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Abstract
Keywords
delirium
attention
inpatient
elderly
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
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.
DOI http://dx.doi.org/
10.1055/s-0035-1564685.
ISSN 0271-8235.
Brown, Douglas
647
Population
Risk factor
Outcome
Incident delirium
1.71 (1.272.23)5
Incident institutionalization
2.41 (1.773.29)5
New-onset dementia
12.52 (1.8684.21)5
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
Incident delirium
Delirium superimposed
on dementia at admission
Postoperative delirium
Functional decline at 3 mo
2.1 (1.23.8)65
Incident delirium
2.0 (1.04.0)66
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
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Table 1 Selected outcomes of inpatient delirium and their associated risk of occurrence
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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
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.
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Encephalitis/meningitis
Thiamine deciency
Untreated pain
Postoperative
Sensory deprivation
Day/night dysregulation
Limited mobility
Presence of lines/tubes/catheters
Hypercarbia or hypoxemia
Cobalamin deciency
Abnormalities of electrolytes,
endocrine, renal, or liver function
Alcohol withdrawal
Toxidrome
Steroid-responsive encephalopathy
Medications
Posttraumatic encephalopathy
Sepsis
Localized infection
(e.g., urinary tract infection, pneumonia)
Social history
MRI
Blood cultures
MRI
Workup
Iatrogenic
Metabolic
Autoimmune
Toxic
Traumatic
Infectious
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)
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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.
Clinical history
Parkinsonism, visual hallucinations,
deterioration with dopamine antagonists
Table 3 (Continued)
Workup
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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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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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
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