Diagnosis and Treatment of Agitation and Delirium in the Intensive Care Unit Patient
Jason P. Caplan
… patients are attacked with insomnolency, so that the disease is not concocted; they become sorrowful, peevish, and delirious; there are flashes of light in their eyes, and noises in their ears; their extremities are cold, their urine unconcocted; the sputa thin, saltish, tinged with an intense color and smell; sweats about the neck, and anxiety; respiration, interrupted in the expulsion of the air, frequent and very large; expression of the eyelids dreadful; dangerous deliquia [syncope]; tossing of the bed-clothes from the breast; the hands trembling, and sometimes the lower lip agitated. These symptoms, appearing at the commencement, are indicative of strong delirium, and patients so affected generally die, or if they escape, it is with a deposit, hemorrhage from the nose, or the expectoration of thick matter, and not otherwise. Neither do I perceive that physicians are skilled in such things as these; how they ought to know such diseases as are connected with debility, and which are further weakened by abstinence from food, and those aggravated by some other irritation; those by pain, and from the acute nature of the disease, and what affections and various forms thereof our constitution and habit engender, although the knowledge or ignorance of such things brings safety or death to the patient.
—Hippocrates, 400
In On Regimen in Acute Diseases, Hippocrates identified agitation as a harbinger of severe illness and poor outcome [1]. His admonition that physicians understand the causes and treatments of agitation remains vital today, for the safety not only of patients but also of hospital staff attending to them. Nowhere is this more pertinent than in the intensive care unit (ICU) and its finely balanced environment of invasive and often delicate treatment modalities, interference with which is rarely as easily corrected as is “tossing of the bed-clothes.” The sudden pulling of precisely placed central lines, intra-aortic balloon pumps, or endotracheal tubes can carry profound consequences for patients and those responsible for their care.
The term “ICU psychosis” has unfortunately entered common medical parlance in reference to agitation and confusion in the ICU patient [2]. This misnomer is inaccurate for several reasons. Classifying agitation as psychosis is usually diagnostically incorrect; moreover, drawing an etiologic connection between the patient’s geography and the development of agitation is nonsensical. Historically, sensory deprivation and interruption of normal sleep patterns alone were thought to result in behavioral disturbances in the ICU, but modern research has not confirmed this relationship [2]. The causal attribution of mental status changes to the environment of the ICU is dangerous because it obviates the need for further diagnostic inquiry that could reveal a previously unidentified pathologic process. As with all new symptoms, careful diagnosis is the first step toward effective treatment.
This chapter reviews the causes, presentations, and treatments of common causes of agitation in the ICU patient, focusing on delirium.
Delirium
Perhaps the most common cause of agitation in the general hospital as a whole, and the ICU in particular, delirium is a neuropsychiatric manifestation of a systemic disturbance (Table 197.1) [3]. As such, the paramount task in its treatment is the identification of its underlying cause(s).
Epidemiology
Prospective studies of all patients admitted to the ICU regardless of pathology have found incidence rates of delirium of 31% on admission [4] and 82% when limited to the population requiring intubation and mechanical ventilation [5].
A diagnosis of delirium exacts a profound toll on both the immediate and long-term well-being of patients and the economic resources required for their care. One study of mechanically ventilated patients in the ICU demonstrated significant increases in length of hospital stay and 6-month mortality, even after adjustment for age, severity of illness, comorbidities, coma, and medication exposure [5]. Another study of patients—limited to those who did not require mechanical ventilation—found that a diagnosis of delirium independently predicted longer hospital stay, even after correction for relevant covariates [6]. When framed in fiscal terms, delirium has been associated with 39% higher ICU costs and 31% higher hospital costs overall [7]. Delirium predicts greater hospital costs across multiple domains, including professional, technical, consultative, and nursing [8].
