title: Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial.
abstract: Antipsychotics are widely used for distressing symptoms of delirium, but efficacy has not been established in placebo-controlled trials in palliative care.
  
  
  
  To determine efficacy of risperidone or haloperidol relative to placebo in relieving target symptoms of delirium associated with distress among patients receiving palliative care.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  anzctr.org.au Identifier: ACTRN12607000562471.
authors.affiliation: Discipline, Palliative and Supportive Services, Flinders University, Daw Park, South Australia, Australia2Centre for Cardiovascular and Chronic Care, Faculty of Health, University of Technology Sydney, Ultimo, New South Wales, Australia3South West Sydney Clinical School, University of New South Wales, Liverpool, New South Wales, Australia4Clinical Trials, Ingham Institute of Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: Meera R
authors.initials: MR
authors.lastname: Agar
authors.affiliation: Division of Palliative Care, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada6Clinical Epidemiology, The Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada7Division of Palliative Care, Bruyere Research Institute, Bruyere Continuing Care, Ottawa, Ontario, Canada.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Lawlor
authors.affiliation: School of Medicine, Flinders University, Repatriation General Hospital, Daw Park, South Australia, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Quinn
authors.affiliation: School of Psychiatry, University of New South Wales, Randwick, Australia.
authors.forename: Brian
authors.initials: B
authors.lastname: Draper
authors.affiliation: Prince of Wales Clinical School, University of New South Wales, Randwick, New South Wales, Australia.
authors.forename: Gideon A
authors.initials: GA
authors.lastname: Caplan
authors.affiliation: Drug and Therapeutics Information Service, Repatriation General Hospital, Daw Park, South Australia, Australia.
authors.forename: Debra
authors.initials: D
authors.lastname: Rowett
authors.affiliation: Department of Palliative Care, Calvary Health Care Kogarah, Kogarah, New South Wales, Australia 13School of Medicine, University of Notre Dame Australia, Darlinghurst, New South Wales, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Sanderson
authors.affiliation: Palliative and Supportive Care, Mater Hospital, Raymond Terrace, Brisbane, Queensland, Australia.
authors.forename: Janet
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Department of Palliative Care, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Brian
authors.initials: B
authors.lastname: Le
authors.affiliation: Australian Health Services Research Institute, University of Wollongong, Wollongong, New South Wales, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Eckermann
authors.affiliation: Discipline, Palliative and Supportive Services, Flinders University, Daw Park, South Australia, Australia8School of Medicine, Flinders University, Repatriation General Hospital, Daw Park, South Australia, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: McCaffrey
authors.affiliation: Discipline, Palliative and Supportive Services, Flinders University, Daw Park, South Australia, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Devilee
authors.affiliation: Discipline, Palliative and Supportive Services, Flinders University, Daw Park, South Australia, Australia.
authors.forename: Belinda
authors.initials: B
authors.lastname: Fazekas
authors.affiliation: Faculty of Medicine, University of New South Wales, Randwick, New South Wales, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Hill
authors.affiliation: Discipline, Palliative and Supportive Services, Flinders University, Daw Park, South Australia, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Currow
mesh_terms: D000284:Administration, Oral; D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D001315:Australia; D003693:Delirium / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D015577:Geriatric Assessment; D006220:Haloperidol / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D010166:Palliative Care / Q000379:methods*; D010919:Placebos; D018967:Risperidone / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D010919:Placebos; D006220:Haloperidol; D018967:Risperidone