1-3 q12h POOlanzapine 2.5-5 q12h PO/IMQuetiapine 25-150 q12h POZiprasidone 20-80 q12h PO/IMAripiprazolee 10-15 qd PO

Side Effects of Neuroleptics/AntipsychoticsAnticholinergicDry MouthConstipationCardiovascular (BP, QT interval)AntihistaminicSedation, Weight GainDopamine BlocadeExtrapyramidal Side EffectsHyperprolctinemiaNeuroleptic Malignant Syndrome

Side Effects of Atypical AntipsychoticsMetabolic SyndromeHyperglycemiaHyperlipidemiaWeight GainOlanzapine and Clozapinehave highest incidenceQT Interval ProlongationTorsade des PointesQTc prolongation beyond 500msecECG should be monitored daily during delirium RXConsider interactions with other agents that prolong QT

Side Effects of Haloperidol vs.Risperidone vs. OlanzapineSide Effect Haloperidol Risperidone OlanzapineEPS >30% >10% >2%ACHE >2% >2% >10%Sedation >2% >10% >30%Hypotension >2% >30% >2%Seizure >2% >2% >2%Bezchlibnyk-Butler & Jeffries, 1999

Neurotransmitter/Receptor Effectsof Antipsychoticsα15HT2Aα1α25HT2AM1 H1α1haloperidolrisperidone5HT2C5HT3olanzapineD1D25HT7D25HT6D4D3D2

Clinical Trials of Delirium ManagementA double-blind, randomized trial of Haloperidol vs.Chlorpromazine vs. Lorazepam in the treatment of delirium inmedically hospitalized AIDS patients with AIDS-relatedcancers (N=244 screened, 30 on trial.)Results:• Both Haloperidol and Chlorpromazine were effective inrapidly resolving the symptoms of delirium utilizing lowdosage regimens• Lorazepam alone was ineffective• No clinically significant side effects• Both hypoactive and hyperactive delirium responded toneurolepticsBreitbart et al Am J Psy 1996

AIDS Delirium StudyDose Haloperidol Chlorpromazine Lorazepam1 0.25 mg 10 mg 0.5 mg2 0.5 mg 20 mg 1.0 mg3 1.0 mg 40 mg 1.5 mg4 2.0 mg 80 mg 2.0 mg5 2.5 mg 100 mg 2.5 mg6 2.5 mg 100 mg 2.5 mg7 2.5 mg 100 mg 2.5 mg8 5.0 mg 200 mg 4.0 mg9 5.0 mg 200 mg 4.0 mgMax 21.25 mg 850 mg 20.5 mgAll doses PO; Dose IM = 1/2 PO

AIDS Delirium StudyDrug Dosages1st 24 hoursHaloperidolChlorpromazineLorazepammean dose 2.6 mgmedian dose 1.75 mgrange .75-6.25 mgmean dose 100 mgmedian dose 70 mgrange 30-257.5 mgmean dose 6.9 mgmedian dose 3.0 mgrange 0.5-20 mg

AIDS Delirium StudyDrug DosagesMaintenance Dose Days 2 - 7Haloperidolmean dose 1.6 mgmedian dose 1.0 mgrange 0.25 – 4.375 mgChlorpromazineLorazepammean dose 40 mgmedian dose 35 mgrange 15 – 175 mgmean dose 1.5 mgmedian dose 1.25 mgrange 1.25 – 2.0 mg

Neuroleptics for Hypoactive Delirium• Both Haloperidol and Chlorpromazine wereeffective in improving the symptoms ofdelirium (as measured by the DRS) for bothhyperactive (N=9), F=19.06, df=1.18,p

An Open Trial of Olanzapine for theTreatment of Delirium in HospitalizedCancer PatientsWilliam Breitbart,M.D.Annie Tremblay, M.D.Christopher Gibson, Ph.D.Memorial Sloan-Kettering Cancer Center

Efficacy of Olanzapine in the Treatment ofDeliriumMDAS Score20181614121086420Baseline Time 1 Time 2t (baseline-Time3) = 10.1, p < .001

Results- Olanzapine Efficacy• Two MDAS cut-off scores were utilized to definedelirium resolution:MDAS below 13 at T3:78.7% improved on olanzapineMDAS below 10 at T3:73.3% improved on olanzapine

Logistic Regression Analysis of Predictors toOlanzapine TreatmentVariable P ORAge: .001 171.5CNS Spread .005 74.9Subtype of Delirium .01 11.3Hypoxia .09 5.9History of Dementia .40 0.34Delirium Severity .1 5.03OR = Odds Ratio

