Delirium in Palliative Care

International Palliative Care NetworkLecture Series 2012 Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012

International Palliative Care Network Lecture Series 2012

Delirium in Palliative Care Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


William Breitbart, M.D.Memorial Sloan-Kettering Cancer Center Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


About the PresenterWilliam Breitbart, M.D. is Chief of the Psychiatry Service, Interim Chairman, and Attending Psychiatrist, Department of Psychiatry & Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY. Dr. Breitbart is also Attending Psychiatrist, Pain & Palliative Care Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center. Dr. Breitbart is board-certified in Internal Medicine, Psychiatry, and Psychosomatic Medicine. He was President of the Academy of Psychosomatic Medicine in 2007, and Immediate Past President of the International Psycho-oncology Society. Dr. Breitbart's research efforts have focused on psychiatric aspects of cancer and palliative care. Dr Breitbart received the 2003 Research Award from the Academy of Psychosomatic Medicine, and the 2007 Donald Oken Award from the American Psychosomatics Society. He is the 2009 recipient of the Arthur Sutherland Lifetime Achievement Award for the International Psycho-oncology Society. In 2011, Dr Breitbart was the recipient of the Thomas P. Hackett Award for Lifetime Achievement from the Academy of Psychosomatic Medicine. Dr Breitbart has edited 8 major textbooks on Psycho-oncology and psychiatric palliative care. He is Editor-in-Chief of the international palliative care journal Palliative &Supportive Care. Published by Cambridge University Press

Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Conflict of Interest or Funding SourceWith respect to the following presentation, there has been no relevant (direct or indirect) financial relationship between the party listed above (and/or spouse/partner) and any for-profit company in the past 24 months which could be considered a conflict of interest.The following lecture contains content on the use of medications that have not been approved by the US Food and Drug Administration for the treatment of Delirium or Depression



Delirium in Advanced CancerHighly Prevalent: ranges from 15% - 30% in hospitalized patients. 40% - 80% in advanced disease, palliative careAssociated with increased morbidity/distress/mortality in patients, family, staff ; increased risk of self harm, harm to staff, and mortality- a harbinger of deathInterferes with symptom assessment and controlUntreated Delirium can progress into dementia or worsen pre-morbid cognitive disorders Pathophysiology of delirium supports the role of psychopharmacologic management (e.g. dopamine blockers) Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Under-recognition and treatment of Delirium Delirium is under-recognized and under-treated.One of the barriers to adequate clinical intervention in delirium is the lack of appreciation for the distress experienced by patients with delirium , as well as the impact of delirium on spouses/caregivers and staff.Patients with hypoactive delirium are often misdiagnosed and /or perceived to be in less distress than agitated patients with hyperactive delirium. Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


DSM-IV Criteria for DeliriumA. Disturbance of consciousness (i.e., disturbance of awareness of the environment) with reduced ability to focus, sustain or shift attention

B. Change in cognition (such as memory deficit, disorientation, language disturbance, perceptual disturbance) that is not better accounted for by a pre-existing, established or evolving dementia



DSM-IV Criteria for Delirium (Cont)C. The disturbance evolves over a short period of time (usually hours to days) and tends to fluctuate during the course of the day

D. There is evidence from the history, physical examination, or laboratory findings of a general medical condition judged to be etiologically related to the disturbance Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Delirium Assessment MethodsDiagnostic classification systemsDSM-III, DSM-III-R, DSM-IV ICD-9, ICD-10

Diagnostic interview instrumentsDelirium symptom interview (DS)Confusion Assessment Method (CAM)- ICU & Peds versions

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) Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Subtypes of DeliriumDelirium is a disturbance of arousal and cognition.Subtypes of delirium are based on the type of motoric or arousal disturbance: Hyperactive Hypoactive Mixed Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Subtypes of DeliriumIn 12 studies, the prevalence of each of the subtypes of delirium has varied widelyA meta-analysis of these studies suggest the following average prevalence for each subtype:Hypoactive: 48% (ranges: 15-71%)Hyperactive: 24% (ranges: 13-46%)Mixed: 36% (ranges: 11-55%)



Hypoactive Delirium: Controversies and Barriers to Treatment- IHypoactive Delirium is thought to be very rare, but in fact accounts for an average of 50% of delirium cases Hypoactive Delirium is thought not to cause morbidity and therefore does not require pharmacologic intervention Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


