The n e w e ng l a n d j o u r na l of m e dic i n e

review article

Current Concepts

Delirium in Older Persons

Sharon K. Inouye, M.D., M.P.H.

D
elirium, an acute decline in attention and cognition, is a com- From the Department of Medicine, Har-
mon, life-threatening, and potentially preventable clinical syndrome among vard Medical School, Boston. Address
reprint requests to Dr. Inouye at the Ag-
persons who are 65 years of age or older. The development of delirium often ing Brain Center, Hebrew Senior Life,
initiates a cascade of events culminating in the loss of independence, an increased 1200 Centre St., Boston, MA 02131.
risk of morbidity and mortality, and increased health care costs.1-6 Delirium in hos-
N Engl J Med 2006;354:1157-65.
pitalized older patients has assumed particular importance because the care of such Copyright © 2006 Massachusetts Medical Society.
patients accounts for more than 49 percent of all hospital days.7 Delirium compli-
cates hospital stays for at least 20 percent of the 12.5 million patients 65 years of
age or older who are hospitalized each year and increases hospital costs by $2,500
per patient,8-10 so that about $6.9 billion (value in U.S. dollars in 2004) of Medicare
hospital expenditures are attributable to delirium. Substantial additional costs ac-
crue after hospital discharge because of the need for institutionalization, rehabili-
tation services, formal home health care, and informal caregiving.
This report examines current clinical practice in delirium, identifies areas of
controversy, and highlights areas for future research.

Epide miol o gy a nd Di agnos t ic Cr i ter i a

In direct contrast to dementia, which is a chronic confusional state, delirium is an

acute confusional state. Rates of delirium are highest among hospitalized older
patients, and the rates vary depending on the patients’ characteristics, setting of care,
and sensitivity of the detection method. The prevalence of delirium at hospital ad-
mission ranges from 14 to 24 percent, and the incidence of delirium arising during
hospitalization ranges from 6 to 56 percent among general hospital populations.11,12
Delirium occurs in 15 to 53 percent of older patients postoperatively11 and in 70 to
87 percent of those in intensive care.13 Delirium occurs in up to 60 percent of pa-
tients in nursing homes or post–acute care settings14,15 and in up to 83 percent of
all patients at the end of life.16,17 Although the overall prevalence of delirium in the
community is only 1 to 2 percent,18,19 the prevalence increases with age, rising to
14 percent among those more than 85 years old. Moreover, in 10 to 30 percent of
older patients presenting to emergency departments, delirium is a symptom11 that
often heralds the presence of life-threatening conditions. The mortality rates among
hospitalized patients with delirium range from 22 to 76 percent,20 as high as the
rates among patients with acute myocardial infarction or sepsis. The one-year mor-
tality rate associated with cases of delirium is 35 to 40 percent.21
The diagnosis of delirium is primarily clinical and is based on careful bedside
observation of key features. Although the criteria continue to evolve,22,23 the diag-
nostic algorithms that are most widely used are presented in the Supplementary
Appendix (available with the full text of this article at www.nejm.org). Delirium is
often unrecognized by the patients’ physicians and nurses,1,24 in part because of
its fluctuating nature, its overlap with dementia, lack of formal cognitive assess-
ment, underappreciation of its clinical consequences, and failure to consider the
diagnosis important.

