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International Palliative Care Network Lecture Series 2012

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International Palliative Care Network Lecture Series 2012

Delirium in Palliative Care

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International Palliative Care Network Lecture Series 2012

William Breitbart, M.D.


Memorial Sloan-Kettering Cancer Center

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International Palliative Care Network Lecture Series 2012

About the Presenter


William 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
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Conflict of Interest or Funding Source


With 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 forprofit 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

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International Palliative Care Network Lecture Series 2012

Delirium in Advanced Cancer


Highly Prevalent: ranges from 15% - 30% in hospitalized
patients. 40% - 80% in advanced disease, palliative care

Associated with increased morbidity/distress/mortality


in patients, family, staff ; increased risk of self harm, harm to staff, and mortality- a harbinger of death

Interferes with symptom assessment and control Untreated Delirium can progress into dementia or worsen
pre-morbid cognitive disorders

Pathophysiology of delirium supports the role of


psychopharmacologic management (e.g. dopamine blockers)
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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.
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International Palliative Care Network Lecture Series 2012

DSM-IV Criteria for Delirium


A. 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
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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
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Delirium Assessment Methods


Diagnostic classification systems DSM-III, DSM-III-R, DSM-IV ICD-9, ICD-10 Diagnostic interview instruments Delirium symptom interview (DS) Confusion Assessment Method (CAM)- ICU & Peds versions Delirium rating scales Delirium Rating Scale (DRS) Confusion Rating Scale (CRS) Memorial Delirium Assessment Scale (MDAS) Cognitive impairment screening scales Mini-Mental State Exam (MMSE) Short Portable Mental Status Questionnaire (SPMSQ) Cognitive Capacity Screening Examination Test (BOMC)
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Subtypes of Delirium
Delirium is a disturbance of arousal and cognition.
Subtypes of delirium are based on the type of motoric or arousal disturbance: Hyperactive

Hypoactive
Mixed
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Subtypes of Delirium
In 12 studies, the prevalence of each of the subtypes of delirium has varied widely A 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%)
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Hypoactive Delirium: Controversies and Barriers to Treatment- I


Hypoactive 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
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Breitbart, et al, Psychosomatics, 2002 ; DiMartini, et al. 2007; Cohen et al, 2009

The Delirium Experience


Delirium is a highly distressing experience for patients, spouses/ caregivers and nurses Delirium is especially distressing when delirium is more severe and is characterized by the presence of delusions and hallucinations Hypoactive delirium is as distressing as hyperactive delirium Symptoms of Delirium are important to treat with antipsychotics because of association with significant suffering in patients, spouses/caregivers and staff
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Hypoactive Delirium: Controversies and Barriers to Treatment- II


Hypoactive Delirium, because of its phenomenologic
differences with Hyperactive Delirium, is thought not to respond to pharmacologic interventions with neuroleptics - antipsychotics

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Phenomenologic Differences between Hypoactive and Hyperactive Delirium


Hypoactive and Hyperactive Delirious patients have
similar ages, delirium severity, and degree of cognitive impairment

Early studies suggest Hyperactive Delirious patients are


more likely to have Hallucinations (57% vs. 3%) and Delusions (50% vs. 3%) than patients with Hypoactive Delirium Ross, et al. 1991
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Differences in MDAS Items Between Hyperactive and Hypoactive Patients (n=101)


Patients with hyperactive delirium had significantly higher incidence of delusions and hallucinations: Delusions: (MDAS# 8) HyperactiveHypoactive78% 43%

Hallucinations: (MDAS# 7)
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HyperactiveHypoactiveInternational Palliative Care Network Lecture Series 2012

70% 51%

Boettger, Passik, Breitbart, Pall Supp Care, 2012 E pub ahead of print

Overview of Delirium Management


DELIRIUM TREATMENT OUTCOME

Pre Terminal Delirium

Aimed at Preventing or Reversing etiology

Delirium is reversible

Terminal Delirium

Aimed at controlling symptomatology

Delirium is irreversible

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Causes of Delirium in Cancer