The Delirium ExperienceDelirium is a highly distressing experience for patients, spouses/ caregivers and nursesDelirium is especially distressing when delirium is more severe and is characterized by the presence of delusions and hallucinationsHypoactive delirium is as distressing as hyperactive deliriumSymptoms of Delirium are important to treat with antipsychotics because of association with significant suffering in patients, spouses/caregivers and staff

Breitbart, et al, Psychosomatics, 2002 ; DiMartini, et al. 2007; Cohen et al, 2009 Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Hypoactive Delirium: Controversies and Barriers to Treatment- IIHypoactive Delirium, because of its phenomenologic differences with Hyperactive Delirium, is thought not to respond to pharmacologic interventions with neuroleptics - antipsychotics Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Phenomenologic Differences between Hypoactive and Hyperactive Delirium Hypoactive and Hyperactive Delirious patients have similar ages, delirium severity, and degree of cognitive impairmentEarly studies suggest Hyperactive Delirious patients are more likely to have Hallucinations (57% vs. 3%) and Delusions (50% vs. 3%) than patients with Hypoactive DeliriumRoss, et al. 1991 Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Differences in MDAS Items Between Hyperactive and Hypoactive Patients (n=101)Patients with hyperactive delirium had significantly higher incidence of delusions and hallucinations:

Delusions: Hyperactive- 78% (MDAS# 8) Hypoactive- 43%

Hallucinations: Hyperactive- 70% (MDAS# 7) Hypoactive-51%Boettger, Passik, Breitbart, Pall Supp Care, 2012 E pub ahead of print Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Overview of Delirium ManagementTerminalDeliriumDELIRIUM TREATMENT OUTCOMEAimed at Delirium isPreventing or reversibleReversing etiology

Aimed at Deliriumcontrolling is irreversiblesymptomatology Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Causes of Delirium in CancerDirectPrimary brain tumorMetastatic spread

IndirectHypoxiaMetabolic encephalopathy due to organ failureElectrolyte imbalanceWithdrawal states Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Causes of Delirium in Cancer Patients (contd)Indirect (contd)Treatment side effects fromChemotherapeutic agents, steroids, biological response modifiersRadiationOpioidsAnticholinergicsAntiemeticsInfectionHematologic abnormalitiesNutritional deficienciesParaneoplastic syndromes Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Assessment of Etiologies of Delirium in the Advanced Cancer Patient (contd)Diagnostic work-up must be consistent with the goals of care minimally invasive in the terminally ill treatments are effective and/or minimally burdensome or distressing Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Non-Pharmacological Prevention and Intervention Strategies for Delirium in Medical Settings Minimize Use of immobilizing catheters, IV lines, physical restraintsMonitor closely for dehydrationMonitor fluid and electrolyte balanceMonitor NutritionControl painMinimize medications facilitate sleep hygieneRe-orient frequentlyInouye S, NEJM 2000 Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Non-Pharmacological Multi-component Prevention Programs for Delirium in Medical Settings Use of Non-Pharmacologic interventions in the prevention of delirium can reduce incidence in non-terminally ill. They all include elimination of medications

These interventions can result in faster improvement of delirium and cognition but no change in mortality risk after delirium Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Pharmacological Prevention of Delirium Prophylactic use of pharmacologic agents in the prevention of delirium have had mixed results at best.Prophylactic neuroleptics do not prevent delirium in palliative care settings. Mixed results when used in prevention of post-op delirium.Dexmedetomidine use as anesthetic may lower post-op delirium significantly.

