Effect of lorazepam with haloperidol vs haloperidol alone on agitated delirium in patients with advanced cancer receiving palliative care: A randomized clinical trial

David Hui, Susan Frisbee-Hume, Annie Wilson, Seyedeh S. Dibaj, Thuc Nguyen, Maxine Grace De La Cruz, Paul W Walker, Donna S Zhukovsky, Marvin Omar Delgado Guay, Marieberta Vidal, Daniel Epner, Akhila S Reddy, Kimberson Cochien Tanco, Janet Williams, Stacy Hall, Diane Liu, Kenneth R Hess, Sapna Amin, William Breitbart, Eduardo Bruera

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Abstract

IMPORTANCE: The use of benzodiazepines to control agitation in delirium in the last days of life is controversial. OBJECTIVE: To compare the effect of lorazepam vs placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium in the setting of advanced cancer. DESIGN, SETTING, AND PARTICIPANTS: Single-center, double-blind, parallel-group, randomized clinical trial conducted at an acute palliative care unit at MD Anderson Cancer Center, Texas, enrolling 93 patients with advanced cancer and agitated delirium despite scheduled haloperidol from February 11, 2014, to June 30, 2016, with data collection completed in October 2016. INTERVENTIONS: Lorazepam (3 mg) intravenously (n = 47) or placebo (n = 43) in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode. MAIN OUTCOMES AND MEASURES: The primary outcome was change in Richmond Agitation-Sedation Scale (RASS) score (range, −5 [unarousable] to 4 [very agitated or combative]) from baseline to 8 hours after treatment administration. Secondary end points were rescue neuroleptic use, delirium recall, comfort (perceived by caregivers and nurses), communication capacity, delirium severity, adverse effects, discharge outcomes, and overall survival. RESULTS: Among 90 randomized patients (mean age, 62 years; women, 42 [47%]), 58 (64%) received the study medication and 52 (90%) completed the trial. Lorazepam + haloperidol resulted in a significantly greater reduction of RASS score at 8 hours (−4.1 points) than placebo + haloperidol (−2.3 points) (mean difference, −1.9 points [95% CI, −2.8 to −0.9]; P < .001). The lorazepam + haloperidol group required less median rescue neuroleptics (2.0 mg) than the placebo + haloperidol group (4.0 mg) (median difference, −1.0 mg [95% CI, −2.0 to 0]; P = .009) and was perceived to be more comfortable by both blinded caregivers and nurses (caregivers: 84% for the lorazepam + haloperidol group vs 37% for the placebo + haloperidol group; mean difference, 47% [95% CI, 14% to 73%], P = .007; nurses: 77% for the lorazepam + haloperidol group vs 30% for the placebo + haloperidol group; mean difference, 47% [95% CI, 17% to 71%], P = .005). No significant between-group differences were found in delirium-related distress and survival. The most common adverse effect was hypokinesia (3 patients in the lorazepam + haloperidol group [19%] and 4 patients in the placebo + haloperidol group [27%]). CONCLUSIONS AND RELEVANCE: In this preliminary trial of hospitalized patients with agitated delirium in the setting of advanced cancer, the addition of lorazepam to haloperidol compared with haloperidol alone resulted in a significantly greater reduction in agitation at 8 hours. Further research is needed to assess generalizability and adverse effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01949662.

Original languageEnglish (US)
Pages (from-to)1047-1056
Number of pages10
JournalJAMA - Journal of the American Medical Association
Volume318
Issue number11
DOIs
StatePublished - Sep 19 2017

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Lorazepam
Delirium
Haloperidol
Palliative Care
Randomized Controlled Trials
Neoplasms
Placebos
Caregivers
Nurses
Antipsychotic Agents
Hypokinesia
Survival
Benzodiazepines

ASJC Scopus subject areas

  • Medicine(all)

