KEY POINT:

DIAGNOSIS AND A Delirium is

primarily a

MANAGEMENT cognitive
disorder

OF DELIRIUM associated with

a fluctuating
presentation;
James A. Bourgeois, Andreea Seritan other psychiatric
symptoms are
usually also (but
variably) present.
ABSTRACT
Delirium is an acute- to subacute-onset impairment in cognitive and other psy-
chiatric functions due to central nervous system (CNS) and/or systemic disturbances.
Thorough evaluation, accurate diagnosis, and thoughtful nonpharmacological and
pharmacological management are necessary to reduce morbidity and improve
prognosis. Due to premorbid CNS illness, neurological patients are exquisitely vul-
nerable to delirium. In addition, several groups of medications used for neurological
illness predispose patients to delirium. Recent literature provides additional insights
into the genesis, diagnosis, classification, and management of delirium. Confident
management of delirium is essential to modern psychiatric and neurological
practice.

INTRODUCTION DEFINITION OF DELIRIUM

Delirium is an acute-/subacute-onset
neuropsychiatric illness that results in
decreased cognitive function accom-
panied with circadian rhythm distur-
bances. Although not necessary for a
diagnosis of delirium, other symptom
clusters suggestive of classic ‘‘psychi-
atric’’ illness, such as depression,
anxiety, and psychosis, frequently co-
occur with cognitive impairment and
neurovegetative disturbances. Partially
due to its heterogeneous nature,
delirium is frequently underdiagnosed
in clinical practice (Burns et al, 2004;
Meagher, 2001). Although often con-
fused with dementia, with which it is
frequently comorbid, delirium is par-
simoniously conceptualized as the
neuropsychiatric expression of sys-
temic disease, rather than as a ‘‘focal’’
central nervous system (CNS) illness.
Nonetheless, CNS disease, on the basis
of the ‘‘vulnerable’’ brain, is an impor-
tant risk factor for the development of
delirium.
Delirium is defined by the Diagnostic
and Statistical Manual of Mental
Disorders, Fourth Edition, Text Revi-
sion (DSM-IV-TR) (American Psychiatric
Association, 2000) as one of the cog-
nitive disorders; that is, the ‘‘core’’
clinical deficit is in cognitive function.
The DMS-IV-TR criteria for a diagnosis
of delirium include the following four
items:
15
A. Disturbance of consciousness . . .
with reduced ability to focus,
sustain, or shift attention.
B. A change in cognition . . . or the
development of a perceptual
disturbance that is not better
accounted for by a preexisting,
established, or evolving dementia.
C. The disturbance develops over a
short period of time . . . and tends
to fluctuate during the course of
the day.
D. There is evidence from the history,
physical examination, or laboratory

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 " DIAGNOSIS AND MANAGEMENT OF DELIRIUM

KEY POINTS:
findings that the disturbance is are associated with delirium include
A DSM-IV-TR
caused by the direct physiological the following (Burns et al, 2004;
classification of
delirium allows consequences of a general medical Meagher, 2001; Weber et al, 2004):
for attribution condition (American Psychiatric
1. Dementia of the Alzheimer’s type
of putative Association, 2000).
2. Vascular dementia
cause(s) of For classification purposes, DSM-IV- 3. Lewy body dementia
delirium. TR further specifies delirium types based 4. Parkinson’s disease
A Central nervous on etiological factors. All of these feature 5. Multiple sclerosis
system illness the clinical findings above but differ in 6. Head trauma
renders the clinical context and putative cause(s) 7. CNS tumors
neurological of the onset of delirium: (1) delirium 8. Seizure disorder
patients due to a general medical condition (in- 9. Depression
especially cludes cases due to the physiological
vulnerable to
10. Alcohol and other substance
effects of a medication); (2) delirium abuse
delirium.
due to multiple etiologies (includes mul-
tiple general medical conditions, mul- In addition, acute or subacute CNS
tiple medications, or a combination); (3) lesions or diseases are commonly as-
substance-induced delirium (substances sociated with delirium in the acute
of abuse); (4) substance-withdrawal de- presentation, likely due to the active
lirium (substances of abuse); (5) delir- injury of CNS tissue. Examples include
ium not otherwise specified (cause[s] the following (Caeiro et al, 2004;
cannot confidently be identified/classified) Samuels and Evers, 2002; Schwartz
(American Psychiatric Association, 2000). and Masand, 2002):
In practice, especially in complex
1. Head trauma
patients, one frequently uses the clas-
2. Cerebrovascular accident
sification of delirium due to multiple
3. CNS lupus erythematosus
etiologies, which is also called multi-
4. Giant cell arteritis
factorial delirium in some literature.
5. Human immunodeficiency virus
DSM-IV-TR has additional codes for the
(HIV) disease, eg, HIV dementia,
co-occurrence of delirium and demen-
HIV-associated CNS lymphoma, or
tia (American Psychiatric Association,
CNS toxoplasmosis
2000).
6. Seizures

ETIOLOGIES Among non-CNS systemic factors

16 Etiologies of delirium are, of course,
legion and cannot be fully tabulated.
It is helpful to think of baseline vulner-
abilities as well as more acute CNS and/
or systemic factors in delirium. Both
groups of factors have relevance to
neurological practice. Among baseline
vulnerabilities to delirium, preexisting
CNS disease is the most important
to the neurologist. In general, any
neurological illness that is associated
with cognitive impairment plausibly
increases the risk of delirium by virtue
of a diminished cerebral cognitive
reserve. Examples of CNS illnesses that
predisposing to delirium, any substan-
tial disturbance in circulation, oxygen-
ation, metabolic balance, or infection
can be associated with delirium. Some
of the more commonly implicated sys-
temic factors in delirium include the
following (Burns et al, 2004; Meagher,
2001; Samuels and Evers, 2002; Schwartz
and Masand, 2002; Tune, 2001; Weber
et al, 2004):
1. Cardiovascular disease
2. Pulmonary disease
3. Liver disease
4. Renal disease
5. Local or systemic infections

