Download Delirium - Canadian Society of Hospital Pharmacists

Management of Dementia/Delirium in Geriatric
Populations
Allan Mills
CSHP-OB AGM
Saturday November 15th, 2008
OR…Is it Delirium or Dementia?
(I Can Never Remember)
Allan Mills
CSHP-OB AGM
Saturday November 15th, 2008
OR… Delirium in an Acute Care Setting is
Bad.
Why do we find that so confusing?
Allan Mills
CSHP-OB AGM
Saturday November 15th, 2008
Overview
From a Pharmacists perspective we will:
Explore the differences between Delirium and
Dementia.
Briefly review the treatment of Dementia
Look at the consequences of delirium in an acute
care setting
Review the incidence, pathophysiology and
presentation
Highlight the importance of identification
Review interventions
4
It’s So Confusing…
Dementia
Insidious onset
Progressive decline
Memory impaired
Global deficits
Normal alertness
Normal vitals
Non reversible
DAT, LBD cause
See O Keefe et al. Emerg Med Clin North Am.
1998 Nov;16(4):701-15
5
Delirium
Rapid onset
Fluctuating course
Attention impaired
Focal deficits
Decreased alertness
Altered vitals
Reversible (maybe)
Drug/acute disease
cause
Dementia
A group of disorders that all:
Are progressive disorders with non reversible loss of function
Cause loss in memory, reasoning and language, motor
function
Have a gradual onset
Can only be diagnosed when other etiologies ruled out
AD dementia can be early-onset (<65 yrs of age) or
late-onset (>65 yrs of age)
Includes:
Alzheimer’s disease
Lewy body disease
Parkinson’s disease
Nutritional deficiencies
Vascular dementia
Pick’s disease
Infections
6
Dementia - statistics
8% of Canadian’s over 65 have dementia
>60% Alzheimer’s (DAT)
~20% Lewy Body Disease
Affects 1 in 20 Canadians aged > 65; 1 in 4 > 85
Half of those with dementias live in the community;
half live in institutions
by 2021 ~600,000 Canadians will have DAT1
Twice as many women as men have dementia
Cost of illness estimates ~ $3.9 billion/yr
CMAJ 1994; 150: 899-913.
7
AD Pathophysiology
5 changes noted in DAT
1) neurofibrillary tangles
twisted tau fibers that build up inside the neuron
2) neuritic plaques
dense layers of β amyloid around neurons
3) amyloid angiopathy
β amyloid around the small vessels
4) granulovascular degeneration
5) Apoptosis
Cellular death secondary to oxidative stress
Net result : decrease in multiple neurotransmitters
The cholinergic system appears most significantly
affected
8
Alzheimer’s Disease Progresses
Through Distinct Stages
Dementia/Alzheimer’s
Stage
Symptoms
Mild
Moderate
Memory loss
Severe
Behavioural,
personality
changes
Gait, incontinence,
motor disturbances
Mood swings
Unable to learn/recall
new info
Personality
changes
Unable to perform
ADL
LT memory affected
Diminished
judgment
Wandering, agitation,
aggression,
confusion
Placement in LTC
needed
Language
problems
Require assistance
w/ADL
9
Bedridden
Mini-Mental State Examination (MMSE)
Natural History of AD
30
25
20
Early diagnosis
Severe
Mild-to-moderate
Symptoms
Diagnosis
Loss of functional
independence
15
Behavioural problems
10
Nursing home placement
5
Death
0
1
2
3
4
Time (years)
5
Feldman and Gracon, 1996.
