Chapter 22

Delirium

Paula T. Trzepacz

Clinical Pearls
• Acute cognitive impairment is delirium until proven otherwise.
• Search broadly for and rectify all possible etiologies for the delirium.
• Manage quiet and animated delirium the same way because it is an altered state
of consciousness irrespective of its overt presentation.

Introduction

The Neuropsychiatric Syndrome of Delirium

Delirium is an acute alteration of consciousness that affects many older persons in

the general hospital and nursing homes. The cognitive, behavioral, and perceptual
symptoms result from a generalized disturbance of neural network functioning
affecting most higher cortical regions, but with intact primary motor and sensory
function. Any preexisting brain impairment increases the likelihood of being deliri-
ous when precipitating physiological or pharmacological perturbations occur.
Therefore, the elderly are at particularly high risk for delirium, related to mild cog-
nitive impairment, cardiovascular and cerebrovascular disease, effects of aging,
neurodegenerative disease, or dementia from any cause. The degree of cognitive
impairment on admission is linearly related to the risk for incident delirium and
delirium severity [1].

P.T. Trzepacz, M.D.

Department of Psychiatry, Indiana University School of Medicine,
Goodman Hall, 355 W 16th St., Suite 4800, Indianapolis, IN 46202, USA
e-mail: pttrzepacz@outlook.com

© Springer International Publishing AG 2017 343

B. Tousi, J. Cummings (eds.), Neuro-Geriatrics,
DOI 10.1007/978-3-319-56484-5_22
344 P.T. Trzepacz

As a rule of thumb based on a variety of studies using different methods, about

20% of patients in the hospital are delirious at any point in time. Ryan et al. [2]
evaluated 311 general hospital patients over a 24-h period and found a point preva-
lence of 19.6% using Diagnostic and Statistical Manual of Mental Disorders, 4th
edition (DSM-IV) criteria. Advancing age (34.5% if over 80) and preexisting cogni-
tive impairment were independently associated with even higher rates. Nurses and
physicians detected different symptoms: nurses noted inattentiveness, lability of
affect and delusions and medical staff noted inattention and short term memory
deficits. Delirium rates are higher in ICU, post-operative, palliative care and nursing
home patients.
There is not an absence of consciousness in delirium as occurs in coma or stupor,
but rather an alteration of aspects of normal consciousness. Normal consciousness
consists of a serially time-ordered, organized, restricted, reflective awareness of
both self and the environment and is an experience of graded complexity and quan-
tity [3]. Alterations in consciousness affect attention, intention, working memory,
awareness, higher level thought, perception and mood/emotion as occurs in delir-
ium. The cerebral cortex is aroused but neural networks that subserve normal con-
sciousness are functioning less than optimally. The person appears to be confused
and cannot make sense of the environment or communicate fully with intact focus
and comprehension.
There are many etiologies that can precipitate delirium (see Sect. “Etiologies of
Delirium”) and the resultant syndrome has essentially the same features. More
severe medical illness is a strong factor for producing delirium. However, as Inouye
[4] articulated, precipitating factors alone do not account for delirium, rather it is the
interplay between those and the threshold for delirium that depends on individual
vulnerability. Advanced age is itself a major risk factor for increased vulnerability,
likely related to both changes in brain infrastructure and increased incidence of
other medical problems and use of pharmaceuticals in the elderly.

Neurophysiology of Delirium

The neuropathogenesis of delirium likely involves a combination of neurotransmit-

ter imbalances, altered neural network connectivity, oxidative stress and neuroin-
flammation, with delirium resultant from a final common neural pathway that
disturbs cortical neural networks [5, 6]. These processes are interrelated and can
exacerbate each other.
Acetylcholine is a major neurotransmitter associated with supporting conscious-
ness and neural activity of higher cortical regions. Cholinergic activity from basal
forebrain nuclei subserves higher cortical activity including cognition and selective
attention, which is integrated with thalamic cholinergic pathways for sensorimotor
gating. The thalamus also receives general arousal stimuli from the brainstem [7].
The underlying neurochemistry of delirium probably involves several neurotrans-
mitter imbalances though a deficiency of cholinergic activity with or without an
22 Delirium 345

