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RLiVIE\vT\RTICI.E

CURRENT CONCEPTS

Delirium in Older Persons

Sharon l(. lnouye, l\,1.D., M.p.H.

ELIRIUM,ANACUTE DECLINE INATTENTION AND COGNITION, ISA COM. From the Department of Medicine, Hatr
mon, life-threatening, and potentially preventable clinical syndrome among vard Medical School, Boston- Address
*r\s$$' persons who are 65 years of age or older. The development ofdelirium often reprint requests to Dr- lnouye at the Ag-
ing Brain Center, Hebrew Senior Life,
initiates a cascade ofevents culminating in the loss ofindependence, an increased 1200 Centre St., Boston, MA 02131.
risk of morbidity and mortaliry, and increased health care costs.l-6 Delirium in hos-
pitalized older patients has assumed particular importance because tie care ofsuch N EnglJ Med 2006;354:1157-55.
Copytight @ 2006 Masechusetts Med;col Seiety.
patients accounts for more than 49 percent of all hospital days.? Delirium compli-
3
cates hospital stays for ar leasr 20 percentofthe 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-lo so riar abour $6.9 billion (value in U.S. dollars in 2004) of Medicare
hospital expendirures are attributable to delirium. Substantial additional cosrs ac-
crue after hospital discharge because ofthe need for institutionalization, rehabili-
tation services, formal home health care, and informal caregiving.
This report examines current clinical practice in delirium, idenrifies areas of
controversy, and highlights areas for future research.

EPIDEMIOLOGY AND DIAGNOSTIC CRITERIA

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

acute confusional state. Rates of delirium are highest among hospitalized older
patients, and the rates vary depending on the patients' characterisrics, setting ofcare,
and sensitivity of the derection metiod. The prevalence of delirium at hospital ad-
mission ranges from \4 to 24 percent, and the incidence ofdelirium arising during
hospitalization ranges from 6 to 56 percentamong general hospital populations.11,12
Delirium occurs in 15 to 53 percent ofolder patients postoperativelyll and in 70 ro
87 percent oftlose in intensive care.13 Delirium occurs in up to 60 percent ofpa-
tients in nursing homes or post-acute care settingsl4'ls and in up to g3 percent of
all patients at the end oflife.16'17 Although the overall prevalence ofdelirium in the
community is only 1 to 2 percent,18,rs ,6. 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 emergencydepartments, delirium is a symptomll that
often heralds the presence of life-threatening conditions. The mortaliry rates among
hospitalized patients with delirium range from 22 to 76 percent, as high as the
rates among patients with acute myocardial infarction or sepsis. The one-year mor-
taliry rate associated with cases ofdelirium is 35 to 40 percenl2l
The diagnosis of delirium is primarily clinical and is based on careful bedside
observation ofkey features. Although the criteria continue to evolve,z,a the diag-
nostic algorithms that are most widely used are presented in the Supplemenrary
Appendix (available with the full text of this article atwww.nejm.org). Deliriurn is
often unrecognizedby the patients'physicians and nurses,1,2a in part because of
its fluetuating nature, its overlap with dementia, lack of formal cognitive assess-
ment, underappreciation of its clinical consequences, and failure to consider the
diagnosis important.

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 Il. NE\+ ENGi--1 Nf} lOLtRNAl, oJ i.t EDIUTNE