n engl j med 354;11 www.nejm.org march 16, 2006 1157

 The n e w e ng l a n d j o u r na l
Cl inic a l Ch a r ac ter is t ic s
Because delirium remains a bedside diagnosis,
understanding its clinical features (Table 1 and
the Supplementary Appendix) is crucial to the di-
agnosis of delirium. Delirium has hypoactive and
hyperactive forms (Table 1). The hypoactive form
of delirium is more common among older persons
and often goes unrecognized.
Etiologic and Risk Factors
The cause of delirium is typically multifactorial.25
In fact, the development of delirium involves the
complex interrelationship between a vulnerable
patient (one with predisposing factors) (Table 2)
and exposure to precipitating factors or noxious
insults (Table 3).26,27 Thus, in patients who are
highly vulnerable to delirium, such as those with
dementia and multiple coexisting conditions, it
may develop as a result of relatively benign in-
sults, such as one dose of a sleeping medication.
Conversely, in patients who are not vulnerable to
delirium, it develops only after exposure to mul-
tiple noxious insults, such as general anesthesia,
major surgery, and psychoactive medications. Ad-
dressing just one contributing factor is unlikely to
resolve delirium in an older person; they should
all be addressed when possible.
Pathogenesis
The pathophysiology of delirium remains poorly
understood. Electroencephalographic studies have
demonstrated diffuse slowing of cortical back-
ground activity, which does not correlate with un-
derlying causes.28 Neuropsychological and neuro-
imaging studies reveal generalized disruption in
higher cortical function, with dysfunction in the
prefrontal cortex, subcortical structures, thalamus,
basal ganglia, frontal and temporoparietal cortex,
fusiform cortex, and lingual gyri, particularly on
the nondominant side.29,30 The leading hypothe-
ses for the pathogenesis of delirium focus on the
roles of neurotransmission, inflammation, and
chronic stress.
Extensive evidence supports the role of cholin-
ergic deficiency. Administration of anticholinergic
drugs can induce delirium in humans and ani-
mals, and serum anticholinergic activity is in-
creased in patients with delirium. Physostigmine
reverses delirium associated with anticholinergic
drugs, and cholinesterase inhibitors appear to have
some benefit even in cases of delirium that are not
induced by drugs.15,29,31
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of m e dic i n e
Dopaminergic excess also appears to contrib-
ute to delirium, possibly owing to its regulatory
influence on the release of acetylcholine.29 Do-
paminergic drugs (e.g., levodopa and bupropion)
are recognized precipitants of delirium, and do-
pamine antagonists (e.g., antipsychotic agents) ef-
fectively treat delirium symptoms. Perturbations
of other neurotransmitters, such as norepineph-
rine, serotonin, γ-aminobutyric acid, glutamate,
and melatonin, may also have a role in the patho-
physiology of delirium, but the evidence is less well
developed.1,29,32 These neurotransmitters may ex-
ert their influence through interactions with the
cholinergic and dopaminergic pathways.
Cytokines, including interleukin-1, interleukin-
2, interleukin-6, tumor necrosis factor α (TNF-α),
and interferon, may contribute to delirium1,29,33
by increasing the permeability of the blood–
brain barrier and altering neurotransmission.
Finally, chronic stress brought on by illness or
trauma activates the sympathetic nervous system
and hypothalamic–pituitary–adrenocortical axis,
resulting in increased cytokine levels and chron-
ic hypercortisolism.34 Chronic hypercortisolism
has deleterious effects on hippocampal serotonin
(5-hydroxytryptamine [5-HT]) 5-HT1A receptors,
which may contribute to delirium.29,35,36 Given
the clinical heterogeneity and multifactorial na-
ture of delirium, it is likely that multiple patho-
genic mechanisms contribute to the development
of delirium.
Approach to Evaluation
A flowchart for the prevention and management
of delirium from the time of admission of an older
patient is shown in Figure 1. This approach, based
on current clinical guidelines and expert opin-
ion,9,20 must be guided by the individual patient’s
medical history, findings on physical and neuro-
logic examination, and clinical setting. Although
the provision of detailed procedures is beyond the
scope of this report, we will highlight common
pitfalls to avoid. When a patient with confusion
is admitted, determining the acuity of the change
in mental status is the essential first step. Neglect-
ing this step is the leading reason for missing the
diagnosis of delirium. If no history can be ob-
tained, then the patient should be assumed to be
delirious until proved otherwise. Every older hos-
pitalized patient should undergo brief but formal
cognitive testing with the use of instruments such
as the Mini–Mental State Examination and the
Confusion Assessment Method, since subtle de-
march 16, 2006
 current concepts

Table 1. Clinical Features of Delirium.*

Acute onset
Occurs abruptly, usually over a period of hours or days
Reliable informant often needed to ascertain the time course of onset
Fluctuating course
Symptoms tend to come and go or increase and decrease in severity over a 24-hour period
Characteristic lucid intervals
Inattention
Difficulty focusing, sustaining, and shifting attention
Difficulty maintaining conversation or following commands
Disorganized thinking
Manifested by disorganized or incoherent speech
Rambling or irrelevant conversation or an unclear or illogical flow of ideas
Altered level of consciousness
Clouding of consciousness, with reduced clarity of awareness of the environment
Cognitive deficits
Typically global or multiple deficits in cognition, including disorientation, memory deficits, and language impairment
Perceptual disturbances
Illusions or hallucinations in about 30 percent of patients
Psychomotor disturbances
Psychomotor variants of delirium
Hyperactive
Marked by agitation and vigilance
Hypoactive
Marked by lethargy, with a markedly decreased level of motor activity
Mixed
Altered sleep–wake cycle
Characteristic sleep-cycle disturbances
Typically daytime drowsiness, nighttime insomnia, fragmented sleep, or complete sleep-cycle reversal
Emotional disturbances
Common
Manifested by intermittent and labile symptoms of fear, paranoia, anxiety, depression, irritability, apathy, anger,
or euphoria

