Hyperactive delirium in hospitalized older adults: Balancing medication choices and QTc prolongation risk

Considerations when starting a QTc-prolonging agent

There are both modifiable and nonmodifiable factors that affect drug-related QT prolongation⁶:

• Nonmodifiable risk factors include age 65 and older, female sex, genetic risk of QT prolongation, and sudden cardiac death in a first-degree relative

• Potentially reversible or modifiable risk factors include electrolyte derangements (hypomagnesemia and hypokalemia), starvation, bradycardia, alcohol use disorder, methamphetamine use disorder, and high doses of methadone

• Factors that are modifiable to some extent with appropriate management include structural heart disease, heart failure, coronary artery disease, impaired renal and hepatic function, and use of 2 or more drugs associated with QT prolongation.

For patients with multiple risk factors, the Association of Medicine and Psychiatry recommends either ordering an electrocardiogram before starting a potentially QT-prolonging medication or selecting a lower-risk agent.⁶ The Association’s consensus-based algorithm identifies patients at high risk for torsade de pointes (QTc > 500 ms), intermediate risk (men with QTc 450–499 ms, women with QTc 470–499 ms), and low risk (men with QTc < 450 ms, women with QTc < 470 ms).

QTc monitoring is recommended for hospitalized patients with risk factors for torsade de pointes and for patients starting nonantiarrhythmic drugs with known, possible, or conditional risks for QT prolongation, such as antipsychotic agents.⁷ Electrocardiogram monitoring in these patients includes baseline and, especially in patients with additional risk factors, serial electrocardiograms. Daily QTc interval monitoring may have limited value in critically ill patients with normal baseline QTc and few risk factors.⁸

Sleep-wake cycle regulation

Medications in the American Geriatrics Society Beers Criteria list, including antihistamines, anticholinergic agents, and benzodiazepines, are best avoided in the treatment of insomnia and all neuropsychiatric syndromes in elderly patients.⁹ Melatonin and ramelteon might help facilitate sleep and maintain circadian rhythm at the hospital and are not associated with QTc prolongation, but caution is advised due to the risk of excessive somnolence with either agent.¹⁰

Trazodone, an antidepressant at high dose, is used at lower doses (50–200 g) for its antihistaminergic hypnotic effect. The risk of QT prolongation is low, but risks of orthostasis-related falls and priapism need to be considered.¹¹

Mirtazapine, an antidepressant that does not affect the QT interval, promotes sleep at lower dose ranges.¹² Potential adverse effects such as daytime drowsiness, confusion, and blurred vision need to be monitored. Although mirtazapine is a serotonergic agent, it has a significantly lower risk of hyponatremia than selective serotonin reuptake inhibitors (SSRIs).

Antipsychotic medications

The typical, or first-generation, antipsychotic agent haloperidol continues to be used in acute, severe cases of delirium-related agitation because of its rapid onset of action and availability in injectable formulations. A potent dopamine (D2) receptor antagonist, haloperidol has a higher risk for extrapyramidal side effects, which is a relevant consideration in elderly patients, specifically in those with parkinsonian syndromes. The risk of QTc prolongation and death is relatively low at the doses given by the oral route, but intravenous doses delivered at 5 to 10 mg are associated with more significant prolongation.¹³

Atypical, or second-generation, antipsychotics have a lower incidence of extrapyramidal side effects than typical antipsychotics, which is their primary advantage. Their primary disadvantage is the increased incidence of metabolic side effects, including weight gain, hyperlipidemia, and hyperglycemia. There is minimal concern for metabolic adverse effects when second-generation antipsychotics are used in delirium management because they are used for a limited time, but careful monitoring is needed for extended use.

The potential for QTc prolongation varies among second-generation antipsychotics^6,8,13,14:

• Ziprasidone is associated with the highest risk of drug-related QTc prolongation among second-generation antipsychotics

• Aripiprazole is associated with the lowest potential for QTc prolongation and is an appropriate choice in patients with documented QTc prolongation but is no longer available in an immediate-release intramuscular formulation

• Quetiapine and risperidone have high QTc-prolonging potential, while olanzapine’s potential is moderate.

