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Agitation in the ICU - By Kenneth E. Wood, DO, FCCP; and John G. McCartney, MD
Effective December 31, 2004, PCCU Volume 16 is available for review purposes only. CME credit for this volume is no longer being
offered.
Objectives
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Recognize the clinical features of delirium in the ICU setting.


Differentiate delirium from other neuropsychiatric disorders.
Identify risk factors for the development of delirium.
Generate a differential diagnosis for mental status changes in an ICU patient.
Outline an approach to treatment of delirium in the ICU.

Key words
Abbreviations

agitation; delirium; haloperidol; ICU; postcardiotomy delirium


DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th Edition

Agitation is a commonly encountered problem in the ICU. Agitated patients have the potential to jeopardize their own care by
disconnecting various life-sustaining modalities. Additionally, these patients pose a risk to the nurse and physician care providers and
compromise the care of other ICU patients by monopolizing limited provider care time. In a recent study, nurses and physicians
described agitated behaviour in 71% of patients occurring during 58% of total patient days; the behaviour was severe or
dangerous in 46% of patients during 30% of total patient days. 1
The onset of mental status changes in an ICU patient is equivalent to neurologic system failure and warrants the same
expeditious and comprehensive evaluation that would be undertaken with any acute organ system failure in a critically ill patient.
Similar to the approach to acute renal failure, reversible and correctable causes should be sought. A differential diagnosis should be
developed that incorporates the evaluation of systemic and metabolic abnormalities, drug toxicities, and possible withdrawal
syndromes. An etiologic characterization should be defined whenever possible as this facilitates the institution of specific and
appropriate therapy, correction of the systemic and metabolic abnormalities, elimination of drug toxicity, and treatment of withdrawal
syndromes. Pain and anxiety are common in ICU patients and should not be overlooked as a cause of agitation. When pain or anxiety
is identified, treatment should be specific with analgesics or anxiolytics, respectively. Frequently, it is not possible to immediately define
the culprit etiologic process and by necessity treatment must be empiric while the evaluation continues.
Definition of Delirium
Traditionally, the behavioural and mental status changes in ICU patients were termed "ICU psychosis." This was initially attributed to
sleep deprivation and sensory overload or monotony. However, it is now recognized that this previously described syndrome is
precipitated by organic stressors on the CNS. The mental status changes observed in ICU patients are most closely aligned with a
diagnosis of delirium.2 Essential features of delirium are presented in Table 1.3,4 Disturbances of consciousness and attention are
characterized by a reduced clarity or awareness of the environment with impaired ability to focus, sustain, or shift attention.
Cognitive dysfunction is manifested by memory deficits, disorientation, and language disturbances or the development of
perceptual disturbances that cannot be accounted for by pre-existing or evolving dementia. Short-term memory deficits and
disorientation to time and place rather than self are common. Dysarthria, dysnomia, or dysgraphia may be observed as well as various
misinterpretations, illusions, and occasionally hallucinations. The latter is dominated by visual phenomena, although tactile
and auditory illusions may occur. The preceding essential features should develop over a short period of time and represent
a sudden and significant departure from the patient's baseline mental status. Reported associations include abnormal sleep
patterns, disturbances of psychomotor activity, and emotional lability.
Table 1Diagnostic Criteria for Delirium Due to a General Medical Condition*
A.
B.
C.

D.

Disturbance of consciousness (ie, reduced clarity of awareness of the environment) with reduced ability to focus,
sustain, or shift attention.
A change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a
perceptual disturbance that is not better accounted for by a pre-existing, established, or evolving dementia.
The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course
of the day.
There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct
physiologic consequences of a general medical condition, the result of medication use or substance intoxication, a
consequence of a withdrawal syndrome or related to more than one of the above etiologies.

