646

Moving Beyond Metabolic Encephalopathy: An

Update on Delirium Prevention, Workup, and
Management
Ethan G. Brown, MD1

Vanja C. Douglas, MD1

1 Department of Neurology, University of California, San Francisco,

California

Address for correspondence Ethan G. Brown, MD, Department of

Neurology, UCSF, Box 0114, 505 Parnassus Avenue, San Francisco, CA
94143 (e-mail: ethan.brown@ucsf.edu).

Abstract

Keywords

delirium
attention
inpatient
elderly

Delirium is a condition that frequently complicates hospitalization and consists of an

acute decline in orientation and attention, often accompanied by other cognitive
changes. Delirium is tied to multiple detrimental outcomes both in the short and long
term, including cognitive and functional decline, inpatient complications, and mortality. Postoperative, elderly medical, and critical care patients have been identied as
populations at particular risk. In this review, the authors discuss current theories on
pathophysiology, recommended workup, and evidence-based prevention and management of inpatient delirium. In general, instituting a system of active screening of at-risk
populations and nonpharmacologic interventions for prevention and treatment seems
to be the most effective method of addressing delirium. More research is needed to
clarify the etiology of delirium and develop safe therapeutic options that address the
underlying pathophysiology.

Epidemiology
Delirium is a neuropsychiatric syndrome characterized by an
acute change in and uctuating level of attention and
orientation. The syndrome often includes psychomotor activation or retardation, confusion, disorganized thinking, and
hallucinations. When psychomotor activation predominates,
the term hyperactive delirium is used; hypoactive delirium
refers to cases where psychomotor retardation predominates.
The condition is often a reason for hospital admission and also
a frequent and impairing complication of hospitalization.
Hospital-acquired delirium complicates as many as 10 to
15% of general medical admissions, 10 to 50% of postoperative
admissions, and 25 to 50% of intensive care unit (ICU)
admissions, with as many as 80% of mechanically ventilated
patients developing delirium.13 Perhaps more telling, a
recent point-prevalence study across almost an entire hospital revealed 17.6% of patients to be delirious, with the highest
rates specically among general medical, orthopedic, and
neurosurgical patients.4

Issue Theme Hospitalist Neurology;

Guest Editors: S. Andrew Josephson, MD,
and Vanja C. Douglas, MD

Regardless of the frequency, the consequences are detrimental (Table 1). Delirium is an independent predictor of prolonged hospital stay, worsened functional status at discharge,
new nursing home placement, and mortality.3,5 Pre-existing
dementia is worsened by inpatient delirium, and development
of new-onset dementia seems more common after an episode of
delirium.6 Hypoactive delirium may have a worse prognosis,
although this has not been adequately studied.7
Whether delirium is merely a marker of worsening disease
severity or has a causal relationship with negative outcomes
is not clear. Two recent studies in the critical care setting
provide some insight into this question. One adjusted for
illness severity as it changed over time between admission
and the development of delirium, instead of merely relying on
admission illness severity.8 When the changing illness severity over the hospital stay was taken into account, delirium did
not independently predict mortality. This study did not
include long-term follow-up of patients, nor did it examine
other clinical outcomes of delirium such as cognitive or
functional decline.

Copyright 2015 by Thieme Medical

Publishers, Inc., 333 Seventh Avenue,
New York, NY 10001, USA.
Tel: +1(212) 584-4662.

DOI http://dx.doi.org/
10.1055/s-0035-1564685.
ISSN 0271-8235.