Quetiapine, the least likely of the second-generation antipsychotics to have extrapyramidal side effects other than clozapine, is an appropriate choice in patients with parkinsonian syndromes, but is available only in oral formulations.^6,8,13 Olanzapine is available in sublingual and injectable forms and is an appropriate option when the parenteral route is required, but its higher anticholinergic burden should be considered. Risperidone, also only available orally in its immediate-release formulation, is an appropriate agent for delirium-related agitation, though potent alpha-1 blockade can result in orthostasis.¹⁴

Clozapine is associated with numerous side effects, including agranulocytosis, myocarditis, constipation, and lowering of the seizure threshold, and is generally not recommended for treatment of delirium.⁶

Table 1 lists nonantipsychotic and antipsychotic drugs used in managing hyperactive delirium along with the degree of QTc prolongation associated with them.^6,8,11–15

To mitigate critical QT prolongation and related mortality when using antipsychotics in delirium management, the following steps are advised⁶:

• Avoid high doses of medications that prolong the QTc interval

• Monitor QTc-prolonging conditions such as hypokalemia and hypomagnesemia

• Recognize potential pharmacokinetic interactions with other QTc-prolonging drugs

• Use the lowest possible dose for the shortest possible time.

With higher-dose intravenous haloperidol or intramuscular ziprasidone, telemetry and electrocardiograms should be checked before each dose and for several days after discontinuation, especially if the patient needs other potentially QTc-prolonging medications.⁶

Underlying cognitive impairment

The US Food and Drug Administration recently approved brexpiprazole for the treatment of agitation related to Alzheimer dementia. Pimavanserin, a nondopamine blocking agent, is approved for psychosis in Parkinson disease. While Alzheimer dementia and Parkinson disease are commonly associated with comorbid delirium, use of brexpiprazole and pimavanserin for delirium-related agitation remains understudied.¹⁴

There is evidence of benefit for the SSRI citalopram in dementia-related agitation, but use of SSRIs in delirium-related agitation is less well studied. Notably, of the SSRIs, citalopram causes the greatest increase in the QTc interval.^13,16

Research to address uncertainties

Formal studies, including randomized controlled trials, to address specific gaps in the literature would enhance the understanding and management of QTc prolongation and torsade de pointes risks in geriatric patients with delirium-related agitation treated with antipsychotic agents. Long-term outcomes of antipsychotic therapy for delirium-related agitation have not been explored thoroughly. Most studies focus on the short-term effects of antipsychotics on QTc intervals in intensive care unit settings.¹⁰ We lack long-term data on the potential persistence of QTc prolongation and the incidence or recurrence of torsade de pointes after the patient is discharged or stops antipsychotic therapy, but evidence suggests it resolves after offending agents are discontinued.^2,4,9

Published recommendations vary on the frequency and duration of electrocardiogram monitoring in delirious patients treated with antipsychotics, and evidence is lacking to support routine or consistent electrocardiogram monitoring in the absence of risk factors. Stollings et al⁸ suggest that daily QTc monitoring may have limited value for patients in the intensive care setting who have normal baseline QTc and few risk factors, but this may not apply to all geriatric patients who are on multiple medications.

Jenraumjit et al¹⁴ describe problems associated with psychotropic drugs in real-world settings, but more extensive observational studies are needed to capture the full spectrum of drug-related problems such as QTc prolongation and torsade de pointes in diverse clinical settings. Polypharmacy, improper use of antipsychotics, and pharmacodynamic and pharmacokinetic interactions relevant to QTc prolongation require further study.^14,17

Data are limited on the use of pharmacologic options for managing acute agitation or combativeness when there is significant QTc prolongation, but evidence suggests a potential role for nonantipsychotic medications such as clonidine or dexmedetomidine based on individualized patient risk assessment.^13,18

Guidelines and an interdisciplinary approach

Guidelines are needed to help identify vulnerable, medically ill, delirious patients treated with antipsychotics and other agents who have risk factors for QTc prolongation and torsade de pointes. Also, Vieweg et al¹⁹ noted that elderly women are disproportionately affected by QTc prolongation and torsade de pointes, highlighting the need for sex-specific guidelines.

An interdisciplinary approach that involves geriatric medicine and psychiatry is desirable for managing symptoms in these patients. A more robust interdisciplinary approach with assistance from cardiology and pharmacy may improve treatment of hospitalized older adults with hyperactive delirium, particularly those who have cardiac comorbidities, documented QTc prolongation, and complex clinical courses, as well as those at risk for polypharmacy.