*From Diagnostic and Statistical Manual of Mental Disorders.3

It is not well appreciated that three clinical variants of delirium have been distinguished; hyperalert-hyperactive, hypoalert-hypoactive,
and mixed.5 The hyperalert-hyperactive patient is easily recognizable but the hypoalert-hypoactive patient with lethargy, drowsiness,
and slow responses to questions may be overlooked and misdiagnosed with depression or over sedation. As clinical outcomes may be
similar among the groups, it is crucial to recognize the hypoalert-hypoactive variant. Although agitation may accompany acute
functional psychosis or complicate dementia, delirium is the most common cause of ICU agitation and will be the focus of
this update.
Pathophysiology and Etiology
Despite its frequency, the etiology of delirium has not been rigorously investigated. In the 1950s, ***Engel speculated (eg, Engel and
Romano6) that a general reduction in cerebral oxidative metabolism in delirious patients was responsible for a decrease in the
synthesis of neurotransmitters that accounted for disturbances of attention and cognition associated with EEG slowing. The proposed
reduction in acetylcholine synthesis may explain why the elderly are particularly prone to delirium when treated with anticholinergic
agents. Alternatively, it has been postulated that a hypercortisolism response to acute stress or focal right hemispheric attention centre
lesions may be responsible.5
Lipowski7 has grouped the causative organic factors known to precipitate delirium into four general categories, depicted in Table 2.
These include primary cerebral diseases, systemic diseases that affect the brain, intoxication with exogenous substances, or
withdrawal from substances of abuse. For intensivists evaluating the patients with delirium, this etiologic classification provides a
template from which to derive a differential diagnosis.
Table 2Causative Organic Factors of Delirium*
Primary cerebral diseases
Infection
Neoplasm
Trauma
Epilepsy
Cerebral vascular accident
Systemic diseases affecting CNS
Metabolic diseases
Infections
Cardiovascular diseases
Collagen diseases
Intoxications
Medical and recreational drugs
Poisons from industrial, plant, and animal origin
Withdrawal states
Substances of abuse, including alcohol and sedative-hypnotics
*Adapted with permission from Lipowski.7
Incidence and Outcome
Although not extensively studied in the ICU population, delirium is common in hospitalized patients and particularly prevalent in the
hospitalized elderly. The overall incidence of delirium in hospitalized patients is estimated to range from 10 to 30% and may approach
40% in the elderly. As many as 25% of cancer patients, 40% of AIDS patients, 50% of postoperative patients, and 80% of the
terminally ill approaching death will develop delirium.4 The incidence of postcardiotomy delirium, which predominately reflects
elderly ICU patients, has remained constant at 32% for the past 25 years.8
Delirium should be viewed as a complication of medical and surgical illness that adversely affects morbidity and mortality. In non-ICU
patients, the development of delirium has been shown to result in significantly longer hospital stays, increased postoperative
complications, long-term disability, and an increased mortality rate. In the elderly, the development of delirium is associated with an inhospital mortality rate of 22 to 76%. 4 The development of delirium during a hospitalization predicts a poor long-term outcome as it is
reported that up to 25% will die within 6 months of discharge. 4 With the increased severity and stress of medical and surgical illness in
the ICU, it is virtually certain that the incidence of delirium in ICU patients is substantially higher than in general hospitalized patients.
With aging of the population, an increasing number of elderly patients will require ICU care and undoubtedly increase the prevalence of
delirium in the ICU. In a recently conducted study of ICU patients that employed a geriatric psychiatric specialist as a reference
standard utilizing Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for delirium, the incidence of
delirium was 27%. Interestingly, in patients who were awake and following commands with a Glasgow Coma Score >14, 25% fulfilled
DSM-IV criteria for delirium.9

