Delirium evolves acutely or subacutely, generally in hours to days. Symptoms fluctuate within each 24-hour period, with a typical waxing-waning course. Patients with delirium exhibit alterations in their level of arousal, ranging from lethargy to hyperactive/agitated. Attention is impaired, as evidenced by distractibility, the need for the examiner to repeat questions, and inability to shift focus to the appropriate stimulus. At least one cognitive deficit can be identified. The patient may become disoriented regarding time, place, and situation, but this is not a prerequisite for a diagnosis of delirium. Memory and language deficits are often apparent, and the patient’s speech may become disorganized and nonsensical (Table 13.2).

Patients with delirium generally have abnormalities in the sleep-wake cycle. For instance, a patient may sleep throughout the day and stay awake only at night. Some of the most dramatic presentations of delirium involve perceptual disturbances. Hallucinating patients may describe animals in the room, furniture floating, or patterns and shapes on the walls. Tactile and auditory hallucinations are not uncommon, and a patient may experience paranoid delusions in response to these altered perceptions. Family members can often recall subtle changes in mood preceding acute presentation; these subclinical syndromes may follow episodes, as well. During an acute episode, the patient may be tearful and emotionally labile. Hypoactive delirium is often mistaken for depression.

Researchers have described three subtypes of delirium based on level of arousal: hyperactive, hypoactive, and mixed. Patients with hyperactive delirium are seldom overlooked, as they tend to become agitated and restless, frequently wandering the unit or trying to get out of bed without assistance. Their speech may become loud, and they can be seen responding to hallucinations. When staff members attempt to redirect or restrain hyperactive delirious patients, they may be uncooperative or even aggressive. These patients are at risk for harming themselves by falling or pulling out needed lines.

Patients with hypoactive delirium appear to be apathetic and withdrawn. Engagement in activities and oral intake are reduced, and the patient spends the day falling in and out of sleep. This listlessness may be misinterpreted as depression, but upon closer examination, cognitive and attentional deficits are present. These patients are at risk for self-harm owing to malnutrition, deconditioning, and passive refusal of medical interventions. Peterson et al. (2006) found that among patients admitted to an intensive care unit, those over the age of 65 years were twice as likely to have hypoactive delirium than were younger patients. This subtype carries a higher mortality risk than does hyperactive delirium.

The mixed subtype refers to presentations alternating between hyperactive and hypoactive.

Understanding the mechanism underlying the development of delirium is helpful when examining specific etiologies. In essence, delirium results from decreased oxygen availability to the brain. This can result from decreased oxygen supply to the brain, such as in hypoperfusion, or increased oxygen demand, such as with illness or surgery. Inadequate oxidative metabolism causes cortical depression owing to the inability of neurons to maintain ionic gradients and eliminate neurotoxic byproducts (Maldonado 2008).

Neuronal dysfunction causes dysregulation of neurotransmitters, thereby precipitating delirium. Specifically, a reduction in cholinergic activity (and corresponding increase in dopaminergic activity) and heightened GABAergic activity in the brain are thought to underlie the development of delirium. The acetylcholine-dopamine imbalance hypothesis is supported by the fact that anticholinergic medications are frequent culprits for delirium as well as by the use of dopamine-blocking antipsychotics in its management . Changes in serotonergic, glutamatergic, and opioidergic activity are implicated in the pathogenesis of delirium, as are cytokines. Overall, high cortical function is impaired by numerous interacting neurotransmitter systems and neuronal pathways.

Researchers have compiled extensive lists of medical conditions and prescription drugs that cause delirium, and referencing them is useful when searching for the cause of altered mental status in a patient (Table 13.3). An important concept to keep in mind is that delirium is usually multifactorial. Therefore, a seemingly minor medical complication or normal medication dose can cause changes in sensorium in a cumulative manner. For example, a patient continuing to take a usual home regimen of an opiate analgesic may be tipped into delirium when admitted to the hospital for pneumonia.