excess of dopaminergic activity appears to have the most support [8]. This theory is
generated from our understanding of neural systems likely involved, preclinical
studies, and our knowledge of conditions that induce delirium such as those that can
cause metabolic mitochondrial dysfunction. Different cholinergic ascending path-
ways are important as contributors to cognition, and overall cortical arousal and gating,
and for sustaining more complex attentional and cognitive functions with some
reciprocal effects with dopaminergic activity [9]. Delirium is associated with gener-
alized EEG slowing, consistent with thalamic dysfunction associated with choliner-
gic deficiency [10].
Functional magnetic resonance imaging (fMRI) and electroencephalogram
(EEG) reports are consistent with altered neural network connectivity in delirium
[11, 12], both supporting alterations in thalamic-cortical activity. Disruptions in the
default mode network may account for cognitive and other symptoms.
Inflammatory pathways affecting the brain are implicated in delirium and pathol-
ogy of the basal forebrain cholinergic system predisposes to cognitive effects of
neuroinflammation [13] and lower plasma cholinesterase activity and higher inflam-
matory mediators levels are associated with delirium [14]. There are many reports
of cytokine abnormalities associated with delirium or its risk, including various
interleukins. A cerebrospinal fluid (CSF) proteomic study reported similar patterns
of altered protein expression of several protein families despite differing etiologies
for the delirium [15]. Elevations of C-reactive protein, a nonspecific marker of
inflammation, have been associated with delirium [16].

Outcomes in the Elderly

Overall, prognosis after a delirium episode is very good and most children and
adults return to normal. However, preexisting cognitive impairment especially
dementia, frailty or medical comorbidities in older persons increase the risk for
delirium as well as a poorer functional recovery and higher mortality post delirium
[17, 18]. Falls and fractures are associated with delirium in the elderly [19].
Patients who can recall their delirium experiences may be frightened and con-
cerned they have lost their minds and that it will happen again, requiring education
and support [20].
During the index hospitalization delirium is associated with longer lengths of
stay and increased mortality in the hospital. Delirious patients may refuse treat-
ments due to fear or inability to comprehend the situation and may be combative.
They cannot give informed consent and may be unable to participate in rehabilita-
tive activities like physical therapy.
There is a large literature noting that older persons have poorer functional
outcomes after an episode of delirium during the index hospitalization as well as
during follow-up after discharge, with increased mortality, reduced indepen-
dence and increase of dementia diagnosis [21, 22]. However, this association
with delirium is usually not addressed as causality of the delirium episode on
346 P.T. Trzepacz

outcomes such as being an independent factor using multivariate analyses and

correction for confounders [23]. Age, illness severity, preexisting cognitive
impairment, impaired arousal in the emergency department, and duration of
intensive care unit (ICU) hospitalization may be more relevant to outcomes than
incidence of delirium [24–26]. Mortality is often attributable to the underlying
medical conditions and their complications, which also precipitated the delirium
during an index hospitalization.
Those who have functional deterioration in the months following discharge may
have had undetected cognitive impairment prior to the hospitalization, and the med-
ical problems causing a delirium appear to be an independent reason for further
brain impairment that results in longer term poor outcomes. Longitudinal studies
show that even subtle preexisting attentional or executive function deficits are asso-
ciated with increased risk of delirium in older persons [27, 28], even without a
preexisting diagnosis of MCI or dementia. Comorbid delirium with preexisting
dementia strongly predicts worse outcomes [29].
Therefore, delirium should be considered an important marker of poor outcomes
in older persons and should signal to clinicians an urgency to determine its causes
and aggressively manage and rectify them.

Detection of Delirium

Despite its high prevalence, delirium is underdetected and underdiagnosed.

Further, it is misdiagnosed as a variety of other disorders, such as depression,
dementia or psychosis, which is problematic because of its high associated mor-
bidity and mortality which requires prompt and accurate diagnosis and manage-
ment. Being aware of its risk factors and employing simple screening methods
can enable better detection in routine care, especially among older persons who
are hospitalized.
Screening for dementia at admission using informant based tools such as the
AD8 or frailty scales can help identify those at risk for delirium [30].

