Delirium in advanced cancer

Delirium is a common symptom in patients with advanced cancer; studies note the incidence of delirium as high as 88% in inpatient deaths due to cancer. It is an independent risk factor for poorer prognosis and a predictor of impending death when patients are in the last phase of their illness. It is a source of much distress for patients and families and can preclude a patient’s wish to die at home due to the challenges in treating these patients. Up to half of delirium episodes go unrecognized or misdiagnosed.

Stephanie Harman

Delirium is defined by the following Diagnostic and Statistical Manual of Mental Disorders-IV criteria:

1. Disturbance of consciousness with reduced ability to focus, shift or sustain attention.
2. Change in cognition or the development of a perceptual disturbance that is not better accounted for by a pre-existing, established or evolving dementia.
3. Development of the disturbance during a short period and tendency to fluctuate during the course of the day.
4. Evidence from the history/physical examination/laboratory studies suggesting that the disturbance is caused by the direct consequences of a general medical condition.

Delirium can be classified by several different subtypes: hyperactive, hypoactive and mixed. Hyperactive delirium is characterized by restlessness, agitation, hypervigilance and hallucinations. Hypoactive delirium is characterized by lethargy, psychomotor retardation, and overall reduced awareness of surroundings; it is more common than the hyperactive subtype, but is often mistaken for depression. The mixed subtype demonstrates periods of hyperactive symptoms alternating with those of the hypoactive subtype.

There are multiple diagnostic tools that can be used for identifying delirium, including the DSM-IV criteria and the Mini-Mental Status Examination and the Confusion Assessment Method, or CAM. CAM has been shown as a simple,/ yet effective instrument in diagnosing delirium, using the features of acute onset with fluctuating course, inattention, and either disorganized thinking or altered level of consciousness to make the diagnosis.

Etiology

The exact pathophysiology of delirium remains elusive. The reticular formation of the brainstem and the neurotransmitters and receptors involved in consciousness are thought to play a significant role. Acetylcholine and dopamine have been the most strongly implicated, with acetylcholine thought to have decreased activity and dopamine thought to have increased activity in delirium.

In patients with advanced cancer, multiple etiologic factors are usually present, the most common being medications, particularly opioids, due to their anticholinergic properties, and steroids. Other frequent etiologies include metabolic disorders and encephalopathies, infection, recent surgery and structural lesions. Delirium in the advanced stages of cancer is often thought to be part of the dying process, but up to 50% of episodes are reversible. The diagnostic work-up for these patients includes a medication review, laboratory testing to identify metabolic abnormalities and infection, as well as CNS imaging, but these tests should be considered in the context of the goals of care for each individual patient.

Management

The mainstay of delirium management is a multidisciplinary approach utilizing both nonpharmacologic and pharmacologic therapies, alongside the treatment of the underlying etiologies. Nonpharmacologic interventions include minimizing the use of restraints and indwelling catheters, implementing orientation techniques (familiar objects, visual and hearing aids), monitoring for bowel/bladder functioning, facilitating a normal sleep-wake cycle with good sleep hygiene, and controlling pain. The distress of families can be mediated with appropriate coaching on what to expect and what they can do to minimize sensory stimulation and promote a relaxed, familiar environment.

Although treating the underlying etiology is a primary treatment strategy, concurrent treatment of the symptoms of the delirium should be implemented. Haloperidol is considered first-line therapy for delirium in advanced disease and has been the most studied, though no medication has been FDA-approved for delirium. Unfortunately, haloperidol is used only in 0.5% to 2% of hospitalized cancer patients with delirium, likely due to under-recognition and under-treatment.

Starting doses of haloperidol begin at 0.25 mg to 0.5 mg parenterally in the elderly or 1 mg to 2 mg in younger patients, given as frequently as every one to two hours in acute agitation to every six to 12 hours for maintenance. This can be converted to an oral dose (1.5 to 2 × the IV), with a maximum daily dose of 20 mg. Haloperidol can be used in all three delirium subtypes. Chlorpromazine is an alternative for the hyperactive form, as it tends to be more sedating. The use of these more typical antipsychotics is limited by their extrapyramidal side effects (tremors, muscle stiffness, dyskinesia) and QTc prolongation, which has led to the FDA black box warnings for sudden death.

The newer, atypical antipsychotics are being used increasingly due to the decreased risk of extrapyramidal side effects. There are few studies in this class of medications; a recent Cochrane review highlighted risperidone and olanzapine as having been shown effective in the management of delirium. Their use is limited as they are primarily available in oral forms, but they do come in orally disintegrating tablets for patients who cannot swallow. Dosing for olanzapine begins at 2.5 mg to 5 mg every 12 to 24 hours and risperidone at 0.25 mg to 1 mg every 12 to 24 hours. Quetiapine, ziprasidone, and aripiprazole have also been used.

Benzodiazepines have also been used in the treatment of delirium for the purpose of palliative sedation. For up to 30% of dying patients, antipsychotic medications alone are not adequate to control the symptoms of delirium. More sedating agents such as benzodiazepines can be used in conjunction with antipsychotics or as primary agents if sedation is the primary goal. Benzodiazepines are not recommended as a first-line agent for delirium due to the risk of worsening agitation (paradoxical effect).

Prevention

Interventions that have been effective for prevention include constant orientation, correction of hearing and visual impairments, early mobilization, and reversal of dehydration, but these have been primarily studied in hospitalized elderly patients and not confirmed in cancer patients. The use of prophylactic medications (antipsychotics) in prevention has not been proven effective. In light of the morbidity and mortality associated with delirium in advanced cancer, more research and study is needed in its diagnosis, treatment and prevention.

Stephanie Harman, MD is a Palliative Care Physician at Stanford University Medical Center and Director of its Inpatient Palliative Care service.

For more information:

• Breitbart W. JAMA. 2008;300:2898-2910.
• Caraceni A. Lancet Oncol. 2009;10:164-172.
• Centenno C. Pall Med. 2004;18:184-194.
• Lonergan E. Cochrane Database Syst Rev. 2007;CD005594.