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 KEY POINTS:
6. Anemia 2001; Rincon et al, 2001; Samuels and
A Many systemic
7. Burns Evers, 2002; Schwartz and Masand,
disturbances
8. Dehydration 2002; Tune, 2001; Turkel and Tavare, may account
9. Sensory deprivation (eg, vision, 2003; Weber et al, 2004). In a large for delirium,
hearing impairment) study of neurological ward patients in especially in
10. Overall severity of the systemic Europe, delirium, dementia, and ‘‘other vulnerable
illness organic mental disorders’’ accounted patients.
11. Poor nutritional status for 20% of neurological patients re-
A Medications that
12. Use of physical restraints ferred for psychiatry consultation (de provoke delirium
13. Polypharmacy Jonge et al, 2001). commonly affect
14. Iatrogenic events (eg, invasive cholinergic,
procedures, urinary PATHOPHYSIOLOGY dopaminergic,
catheterization) A classic paper by Engel and Romano -aminobutyric
15. Increased age and male gender (1959, reprinted 2004) memorably acid–ergic, or
16. Sleep disturbance described delirium as a ‘‘syndrome of opioid-receptor
cerebral insufficiency.’’ As such, one function.
Many commonly used medication
classes are associated with delirium. can posit that many possible causes act A Delirium is more
Many of these are notable for their simultaneously in most cases (Engel common in
direct CNS effects, especially those that and Romano, 2004). This paper in- vulnerable
alter the cholinergic, dopaminergic, cluded a discussion of the classic elec- patient
troencephalogram (EEG) slowing in populations,
and -aminobutyric acid (GABA)-ergic
delirium, with which investigators cor- especially
neurotransmitter systems. Examples in-
related cerebral insufficiency, EEG patients with
clude the following (Burns et al, 2004; neurological
Meagher, 2001; Schrag, 2004; Tune, slowing, decreased level of conscious-
disease.
2001): ness (LOC), and slowing of other
cognitive processes, thus leading to
1. Opioids
the essential construct of delirium as a
2. Antihistamines
cognitive disorder (Engel and Romano,
3. Anticholinergics
2004). Because of the essentially wide-
4. Benzodiazepines
spread nature of metabolic and neuro-
5. Barbiturates
chemical dysfunction in delirium, in
6. Other sedatives
addition to the cognitive impairment,
7. Psychotropics
‘‘. . . all varieties of neurotic and psy-
8. Anticonvulsants
chotic behavior may become manifest
9. Antiparkinsonian medications
or accentuated in the course of delir-
10. Corticosteroids
ium’’ (Engel and Romano, 2004). 17
11. Immunosuppressants
The current pathophysiological model
12. Cardiovascular medications
to explain delirium consists of simul-
13. Gastrointestinal medications
taneous cholinergic deficit and dopa-
14. Antibiotics
mine excess as the most validated
15. Muscle relaxants
notable neurotransmitter disturbances
(Trzepacz, 2000); however, these alter-
EPIDEMIOLOGY nations in acetylcholine and dopamine
Delirium is common in hospitalized levels are best regarded as part of a
patients (especially those who are in more global derangement of multiple
intensive care units or are postopera- neurotransmitter systems (Burns et al,
tive), in elderly persons and children, 2004; Caeiro et al, 2004; Gaudreau and
in nursing home residents, in patients Gagnon, 2005; Samuels and Evers,
with cancer, and in terminally ill 2002; Tune, 2001). Exposure to anticho-
patients (Burns et al, 2004; Meagher, linergic medications and higher serum

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 " DIAGNOSIS AND MANAGEMENT OF DELIRIUM

KEY POINT:
anticholinergic levels correlate with
A Delirium
the onset of delirium (Tune, 2001).
pathophysiology
relates to The use of anticholinergic medications
cholinergic, has been shown to increase the risk of
delirium following stroke (Caeiro et al,
dopaminergic,
and other 2004). Dementia highly predisposes to
neurotransmitter episodes of delirium, while cholines-
disturbances. terase inhibitors to treat dementia may
improve symptoms of delirium (Burns
et al, 2004; Samuels and Evers, 2002;
Tune, 2001).
Gaudreau and Gagnon (2005) pres-
ent a synthesis of neurotransmitter
alterations in delirium, which also high-
lights interactions of cholinergic and
dopamine systems with glutamergic and
GABA pathways. They propose a model
of thalamic gating in delirium that may
partially account for the simultaneous
cognitive and psychotic symptoms seen
in delirium. Another proposed mecha-
nism in delirium is the presence of
widespread decreased oxidative metab-
olism in the brain (Samuels and Evers,
2002). Burns and colleagues (2004)
described two neuronal networks in
different anatomical sites as important
in delirium. The first network diffusely
involves the thalamus and both cortical
hemispheres, while the other involves
the frontal and parietal cortex in the
right hemisphere.
MOTORIC SUBTYPES
Delirium can be separated into clinical
subtypes based on the level and per-
sistence of motoric activity (Samuels
and Evers, 2002; Schwartz and Masand,
2002). Hyperactive delirium is charac-
terized by motor overactivity, frequently
described as agitation or anxiety by
medical personnel (Samuels and Evers,
2002). These patients are especially
likely to exhibit agitation late in the
day and overnight. Because of these
patients’ tendency to disrupt the care
environment, they are more readily
identified than hypoactive-delirium
patients (Case 2-1).
Hypoactive delirium, in contrast,
features profoundly decreased motoric
activity. Even though some evidence
suggests that hypoactive delirium is
associated with a worse prognosis than
hyperactive (Samuels and Evers, 2002),
hypoactive cases may generate less
clinical concern (because these patients
are not as disruptive). These patients