Clinical Manifestations

Delirium is assessed through history for onset and types of symptoms during clini-
cal interview with the patient and observers, and a thorough mental status examina-
tion. Delirium broadly affects cognition plus many other higher cerebral cortical
functions affecting thought, language, and affect, as well as motor behavior and
sleep-wake cycle. It does not present with primary motor or sensory abnormalities,
though if those are affected they might be related to an underlying medical cause for
the delirium.
22 Delirium 347

Core Domain Symptoms

A number of studies of delirium phenomenology reveal that certain symptoms are

more common and characteristic, and which comprise three core domains:
Cognitive, Circadian and Higher level thinking [31]. These persist throughout the
episode [32].
Inattention is the cardinal symptom and disproportionately affected as compared
to deficits in other cognitive domains: short and long term memory, visuospatial
function and orientation. These deficits can be elicited during the interview, observed
by staff and more formally assessed using bedside tests. The person may be inatten-
tive, distractible or hyperalert. Disorientation first affects time, then place and then
person, with less familiar people not being recognized before family and friends.
Not recognizing one’s own identity can occur in severe delirium but is rare.
Circadian disturbances affect sleep-wake cycle and motor presentation in ways that
are inappropriate for the person at that time of day or night. Motor activity alterations
are almost always present and reflect hyperactivity, hypoactivity or a mixed state [33].
These patterns have been documented using 24-h actigraphy which also finds sleep-
wake disruptions in delirium [34, 35]. Sleep-wake cycle dysfunction can be mild with
restlessness or insomnia or more severe with frequent daytime napping, wakefulness
at night or complete reversal and disintegration of the sleep-wake cycle pattern.
Higher level thinking abnormalities can affect thought process, naming ability and
semantic language—sometimes referred to as incoherence or confusion because the
person is unable to communicate in a meaningful and understandable fashion and
cannot correctly comprehend what they are experiencing introspectively or in the
environment. Thought process can involve tangentiality and circumstantiality or even
loose associations where the train of thought does not connect logically. In delirium’s
most severe presentations the person may sound aphasic or even mute. Often family
and friends who know the person will detect this and worry the person is “demented”
or “going crazy.” While listening to a delirious person an interviewer may get a gut
feeling of having a disconnected or non-meaningful interpersonal interaction.
Temporal course classically has an acute or abrupt onset, and is a distinct change
from baseline for that person. This may be ascertained through history or observed
by the clinical team. Symptom severity classically fluctuates over a 24-h period
such that the person appears lucid and then inexplicably becomes impaired again.
Severe delirium may not have discernable symptom severity fluctuations, especially
when it borders on stupor.

Noncore Symptoms

Noncore symptoms occur much less often than core symptoms but can be notice-
able and jarring to family and clinical staff. Their presence or absence should not be
relied upon to diagnose delirium or dictate therapy, however. It is important to
348 P.T. Trzepacz

gather history for the nature of any preexisting noncore symptoms attributable to a
dementia, common in more advanced Alzheimer’s disease. Psychotic symptoms
can be very frightening to the patient and their family, and some remember these
following the episode, requiring a reassuring explanation from the clinician.
Psychotic noncore symptoms include abnormal thought content, which can reach
delusional proportions but unlike schizophrenia or Alzheimer’s disease the delu-
sions are more poorly formed and not well-systematized such that they might
change in content over time and can even include bits of context from the clinical
situation. These are usually persecutory in nature but may be grandiose.
Perceptual disturbances are usually visual in nature but auditory are also com-
mon. Olfactory, tactile or gustatory illusions and hallucinations in a medically ill
person usually cue delirium, and occur more often in delirium than in primary psy-
chiatric disorders. Tactile hallucinations suggest anticholinergic toxicity.
Noncore symptoms also include affective lability, which can present as any
emotion—sad, anxious, irritable, happy, angry, etc. Characteristically the emotions
change rapidly from one to another and are not congruent with the context or con-
versation. This type of lability is indicative of a medical etiology affecting the brain
and uncommon in primary psychiatric disorders except perhaps in severe mania.

Diagnostic Approach

Tools to Detect and Measure Delirium

A variety of tools exist that are used to detect, screen for, diagnose or measure sever-
ity of delirium. Not all include descriptive anchors or a breadth of symptoms. Many
rate symptoms and features categorically without rating severity. Some are more
sophisticated and require advanced understanding of delirium’s features and how to
interview for accuracy and subtle presence of symptoms, while others are simpler
and intended for use among nonspecialists or nurses. Only the more common tools
are described here. Figure 22.1 shows a diagnostic approach to delirium.