CLI NICAL CHARACTER ISTICS Dopaminergic excess also appears to contrib-

ute to delirium, possibly owing ro irs regulatory
Because delirium remains a bedside diagnosis, influence on the release of acetylcholine.2e Do-
understanding its clinical fearures (Table 1 and paminergic drugs (e.g., levodopa and bupropion)
the Supplementary Appendix) is cruciai to the di- are recognized precipitants of delirium, and do-
agnosis of delirium. Delirium has hypoactive and pamine antagonists (e.g., a*ipsychotic agents) eF
hyperactive forms (Table 1). The hypoactive form fectively treat delirium s)nnptoms. Perturbations
of delirium is more common among olderpersons of other neurotransmitters, such as norepineph-
and often goes unrecognized. rine, serotonin, 7-aminoburyric acid, gluramate,
and melatonin, may also have a role in the patho-
ETIOLOGIC AND R]SK FACTORS physiology ofdelirium, but the eyidence is less well
The cause of delirium is typically multifactorial.zs developed.l'2e32 These neuroffansmitters may ex-
In fact, the development of delirium involves the ert their influence through interactiols wirh the
complex interrelationship berween a vulnerable cholinergic and dopaminergic parhways.
patient (one with predisposing factors) (Table 2) Cytokines, including interleukin-1, interleukin-
and exposure to precipitating factors or noxious 2, interleukin-6, rumor necrosis factor a (TNF-a),
insults (Table 31.20'zz Thus, in patients who are and interferon, may contribute to deliriuml'2e'33
highly vulnerable to delirium, such as those with by increasing the permeabiliry of the blood-
dementia and multiple coexisting conditions, it brain barrier and altering neurotransmission-
may develop as a result of relatively benign in- Finally, chronic stress brought on by illness or
sults, such as one dose of a sleeping medication. trauma acLivates the sympathelic nervous system
Conversely, in patients who are not vulnerable to and hypothalam ic-piruitary-adrenocortical axis,
delirium, it develops only after exposure to mul- resulting in increased cytokine levels and chron-
tiple noxious insults, such as general anesthesia, ic hypercortisolism-3a Chronic hypercortisolism
major surgery, and psychoactive medications. Ad- has deleterious effects on hippocampal serotonin
dressingjust one conrributing factor is unlikely to (5-hydroxytryptamine [5-ffi) 5-HT,o receptors,
resolve delirium in an older person; they should which may contribute to delirium.2e'35'36 Given
all be addressed when possible. the clinical heterogeneiry and multifactorial na-
ture of delirium, it is likely that multiple patho-
PATHOGENESIS genic mechanisms contribute to the development
The pathophysiology of delirium remains poorly of delirium.
understood. Electroencephalographic studies have
demonstrated diffuse slowing of cortical back- APPROACH TO EVALUATION
ground activiry, which does not correlate with un- A flowchart for the prevention and management
derlying causes.a Neuropsychological and neuro- ofdelirium from the time ofadmission ofan older
imaging studies reveal generalized disruption in patient is shown in Figure 1. This approach, based
higher corrical funcrion, with dysfunction in the on current clinical guidelines and expert opin-
prefrontal cortex, subcortical strucnlres, thalamus, ion,o''o must be guided bythe individual patient's
basal ganglia, frontal and temporoparietal cortex, medical history, findings on physical and neuro-
fusiform cortex, and lingual gyri, particularlyon logic examination, and clinical setting. Although
the nondominant side.2e'3o The leading hypothe- the provision ofdeuiled procedures is beyond the
ses for the pathogenesis ofdelirium focus on the scope of this report, we will highlight common
roles of neurotransmission, inflammation, and pitfalls to ayoid- When a parient with confusion
chronic stress. is admitted, determining the acuiry of the change
Extensive evidence supports the role ofcholin- in menal satus is the essential Fust step. Neglect-
ergic deficienry. Adminisnarion of anticholinergic ing this step is the leading reason for missing the
drugs can induce delirium in humans and ani- diagnosis of delirium- If no history can be ob-
mals, and serum atrticholinergic activity is in- tained, then the patient should be assumed to be
creased in patients with delirium. physostigmine delirious until proved otherwise. Every older hos-
reverses delirium associated with anricholinergic pitalized patient should undergo brief but formal
drugs, and cholinesterase inhibitors appear to have cognitive testing\ryith the use ofinstruments such
some benefit even in cases ofdelirium that are not as the Mini-Mental State Examination and the
induced bY drugs.ls'2e;1 Confusion Assessment Method. since subtle de-

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 CURRENT CONCEPTS

Table ]. Clinical Features of Delirium.*

Acute onset
Occurs abruptly, usuaily over a period ofhours or days
Reliable informant ofien needed to ascertain the time course ofonset
Fluctuating course
symptoms tend to come and go or increase and decrease in severity over a 24-hour period
Characteristic lucid intervals
lnattention
Difticulty focusing, sustaining, and shifting attention
Difficulty mainiaining conversation or following commands
Disorganized thinking
Manifested by disorganized or incoherent speech
Rambling or irrelevant conversation or an uncrear or iilogicar flow ofideas
Altered level of consciousness
Clouding ofconsciousness, with reduced clarity ofawareness ofthe environment
Cognitive deficits
Typically global or multiple deficits in cognition, including disorientation, memory
deficits, and [anguage ;mpairment
PerceptuaI disturbances

