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1. UPDATE ON DELIRIUM IN
PALLIATIVE AND HOSPICE CARE
LINDA GANZINI, MD, MPH
Associate Director, HSR&D Center of
Innovation, Portland VA Health Care
System
Professor of Medicine and Psychiatry,
Oregon Health & Science University

2. What is Delirium?
Delirium is a transient organic mental
syndrome of acute onset, characterized by
global impairment of cognitive function, a
reduced level of consciousness, attention
abnormalities, increased or decreased
psychomotor activity, and disordered sleep-
wake cycle.
•In DSM-5, primarily a disorder of attention,
awareness and cognition
•In DSM4-level of consciousness was of
primary importance over awareness.

3. Terms Used/Misused to Denote
Delirium
•Acute brain failure
•Acute brain syndrome
•Acute confusional state
•Acute organic brain
syndrome
•Organic brain
syndrome
•Cerebral insufficiency
•Confusional state
•ICU psychosis
•Metabolic
encephalopathy
•Toxic encephalopathy
•Terminal agitation
•Terminal restlessness
•Altered mental status

4. Delirium—why important
•Remains underrecognized
•Preventable condition in 30-40% of cases
•Costly--$160 billion year in US.
•Leads to a variety of potentially morbid outcomes
•Multiple patient safety issues
•Highly distressing for patients and their supports
•Most common reasons for palliative sedation at the
end of life.
Inouye, Lancet Psychiatry 2014, Schur BMC Palliative Care, 2016, Mercanti JPSM 2012; Omalley,
Finucane, Psychology, 2017; de la Cruz, Support Care Cancer, 2015

5. Epidemiology
•1-2% of community living elderly
•14-56% of hospitalized elderly
•70-87% of elderly in ICU
•28-42% on admission to palliative care unit
•90% in cancer patients in last weeks of life
(Lawlor, Arch Inter Med, 2000, Inouye, Lancet Psychiatry, 2014)

6. Adverse outcomes
•Increased mortality (1.5-4 fold depending on
setting)
•Extended cognitive impairment following episode
of delirium
•Increased physical function impairment for 30
days after discharge
•Higher rates of institutionalization
Inouye, Lancet Psychiatry, 2014

7. Clinical Features of Delirium
Prodrome Restlessness, anxiety, sleep disturbance,
irritability

•Attention decreased (easily distractible)
•Altered arousal and psychomotor abnormality
•Sleep-wake disturbance (usually worsens at night)
•Impaired memory (can’t register new information)
•Disorganized thinking and speech
•Disorientation—time, place, person
•Perceptions altered—misperceptions, illusions,
delusions (poorly formed), hallucinations
•Emotional lability

8. Attention
•Normal Able to mobilize, direct, focus, sustain, and
shift attention voluntarily and intentionally
•Measures at the bedside
•Days of week backward--0 errors
•Months of year backward--not more than one
error

9. Arousal
Waxing and waning of level of
consciousness with periods of
lethargy/somnolence is common,
but not necessary for the
diagnosis

10. Sleep
•Fragmented sleep/wake cycle
•Nighttime awakenings
•Often first signs of delirium at
night
•Delirium may be worse at night,
but some studies show morning
worsening

11. Delirium Subtypes:
Hypomotoric
•“Quiet” delirium
•Patients appear lethargic, listless, apathetic
•Has worse prognosis than hyperactive form
•Patients often perceived as depressed
•Often overlooked, permissively approached,
even normalized in palliative and hospice
care
•Most common form in palliative care settings
•Can change to hyperactive form

12. Hyperactive Delirium
•Patients vigilant, restless, loud,
irritable, agitated
•Called “terminal restlessness” or “
terminal agitation” in palliative care
•Associated with increased self-harm,
caregiver burden and distress, need
for hospital admission from hospice
•Hallmark of a “bad death”

13. Delirium –Qualitative Experience
•Fear, anxiety, feeling threatened, shame, hopelessness
•Dream like state with no control
•Distress when cannot communicate with loved ones
•Lability, tearfulness, anger
•For those who remember delirium, high degrees of
distress-fear of delirium returning, embarrassment,
remorse.
•Visual hallucinations, delusions and misinterpretations—
lead to anxiety and fear
•Family members—very distressed, wanted more
explanation about delirium.
•O’Malley, J Psych Research, 2008; Finucane Psychooncology, 2017

14. Delirium is Very Distressing for Patients
and Caregivers
•154 patients with cancer and delirium
•53% recalled delirium
•Mean delirium-related distress on 0-4 scale,
was 3.2 for patients, 3.75 for spouses and
caregivers
•Delusions were the most predictive of patient
distress
•No difference in patient distress between
hypoactive and hyperactive delirium
•Low functional status was most predictive of
caregiver distress
Breitbart, et al Psychosomatics, 2002