Brief Tests

The most commonly used brief tool is the 4-item Confusion Assessment Method
(CAM) [36] also available as the CAM-ICU version [37]. It is a diagnostic tool with
presence or absence rated of its items, but not severity. Though training is not
required, its performance metrics improve with rater training, though it both over
and under-diagnoses delirium relative to psychiatric interview using diagnostic cri-
teria or more detailed scales in the hands of specialists.
22 Delirium 349

Fig. 22.1  Diagnostic approach to delirium

350 P.T. Trzepacz

Some clinicians simply screen for delirium by evaluating attention. Months of

the year backwards, an auditory letter vigilance test, digit span, etc. can be used and
when performance is abnormal other history and testing for other delirium symp-
toms can follow. Months of the year backwards had high accuracy for delirium
screening detection in older patients [38].

Delirium Symptom Severity Scales

There are two scales that measure a broader range of symptoms that are well-­
validated and observer rated—the Memorial Delirium Assessment Scale (MDAS)
[39] and the Delirium Rating Scale-Revised-98 (DRS-R98) [40]. The MDAS is a
10-item tool using simple Likert scale severity ratings for each item and needs to be
used in conjunction with diagnostic criteria for delirium. The DRS-R98 is a 16-item
scale with a separately validated 13-item Severity Scale that is used for repeated
measures after the diagnosis is already established using the 16-item Total Scale
score. The DRS-R98 is unique in that each item has phenomenologically worded
descriptors anchoring each item’s severity level, and requires the rater to have
expertise in interviewing delirious patients.

Bedside Cognitive Tests

Many use multi-domain bedside tests like the Mini-Mental State Examination
(MMSE) [41] or the Montreal Cognitive Assessment (MoCA) [42] to evaluate over-
all cognitive level. These are relatively easy and fast to administer and each has a
0-30 point scale. Both have a ceiling effect though this is worse with the MMSE
than the MoCA which is a more challenging test. The MoCA has alternate forms for
repeated testing. Neither of these tests will specifically help to diagnose delirium or
distinguish it from dementia or other cognitive disorders, rather just establishes a
level of cognitive impairment.
The Cognitive Test for Delirium [43] has been designed for and validated in
delirious patients and has a high correlation with the DRS-R98 [40].

Etiologies of Delirium

Often delirium has multifactorial etiologies which may be concurrent, serial or

complications of another etiology. For example, hypoxemia from pneumonia
causes delirium which begins to improve after oxygenation and starting antibiotics,
but then benzodiazepines are administered for ethanol withdrawal which worsens
the breathing capacity and delirium relapses. Every bodily system needs to be
reviewed and considered for etiologies. See Table 22.1 for The Delirium Etiology
22 Delirium 351

Checklist which can be used to ensure a broad consideration of potential etiologies

for delirium.
Also every drug taken or recently discontinued that could cause a withdrawal
syndrome needs to be assessed as a contributor for delirium. These may have been
taken illicitly or prescribed prior to admission or surgery. Ethanol withdrawal may
be underestimated in older persons.
Importantly, any drug with sedating (benzodiazepine), anticholinergic, and opi-
oid characteristics are particular culprits and should be reduced or stopped.
Anticholinergic medications in frail elderly and palliative care settings increase
falls and delirium [44, 45]. Benzodiazepine sedatives are especially problematic in
the ICU units where they are over-prescribed and can contribute to difficulty wean-
ing patients from ventilators and causing a vicious cycle with delirium also mak-
ing weaning difficult [46]. Over the counter medications are often underreported.

Table 22.1 
DELIRIUM ETIOLOGY CHECKLIST
This checklist accounts for multifactorial etiologies precipitating or causing delirium in a given patient by using a
weighted approach for each of 13 categories. The relative importance all available information (history,
examination, and tests) is based on the judgment of the clinician who best knows the patient and then rated in this
summary table.

The DEC Worksheet captures more details about the conditions in order to organize the data before rating the
categories in the table. Check each box in the category table according to their degree of contribution to the
delirium (either definite, likely, possible etc).

For research use the small numbers for column categories and row labels to represent your ratings.