10
6
7
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Agents for Dementia
“Memory”
Cholinesterase inhibitors
Donepezil, rivastigmine, galantamine
NMDA Receptor antagonists
Memantine
“Behavior”
Neuroleptics
Antidepressants
Benzodiazepines
Mood stabilizers/ anti-epileptic agents
Cholinesterase inhibitors
11
Donepezil (Aricept®)
Second-generation cholinesterase inhibitor
Noncompetitive, reversible, long-lasting
Half-life of 70 hours
Well absorbed (~100%), food no effect
Metabolized by Cytochrome P450 2D6 and 3A4 metabolic
pathways – potential for drug interactions
Once-a-day dosing of 5 to 10 mg
Higher doses associated with cholinergic
side effects - but generally well-tolerated
12
Rivastigmine (Exelon®)
Second-generation cholinesterase inhibitor
Noncompetitive, pseudo-irreversible
Moderate half-life of 1.5 hours
Twice-a-day dosing: 3 - 12 mg/d
Bio-availability ~40% - food delays
Metabolism is almost totally independent
of the hepatic cytochrome P450 system
(cholinesterase-mediated hydrolysis )
Common gastrointestinal adverse events,
including weight loss
13
Galantamine (Reminyl®)
Two mechanisms of action
Nicotinic modulation
Acetylcholinesterase inhibition
Half-life: 6–8 hours
Low (18%) plasma protein binding
Levels in brain 2x–3x higher than in plasma
Twice a day dosing: 8-24 mg/day
CR form available – daily dosing
Hepatic metabolism CYP 2D6 and 3A4
Common GI side effects: Nausea, vomiting
14
MOA of Cognitive Enhancers
ACh
Presynaptic
nerve terminal
N = nicotinic
M = muscarinic
ACh =
acetylcholine
M receptor
N receptor
2
Donepezil
Galantamine
Rivastigmine
Galantamine
1
Acetylcholinesterase
ACh
Postsynaptic
nerve 1 Increased availability of ACh at synapse (AChE inhibition)
terminal
Increased release of ACh into synapse
2
(allosteric modulation15of presynaptic nicotinic receptors)
Efficacy in AD Outcomes
Agent
Donepezil
Rivastigmine
Galantamine
DAT
Global
Function
Behaviour
LBD


()









Raskind, et al. Neurology 2000;54:2261-2268. Tariot PN et al. Neurology 2000;54:2269-2276.
Wilcock GK et al. BMJ 2000;321:1445.
16
Change in ADAS-cog After Withdrawal
Double-blind
GAL-INT-2 (US)
-2.0
Withdrawal
GAL-USA-5
-1.5
Improvement
-1.0
Mean (± SE)
Change
-0.5
From
Baseline in
0
ADAS-cog
Score
0.5
Placebo/Placebo (n = 42)
1.0
Galantamine/Galantamine (n = 30)
1.5
Galantamine/Placebo (n = 36)
2
1
Months
GAL-USA-5
17
Deterioration
3
4.5
Adverse Events
Cholinergic based adverse events
Nausea (19%)
Diarrhea (15%)
Insomnia (14%)
Vomiting (8%)
Fatigue (8%)
Anorexia (7%)
Muscle Cramps (8%)
Other possible side effects: bradycardia,
precipitation of heart block, reduction of seizure
threshold, bronchoconstriction
18
Monitoring Parameters
Baseline MMSE, EKG: repeat if CVS symptoms or
baseline risk (bradycardia, arrythmia)
follow for side effects
diarrhea, nausea, insomnia, vomiting, fatigue,
anorexia, muscle Cramps -most common
also follow for syncope, seizures,
bronchoconstriction (SOB)
After 6-12 weeks : repeat MMSE; adjust dose based
on side effects, MMSE or behavior changes
Patient should always be titrated to the highest
tolerable dose.
19
Memantine (Ebixa®)
Low to moderate affinity to the NMDA receptor blocker
NMDA receptor activated by glutamate
Glutamate levels are increased in DAT
Theory: high levels of glutamate activation leads to
increased Ca+2 influx, abnormal cell function
(symptoms of DAT) and eventually apoptosis
(programmed cell death)
Possibly due to oxidative stress due to
excessive glutamate and calcium
20
Glutamate and Cognitive
Decline
Abnormal glutamate levels leads to
a decrease in NMDA receptor
activity
Cell death due to
chronic insult
Cognitive decline
( Calcium and
glutamate)
21
Memantine
No affinity for other receptors
Well absorbed, t1/2 =60-80 hours (+/- food)
Mostly cleared via tubular secretion with slight
metabolism by CYP450 (no significant effect)
Drug Interactions: Few – noted agents that
alkalinize the urine (Bicarb, acetazolamide)
Available 5 and 10mg tablets
Dosing start with 5mg daily and increase by 5 mg per day
until 10mg bid reached
Dosage adjustment in RF?