The presence of delirium has enormous potential to influence the outcome of ICU patients. The patient with unrecognized hypoactive
delirium is at jeopardy for a prolonged duration of mechanical ventilation and the associated complications of aspiration, nosocomial
pneumonia, decubitus ulcer, and venous thromboembolic disease. The patient with hyperactive delirium is frequently sedated into a
state of "suspended animation" that results in similar jeopardy. 10 Given the potential for adverse and costly outcomes, it is crucial to
identify risk factors that will allow for earlier recognition and appropriate treatment of delirium.
Risk Factors
Advanced age, underlying dementia or cognitive impairment, metabolic or electrolyte abnormalities, and medication use against the
background of medical and surgical illness are traditionally identified risk factors. However, it has recently been emphasized
that the development of delirium is the result of the dynamic interplay between patient baseline vulnerability, which is defined as
predisposing risk factors present at the time of admission, and precipitating factors, which are defined by noxious insults or hospitalrelated factors that contribute to delirium.11 Development of delirium in a patient with low baseline vulnerability will necessitate
greater provocation than a patient with greater baseline risk.
Although not well studied in the ICU population, vulnerability and precipitating factors have been identified and predictive models for
delirium have been developed for the elderly medical population. Impaired vision, severity of illness, cognitive impairment, and high
BUN-to-creatinine ratio have been identified as independent baseline risk factors that have been prospectively validated as predictors
of delirium.12 Similarly, the use of physical restraints, malnutrition, more than three medications added after admission, use of bladder
catheterization, and an iatrogenic event have been identified as independent precipitating factors that have been prospectively
validated as predictors of delirium.11 Similar findings are reported in studies that did not differentiate between baseline and precipitating
factors: abnormal sodium levels, severity of illness, dementia, fever or hypothermia, psychoactive drug use, and azotemia. 13 In the
above studies, the incidence of delirium was between 18 and 22%, directly proportional to the number of risk factors and associated
with worse medical outcomes and increased length of stay.11-13
Similarly, clinical prediction rules for delirium after elective noncardiac surgery have been devised. In a population that included general
surgery, orthopaedic surgery, and gynaecology services, postoperative delirium occurred in 9% of patients. Independent correlates that
were reported included age >70 years; self-reported alcohol abuse; poor baseline cognitive status; poor functional status; markedly
abnormal preoperative serum sodium, potassium, or glucose level; noncardiac thoracic surgery; and aortic aneurysm surgery. Using
these seven preoperative factors, a predictive rule was developed and validated in an independent population that stratified patients
into low (2%), medium (8 to 13%), and high (50%) risk groups.14 The role of medications with known psychoactive properties and
the development of postoperative delirium was examined in this population. Compared with matched controls, delirium was
significantly associated with postoperative exposure to meperidine and benzodiazepines. Meperidine was associated with delirium
independent of the administration route (epidural or patient-controlled routes). For benzodiazepines, long-acting agents and high-dose
exposures had a greater association with the development of delirium. Interestingly, neither narcotics nor anticholinergics were
significantly associated with delirium, although the latter were infrequently used.15 Consistent with the medical patients, the surgical
patients who developed delirium had increased rates of major complications, longer lengths of stay, and higher rates of discharge to
long-term care or rehabilitative facilities.14,15
Differential Diagnosis
The evaluation of the agitated ICU patient with mental status changes is challenging and must proceed expeditiously with a broad
differential diagnosis. Pain and anxiety are common in ICU patients and frequently manifest as agitation. Both should always be
considered in the initial differential diagnosis and when present, treated appropriately with analgesic or anxiolytic medication.
An evaluation of the agitated patient usually requires differentiating between dementia, dementia with superimposed
delirium, functional psychosis, psychogenic dissociative disorders, secondary mania, complex partial seizures, and delirium.
An appreciation of the patient's immediate past medical history is integral to the assessment. Global cognitive impairment is common to
both dementia and delirium. However, in contrast to delirium, dementia is characterized by a chronic insidious course; stability in a 24-h
period; clear consciousness; normal arousal and attention; the absence of hallucinations, delusions or involuntary movements; normal
psychomotor activity; and perseverated speech patterns. Delirium occurs suddenly against the background of medical/surgical illness
and has a fluctuating character that is associated with a reduced consciousness, disordered attention, and hallucinations or delusions.
Psychomotor activity is widely variable and unpredictable, often associated with involuntary movements, such as asterixis or tremor.
Determining the relative contribution of superimposed delirium to the agitated state in the elderly patient with baseline dementia may
not be possible. In this case, a review of the aforementioned risk factors and precipitating factors can be useful. Similar to delirium,
the patient with acute functional psychosis can present with a sudden onset of agitation. Differentiating features of acute
functional psychosis include the following: a past history of psychosis and/or treatment, a normal sensorium and consciousness, wellsystemized delusions, and auditory hallucinations. Affective disorders with acute disturbance of mood such as manic depression or
secondary mania may be impossible to differentiate from delirium in the acute phase. The suspicion of mania should prompt a thorough
investigation for a toxic or organic cause. Complex partial seizures originating in the temporal lobes can produce behavioural and
mental status changes. The EEG will be focally abnormal in this scenario, whereas it will be globally abnormal in delirium and normal in
acute functional psychosis and psychogenic dissociative states.
The differential diagnosis and etiologic categorization of delirium is depicted in Table 2. 7 Primary intracranial causes could include
infections such as meningitis or encephalitis, tumours, seizures, and vascular events. Systemic diseases affecting the brain include
multiple endocrine and metabolic abnormalities, post ischemic brain injury, systemic infection, and various nutritional deficiencies.
Intoxication with exogenous substances could include an overdose of prescribed, over-the-counter, or recreational drugs or the side
effects of prescribed medications. Withdrawal from alcohol, narcotics, and benzodiazepines should always be considered even when
not obvious in the history.
Postcardiotomy Delirium