* Additional details are provided in Table 2 in the Supplementary Appendix.

lirium is often missed. Older patients should be
aroused during rounds and evaluated daily for
the hypoactive form of delirium, which is often
overlooked.
When clinicians search for the underlying cause
of delirium, they need to be aware of the possibil-
ity of occult or atypical presentations of many
diseases in the elderly, including myocardial in-
farction, infection, and respiratory failure, because
delirium is often the sole manifestation of serious
underlying disease. All preadmission and current
medications should be reviewed; even long-stand-
ing medications can contribute to delirium and
should be reevaluated. If changes in long-term
medications are appropriate after the indications
and risk–benefit ratios have been carefully weighed,
the hospital represents the ideal venue for making
these changes. A medical history must be meticu-
lously obtained to detect occult alcohol or benzo-
diazepine use, which can contribute to delirium.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

ma, those with fever and acute changes in mental

Table 2. Predisposing Factors for Delirium.
status in whom encephalitis is suspected, or those
Demographic characteristics with no other identifiable cause of the delirium.12
Age of 65 years or older However, neuroimaging should be considered
Male sex when the history cannot be obtained or the neu-
Cognitive status
rologic examination cannot be completed (e.g.,
when the patient is combative) so as not to miss
Dementia
uncommon conditions that are life-threatening
Cognitive impairment but treatable, such as subarachnoid hemorrhage
History of delirium and encephalitis.
Depression
Functional status Pr e v en t ion a nd M a nage men t
Functional dependence
Preventing delirium is the most effective strategy
Immobility
for reducing its frequency and complications. Suc-
Low level of activity
cessful preventive strategies include multicompo-
History of falls nent approaches to reduce risk factors. Because
Sensory impairment delirium has many causes, multicomponent ap-
Visual impairment proaches represent the most effective and clini-
Hearing impairment cally relevant ones. The Yale Delirium Prevention
Decreased oral intake
Trial8 demonstrated the effectiveness of interven-
tion protocols targeted toward six risk factors:
Dehydration
orientation and therapeutic activities for cognitive
Malnutrition impairment, early mobilization to avert immobi-
Drugs lization, nonpharmacologic approaches to mini-
Treatment with multiple psychoactive drugs mize the use of psychoactive drugs, interventions
Treatment with many drugs to prevent sleep deprivation, communication meth-
Alcohol abuse ods and adaptive equipment (particularly eye-
glasses and hearing aids) for vision and hearing
Coexisting medical conditions
impairment, and early intervention for volume de-
Severe illness
pletion. A randomized clinical trial involving pa-
Multiple coexisting conditions tients who had had hip fractures demonstrated
Chronic renal or hepatic disease the effectiveness of a multicomponent strategy
History of stroke for geriatric consultation targeted toward 10
Neurologic disease domains38: oxygen delivery to the brain, fluid
Metabolic derangements
and electrolyte balance, pain management, re-
duction in the use of psychoactive drugs, bowel
Fracture or trauma
and bladder function, nutrition, early mobiliza-
Terminal illness tion, prevention of postoperative complications,
Infection with human immunodeficiency virus appropriate environmental stimuli, and treatment
of symptoms of delirium.
Electroencephalography has a limited role in Once delirium occurs, the key steps in man-
the diagnosis of delirium, because of its false agement are to address all evident causes, pro-
negative rate of 17 percent and false positive rate vide supportive care and prevent complications,
of 22 percent12; it is most useful for detecting and treat behavioral symptoms. Because delirium
occult seizures and differentiating delirium from can be a medical emergency, the first aim of man-
psychiatric disorders. Neuroimaging studies have agement is to address predisposing and precipi-
a low clinical yield (the number of positive results tating factors promptly (Fig. 1). Supportive care
divided by the total number of studies performed) should include protecting the patient’s airway,
in the evaluation of delirium and should be re- maintaining hydration and nutrition, position-
served for patients with new focal neurologic ing and mobilizing the patient to prevent pressure
signs, those with a history or signs of head trau- sores and deep venous thrombosis, avoiding the