4Present but 5Ruled

3Present and
1Definite 2Likely Apparently Out/Not
Category Cause Cause
Possible
not Present/Not
Contributory
Contributory Relevant
1Drug Intoxication

2Drug Withdrawal

3Metabolic/Endocrine Disturbance

4Traumatic Brain Injury

5Seizures

6Infection (intracranial)

7Infection (systemic)

8Neoplasm (intracranial)

9Neoplasm (systemic)

10Cerebrovascular

11Organ Insufficiency

12Other CNS

13Other

© Trzepacz 1999
352 P.T. Trzepacz

DELIRIUM ETIOLOGY CHECKLIST

Worksheet

?
22 Delirium 353

Imaging

Imaging during delirium evaluation may include a computed tomography (CT) or

MRI of the brain to look for mass lesions, strokes, atrophy, trauma, hematoma, or
white matter pathology that could be responsible for the delirium. Positron emission
tomography (PET) or fMRI brain scans are generally not indicated. There is not a
reliable pattern of abnormality using any neuroimaging modality that is specific to
delirium per se; rather pathology cues underlying etiologies or risk factors (e.g.,
atrophy). Ischemic lesions and white matter hyperintensities are associated with
increased delirium risk [47] and duration [48].
Imaging of other body parts is used when evaluating for medical conditions that
contribute to delirium so that specific therapies can then be instituted to rectify
those, thereby indirectly improving delirium.

Electroencephalography

The EEG is characteristically diffusely slowed in delirium [49], with the domi-
nant posterior rhythm falling into the theta or even delta range [50, 51], which
can be related to a deficiency of brain acetylcholine. This EEG pattern suggests
that dysfunction of the thalamus is involved because it drives the cortical EEG
rhythm.
Other less common EEG patterns found in delirium include that for seizures
including partial complex status epilepticus and nonconvulsive status epilepticus
[52], and confusional migraine when those are the specific etiology. Continuous
EEG may be needed to diagnose these patterns.
EEG is usually reserved for difficult differential diagnosis or suspected seizure
cases.

Diagnostic Criteria for Delirium

Delirium is considered a major neurocognitive disorder, along with dementia. The

International Classification of Diseases (ICD) and DSM versions have delineated
specific criteria to support a diagnosis of delirium. Most recently DSM-5 and ICD-­
10 (see Table 22.2) have been used, though they do not share full concordance for
delirium diagnosis and the ICD-10 is less inclusive of cases considered delirious
than DSM-5 [53]. Compared to DSM-IV, DSM-5 risks under-diagnosis if aware-
ness in its “A” criterion is too narrowly defined as disorientation to place [54].
However, both DSM-IV and DSM-5 tend to over-diagnose delirium cases because
they are less restrictive than DSM-III-R or ICD-10 and may be capturing some sub-
syndromal cases.
354 P.T. Trzepacz

Table 22.2  Diagnostic criteria for delirium (from DSM-5 and ICD-10)
DSM-5 criteria for delirium
A. Disturbance in attention (i.e. reduced ability to direct, focus, sustain and shift attention) and
awareness (reduced orientation to the environment)
B. Disturbance develops over a short period of time (usually hours to days), represents a
change from baseline attention and awareness, and tends to fluctuate in in severity during
the course of a day
C. An additional disturbance in cognition (e.g. memory deficit, disorientation, language,
visuospatial ability, or perception)
D. The disturbances in A and C are not better explained by another preexisting, established, or
evolving neurocognitive disorder and do not occur in the context of a severely reduced level
of arousal, such as coma
E. There is evidence from the history, physical examination, or laboratory findings that the
disturbance is a direct physiologic consequence of another medical condition, substance
intoxication or withdrawal (i.e. due to a drug of abuse or medication), or exposure to a
toxin, or is due to multiple etiologies
ICD-10 criteria for delirium
A. Clouding of consciousness, i.e. reduced clarity of awareness of the environment, with
reduced ability to focus, sustain or shift attention
B.  Disturbance of cognition, manifest by both:
  1.  Impairment of immediate recall and recent memory, with relatively intact remote
memory;
  2.  Disorientation to time, place or person
C.  At least one of the following psychomotor disturbances:
  1.  Rapid, unpredictable shifts from hypoactivity to hyperactivity;
   2. Increased reaction time;
  3.  Increased or decreased flow of speech;
   4. Enhanced startle reaction
D.  Disturbance of sleep or the sleep-wake cycle, manifest by at least one of the following:
   1. Insomnia, which in severe cases may involve total sleep loss, with or without daytime
drowsiness, or reversal of the sleep-wake cycle;
   2.  Nocturnal worsening of symptoms;
   3. Disturbing dreams and nightmares which may continue as hallucinations or illusions
after awakening
E.  Rapid onset and fluctuations of the symptoms over the course of the day
F. Objective evidence from history, physical and neurological examination or laboratory tests
of an underlying cerebral or systemic disease that can be presumed to be responsible for
the clinical manifestations in A-D