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Metabolic Encephalopathy: Update on Delirium Prevention, Workup, Management

Brown, Douglas

647

Population

Risk factor

Outcome

Adjusted odds ratio

(95% confidence interval)

Mixed medical and

surgical patients

Incident delirium

Postdischarge mortality (348 mo)

1.71 (1.272.23)5

Incident institutionalization

2.41 (1.773.29)5

New-onset dementia

12.52 (1.8684.21)5

Subjective cognitive impairment

2.41 (1.573.69)62

Complications

6.5 (2.715.6)63

Incident institutionalization

5.0 (2.88.9)64

Walking dependence

15.5 (5.642.7)64

Mortality

1.8 (1.12.8)64

Critical care patients

Patients admitted to
a rehabilitation unit

Incident delirium
Delirium superimposed
on dementia at admission

Patients admitted for

noncardiac surgery

Postoperative delirium

Functional decline at 3 mo

2.1 (1.23.8)65

Patients after stroke

Incident delirium

Death or impaired function

2.0 (1.04.0)66

The BRAIN-ICU study addressed these details, nding a

signicant burden of cognitive impairment in previously healthy
people a year after critical care admission, with 34% showing
cognition scores similar to patients with mild traumatic brain
injury (TBI).9 Duration of delirium in the intensive care unit (ICU)
was an independent risk factor for impaired global cognition.
Whether or not long-term cognitive impairment would be
similarly explained by worsening disease severity as in the
previous study, or if delirium on the general wards predicts
such detrimental cognitive outcomes, is yet to be seen.

Pathophysiology
Although the serious outcomes of delirium are appreciated,
gains in understanding its pathophysiology have been elusive.
The insults that precipitate delirium are most likely multifactorial and different from case to case. A practical approach to
understanding these precipitants includes separating them into
direct and indirect factors, though in reality these precipitants
likely have signicant mechanistic overlap.10
Direct insults include metabolic derangements (e.g., hypoglycemia, hypoxia, hypercarbia), direct tissue damage (e.
g., TBI), or medications. Medications are among the most
common precipitants of hospital-acquired delirium, with
implicated drug classes including benzodiazepines, other
sedative hypnotics, and opioids. These medications are
thought to precipitate delirium through agonism of gamma-aminobutyric acid (GABA) and increased inhibitory
tone, presumably disrupting the network connectivity in
the brain that supports attention.11 Anticholinergic (e.g.,
second-generation antihistamines, tricyclic antidepressants, antispasmodic agents for urinary incontinence or
gastric motility) and less commonly dopaminergic medications (e.g., antiparkinsonian medications) also precipitate
delirium, emphasizing the direct role of these neurotransmitters in cognitive function.12

Indirect causes, on the other hand, involve systemic stress

responses that change the biochemical atmosphere of the
periphery. A systemic inammatory response, either to
surgery or infection, can affect microglia in the central
nervous system (CNS) through direct cytokine transport
across the bloodbrain barrier, neuronal activation through
vagal afferents, or endothelial activation and changes in blood
ow.10 This CNS inammatory activation is exaggerated with
age, cerebrovascular disease, and neurodegenerative disease.13 Excess cortisol and improper regulation of the stress
response along the hypothalamicpituitary axis, another
dysfunction associated with aging, is also thought to disrupt
attention; pain, sleep, and sensory deprivation, and general
anxiety may induce delirium through these mechanisms.
Although the pathophysiology of delirium in general is still
unclear, more progress has been made in understanding
some specic syndromes. Confusion in hepatic encephalopathy at least partially arises from cerebral edema, after high
levels of ammonia are converted to glutamine and intracellular osmolarity increases.14 Animal models of septic encephalopathy support changes in microcirculation and cerebral
blood ow, bloodbrain-barrier permeability, and oxidative
stress as mechanisms of CNS insult in systemic infection.15
Studies of cytokine proles have been largely nonspecic or
conicting. Studying the pathophysiology of delirium in the
context of cause and setting may identify more specic
objective markers of disease.
A potential nal common pathway for many of the above
precipitants is impaired acetylcholine neurotransmission. Acetylcholine likely mediates attention through increasing salience
of thalamic inputs to sensory association and prefrontal cortical
areas, and inhibiting the representation of other distracting
stimuli.16 Acetylcholine may also inhibit microglial inammatory cascades in the CNS; its decit would allow systemic inammatory activation to induce more detrimental neurotoxicity.17
These functions may explain why patients with
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Table 1 Selected outcomes of inpatient delirium and their associated risk of occurrence

