Delirium is a neuropsychiatric complication that can occur in patients with cancer, particularly in those with advanced disease. The prevention of delirium in the patient with cancer has not been systematically examined, but studies in hospitalized elderly patients suggest that early identification of risk factors reduces the occurrence rate of delirium and the duration of episodes.[
Delirium has been defined as a disorder of global cerebral dysfunction characterized by disordered awareness, attention, and cognition.[
Other associated noncore clinical criteria features include sleep-wake cycle disturbance, delusions, emotional lability, and disturbance of psychomotor activity. The latter forms the basis of classifying delirium into three different subtypes:[
In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.
The clinical presentation of delirium is associated with a high level of distress in patients, family members, and health care personnel.[
Dysfunctional cognition in the delirious patient hinders communication between patient and family and between patient and health care personnel. As a result, reliable symptom assessment, counseling, and active patient participation in the therapeutic decision-making process are all compromised.[
A psychosocial intervention for family caregivers of patients with advanced cancer may be beneficial in providing knowledge of delirium and detection rates and in increasing family caregiver self-confidence in decision making.[
Occurrence rates range from 28% to 48% in patients with advanced cancer on admission to hospital or hospice,[
Although delirium clearly has a recognized association with the dying phase, many episodes of delirium are reversible; therapeutic intervention can result in delirium reversal, or at least improvement, in 30% to 75% of episodes.[
Delirium is often multifactorial, especially in the setting of advanced cancer. General etiologic factors include the following:[
Despite the very limited systematic study of risk factors for delirium in patients with cancer, risk factors have been identified in hospitalized elderly patients (some of them with cancer) and include the following:[
Studies of hospitalized elderly patients suggest that the level of risk is proportionate to the number of risk factors present.[
Distinct from delirium, older (65 years or older), long-term (>5 years) cancer survivors are also at increased risk of cognitive deficits and possibly dementia, as noted in a co-twin control design study of 702 Swedish cancer survivors.[
The diagnosis of delirium should be considered for any patient with cancer demonstrating the following:
However, the diagnoses of delirium and cognitive impairment are frequently missed and poorly documented.[
Medical and nursing staff, as well as family members, may attribute a functional cause to some of the early, prodromal, and more subtle signs of delirium such as increased anxiety, restlessness, and emotional lability.[
Differentiating delirium from dementia or recognizing delirium superimposed on dementia can be difficult because of some shared clinical features such as disorientation and impairment of memory, thinking, and judgment.[
Vigilance on the part of nursing staff and a systematic approach to recording serial observations assist in the detection of delirium. Regular cognitive screening facilitates the diagnosis of delirium in cancer patients.[
Instruments that have favorable psychometric properties and are brief enough to allow repeated administration in cancer patients include the following:[
An integrated approach to management involves educating family members about the nature of the delirium syndrome and its potential treatment.[
Regardless of the level of investigational or therapeutic aggression, symptomatic treatment is usually required for most patients. Monitoring and reassessment should be ongoing, particularly when pharmacological sedation is required to initially control symptoms.[
Nonpharmacologic Aspects of Symptom Management
Various environmental strategies have been proposed to reduce the symptomatic distress associated with delirium. These strategies include the following discrete efforts at reorientation:[
Although some controversy surrounds the use of physical restraints, their judicious use may sometimes be necessary to prevent self-harm or physical aggression directed at caregivers.
