Delirium in Advanced Cancer:
An Evidence Based Update
David Hui, MD, MSc
MD Anderson Cancer Center, USA
2nd Sapporo Conference for Palliativeand Supportive Care in Cancer
Sapporo, Japan
June 16, 20171

Outline• Introduction• Treatment– Setting therapeutic goals– Treatment of underlying causes– Non-pharmacologic approaches– Pharmacologic approaches• SummaryCardinal Features
DSM-IV Criteria

DSM-5 Criteria

European Delirium Association & American Delirium Association BMC Medicine 2014

Delirium is Common•••

Patient characteristics are different
Etiology may be different
Outcomes are different

80%13-42% atadm
26-62%
duringadm

50%
10-31% atadm

59-88%
beforedeath

11-42%
duringadm

General inpatient(Siddiqi et al. 2006)

Geriatric postop(Neufeld et al. 2013)

Intensive care vented Palliative care inpatient(Pun et al. 2007)(Hosie et al. 2012)

Causes and Outcomes
Drugs

Structural abnormalities

Infections

Metabolic changes

Underlying
disease, frailty,& comorbidities

Delirium
Associated Complications
Increased morbidity
Increased safety concerns
Increased distress
Increased length of stay
Increased healthcare costs
Increased institutionalization
Increased mortality

Delirium Recall and Related Distress
99 patients
recovered fromdelirium73 (74%) had
delirium recall

21 (26%) had nodelirium recall

59 (81%)
reported it was
distressing

11 (42%)reported it was
distressing

Bruera et al. Cancer 2008

Delirium Assessment
Missed Delirium
MissedReversible

Delirium

Delirium

61%

67%

252/771 (33%) patients who
had an inpatient palliative
care consult found to havedelirium by the palliative careteam. 99 (39%) diagnosed
with delirium by oncology
team

55/82 (67%) patientswith reversible delirium
had a missed diagnosis
initially

Routine screening is key!
De La Cruz et al. Supp Care Cancer 2015

Delirium Assessment
Screening Tools

BurdenSens

Spc

LR- (95% CI)

LR+ (95% CI)

Confusion Assessment
Method (CAM)

4 items<5 min86%

93%

0.16 (0.09, 0.29)

9.6 (5.8, 16)

Delirium Rating Scale(DRS)

10 items
Cutoff ≥10/32

95%

79%

0.07 (0.03, 0.37)

4.3 (2.1, 9.1)

Memorial Delirium
Assessment Scale (MDAS)

10 items<10 min
Cutoff ≥10/30

92%

92%

Delirium Observation
Screening Scale(DOS/DOSS)

13/25 items<5/<10 min

92%

82%

12 (2.4, 15.8)

0.1 (0.03, 0.37)

5.2 (2.7, 9.9)

Greer et al. VA-ESP Project #09-009 2011

Outline• Introduction• Treatment– Setting therapeutic goals– Treatment of underlying causes– Non-pharmacologic approaches– Pharmacologic approaches• SummaryPrognosis-Based Decision Making
Delirium in Advanced Cancer“End of life”, “terminally ill”: months or less of survival

Advanced cancer(months to years)

Far advanced cancer(weeks to months)

Actively dying(days to weeks)

Post-Op Delirium

Medical Delirium

Terminal Delirium

Transient, reversible
Goals: prevention,short term treatment

Possibly reversible
Goals: treat underlying
cause, control delirium
symptoms

Often less reversible
Part of dying process
Goals: palliation,
control agitation

Medical/Surgical Settings
Palliative Care Settings

Hui et al. Curr Opin Supp Palliat Care 2016

Delirium Management
Setting Realistic Goals
Variable level of evidence in different care settings

Prevention of delirium•Incidence•Length of delirium•Severity of delirium

NonPharmacologic
Interventions

Pharmacologic
Interventions

Reversal of delirium• Reversibility•TreatLengthreversibleof delirium
causes• Severity of delirium

NonPharmacologic
Interventions

Pharmacologic
Interventions

Palliation of delirium
symptoms• Agitation• Hallucinations• Delusions

Pharmacologic
Interventions• Patients• Caregivers• Nurses

Pharmacologic
Interventions

Reduce delirium related
distressReversibility of Delirium
Palliative Care Setting• 71 patients with advanced cancer admitted to palliative caredeveloped delirium– Reversal in 46/94 (49%) episodes– Terminal delirium in 46/52 (88%) APCU deaths– Median survival ~25 days