Case 2-1
A 30-year-old male patient with trauma has a closed head injury and multiple
fractures and has been receiving pain relief with intravenous (IV) opioids. Three
days later, he reports seeing ‘‘animals in the room at night,’’ and he is voicing
18 paranoid delusions about nursing staff ‘‘threatening’’ him. He is awake and
agitated at night, sedated or somnolent during the day. During his periods of
arousal, he appears anxious. Psychiatric history is limited to substance use
disorder. Computed tomography (CT) of the head is normal. Screening
laboratory studies are normal. On examination, he has a variable LOC, is anxious
appearing, and scores 22 on the Mini-Mental State Examination (MMSE).
He is treated with risperidone 1 mg by mouth (PO) every night, and
opioids are decreased and eventually discontinued. Three days later, he has
a normal sleep-wake cycle and scores 30 on the MMSE. He no longer is
agitated and does not report hallucinations.
Comment. This patient represents hyperactive delirium with cognitive,
psychotic, and sleep-wake cycle disturbances. Likely contributing factors
are trauma, closed head injury, and use of opioids. His recovery followed
minimization of the use of opioids and nighttime use of an antipsychotic
agent.

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are frequently misdiagnosed as being
‘‘just depressed’’ (Samuels and Evers,
2002). The distinction between depres-
sion and hypoactive delirium requires
demonstration of the cognitive and
circadian disturbances characteristic of
delirium in the hypoactive delirium
case. In addition, hypoactive delirium
cases may be missed when diagnostic
criteria for delirium focus on hyperac-
tive symptoms, as compared with the
more inclusive nature of the DSM-IV-TR
criteria (Cole et al, 2003) (Case 2-2).
Mixed delirium, which refers to
cases with variable elements of hyper-
active and hypoactive delirium at dif-
ferent points of time within a single
episode of delirium, has been reported
to be the most common subtype
(Samuels and Evers, 2002). A ‘‘normal’’
psychomotor delirium, where psycho-
motor activity is not affected by delir-
KEY POINTS:
ium has also been described (Samuels
A Motoric subtypes
and Evers, 2002).
in delirium
include
PSYCHIATRIC DIFFERENTIAL
hyperactive,
DIAGNOSIS
hypoactive, and
The psychiatric differential diagnosis mixed subtypes.
of delirium is broad, as a myriad of
A Hyperactive
psychiatric symptoms can be manifest
delirium
in delirium cases; eg, the patient may patients may
appear depressed, anxious, agitated, appear anxious,
psychotic, or primarily cognitively im- while hypoactive
paired, or a combination of these patients may
(Meagher, 2001). The ‘‘acute’’ psychi- appear
atric presentation of a patient in de- depressed.
lirium, eg, psychotic, depressed, or
anxious, is not indicative of an ongoing
psychotic, mood, or anxiety disorder
and can be conceived of as an ‘‘acute’’
consequence of the delirium itself.
The psychotic symptoms in delirium
(eg, hallucinations and delusions) tend
to fluctuate throughout the course of

Case 2-2
A 75-year-old man with multiple vascular risk factors, including diabetes
mellitus, hypertension, and smoking, is admitted for angina. Cardiac
catheterization reveals severe three-vessel disease. Psychiatric history is
unremarkable, but he has been noted by family members to have had
trouble with memory and naming of objects for several months. He
undergoes coronary artery bypass graft surgery, but postoperatively he
develops quiet confusion and hallucinations and is seen talking to unseen
people in his intensive care unit room. Examination reveals depressed
affect, variable LOC, and MMSE of 16, with significant problems with
orientation and memory. He cannot perform any category generation
tests, and his judgment and insight are poor. Laboratory studies reveal
white matter disease, cortical atrophy, and an old cardiovascular accident
19
on CT. Laboratory studies are otherwise unrevealing. He is weaned off
opioids, provided with frequent reorientation, and given quetiapine 25 mg
PO twice daily. Four days later, he is improved and has a normal sleep-wake
cycle. He is no longer grossly confused and no longer hallucinating, but
his MMSE improves only to 22, with residual deficits in memory, orientation,
and naming. He is maintained on quetiapine, and donepezil 5 mg PO every
night is added.
Comment. This case illustrates a patient with previously occult mild
vascular dementia who develops hypoactive delirium post–coronary artery
bypass graft. Treatment with an antipsychotic is indicated for both
hypoactive and hyperactive delirium. With treatment, his psychiatric status
improves, but he continues to have cognitive impairment after the
delirium clears. Donepezil is started for cognitive protection; this agent
enhances a favorable balance of cholinergic and dopaminergic function.

