Meera R Agar1, Peter G Lawlor2, Stephen Quinn3, Brian Draper4, Gideon A Caplan5, Debra Rowett6, Christine Sanderson7, Janet Hardy8, Brian Le9, Simon Eckermann10, Nicola McCaffrey11, Linda Devilee12, Belinda Fazekas12, Mark Hill13, David C Currow12. 1. 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. 2. 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. 3. School of Medicine, Flinders University, Repatriation General Hospital, Daw Park, South Australia, Australia. 4. School of Psychiatry, University of New South Wales, Randwick, Australia. 5. Prince of Wales Clinical School, University of New South Wales, Randwick, New South Wales, Australia. 6. Drug and Therapeutics Information Service, Repatriation General Hospital, Daw Park, South Australia, Australia. 7. 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. 8. Palliative and Supportive Care, Mater Hospital, Raymond Terrace, Brisbane, Queensland, Australia. 9. Department of Palliative Care, Royal Melbourne Hospital, Parkville, Victoria, Australia. 10. Australian Health Services Research Institute, University of Wollongong, Wollongong, New South Wales, Australia. 11. Discipline, Palliative and Supportive Services, Flinders University, Daw Park, South Australia, Australia8School of Medicine, Flinders University, Repatriation General Hospital, Daw Park, South Australia, Australia. 12. Discipline, Palliative and Supportive Services, Flinders University, Daw Park, South Australia, Australia. 13. Faculty of Medicine, University of New South Wales, Randwick, New South Wales, Australia.
Abstract
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. Design, Setting, and 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: anzctr.org.au Identifier: ACTRN12607000562471.
RCT Entities:
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. Design, Setting, and 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: anzctr.org.au Identifier: ACTRN12607000562471.
Authors: Richard A Taylor; Cardinale B Smith; Heather Coats; Laura P Gelfman; J Nicholas Dionne-Odom Journal: J Palliat Med Date: 2017-09-28 Impact factor: 2.947
Authors: Maurice J D L van der Vorst; Elisabeth C W Neefjes; Manon S A Boddaert; Bea A T T Verdegaal; Aart Beeker; Saskia C C Teunissen; Aartjan T F Beekman; Janneke A Wilschut; Johannes Berkhof; Wouter W A Zuurmond; Henk M W Verheul Journal: Oncologist Date: 2019-12-04
Authors: Matthew Basciotta; Wenxiao Zhou; Long Ngo; Michael Donnino; Edward R Marcantonio; Shoshana J Herzig Journal: J Am Geriatr Soc Date: 2019-11-19 Impact factor: 5.562