Disruptive behavior poses a grave risk of acute injury to the delirious ICU patient because of the extensive use of invasive technology in the ICU. This hazard has been specifically studied in patients who extubate themselves. Restlessness and agitation—two of the most frequent concomitants of delirium—independently predict self-extubation, which results in laryngeal and vocal cord trauma, emesis, aspiration, cardiac arrhythmia, respiratory arrest, and death [9].
Etiology
An exhaustive review of conditions that may precipitate delirium would likely cover the breadth of medical and surgical practice. Given the near limitless number of possible etiologies,
when searching for a possible cause of delirium, it often proves useful to scan the clinical data searching for broad categories of pathology. The mnemonic “I WATCH DEATH” (Table 197.2) lists the processes most commonly related to delirium; the mnemonic “WWHHHHIMPS” (Table 197.3) aids recall of immediately life-threatening causes.
when searching for a possible cause of delirium, it often proves useful to scan the clinical data searching for broad categories of pathology. The mnemonic “I WATCH DEATH” (Table 197.2) lists the processes most commonly related to delirium; the mnemonic “WWHHHHIMPS” (Table 197.3) aids recall of immediately life-threatening causes.
Table 197.1 Diagnostic Criteria for Delirium | ||
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With complicated conditions requiring interventions on multiple fronts, patients in the ICU are often subjected to polypharmacy. A review of the patient’s medication list with an eye toward certain categories of medications frequently causative of, or contributory to, delirium is warranted (Table 197.4). Particular offenders include anticholinergics, antihistamines, corticosteroids, opioids, and benzodiazepines [10,11].
Pathology
Alertness is subserved by the ascending reticular activating system (RAS) and its bilateral thalamic projections; attention is mediated by neocortical and limbic inputs to this system [12]. Structural or neurochemical interference with these pathways could theoretically result in the deficits in alertness and attention that are the hallmarks of delirium. Because the primary neurotransmitter of the RAS is acetylcholine, the relative deficit of cholinergic reserve in the elderly (e.g., due to microvascular disease or due to atrophy) may be the neural basis of the heightened risk of delirium in the geriatric population. Medications with anticholinergic activity are likely to disrupt this system’s functioning even further.
Table 197.2 I Watch Death: A Mnemonic for Common Causes of Delirium | ||||||||||||||||||||||||
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Table 197.3 WWHHHHIMPS: A Mnemonic for Life-Threatening Causes of Delirium | ||
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In the setting of impaired oxidative metabolism, dopaminergic neurons have been found to release excess amounts of dopamine; its subsequent reuptake and extracellular metabolism are also disrupted. Because, at high levels, dopamine is theorized to facilitate the excitatory effects of glutamate [13], this dopaminergic hypothesis constitutes a proposed mechanism for the agitation seen in delirium. In fact, oxidative dysfunction predicts increased risk of delirium [14].
Risk Factors and Detection
Risk factors for delirium can be divided into three broad categories: properties of the illness (acute physiologic), preexisting properties of the patient (chronic physiologic), and properties of the environment (iatrogenic) (Table 197.5) [15].
The majority of patients suffering from delirium present with the hypoactive subtype. Withdrawn and psychomotorically retarded, the patient with hypoactive delirium is frequently thought by caretakers and family to be depressed. Although these patients cause little disruption to the ICU environment and provoke less acute distress in their treaters, they are no less subject to the adverse outcomes of an altered sensorium. Although the immediate threat to safety may be less apparent in these cases, hypoactive delirium can rapidly and unpredictably evolve into acute agitation as a result of unchecked, upsetting delusions. Moreover, the subjective experience of hypoactive delirium is as intense and distressing as the agitated variety [16].
Two delirium screening scales have been validated for use by nonpsychiatric personnel in the ICU. The Confusion Assessment Method for the ICU (CAM-ICU) features a four-domain assessment that can be administered in less than 1 minute [17]. Both sensitivity and specificity are > 90%, and it has been translated into several languages. The Intensive Care Delirium Screening Checklist (ICDSC) features eight items, each scored present or absent. Sensitivity and specificity of the ICDSC are
99% and 64%, respectively [18]. The minimal time required to complete either of these scales allows for scoring several times daily, which is an important feature, given the waxing and waning nature of delirium. Both scales are available at www.icudelirium.org. Careful screening and early detection can limit the sequelae of delirium and forestall the additional consequences attendant to the evolution of hypoactive delirium into agitation.