The incidence of postcardiotomy delirium has remained fixed at approximately 30% for the past 30 years and shows only a
slight correlation with age. Several consistent features of postcardiotomy delirium emerge from meta-analysis of the reported
literature.8 Illness variables associated with delirium reveal a higher prevalence of delirium in patients with noncongenital heart disease.
Patients with congenital heart disease spend less time on bypass, which may be a factor. Patients with calcified mitral or aortic valves
are reported to have more neuropsychiatric abnormalities, which are attributed to increased embolic events, although these patients
are typically older and have longer times on bypass. Preoperative variables associated with delirium include the severity of illness
assessed by New York Heart Association Functional Class or the preoperative presence of brain damage, organicity, or the presence of
preoperative neurologic signs. Interestingly, the meta-analysis reported that preoperative psychiatric intervention was the single most
predictive variable (negative correlation) and was associated with a low prevalence of postoperative delirium, which suggests
opportunity and implications for prevention. Intraoperative time on bypass was found to have an inconsistent relationship with the
development of delirium.8 A recent study of delirium in patients who have undergone coronary artery bypass revealed an
incidence of 32% and identified a history of stroke, longer duration of bypass, and a postoperative low cardiac output as risk factors.
Thus, postcardiotomy delirium remains a common problem without consistently defined risk factors and should be
anticipated in one third of cases.16
Prevention
Effective prevention of delirium is predicated on recognizing the previously identified predisposing risk/precipitating factors and
mitigating their impact. Prompt treatment of the medical or surgical illness necessitating ICU admission is essential. Correction of
metabolic or endocrine abnormalities should be undertaken expeditiously. Temperature abnormalities should be normalized. The
addition of multiple new medications or complex polypharmacy and the potential for drug interactions should be minimized. A vigilant
review of the social history for alcohol or drug abuse may establish a heightened sense of awareness for substance withdrawal and
lower the threshold to initiate treatment for withdrawal states.
In a recent study of elderly patients at high risk for developing delirium, a multicomponent prevention program was implemented. 17
Utilizing a multidisciplinary team of physicians, nurse specialists, and physical/recreational therapists, six targeted risk factors were
approached with a standardized interventional protocol: Cognitive impairment was addressed with an orientation and therapeutic
activity protocol, sleep deprivation was minimized by nonpharmacologic and sleep enhancement strategies, immobility was decreased
by active physical therapy, visual and hearing impairment was routinely assessed and modified when possible, and a dehydration
protocol allowed for early recognition of electrolyte abnormalities. Although differences in the severity of delirium or recurrences were
not detected, there was a significant reduction in the number and duration of the episodes of delirium. Although no similar trials are
reported in the ICU literature, it would seem reasonable to pragmatically apply the preceding to ICU patients at risk.
Treatment
The approach to therapy of delirium often proceeds along two parallel paths: identification and correction of the suspected underlying
abnormality and symptomatic treatment of the agitation. It is crucial to discriminate pain and/or anxiety from delirium given the
differences in treatment. Pain should be quantified and treated with opioid analgesics. Anxiety should be treated judiciously with
anxiolytic benzodiazepines given the potential for sedative benzodiazepines to either compound or potentiate delirium.
The use of nonpharmacologic modalities are crucial to minimize the adverse effects of delirium and protect the patient and
care staff. Frequent reorientation, maintenance of sleep-wake cycles, soft physical restraints, and creation of a nonthreatening
environment have all been reported.2,4,18 When these modalities are ineffective in controlling the agitation associated with
delirium, pharmacologic agents are often required. Although benzodiazepine sedation is frequently combined with narcotic
analgesia in the mechanically ventilated patient, these agents may induce or worsen delirium and agitation in the elderly and others at
risk.18 Haloperidol has now become accepted as the therapy of choice for short-term chemical sedation in the ICU setting. 2,18
Haloperidol consistently provides sedation with minimal effect on the cardiovascular and respiratory system. It has less anticholinergic
effect than other low-potency neuroleptics and has less potential to further exacerbate delirium. 18 Haloperidol can be administered
orally, IM, or IV. It has onset of action reported from 10 to 30 min with IV administration and a half life of 10 to 26 h. Dosing
recommendations of 0.5 to 2.0 mg for mild agitation, 2.0 to 5.0 mg for moderate, and 10.0 to 20.0 mg for severe agitation have been
published.18 The maximal dose of haloperidol is not well reported because the drug is frequently titrated to clinical effect. Administration
of up to 485 mg over a 24-h period has been reported for the control of severely agitated patients. 19 Side effects of haloperidol are
usually minimal, although occasional hypotension may be observed with IV dosing and QT prolongation with torsades de pointes has
been reported.18
Conclusion
Delirium is a common and complicated occurrence when patients are cared for in the ICU. The evaluation for causative
processes must be expeditious and thorough. Reversible factors, including withdrawal states, intoxications, and metabolic
abnormalities, need to be addressed and corrected. During this process, empiric therapy is often required for safety of both the
patient and medical staff. With future studies targeted at identifying those ICU patients at highest risk for developing delirium, and
validating prevention programs, more directed interventions can be formulated.
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