Breitbart & Alici, JAMA, 2008; JCO 2012; Maldonado J, Psychosomatics, 2009 Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Cochrane Review Recommendations on the Efficacy of Antipsychotics in DeliriumHaloperidol and selected atypical antipsychotics, such as, olanzapine and risperdal, are effective in managing the symptoms of delirium.The Cochrane Review found only 2 RCTs eligible to be included in a meta-analysisThe overall extrapyramidal side effects of the atypicals did not differ significantly from haloperidol when doses of haloperidol were less than 4.5mgs/dLonergan E, et al, Cochrane Database Syst Rev 2007 Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Pharmacological Management of Delirium Approximate daily Generic Name dosage range (mg) Route Neuroleptics Haloperidol 0.5-5 q2-12h PO, IV, SC, IM Thioridazine 10-75 q4-8h PO Chlorpromazine 12.5-50 q4-12h PO, IV, IM Methotrimeprazine 12.5-50 q4-8h IV, SC, PO Droperidol 0.5-5 q12h IM, IV Molindone 10-50 q8-12h PO



Pharmacological Management of Delirium Approximate daily Generic Name dosage range (mg) Route

Atypical Antipsychotics Risperidone 1-3 q12h PO Olanzapine 2.5-5 q12hPO/IM

Quetiapine25-150 q12hPO

Ziprasidone20-80 q12hPO/IM

Aripiprazolee10-15 qd PO Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Pharmacological Management of Delirium (contd) Approximate daily Generic Name dosage range (mg) RouteBenzodiazepines Lorazepam 0.5-2.0 q1-4h PO, IV, IM Midazolam 30-100 per 24h IV, SC Anesthetics Propofol 10-50 q1h IV



Randomized Clinical Trials of Delirium ManagementA double-blind, randomized trial of Haloperidol vs. Chlorpromazine vs. Lorazepam in the treatment of delirium in medically hospitalized AIDS patients with AIDS-related cancers (N=244 screened, 30 on trial)Results:Both Haloperidol and Chlorpromazine were effective in rapidly resolving the symptoms of delirium utilizing low dosage regimensLorazepam alone was ineffectiveNo clinically significant side effectsBoth hypoactive and hyperactive delirium responded to neurolepticsBreitbart et al Am J Psy 1996



Neuroleptics for Hypoactive DeliriumBoth Haloperidol and Chlorpromazine were effective in improving the symptoms of delirium (as measured by the DRS) for both hyperactive (N=9), F=19.06, df=1.18, p

RCT of Risperidone for DeliriumA double-blind, randomized trial of Risperidone vs. Haloperidal in the treatment of delirium in 24 medically hospitalized cancer patients:Results:Both Risperidone and Haloperidol were equally effective in resolving the symptoms of delirium utilizing low dosage regimensNo significant difference in side effectsAnalysis and reporting of response rates, dosage regimens and side effects is insufficient, thus limiting the value of this trial Han and Kim, Psychosomatics, 2004



RCT of Olanzapine vs Haloperidol vs Placebo for DeliriumDouble-blind RCT of hospitalized patients with delirium treated with olanzapine (n 75),intramuscular haloperidol(n 72), or placebo (n 29).7 days. The improvement in DRS scores was significantly higher in the olanzapine (72%) and haloperidol (70%) groups v placebo (29.7%; P .01). Increased rates of extrapyramidal symptoms were observed in the haloperidol group.Comparison of oral olanzapine and oral placebo with intramuscular haloperidol hinders the quality of double-blind study design. Hu et al Chongqing Med Journal, 2004



An Open Trial of Olanzapine for the Treatment of Delirium in Hospitalized Cancer Patients William Breitbart,M.D. Annie Tremblay, M.D.Christopher Gibson, Ph.D. Memorial Sloan-Kettering Cancer Center

Breitbart et al. Psychosomatics, 2002 Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Results- Olanzapine EfficacyTwo MDAS cut-off scores were utilized to define delirium resolution: MDAS below 13 at T3:78.7% improved on olanzapine MDAS below 10 at T3:73.3% improved on olanzapine Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Effect of Age on Olanzapine ResponseX2= 22.8p .001


Efficacy of Olanzapine in Hypoactive and Hyperactive DeliriumF= 9.51p .003


Olanzapine DosageMean olanzapine dosage:Baseline :3.0 mgs (SD=0.14) range = 2.5 to 10 mgsT2 (day2-3): 4.6 mgs (SD=0.27)range = 2.5 to 15 mgsT3 (day4-7): 6.3 mgs (SD=0.52)range = 2.5 to 20 mgs Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Olanzapine Side EffectsOlanzapine side effects were common but rarely interfered with treatment or worsened delirium:Side EffectT2%T3%Sedation29%29%EPS 0% 0%Delirium1.2%1.2%Other3.7%----