99% and 64%, respectively [18]. The minimal time required to complete either of these scales allows for scoring several times daily, which is an important feature, given the waxing and waning nature of delirium. Both scales are available at www.icudelirium.org. Careful screening and early detection can limit the sequelae of delirium and forestall the additional consequences attendant to the evolution of hypoactive delirium into agitation.
Table 197.4 Common ICU Drugs Associated with Delirium | ||||
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Diagnostic Evaluation
In ambiguous cases of delirium, an electroencephalogram (EEG) may provide objective data to aid diagnosis. Although the association of delirium and EEG changes was first described in the 1940s, no objective test since has demonstrated better performance in accurately detecting delirium. In their classic studies, Engel and Romano described three landmark electrographic findings in delirious patients: generalized slowing, consistency of this slowing despite wide-ranging underlying conditions, and resumption of a normal rhythm with treatment [19]. For all presentations of delirium, generalized slowing in the delta-theta range (delta: 0 to 4 Hz, theta: 4 to 8 Hz), poor organization of the background rhythm, and loss of reactive changes to eye opening and closing are considered diagnostic [20]. Recent studies have estimated the sensitivity of EEG in the diagnosis of delirium to be approximately 75%, with false–negative results likely a result of slowing not sizable enough to drop the patient’s baseline rhythm from one range to the next.
EEG may also prove helpful in discerning the etiology of a delirium, since delirium tremens (DTs) as a result of alcohol or sedative–hypnotic withdrawal is associated with low-voltage fast activity superimposed on slow waves, while sedative–hypnotic toxicity is associated with fast beta activity (> 12 Hz) [20]. EEG may also detect previously undiagnosed deliriogenic conditions, including nonconvulsive status epilepticus, complex partial seizures, or cerebral lesions that may act as seizure foci.
Once delirium is confirmed, the search for an underlying medical cause should commence. A careful step-by-step approach can help prune a near-endless list of possible etiologies. Although no evidence-based protocol of diagnostic studies most likely to identify a culprit exists, broad-based, relatively inexpensive, and noninvasive laboratory testing can often be informative (Table 197.6).
In most circumstances, psychiatric consultation is beneficial to the patient and the consultee. A consultation psychiatrist’s familiarity with delirium and its causes and treatments usually speeds diagnosis and intervention. Delay in psychiatric consultation predicts lengthier hospitalization [21].
Pharmacologic Management
The definitive treatment of delirium is the identification and treatment of the underlying cause(s). In addition, numerous interventions may reduce its potentially harmful sequelae.
Cholinergic Agents
Given the hypocholinergic/hyperdopaminergic neurophysiological model of delirium, the intuitive goals of pharmacologic treatment are to increase cholinergic and decrease dopaminergic activities. By reversibly inhibiting metabolism of acetylcholine, the cholinesterase inhibitor physostigmine has been shown to reverse delirium resulting from multiple etiologies, but its clinical utility is limited by a brief duration of efficacy and a narrow therapeutic window. Therefore, physostigmine is usually used only when delirium is known (or highly suspected) to be caused by anticholinergic toxicity, for which it is considered the agent of choice [22].
Some small studies and case series of dementia-treating cholinesterase inhibitors have demonstrated possible delirioprotective effects [23,24], but these agents’ utility in the acute setting is hampered by their long half-lives and subsequent extended interval before therapeutic serum levels are reached. Two randomized, double-blind, placebo-controlled trials failed to demonstrate any benefit of donepezil in either preventing or treating postoperative delirium [25,26]. An additional randomized, placebo-controlled trial of rivastigmine for delirium prevention also failed to demonstrate any such benefit [27].
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