lllusions or hallucinations in about 3O percent ofpatients

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 slee5wake cycle
Characteristic sleep-cycle disturbances
Typically ddytime drowsiness, nighttime insomnia, lragmented sleep, or complete
sleep-cycle reversal
Emotional disturbances
Common
Manifested by intermittent and labile symptoms offear, 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 underlying disease. All preadmission and
current
aroused during rounds and evaluated dajlv for medications should be reviewed; even
long-stand-
the hypoactive form of delirium, which is often ing medications can contribute to
delirium and
overlooked. should be reevaluated. If changes in long-term
When clinicians search for the underlying cause medications are appropriate
after the indications
of delirium, they need to be aware of the possibil- and risk-benefit ratios have been carefullyweighed,
iry of occult or atypical presentations of many the hospiul represents the ideal venue for
making
diseases in the elderly, including myocardial in- these changes. A medical history
must be medcu-
farction, infection, and respiratory failure, because Iously obtained to detect occult alcohol
or benzo-
delirium is often the sole manifestation of serious diazepine use, which can contribute to delirium.

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 1r; NEIV ENcl-AND IC)URNAL oJMEtltCINa

Table 2. Predisposing Factors for Deliriurn ma, those with fever and acute changes in mental
satus in whom encephaiitis is suspecred, or those
Demographic characteristics with no other identiflable cause of the delirium-r2
Age of65 years or older However, neuroimaging should be considered
Male sex when the history cannot be obrained or rhe neu-
Cognit;ve status rologic examination cannor be completed (e.g.,
when the parient 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 PREVENTION AND MANAGEM ENT
Functional dependence
Immobility Prevenring delirium is the most effective strategy
for reducing its frequency and complications- Suc-
Low level ofactivity
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 proeches represent the most effecrive and clini-
Hearing impairment cally relevant ones. The Yale Delirium Prevenrion
Decreased oral intake Trial8 demonstrated the effectiveness of interven-
Dehydration
tion protocols targeted toward six risk factors:
orientation and therapeutic activities for cognitive
Malnutrition
impairment, early mobilization to avert immobi-
Drugs
lization, tronpharmacologic approaches to mini-
Treatment with multiple psychoactive drugs mize the use ofpsychoactive 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 rrial involving pa-
M ultiple coexisting conditions
lients who had had hip fractures demonstrated
Chronic renal or hepatic disease the efFectiveness of a multicomponent strategy
History ofstroke for gerianic consultation targeted toward 10
Neurologic disease domains3s: oxygen delivery to the brain, fluid
Metabolic derangements and electrolyte balance, pain management, re-
Fracture or trauma
duction in the use of psychoacrive drugs, bowel
and bladder function, nutrition, early mobiliza-
Terminal illness
lion, 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 causesr pro-
negative rute of 17 percent and false positive rate vide supportive care and prevent complications,
of 22 percent2; it is most usefuI for detecting and treat behavioral symptoms. Because delirium
occult seizures and differenriadng delirium from can be a medical emergency, the frst aim of man-
psychiatric disorders. Neuroimaging studies have agement is to address predisposing and precipi-
a low clinical yield (the number of posirive results lxting factors promptly (Fig. 1;. Supporrive care
divided by the toul number ofsftdies performed) should indude protecting the patient,s airway,
in the evaluation ofdelirium and should be re- mainaining hydration and nutriiion, position-
served for patients with new focal neurologic ingand mobilizing the patient to preventpressure
signs, those with a history or signs of head trau- sores and deep venous thrombosis, avoiding the

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 CURRENT CONCEPTS

use ofphysical restraints, and supporting the pa-

rient's daily care needs. Nonpharmacologic ap- Table l. Precipitating Fators or Insults That Can Contritute to Delirium.

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
from home; regular reorienling communication Treatment with multiple drugs
with staffmembers; involving family members in Alcohol or drug withdrawat
supportive care; Iimiting room and staff chang- Primary neurologic diseases
es; coordinadng 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-
ing; and encouraging normal sleep-wake cycles lntercurrent illnesses

by opening blinds and encouraging wakefulness lnfections

and mobility during the dayrime. Since delirium latrogenic complications
may take weeks or months to resolve, patients Severe acute illness
must be cared for in supervised settings. Close Hypoxia
dinical follow-up after discharge is needed, es-
)nocK
pecially because ofthe poor long-term prognosis
Fever or hypothermia
associated with delirium-
Pharmacologic management should be reserved Anemia
for patients whose symptoms of delirium would Dehydration
threaten their own safety or tie safety of other Poor nutritional status
persons or would result in the inrerruption ofes- Low serum albumin level
sential therapy, such as mechanical ventilation or
Metabolic derangements (e-g., electrolyte, glucose, acid-base)
central venous catheters. Pharmacologic treatrnent
Surgery
strategies are outlined in Table 4-
Orthopedic surgery
Cardiac surgery
RELATIONSHIP BETWEEN DELIRIUM
AND DEMENTIA Prolonged cardiopulmonary bypass
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-
um and dementia, investigation oftheir intersec- Use ofbladder catheter