The “A” criterion across diagnostic systems is the cardinal one and captures
inattention, and also in some diagnostic systems reduced awareness or clouding of
consciousness is included. Acute onset of symptoms is required, though this may
have occurred prior to the evaluation and an observer is needed to obtain that
history.
Unfortunately, the three core domains of delirium are not well represented in
current diagnostic systems. However, recently proposed delirium research criteria
do require symptoms from each core domain, and when compared to performance
22 Delirium 355

of DSM-5 and ICD-10 in differentiating cluster analysis-defined delirium and non-

delirium groups, have high sensitivity and specificity, positive predictive value and
outperformed DSM-5 and ICD-10 [53]. While most clinicians will rely on DSM-5
criteria, looking for presence of all three core domain symptoms can enhance diag-
nosis and clinical detection of delirium.

Subsyndromal Delirium

There is increasing awareness that subsyndromal delirium is worth detecting,

though by definition it is less severe than full syndromal delirium, and carries an
intermediate level of prognosis between no delirium and delirium. Reports have
used different methods to define SSD, including just one or two symptoms which is
inadequate to ensure it is syndromally related to delirium. However, studies that
used broader assessment of delirium symptoms have discerned that its symptom
profile is similar to that of delirium, especially for presence of core domain symp-
toms, but present at a lower severity [55, 56].
There are no widely accepted diagnostic criteria for subsyndromal delirium
(SSD) and DSM-5 simply describes it as “attenuated” without any details. Clinical
criteria to diagnose SSD, based on cluster analysis [56], were suggested as mild
impairments of attention, orientation, visuospatial ability, sleep-wake cycle, and
thought process in the setting of an acute change from baseline.

Differential Diagnosis of Delirium

Because delirium encompasses a wide breadth of neuropsychiatric features and

both hyperactive and hypoactive presentations, it can be mistaken for many other
conditions, most likely when the examiner does not assess for the full range of
symptoms. Misdiagnosis as depression or dementia are common. Referrals to spe-
cialists sometimes state “behavior problem” or “incoherence” as the reason.
Distinguishing delirium from dementia alone is an important exclusion criterion
for delirium diagnosis though this requires history-taking from someone who knows
the patient because these conditions can overlap in their symptom profile and are
often comorbid. Most research shows that delirium symptoms overshadow demen-
tia symptoms when they are comorbid [57]. Simple tests of inattention including
months of the year backwards can aid in diagnosing delirium even in the setting of
comorbid dementia [58].
Therefore, in clinical practice a person is considered “delirious until proven
otherwise” and managed as such, with whatever lingering cognitive and behav-
ioral impairments being attributed to dementia or mild cognitive impairment after
delirium is resolved. A history of an acute onset of cognitive impairment or wors-
ening of an impaired baseline helps to distinguish delirium from dementia, except
356 P.T. Trzepacz

where a large lesion like stroke is the cause. Dementia with Lewy bodies involves
visual hallucinations and fluctuating symptom severity and can be misdiagnosed
as delirium.

ICD-10

ICD-10 criteria were intended for research and are more detailed than those in
DSM-5. They do include more symptoms of the core domains. Being more restric-
tive than DSM-5, they may tend to diagnose fewer cases which are more specific to
delirium, though less sensitive [53] (see Table 22.2).

Therapeutics and Management of Delirium

General Guidance

Delirium is a medical urgency and must be actively managed as soon as possible.