Direct Primary brain tumor Metastatic spread Indirect Hypoxia Metabolic encephalopathy due to organ failure Electrolyte imbalance Withdrawal states
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Causes of Delirium in Cancer Patients


(contd)

Indirect (contd) Treatment side effects from Chemotherapeutic agents, steroids, biological response modifiers Radiation Opioids Anticholinergics Antiemetics Infection Hematologic abnormalities Nutritional deficiencies Paraneoplastic syndromes
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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

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Non-Pharmacological Prevention and Intervention Strategies for Delirium in Medical Settings

Minimize Use of immobilizing catheters, IV lines, physical restraints Monitor closely for dehydration Monitor fluid and electrolyte balance Monitor Nutrition Control pain Minimize medications facilitate sleep hygiene Re-orient frequently Inouye S, NEJM 2000
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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
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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
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Cochrane Review Recommendations on the Efficacy of Antipsychotics in Delirium


Haloperidol 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-analysis The overall extrapyramidal side effects of the atypicals did not differ significantly from haloperidol when doses of haloperidol were less than 4.5mgs/d
Lonergan E, et al, Cochrane Database Syst Rev 2007
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Pharmacological Management of Delirium


Generic Name Neuroleptics Haloperidol Thioridazine Chlorpromazine Methotrimeprazine Droperidol Molindone Approximate daily dosage range (mg) Route

0.5-5 q2-12h 10-75 q4-8h 12.5-50 q4-12h 12.5-50 q4-8h 0.5-5 q12h 10-50 q8-12h

PO, IV, SC, IM PO PO, IV, IM IV, SC, PO IM, IV PO

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Pharmacological Management of Delirium


Generic Name Atypical Antipsychotics Risperidone Olanzapine 1-3 q12h 2.5-5 q12h PO PO/IM Approximate daily dosage range (mg) Route

Quetiapine
Ziprasidone Aripiprazolee

25-150 q12h
20-80 q12h 10-15 qd

PO
PO/IM PO

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Pharmacological Management of Delirium (contd)


Generic Name Benzodiazepines Lorazepam Midazolam Anesthetics Propofol Approximate daily dosage range (mg) 0.5-2.0 q1-4h 30-100 per 24h Route PO, IV, IM IV, SC

10-50 q1h

IV

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Randomized Clinical Trials of Delirium Management


A 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 regimens Lorazepam alone was ineffective No clinically significant side effects Both hypoactive and hyperactive delirium responded to neuroleptics Breitbart et al Am J Psy 1996
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Neuroleptics for Hypoactive Delirium


Both 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<0.001, as well as hypoactive delirium(N=11), F=21.15, df=1.18, p<0.001
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RCT of Risperidone for Delirium


A 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 regimens No significant difference in side effects Analysis and reporting of response rates, dosage regimens and side effects is insufficient, thus limiting the value of this trial Han and Kim, Psychosomatics, 2004
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RCT of Olanzapine vs Haloperidol vs Placebo for Delirium


Double-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
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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


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Results- Olanzapine Efficacy


Two 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

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Effect of Age on Olanzapine Response


100% 90% 80% 70% Percent of 60% Patients w/ 50% MDAS < 10 40% 30% 20% 10% 0%

Under 50

51-60

61-70

Over 70
X2= 22.8 p .001

Efficacy of Olanzapine in Hypoactive and Hyperactive Delirium


20 18 16 14 12 MDAS Score 10 8 6 4 2 0

Hypoactive Hyperactive

Baseline

Time 1

Time 2
F= 9.51 p .003

Olanzapine Dosage
Mean olanzapine dosage:
Baseline : 3.0 mgs (SD=0.14) range = 2.5 to 10 mgs

T2 (day2-3):
T3 (day4-7):

4.6 mgs (SD=0.27)


range = 2.5 to 15 mgs 6.3 mgs (SD=0.52) range = 2.5 to 20 mgs

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Olanzapine Side Effects


Olanzapine side effects were common but rarely interfered with treatment or worsened delirium: Side Effect Sedation EPS Delirium Other
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T2% 29% 0% 1.2% 3.7%


