Delirium in hospitalized patients: Risks and benefits of antipsychotics

SCOPE OF THE PROBLEM

Delirium is common and serious, affecting 11% to 42% of patients hospitalized on general medical wards.¹ The burden to the public and individual patient is extremely high. Delirium has been found to result in an additional $16,303 to $64,421 per delirious patient per year, with a subsequent total 1-year health-attributable cost between $38 billion and $152 billion in the United States.² Furthermore, many patients who become delirious in the hospital lose their independence and are placed in long-term care facilities.³

Although delirium was originally thought to be a time-limited neurocognitive disorder, recent evidence shows that it persists much longer⁴ and that some patients never return to their previous level of function, suggesting that a single episode of delirium can significantly alter the course of an underlying dementia with the dramatic initiation of cognitive decline.³ Most alarmingly, delirium is associated with an increased rate of death.¹

DSM-5 DEFINITION

According to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5),⁵ delirium is a neurocognitive disorder characterized by the acute onset of disturbance in attention, awareness, and cognition that fluctuates in severity throughout the day and is the direct physiologic consequence of another medical condition. The cognitive impairment seen in delirium is typically global and can affect memory, orientation, language, visuospatial ability, and perception. Other prominent features include psychomotor disturbance, sleep-cycle derangement, and emotional lability.

The pathogenesis of delirium is not clearly delineated but may relate to cholinergic deficiency and dopaminergic excess.

THE FIRST STEPS: NONPHARMACOLOGIC MANAGEMENT

Inouye³ outlined a general 3-part approach to managing delirium:

Identify and address predisposing factors. All patients found to have an acute change in mental status should be evaluated for the underlying cause, with special attention to the most common causes, ie, infection, metabolic derangement, and substance intoxication and withdrawal. A thorough medication reconciliation should also be done to identify medications with psychoactive or anticholinergic effects.

Provide supportive care, eg, addressing volume and nutritional status, mobilizing the patient early, and giving prophylaxis against deep venous thrombosis.

Manage symptoms. Behavioral strategies should be instituted in every delirious patient and should include frequent reorientation, use of observers, encouragement of family involvement, avoidance of physical restraints and Foley catheters, use of vision and hearing aids, and normalizing the sleep-wake cycle.

ANTIPSYCHOTICS: ARE THEY SAFE AND EFFECTIVE?

The US Food and Drug Administration (FDA) has not approved any medications for delirium. However, multiple consensus statements, including those by the American Psychiatric Association,⁶ the Canadian Coalition for Seniors’ Mental Health,⁷ and the UK National Institute for Health and Care Excellence,⁸ advocate for psychopharmacologic management of delirium symptoms in the following situations:

• The patient is in significant distress from his or her symptoms

• The patient poses a safety risk to self or others

• The patient is impeding essential aspects of his or her medical care.

Guidelines from these organizations recommend antipsychotic medications as the first-line drugs for managing delirium symptoms not caused by substance withdrawal. Nevertheless, the use of antipsychotics in the management of delirium remains controversial. While a number of studies suggest these drugs are beneficial,^9–11 others do not.¹² These consensus panels advocate for the judicious use of antipsychotics, limited to the specific situations outlined above.

The use of antipsychotics in elderly and medically complex patients poses risks. One of the most significant safety concerns is increased risk of death due to adverse cardiac events caused by prolongation of the QT interval.

Antipsychotics, QT prolongation, and torsades de pointes Most antipsychotics have the potential to prolong the time of ventricular depolarization and repolarization and the QT interval to some extent, which can lead to torsades de pointes.¹³ Other risk factors for prolonged QT interval and torsades de pointes include:

• Long QT syndrome (a genetic arrhythmia)

• Female sex

• Old age

• Electrolyte abnormalities (hypokalemia, hypocalcemia, hypomagnesemia)

• Preexisting heart conditions such as bradycardia, left ventricular dysfunction, heart failure, mitral valve prolapse, and previous myocardial infarction

• Medical conditions that cause electrolyte derangements

• Medications, including antiarrhythmics, antibiotics (macrolides, quinolones), anti-fungals, antimalarials, antiemetics, some opioids (methadone), and most antipsychotics.

