Agar MR, Lawlor PG, Quinn S, et al.   Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial.
JAMA Intern Med. 2017 Jan 1;177(1):34-42. doi: 10.1001/jamainternmed.2016.7491.   (Original Study)   PMID: 27918778
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Clinical Evidence Topic:
Delirium at the end of life
Physician Disciplines Relevance to practice Is this news?
Hospital Doctor/Hospitalists
Internal Medicine
Oncology - Palliative and Supportive Care
General Internal Medicine-Primary Care(US)
General Practice(GP)/Family Practice(FP)
Special Interest - Pain -- Physician

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Importance: Antipsychotics are widely used for distressing symptoms of delirium, but efficacy has not been established in placebo-controlled trials in palliative care.
OBJECTIVE: To determine efficacy of risperidone or haloperidol relative to placebo in relieving target symptoms of delirium associated with distress among patients receiving palliative care.
PARTICIPANTS: A double-blind, parallel-arm, dose-titrated randomized clinical trial was conducted at 11 Australian inpatient hospice or hospital palliative care services between August 13, 2008, and April 2, 2014, among participants with life-limiting illness, delirium, and a delirium symptoms score (sum of Nursing Delirium Screening Scale behavioral, communication, and perceptual items) of 1 or more.
INTERVENTIONS: Age-adjusted titrated doses of oral risperidone, haloperidol, or placebo solution were administered every 12 hours for 72 hours, based on symptoms of delirium. Patients also received supportive care, individualized treatment of delirium precipitants, and subcutaneous midazolam hydrochloride as required for severe distress or safety. Main Outcome and Measures: Improvement in mean group difference of delirium symptom score (severity range, 0-6) between baseline and day 3. Five a priori secondary
OUTCOMES: delirium severity, midazolam use, extrapyramidal effects, sedation, and survival.
RESULTS: Two hundred forty-seven participants (mean [SD] age, 74.9 [9.8] years; 85 women [34.4%]; 218 with cancer [88.3%]) were included in intention-to-treat analysis (82 receiving risperidone, 81 receiving haloperidol, and 84 receiving placebo). In the primary intention-to-treat analysis, participants in the risperidone arm had delirium symptom scores that were significantly higher than those among participants in the placebo arm (on average 0.48 Units higher; 95% CI, 0.09-0.86; P = .02) at study end. Similarly, for those in the haloperidol arm, delirium symptom scores were on average 0.24 Units higher (95% CI, 0.06-0.42; P = .009) than in the placebo arm. Compared with placebo, patients in both active arms had more extrapyramidal effects (risperidone, 0.73; 95% CI, 0.09-1.37; P = .03; and haloperidol, 0.79; 95% CI, 0.17-1.41; P = .01). Participants in the placebo group had better overall survival than those receiving haloperidol (hazard ratio, 1.73; 95% CI, 1.20-2.50; P = .003), but this was not significant for placebo vs risperidone (hazard ratio, 1.29; 95% CI, 0.91-1.84; P = .14). Conclusions and Relevance: In patients receiving palliative care, individualized management of delirium precipitants and supportive strategies result in lower scores and shorter duration of target distressing delirium symptoms than when risperidone or haloperidol are added.
TRIAL REGISTRATION(S): Identifier: ACTRN12607000562471.

Comments from Clinical Raters
General Internal Medicine-Primary Care(US)
Very nice study addressing the issue of managing delirium. The authors did a great job in teasing out the efficacy of the antipsychotic drugs in this setting. This emphasizes that conservative management is the first-line treatment for delirium in a terminal setting.
Hospital Doctor/Hospitalists
A very helpful RCT that will hopefully curb a previous non-evidence-based approach to delirium in palliative patients.
Hospital Doctor/Hospitalists
For hospitalists like me that frequently care for patients at the end of life, terminal delirium is one of the more difficult things we deal with, and is frustrating to both patients and families. I can also say that when I am in the position of treating terminal delirium, I frequently turn to antipsychotics. This trial was a game-changer for me. The fact that placebo beat both haloperidol and risperidone tells me that this is the wrong direction.
Oncology - Palliative and Supportive Care
This study has very high clinical meaning and impact for daily practice since such issues are commonly encountered without evidence-based treatments. The study result may provide a guideline for future care of the delirium in palliative care.
Oncology - Palliative and Supportive Care
Wow, not the expected result. This is important information because we believe we treat delirium with these antipsychotics and worry less about survival implications in a palliative care population. From a well-blinded RCT, we can now see that we are not helping increase comfort in the dying population with these 2 medicines.
Special Interest - Pain -- Physician
This article should begin to force palliative care doctors to change their practice. While these patients are slightly sicker than those in some of our practices, it is an important and very well done trial. The outcomes are clinically relevant and well collected.