Open-label Trials of Olanzapine for Delirium3 Other Open label trials of Olanzapine have been published in the literature using DRS, or the DISipahimalani & Masand (1998)- 11 patients, 90% improved, average dose-8.2mgs/dayKim, et al (2001)- 20 patients, 70% improved, average dose-5.8mgs/day, 5% got worseSkrobik, et al (2004)- 28 patients, DI significantly improved, average dose-4.5mgs/day



Open-label Trials of Risperidone for Delirium3 Open label trials of Risperidone have been published in the literature using DRSHorikawa, et al (2003)- 10 patients, 80% improved average dose- 1.7mgs/dayMittal, et al (2004)- 10 patients, 80% improved, mean starting dose-1.35, maintenance dose-0.75mgParellada, et al (2004)- 64 patients, 91% improved, average dose-2.6mgs/day



Open-label Trials of Quetiapine for Delirium3 Open label trials of Quetiapine have been published in the literature using DRS. Disadvantages noted included: need for titration, sedation, hypotensionKim et al (2003)- 12 patients, 25mgs po bid starting dose, titration-25mgs e.o.d, average dose- 94 mgs/day. Mean DRS dropped from 18.25 to 8Sasaki, et al (2003)- 12 patients, avg dose 45mgs/d mean DRS dropped from 18.1to 9.3Pae, et al (2004)- 22 patients mean dose-127mg/day 86% marked improvement, DRS- 21.8 to 9.3



Open-label Trials of Aripiprazole for DeliriumProspective, case-matched control comparison trial of patients with cancer who had delirium and were treated with aripiprazole (n 21) v haloperidol (n 21).Mean aripiprazole dose was 15.2 mg at study entry and18.3 mg at the end. Mean haloperidol dose was 4.9 mg at study entry and 5.5mg at the end.The delirium resolution rate was 76.2% for aripiprazole and 76.2% for haloperidol.Aripiprazole appears to be somewhat more efficacious in the treatment of hypoactive delirium Boettger S, Friedlander M, Breitbart W, et al Aust N Z J Psychiatry 2011 Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


RCTs of Antipsychotics for Delirium in ICUs4 Double or single blind RCTS of Atypical antipsychotics in ICU or post-operative settings.Girard et al (2010)- haloperidol vs ziprasidone in ICU. Bothe effective for delirium, no differences in adverse effectsDevlin , et al (2010)- quetiapine plus prn haloperidol vs placebo, demonstrated benefit, but more somnolenceTahir, et al (2010)- quetiapine vs placebo. Quetiapine group responded 82% faster. No differences in adverse effects.Grover, et al (2011)- single blind, haloperidol vs risperidone, vs olanzapine. All improved delirium, no differences between drugs



Side Effects of Neuroleptics/AntipsychoticsAnticholinergicDry Mouth ConstipationCardiovascular (BP, QT interval)AntihistaminicSedation, Weight GainDopamine BlocadeExtrapyramidal Side Effects HyperprolctinemiaNeuroleptic Malignant Syndrome Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Side Effects of Atypical AntipsychoticsMetabolic SyndromeHyperglycemiaOlanzapine and ClozapineHyperlipidemiahave highest incidenceWeight Gain

QT Interval Prolongation Torsade des PointesQTc prolongation beyond 500msecECG should be monitored daily during delirium RXConsider interactions with other agents that prolong QT Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


FDA Black Box Warning on Atypical Antipsychotics Atypical antipsychotic drugs , pre- 2005,carry warnings for : increased risk of stroke or CV events; increased risk of death from stroke; Prolonged QTc interval with risk of fatal cardiac arrhythmias; Association with hyperglycemia and onset of diabetes, ketoacidosis, coma and deathIn 2005 FDA added warning of: increased risk of death related to their use in managing psychosis or behavioral problems in elderly patients with dementia.A review of 17 trials, 5,106 patients; 1.6 fold increase in mortality Schneider, et al JAMA 2005



FDA Black Box Warning on Typicals ( e.g. Haldol) Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Cochrane Review Recommendations on the Efficacy and Safety of Antipsychotics in Delirium Despite the risks associated with antipsychotic drugs there is insufficient evidence to suggest that psychotropics other than antipsychotics represent an effective, safer, or better treatment choice for psychosis or agitation in dementia (or delirium).Lonergan E, et al, Cochrane Database Syst Rev 2007 Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Summary: Safety of Short Term Use of Antipsychotics

A retrospective, exploratory, secondary analysis of the association between antipsychotic use and mortality in elderly patients with delirium. Elie M, Boss K, Cole MG, McCusker J, Belzile E, Ciampi A.