Metabolic Encephalopathy: Update on Delirium Prevention, Workup, Management

neurodegenerative diseases involving selective loss of cholinergic neurons are particularly vulnerable to delirium. Nevertheless,
how cholinergic dysfunction is triggered in delirium is unclear. In
addition, early trials of cholinesterase inhibitors for delirium
prevention have been disappointing.18,19

Diagnosis and Evaluation

One of the most important lessons from delirium prevalence
and incidence studies is that although many cases come to the
attention of hospital staff because of agitated and disruptive
behavior or through family members noticing their loved
ones confusion, many cases go undetected; physicians should
have a high index of suspicion when caring for patients at risk.
Risk factors for development of new-onset delirium in the
hospital include older age, severe illness, dehydration, preexisting cognitive impairment, poor functional status, and
vision and hearing impairment.2022 Alcohol abuse and CNSactive medications, including antidepressants and antipsychotics, are also risk factors.20 As mentioned, starting a
benzodiazepine or opioid during hospitalization, or indeed
starting more than three to ve new medications of any type,
are independent risk factors for delirium.12 In critical care
patients, acidosis, admission for a neurologic or neurosurgical
indication, and comatose state are also risk factors for subsequent incident delirium.23 Various predictive scores have
been developed based on these risk factors and can be used
at admission by nursing staff or physicians to identify those
most likely to develop delirium (Table 2).
Presence of these risk factors should heighten suspicion for
the development of delirium during the hospital course and
encourage more frequent assessment. Formal, validated delirium screening methods are available and have the benet
of objective quantication for assessing trends and are essential in research or hospital-wide protocols. Among the most
commonly used is the confusion assessment method (CAM), a
test that involves brief bedside cognitive assessment and
supports a diagnosis of delirium if the patients symptoms
have an acute onset, a uctuating course, and involve inattention with either disorganized thinking or an altered level
of consciousness.24 The test has high sensitivity and specicity (94% and 89%, respectively) with moderate to high interrater reliability (0.71.0) across many studies, but requires
specic training.25 The CAM-ICU, designed for use in mechanically ventilated patients, uses a bedside assessment that
only involves yes/no questions, and maintains similarly high
sensitivity and specicity.26
Once a patient develops delirium, the goals of neurologic
assessment should be to (a) conrm the diagnosis, (b) establish a patients delirium risk factors, (c) identify as best as
possible the inciting factor(s) of the condition (Table 3), and
(d) recommend and help guide management, both in the
hospital and after discharge.
Time should be spent discussing the course of confusion
with nursing staff and caregivers, eliciting any uctuation
over the day as well as the severity of agitation. In addition to
reviewing the medical history, providers should ask family
about prior episodes of delirium, substance abuse, cognitive
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decline, sleep deprivation, and recent medication changes. All