Cancer patients have characteristics that are risk factors for delirium. Cancer rates increase with age, as does the prevalence of cognitive impairment and dementia. Underlying dementia is a well-established risk factor for delirium. Elderly patients may have mild cognitive impairment or pre-existing dementia at baseline, thereby increasing their risk of delirium when acutely ill. Substance abuse and dependence—specifically, alcohol and tobacco—are risk factors for certain types of cancer. Patients abusing these substances are also at risk for intoxication or withdrawal syndromes, resulting in agitation and/or altered mental status.

Cancer patients are particularly vulnerable to delirium at certain junctures of their disease. The perioperative period poses risks because of anesthesia, the physical trauma of the surgery itself, shifts in fluid and electrolyte level, pain, use of opiate analgesics, and complications including wound infection, urinary tract infection, pneumonia, anemia, autonomic instability, and hypoxia.

Hospitalization is frequently required at various time points in the patient’s illness. This poses numerous risks for the development of delirium in addition to the medical situation necessitating hospitalization. These include a change in environment, lack of access to substances of abuse (precipitating withdrawal syndrome), sensory impairment (if access to glasses or hearing aids is restricted), sleep deprivation, polypharmacy, and use of intravenous (IV) lines, bladder catheters, and physical restraints.

Certain cancer treatments may place the patient at increased risk for delirium. Intrathecal chemotherapy and whole-brain irradiation are examples. Immunosuppressants, including tacrolimus and mycophenolate, can directly cause delirium via neurotoxicity, and they increase the risk of central nervous system (CNS) infections in patients presenting with altered mental status. Some chemotherapeutic agents, including methotrexate, cytarabine, fluorouracil, vincristine, vinblastine, bleomycin, bis-chloronitrosurea, cis-platinum, ifosfamide, asparaginase, and procarbazine, can cause mental status changes. Immunotherapeutics such as high-dose interleukin and interferon also are associated with delirium.

In the terminal stages of cancer, delirium typically manifests in the final days. One study found delirium to be present in 88 % of patients at least 6 h before death (Lawlor et al. 2000a).

Many types of cancer have CNS involvement, for example, primary and metastatic brain tumors and leptomeningeal carcinomatosis. Altered mental status may stem from the direct effects of these diseases or secondary seizures. Paraneoplastic syndromes occur when a tumor produces substances that cause remote effects at a distance from it. The paraneoplastic syndrome encephalopathy is most commonly associated with squamous cell lung cancer and breast cancer.

Medical history will reveal the acute or subacute temporal course of mental status changes, which helps distinguish delirium from dementia and underlying chronic psychiatric illnesses. Baseline cognitive status is key to the differential. A history of substance abuse is an important component of the evaluation, and collateral sources of information may be required. In addition, a complete medication list and any recent changes provide valuable clues about delirium. Upon physical examination, the clinician may find signs of a medical condition or systemic signs of medication side effects. Mental status testing, particularly the cognitive examination, is essential to the diagnosis of delirium.

Structured instruments are available for screening and monitoring delirium. The Memorial Delirium Assessment Scale measures the severity of delirium and is designed to be repeated throughout the day to monitor treatment response (Lawlor et al. 2000b). It is quite useful as a screening tool, and researchers have validated it in hospitalized patients with advanced cancer. The Delirium Rating Scale-Revised-98 is another useful instrument for rating delirium severity (Trzepacz et al. 2001). The Confusion Assessment Method has been simplified into a 4-item screen for delirium (Inouye et al. 1990). It has lower sensitivity and specificity than the Memorial Delirium Assessment Scale and Delirium Rating Scale-Revised-98, but it can be administered by nonpsychiatrists.

Laboratory workup for delirium is based on clinical suspicion of the underlying etiology. This includes complete blood count; measurement of electrolytes, blood urea nitrogen/creatinine, glucose, thyroid-stimulating hormone, vitamin B12, folate, arterial blood gas, and serum drug levels; liver function tests; urine drug screening; urinalysis; electrocardiography; and a chest X-ray. Brain imaging (computed tomography and magnetic resonance imaging) and lumbar puncture are frequently indicated in the cancer population for the differential diagnoses discussed in detail above, including for brain tumors, stroke, intracranial bleeding, CNS infection, and leptomeningeal disease . Electroencephalography not only assesses patients for seizures but also shows generalized slowing in the dominant posterior rhythm in 81 % of delirium cases. In contrast, it reveals diffuse slowing in 33 % of dementia cases, and these changes generally occur only at during the latter stages of dementia (Jacobson and Jerrier 2000).