tion may yield importanr insighrs that will ad-
yance our understanding ofboth conditions (see
Table 3 in the Supplemenury Appendix). Demen-
tia is the leading riskfactor for delirium, and Fully
two thirds of cases of delirium occur in Datients
with dementia.1,3e Thus, the underlying vulnera-
biliry of the brain in patients with dementia may
predispose them to the development of delirium
as a result of insults related ro acute medical ill-
nesses, medications, or environmental perturba-
tions. Recent srudies suggest that delirium per-
sists much longer than previously believed,+,+o-++
with slnnptoms in many patients lasting months
or years. The existence ofthe well-described enti-
Use of multiple procedures
Pain
Emotional stress
Prolonged sleep deprivation
ties of persistent delirium+ffi and reyersible de-
mentiaas blurs the boundaries between these con-
ditions. Moreover, studies have shown thatdelirium
and dementia are both associated with decreased
cerebral metabolism, cholinergic deficiency, and
inflammation,6 reflecting their overlapping clini-
cal, metabolic, and cellular mechanisms. In fact,
delirium and dementia may represent points along

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 1-nf NEw IlNCl.ANt) l()UR.Nlt, of l\tEDICtNE

a continuum ofcognitive disorders, rather than two

Figure I pcing pagef . Prevention and Menagement
entirely separate conditions.3e
of Delirium in the Older Hospitalized Patient.
Does delirium contribute ro dementia? Af Thyroid-function tests include measurement of the
though it is not likely rhat the delirium itself thyroxine level, thyroid index, and thyrotropin level.
causes the pathologic changes ofdementia, there More information about pharmacologic treatment can
is no question that delirium contributes to wors- be found in Table 4.
ening functional status, loss ofindependence, and
poorer outcomes among patients with dementia- sequelae. Srudies investigating the pathogenesis
The long-standing rraditional view is thar delir- of delirium with the use of neuropsychological
ium and dementia are rwo separate conditions; testing, neuroimaging methods, elecfophysiologi-
however, emerging evidence has highlighted their cal methods, laboratory markers, genetic studies,
overlap. First, epiderniologic studies have docu- and neuropathological approaches are greatly
mented long-term cognitive decline in patients needed. Investigation of delirium provides an
with delirium, after controlling for relevant co- important opportuniry to clarif! rhe link befween
variates.aT Second, several causes ofdelirium may brain pathophyriology and behavioral manifesta-
not be completely reversible, parricularly those tions, which might hold broader implications for
resulting in neuronal injury and permanent cog- other cognitive and psychiatric disorders. New
nitive sequelae, such as prolonged hypoxia or hy- prospects for therapy include strategies to in-
poglycemia.3e Third, neuroimaging studies dem- crease acetfcholine activity in the brain (e,g.,
onstrate regions ofhypoperfusion in patients with through the use of procholinergic agents and
delirium.as Thus, delirium may herald the onser avoidance of highly anticholinergic drugs), the
of dementia in many instances. Fourth, dementia use ofselecdve dopamine antagonists that affect
with Lewy bodies, which includes fluctuating cog- D1, D2, De, and Do receptors differently, and the
nition and visual hallucinations as core signs, il- use ofdrugs to enhance cerebrovascular flow (e.g.,
lustrates the overlap of delirium and dementia. an[iinflammatory or antiplateler agents). Finally,
Delirium can alter the course of an underly- targeting delirium with new rherapeudc approach-
ing dementia, with dramatic worsening of the es may offer opportunities for early intervention,
trajectory oFcognitive decline, resulting in more preservation of cognitive-reserve capacity, and
rapid progression offunctional losses and worse preyention of permanent cognitive damage, which
long-term outcomes. This phenomenon has been may potentially delay or abate the ultimate de-
well recognized clinically in elderly patients with velopment of dementia.
dementia: clinicians and family members have
noted that the patients "never returned to base- DELIRTUM AS AN INDICATOR OF THE QUALITY
Iine" after an episode of delirium. In follow-up OF HEALTH CARE
srudies, parients in whom delirium develops have Delirium represents one of the most common
worse outcomes tJran those witJr dementia alone, preventable adverse events among older persons
including worsened cognitive function and in- during hospiulizations3r4 and meets Williamson's
creased rates of hospitalization, institutionaliza- miteria for an indicator of the qualiry of health
tion, and death.4e-52 careFs: tlte condition is common, frequently iatro-
Delirium may serve as an important model for genic, and integrallylinked to processes ofcare.
research by offering a unique approach to advance Although many cases ofdelirium may be unavoid-
our general undersanding of cognitive disorders able, clinical trialssss provide compelling evidence
and dementias (see Table 3 in the Supplementary that at least 30 to 40 percent ofcases may be pre-
Appendix). The development of delirium in cer- ventable. Many aspects of hospial care contribute
tain persons may help to identify those who are to the developmenf of delirium, including adverse
vulnerable to cognitive decline through genetic effects of medications, complications of invasiye
predisposition or ttrrough the presenceof early procedures, immobilization, malnutrition, dehy-
dementia or mild cognitive impairment that may dration, the use ofbladder catheters, and sleep
otherwise remain unidentified. Moreover. a bet- deprivation.e Delirium is currently included as a
ter understanding oFthe pathogenesis of detiri marker of the quality of care and padent safety
um may help elucidate factors thatlead directly to by the National Quality Measures Clearinghouse
neuronal injury and, thus, to permanent cognitive oFthe Agenry for Healthcare Research and Qual-