too often progressive cognitive decline is unrecognized by
family members or attributed to normal aging, but brought to
light in the setting of a hospitalization complicated by
delirium.
The general physical exam should focus on common
secondary toxic and metabolic causes of delirium: signs of
infection including meningismus, substance withdrawal or
toxidrome, asterixis and other signs of end-stage liver disease
or uremia, pulmonary crackles or wheezing suggesting hypoxemia or hypercarbia, and signs of head trauma.
The neurologic examination should begin with cognitive
testing. Loss of awareness of ones surroundings and disorientation to place and time is a hallmark of delirium; the degree
of orientation can be followed over time and assessed frequently to allow for reorientation. The second hallmark of
delirium is impaired attention, and much of the time at the
bedside should be spent in its assessment. Numerous tests of
attention are available: forward and backward digit span, the
vigilance A test (reading a list of letters and having the
patient indicate whenever the letter A is mentioned), serial
calculations, or spelling WORLD backward. The months-ofthe-year backward test, asking a patient to recite the months
of the year forward, then backward, and scoring the task as
incorrect unless he or she makes it to at least July, has been
found to have a sensitivity of 83.3% and a specicity of 90.8%
for delirium in a general inpatient population.27 Some data
suggest impairment in visual attention may be specic for
delirium, and bedside tests such as the spatial span forward
have shown promise in differentiating delirium from
dementia.28
The elemental neurologic examination should screen for
focal lesions that would change the diagnosis or prompt
further workup. Focal brain lesions uncommonly cause a
clinical picture similar to delirium, but thalamic lesions,
especially in the paramedian region from occlusion at the
top of the basilar artery, can cause behavioral changes similar
to delirium, as can nondominant temporal-parietal lesions or
a shower of emboli to both hemispheres.29 To detect these
lesions, neglect, gaze palsy, visual eld decits, and subtle
hemiparesis or hemiataxia should all be looked for in
particular.
After discussion with caregivers and assessment of the
patient, the next essential step is reviewing medications. Any
high-risk medications, including opiates and those with a
GABA-ergic, anticholinergic, or less commonly, dopaminergic
effect should be noted and reduced or discontinued if possible.30 Recent dose changes, potential interacting medications,
or recent changes in metabolism due to changes in liver
function or glomerular ltration rate should also be
considered.
In most cases a complete blood count and comprehensive
metabolic panel with calcium, phosphorous, magnesium,
renal and liver function tests, a urinalysis, and a urine culture
are necessary. The recent trends of certain laboratories,
including sodium and glucose, are important to review, as
large shifts in these electrolytes can cause osmotic demyelination. Further studies that may be helpful on a case-by-case

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649

Population

Outcome

Predictive Factors

C-statistic in
validation
cohort

Reference

ICU
(PRE-DERILIC)

Development of
delirium during ICU stay

Age
Apache-II score
Level of consciousness
Admission service
Presence of infection
Presence of metabolic
acidosis
Use of morphine
Use of sedatives
Urea concentration
Urgent admission

0.77

Van den
Boogaard et al23

Patients admitted
for stroke

Development of
delirium during admission

Age
NIHSS
Stroke subtype
Presence of infection

0.83

Oldenbeuving et al67

General medicine
patients

Development of inpatient
delirium baseline risk factors

Visual impairment
Severe illnessa
MMSE < 24
BUN:Cr ratio  18

0.66

Inouye et al22

General medicine
patients
(AWOL)

Development of delirium
during admission

Age > 80
Inability to spell
WORLD backward
Disorientation to place
Moderate or severe
illness severityb

0.69

Douglas et al21

General medicine
patients

Development of delirium
during admission

BUN/Cr ratio
Barthel Index

0.78

Carrasco et al20

General medicine
patients

Development of delirium
during admission

85 years old or above

Dependent in 5 or
more ADLs
Taking psychotropic
medications

0.85

Martinez et al68

General medicine
patients

Persistence of delirium
at discharge

Dementia
Vision impairment
ADL impairment
Charlson score
Restraint use during delirium

0.75

Inouye et al69

Abbreviations: ADL, activities of daily living; BUN, blood urea nitrogen; Cr, creatinine; ICU, intensive care unit; MMSE, mini mental state examination;
NIHSS, National Institute of Health Stroke Scale; PRE-DERILIC, PREdiction of DELIRium in ICu patients.
a
APACHE II score > 16 or nursing rating.
b
Based on nursing assessment.

basis include ammonia, thyroid function tests and potentially

antithyroid antibodies, human immunodeciency virus, arterial blood gas, rapid plasma regain, vitamin B12, coagulation factors, and blood cultures.
A frequent question for the consulting neurologist is
whether further workup is appropriate, especially if the
above assessment does not indicate any clear underlying
secondary pathology. Head imaging is often obtained, but
without any focal ndings its yield is low. A noncontrast
computed tomography (CT) scan is sufcient to evaluate for
hydrocephalus or hemorrhage; subacute strokes and large
mass lesions can also be detected. A retrospective study of
patients presenting to the emergency room with acute confusion found that a focal neurologic exam or history of a fall