Identification of Underlying Causes and Their Treatment
Delirium reversal is consistent with the goals of care; therefore, the standard management approach in patients with cancer is to search for and treat the reversible precipitants of delirium.[
This process typically involves a careful history and physical examination in addition to basic laboratory tests and imaging.[
Opioid analgesics, required for most patients with advanced disease, are among the psychoactive agents that precipitate delirium most frequently.[
Patients with delirium should be assessed for other symptoms that suggest opioid neurotoxicity, for example, tactile hallucinations, agitation, myoclonus, allodynia, hyperalgesia, and possibly seizures. It is postulated that this toxic state relates to the accumulation of the parent opioid compound or its metabolites.[
On identifying opioid toxicity, therefore, it is important to search for other precipitants such as dehydration or infection.[
Symptomatic Management: The Role of Pharmacologic Agents
No pharmacological treatment has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of delirium. Evidence and clinical experience suggest that antipsychotics play a major role in the treatment of delirium; however, only a few of these studies were conducted in patients with cancer. Antipsychotics are antidopaminergic agents and include typical antipsychotics such as haloperidol [
All antipsychotics presumably work by blocking the postsynaptic dopamine receptors, primarily in the mesolimbic region. However, simultaneous blockade of striatal dopamine receptors by these agents can cause extrapyramidal side effects (EPS) such as abnormal involuntary movements, akathisia, parkinsonian symptoms, and cogwheeling. The typical antipsychotics such as haloperidol carry a higher risk of EPS. The newer atypical antipsychotics have additional effects on the serotonin system that help reduce the EPS.
Antipsychotics have a complex mechanism of action with effects on several other neurotransmitter systems. Atypical antipsychotics have been associated with higher risk of weight gain and metabolic issues because of these effects on other neurotransmitter systems. All antipsychotics have been associated with anticholinergic side effects and negative effects on the cardiovascular and cerebrovascular systems, depending on the medication and dosing used.
Haloperidol, a neuroleptic agent with potent antidopaminergic properties, is still considered the drug of choice for the treatment of delirium in the patient with cancer;[
Haloperidol can be administered orally, intravenously, subcutaneously, or intramuscularly. Parenteral doses are roughly twice as potent as oral doses. Peak plasma concentrations are achieved 2 to 4 hours after an oral dose, and measurable plasma concentrations occur 15 to 30 minutes after intramuscular administration. Haloperidol may cause fewer EPS when administered intravenously. The EPS can be treated with agents such as benztropine in doses of 1 to 2 mg once or twice a day. Neuroleptic malignant syndrome, a rare complication with haloperidol use, is characterized by hyperthermia, increased mental confusion, leukocytosis, muscular rigidity, myoglobinuria, and high serum creatine phosphokinase. Injectable haloperidol is approved by the FDA only for intramuscular administration. However, it is frequently administered intravenously to treat agitated delirium.
Intravenous administration and higher doses of haloperidol have been associated with risk of sudden death due to Torsades de Pointes (TdP) and QTc prolongation. In this context, an FDA alert raised concerns about intravenous use of haloperidol.[
Evidence suggests that QTc prolongation and TdP might be primarily associated with higher haloperidol doses (6 mg or higher). No cases of QTc prolongation or TdP have been reported with a cumulative intravenous dose smaller than 2 mg. The presence of certain risk factors might increase the risk of QTc prolongation and TdP. Major risk factors include the following:
Elderly patients, female patients, and patients with endocrine disorders (e.g., diabetes) may carry a higher risk of QTc and TdP. In patients with cancer, special attention should be paid to past or concomitant use of cardiotoxic chemotherapy regimens such as anthracycline-based regimens. Baseline and continuous ECG monitoring is recommended in patients receiving high doses of haloperidol and/or with known risk factors for developing QTc prolongation. Many of the alternatives (i.e., currently available typical and atypical antipsychotics) are also associated with QTc prolongation and TdP.[
In select cases, the risk-benefit equation might favor intravenous use of haloperidol, especially in patients with established intravenous access; in addition, no other currently available antipsychotics can be delivered intravenously. Before the newer atypical antipsychotics became available, chlorpromazine was considered an alternative to haloperidol, although it is associated with orthostatic hypotension and a greater level of sedation.
