Original Article|Articles in Press

Visualizing How to Use Antipsychotics for Agitated Delirium in the Last Days of Life



      How physicians use antipsychotics for agitated delirium in the last days of life varies markedly, which could hamper the quality of care.


      To examine adherence to an algorithm-based treatment for terminal agitated delirium, and explore its effectiveness and safety.


      A single-center, prospective, observational study was conducted in a 27-bed palliative care unit in Japan. All adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS) of +1 or more were included; the palliative care specialists determined that the etiology was irreversible, the estimated survival was three weeks or less, and the Eastern Cooperative Oncology Group (ECOG) performance status was three or four. Patients were treated with an algorithm to visualize how to use antipsychotics, with the treatment goal defined as no agitation (RASS≤0) or acceptable agitation for patients and families. We provided all patients nonpharmacological management to alleviate the symptoms of delirium and administered antipsychotic medications when the nonpharmacological approach was insufficient. We measured the adherence rate, RASS, Nursing Delirium Screening Scale items 2, 3, 4 (Nu-DESC), and Agitation Distress Scale item 2 (ADS) on days 0, 1, 3, 7, 14, 21, and 24 hours before death.


      A total of 164 patients were enrolled. Adherence rates were 99, 94, and 89%, and treatment goals were achieved in 66, 83, and 93% on days one, three, and seven, respectively. The mean RASS decreased from +1.41 to –0.84 on day three; Nu-DESC decreased from 4.19 to 1.83, and ADS decreased from 1.54 to 0.38. There were seven severe adverse events (Common Terminology Criteria for Adverse Events (CTCAE) of 3), including aspiration (n = 3), apnea (n = 2), tremor (n = 1), and muscle rigidity (n = 1) on day three.


      The algorithm-based treatment could be feasible, effective, and safe. Visualizing how palliative care specialists provide pharmacological management could be beneficial for nonspecialist clinicians, and clinical, educational, and research implications warrant further empirical testing.

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        • Bramati P
        • Bruera E.
        Delirium in palliative care.
        Cancers (Basel). 2021; 13: 5893
        • Agar M
        • Bush SH.
        Delirium at the end of life.
        Med Clin North Am. 2020; 104: 491-501
        • Finucane AM
        • Jones L
        • Leurent B
        • et al.
        Drug therapy for delirium in terminally ill adults.
        Cochrane Database Syst Rev. 2020; 1CD004770
        • Hosker CM
        • Bennett MI.
        Delirium and agitation at the end of life.
        BMJ. 2016; 353: i3085
        • Bruera E
        • Bush SH
        • Willey J
        • et al.
        Impact of delirium and recall on the level of distress in patients with advanced Cancer and their family caregivers.
        Cancer. 2009; 115: 2004-2012
        • Breitbart W
        • Gibson C
        • Tremblay A.
        The delirium experience: delirium recall and delirium-related distress in hospitalized patients with Cancer, their spouse/caregivers, and their nurses.
        Psychosomatics. 2002; 43: 183-194
        • Morita T
        • Hirai K
        • Sakaguchi Y
        • et al.
        Family-perceived distress from delirium-related symptoms of terminally ill Cancer patients.
        Psychosomatics. 2004; 45: 107-113
        • Hatano Y
        • Morita T
        • Mori M
        • et al.
        Association between experiences of advanced Cancer patients at the end of life and depression in their bereaved caregivers.
        Psychooncology. 2022; 31 (Online ahead of print): 1243-1252
        • Beller EM
        • van Driel ML
        • McGregor L
        • Truong S
        • Mitchell G.
        Palliative pharmacological sedation for terminally ill adults.
        Cochrane Database Syst Rev. 2015; 1CD010206
        • Bush SH
        • Lawlor PG
        • Ryan K
        • et al.
        Delirium in adult Cancer patients: ESMO Clinical Practice Guidelines.
        Ann Oncol. 2018; 29: iv143-iv165
      1. National Comprehensive Cancer Network NCCN Guidelines Palliative Care. Available at: Accessed October 11, 2022.