captured all cases with abnormal CT ndings.31 Magnetic

resonance imaging (MRI) is also uncommonly helpful, unless
a focal nding is appreciated, or if other pathology such as
posterior reversible encephalopathy syndrome, diffuse axonal injury, or multiple small strokes are likely. A retrospective
study of patients admitted for any type of acute confusion
found that without any focal neurologic ndings on exam, the
likelihood of normal imaging (either CT or MRI) was 93%; if
patients were demented or had indications of a systemic
process including a fever or dehydration, the likelihood of
normal imaging approached 100%.32 Nevertheless, in cases
where no secondary cause of delirium can be identied, brain
imaging occasionally reveals a surprising and actionable
nding.
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Table 2 Prediction scores for delirium

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Recent neurosurgical procedure, immunocompromise,

encephalopathy did not develop in hospital, meningismus

Encephalitis/meningitis

Ataxia, nystagmus, diplopia, confabulation

Thiamine deciency

Untreated pain

Postoperative

Sensory deprivation

Day/night dysregulation

Limited mobility

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Lack of hearing aids, glasses

Presence of lines/tubes/catheters

Wheezing, crackles, dyspnea

Hypercarbia or hypoxemia

Cobalamin deciency

Seizures, asterixis, myoclonus

Chronically ill or prolonged hospital stay
Diarrhea or insensible water loss

Multiple focal neurologic decits

Abnormalities of electrolytes,
endocrine, renal, or liver function

Acute disseminated encephalomyelitis

Hypertension, tachycardia, hyperthermia, tremulousness

Alcohol withdrawal

Myoclonus, diffuse hyperreexia, psychosis, seizures

Signs vary depending on exposure

Toxidrome

Steroid-responsive encephalopathy

Recently starting more than 2 medications,

prolonged hospital stay

Medications

Posttraumatic encephalopathy

Scalp lacerations, history and mechanism of trauma

Systemic inammatory response syndrome

Sepsis

Diffuse axonal injury

Elderly, pre-existing cognitive dysfunction,

presence of indwelling urinary catheter

History of hypertension, pregnancy,

exposure to calcineurin inhibitors

Posterior reversible encephalopathy

syndrome (PRES)

Localized infection
(e.g., urinary tract infection, pneumonia)

History of prior lobar hemorrhage

Cerebral amyloid angiopathy

Empiric multicomponent nonpharmacological

intervention

Serum B12 level

MRI to look for mammillary body necrosis

Empiric use of IV thiamine

Arterial blood gas

Serum measurement of electrolytes, renal and

liver function, ammonia, glucose, thyroid
function studies, morning cortisol

MRI with gadolinium

Antithyroid peroxidase or antithyroglobulin

antibodies; autoimmune encephalitis
antibody panel

Social history

Urine toxicology screen

Pharmacy consult for review of

medication interactions

MRI

Lumbar puncture, HIV antibody

Blood cultures

Urinalysis, urine culture, chest X-ray

MRI

MRI with iron-sensitive imaging

MRI and MR angiogram, lumbar puncture,

brain biopsy

CT scan, MRI with DWI

Focal ndings suggestive of nondominant parietal,

thalamic, brainstem, bilateral cerebral hemispheric injury
Systemic signs of vasculitis

Workup

Other findings suggestive of cause

Metabolic Encephalopathy: Update on Delirium Prevention, Workup, Management

Iatrogenic

Metabolic

Autoimmune

Toxic

Traumatic

Infectious

Stroke (ischemic or hemorrhagic)

Vascular

Vasculitis

Specific causes

Major etiologic
category

Table 3 Potential causes of acute confusion according to the mnemonic VITAMIN E (with the most common in-hospital causes in bold)