Haloperidol. Postmarketing analysis in 2007 found 73 cases of haloperidol-related torsades de pointes. However, many of these were confounded by other QT-prolonging medications and medical conditions.¹⁴

The QT-prolonging effect of haloperidol administered orally or intramuscularly is actually quite small. The equivalent oral dose of 15 mg of haloperidol (assuming 50% bio-availability) given orally or intramuscularly increases the corrected QT interval (QTc) by only 7 to 8 milliseconds. But intravenous haloperidol can cause much more significant QT prolongation: 8 of the 11 reported cases of fatal torsades de pointes occurred when haloperidol was given intravenously.¹⁴ Therefore, the FDA recommends cardiac monitoring for all patients receiving intravenous haloperidol.

Oral olanzapine, risperidone, and quetiapine prolong the QT interval approximately as much as oral haloperidol.

Aripiprazole has not been associated with significant QT prolongation.¹³

SELECTING AND USING ANTIPSYCHOTICS TO TREAT DELIRIUM

Identifying a single preferred agent is difficult, since we lack enough evidence from randomized controlled trials that directly compared the various antipsychotics used in delirium management.

Both typical and atypical antipsychotics are used in clinical practice to manage delirium. The typical antipsychotic most often used is haloperidol, while the most commonly used atypical antipsychotics for delirium include olanzapine, quetiapine, risperidone, and (more recently) aripiprazole.

The American Psychiatric Association guidelines⁶ suggest using haloperidol because it is the antipsychotic that has been most studied for delirium,²⁰ and we have decades of experience with its use. Despite this, recent prospective studies have suggested that the atypical antipsychotics may be better because they have a faster onset of action and lower incidence of extrapyramidal symptoms.^18,21

Because we lack enough head-to-head trials comparing the efficacy of the 5 most commonly used antipsychotics for the management of delirium, and because the prospective trials that do exist show equal efficacy across the antipsychotics studied,²² we suggest considering the unique pharmacologic properties of each drug within the patient’s clinical context when selecting which antipsychotic to use.

Table 1^23–25 summarizes some key characteristics of the 5 most commonly used antipsychotics.

BALANCING THE RISKS

Antipsychotic drugs have been shown to be effective and generally safe. Antipsychotics do prolong the QT interval. However, other than with intravenous administration of haloperidol, the absolute effect is minimal. Although large meta-analyses have shown a higher rate of all-cause mortality in elderly outpatients with dementia who are prescribed atypical antipsychotics, an increase in death rates has not been borne out by prospective studies focusing on hospitalized patients who receive low doses of antipsychotics for a limited time.

There are no head-to-head randomized controlled trials comparing the efficacy of all of the 5 most commonly used antipsychotics. Therefore, we suggest considering the unique psychopharmacologic properties of each agent within the patient’s clinical setting, specifically taking into account the risk of cardiac arrhythmia, risk of orthostasis and falls, history of extrapyramidal symptoms, other comorbidities such as Parkinson disease and cancer, and the desired route of administration.

At the time the patient is discharged, we recommend a careful medication reconciliation and discontinuation of the antipsychotic drug once delirium has resolved. Studies show that at least 26% of antipsychotics initiated in the hospital are continued after discharge.^36,37

Current delirium consensus statements recommend limiting the use of antipsychotics to target patient distress, impediment of care, or safety, because of the putative risks of antipsychotic use in the elderly. However, a growing body of evidence shows that low-dose, time-limited antipsychotic use is safe and effective in the treatment of delirium. In fact, González et al found that delirium is an independent risk factor for death, and each 48-hour increase in delirium is associated with an increased mortality risk of 11%, suggesting that delay in treating delirium may actually increase the risk of death.³⁸

Therefore, we must balance the risks of prescribing antipsychotics in medically vulnerable patients against the increasing burden of evidence supporting the serious risks of morbidity and mortality of delirium, as well as the costs. Much remains to be studied to opti-mize antipsychotic use in delirium.