All clinical staff should be made aware of the patient’s condition and delirium spe-
cifically noted in the medical chart. Some institutions have a standardized delirium
management protocol that can be ordered. Figure 22.1 shows the key steps in man-
agement of delirium.
The first and foremost step in management is to identify risk factors and all
possible etiologies (see Table  22.1) and work toward quickly rectifying them.
This requires a careful review of the patient’s history by reading medical charts,
intraoperative records, talking with those who know the patient, pharmacy records,
laboratory test results, etc. Testing should be done to address common problems
using laboratory testing and more advanced tests such as neuroimaging, CSF
examination, EEG and so on tailored to a particular patient.
Treatment includes nonpharmacological and pharmacological methods (see
Fig. 22.2).
Overdoses causing delirium include intentional and iatrogenic. These need to
be quickly identified and addressed. Intentional overdoses require supportive
medical care with monitoring and observation during the period of time that the
half-lives and expected elimination times suggest that the drugs taken have
cleared the body. Generally the person’s delirium clears quickly when the
offending agent is metabolized and cleared. This is similar to conservative man-
agement of emergence delirium in post-anesthesia recovery following surgery or
a procedure.
Iatrogenic drug toxicities can occur due to polypharmacy, doses too high for the
person to metabolize, and intentional such as occurs in ICUs. Virtually any drug
given at neurotoxic doses can cause delirium.
22 Delirium 357

Fig. 22.2  Management of delirium

358 P.T. Trzepacz

Special Populations

Intensive care units are problematic situation because patients have a high medical
or post-operative morbidity which predisposes them to delirium at a higher rate than
in general medical and surgical inpatient units. On the other hand, there is a ten-
dency to overmedicate and sedate these patients, perhaps so they are less trouble-
some or to help them to not remember the experience [46]. Use of opiates and
benzodiazepines are associated with longer delirium duration in ICU patients [59].
A substantial research literature reveals that preferential use of dexmedetomidine
during anesthesia and sedation in intensive care reduces delirium incidence [60, 61].
Improving anesthesia care by addressing potentially modifiable factors including
blood pressure variability can reduce impact of some operative and postoperative
contributors to delirium [62]. Monitoring the depth of anesthesia using the bispec-
tral index to guide anesthesia decreased postoperative delirium such that episodes of
deep anesthesia were independently predictive for delirium [63]. Further, lightening
the level of sedation (nonbenzodiazepine) in ventilated patients can reduce delirium
and enhance respiratory recovery in ICU patients [46]. Additionally, managing pre-
operative pain and depression can reduce postoperative delirium [64].
Palliative care, hospice and nursing home populations involve different
approaches to delirium treatment than general hospital acute care settings. Often the
use of opioids and sedation are carefully titrated in conjunction with use of neuro-
leptics to balance risk and reduction of delirium in end of life patients [65]. Nursing
home patients have a high incidence of dementia so that neuroleptics should be used
only short term for delirium due to safety issues because of increased mortality and
stroke associated with their use in agitated dementia.

Nonpharmacological Approaches

Simple bedside techniques may help delirious patients to reorient but by themselves
cannot alter the depth or resolution of delirium. Family photos, clocks and calendars
in view are easy to implement. Ensuring that hearing aids, eyeglasses, dentures, and
so on are being used is important. Reminders by staff that the person is in the hos-
pital and is sick can also help and be reassuring. Physical restraints should be
avoided and sitters, including family, employed instead. Adapting the environment
to better represent normal daylight and nighttime quiet and darkness to enhance
sleep is important including in ICUs [66], where single bed rooms are less associ-
ated with delirium [67].
More beneficial is prophylaxis of delirium in elderly by identifying modifiable
risk factors early during the admission [68]. Studies differ on which are best to
focus on and remediate, but these include dehydration, urinary tract infection, pain,
depression, hypertension, sensory impairment, immobilization, sleep deprivation,
medications, sleep apnea, etc. A daily multicomponent nurse intervention random-
22 Delirium 359

ized study found significantly lower delirium incidence, prevalence, and severity vs.
controls by addressing orientation, sensory deficits, sleep, immobilization, hydra-
tion, nutrition, drug review, oxygenation, and pain [69].

Pharmacological Approaches to Delirium Treatment

There are no medications with an approved indication to treat delirium and there is
a paucity of adequately powered double blind, randomized placebo-controlled clini-
cal trials. There are over 30 prospective trials, either open label, comparative and
single or double blind randomized for acute efficacy or prophylaxis [70, 71].
Neuroleptics are the most studied drugs for acute efficacy and prophylaxis, and
about 75% of patients receiving them acutely for delirium have a positive response
[71]. A variety of other medications have been tried for delirium, most without suf-
ficient supporting evidence [72].
Because of its high morbidity and associated mortality medications are used to
manage the delirium symptoms. Psychiatrists and palliative care physicians are gener-
ally less conservative regarding use of psychotropic medications in delirium than geri-
atricians. Haloperidol remains the practice standard in palliative care [73] and general
hospitals. Some reserve neuroleptics for agitated patients but it is not recommended to
withhold treatment from any delirium patient based on their motor presentation.
Prophylactic and acute treatment have been studied, where agents may have dif-
ferential efficacy for one of these uses.