Lawlor et al. Arch Intern Med 2001

Reversibility of Delirium
Thiamine Deficiency• Wernicke encephalopathy
diagnosed clinically and treated
before lab values confirmed
Case 1Case 2

Case 3

Patient

71yo M

66yo F

77yo FDRS baseline

21

24

24

Onset

GradualGradualGradualAtaxia

Yes

NA

Yes

Ocular

No

No

Yes

Thiamine lvl

18ng/ml

15ng/mlNA

Reversed
after tx

Yes

After 3days

After 3days

Onishi et al. Supp Care Cancer 2004

• 70 year old woman with delirium,
disorientation, cognitive
impairment but no ocularchanges or gait abnormalities– Thiamine level 14 (normal 20-50
ng/ml), started IV thiamine 100
mg/day– Day 1: DRS 24– Day 2: improvement in cognition andinsomnia– Day 3: able to communicate– Day 4: DRS 3. Thiamine level 679
ng/ml– Died 10 days laterYae et al. Palliat Supp Care 2005

Treat Underlying Cause(s)Take Home Message

Risks

Benefits

Delirium Management
Setting Realistic Goals
Variable level of evidence in different care settings

Prevention of delirium

Reversal of delirium• Reversibility•TreatLengthreversibleof delirium
causes• Severity of delirium

NonPharmacologic
Interventions

Pharmacologic
Interventions

NonPharmacologic
Interventions

Pharmacologic
Interventions

Palliation of delirium
symptoms

Pharmacologic
Interventions

Reduce delirium related
distress

Pharmacologic
Interventions

Non-Pharmacologic Measures
Hydration for Delirium Prevention
Double blind, randomized controlled trial

1000 mL per day until off study
129 cancer
patients in
hospiceR
100 mL per day until off study

Bruera et al. J Clin Oncol 2013

Non-Pharmacologic Measures
Hydration for Delirium Prevention
Assessments

Composite outcome [fatigue,
drowsiness, hallucinations,
myoclonus], mean (95%
confidence interval)
MDAS, median (IQR)
NuDESC , median (SD)Day
EveningNight

Caveats••••

Change between Baseline and Day 4
Hydration
Placebo
PN=49
N=51
value

Change between Baseline and Day 7
Hydration
Placebo
PN=44
N=49
value

-3.3 (-1.1, -5.4)-2.8 (-0.2, -5.3)

0.77-4.9 (-2.2, -7.7)-3.8 (-1.1, -6.4)

0.54

1 (-2, 5.8)

3.5 (-0.3, 14.5)

0.08

2 (-2, 10)

2.5 (-1, 14)

0.44

0 (-1, 1)
0 (-1, 1)
0 (-1, 0)0 (-1, 2)
0 (-1, 2)
0 (-1, 2)

0.13
0.40
0.03

0 (0, 0)0 (-1, 1)
0 (-1, 1)

0 (0, 1)0 (-1, 3)
0 (-1, 1)

0.36
0.39
0.79

Only patients with mild-moderate dehydration
Delirium was a secondary outcome (floor effect)
Patients with days-weeks of survival
May need multi-model intervention
Bruera et al. J Clin Oncol 2013

Multicomponent Intervention
Delirium Prevention
Open label, matched cohort study

852 geriatrichospitalized
patients atintermediate/highrisk of delirium*

N=426

M
N=426

Elder Life Program (intervention unit)• Interdisciplinary team (geriatrician, nurse specialist, recreation
specialist, Elder life specialists, physical therapy, volunteers)• Targeted 6 risk factors (cognitive impairment, sleep deprivation,
immobility, visual impairment, hearing impairment, dehydration)

Usual Care (control units) with same attending physician* Four risk factors: visual impairment, severe illness, cognitive impairment, high BUN/Cr• Intermediate risk: 1-2 risk factors• High risk: 3-4 risk factors

Inouye et al. NEJM 1999

Multicomponent Intervention
Delirium Prevention
DomainOrientation
protocolInterventions
Board with names of care team members listed, communication to reorient tosurroundings
Therapeutic activities protocol TID, as tolerated; includes family involvement andstructured reminiscence

SleepprotocolWarm drink at bedtime, relaxation music, unit-wide noise reduction strategies,schedule adjustments to allow sleep (rescheduling of vitals, medications, andprocedures)

