Lesson 9, Volume 16—Agitation in the ICU

By Kenneth E. Wood, DO, FCCP; and John G. McCartney, MD

Objectives

1. Recognize the clinical features of delirium in the ICU setting.
2. Differentiate delirium from other neuropsychiatric disorders.
3. Identify risk factors for the development of delirium.
4. Generate a differential diagnosis for mental status changes in an ICU patient.
5. Outline an approach to treatment of delirium in the ICU.

Key words

agitation; delirium; haloperidol; ICU; postcardiotomy delirium

Abbreviations

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 behavior in 71% of patients occurring during 58% of total patient days; the behavior 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 behavioral 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.

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 oversedation. 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 center 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.

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 in-hospital 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 hospital-related 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, orthopedic surgery, and gynecology 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, well-systemized 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 behavioral 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, tumors, seizures, and vascular events. Systemic diseases affecting the brain include multiple endocrine and metabolic abnormalities, postischemic 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.

References

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15. Marcantonio ER, Juarez G, Goldman L, et al. The relationship of postoperative delirium with psychoactive medications. JAMA 1994; 272:1518–1522
16. Rottson DB, McElhaney JE, Rockwood K, et al. Incidence and risk factors for delirium and other adverse outcomes in older adults after coronary artery bypass surgery. Can J Cardiol 1999; 15:771–776
17. Inouye SK, Bogardus ST, Charpentier PA, et al. A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340:669–676
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