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 " DIAGNOSIS AND MANAGEMENT OF DELIRIUM
KEY POINTS:
an episode of delirium and are ac-
A Any psychiatric
companied by cognitive deficits, while
symptom
cluster can be psychotic symptoms in schizophre-
presented in nia and other psychotic disorders are
delirium, thus more persistent and less likely to be
complicating concurrent with cognitive impairment
the psychiatric (Samuels and Evers, 2002). Lewy body
differential dementia, which features psychotic
diagnosis. symptoms and a fluctuation in cogni-
A The psychiatric
tive status as part of its dementia syn-
symptoms drome, is challenging to distinguish
presenting with from delirium (Meagher, 2001). Intoxi-
delirium do not cation or withdrawal from substances
necessarily of abuse can cause maladaptive behav-
reflect the ioral changes (including anxiety, mood,
premorbid or psychotic, and cognitive symptoms)
chronic that do not necessarily meet full crite-
psychiatric ria for delirium (especially if the symp-
status. toms do not have a waxing and waning
A Delirium is course and are not associated with
associated with circadian rhythm disturbances).
poor functional
prognosis and PROGNOSIS
poor medical
outcomes. Prognosis for delirium can be grim, as
delirium is associated with increased
A Diagnosis of
morbidity and mortality, increased hos-
delirium
pital length of stay, longer postoperative
requires
recovery periods, long-term disability,
simultaneous
and increased rate of institutionali-
medical and
zation (Burns et al, 2004; Meagher,
psychiatric
examination,
2001; Samuels and Evers, 2002;
including Saravay et al, 2004; Saravay and Lavin,
standardized 1994; Schwartz and Masand, 2002;
assessment of Weber et al, 2004). The natural history
20 cognitive of delirium can be hard to quantify
function. since, once recognized, patients ide-
ally receive prompt evaluation and
care, such that the ‘‘natural history’’
of untreated delirium in a modern
medical care setting is a bit of a mis-
nomer. In a recent review, Weber
and colleagues (2004) summarized
that delirium typically resolves in 10
to 12 days.
EVALUATION
Diagnosis and management in delirium
are simultaneous and continuous pro-
cesses, with frequent reassessment of
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
progress an integral part of manage-
ment (Meagher, 2001). Evaluation of
delirium should include review of medi-
cal and psychiatric history, review of
prescription and over-the-counter medi-
cations, and alcohol and other sub-
stance abuse history (Samuels and
Evers, 2002). Physical examination
should address all the possibly impli-
cated systems described above, and
the mental status examination needs
to be detailed, including assessment
of orientation, memory/concentration,
naming, language use, mood/affect,
and assessment of psychosis.
Standardized observational measure-
ment and assessment of cognition by
validated instruments such as the Con-
fusion Assessment Method, Folstein
MMSE, Delirium Rating Scale (both
original and revised versions DRS and
DRS-R-98), Confusional State Evalua-
tion, Memorial Delirium Assessment
Scale, and Delirium Symptom Interview
are recommended (Breitbart et al, 1997;
Meagher, 2001; Samuels and Evers,
2002; Schwartz and Masand, 2002;
Trzepacz et al, 2001). Other bedside
assessments of cognitive function such
as sustained attention, clock drawing,
fund of knowledge, cognitive esti-
mations, ability to make abstract con-
nections, category generation, and
response inhibition tests may be
impaired in delirium.
Laboratory studies to consider rou-
tinely include serum electrolytes, chem-
istry panel, liver-associated enzymes,
ammonia, complete blood count, urine
drug screen, blood alcohol, thyroid-
stimulating hormone, calcium, magne-
sium, phosphate, pulse oximetry, and
urinalysis. Any suspicion of infection
should lead to cultures of urine, blood,
and sputum as needed. Radiological
studies include chest x-ray and unen-
hanced CT of the head. Other studies
to consider, depending on the clinical
circumstances, include arterial blood
gases, cerebrospinal fluid analysis, HIV,

and hepatitis serology. EEG is not
routinely indicated but may help in
equivocal cases, as it presents with
diffuse bilateral slowing in most cases
of delirium (Burns et al, 2004; Schwartz
and Masand, 2002).
MANAGEMENT
Prevention
Ideally, patients at high risk for delir-
ium should be identified and preven-
tive strategies employed. Weber and
colleagues (2004) reviewed the lit-
erature on clinical trials to prevent
delirium and summarized that the
following courses of action have been
shown to be helpful: interventions to
correct circadian disturbances; nursing
staff education; cognitive screening;
limiting physical immobility; avoidance
of sensory deprivation; prevention of
dehydration; advice from geriatrics con-
sultants, geriatric specialty nurses, and
psychogeriatricians; and a scheduled
pain management protocol. Preopera-
tively, psychological support may de-
crease the risk for later postoperative
delirium (Meagher, 2001).
Nonpharmacological
Intervention
The most important intervention for
managing delirium is correction of the
underlying systemic condition(s) re-
sponsible for the delirium (Schwartz
and Masand, 2002). The inpatient
management of the delirious patient
requires several nonpharmacological
measures. Frequent vital signs and
nursing assessments assure that nurs-
ing personnel will reassess the patient
so as to document behavioral safety,
monitor intake and output status, and
describe the sleep-wake cycle. Safety
and behavioral control are paramount.
Confused/combative delirious patients
require constant eyes-on supervision
by sitters or other nursing personnel
(Samuels and Evers, 2002). Restraints
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KEY POINTS:
are routinely needed for combative/
A Laboratory and
physically dangerous delirious patients.
imaging
Private, rather than shared, hospital assessment of
rooms may help decrease stimulation delirium must
(Meagher, 2001). Orientation devices address all
such as prominently displayed clock, possible
calendar, and television news program- systemic
ming may help to reorient the patient disturbances.
(Meagher, 2001). Visitors may provide
A Preventive
a calming influence as familiar persons strategies for
to the delirious patient and should delirium are
be encouraged to actively reorient the relatively simple
delirious patient on each encounter and intuitive
(Meagher, 2001). Provision of adequate and may
lighting with daily changes in the am- prevent
bient lighting level to promote a nor- morbidity.
mal circadian rhythm may be useful A Twenty-
(Meagher, 2001). four–hour
In intensive care units, delirious pa- observation
tients may become confused by medi- and assurance
cal equipment and may use a piece of of safety are
equipment as a weapon. In addition, necessary in
noises of the hospital may compromise managing
an already disordered sleep-wake cycle. delirium.
Assessment of swallowing function may
be necessary before oral feedings are
allowed (Samuels and Evers, 2002).
Close monitoring of fluid-electrolyte
status and respiratory and cardiovas-
cular status is critical (Samuels and
Evers, 2002).
After recovery, delirious patients
may recall fragments of the delirium
episode, which often produce anxiety
(Samuels and Evers, 2002). Psychoedu-
cational interventions to normalize 21
and/or reconstruct experiences of de-
lirium may prove helpful to recovery.
Patients’ later recall of events during
an episode is variable (Burns et al,
2004). In a study of 154 delirium pa-
tients, 53.5% were later able to recall
their delirium experience (Breitbart
et al, 2002a). Delirium severity, per-
ceptual disturbances, and short-term
memory impairment were the vari-
ables most notably associated with later
poorer recall of delirium (Breitbart
et al, 2002a). The majority of patients
who recalled their episode described
 " DIAGNOSIS AND MANAGEMENT OF DELIRIUM