15. Diagnosis
•Confusion Assessment Method (CAM)
- Acute on mental status changes plus
inattention
- Either disorganized thinking or change in
level of consciousness
-94% sensitive, 89% specific, improved with
formal measures of cognition such as MOCA
Requires moderate levels of some training
Inouye, Lancet Psychiatry, 2014

16. Delirium Incidence and Outcomes
in Advanced Cancer
•Delirium is the most common mental disorder
in dying cancer patients—occurs in 80-90%
before death
•Delirium independently predicts death, even
when functional status, weight loss and
dyspnea are taken into account.
•Relapsing/remitting course—half of patients
with advanced cancer who develop delirium
will improve significantly before death, many
without intervention
•Lawlor, Arch Inter Med, 2000

17. Reversibility of Delirium in
Palliative Care
•Initial deliria reversible in half of palliative care patients
•Reversibility associated with psychoactive medications
(particularly opiates) , dehydration, hypercalcemia
•Nonreversible deliria associated with hypoxia and
metabolic factors in univariate analyses, also
nonrespiratory infections in multivariate analyses
•Half the time no cause found
Lawlor et al, Arch Int Medicine, 2000; Morita et al, JPSM, 2001; Bruera et al,
1992,

18. Reversibility of delirium in cancer patients in palliative care

19. Goals of Care
•Awake, alert, calm, cognitively intact, able to
communicate coherently with family and caregivers
•Work-up of delirium must be balanced between
likelihood of facilitating above and minimizing invasive
or burdensome procedures and stress
•Some normalization of quiet delirium in hospice—some
palliative care clinicians see hallucinations and
delusions of deceased relatives as an appropriate
transition called “decathexis”
Freidlander and Breitbart, Oncology, 2004

20. Risk factors for Delirium
•Dementia or any cognitive impairment
•Functional impairment
•Vision impairment
•Advanced age
•History of alcohol abuse
•Additional in palliative care population
•Poor nutrition
•Chronic renal disease.
Inouye, Lancet Psychiatry, 2014; Bush, Drugs, 2017

21. Causes: The List is Very
Long
•Primary cerebral disease
•Systemic disease affecting the brain
secondarily--especially infections,
electrolyte abnormalities (Na+, hyper
Ca++, end organ disease (kidney, liver,
lung)
•Intoxication with exogenous substances
(prescribed and illegal drugs)
•Withdrawal from substances of abuse

22. Drug Causes of Delirium
•The big three
•Opioids
•Benzodiazepines
•Anticholinergics
Others sometimes implicated
•Corticosteroids
•Dopaminergic agonists
•Anticonvulsants
•Quinolone antibiotics
Bush, Drugs, 2017

23. Evaluation of Delirium
•Maintain safety
•Search for causes
•Manage symptoms

24. Evaluation of Delirium
•Measure of cognition
•Evaluation for behavioral problems, suicidality,
elopement risk
•Review medications, alcohol and benzo use
•Assess for pain, discomfort, sensory impairments
•CBC, lytes, BUN/Cr, glucose, Ca, LFTs, TFTs,
UA, drugs levels, CXR
•Consider ABG, B12,UDS, ECG

25. Evaluation of delirium
•LP if fever, headache, meningeal signs
•Neuroimaging if focal changes, history of
head trauma
•EEG for seizures, to differentiate
psychiatric conditions

26. Interventions for Delirium—Research Issues
•Very difficult clinical trials to perform—issues of consent, heterogeneity of
causes, lack of generalizability
•Prevention versus treatment
•Measurement of outcome—
•development of delirium (incidence)
•severity of delirium
•length of delirium
•adverse outcomes of delirium
•severity of behavioral issues
•Length of hospital stay
•Differences in site
•ICU
•palliative care
•post operative

27. Non pharmacological interventions
Two types
•Proactive geriatric consultation for patients at risk of developing
delirium
•Multicomponent interventions
•Effective to prevent delirium, but more limited impact on
established delirium (Abraha, 2015, PLOS ONE)
•Generally safe
•Cognitive remediation and early mobilization, however,
may worsen agitation and distress (Meagher, Int J Geriatr Psychiaty 2017)
•May be costly if delivered by specialized teams

28. Management of delirium—Non pharmacological
approaches
•Remove psychoactive drugs
•Maintain hydration and nutrition
•Encourage family involvement
•Therapeutic companion for safety issues
•Eye glasses and hearing aids
•Ambulate patients
•Facilitate awake during day, sleep at nigh
•Quiet room, low level light
•Avoid restraints and bed alarms
•Inouye, Lancet Psychiatry, 2014