650
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Brown, Douglas

As continuous electroencephalography (EEG) monitoring has become more widely available, the role of nonconvulsive status epilepticus as an important cause of
delirium and encephalopathy has been better appreciated.
Most often, the EEG is nonspecic in delirium, showing
either generalized slowing of the background, triphasic
waves, or generalized epileptiform discharges without
seizure, none of which necessarily change inpatient management. On the other hand, an EEG ordered for acute
confusion in the hospital has a reasonable yield in retrospective studies: Nonconvulsive seizures were found in
these cases 16% of the time in the surgical ICU, 10% in the
medical ICU, and 7% on the general inpatient oor.3335 Risk
factors for seizures on EEG vary from study to study, but
include sepsis in the ICU, a history of seizures prior to EEG,
and on the general inpatient ward, an intracranial mass and
spells as the indication for EEG monitoring.33,35
Lumbar puncture is a less useful test in hospital-acquired delirium. Retrospective studies of lumbar puncture
in patients with acute mental status changes starting
during hospitalization nd exceedingly low rates of meningitis, regardless of the presence or absence of fever. All
nonneurosurgical cases from such studies with positive
cerebrospinal uid cultures were either immunosuppressed or already suspected of having community-acquired meningitis because of symptoms that developed
prior to admission.3639 Based on these studies, lumbar
puncture should be considered for patients in whom acute
confusion developed prior to hospitalization and in patients with recent neurosurgical procedures (including
placement of intracranial pressure monitors), immunosuppression, or patients with recent TBI.
If the above investigations do not suggest the underlying
cause of delirium, it is likely the condition was triggered by
the stress of hospitalization or iatrogenic precipitants. These
may include sleep deprivation, restraint use, urinary catheters, immobilization, or simply the placement of a patient
with vision, hearing, and memory decits in an unfamiliar
environment. Identifying such precipitants alerts hospital
caregivers to the specic vulnerabilities in a given patient,
and guides targeted interventions to minimize the impact
and duration of the delirious episode. For instance, a patient
with sleep deprivation or disorientation may benet in
particular from a window room, a large clock, and frequent
reorientation by hospital staff and family members. Through
these mechanisms, identifying iatrogenic precipitants may
improve outcome.40
Finally, beyond the initial workup and assessment, followup evaluation during the course of the hospital stay and
beyond is crucial. Although delirium is often a transient
condition, a systematic review found persistent delirium to
be present in in 44.7%, 25.6%, and 21% of patients at 1, 3, and
6 months after discharge, respectively; functional, cognitive,
and mortality outcomes were worse the longer delirium
lasted.41 Re-evaluation before discharge and counseling of
caregivers is important to address ongoing delirium in these
cases, and the effect of interventions on long-term outcomes
should be evaluated in future studies.
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Abbreviations: CJD, Creutzfeldt-Jakob disease; DWI, Diffusion weighted imaging; EEG, electroencephalogram; HIV, human immunodeciency virus; MRI, magnetic resonance imaging.

Continuous EEG monitoring

MRI helpful in some cases (e.g., CJD)

Clinically appropriate history
Rapidly progressive dementias

History of seizures, intracranial mass, or encephalomalacia

Epileptic

Paraneoplastic antibody screen

Clinical history
Parkinsonism, visual hallucinations,
deterioration with dopamine antagonists

Sensory neuropathy, ataxia, opsoclonus-myoclonus

Paraneoplastic meningitis

Lewy body dementia

Neurodegenerative

Lumbar puncture for ow cytometry

and cytology
Headache, cranial neuropathy, radiculopathy;
history of leukemia, lymphoma,
breast cancer, lung cancer, melanoma
Carcinomatous meningitis

MRI with gadolinium

History of weight loss, known primary malignancy,
focal neurologic decit
Primary or metastatic CNS cancer
Neoplastic

Table 3 (Continued)

Other findings suggestive of cause

Specific causes
Major etiologic
category

Workup

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Metabolic Encephalopathy: Update on Delirium Prevention, Workup, Management

Prevention and Treatment

Addressing delirium can be generally divided into pharmacologic and nonpharmacologic methods; among these, there
are both strategies for prevention in at-risk populations, and
treatment options in those patients who develop delirium.