KEY POINT:
delirium as highly distressing, and
A Amnesia for the
spouses, caregivers, and nurses also
delirium episode
is variable, and reported episodes of delirium as highly
recall of delirium distressing (Breitbart et al, 2002a).
events may be
fragmentary. Pharmacological Intervention
‘‘Primum non nocere’’ is the first dic-
tum for the physician. Known ‘‘delir-
iogenic’’ or ‘‘psychotoxic’’ medications
(eg, antihistamines, anticholinergics,
opioids) should be minimized or
avoided completely (Burns et al, 2004;
Tune, 2001). Regular monitoring of
metabolic parameters (chemistry panel,
liver-associated enzymes, complete
blood count) should be routinized as
part of the surveillance of pharmaco-
therapy of the delirium patient. Phar-
macological management of delirium
proceeds with the paired fundamental
imperatives of (1) correction of the
putative underlying medical illness/
drug exposure; and (2) avoidance of
exacerbation of delirium by adminis-
tering ‘‘psycho-toxic’’ or deliriogenic
medications. No pharmacological agents
have been specifically approved for
delirium by the US Food and Drug
Administration (USFDA). Pharmaco-
therapy for delirium consists primarily
of the judicious application of psycho-
pharmacological agents developed for
other psychiatric conditions, with some
nuances specific to this challenging
22 condition.
Typical Antipsychotics
The best-established medications for
delirium are the typical antipsychotics;
generally, the most practical is halo-
peridol (Meagher, 2001; Samuels and
Evers, 2002; Weber et al, 2004). Anti-
psychotics are indicated for delirium
episodes regardless of motor subtype
and generally improve cognitive func-
tion because they contain aberrant
motor behavior, decrease psychotic
symptoms, and promote normalization
of the sleep-wake cycle (Meagher,
2001). Haloperidol is chosen primarily
because of its classification as a high-
potency antipsychotic; ie, it has high
potency for D2 blockade and produces
less blockade of acetylcholine recep-
tors and also causes less orthostatic
hypotension than other typical anti-
psychotics (Meagher, 2001; Samuels
and Evers, 2002). As such, it is appeal-
ing as an intervention for delirium,
which is modeled as an acetylcholine-
deficient and hyper-dopaminergic state.
Haloperidol can be administered PO,
intramuscularly (IM), or by IV, although
the IV route of administration is not
USFDA approved.
Doses of haloperidol for delirium
are variable and hard to advise precisely.
Elderly and/or hypoactive delirium
patients can be started at doses of 0.5
to 1.0 mg every 12 hours, while young
and severely agitated hyperactive de-
lirium patients can be started at 10 mg
IV every 2 hours (Burns et al, 2004;
Meagher, 2001; Samuels and Evers,
2002). If initial doses are ineffective at
reversing symptoms, the initial dose
can be doubled in a second dose
30 minutes later unless adverse ef-
fects have occurred (Meagher, 2001).
This pattern of dose escalation can
be continued with close monitoring
until behavioral control is obtained
(Meagher 2001). Prompt response to
treatment and frequent adjustments of
doses are the rule, not the exception,
in managing delirium with haloperidol
(Meagher, 2001). The risk for extrapy-
ramidal symptoms (EPSs) attributable
to haloperidol is less with the IV
than the PO or IM delivery because
the hepatic ‘‘first pass’’ is avoided
(Meagher, 2001). QT corrected for
heart rate (QTc) prolongation has been
reported with haloperidol (as well as
with pimozide, droperidol, and thiorid-
azine); therefore, pretreatment electro-
cardiogram (ECG) and regular ECG
monitoring are needed (Glassman and
Bigger, 2001). A QTc of greater

