September 2016, Vol. 5, No. 7

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Delirium Symptoms More Severe in Patients Treated with Antipsychotics


Adult hospice and palliative care patients with hyperactive delirium symptoms who were given risperidone or haloperidol experienced greater delirium symptoms at 72 hours than those given placebo, according to new research presented by Meera Agar, MD, at the 2016 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology Annual Meeting on Supportive Care in Cancer.

The study tested antipsychotics for the treatment of delirium, which is an off-label use for these drugs.

Effective Strategies for Delirium Management

According to Dr Agar, Professor of Palliative Medicine at the University of Technology Sydney, Australia, effective strategies for managing delirium include a combination of targeted risk factor management and early recognition of delirium and its underlying precipitants.

“Even in advanced cancer and palliative care, detecting delirium early and treating precipitants in a timely fashion can reverse delirium in up to half of patients,” said Dr Agar, whose main research interest lies in the supportive care needs of people suffering from advanced brain illnesses.

Current Evidence and Practice for Antipsychotics

The current level of evidence for antipsychotics includes several randomized controlled studies comparing antipsychotics and a number of open-label, single-arm studies that did demonstrate a reduction in delirium scores, she reported. “But these studies can’t account for the natural history of delirium resolution as you treat the underlying precipitants,” she said.

Prior placebo-controlled trials outside the intensive care unit (ICU) have been underpowered, have not assessed symptom control, and/or were inadequately blinded. Inside the ICU, placebo-controlled trials have not shown an increase in delirium- or coma-free days, she added.

There is currently no drug approved or registered for the management of delirium, either by the FDA or by similar international bodies. According to Dr Agar, the current guidelines recommend the targeted use of antipsychotics for specific symptoms, but this approach has not been evaluated in randomized trials. The clinical issues around the correct use of antipsychotics for delirium led Dr Agar and her colleagues to conduct a placebo-controlled trial.

Study Design

The study aimed to determine if risperidone or haloperidol, when given in addition to managing precipitants of delirium and providing individualized supportive nursing care, would provide additional benefits in reducing hyperactive delirium symptoms when compared with placebo.

The study population included adult hospice/palliative care patients receiving inpatient care with incident or prevalent delirium who were able to swallow an oral liquid. Hyperactive delirium symptoms were measured with the Nursing Delirium Screening Scale (Nu-DESC).

A total of 247 patients were randomized 1:1:1 to oral risperidone solution (n = 82), oral haloperidol solution (n = 81), or oral placebo solution (n = 84) every 12 hours. Dosing was titrated to effect based on a dosing algorithm, and the primary outcome was change in mean delirium symptom score (Nu-DESC items 2, 3, and 4) between baseline and follow-up.

Participants ≤65 years of age received a loading dose (0.5 mg) with the first dose of 0.5 mg, then a maintenance dose of 0.5 mg every 12 hours. For participants >65 years, loading, initial, and maximum doses were halved.

“After much deliberation by the study team, it was decided to pursue a rescue protocol,” said Dr Agar. Rescue midazolam 2.5 mg was available for safety and distress, with very specific criteria for its use.

“This was an older group with mild to moderate delirium symptoms. A reasonable proportion had prior cognitive impairment, and opioid and benzodiazepine doses which were not out of keeping with the palliative care population,” she said. “These were people who were not completely bedbound, but were getting close to being there.”

Greater Delirium Symptoms with Risperidone and Haloperidol

In primary intention-to-treat analyses, those in the risperidone and haloperidol groups experienced greater delirium symptoms at 72 hours than those in the placebo group (risperidone 0.48 units higher on average, P = .016; haloperidol 0.24 units higher on average, P = .009). This was maintained after adjusting for the baseline covariates of prior cognitive impairment, comorbidity, vision/hearing impairment, daily oral morphine and diazepam equivalents, and performance status.

A total of 34 participants (13.7%) died during the study period: 16 in the risperidone arm, 9 in the haloperidol arm, and 9 in the placebo arm. No serious toxicities were observed in patients on either treatment drug, but midazolam use was significantly lower in the placebo arm compared with the other arms on each study day (13.6% vs 29.6% use on day 3; P = .016).

The researchers observed that behavioral, communication, and perceptual symptoms were greater in people treated with antipsychotics than with placebo. Based on these data, they suggest the use of measures for the early identification of delirium and its underlying precipitants.

Dr Agar also emphasized the importance of informing families and giving them the tools to advocate for care, since the care given in trials is often much better than what is achieved outside the trial context. “By doing a trial in this setting, we learned that we had to talk to our patients, our clinicians, and our interdisciplinary team about what delirium was and how to inform patients and families about what delirium care should look like,” she said. “I think families engaged in that process were able to advocate for care.”


Agar M, Lawlor P, Quinn S, et al. Phase III randomized double-blind controlled trial of oral risperidone, haloperidol or placebo with rescue subcutaneous midazolam for delirium management in palliative care. Presented at: MASCC/ISOO Annual Meeting on Supportive Care in Cancer; June 23-25, 2016; Adelaide, Australia. Abstract PS093.
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