Neuroleptic

Neuroleptic (also called antipsychotic) agents include conventional and atypical

agents. Haloperidol is most often used though many atypical agents are preferred as
they carry lower risk of extrapyramidal side effects. Those include quetiapine, olan-
zapine, risperidone and aripiprazole. Doses in delirium are usually much lower
(e.g., 0.25–0.5 mg haloperidol) than those used for primary psychiatric disorders.
Bedtime or twice daily dosing is common for starting treatment with titration up or
downward according to symptom severity. Clinicians usually report fast response
after treatment initiation. Most are used orally though parenteral administration is
possible with haloperidol and some atypicals.
Reports indicate good tolerance and suggest similar efficacy for haloperidol, olanzap-
ine, risperidone, and quetiapine though trial designs have often been a limitation [74]. A
number of comparative trials report similar efficacy among neuroleptics [69, 75, 76].
A double blind placebo controlled prophylaxis trial using low dose haloperidol
found significantly decreased delirium severity and duration and decreased length of
stay (LOS), though the trial was not adequately powered or dosed to detect delirium
incidence differences [77]. A randomized blinded placebo-controlled trial of
­prophylactic risperidone in subsyndromal delirium found significant reduction in
360 P.T. Trzepacz

delirium occurrence [78]. A double-blind randomized placebo controlled prophylaxis

trial of intravenous haloperidol in 457 elderly surgical ICU patients found signifi-
cantly lower delirium incidence, longer time to delirium and more delirium-­free days
and shorter LOS [79]. A double-blind randomized placebo-controlled prophylaxis
trial of low dose olanzapine in 495 elderly joint replacement surgery patients found
significantly lower incidence of postoperative delirium in the treatment group [80].
One potential issue using neuroleptics in elderly is the risk of death and stroke
reported with their chronic use in agitated demented patients, resulting in a boxed
warning by FDA. Therefore, neuroleptic use for delirium should be acute and tem-
porary, and patients not discharged on neuroleptics without planned reassessment.
Serious adverse events associated with neuroleptic use for delirious hospitalized
elderly were low (0.9% in 2834 cases) where aspiration pneumonia was most com-
mon and no deaths were reported [81].

Benzodiazepines

Benzodiazepine use in elderly is a risk factor for delirium and their use avoided.
Benzodiazepines should not be used to treat delirium with the exception of managing
alcohol and sedative-hypnotic withdrawal states, seizures and end of life situations.

Sleep Agents

Melatonin and ramelteon (melatonin agonist) administered at bedtime are reported

to prevent delirium in controlled studies [82–84], possibly through addressing the
circadian component of delirium [85]. Though not all studies found positive results
on reducing delirium incidence for melatonin [86], it is an endogenous neurochemi-
cal and its low adverse event profile makes it useful to try clinically.

Cholinesterase Inhibitors

Given the evidence that cholinergic activity deficits may underpin delirium, cholin-
esterase inhibitors have been evaluated for value in delirium treatment. No efficacy
has been found for acute treatment, possibly related to slow onset of action due to
long half-lives of agents administered orally.
A multicenter double blind placebo-controlled randomized prophylaxis trial was
stopped prematurely due to increased mortality in the rivastigmine group [87].
ICD-10 Codes
F05 Delirium, not induced by alcohol and other psychoactive substances
F05.0 Delirium, not superimposed on dementia, so described
F05.1 Delirium, superimposed on dementia
F05.8 Other delirium
F05.9 Delirium, unspecified
22 Delirium 361

Disclosures  Dr. Trzepacz is President and Chief Executive Officer of conXiome,

LLC, Zionsville, Indiana. Dr. Trzepacz is on the Board of Trustees of Franciscan
University of Steubenville, Steubenville, Ohio. She is a member of the Scientific
Advisory Board for Lympro, Amarantus BioScience Holdings, Inc., San Francisco,
CA and an Advisory Board member for Brain Test and AirG Inc., Vancouver, BC,
Canada.

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