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


than 500/ms at baseline or treatment-
emergent makes torsades de pointes
more likely and calls for a discontinu-
ation of haloperidol.
Atypical Antipsychotics
There is growing recent literature on
the use of atypical antipsychotics for
delirium (Meagher, 2001; Samuels and
Evers, 2002; Schwartz and Masand,
2002). Owing to their common mecha-
nism of action of variable D2 receptor
blockade and concurrent blockade of
the 5-hydroxytryptamine (5-HT)2 re-
ceptor, they all carry less risk for se-
dation and EPS than haloperidol and
other high-potency typical antipsychotic
agents (Breitbart et al, 2002b; Meagher,
2001; Schwartz and Masand, 2002).
Mittal and colleagues (2004) treated
10 delirium patients (mean age 65
years) with a mean dose of 0.75 mg/d
of risperidone and found improvement
in cognitive and behavioral symptoms;
no patients experienced EPS. Parellada
and colleagues (2004) treated 64 delir-
ium patients (mean age 67 years) with
a mean dose of 2.6-mg risperidone
per day; 90% improved, and only 3%
experienced adverse events, none of
which was EPS. Han and Kim (2004)
completed a double-blind study of
risperidone (1.0 mg/d) and haloperidol
(1.5 mg/d) for delirium in 28 patients
(mean age 66 years) and found no
significant difference in efficacy or
response rate between the two agents.
Isolated cases of delirium apparently
having been induced by risperidone
have been reported, so due caution is
warranted (Chen and Cardasis, 1996;
Doig et al, 2000; Ravona-Springer et al,
1998; Tavcar and Dernovsek, 1998).
Sipahimalani and Masand (1998)
treated 11 delirium patients with olan-
zapine (mean dose 8.2 mg/d) and 11
with haloperidol (mean dose 5.1 mg/d)
and found similar rates of clinical
improvement (five olanzapine and six
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS:
haloperidol patients with ‘‘marked’’
A Haloperidol is the
improvement). However, no olanza- best-established
pine patient had significant side effects, psychopharma-
while five haloperidol patients expe- cological agent
rienced excess sedation or EPS. A for delirium.
prospective trial of olanzapine in 79
delirious cancer patients revealed 76% A Haloperidol is
associated with
of cases with complete resolution of
QT corrected
delirium; 30% of cases experienced
for heart rate
sedation (Breitbart et al, 2002b). Mean prolongation and
initial olanzapine dose was 3.0 mg/d; at extrapyramidal
the end of the study the mean dose symptoms.
was 6.3 mg/d. Among several variables
examined, age over 70 was most highly A Haloperidol can
be delivered
associated with a poorer response to
by mouth,
olanzapine.
intramuscularly,
Sasaki and colleagues (2003) treated and
12 delirium patients with quetiapine intravenously.
(mean dose 44.9 mg/d) and found
that all patients achieved remission of A Atypical
delirium symptoms with no excess se- antipsychotic
agents offer
dation or EPS. Torres and colleagues
some advantages
(2001) successfully treated two delir-
over haloperidol
ium cases with quetiapine (doses were and in a limited
50 mg/d and 25 mg/d, respectively) with- number of
out adverse effects. Leso and Schwartz studies appear
(2002) successfully treated a delirium safe and
case with ziprasidone (100 mg/d) in effective for
a patient at risk for movement dis- delirium.
orders with risperidone; the patient
did, however, experience an 8.4% in-
crease in QTc plus premature ventricu-
lar contractions, necessitating eventual
discontinuation of ziprasidone. Crea-
tive use of one-time ziprasidone 20-mg
dose via the IV route has been de- 23
scribed in a case report of an inten-
sive care unit patient with delirium
who failed to respond to haloperidol
therapy. After the patient was extu-
bated, ziprasidone was continued via
the oral route, although the daily
dose used was unclear (Young and
Lujan, 2004).
In delirium in elderly patients, rec-
ommended starting doses for risper-
idone are 0.25 to 0.5 mg twice daily; for
olanzapine, 2.5 to 5.0 mg every night;
and for quetiapine, 12.5 mg every
night, with cautiously increased doses
 " DIAGNOSIS AND MANAGEMENT OF DELIRIUM

KEY POINTS:
as needed (Breitbart et al, 2002b; dol if prolonged QTc follows haloper-
A QT corrected for
Samuels and Evers, 2002; Schwartz idol use in delirium. Olanzapine is
heart rate
prolongation and Masand, 2002). In younger pa- associated with risk of increased se-
may be present tients, higher doses of risperidone rum glucose and should be used only
with risperidone (mean dose 1.59 mg/d), olanzapine with extreme caution in patients with
and ziprasidone (mean dose 8.2 mg/d), and quetia- diabetes or serious risk for diabetes.
as well as with pine (mean dose 211.4 mg/d) have Clozapine, which is significantly anti-
haloperidol. been reported to be successful in man- cholinergic, is contraindicated in de-
A Atypical aging delirium (Schwartz and Masand, lirium; olanzapine also has potential
antipsychotic 2002). Recommended as-needed doses anticholinergic effects and may be
agents are 0.25 to 0.5 mg of risperidone every theoretically problematic in this re-
offer some 4 hours and 25 mg to 50 mg of gard (Breitbart et al, 2002a; Tune,
advantages over quetiapine every 4 hours (Schwartz 2001). Risperidone is available in a
haloperidol and and Masand, 2002). As of this writing, liquid formulation, which allows for
in a limited too few studies of ziprasidone have convenient dosing by nasogastric tube.
number of been done to make specific recom- Olanzapine and risperidone are avail-
studies appear mendations for delirium. able in quickly dissolving oral tablets
safe and
The two atypical antipsychotics (Table 2-2).
effective for
risperidone and ziprasidone carry a None of the atypical antipsychot-
delirium.
risk of QTc prolongation (Glassman ics is available in IV form, although
and Bigger, 2001; US Food and Drug risperidone, olanzapine, and ziprasi-
Administration, 2000) (Table 2-1). It done are available in IM form. The IM
may be safest to use olanzapine or risperidone is intended to be given
quetiapine as alternatives to haloperi- every 2 weeks (initial dose 25 mg IM),
does not establish therapeutic levels
quickly, and thus is of limited use
in delirium unless the patient is at
TABLE 2-1 QT Corrected for risk for persistent delirium (eg, end
Heart Rate stage cancer) and simultaneously un-
Prolongation
able to take oral medications (Kane
With Certain
Antipsychotics et al, 2003). The IM preparations of
olanzapine and ziprasidone are rapid
QTc onset.
Prolongation Of concern is the recent USFDA
Agent Time Public Health Advisory (US Food and
24 Drug Administration, 2005) citing an
Thioridazine 35.6 ms
increased risk of death in elderly
Ziprasidone 20.3 ms patients with dementia who have
Quetiapine 14.5 ms received the atypical antipsychotics
risperidone, olanzapine, quetiapine,
Risperidone 10.0 ms
and aripiprazole. The increased risk
Olanzapine 6.4 ms of death was reported as a ‘‘1.6–1.7
Haloperidol 4.7 ms fold increase in mortality’’ (US Food
and Drug Administration, 2005). Car-
US Food and Drug Administration Psy-
chopharmacological Drugs Advisory Com- diac and infectious causes were asso-
mittee. Briefing document for Zeldox ciated with most of the increased
capsules (Ziprasidone HCl). [online] 2000;
825:1–173 [cited March 7, 2006]. Avail- deaths. The implications of this devel-
able from: http://www.fda.gov/ohrms/dockets/ opment for the management of delir-
ac/00/backgrd/3619b1a.pdf.
ium are unclear, but as many delirium
patients have comorbid dementia,