Mobilization
protocolPhysical/occupational therapy assessment, minimal use of immobilizing
equipment

VisionprotocolVisual aids (e.g., glasses or magnifying lenses), adaptive equipment (e.g., large
illuminated telephone keypads) for patients with visual impairments,
reinforcement of their use

Hearing
protocolPortable amplifying devices, special communication techniques for patients withhearing impairments, daily reinforcement of these adaptations

Dehydration
protocolEarly recognition of dehydration and volume repletion (e.g., encourage oral
intake or parenteral hydration)

Multicomponent Intervention
Delirium Prevention

Inouye et al. NEJM 1999

Delirium Prevention
Systematic Review and Metaanalysis• Multicomponent Intervention (RR 0.63, 95% CI 0.43-0.92)• Pharmacologic therapies (inadequate evidence)– Antipsychotics (RR 0.73, 95% CI 0.33-1.59)• Haloperidol (RR 1.05, 95% CI 0.69-1.60)• Olanzapine (RR 0.36, 95% CI 0.24-0.52)– Melatonin (RR 0.41 95% CI 0.09-1.89)– Cholinesterase inhibitors (RR 0.68 95% CI 0.17-2.62)
Siddiqi et al. Cochrane Database 2016

Multicomponent Intervention
Delirium Treatment
4 geriatric, unblinded randomized controlled trials
Population

Intervention (vs.usual care)

OutcomeComments

Cole et al.
CMAJ 1994

88 pts withdelirium
Medical unit
Age 75 or older

Consultation by geriatrician or psychiatrist
and followup by liaison nurse (environment,orientation, familiarity, communication,
activities) during admission

Crichton Geriatric Behavioural Rating Scale (-8.1
vs. -3.5, P<0.05) over 8 wks
Short Portable Mental Status Questionnaire (-0.5
vs. -0.6, p=0.06)
No difference in restraints, length of stay,discharge outcomes or mortality

Non-pharm on
delirium; mixed
findings andlimitedimprovement

Cole et al.
CMAJ 2002

227 pts withdelirium
Medical units
Age 65 or older

Consultation by geriatrician or psychiatrist
and followup by liaison nurse (environment,orientation, familiarity, communication,
activities) during admission

Time to improvement (HR 1.1, 95% 0.74-1.63)
Delirium improvement (48% vs. 45%)
No difference in Delirium Index score, Barthel
Index score, length of stay, discharge outcomes orsurvival

Non-pharm on
delirium; no
improvement

Lundstrom
et al. JAGS2005

125 pts withdelirium
275 pts without
delirium
Medical service
Age 70 or older

2 day course in geriatric medicine focusing
on delirium
Education concerning caregiver-patientinteraction
Reorganization of nursing care
Guidance for nursing staff once a monthComplete remission rate on day 7 (70% vs. 40%,
P=0.001)
Able to return to home (78% vs. 60%, P=0.05)
Length of stay (11 d vs. 21 d)Lower mortality (3% vs. 14%, P=0.03)

Educational/
system change;
lots ofimprovement

Pitkala et al.
J
Gerontology
2006

174 pts withdelirium
Medicalservices
Age 69 or older

Comprehensive geriatric assessment atbaseline, avoid conventional neuroleptics,
orientation, physiotherapy, geriatricinterventions (nutrition supplements,
calcium, hip protectors), cholinesterase
inhibitors

Mortality at 1 year (61% vs. 64%, P=0.64)
Days in hospital (126 vs. 140, P=0.69)
Delirium MDAS improvement by day 8 (~50% vs.
~20%)
MMSE 6 months (8.4 vs. 15.8, P=0.047)
Barthel Index 6 months (70.2 vs. 63.8, P=0.14)

Non-pharm;
Deliriumsecondary
endpoint andpositive

Ahraha et al. PLOS One 2015

Multicomponent Intervention
Take Home Message
Prevention

Risks

Benefits

Treatment

Risks

Benefits

Paucity ofevidence

Potentially
useful to treat
delirium

Hard tostandardize

Improvescomorbidities

Delirium Management
Setting Realistic Goals
Variable level of evidence in different care settings

Prevention of delirium

Reversal of delirium• Reversibility•TreatLengthreversibleof delirium
causes• Severity of delirium