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 current concepts

use of physical restraints, and supporting the pa-

Table 3. Precipitating Factors or Insults That Can Contribute to Delirium.
tient’s daily care needs. Nonpharmacologic ap-
proaches to managing symptoms of delirium Drugs
should be instituted in every patient. These ap- Sedative hypnotics
proaches include creating a calm, comfortable en- Narcotics
vironment with the use of orienting influences, Anticholinergic drugs
such as calendars, clocks, and familiar objects
Treatment with multiple drugs
from home; regular reorienting communication
with staff members; involving family members in Alcohol or drug withdrawal
supportive care; limiting room and staff chang- Primary neurologic diseases
es; coordinating schedules for administering drugs, Stroke, particularly nondominant hemispheric
obtaining vital signs, and performing procedures Intracranial bleeding
to allow the patient an uninterrupted period for Meningitis or encephalitis
sleep at night with low levels of noise and light-
Intercurrent illnesses
ing; and encouraging normal sleep–wake cycles
Infections
by opening blinds and encouraging wakefulness
and mobility during the daytime. Since delirium Iatrogenic complications
may take weeks or months to resolve, patients Severe acute illness
must be cared for in supervised settings. Close Hypoxia
clinical follow-up after discharge is needed, es- Shock
pecially because of the poor long-term prognosis Fever or hypothermia
associated with delirium.
Anemia
Pharmacologic management should be reserved
for patients whose symptoms of delirium would Dehydration
threaten their own safety or the safety of other Poor nutritional status
persons or would result in the interruption of es- Low serum albumin level
sential therapy, such as mechanical ventilation or Metabolic derangements (e.g., electrolyte, glucose, acid–base)
central venous catheters. Pharmacologic treatment Surgery
strategies are outlined in Table 4.
Orthopedic surgery
Cardiac surgery
R el at ionship be t w een Del ir ium Prolonged cardiopulmonary bypass
a nd De men t i a
Noncardiac surgery
Delirium and dementia are highly interrelated, Environmental
yet the nature of their interrelationship remains Admission to an intensive care unit
poorly examined. Although a cause-and-effect Use of physical restraints
relation has not been established between deliri-
Use of bladder catheter
um and dementia, investigation of their intersec-
tion may yield important insights that will ad- Use of multiple procedures
vance our understanding of both conditions (see Pain
Table 3 in the Supplementary Appendix). Demen- Emotional stress
tia is the leading risk factor for delirium, and fully Prolonged sleep deprivation
two thirds of cases of delirium occur in patients
with dementia.1,39 Thus, the underlying vulnera-
bility of the brain in patients with dementia may ties of persistent delirium4,40-44 and reversible de-
predispose them to the development of delirium mentia45 blurs the boundaries between these con-
as a result of insults related to acute medical ill- ditions. Moreover, studies have shown that delirium
nesses, medications, or environmental perturba- and dementia are both associated with decreased
tions. Recent studies suggest that delirium per- cerebral metabolism, cholinergic deficiency, and
sists much longer than previously believed,4,40-44 inflammation,46 reflecting their overlapping clini-
with symptoms in many patients lasting months cal, metabolic, and cellular mechanisms. In fact,
or years. The existence of the well-described enti- delirium and dementia may represent points along