Int Psychogeriatr. 2009 Jun;21(3):588-92. Epub 2009 Apr 16.326 elderly hospitalized patients were identified with delirium at an acute care community hospital. In elderly medical inpatients with delirium, administration of APs was not associated with a statistically significant increased risk of mortality Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Short-Term Use of Atypical Antipsychotics in the Medically Ill: Assessment of Adverse Metabolic Effects and QTc ProlongationYesne Alici-Evcimen, MD*, Chris Nelson, PhD**, William Breitbart, MD **

*University of Pennsylvania, Department of Psychiatry, Section on Geriatric Psychiatry**Memorial Sloan-Kettering Cancer Center, Department of Psychiatry and Behavioral Sciences8PSYCHOSOMATICS, in Press Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Summary: Safety of Short Term Use of Antipsychotics In a sample of 115 cancer patients with delirium treated with Atypical Antipsychotics: primarily Olanzapine, mean age 63.3yrs (range 19-91); women 55%; CCI 7.53.2 (range 0-14); Mean duration of use 8.6 days ( range of 2 - 30 days)No significant change in fasting blood sugar, body weight for any atypical or for olanzapine specificallyNo significant change in QTc interval between baseline and end of treatment within 30 days



Evidence Based Recommendations on Delirium Management in Cancer I - Breitbart & Alici, JCO 2012 Current evidence is supportive of short-term use of antipsychotics inthe treatment of symptoms of delirium with close monitoring forpossible adverse effects especially in elderly patients with multiplemedical comorbidities.

The longest clinical and research experience and safety/efficacy dataavailable is for haloperidol. Low-dose haloperidol is still considered the gold standard in treatment of delirium. There is growing evidence for the efficacy of atypical antipsychotics in the management of delirium as well. The choice of antipsychotic medication for the treatment of delirium should be based on the clinical presentation of the patient and the adverse effect profile of each antipsychotic drug, given that none of the antipsychotics were found to be superior to others in comparison trials Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


Evidence Based Recommendations on Delirium Management in Cancer II - Breitbart & Alici, JCO 2012 II. It is strongly recommended to implement nonpharmacologic interventions in the routine care of patients who are at risk for delirium and of patients with established delirium, based on the evidence from non-oncology settings. There are no known risks associated with the use of nonpharmacologic interventions.III. There is no evidence to support the use of cholinesterase inhibitorsin treatment or prevention of delirium in patients with cancer.IV. Psychostimulants cannot currently be recommended in the treatment of patients with cancer with delirium.V. Current evidence is not supportive of the use of antipsychotics forthe prevention of delirium in patients with cancer.VI. The evidence supporting the use of intravenous dexmedetomidinefor the prevention of delirium has been mixed and is limited to patientsin intensive care settings only; there is currently no evidence tosupport its use in patients with cancer as a treatment for delirium. Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


ConclusionsPalliative Care practitioners must be familiar with the proper assessment, diagnosis, and management of delirium. Despite the risks associated with antipsychotic drugs there is insufficient evidence to suggest that psychotropics other than antipsychotics represent an effective, safer, or better treatment choice for controlling the symptoms of delirium while the underlying etiologies are identified and treated.Antipsychotic use in delirium is generally time limited and brief . New evidence suggests low incidence of many adverse effects when use is limited to 30 days or lessMonitoring QTc interval and EPS is necessaryNon-pharmacologic interventions should be optimized



AcknowledgementsDr. Breitbarts research work has been supported over the last 25 years by grants from the National Cancer Institute, the National Institute of Mental Health, the National Institute of Nursing Research, the National Center for Complementary and Alternative Medicine, Project on Death in America-Open Society Institute, the Fetzer Foundation, the Kohlberg Foundation, the Kornfeld Foundation, and the American Cancer Society Palliative Care NetworkInternational Palliative Care Network Lecture Series 2012


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