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 2-2 Antipsychotic Preparations
Haloperidol Risperidone
PO tablet + +
PO liquid + +
PO; disintegrating – + M-Tab*
tablet
Intramuscular + + Constaz
Intravenous + –
*Quick dissolving, available in standard tablet.
y
Quick dissolving, available in standard tablet.
z
Two-week injectable.
PO = by mouth; + = available; – = not available.
clearly, caution is in order and large-
scale studies would be desirable to
clarify this issue.
Benzodiazepines
Benzodiazepines have two roles in the
management of delirium. In cases of
delirium due to multiple causes or a sin-
gle cause other than alcohol or benzo-
diazepine withdrawal, benzodiazepines
are an adjunctive to antipsychotics
(Meagher, 2001; Samuels and Evers,
2002). If patients remain agitated and
unresponsive to treatment after several
doses of antipsychotic monotherapy
(as described above), a useful combi-
nation is haloperidol 5 mg with lor-
azepam 1 mg, repeated as needed.
Used in this fashion, a functional po-
tentiation of effects exists between the
two agents.
In addition to this adjunctive use
of benzodiazepines, benzodiazepine
monotherapy is the treatment of
choice when delirium is due to al-
cohol, benzodiazepine, or barbiturate
withdrawal or when delirium is due
to seizures (Meagher, 2001; Samuels
and Evers, 2002). Patients suspected
of alcohol-withdrawal delirium should
receive IV thiamine 100 mg/d and fo-
late 1 mg/d; thiamine should precede
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Olanzapine Quetiapine Ziprasidone
+ + +
– – –
y
+ Zydis – –
+ – +
– – –
IV glucose. Starting doses for benzo-
diazepine monotherapy for alcohol/
sedative/hypnotic withdrawal delir-
ium in an elderly patient is 0.5 of
lorazepam every 8 hours, cautiously
increased as needed (Samuels and
Evers, 2002). Younger and otherwise
healthier patients should receive more
robust doses. Lorazepam is a prefera-
ble benzodiazepine in delirium be-
cause of its properties of sedation,
rapid onset, short (thus controllable)
duration of action, lack of major ac-
tive metabolites, and low risk of accu-
mulation (Burns et al, 2004; Meagher,
2001). Close monitoring of vital signs
is needed in such cases, as benzo-
diazepine doses should be adequate 25
to counter the hyperadrenergic state
of alcohol, sedative, or hypnotic with-
drawal delirium as reflected by in-
creased temperature, increased blood
pressure, tachycardia, tremors, and di-
aphoresis. Once vital signs have nor-
malized and mental status has cleared,
benzodiazepines can then be slowly
tapered.
For alcohol-withdrawal delirium that
also includes hallucinations, adjunc-
tive use of antipsychotics should be
included, eg, a 1-mg dose of risper-
idone every 12 hours as needed
 " DIAGNOSIS AND MANAGEMENT OF DELIRIUM

KEY POINTS:
A Benzodiazepines Case 2-3
have primary A 45-year-old alcohol-dependent man is admitted after several days of
and adjunctive sobriety. He is tremulous, diaphoretic, and tachycardic. Laboratory studies
roles in delirium. reveal diffuse cortical and cerebellar atrophy on CT and increased mean
A Lorazepam corpuscular volume and elevated liver-associated enzymes. He is hyperalert
offers several and agitated, but confused, with an MMSE of 19. He receives thiamine,
advantages folate, and multivitamins. He is placed on lorazepam 2 mg every 4 hours.
over the He reports occasionally seeing ‘‘bugs on the wall’’ and receives risperidone
benzodiazepines 1 mg PO every 6 hours as needed. Within 3 days, he is improved, his
in delirium. tremulousness and diaphoresis resolve, and his MMSE climbs to 27.
Lorazepam is slowly tapered, and he requires no further as-needed doses
of risperidone.
Comment. This is a typical case of alcohol-withdrawal delirium with
intermittent psychotic symptoms. The main intervention is benzodiazepines,
with adjunctive use of an antipsychotic for breakthrough psychotic
symptoms. Thiamine is indicated to protect against Wernicke-Korsakoff
disease.

for hallucinations or delusions. When chotropics, anesthetic agents such as

benzodiazepine monotherapy is used
for delirium of uncertain mechanism,
there is a risk of paradoxical increase
in delirium. Excess sedation, respira-
tory depression, ataxia, and amnesia
can result from benzodiazepines for
delirium (Samuels and Evers, 2002)
(Case 2-3).
Cholinergics
Some work has been done on the
use of physostigmine for delirium,
consonant with the model of delirium
as a hypo-cholinergic state (Meagher,
2001; Samuels and Evers, 2002). While
26 this is not a common clinical practice
and not USFDA approved, use of
physostigmine might be appropriate
in conditions of a known anticholiner-
gic load (eg, an overdose of diphenhy-
dramine) as the putative risk factor for
delirium (Samuels and Evers, 2002).
Cholinergic agents should be avoided
in delirium patients with cardiac dis-
ease, asthma, diabetes, or obstructed
bowel (Samuels and Evers, 2002).
Anesthetic Agents
For dangerously agitated patients who
do not respond to more typical psy-
propofol can be considered for short-
term use (Jacobi et al, 2002). Because
of the risk of respiratory depression,
either a secure airway or the availability
of prompt intubation is necessary;
thus, propofol should be administered
under the guidance of an anesthesiol-
ogist (Hogarth and Hall, 2004). Propo-
fol has a rapid onset of action and short
half-life (Hogarth and Hall, 2004; Jacobi
et al, 2002). A maximum recommended
dose is 75 g/kg/min (Hogarth and Hall
2004). Additional risks of propofol are
hypertriglyceridemia, myocardial failure,
hypotension, bradycardia, elevation of
pancreatic enzymes, and lactic acido-
sis (Hogarth and Hall, 2004; Jacobi
et al, 2002).
Other Agents
A few other psychotropic agents may
have a place in managing delirium in se-
lected patients. For patients who have
complications from antipsychotics and
do not respond well to benzodiazepines,
IV valproic acid may be a useful ad-
junctive agent (Bourgeois et al, 2005).
This may be attractive in cases of co-
morbid delirium and seizure disorder.
IV valproate initial dosing is 10 mg/kg/d

