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Lorazepam and other benzodiazepines are typically avoided when managing end-of-life agitated delirium in patients with cancer because these drugs can precipitate, even worsen, delirium.

But a new multicenter trial found that patients with advanced cancer and delirium experienced greater reductions in agitation and restlessness at the end-of-life when given lorazepam compared with the more frequently used haloperidol.

“Lorazepam-based regimens were found to be more efficacious than haloperidol alone or placebo in reducing agitation and restlessness in patients who were admitted to the palliative care unit with persistent agitated delirium,” said study lead author David Hui, MD, professor of palliative, rehabilitation and integrative medicine at the University of Texas MD Anderson Cancer Center, Houston.

Delirium — a serious change in mental abilities that leads to confused thinking and a lack of awareness — affects more than 90% of patients in their last days or weeks of life, with up to 70% of these patients developing restlessness, agitation, or both. Although a common issue at the end-of-life, delirium often goes underrecognized and there are no guidelines for treating it.

The current analysis found that patients with advanced cancer and delirium who received lorazepam or a combination of haloperidol and lorazepam had lower Richmond Agitation-Sedation Scale (RASS) scores than those given haloperidol alone and required rescue medications less frequently to control breakthrough restlessness or agitation.

Although lorazepam-based regimens led to better symptom control in this patient population, the findings don’t necessarily mean that all should receive a benzodiazepine, Hui told Medscape Medical News.

Managing delirium requires achieving a delicate balance between lowering the symptoms and preserving patients’ alertness.

These final days are “one of the most precious times for families to interact with the patients,” Hui explained, and these new data can help oncologists and families “develop a personalized approach to the best management of delirium for a specific patient.”

Treating End-of-Life Delirium: The Data 

Hui and his colleagues conducted the current study to better understand the risks and benefits of using neuroleptic or benzodiazepine agents to control restlessness and agitation intensity in patients with cancer and delirium receiving palliative care.

The study included patients aged 18 years or older with an advanced cancer diagnosis who had been admitted to an acute palliative care unit in Taiwan or the US from July 2019 to June 2023. Patients had delirium, a history of hyperactivity, and were taking standard-dose haloperidol (< 8 mg/d) or required 4 mg/d or more of rescue haloperidol for agitation in the past 24 hours.

Overall, 72 patients were randomized to one of four groups — scheduled haloperidol with dose escalation (12 mg/d), lorazepam alone, lorazepam plus haloperidol, and placebo on restlessness and agitation intensity in the advanced cancer patients. “For ethical reasons,” the authors said, the placebo group received lorazepam as a rescue medication.

The primary outcome was change in RASS score during the first 24 hours of treatment, though patients were followed for 30 days after medication administration. RASS scores spanned a 10-point scale, ranging from -5 to 4, with -5 representing deeply sedated or unarousable and 4 being combative.

At enrollment, all patients started taking 2 mg of haloperidol intravenously every 6 hours and 2 mg intravenously every hour as needed. Patients were monitored until they reached an RASS score of at least 1, at which time researchers switched to the blinded phase in which patients were randomized to their scheduled medication every 4 hours, plus a rescue medication every hour as needed.

RASS scores were initially similar in the four groups: 1.7 for haloperidol, 1.6 for lorazepam alone, 1.3 for lorazepam plus haloperidol, and 1.6 for placebo.

Within the first hour, RASS scores decreased significantly in all four groups, with the lowest scores in the two lorazepam groups.

The mean RASS change at 24 hours was -2.3 for the haloperidol alone group, -4.5 for the lorazepam group, -4.3 for the combination group, and -2.8 for the placebo group.

Compared with patients in the haloperidol group, those in the lorazepam and combination group had significantly lower RASS scores, with a mean difference of about -2.

The difference in RASS scores between the haloperidol and placebo groups was not significant (-0.5; 95% CI, -1.7 to 0.7), nor was the difference between the combination and lorazepam groups (0.2; 95% CI, -1.1 to 1.4).

The combination and lorazepam groups needed significantly fewer rescue medications for breakthrough restlessness or agitation (32% and 37%, respectively) than the haloperidol and placebo groups (56% and 83%, respectively).

Hiu and colleagues also noted no differences in survival or adverse events between the groups.

“Taken together, these study findings highlight three options with light (haloperidol), moderate (lorazepam), and heavy (combination) sedation for persistent restlessness and agitation in the end-of-life setting,” the authors wrote.

Perspectives: Striking a Balance

Thomas B. Strouse, MD, who was not involved in the study, explained that overall “most practitioners would agree that combining a sedative-hypnotic like lorazepam or midazolam with an antipsychotic like haloperidol or olanzapine are reasonable strategies” for treating agitated delirium in the last days of life for someone with advanced cancer.

Strouse, David Geffen School of Medicine, UCLA, explained that he and many colleagues often use antipsychotic agents other than haloperidol, such as olanzapine or quetiapine, which he said are more sedating with generally fewer side effects, particularly akathisia or motor restlessness that “can sometimes be hard to distinguish from the agitated delirium one is trying to reduce.”

In an invited commentary, palliative care experts Justin J. Sanders, MD, MSc, and James Downar, MDCM, MHSc, highlighted important questions raised by the trial.

Notably, the goal of managing agitated delirium is not typically about lowering RASS as much as possible but rather about achieving a mid-range of 0 to -2 where patients are calm but not over-sedated. However, most patients in the lorazepam groups achieved a mean RASS score below that target, meaning these patients were more heavily sedated, Sanders, of McGill University, Montreal, Quebec, Canada, and Downar, of the University of Ottawa, Ottawa, Ontario, Canada, explained.

When managing delirium, there is often a trade-off between managing the agitated delirium and keeping patients aware and conscious enough to continue communicating, Sanders explained in an interview with Medscape Medical News.

Sanders discusses this trade-off with patients and families, telling them that “we have medications that can treat the delirium, but it will come at the expense of alertness.” He then works with families to help make the best decisions based on their values.

Overall, Sanders called this study “an extraordinary trial in our field,” citing its level of complexity, including the contributions from patients and families.

In a comment reacting to the study, Hiroyuki Otani, MD, of Kyushu Cancer Center in Fukuoka, Japan, agreed and elaborated on ambiguity of these end-of-life decisions.

“Deep sedation occupies a complex emotional and ethical space,” Otani wrote. “While it may relieve visible distress, it may also preclude final opportunities for expression — a glance, a whispered farewell, a final touch.”

The trial, Otani concluded, “calls us to reimagine sedation not merely as symptom control but as a final act of care — where relief, reverence, and relational presence converge at the threshold of life’s end.”

Hui, Sanders, Strouse, and Otani had no disclosures.