29. Melatonin agonists for prevention and treatment
•145 elderly individuals admitted through ED to medical unit—included
prevalent delirium (Al-Aama Int J geriatr Psych, 2011)
•Statistically lower occurrence of delirium with melatonin
•Not intention to treat
•Small (N = 67) study of ramelteon for prevention of delirium in ICU
patients (Hatta, Jama Psychiatry 2014)
•Non blinded, obvious differences in look of placebo and ramelteon.
•Statistically lower incidence of delirium with ramelteon
•A large (452 patients) well done study of patients with hip fracture (de
jonghe CMAJ, 2014)
•Half of the patients had premorbid dementia
•No effect on incidence of delirium, mortality, or three month
cognitive or functional outcomes.
•Melatonin group had fewer patients with prolonged delirium

30. Melatonin
•Advantages
•Inexpensive (21 cents per 3mg pill)
•Single daily dose of 3mg at bedtime
•Minimal adverse effects
•Adverse effects
•Dizzyness
•Headache
•Short term low mood
•Morning sleepiness
•Irritability
•Abdominal cramps
Drug interactions
Warfarin
Four large trials underway—more definitive answers to effectiveness pending

31. Antipsychotic Medication for Prevention and Treatment of Delirium in Hospitalized Adults: A
Systematic Review and Meta Analysis
‐
Journal of the American Geriatrics Society
Volume 64, Issue 4, pages 705-714, 23 MAR 2016 DOI: 10.1111/jgs.14076
http://onlinelibrary.wiley.com/doi/10.1111/jgs.14076/full#jgs14076-fig-0002

33. Australian palliative care delirium
trial
•Participants
•Receiving hospice or inpatient palliative care
•Had delirium, with innapropriate behavior/communications, or
hallucinations
•Intervention
•risperidone, haloperidol or placebo.
•All received treatment of reversible precipitants, and non
pharmacological measures
•Outcomes
•Primary--Delirium symptoms on day three
•Secondary-delirium severity, EPS, daily midazolam use, survival.
•Agar et al, Jama IM, 2017
•

34. Date of download: 9/1/2017
Copyright © 2017 American Medical
Association. All rights reserved.
From: Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in
Palliative CareA Randomized Clinical Trial
JAMA Intern Med. 2017;177(1):34-42. doi:10.1001/jamainternmed.2016.7491
Secondary Multivariable Mixed-Model Analysis of DeliriumThe dependent variable was delirium score at each day. The
independent variables comprise the covariates in Table 2, group, time, and 2 interaction terms, time
 × risperidone and time × 
haloperidol. The relative difference in improvement between groups at 72 hours was determined using the lincom function in Stata.
Placebo vs risperidone: P
 < .001; placebo vs haloperidol: P = .002. Error bars indicate 95% CIs.
Figure Legend:

35. Australian palliative care delirium trial—Main
findings
•247 participants, 88% with cancer
•Baseline—haloperidol group had more severe baseline delirium and great
opioid use.
•Greater delirium symptom scores and longer duration of delirium in both
antipsychotic treated groups.
Less rescue medication (midazolam) in placebo group.
•Higher mortality in antipsychotic treated groups—statistically significant in the
haloperidol group (similarly finding in large studies of antipsychotics for
dementia)
•Overall higher EPS in antipsychotic groups.
•Tendency for placebo group to improve may reflect regression to mean or
efficacy of non pharmacological interventions.
•Agar et al, Jama IM, 2017

36. Antipsychotic adverse effects
•Drug- induced parkinsonism
•Comes on over days
• dose related
•Increased risk of falls, reduced bed mobility
•Common with haloperidol and risperidone
•Akathisia
•uncomfortable restlessness that may worsen agitation.
•Comes on quickly,
•dose related
•Occurs in about 10%
•Orthostatic hypotension
•Increased risk of falls
•Quetiapine, risperidone, olanzapine
•QT prolongation
•Increased with IV haloperidol
•Unusual with low dose oral preparations
•But avoid of QTC greater than 500ms

37. Other negative trials for delirium
•Benzodiazepines
•Causes delirium and worsens delirium severity, falls
•Only use when goals of care no longer include clarity of thinking
and patient no longer ambulatory
•Acetylcholinesterase inhibitors such as rivastigmine and
donepezil
•Five trials, all negative.
•Regional versus general anesthesia
•Two trials, both negative
•Dexmedetomidine in intubated ICU patients
•Four trials, lower delirium compared to midazolam, propofol, or
morphine, but mostly not relevant to hospice and palliative care
•Friedman et al, Am J Psychiatry 2014

38. Summary
•Delirium most common mental disorder at end of life
•Often misdiagnosed as depression or ignored
•Permissive approach probably increases suffering, but workup must be
balanced against burdens, likelihood of reversal
•Very distressing for patients and family
•Non-pharmacological treatments are recommended for prevention
•Melatonin has uncertain efficacy, but fewer adverse effects than
antipsychotics
•Do not use antipsychotics routinely
•Preserve for severe agitation, psychosis or hallucinations (NICE
guidelines, 2010)
•In some cases palliative sedation needed