Treatment of delirium requires identification of the underlying cause and implementation of appropriate medical intervention. Potential medical etiologies and appropriate workup are discussed above. If the altered mental status is thought to be medication-induced, discontinue or minimize the use of deliriogenic medications. If safe, effective alternatives exist, switching medications is indicated. Benzodiazepines and anticholinergics should be tapered and avoided (unless the etiology is alcohol or benzodiazepine withdrawal). With opiate pain medications, a balance must be achieved between their delirium-exacerbating potential and the risk of uncontrolled pain causing agitation. Opiate pain medications can be rotated, and use of meperidine should be avoided owing to high rates of neurotoxicity. Potential interactions that affect the pharmacokinetics or clinical effects of a drug should be identified. This can be done conveniently and quickly using one of many available online drug interaction programs.

During the search for the medical etiology of delirium, behavioral and cognitive symptoms must be managed. In fact, even after treatment of the medical problem and eliminating deliriogenic medications, symptoms of delirium can persist for an indefinite period.

Safety concerns should be addressed first. Tips for calming an agitated patient are described above. A one-to-one sitter may be required for constant redirection and supervision. Fall precautions should be instituted, and the medical staff must be made aware of the change in mental status. The patient should be moved to a room closer to the nursing station, and dangerous objects should be removed from the room. In extreme cases of agitation when a patient is at risk for self-harm, violence toward other patients, or pulling out essential medical devices, physical restraints may be necessary. Because this intervention can exacerbate agitation, frequent attempts to remove restraints should be made, especially as other management strategies are instituted.

Nonpharmacologic strategies are very helpful in both the prevention and management of delirium. Correct malnutrition, dehydration, and electrolyte abnormalities. Supplement oxygen delivery and remove immobilizing lines such as bladder catheters, IV lines, and drains as soon as possible. Make glasses and hearing aids available to the patient to prevent sensory deprivation and disorientation. Ensure bladder and bowel function. Light (e.g., windows) and noise (e.g., music, television) can be used to promote a normal sleep-wake cycle. Minimize nighttime awakening by staff. Reduce environmental isolation by encouraging family presence, frequent staff visits, or use of a one-to-one sitter. Frequent reorientation and prominent display of cues such as a clock, a calendar, and location signs are helpful for the confused patient.

Avoid the use of physical restraints, as it may exacerbate agitation. Restraints are sometimes necessary to prevent self-harm when less restrictive alternatives are unavailable, but frequent attempts to remove restraints should be made. Two-point arm restraints, four-point arm and leg restraints, lap belts, and Posey vests are types of physical restraints. Mitts can be helpful in preventing patients from pulling out IV lines and drainage tubes. Knowledge of institutional policies regarding the use of physical restraints as well as monitoring and order requirements is important. Of note, cancer patients should be restrained carefully owing to risk of fractures, and prolonged immobilization increases their risk of clots.

The goal of medical intervention for delirium is to calm the patient while maintaining arousal and ability to communicate. Chemical restraint refers to using psychotropics to sedate patients and keep them quiet. This is not an appropriate management goal. In terminally ill patients, the focus is on providing comfort; level of arousal is sometimes affected in this population.

Antipsychotics represent the pharmacologic treatment of choice for delirium. Although prescribed more commonly to control agitation, both haloperidol and chlorpromazine are effective in improving symptoms and cognitive function in patients with hypoactive delirium (Breitbart et al. 1996). Benzodiazepines may actually worsen confusion, predispose a patient to falls, cause paradoxical disinhibition, and prolong the delirium episode. Lorazepam is used in combination with haloperidol (0.5–2.0 mg intravenously) if haloperidol does not calm the patient (see below), but it should not be given alone. However, as described below, benzodiazepines represent the mainstay of therapy in cases of alcohol withdrawal. Diphenhydramine has sedative properties, but it should not be administered to calm an agitated, confused patient owing to its significant anticholinergic activity, which exacerbates delirium.