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


to 15 mg/kg/d, dosed either 2 times
daily or 3 times daily. The recom-
mended serum trough level is 50 mg/L
to 100 mg/L. Valproate should not be
used in patients with hepatic disease,
history of pancreatitis, hyperammone-
mia, pregnancy, or thrombocytopenia
(Bourgeois et al, 2005).
Some literature supports the use of
5-HT3 blocking agents (eg, ondan-
setron) for delirium (Bayindir et al,
2000), indirectly suggesting a role for
serotonin in symptoms of delirium.
One study of 35 patients with post-
cardiotomy delirium showed a favor-
able response to a single dose of 8-mg
ondansetron (Bayindir et al, 2000).
Trazodone and mianserin, two antide-
pressants with 5-HT2-receptor blockade
properties, have been used success-
fully in open-label trials for delirium
(Burns et al, 2004; Meagher, 2001).
Postdelirium Prophylaxis
The literature is silent on the issue of
postrecovery prophylaxis of delirium.
Clinical prudence suggests that the
physician reassess the patient’s neuro-
logical and psychiatric status closely
upon recovery. For example, it is not
unusual to diagnose a recovered de-
lirium patient with a previously un-
recognized mild dementia (which, in
retrospect, had predisposed the pa-
tient to delirium). In such cases of ‘‘oc-
cult dementia presenting as delirium,’’
conventional approaches to dementia
pharmacology (usually including cho-
linesterase inhibitors and antipsychot-
ics) may maximize cognitive function
and simultaneously maintain a favor-
able cholinergic/dopaminergic balance
to make a recurrence of delirium less
likely. Similarly, in patients at risk
for chronic delirium (eg, patients in
liver failure or those with dissemi-
nated cancer), maintenance antipsy-
chotics are prudent, as the recurrence
risk for delirium is high. However, in
patients who recover to a cognitively
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT:
and otherwise psychiatrically intact
A Postdelirium
baseline, postdelirium prophylaxis is
prophylaxis may
unnecessary. be needed in
patients with
central nervous
CONCLUSION system disease
Delirium is an acute- to subacute- and/or certain
onset cognitive disorder that is the systemic illnesses.
neuropsychiatric consequence of CNS
and/or systemic disturbances. Once
manifest, delirium is associated with a
worrisome prognosis and higher rates
of morbidity and mortality. A constel-
lation of clinical findings, including
altered consciousness, disturbed sleep-
wake cycle, cognitive impairment, mood/
anxiety/psychotic symptoms, and a vari-
able course of illness, is characteristic.
Paying simultaneous attention to the
legion of causes while managing be-
havioral symptoms remains the cor-
nerstone of clinical management of
delirium.
Delirium is particularly important to
the neurologist for several reasons.
Chronic neurodegenerative disorders
are associated with higher rates of
episodic delirium by virtue of the
ongoing CNS illness, which renders
patients vulnerable to delirium in
the context of systemic disturbances
(Case 2-4).
Acute neurological illnesses (eg, car-
diovascular accident, traumatic brain
injury) will often present with delirium
as a component of the initial clinical 27
presentation. Pharmacological interven-
tions for many neurological illnesses
(eg, corticosteroids, other immunosup-
pressant agents, antiparkinsonian agents,
anticonvulsants) are associated with
delirium as medication side effects,
thus often compounding a risk for
delirium due to the underlying neu-
rological illness. Finally, a previously
unknown patient presenting with de-
lirium is often ultimately diagnosed
with a neurological disorder, such as
dementia, that had rendered the pa-
tient vulnerable to delirium.
 " DIAGNOSIS AND MANAGEMENT OF DELIRIUM

A high index of suspicion for cases prehensive neurological practice. Col-

of delirium, a systems-based thorough laboration between neurologists and
approach to diagnosis, and skill at consulting psychiatrists for clarifica-
behavioral and pharmacological man- tion and management of enigmatic
agement of delirium are part of com- cases of delirium is advised.

Case 2-4
A 40-year-old woman with multiple sclerosis (MS) is admitted for a
flare-up of her MS and is put on a brief course of high-dose prednisone.
Two days later, she is confused, agitated, cannot sleep, and is hallucinating
images of ‘‘people all over the room.’’ The ‘‘people’’ make threatening
gestures and statements to her. On examination, she is anxious, labile,
hallucinating, and has an MMSE of 25. She is hyperalert and tremulous.
CT reveals white matter disease. Laboratory studies are unrewarding.
She is placed on olanzapine 5 mg PO every night. Within 3 days, she
has a restored and intact sleep-wake cycle, is no longer hallucinating, and
her MMSE has improved to 29.
Comment. This is a case of hyperactive delirium due to a combination
of a chronic CNS disease and the use of high-dose corticosteroids.
Olanzapine may be helpful in cases with significant psychomotor agitation
(especially at night) as it is quite sedating. This patient may be at risk
for subsequent episodes of delirium recurrence if future courses of
prednisone are needed for MS exacerbations.

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