NonPharmacologic
Interventions

Pharmacologic
Interventions

NonPharmacologic
Interventions

Pharmacologic
Interventions

Palliation of delirium
symptoms

Pharmacologic
Interventions

Reduce delirium related
distress

Pharmacologic
Interventions

Pharmacologic Interventions
Delirium Prevention• Antipsychotics (RR 0.73, 95% CI 0.33-1.59)– Haloperidol (RR 1.05, 95% CI 0.69-1.60)– Olanzapine (RR 0.36, 95% CI 0.24-0.52)• Melatonin (RR 0.41 95% CI 0.09-1.89)• Cholinesterase inhibitors (RR 0.68 95% CI 0.17-2.62)

Siddiqi et al. Cochrane Database 2016

Pharmacologic Interventions
Delirium Prevention• Antipsychotics for prevention of post-op delirium– 2 of 3 haloperidol trials +ve (Kaneko et al. 1999 ICU; Wang et al. 2012 ICU)
– 2 of 2 risperidone trials +ve (Prakanrattana et al. 2007 ICU; Hakim et al.
2012 ICU)– 1 of 1 olanzapine trial +ve (Larsen et al. 2010 Geriatric)• Cholinesterase inhibitors for prevention of post-op delirium– 0 of 3 donepezil trials +ve– 0 of 2 rivastigmine trials +ve

Friedman et al. Am J Psych 2014

Pharmacologic Interventions
Delirium Treatment• Antipsychotics for treatment of delirium– 0 of 1 haloperidol-placebo trial +ve (Girard et al. 2010 ICU)
– 0 of 1 ziprasidone-placebo trial +ve (Girard et al. 2010 ICU)
– 0 of 2 quetiapine-placebo trial +ve (Devlin et al. 2010, Tahir et al. 2010)• Miscellaneous treatments– 0 of 1 melatonin trial +ve (Al Aama et al. 2011)– 0 of 1 ketamine trial +ve (Hudetz et al. 2009)Friedman et al. Am J Psych 2014

Neuroleptics
Delirium Treatment

Kishi et al. J Neurol Neurosurg Psychiatry 2016

Neuroleptics
Delirium Prevention and Treatment
12 treatment trials: 10 RCTs, 5 had placebo
7 prevention trials: all post-operative setting

Neufeld et al. JAGS 2016

Neuroleptics
Terminally Ill Patients

Candy et al. Cochrane Database 2012Are You Confused Yet?

Delirium Literature
It is Confusing!
••••

Different patient populations and settings
Different doses and dosing schedules
Different comparison arms
Different outcome measures (variable degree of validation)• Different systematic reviews included different studies• Different quality of studies• Different languages
Result: Different opinions!

Benzodiazepines
Delirium Treatment• Pandharipande et al. JAMA 2017
– Dexmedetomidine vs. lorazepam– Only study included in systematic review• Breitbart et al. Am J Psych 1996
– Haloperidol vs. chlorpromazine vs. lorazepam– Not included as lorazepam arm terminated early• Christensen et al. JAGS 1998
– Haloperidol vs. alprazolam– Not included because mixed dementia/delirium/amnesic/cognitive disorder

Lonergen et al. Cochrane 2009

Haloperidol vs. Chlorpromazine vs.
Lorazepam: HIV Patients, Front Line
Double-blind, randomized controlled trial

N=1130 HIV patientswith delirium(mean KPS 52%)

R

N=14

N=6

Haloperidol x6d
Chlorpromazine x6d

Lorazepam x6d

Outcomes• Delirium Rating Scale• Mini-Mental State Examination• Extrapyramidal Symptom Rating Scale• Other Side Effects• Karnofsky Performance Status• Medical Status Profile

Breitbart et al. Am J Psychiatry 1996

Haloperidol vs. Chlorpromazine vs.
Lorazepam: HIV Patients, Front Line• Mean drug doses in first 24 h
• Haloperidol 3.8 (2.4) mg• Chlorpromazine 50 (23.1) mg• Lorazepam 3 (3.6) mg• Mean maintenance drug doses• Haloperidol 1.4 (1.2) mg• Chlorpromazine 36 (18.4) mg• Lorazepam 4.6 (4.7) mg

Day 1: Increase dose to next level every hour if DRS >13
Day 2-6: Give total dose from day 1, div BID