Pharmacologic Intervention
Pharmacotherapy is often a convenient option for the delirious patient, especially overnight when staff may be sparser
and symptoms worse. However, many of these medications
may have deleterious side effects, especially in older patients
with medical comorbidities, and studies showing benet are
relatively few.

Dopamine Antagonists
Despite how frequently this class of medications is used to
treat delirium, the few studies that have examined antipsychotics in hospital-acquired delirium do not support
their routine use, and none are approved by the United
States Food and Drug Administration (FDA) for this indication. A trial studying the efcacy of haloperidol in preventing delirium in all admissions to the ICU showed no
difference compared with placebo, and no differences in
secondary clinical outcomes.42 In patients undergoing elective surgery, several moderately sized randomized, placebo-controlled prevention trials have been performed, but
with inconsistent results. Differences in specic medications, dosing regimens, surgical procedures, and importantly, methods of identifying delirium, make denitive
recommendations difcult.43 However, some of these studies in surgical patients showed reductions in delirium
incidence, justifying the need for larger studies with
gold-standard outcome measurements.
Fewer studies have examined treatment of patients with
delirium. One large, randomized controlled trial compared
haloperidol, ziprasidone, and placebo. Although the study
enrolled all patients admitted to the ICU with an altered level
of consciousness, treatment was titrated based on the presence or absence of delirium; no differences in delirium
duration or clinical outcomes were found.44 Another very
small trial randomized 36 delirious patients in the ICU
requiring as needed haloperidol to quetiapine or placebo,
and found reduced duration of delirium with quetiapine.45
Only one small randomized controlled trial has examined
antipsychotic use to treat delirium in patients on general
medical wards. This study also compared quetiapine to
placebo, and showed no difference in resolution of delirium
between the two groups, though delirium severity improved
faster in those receiving quetiapine.46 However, improvement was based on diminished agitation rather than improved cognition and may simply reect the sedating effect of
quetiapine rather than an effect on delirium per se.
Any potential benet should be weighed against the
known risks of antipsychotic medications, especially in the
elderly, who are more likely to develop delirium. There is an
increased risk of sudden death, in a dose-related fashion,
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thought to be from cardiac arrhythmias, with both typical and

atypical antipsychotics, leading to an FDA advisory against
the use of these medications in the elderly.47,48 Other hospital-related side effects include orthostatic hypotension and
sedation. Finally, typical antipsychotics can be dangerous in
patients with dementia with Lewy bodies, a condition that is
unfortunately very prone to delirium.
Overall, controlled data do not support the routine use of
antipsychotics in the prevention or treatment of delirium. In
light of more efcacious nonpharmacologic solutions discussed below, antipsychotics should be used sparingly, in low
doses, and only when agitation threatens patient or caregiver
safety.

Melatonin and Melatonin-Agonists, Cholinesterase

Inhibitors, and Dexmedetomidine
Several small to moderately sized randomized trials have
explored the use of melatonin and ramelteon, a melatonin
agonist, in delirium prevention; however, similar to trials in
antipsychotics, methodological differences and conicting
results prevent denitive conclusions about efcacy.4951
Given the proposed role of cholinergic deciency in delirium
etiology, acetylcholinesterase inhibitors have been studied in
delirium prevention, but no randomized, controlled trial has
shown positive results.18,19,52 Dexmedetomidine, an -2
adrenergic receptor agonist, appears to be a less deliriogenic
alternative to benzodiazepines and opiates for sedation in the
ICU.53,54 Current critical care guidelines do not recommend
routine use of dexmedetomidine sedation in the ICU for
delirium prevention, but recommend considering this sedative as an alternative in patients who become delirious.55