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 The n e w e ng l a n d j o u r na l
a continuum of cognitive disorders, rather than two
entirely separate conditions.39
Does delirium contribute to dementia? Al-
though it is not likely that the delirium itself
causes the pathologic changes of dementia, there
is no question that delirium contributes to wors-
ening functional status, loss of independence, and
poorer outcomes among patients with dementia.
The long-standing traditional view is that delir-
ium and dementia are two separate conditions;
however, emerging evidence has highlighted their
overlap. First, epidemiologic studies have docu-
mented long-term cognitive decline in patients
with delirium, after controlling for relevant co-
variates.47 Second, several causes of delirium may
not be completely reversible, particularly those
resulting in neuronal injury and permanent cog-
nitive sequelae, such as prolonged hypoxia or hy-
poglycemia.39 Third, neuroimaging studies dem-
onstrate regions of hypoperfusion in patients with
delirium.48 Thus, delirium may herald the onset
of dementia in many instances. Fourth, dementia
with Lewy bodies, which includes fluctuating cog-
nition and visual hallucinations as core signs, il-
lustrates the overlap of delirium and dementia.
Delirium can alter the course of an underly-
ing dementia, with dramatic worsening of the
trajectory of cognitive decline, resulting in more
rapid progression of functional losses and worse
long-term outcomes. This phenomenon has been
well recognized clinically in elderly patients with
dementia: clinicians and family members have
noted that the patients “never returned to base-
line” after an episode of delirium. In follow-up
studies, patients in whom delirium develops have
worse outcomes than those with dementia alone,49
including worsened cognitive function and in-
creased rates of hospitalization, institutionaliza-
tion, and death.49-52
Delirium may serve as an important model for
research by offering a unique approach to advance
our general understanding of cognitive disorders
and dementias (see Table 3 in the Supplementary
Appendix). The development of delirium in cer-
tain persons may help to identify those who are
vulnerable to cognitive decline through genetic
predisposition or through the presence of early
dementia or mild cognitive impairment that may
otherwise remain unidentified. Moreover, a bet-
ter understanding of the pathogenesis of deliri-
um may help elucidate factors that lead directly to
neuronal injury and, thus, to permanent cognitive
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of m e dic i n e
Figure 1 (facing page). Prevention and Management
of Delirium in the Older Hospitalized Patient.
Thyroid-function tests include measurement of the
thyroxine level, thyroid index, and thyrotropin level.
More information about pharmacologic treatment can
be found in Table 4.
sequelae. Studies investigating the pathogenesis
of delirium with the use of neuropsychological
testing, neuroimaging methods, electrophysiologi-
cal methods, laboratory markers, genetic studies,
and neuropathological approaches are greatly
needed. Investigation of delirium provides an
important opportunity to clarify the link between
brain pathophysiology and behavioral manifesta-
tions, which might hold broader implications for
other cognitive and psychiatric disorders. New
prospects for therapy include strategies to in-
crease acetylcholine activity in the brain (e.g.,
through the use of procholinergic agents and
avoidance of highly anticholinergic drugs), the
use of selective dopamine antagonists that affect
D1, D2, D3, and D4 receptors differently, and the
use of drugs to enhance cerebrovascular flow (e.g.,
antiinflammatory or antiplatelet agents). Finally,
targeting delirium with new therapeutic approach-
es may offer opportunities for early intervention,
preservation of cognitive-reserve capacity, and
prevention of permanent cognitive damage, which
may potentially delay or abate the ultimate de-
velopment of dementia.
Delirium as an Indicator of the Quality
of Health Care
Delirium represents one of the most common
preventable adverse events among older persons
during hospitalization53,54 and meets Williamson’s
criteria for an indicator of the quality of health
care55: the condition is common, frequently iatro-
genic, and integrally linked to processes of care.
Although many cases of delirium may be unavoid-
able, clinical trials8,38 provide compelling evidence
that at least 30 to 40 percent of cases may be pre-
ventable. Many aspects of hospital care contribute
to the development of delirium, including adverse
effects of medications, complications of invasive
procedures, immobilization, malnutrition, dehy-
dration, the use of bladder catheters, and sleep
deprivation.9 Delirium is currently included as a
marker of the quality of care and patient safety
by the National Quality Measures Clearinghouse
of the Agency for Healthcare Research and Qual-
march 16, 2006
 Hospital admission

Monitor cognitive function Prevention of delirium

Perform formal cognitive assessment Address risk factors for delirium
Establish baseline cognitive function Provide orienting communication
and recent changes Encourage early mobilization
Monitor patient for changes in Use visual and hearing aids
mental status Prevent dehydration
Provide uninterrupted sleep time
Avoid psychoactive drugs
Change in mental status

Chronic Acute

Perform cognitive assessment

Perform dementia evaluation

n engl j med 354;11

and evaluation for delirium

Rule out depression, mania,

Delirium confirmed
acute psychosis

www.nejm.org
Identify and address predisposing Provide supportive care and
Manage symptoms of delirium
current concepts

and precipitating factors prevent complications

Initial evaluation Review medications Prevent complications All patients Patients with severe agitation
Obtain history (including alcohol Review the use of prescription Protect airway, prevent
and benzodiazepine use) drugs, as-needed drugs, aspiration