        • 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; 177: 34-42
        • Hui D
        • Frisbee-Hume S
        • Wilson A
        • et al.
        Effect of lorazepam with haloperidol vs haloperidol alone on agitated delirium in patients with advanced Cancer receiving palliative care: a Randomized Clinical Trial.
        JAMA. 2017; 318: 1047-1056
        • Hui D
        • De La Rosa A
        • Wilson A
        • et al.
        Neuroleptic strategies for terminal agitation in patients with cancer and delirium at an acute palliative care unit: a single-centre, double-blind, parallel-group, Randomised Trial.
        Lancet Oncol. 2020; 21: 989-998
        • Tang M
        • Chen M
        • Bruera E
        • Hui D.
        Association among rescue neuroleptic use, agitation, and perceived comfort: secondary analysis of a Randomized Clinical Trial on Agitated Delirium.
        Support Care Cancer. 2021; 29: 7887-7894
        • Mori M
        • Kawaguchi T
        • Imai K
        • et al.
        Visualizing how to use parenteral opioids for terminal Cancer Dyspnea: a pilot, multicenter, prospective, observational study.
        J Pain Symptom Manage. 2021; 62: 936-948
        • Imai K
        • Morita T
        • Yokomichi N
        • et al.
        Efficacy of proportional sedation and deep sedation defined by sedation protocols: a multicenter, prospective, observational comparative study.
        J Pain Symptom Manage. 2021; 62: 1165-1174
        • Benítez-Rosario MA
        • Castillo-Padrós M
        • Garrido-Bernet B
        • et al.
        Appropriateness and reliability testing of the modified Richmond Agitation-Sedation Scale in Spanish patients with advanced Cancer.
        J Pain Symptom Manage. 2013; 45: 1112-1119
        • Imai K
        • Morita T
        • Mori M
        • et al.
        Development and linguistic validation of the Japanese version of the modified Richmond Agitation-Sedation Scale.
        Palliat Care Res. 2016; 11 (in Japanese): 331-336
        • Mori M
        • Morita T
        • Matsuda Y
        • et al.
        How successful are we in relieving terminal dyspnea in Cancer patients? A real-world multicenter prospective observational study.
        Supportive Care Cancer. 2020; 28: 3051-3060
        • Uchida M
        • Morita T
        • Akechi T
        • et al.
        Are common delirium assessment tools appropriate for evaluating delirium at the end of life in Cancer patients?.
        Psychooncology. 2020; 29: 1842-1849
        • Hui D
        • De La Rosa A
        • Urbauer DL
        • Nguyen T
        • Bruera E.
        Personalized sedation goal for agitated delirium in patients with cancer: Balancing comfort and communication.
        Cancer. 2021; 127: 4694-4701
        • Morita T
        • Akechi T
        • Ikenaga M
        • et al.
        Terminal delirium: recommendations from bereaved families' experiences.
        J Pain Symptom Manage. 2007; 34: 579-589
        • Morita T
        • Tsunoda J
        • Inoue S
        • et al.
        Communication capacity scale and agitation distress scale to measure the severity of delirium in terminally ill Cancer patients: a validation study.
        Palliat Med. 2001; 15: 197-206
        • Maeda I
        • Ogawa A
        • Yoshiuchi K
        • et al.
        Safety and effectiveness of antipsychotic medication for delirium in patients with advanced Cancer: a large-scale multicenter prospective observational study in real-world palliative care settings.
        Gen Hosp Psychiatry. 2020; 67: 35-41
        • Gaudreau JD
        • Gagnon P
        • Harel F
        • Tremblay A
        • Roy MA.
        Fast, systematic, and continuous delirium assessment in hospitalized patients: the nursing delirium screening scale.
        J Pain Symptom Manage. 2005; 29: 368-375
      2. National Cancer Institute. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events v5.0. Available at: Accessed September 23, 2022.

        • Matsuoka H
        • Agar M
        • Vandersman Z
        • et al.
        Harms from Haloperidol for symptom management in palliative care-a post hoc pooled analysis of three randomized controlled studies and two consecutive Cohort Studies.
        J Pain Symptom Manage. 2019; 58: e6-e8
        • Crawford G
        • Agar M
        • Quinn S
        • et al.
        Pharmacovigilance in hospice/palliative care: net effect of haloperidol for delirium.
        J Palliat Med. 2013; 16: 1335-13341
        • Yamashita R
        • Arao H
        • Takao A
        • et al.
        Unfinished business in families of terminally Ill with Cancer patients.
        J Pain Symptom Manage. 2017; 54: 861-869
        • Steinhauser KE
        • Clipp EC
        • McNeilly M
        • et al.
        In search of a good death: observations of patients, families, and providers.
        Ann Intern Med. 2000; 132: 825-832
        • Miyashita M
        • Sanjo M
        • Morita T
        • Hirai K
        • Uchitomi Y
        Good death in Cancer care: a nationwide quantitative study.
        Ann Oncol. 2007; 18: 1090-1097