Nonpharmacologic Intervention
Over the last 15 years, randomized studies have looked at
several nonpharmacologic interventions to prevent and treat
delirium with effective results. The most common approach
involves multicomponent and multidisciplinary interventions including frequent reorientation, nonpharmacologic
sleep hygiene improvements to normalize the sleepwake
cycle, early physical therapy, reduction of restraints, early oral
rehydration, and prevention of sensory deprivation by ensuring hearing and visual aids are available when needed.
Randomized trials have repeatedly shown efcacy in these
strategies reducing the incidence and duration of delirium;
two recent meta-analyses also demonstrated a reduction in
falls.40,56 Multicomponent interventions to prevent delirium
are supported by national guidelines in the United Kingdom.57 In the ICU, early physical and occupational therapy
during sedation interruptions led to reduced incidence and
duration of delirium, less days intubated, and a more likely
return to independent functional status at discharge.58
These interventions are often enacted on a case-by-case
basis through geriatric consultation and targeted education of
nurses and family. Integrating them into daily practice requires more systematic and infrastructural changes, which
has been a barrier to widespread adoption. The Hospital for
Elder Life Program (HELP) and Acute Care for Elders (ACE)

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Brown, Douglas

Fig. 1 Algorithmic approach to a workup of delirium. ABG, arterial blood gas; CBC, complete blood count; CT, computed tomography; EEG,
electroencephalography; HIV, human immunodeciency virus; LFTS, liver function tests; MRI, magnetic resonance imaging; RPR, rapid plasma
reagin; TSH, thyroid-stimulating hormone; UA, urinalysis.

models are approaches designed to incorporate nonpharmacologic delirium prevention and treatment throughout hospital units; they have been implemented in many different
hospitals across the country in both academic and community settings.59,60 With HELP or ACE integration, studies have
found lower delirium incidence, fewer complications, shorter
hospital and subsequent nursing home stays, and lower
hospital and subsequent nursing home costs.60,61
The benet of these strategies when compared with
pharmacologic approaches can perhaps be understood in
the context of the precipitants and presumed pathophysiology of delirium discussed earlier. Although the chemical effects
of multicomponent nonpharmacologic interventions have
not been studied, manyincluding frequent reorientation,
restoration of sensory perception, early mobilization, and
light therapymay reduce cortisol and adrenergic levels
through improving anxiety or pain and help restore or
maintain circadian rhythms. Oral hydration may improve
electrolyte imbalance. In this way, nonpharmacologic strategies may directly address the presumed mechanisms of
delirium.

Summary
Although clinically quite variable with a complex pathophysiology, delirium has clear risk factors and precipitants,
and established methods of prediction, screening, and
diagnosis. Given how common and detrimental the condition is, a consistent response should be in place for whenever it arises. Those at high risk can be identied early and
nonpharmacologic measures undertaken to help mitigate

iatrogenic precipitants in the hospital, with randomized

trial data suggesting delirium incidence can be reduced by
one-third by such a strategy. Once delirium develops, a
routine set of studies should be performed to evaluate for
common treatable causes and potentially offending medications should be eliminated (Fig. 1). Continuing therapy
should focus on addressing any precipitants identied, and
enhancing nonpharmacologic measures through nursing
and caregiver education and involvement of rehabilitation
services when appropriate. Care pathways are a potential
way to streamline and standardize such a comprehensive
approach (Fig. 2).
Delirium itself is not an indication for pharmacologic
therapy. However, if a patient becomes agitated to the point
where personal or staff safety is threatened, light sedation
with low-dose antipsychotics, or if in the critical care unit,
dexmedetomidine can be attempted. Opiates should be
avoided and benzodiazepines should be reserved for patients
with delirium due to alcohol withdrawal.
Neurologists have traditionally played a role in the evaluation of delirious patients by performing a careful neurologic
examination to identify evidence of focal processes and
suggest additional studies to reveal the underlying cause in
more mysterious cases. However, the neurohospitalist can
play a larger role in the treatment of delirious patients by
engaging with hospital and nursing administration to enact
comprehensive delirium care pathways that incorporate prediction, prevention, screening, and standardized treatment.
In this way one can play a direct role in reducing delirium
incidence and likely improve outcomes in the cases that do
occur.
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11 Sanders RD. Hypothesis for the pathophysiology of delirium: role

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Fig. 2 Potential care pathway for delirium prevention and treatment.

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