march 16, 2006

Obtain vital signs over-the-counter drugs, Maintain volume status Pharmacologic management
Nonpharmacologic treatment
Perform physical and neuro- herbal remedies Provide nutritional support Reserve this approach for patients
strategies
logic examination Identify psychoactive effects Provide skin care, prevent with severe agitation at risk
Continue delirium prevention
Order selected laboratory tests and drug interactions pressure sores for interruption of essential
Reorient patient, encourage family
Search for occult infection Use mobilization, prevent medical care (e.g., intubation)
involvement
deep venous thrombosis, or for patients who pose
Use sitters
pulmonary embolus safety hazard to themselves
Avoid use of physical restraints and
Potential contributing factor Remove or alter potentially or staff
Foley catheters
identified harmful drugs Start low doses and adjust until
Use nonpharmacologic approaches
Change to less noxious alter- effect achieved
for agitation: music, massage,
native Maintain effective dose for
relaxation techniques
Lower doses 2–3 days
Yes No Use of eyeglasses, hearing aids,
Nonpharmacologic approaches
interpreters
Maintain patient’s mobility and
Further options self-care ability
Evaluate and Normalize sleep–wake cycle,
Order laboratory tests: thyroid-function tests, measurement of drug levels, toxicology screen,
treat as discourage naps, aim for
measurement of ammonia or cortisol levels, test for vitamin B12 deficiency and arterial
appropriate uninterrupted period of sleep
blood gas levels
for each at night
Electrocardiography
contributing At night, have patient sleep in
Neuroimaging
factor quiet room with low-level lighting
Lumbar puncture, electroencephalography

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 4. Pharmacologic Treatment of Delirium.

Class and Drug Dose Adverse Effects Comments

Antipsychotic
Haloperidol 0.5–1.0 mg twice daily orally, with Extrapyramidal symptoms, espe- Usually agent of choice
additional doses every 4 hr as cially if dose is >3 mg per day Effectiveness demonstrated in ran-
needed (peak effect, 4–6 hr) Prolonged corrected QT interval domized, controlled trials20,37
0.5–1.0 mg intramuscularly; ob- on electrocardiogram Avoid intravenous use because of
serve after 30–60 min and re- Avoid in patients with withdrawal short duration of action
peat if needed (peak effect, syndrome, hepatic insuffi-
20–40 min) ciency, neuroleptic malignant
syndrome
Atypical antipsychotic
Risperidone 0.5 mg twice daily Extrapyramidal effects equivalent Tested only in small uncontrolled
Olanzapine 2.5–5.0 mg once daily to or slightly less than those studies
Quetiapine 25 mg twice daily with haloperidol Associated with increased mortality
Prolonged corrected QT interval rate among older patients with
on electrocardiogram dementia
Benzodiazepine
Lorazepam 0.5–1.0 mg orally, with additional Paradoxical excitation, respirato- Second-line agent
doses every 4 hr as needed* ry depression, oversedation Associated with prolongation and
worsening of delirium symp-
toms demonstrated in clinical
trial37
Reserve for use in patients under-
going sedative and alcohol with-
drawal, those with Parkinson’s
disease, and those with neuro-
leptic malignant syndrome
Antidepressant
Trazodone 25–150 mg orally at bedtime Oversedation Tested only in uncontrolled studies

* Intravenous use of lorazepam should be reserved for emergencies.

ity (as explained at www.qualitymeasures.ahrq.
gov/). After adjusting for case mix, higher deliri-
um rates would be expected to correlate with
lower quality of hospital care. The Assessing Care
of Vulnerable Elders Project has ranked delirium
among the top three conditions for which the
quality of care needs to be improved.56 Total na-
tional costs related to preventable adverse
events are estimated to be between $17 billion
and $29 billion per year,57 and delirium may ac-
count for at least a quarter of these costs.53,54,57,58
The changes required to reduce the incidence of
delirium on a national scale would require shifts in
local and national policies and system-wide chang-
es to provide high-quality care for older persons.9
Supported in part by grants (R21AG025193 and K24AG00949)
from the National Institute on Aging.
No potential conflict of interest relevant to this article was
reported.
This article is dedicated to the memory of Joshua Bryan In-
ouye Helfand.
I am indebted to Dr. Joseph Agostini for his helpful review of
the manuscript and to Sarah Dowal and Patty Fugal for their
assistance with the preparation of the manuscript.

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 Supplementary Appendix

This appendix has been provided by the author to give readers additional information about their work.

Supplement to: Inouye SK. Delirium in Older Persons. N Engl J Med 2006;354:1157-65.
 WEB-ONLY SUPPLEMENT
SUPPLEMENT TABLE 1. DIAGNOSTIC CRITERIA FOR DELIRIUM

Diagnostic and Statistical Manual (DSM-IV) Diagnostic Criteria 1

A. Disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced

ability to focus, sustain, or shift attention.