Breitbart et al. Am J Psychiatry 1996

Haloperidol vs. Chlorpromazine vs.
Lorazepam: HIV Patients, Front Line••

Improvement seen within 24 hours of treatment in haloperidol andchlorpromazine arms
All 6 patients on lorazepam arm developed treatment limiting side effects(sedation, disinhibition, ataxia, increased confusion)
Breitbart et al. Am J Psychiatry 1996

Haloperidol vs. Chlorpromazine vs.
Lorazepam: HIV Patients, Front Line• Strengths– First delirium study in palliative care setting– Rapid titration to identify optimal doses• Limitations– No placebo group– Small sample size
– Intensive titration schedule– Lorazepam arm terminated early (n=6)

Main implication: Neuroleptics are superior
to benzodiazepine for delirium in thepalliative care settingRisperidone vs. Haloperidol vs. Placebo
Palliative Care, Front Line
Double-blind, randomized controlled trial

247 patients withlife limiting illness,
symptomaticdelirium (MDAS>=7, DSM IV-R)

Risperidone PO 1 mg loading, then 0.5 mg BID, max 4 mg/d
(halved if age >65), midazolam 2.5 mg SC q2h PRN

RHaloperidol PO 1 mg loading, then 0.5 mg BID, max 4 mg/d
(halved if age >65), midazolam 2.5 mg SC q2h PRN
Placebo PO, midazolam 2.5 mg SC q2h PRN

Outcomes• Primary: NuDesc inappropriate behaviour, inappropriate communication,
illusions/hallucinations at 72 h
• Patient/caregiver/health professional rated distress• Dosage or length of administration• Toxicity (extrapyramidal effects, sedation)• Pathophysiologic correlates (S100B, cytochrome C, caspase 3, neuron specific enolase)

Agar et al. JAMA Intern Med 2017

Risperidone vs. Haloperidol vs. Placebo
Palliative Care, Front Line
Risperidone vs. Placebo

Haloperidol vs. Placebo

Effect (95% CI)

P-value

Effect (95% CI)

P-value

Delirium symptoms

0.48 (0.09, 0.86)

0.02

0.24 (0.06, 0.42)

0.009

MDAS scores/day

0.96 (0.16, 1.77)<0.0010.76 (-0.03, 1.51)

0.06

RASS/day-0.05 (-0.19-0.09)

0.52-0.14 (-0.28, 0)

0.048

Extrapyramidal effects

0.73 (0.09, 1.37)

0.03

0.79 (0.17, 1.41)

0.01

Overall survival (HR)1.29 (0.91, 1.84)

0.14

1.73 ( 1.20, 2.50)

0.003

Median survival

17 d vs. 26 d

16 d vs. 26 d

Agar et al. JAMA Intern Med 2017

Risperidone vs. Haloperidol vs. Placebo
Palliative Care, Front Line• Midazolam use (placebo vs. neuroleptics)– Day 1: 13/75 (17%) vs. 50/144 (35%), P=0.007– Day 2: 11/68 (17%) vs. 40/121 (33%), P=0.01– Day 3: 9/66 (14%) vs. 32/108 (30%), P=0.02• Midazolam dose/day (among pts who got it)– Placebo: median 2.5 mg (2.5-5.0 mg)– Risperidone: median 2.5 mg (2.5-5.0 mg)– Haloperidol: median 4 mg (2.5-5.0 mg)

Implications:1.
2.

Neuroleptics are inferior to placebo for delirium in the palliative care setting
Benzodiazepines alone may be considered for rescue
Agar et al. JAMA Intern Med 2017

Risperidone vs. Haloperidol vs. Placebo
Palliative Care, Front Line• Primary outcome– Has not been validated– Observed difference statistically significant but clinical significant
unknown• Patient population– Relatively low MDAS scores (median 13.7-15.1 – placebo best)– Did not exclude dementia patients• Adverse effects– Despite very small doses for short duration (72 h)– Secondary outcomes = hypothesis generating only

Hui et al. JAMA Intern Med 2017 (in press)

How about agitation…

RASS +1
Restless

RASS +2
Agitated

RASS +3
Aggressive

Haloperidol  Lorazepam
Palliative Care, Persistent Agitation• Double-blind, randomized controlled
trial

Cancer patients in APCU with
mixed/hyperactive delirium despite
regular haloperidol use (<8 mg/d)• Single dose instead of repeated dosingR– Short survival (i.e. hours to days)– Uncertain risks associated with lorazepam
in a frail population• Study outcomes:
–
–
–
–
–
–
–