22
Memantine Efficacy (ADAS-cog)
2
*
0
 Memantine
-2
Improvement
Mean change from baseline
Worsening
ADAS-cog score difference
ITT, LOCF
(20 mg/day)
 Placebo
-4
0
12
Week
23
28
* p < 0.05 versus placebo
Wilcock et al., Int Clin Psychopharmacol 2002
Memantine Efficacy (SIB)
Mean change from baseline
N = 119
2
N = 107
N = 126
0
both groups
-2
*
N = 117
N = 97
-4
-6
 Memantine
(20 mg/day)
-8
-10
N = 106
N = 83
 Placebo
Worsening
SIB score difference
4
Improvement
OC analysis
-12
0
4
12
Week
Reisberg et al NEJM 2003; 348:1333-41
24
28
* p = 0.002 versus placebo
ed 2003
Adverse Events
Generally well tolerated:
Monitor for agitation/confusion, diarrhea, vomiting
and nausea.
Headache and dizziness also reported.
Noted in one trial to cause insomnia, increase in
pain and hypertension (inconsistent data).
Does not appear to have any significant direct
cardiac effects
25
Other Agents
NSAIDs
Possible protective effect observed in epidemiological studies
Decreased incidence of DAT in patients treated with
NSAIDs
May decrease inflammation reaction and protect against
disease progression
Requires further trials as initial RCT too small
ADAPT – trial comparing naproxen or celecoxib to
placebo stopped early due to naproxen CVS risk
Other trials showed increased risk with celecoxib
Great debate…
Prince Neurology 1998; Rogers, Neurology 1996; Veld NEJM 2001
26
Other Agents
Gingko:
Shown to improve ADAS-Cog by 1.4 pts
High drop out rate, unregulated product
Antiplatelet effect, effect on ASA, Warfarin
Vitamin E
Moderate DAT:delayed some negative outcomes
High doses studied but not recommended
LeBars JAMA 1997; Sano NEJM 1997
27
Experimental Treatments
β amyloid production/handling (Plaques)
Flurizan - tarenflurbil
Alters gamma-secretase enzyme which creates β amyloid,
mixed results
Bapineuzumab: monoclonal antibody binds β amyloid (?serious
s/e –microhemorrhage)
Simvastatin – effect on β amyloid and vascular. (Yes statins!)
PBT2 – prevent interaction with minerals
Heparan Sulphates, LY450139, ELND005, PRX-03140 –early
stages
Tau proteins (Tangles)
methylthioninium chloride (Rember)
To prevent aggregation of tau – early trials
Receptor for Advanced Glycation Endpoints (RAGE)
PF-04494700 – inhibits receptor – decreased inflammation/plaque
Other
Souvenaid - Proposed to enhance synapse production (?)
T-817MA – stimulates cell regrowth (?)
28
Delirium
Definition:
Delirium is a change in mental state, which comes
on suddenly, fluctuates over 24 hours, alters
consciousness, disturbs thinking and attention, and
results in changed behaviour.
Symptoms:
Problems with attention, thinking, memory,
psychomotor changes (+/-) and the sleep-wake
cycle
(DSM-IV-TR, 2000).
29
Delirium
Statistics
For people > 75 yo:
Present on arrival to ER in up to 30% of elders
Present in 72% of all elder admissions in
ICU (UK data 2003)
25-60% will experience delirium post
discharge
56% may develop delirium in hospital
30-40% become delirious after hip surgery
Mean LOA 27.3 days (UK 2003)
40-60% of residents in skilled nursing facilities
experience delirium
Culp et al, J of Neuroscience Nursing,
Inouye SK N Engl J Med 2006;354:1157-65.
Pun BT et al. Chest. 2007 132(2):624-36
30
Delirium on Dementia:
Cumulative Rates
31
Consequences of Delirium
Study reviewed 229 older individuals with delirium –
case matched controls
Length of Stay:
12.1 days in the hospital vs 7.2 days for controls
Institutionalization
16% vs 3% for controls
Death:
8% vs 1% for controls
Most likely causes: electrolyte changes (sodium), acute illness,
baseline dementia, fever or hypothermia, psychoactive drug
use and azotemia
Frances et al. JAMA 263(8):1097-1101.
32
Pathophysiology of Delirium
Guesses:
Cholinergic deficit – acute reduction/alteration in
acetylcholine levels
Anticholinergic drugs shown to cause
Dopaminergic excess – regulatory affect on
acetylcholine
Levodopa, Buproprion shown to cause
Cytokines/inflammation – May lead to increased
permeability of the blood brain barrier
Stress may activate HPA – cytokines and
cortisol
Likely to be multifactoral
Inouye SK. N Engl J Med 2006;354:1157-65.