International Palliative Care Network Lecture Series 2012

T3% 29% 0% 1.2% ----

Open-label Trials of Olanzapine for Delirium


3 Other Open label trials of Olanzapine have been published in the literature using DRS, or the DI Sipahimalani & Masand (1998)- 11 patients, 90% improved, average dose-8.2mgs/day Kim, et al (2001)- 20 patients, 70% improved, average dose-5.8mgs/day, 5% got worse Skrobik, et al (2004)- 28 patients, DI significantly improved, average dose4.5mgs/day
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Open-label Trials of Risperidone for Delirium


3 Open label trials of Risperidone have been published in the literature using DRS Horikawa, et al (2003)- 10 patients, 80% improved average dose- 1.7mgs/day Mittal, et al (2004)- 10 patients, 80% improved, mean starting dose-1.35, maintenance dose0.75mg Parellada, et al (2004)- 64 patients, 91% improved, average dose-2.6mgs/day
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Open-label Trials of Quetiapine for Delirium


3 Open label trials of Quetiapine have been published in the literature using DRS. Disadvantages noted included: need for titration, sedation, hypotension Kim 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 8 Sasaki, et al (2003)- 12 patients, avg dose 45mgs/d mean DRS dropped from 18.1to 9.3 Pae, et al (2004)- 22 patients mean dose-127mg/day 86% marked improvement, DRS- 21.8 to 9.3
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Open-label Trials of Aripiprazole for Delirium


Prospective, 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 and 18.3 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
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RCTs of Antipsychotics for Delirium in ICUs

4 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 effects Devlin , et al (2010)- quetiapine plus prn haloperidol vs placebo, demonstrated benefit, but more somnolence Tahir, 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
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Side Effects of Neuroleptics/Antipsychotics


Anticholinergic Dry Mouth Constipation Cardiovascular (BP, QT interval) Antihistaminic Sedation, Weight Gain Dopamine Blocade Extrapyramidal Side Effects Hyperprolctinemia Neuroleptic Malignant Syndrome
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Side Effects of Atypical Antipsychotics


Metabolic Syndrome Hyperglycemia Hyperlipidemia Weight Gain Olanzapine and Clozapine have highest incidence

QT Interval Prolongation Torsade des Pointes QTc prolongation beyond 500msec ECG should be monitored daily during delirium RX Consider interactions with other agents that prolong QT
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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 death

In 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
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FDA Black Box Warning on Typicals ( e.g. Haldol)


In 2008 FDA expanded the warning of: increased risk of death
related to the use of all neuroleptic antipsychotics (including haloperidol ) in managing psychosis or behavioral problems in elderly patients with dementia.

A retrospective study of 23,000 elderly found slightly higher


mortality rates with typical than atypical antipsychotics, whether they had dementia or not.

Prolonged QTc interval and cardiac deaths also black boxed with
haloperidol. Wang et al NEJM 2005
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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
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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

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Short-Term Use of Atypical Antipsychotics in the Medically Ill: Assessment of Adverse Metabolic Effects and QTc Prolongation
Yesne 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 Sciences8

PSYCHOSOMATICS, in Press

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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 specifically No significant change in QTc interval between baseline and end
of treatment within 30 days
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Evidence Based Recommendations on Delirium Management in Cancer I - Breitbart & Alici, JCO 2012
Current evidence is supportive of short-term use of antipsychotics in the treatment of symptoms of delirium with close monitoring for possible adverse effects especially in elderly patients with multiple medical comorbidities. The longest clinical and research experience and safety/efficacy data available 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

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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 inhibitors in 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 for the prevention of delirium in patients with cancer. VI. The evidence supporting the use of intravenous dexmedetomidine for the prevention of delirium has been mixed and is limited to patients in intensive care settings only; there is currently no evidence to support its use in patients with cancer as a treatment for delirium.

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Conclusions
Palliative 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 less

Monitoring QTc interval and EPS is necessary Non-pharmacologic interventions should be optimized

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Acknowledgements
Dr. 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
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