Richmond Agitation Sedation Scale (1)Use any additional psychotropic agents
Perceived patient comfort
MDAS, ESAS, DEQ
Communication capacity
Adverse effects
Discharge outcomes, survival

Haloperidol 2 mg q6h and q1h PRNFirst occurrence of RASS ≥+1 & meds needed

Haloperidol 2 mg
PLUS
Lorazepam 3 mg
x1 doseHaloperidol 2 mg
PLUS
Placebox1 doseHui et al. ASCO 2017

Haloperidol  Lorazepam
Palliative Care, Persistent Agitation• Lorazepam/haloperidol was associated with a significantly greater
reduction of RASS compared to placebo– 0-30 min: mean  -2.0, 95% CI -2.9, -1.1, P<0.001– 0-8 h: mean  -1.9, 95% CI -2.8, -0.9, P<0.001

Hui et al. ASCO 2017

Haloperidol  Lorazepam
Palliative Care, Persistent Agitation
Placebo + Haloperidol

Hui et al. ASCO 2017

Haloperidol  Lorazepam
Palliative Care, Persistent Agitation
Lorazepam + Haloperidol

Hui et al. ASCO 2017

Haloperidol  Lorazepam
Palliative Care, Persistent Agitation
Neuroleptic use during the first 8 hours

Scheduled HEDD, median (IQR), mg
Rescue HEDD, median (IQR), mg
Total HEDD, median (IQR), mg
Number of rescue doses, median (IQR), mg
Need for chlorpromazine during first 8 hours,
No./total No. of observations (%)
Change in MDAS, mean (SD)
Change in Edmonton Symptom Assessment
Scale, mean (SD)Pain
Fatigue
NauseaDepression
AnxietyDrowsiness
Shortness of Breath
Appetite
Sleep
Feeling of Well-being

Lorazepam +Haloperidol(n=29)
2.0 (2.0, 4.0)
2.0 (2.0, 2.0)
6.0 (4.0, 6.0)
1.0 (1.0, 1.0)
2/29 (6.9%)

Placebo +Haloperidol(n=29)
2.0 (2.0, 4.0)
4.0 (2.0, 5.0)
6.0 (4.0, 8.0)
2.0 (1.0, 2.0)
4/29 (13.8%)

Difference
between arms
(95% CI)-0.1 (-0.9, 0.6)
-2.2 (-3.8, -0.5)-2.3 (-4.2, -0.5)-0.9 (-1.6, -0.2)-0.1 (-0.3, 0.2)

Pvalue
0.68
0.009
0.03
0.008
0.67

2.5 (4.5)

0.4 (6.2)

2.1 (-1.0, 5.2)

0.18

-2.4 (2.7)
0.1 (1.9)-0.7 (3.4)-1.4 (4.0)-3.4 (3.8)
1.9 (3.5)-1.0 (2.2)
0.6 (1.6)-2.9 (3.8)-2.3 (3.3)-1.7 (4.2)-1.8 (3.2)-2.7 (3.9)
0.2 (2.9)-2.1 (4.7)-2.0 (3.1)-0.4 (4.5)
2.1 (3.2)-2.4 (3.8)-1.5 (3.3)-0.7 (-3.6, 2.2)
1.9 (-0.7, 4.5)
2.0 (-1.7, 5.7)
-1.6 (-5.3, 2.2)
-1.3 (-5.0, 2.4)
3.9 (0.8, 7.1)
-0.6 (-3.3, 2.2)
-1.5 (-3.6, 0.6)
-0.5 (-4.0, 3.1)
-0.8 (-4.2, 2.6)

0.67
0.23
0.49
0.56
0.55
0.03
0.41
0.26
0.74
0.51

Hui et al. ASCO 2017

Haloperidol  Lorazepam
Palliative Care, Persistent Agitation
Patients on lorazepam/haloperidol arm were perceived to be more
comfortable after the study medication by blinded caregivers andnurses

84%

77%

37%
30%

Hui et al. ASCO 2017

Haloperidol  Lorazepam
Palliative Care, Persistent Agitation• No significant difference in– Delirium recall– Communication capacity– Adverse effects– Discharge outcomes– Overall survival

Median survival
68 h vs. 73 h, P=0.56
HR 1.2 (95% CI 0.7-2.2)