B. A change in cognition (such as memory deficit, disorientation, language disturbance) or the

development of 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 (usually hours to days) and tends to

fluctuate during the course of the day.

D. There is evidence from the history, physical examination, or laboratory findings that the

disturbance is caused by the direct physiological consequences of a general medical condition.

ICD-10 Diagnostic Criteria 2

For a definite diagnosis, symptoms, mild or severe, should be present in each one of the following areas:

a. impairment of consciousness and attention (on a continuum from clouding to coma; reduced

ability to direct, focus, sustain, and shift attention);

b. global disturbance of cognition (perceptual distortions, illusions and hallucinations-- most often

visual; impairment of abstract thinking and comprehension, with or without transient delusions,

but typically with some degree of incoherence; impairment of immediate recall and of recent

memory but with relatively intact remote memory; disorientation for time as well as, in more

severe cases, for place and person)

c. psychomotor disturbances (hypo- or hyperactivity and unpredictable shifts from one to the other;

increased reaction time; increased or decreased flow of speech; enhanced startle reaction);

d. disturbance of the sleep - wake cycle (insomnia or, in severe cases, total sleep loss or reversal of

the sleep - wake cycle; daytime drowsiness; nocturnal worsening of symptoms; disturbing dreams

or nightmares, which may continue as hallucinations after awakening);

1
 SUPPLEMENT TABLE 1 (cont)

e. emotional disturbances, e.g. depression, anxiety or fear, irritability, euphoria, apathy, or

wondering perplexity.

The Confusion Assessment Method (CAM) Diagnostic Algorithm* 3

Feature 1. Acute onset and fluctuating course

This feature is usually obtained from a reliable reporter, such as a family member, caregiver, or

nurse and is shown by positive responses to these questions: Is there evidence of an acute change

in mental status from the patient’s baseline? Did the (abnormal) behavior fluctuate during the

day, that is, tend to come and go, or did it increase and decrease in severity?

Feature 2. Inattention

This feature is shown by a positive response to this question: Did the patient have difficulty

focusing attention, for example, being easily distractible, or have difficulty keeping track of what

was being said?

Feature 3. Disorganized thinking

This feature is shown by a positive response to this question: Was the patient’s thinking

disorganized or incoherent, such as rambling or irrelevant conversation, unclear or illogical flow

of ideas, or unpredictable switching from subject to subject?

Feature 4. Altered level of consciousness

This feature is shown by any answer other than “alert” to this question: Overall, how would you

rate this patient’s level of consciousness (alert [normal], vigilant [hyperalert], lethargic [drowsy,

easily aroused], stupor [difficult to arouse], or coma [unarousable])?

* The ratings for the CAM should be completed following brief cognitive assessment of the patient, for example,

with the Mini-Mental State Examination. The diagnosis of delirium by CAM requires the presence of features 1

and 2 and of either 3 or 4.

2
 SUPPLEMENT TABLE 2. CLINICAL FEATURES OF DELIRIUM (DETAILED VERSION)

Acute onset Disturbance occurs abruptly, usually over hours to days, but onset over

weeks described. Because the patient is often unable to provide an accurate

history, a reliable informant is needed to ascertain the time course of onset.

Fluctuating course Symptoms tend to come and go, or increase and decrease in severity over a

24-hour period. Lucid intervals are characteristic.

Inattention Difficulty focusing, sustaining, and shifting attention. Patients are easily

distracted, have difficulty maintaining conversation or following commands.

Patients perform poorly on simple bedside tests of attention, such as digit

spans and reciting months backwards.

Disorganized thinking Manifested by disorganized or incoherent speech, reflecting abnormalities in

form and content of thinking. Patients demonstrate rambling or irrelevant

conversation, unclear or illogical flow of ideas, or unpredictable switching

between subjects. Patients may be unable to make decisions, solve

problems, or plan and sequence activities. Judgment and insight may be

impaired.

Altered level of consciousness Clouding of consciousness with reduced clarity of awareness of the

environment. This is typically manifested by lethargy, where the patient is

abnormally drowsy and difficult to keep aroused. The patient may also be

hyperalert, vigilant, and unable to filter out environmental stimuli.

3
 SUPPLEMENT TABLE 2 (cont)

Cognitive deficits Global or multiple deficits in cognition are typical. Disorientation to time

and place are common; disorientation to person is present in more severe

cases. Memory deficits for immediate and short-term memory are typical,

with preserved remote memory. Language functions are often abnormal,

with tangential or slurred speech, paraphasias, and word-finding difficulty

progressing to aphasia in severe cases.