Among the atypical antipsychotics, olanzapine has been studied more extensively. In an open trial of 79 hospitalized cancer patients with delirium,[
Predictors of a poor response included the following:
Olanzapine is also reported to have antiemetic and possibly analgesic properties, although it is not used primarily for these indications.[
Risperidone, another atypical antipsychotic, is also used extensively to treat delirium in clinical practice. In a single-blind randomized trial, the effectiveness of risperidone (n = 17) was compared with that of olanzapine (n = 15) for the treatment of delirium in patients with cancer. Both groups showed significant improvement in delirium as assessed by the Delirium Rating Scale. The response rates for improvement did not differ between the two groups. At the last observation, the mean dose of risperidone was 0.9 mg per day and that of olanzapine was 2.4 mg per day.[
Other atypical antipsychotics—specifically, quetiapine [
Except for lorazepam and midazolam in selected situations, benzodiazepines are generally not recommended for the treatment of delirium.[
Another exception is midazolam, a very short-acting benzodiazepine, which is given by continuous subcutaneous or intravenous infusion in doses ranging from 30 to 100 mg over 24 hours. Midazolam is used to achieve deep sedation, especially in a terminal hyperactive or mixed delirium when agitation is refractory to other treatments, for example, doses of haloperidol in the region of 20 mg per day.
The decision to use a deep level of pharmacologically induced sedation in the treatment of agitated delirium often raises ethical concerns, fueled by the marked variability in the reported frequency (ranging from 10% to 52%) for this practice in patients dying from advanced cancer. Consistent with the goals of care, it is important that appropriate efforts are made to assess the reversibility of delirium, clarify the intent of sedation (the relief of refractory symptoms), and maintain clear communication with family members and health care team members regarding rationale and process.[
Some preliminary evidence suggests that the hypoactive subtype of delirium is less responsive to neuroleptic treatment.[
Sedation for Refractory Delirium and Other Intractable Symptoms
Delirium at the end of life often requires a pharmacological sedative approach. This issue cannot be considered in isolation from the ethical dilemma that it evokes. The need to sedate terminally ill patients for poorly controlled symptoms that include delirium, pain, dyspnea, and psychological effects has been reported frequently.[
A systematic review of the definitions of sedation for symptom relief noted a marked variation in the literature.[
This review defined palliative sedation as "the use of sedative medications to relieve intolerable and refractory distress by the reduction in patient consciousness." The identified inconsistencies in the definition of sedation (i.e., primary versus secondary, light versus deep, and intermittent versus continuous sedation) should be subcategories of palliative sedation.[
The use of palliative sedation for psychosocial and existential symptoms can be particularly controversial. Many ethical and clinical questions can arise for the clinician—questions that are more easily resolved in the case of palliative sedation for pain and physical symptoms.
For example, the ethical basis for the use of terminal sedation (double effect) is less clearly applicable in the case of psychiatric symptoms. Under this principle, the intended effect (relieving psychological suffering) would be considered allowable as long as any risks or negative effects (i.e., shortened survival) are unintended by the professional. Difficulty arises here because the principle discusses only the professional's intention, when it is the patient's intention that can be unclear and potentially problematic. Questions that can arise for clinicians include the following:
Clinicians who feel uncomfortable in such situations might want to seek guidance from their ethics committees. Other difficult questions can arise from the potentially negative value that is culturally assigned to "zoning out" as a lower form of coping.
When dealing with such requests, professionals should consider their own cultural and religious biases and the cultural and/or religious backgrounds of patients and their families.
Few studies detail the use of terminal sedation for psychiatric symptoms. Four palliative care programs in Israel, South Africa, and Spain participated in one survey.[
Noting the limitations of surveys and retrospective chart reviews,[
The relatively short period between onset of sedation and death has been consistently reported as 1 to 6 days.[
Various medications have been utilized for palliative sedation.[
Midazolam is the drug most frequently reported as useful because of its rapid onset and ease of titration. Choice of medication is often determined by clinician preference and/or institutional policy.
Given the common association between delirium and sedation, it is important to have some understanding of the extensive literature on the ethical validity of using sedation management.[
Some families may need continuous information and professional guidance when palliative sedation is used, and this need increases with the duration of the sedation. Individuals or groups outside the family and health care team may have strong opinions about palliative sedation and may offer unsolicited guidance that conflicts with what the patient desires. Concerns identified in a study conducted in The Netherlands relate to the following:[
Current Clinical Trials
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of delirium. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
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PDQ® Supportive and Palliative Care Editorial Board. PDQ Delirium. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/side-effects/memory/delirium-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389173]
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Last Revised: 2016-01-04
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