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 CURRENT CONCEPTS

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 lhc NElV ENCt-.,\ND jouliNAL oJ i\,tht)l{_-iNE

Table 4- Pharnracologic 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 ofchoice
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 trials2o.rt
0.5-1.0 mg intramuscularly; ob- on electrocardiogram Avoid intravenous use because of
serve after 3O-60 min and re- Avoid in patients with withdrawal short duration of action
peat ifneeded (peak effect. syndrome, hepatic insufii-
20-40 min) ciency, neuroleptic malignant
syndrome
Atypical antipsychotic
Risperidone 0.5 mg twice daily Extrapyram idal 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 intervat rate among older patients with
on electrocardiogram dementia
Benzodiazepine
Lorazepam o'5-I-0 mg orally, with additional paradoxical excitation, respirato- second-line aeent
doses every 4 hr as needed* ry depression, ou"r."dation A;;;;;rJ-;il prolongation and
worsening of delirium symp_
toms demonstrated in clinical
lrial3T
Reserue for use in patients under-
going sedative and alcohol with-
drawal, those with parkinson's
disease, and those with neuro-
leptic malignant syndrome
Antidepress ant
Trazodone 2i-150 mg orally at bedtime Oversedation Tested only in uncontrolled studies
* lntravenous use oflorazepam should be reserved for emergencies.

ity(as explained at www.qualirymeasures.ahrq.

The changes required to reduce the incidence of
gov/). After adjusting for case mix, higher deliri. delirium on a national scale would require shifts in
um rates would be expected to correlate with Iocal and national policies and system-wide chang-
lower qualiry ofhospiul care. The Assessing Care es to provide high-qualiry care for older persons-e
ofVulnerable Elders project has ranked delirium Supported in part by grants (R21AG06193 and K24AG009|9)
among the top three conditions for which the fmm the National Institute on Aging.
qualty ofcare needs to be improved.s6 Total na- No porential confliet ofinterest releyant to tlis article was
reported.
tional costs related to preventable adverse This article is dedicated to the memory ofJoshua Bryan In-
events are estimated to be between $17 billion ouye Helfand.
and $29 billion per year,57 and delirium may ac- - I am indebted m Dr. Joseph Agostini fur his helpfirl review of
theminnscripl and to Sarab Dowal and latty fugat for tlreir
countforat least a quarter ofthese costs.s3,s4,s7,5a assistance with t}e preparation
ofthe manuscript.

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CORRECTION

Delirium in Older Persons

Delirium in Older Persons - On page 1164, in Table 4, the dose for

quetiapine should have been "25 mg twice daily," rather than "2-5-
5.O mg once daily," as printed. The article has been corrected on the
Journal'sWeh site at www.nejm.org.

N Engl J Med 2006;33t:1655-a

Downloaded from www.neim.org at NATIONAL UN|V OF SINGAPOBE-CENTML LIBRARY on July B,2006 .

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