Perceptual disturbances Significant perceptual disturbances occur in up to 30% of delirious patients.

Initial changes include distortions with abnormalities in the perception of

size of objects (macropsia, micropsia), shape, position, movement, or

derealization. Illusions are frank misinterpretations of environmental stimuli

(such as mistaking a pile of laundry for a person, or hallway sounds for

gunshots). Both visual and auditory hallucinations occur with delirium;

tactile hallucinations are less common. The perceptual disturbances may be

frightening to patients and may result in significant behavioral disturbances.

Psychomotor disturbances Delirium demonstrates three psychomotor variants: hyperactive, hypoactive,

and mixed. In the hyperactive form of delirium, the patient is agitated (i.e.,

restless, picking at clothing, tapping fingers, making frequent changes of

position), often vigilant and hallucinating. In the hypoactive form of

delirium, the patient has a markedly decreased level of motor activity (i.e.,

sluggishness, staring into space), often lethargic or passive. Patients may

alternate between the hyperactive and hypoactive subtypes.

4
 SUPPLEMENT TABLE 2 (cont)

Altered sleep-wake cycle Sleep cycle disturbances are characteristic. Daytime drowsiness, nighttime

insomnia, fragmented sleep, or complete sleep-cycle reversal are typical

with delirium.

Emotional disturbances Emotional disturbances are common, manifested by intermittent and labile

symptoms of fear, anxiety, depression, irritability, apathy, anger, or

euphoria. Paranoid delusions may occur.

5
 SUPPLEMENT TABLE 3
A PROPOSED RESEARCH AGENDA TO EXPLORE DELIRIUM AND THE INTER-
RELATIONSHIP OF DELIRIUM AND DEMENTIA

Epidemiology

• Diagnosis of delirium: What is the sensitivity, specificity, clinical yield and cost-effectiveness of
various evaluation approaches to delirium? What is the optimal diagnostic approach?
• Long-term follow-up studies of delirious patients: Does delirium itself lead to permanent
cognitive impairment? How often does delirium lead to mild cognitive impairment or dementia?
• Delirium superimposed on dementia: Does delirium alter the trajectory of cognitive decline in
patients with dementia?
• Cognitive reserve capacity/recovery from delirium: Are there factors that assist in cognitive
recovery after delirium, such as educational level, exercise, health habits, medications (e.g.,
cholinesterase inhibitors)?
• Genetic factors: Are there genetic determinants of the risk of development of delirium, or lack of
recovery from delirium? What is the role of APOE-ε4?
• Identification of high-risk populations: Does delirium exert its maximal detrimental effects only
in certain high-risk subgroups? Or high-risk settings (e.g., post-operative, intensive care)?
• Impact of delirium: What are the economic and societal costs associated with delirium and
delirium superimposed on dementia?

Pathophysiology
• Neuroimaging, neuropsychological, and neuropathological studies: Does delirium lead to
permanent neurological sequelae?
• Structural and functional imaging methods: Do preexisting abnormalities (e.g., white matter
hyperintensities, volume losses) or functional changes predict the development of delirium, as
well as longer-lasting cognitive decline?
• Amyloid imaging: Does degree of amyloid pathology correlate with the risk of delirium or the
likelihood of recovery from delirium?
• Animal models: Are there pathologic changes after induced delirium (e.g., general anesthesia) in
normal and dementia models?
• Laboratory, electrophysiologic, or neuroimaging markers: Can we identify markers that will
assist in diagnosis of delirium? Can we identify markers for delirium that is likely to lead to
chronic cognitive impairment or dementia?

6
 • Behavioral manifestations: What is the underlying pathophysiology of behavioral manifestations
of delirium (e.g., hyperactive vs. hypoactive form)? Do genetic factors or neuroreceptor subtypes
play a role?

Prevention and Treatment

• Prevention of delirium: Does prevention of delirium with proven non-pharmacologic
intervention strategies mitigate or abate future cognitive decline?
• Treatment of delirium: Randomized trials to evaluate treatment strategies for delirium in
cognitively normal and in dementia patients (e.g., nonpharmacologic approaches, cholinesterase
inhibitors, dopamine antagonists, anti-inflammatory agents, anti-platelet agents, lipid-lowering
agents, antioxidant or neuroprotective drugs). Will early recognition and treatment of delirium
mitigate or abate subsequent cognitive decline?

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