Effect of Age on Olanzapine ResponsePercent ofPatients w/MDAS < 10100%90%80%70%60%50%40%30%20%10%0%Under 50 51-60 61-70 Over 70X 2 = 22.8p < .001

Efficacy of Olanzapine in Hypoactive andHyperactive DeliriumMDAS Score20181614121086420Baseline Time 1 Time 2HypoactiveHyperactiveF= 9.51p < .003

Olanzapine Dosage• Mean olanzapine dosage:Baseline :T2 (day2-3):T3 (day4-7):3.0 mgs (SD=0.14)range = 2.5 to 10 mgs4.6 mgs (SD=0.27)range = 2.5 to 15 mgs6.3 mgs (SD=0.52)range = 2.5 to 20 mgs

Olanzapine Side Effects• Olanzapine side effects were common but rarelyinterfered with treatment or worsened delirium:Side Effect T2% T3%Sedation 29% 29%EPS 0% 0%Delirium 1.2% 1.2%Other 3.7% ----

Clinical Trial of Risperidone for DeliriumA double-blind, randomized trial of Risperidone vs. Haloperidalin the treatment of delirium in 24 medically hospitalizedcancer patients:Results:• Both Risperidone and Haloperidol were equally effective inresolving the symptoms of delirium utilizing low dosageregimens• No significant difference in side effects• Analysis and reporting of response rates, dosage regimens andside effects is insufficient, thus limiting the value of this trialHan and Kim, Psychosomatics, 2004

Pharmacological Management of DeliriumApproximate dailyGeneric Name dosage range (mg) RouteNeurolepticsHaloperidol 0.5-5 q2-12h PO, IV, SC, IMThioridazine 10-75 q4-8h POChlorpromazine 12.5-50 q4-12h PO, IV, IMMethotrimeprazine 12.5-50 q4-8h IV, SC, PODroperidol 0.5-5 q12h IM, IVMolindone 10-50 q8-12h PONovel AntipsychoticsRisperidone 1-3 q12h POOlanzapine 2.5-5 q12h PO/IM

Pharmacological Managementof Delirium (cont’d)Approximate dailyGeneric Name dosage range (mg) RouteBenzodiazepinesLorazepam 0.5-2.0 q1-4h PO, IV, IMMidazolam 30-100 per 24h IV, SCAnestheticsPropofol 10-50 q1h IV

Pharmacological Management of Delirium SymptomsDeliriumDiagnosedIdentifyand TreatEtiologyAssess safetyand assuresafeenvironmentHyperactive agitated deliriumAdd lorazepam0.5-2mg IV q4h forincreased sedationHaloperidol IV/PO 2-10mg q4-12h& prn for agitationAdd benztropine0.5-1mg IV (po tid) for EPSSwitch tochlorpromazine25-50mg IV q4-12hfor increased sedationAdjust dosage for optimal controlof symptomsContinue indefinitelyor until etiology is reversedand taper off slowlySwitch to olanzapine ifregimen not tolerated or if EPSis an issue

Pharmacological Management of Delirium SymptomsDeliriumDiagnosedIdentifyand TreatEtiologyHypoactive DeliriumHaloperidol PO/IV0.5-6 mg q4-12h& prn for hallucinations/agitationAdd benztropine0.5-1mg IV (po tid) for EPSAssess safetyand assuresafeenvironmentReduce doseif sedatedContinue indefinitelyor until etiology is reversedand taper off slowlyUse olanzapine2.5-5mg PO bidif EPS is anincreasing concern

Conclusions• Delirium is a common neuropsychiatriccomplication in terminal cancer• Psychiatrists must be familiar with the properassessment, diagnosis, and management of delirium• Appropriate management of delirium is important tominimize morbidity and improve quality of care

THE HANDBOOK OFPSYCHIATRY IN PALLIATIVEMEDICINEEdited byHarvey M. Chochinovand William BreitbartTo order:The Handbook of Psychiatry in Palliative MedicinePlease contact:Order Department, Oxford University Press2001 Evans RoadCary, NC 27513Tel: 1-800-451-7556; Fax: 1-919-677-1303Website: http://www.oup-usa.org/$75.00, ISBN: 0195092996

New JournalPalliative & Supportive CareWilliam Breitbart, M.D.Editor-in-ChiefMemorial Sloan-Kettering Cancer CenterNew York, NYEmail: Breitbaw@mskcc.orgFor Information: email: palliative@mskcc.orgSubscriptions:email:journals_subscriptions@cup.org