Hui et al. ASCO 2017

Haloperidol  Lorazepam
Palliative Care, Persistent Agitation• Lorazepam and haloperidol, given to the right individuals forthe right reason at the right time, may reduce agitation andimprove comfort.
• Limitations:– Single center study– Small study not powered to examine secondary outcomes– Only examined a single dose of lorazepam (3 mg)• Further research is needed to examine the role ofbenzodiazepines and neuroleptics in delirium management.
Hui et al. ASCO 2017

Placebo-Controlled Trials
Delirium Treatment
AgentsHaloperidol

ICU

Medical/SurgicalGirard Crit Care Med 2010

Palliative Care
Agar JAMA Intern Med 2017
Agar JAMA Intern Med 2017

Risperidone
Ziprasidone

Girard Crit Care Med 2010

Quetiapine

Devlin Crit Care Med 2010

Tahir J Psychosom Res 2010

Olanzapine
Lorazepam
Midazolam

Hui (submitted)

Pharmacologic Therapies
Take Home Message
Neuroleptics

Benzodiazepines

Risks

Benefits

Risks

Benefits

Some studies
suggest harmSome studies
suggestimprovement

Some studies
suggest harmSome studies
suggestbenefits

Adverseeffects

May reduceagitation

Adverseeffects

May reduceagitation

Prevention: Mixed evidence
Treatment: Limited evidence; however, may
be considered for selected patients given
limited options

Prevention: No evidence
Treatment: Some evidence for agitation
control; use with great caution

Neuroleptic Rotation
Palliative Care, Persistent Agitation• Haloperidol use

Delirium in APCU
(n=167)– Initial doses 5 (3-7) mg– Median duration 5 (3-7) days

• Chlorpromazine use– Initial dose 150 (100-150) mg– Median duration 3 (2-6) days

Haloperidol only
(n=128, 77%)

Reduced symps(n=91, 71%)

Haloperidol +another agent(n=39, 23%)

Rotated tochlorpromazine(n=37, 29%)

Reduced symps

Did not improve(n=13, 33%)

(n=24, 67%)

Shin et al. Cancer Treat Res 2015

Neuroleptics
Impact on Delirium Recall and Related DistressDistress

Distress

HEDD (mg)

Reactive therapy

Distress

Ineffective therapy

Effective therapy

HEDD (mg)

HEDD (mg)Neuroleptics
Impact on Delirium-Related Distress
Patients

Caregivers

NursesPC specialists

Disorientation
to placeHL

2.6 (N=36)
1.8 (N=48)
p=0.482.0 (N=55)
2.8 (N=35)
p=0.247.0 (N=8)
2.5 (N=65)
p=0.002

3.3 (N=13)
2.0 (N=76)
p=0.32

Disorientation
to timeHL

2.5 (N=40)
2.7 (N=45)
p=0.94

1.8 (N=52)
3.0 (N=41)
p=0.547.0 (N=6)
2.5 (N=69)
p=0.008

3.7 (N=16)
2.0 (N=75)
p=0.18Hallucinations

HL

3.5 (N=33)
2.0 (N=47)
p=0.303.2 (N=47)
1.7 (N=43)
p=0.144.6 (N=6)
2.5 (N=63)
p=0.207.5 (N=10)
2.0 (N=79)
p=0.006

DelusionsHL

2.5 (N=23)
2.5 (N=57)
p=0.901.8 (N=36)
2.8 (N=49)
p=0.524.3 (N=7)
2.3 (N=64)
p=0.041

4.0 (N=9)2.0 (N=80)
p=0.75

Agitation

HL

2.5 (N=45)
1.8 (N=40)
p=0.272.5 (N=69)
1.6 (N=22)
p=0.366 (N=11)
1.9 (N=62)p<0.001

4.3 (N=23)
1.9 (N=69)
p=0.006

Hui et al. J Pain Symp Manage 2010

Delirium Treatment
Implications
Onset of delirium
Early interventions• Treat reversible causes• Non-pharmacologic measures• More effective pharmacologic measures
Worseningdelirium
symptoms

Administration ofneuroleptics

Delirium
related distress
Patients and caregivers
RNs and PC specialists

Treatment of Delirium
NCCN Clinical Practice Guideline

Dans et al. NCCN Palliative Care v1.2017

Delirium Literature
More Research is Needed• Better understanding of pathophysiology– Classify subtypes– Identify novel interventions• More validated outcomes are needed– Appropriate outcome based on goals of care
– Minimal clinically important difference• Interventions– Dose-finding studies– Multimodal interventions• Control arms
– Placebos are needed• More adequately powered studies needed– Homogeneous populations– We need funding and collaborations
Hui et al. J Palliat Care 2014

Summary• Think Delirium!
– Routine screening– Match setting with goals of care

• Prevention– Treat potential contributors of delirium (if any)
– Multicomponent intervention – high quality evidence in most settings– Pharmacologic therapy – nothing definitive yet!