33
Who has it?
Could I predict who has it?
Physical restraints, new medications,
infection, dehydration.
How do I confirm it?
Confusion Assessment Method (CAM)
4 domains:
Fluctuating mental status
Inattention
Disorganized thinking
Altered level of consciousness
Only 15% are hyperactive – we miss +++
34
Delirium Presentation
35
CAM-ICU
36
The RASS Scale
Scale
Definitions
Description
+4
Combative
Combative, violent, immediate danger to staff
+3
Very agitated
Pulls or removes tubes or catheters; aggressive
+2
Agitated
Frequent nonpurposeful movement, fights ventilator
+1
Restless
Anxious and apprehensive, but movements not
aggressive or vigorous
0
Alert and calm
–1
Drowsy
–2
Light sedation
–3
Moderate sedation
–4
Deep sedation
–5
Not arousable
Not fully alert, has eye opening to voice and sustained
eye contact (> 10 s)
Briefly awakens to voice with eye opening and eye
contact (< 10 s)
Movement or eye opening to voice (but no eye contact)
No response to voice, but movement or eye opening to
physical stimulation
No response to voice or physical stimulation
Sessler CN et al. Am J Respir Crit Care Med 2002;166,1338-1344
37
Risk Factors
Inadequate fluid intake
Dementia (or baseline cognitive deficits)
Sensory impairment
Falling in past 30 days
Medications
Age
Research in Nursing & Health, 1999,22,95-105
38
Delirium
D rugs
E lectrolyte
L ack of drugs
I nfection
R educed sensory input
I ntracranial
U rinary retention
M yocardial
39
Delirium –Causes (1)
Metabolic disorders:
40% of all cases
Organ failure (liver or kidney)
Accumulation of waste products (ammonia,
nitrogenous waste) and electrolyte disturbances
Diabetes mellitus
Hyperthyroidism and hypothyroidism,
40
Delirium –Causes (2)
Illness:
Infection/ fever
head trauma /epilepsy /stroke / tumour
hypoxemia OR hypercapnia
Surgery – common post-surgical complication
One in ten hip # admissions
Dehydration
Pain
Constipation, urinary retention, impaction
Cardiac (MI, CHF)
Worsening of a pre-existing condition
CHF, DM, COPD….
41
Delirium –Causes (3)
Drugs
Anticholinergics
Ethanol
Anticonvulsants
Corticosteroids
Lithium
Antibiotics
Sedatives
Antidepressants
(NSAIDs)
Anticancer drugs
H2RA/Antihistamines
Dopamine agonists
DRUG WITHDRAWAL
42
Lorazepam is an independent risk factor
for transitioning to delirium in the ICU
Pun, B. T. et al. Chest
2007;132:624-636
43
Delirium –Causes (4)
Street Drugs
ethanol (drinking alcohol)
marijuana
LSD and other hallucinogens
amphetamines
cocaine
opiates, including meperidine, heroin and morphine
PCP (phencyclidine)
inhalants
44
Delirium - Treatment
Prevent it:
Identify those individuals at risk on your unit:
Baseline cognitive impairment1
Sensory impairment (deaf, blind)
Prolonged mechanical ventilation/ICU stay in elders
Metabolic disturbances
Reduce incidence by 40% by making sure patients:2
Remain mobile
Are properly hydrated
Get proper sleep
Have their hearing and visual aids
Evidence for routine use of an assessment tool in the ICU3
Evidence suggests anesthesia is not a risk factor4
1 Pun BT et al. Chest. 2007 132(2):624-36
2 Inouye SK,et al. NEJM 1999; 340(9):669-76
3 Devlin J et al Intensive Care Medicine. 2007; 33(6):929-40
4 Bryson GL et al. Canadian Journal of Anaesthesia. 2006; 53(7):669-77
45
Preventable DRI have been associated with a
higher incidence of delirium:
Meperidine as a post op analgesic1
Psychotropic drug use (BDZ, others)2
Nicotine withdrawal3
Inadequate pain control or excessive narcotic
dosage.3-5
Assess medication changes
1 Fong HK et al. Anesthesia & Analgesia. 2006; 102(4):1255-66
2 Dasgupta M et al Journal of the American Geriatrics Society. 2006; 54(10):1578-89
3 Weins C et al Postgraduate Medical Journal. 2004; 80(945):388-93
4 Gaudreau JD et al. Psychosomatics. 2005; 46(4):302-16
5 Gunther ML et al Critical Care Clinics. 2008; 24(1):45-65
46
Delirium - Treatment
Identify underlying condition and correct
Constipation, pain, urinary retention, DM, CHF…
Maintain consistent environment
Daytime stimulation – activities
Quiet time at night