• Treatment– Treat reversible causes (up to 50% even in palliative care setting)– Non-pharmacologic approaches – limited evidence but limited harm
– Neuroleptics – consider for agitation, optimal dose undefined– Benzodiazepines – consider for agitation, optimal dose undefined– Dexmedetomidine – limited to intensive careSummary
Delirium Management by Setting
Post-Op(months-years)

Medical(weeks-months)

Palliative Care(days-weeks)

Prevention of delirium

Multicomponent

Multicomponent?Multicomponent

Reversal of delirium

Treat etiology

Treat etiology

Treat etiology?Neuroleptics?Neuroleptics?Benzos

Palliation of delirium
symptoms (agitation)
Reduce delirium related
distress??Neuroleptics??Benzosありがとうございます•

MDA Palliative Care
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•

Dr. Eduardo Bruera
Dr. Joseph Arthur
Dr. Ashan Azhar
Dr. Shalini Dalal
Dr. Maxine De La Cruz
Dr. Marvin Delgado Guay
Dr. Rony Dev
Dr. Daniel Epner
Dr. Ali Haider
Dr. Kevin Madden
Dr. Akhila Reddy
Dr. Suresh Reddy
Dr. Kimberson Tanco
Dr. Marieberta Vidal
Dr. Paul Walker
Dr. Angelique Wong
Dr. Sriram Yennu
Dr. Donna Zhukovsky

PC Research Team
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Susan Frisbee Hume
Kelly Kilgore
Hilda Rofheart
Swati Bansal
Nancy Shinn
Helen House
Charles J Masino
Jewel Ochoa
Kresnier Perez Zapata
Vera De La Cruz
Janet Williams
Julio Allo
Yvette Ross•

MDA Collaborators
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•

•

•

Thoracic Med Onc (Dr. Anne Tsao, Dr.
Fossella, Dr. Katherine Pisters)
Pulmonary Medicine (Dr. Dave
Balachandran, Dr. George Eapen)
Cardiology (Dr. Juan Lepez-Mattei, Dr. Kara
Thompson)
Leukemia (Dr. Jorge Cortes)
PROSPR (Dr. Basen Engquist, Carol
Harrison)

Biostatistics–––

Dr. Kenneth Hess
Diane Liu
Minjeong Park

Acute Palliative Care Unit Nursing
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Annie Wilson
Thuc Nguyen
Stacy Hall
Ylaine Ong Gabat
Leela Kuriakose
Kristy Rofheart
Ruben Rivera
Yu Hu
Chanelle Clerc
Jian Zhu
Sally Xu
Vienna Vivares
Jeane Rummel
Annie Gaskin•

National/International Collaborators
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Dr. Omar Shamieh (Jordan)
Dr. Odai Kamesh (Jordan)
Dr. Carlos Paiva (Brazil)
Dr. Renata dos Santos (Brazil)
Dr. Maria Salete Angelis (Brazil)
Natalia Campacci (Brazil)
Camila Crovador (Brazil)
Dr. Jung Hye Kwon (Korea)
Dr. Jung Hun Kang (Korea)
Dr. Seong Hoon Shin (Korea)
Dr. Pedro Perez Cruz (Chile)
Dr. Mary Ann Muckaden (India)
Dr. Florian Strasser (Swiss)
Dr. Nathan Cherny (Israel)
Dr. Wadih Rhondali (France)
Dr. Bill Brietbart (MSK)
Dr. Donald Mahler (Dartmouth)

Funding Support
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American Cancer Society
National Cancer InstituteMD Anderson IRG
Sabin Family Fellowship Grant
MD Anderson Startup Fund
Sister Network Institution Fund
Helsinn Therapeutics Inc
Depomed Pharmaceutical
Teva Pharmaceutical Industries
Insys Therapeutics Inc.