Familiar items
May require family support, family education
Visual and auditory stimulation
Reduce the stimulation by removing glare,
provide even lighting, give them something
interesting to view, decrease background noise
Inouye SK,et al. NEJM 1999; 340(9):669-76
47
Pharmacotherapy
Most guidelines suggests neuroleptics:
Well designed RCT data lacking
Baseline comparisons
No comparison to non pharm tx
Inadequate data to suggest any neuroleptic better then
any other
Inadequate data for atypicals
A single trial suggests haloperidol is as effective as
atypicals
Poor data regarding adverse events
So…Haloperidol generally suggested first line
Consensus and experience
Seitz D et al. Journal of Clinical Psychiatry. 2007; 68(1):11-21
Lacasse H et al. Annals of Pharmacotherapy. 2006; 40(11):1966-73,
Boettger S Palliative & Supportive Care. 2005; 3(3):227-37
48
Antipsychotics
Side Effects
Extrapyramidal symptoms frequent
Tardive dyskinesia -26% after 1 year of use
Sedation
Orthostasis, Anticholinergic effects
Atypical agents:
Wt gain (Obesity)
DM
CV – Lipids, QT, Stroke
Hyperprolactinemia
Tune LE et al. Psychiatr Clin North Am 1991;14(2):353-373.
49
Caution with Neuroleptics
Issues with the use of neuroleptics in the
elderly:
Data regarding atypical agents show increased
mortality
Short term use: most widely utilized agents
show greatest issue.
Haloperidol generally suggested first line:
Use the lowest dose (<3mg), for the shortest
duration, only when patient risk to themselves or
others
50
Deaths Based on Total Drug and Placebo Exposures Pooled
by Drug
Schneider, L. S. et al. JAMA 2005;294:1934-1943.
Copyright restrictions may apply.
51
Change in Expert Opinion?
“Within the limits of expert opinion and with the
expectation that future research data will take
precedence, these guidelines suggest that the
Second Generation Antipsychotic Agents are
now preferred for agitation in the setting of
primary psychiatric illnesses but that
Benzodiazepines are preferred in other
situations”
Allen MH et el. Treatment of behavioral emergencies 2005. J Psychiatr Pract. 2005 Nov;11 Suppl 1:5-108;
52
What about ACHEI?
Systematic review of ACHEI found limited data
One RCT with donepezil in post op patients with
delirium
No clinical difference noted
Further study required before routine use can be
suggested (currently underway)
Overshott R et al. Cochrane Database of Systematic Reviews. (1):CD005317, 2008
53
Ideally…
Early identification/prevention via standardized
identification methods should be used
Particularly in high risk areas
Studies prove a multimodal approach is most
effective:
Nursing intervention
Environmental modification
Remove causative agents (sedatives…)
Aggressive treatment of underlying illness
Targeted pharmacotherapy (neuroleptics possibly BDZ)
Anderson D. British Medical Bulletin. 2005; 73-74:25-34
Millison K et al. Journal of Advanced Nursing. 2005; 52(1):79-90.
Robinson T et al. Clinical Interventions In Aging. 2008; 3(2):351-5
Inouye, Sharon K. Cleveland Clinic Journal of Medicine. 2004; 71(11):890-6
54
Delirium – Key Points
Delirium is:
A sudden onset of altered behaviour and mental
status
Transient - treatment of underlying cause(s) will
usually reverse it.
Easy to miss - is frequently misdiagnosed—
mental status changes are missed or wrongly
attributed to dementia.
Exacerbated by environmental changes and/or
psychosocial issues in the older person’s life.
A warning Sign of acute illness.
Almost any illness or medication can lead
to delirium in the older adult.
55
Summary
Dementia and Delirium may have similar features but
are different causes and treatment strategies.
Early identification of Delirium and its cause is critical
Pharmacists play a significant role in the management
of delirium – as part of the team altering medication to
remove causative agents and enhancing treatment of
causes
Choice of treatment strategies needs to include non
pharmacological approaches.
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