Cite this

@article{e5f61fe601d44112a6370a6387adb5d4,
title = "Effect of lorazepam with haloperidol vs haloperidol alone on agitated delirium in patients with advanced cancer receiving palliative care: A randomized clinical trial",
abstract = "IMPORTANCE: The use of benzodiazepines to control agitation in delirium in the last days of life is controversial. OBJECTIVE: To compare the effect of lorazepam vs placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium in the setting of advanced cancer. DESIGN, SETTING, AND PARTICIPANTS: Single-center, double-blind, parallel-group, randomized clinical trial conducted at an acute palliative care unit at MD Anderson Cancer Center, Texas, enrolling 93 patients with advanced cancer and agitated delirium despite scheduled haloperidol from February 11, 2014, to June 30, 2016, with data collection completed in October 2016. INTERVENTIONS: Lorazepam (3 mg) intravenously (n = 47) or placebo (n = 43) in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode. MAIN OUTCOMES AND MEASURES: The primary outcome was change in Richmond Agitation-Sedation Scale (RASS) score (range, −5 [unarousable] to 4 [very agitated or combative]) from baseline to 8 hours after treatment administration. Secondary end points were rescue neuroleptic use, delirium recall, comfort (perceived by caregivers and nurses), communication capacity, delirium severity, adverse effects, discharge outcomes, and overall survival. RESULTS: Among 90 randomized patients (mean age, 62 years; women, 42 [47{\%}]), 58 (64{\%}) received the study medication and 52 (90{\%}) completed the trial. Lorazepam + haloperidol resulted in a significantly greater reduction of RASS score at 8 hours (−4.1 points) than placebo + haloperidol (−2.3 points) (mean difference, −1.9 points [95{\%} CI, −2.8 to −0.9]; P < .001). The lorazepam + haloperidol group required less median rescue neuroleptics (2.0 mg) than the placebo + haloperidol group (4.0 mg) (median difference, −1.0 mg [95{\%} CI, −2.0 to 0]; P = .009) and was perceived to be more comfortable by both blinded caregivers and nurses (caregivers: 84{\%} for the lorazepam + haloperidol group vs 37{\%} for the placebo + haloperidol group; mean difference, 47{\%} [95{\%} CI, 14{\%} to 73{\%}], P = .007; nurses: 77{\%} for the lorazepam + haloperidol group vs 30{\%} for the placebo + haloperidol group; mean difference, 47{\%} [95{\%} CI, 17{\%} to 71{\%}], P = .005). No significant between-group differences were found in delirium-related distress and survival. The most common adverse effect was hypokinesia (3 patients in the lorazepam + haloperidol group [19{\%}] and 4 patients in the placebo + haloperidol group [27{\%}]). CONCLUSIONS AND RELEVANCE: In this preliminary trial of hospitalized patients with agitated delirium in the setting of advanced cancer, the addition of lorazepam to haloperidol compared with haloperidol alone resulted in a significantly greater reduction in agitation at 8 hours. Further research is needed to assess generalizability and adverse effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01949662.",
author = "David Hui and Susan Frisbee-Hume and Annie Wilson and Dibaj, {Seyedeh S.} and Thuc Nguyen and {De La Cruz}, {Maxine Grace} and Walker, {Paul W} and Zhukovsky, {Donna S} and {Delgado Guay}, {Marvin Omar} and Marieberta Vidal and Daniel Epner and Reddy, {Akhila S} and Tanco, {Kimberson Cochien} and Janet Williams and Stacy Hall and Diane Liu and Hess, {Kenneth R} and Sapna Amin and William Breitbart and Eduardo Bruera",
year = "2017",
month = "9",
day = "19",
doi = "10.1001/jama.2017.11468",
language = "English (US)",
volume = "318",
pages = "1047--1056",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "11",

}

TY - JOUR

T1 - Effect of lorazepam with haloperidol vs haloperidol alone on agitated delirium in patients with advanced cancer receiving palliative care

T2 - A randomized clinical trial

AU - Hui, David

AU - Frisbee-Hume, Susan

AU - Wilson, Annie

AU - Dibaj, Seyedeh S.

AU - Nguyen, Thuc

AU - De La Cruz, Maxine Grace

AU - Walker, Paul W

AU - Zhukovsky, Donna S

AU - Delgado Guay, Marvin Omar

AU - Vidal, Marieberta

AU - Epner, Daniel

AU - Reddy, Akhila S

AU - Tanco, Kimberson Cochien

AU - Williams, Janet

AU - Hall, Stacy

AU - Liu, Diane

AU - Hess, Kenneth R

AU - Amin, Sapna

AU - Breitbart, William

AU - Bruera, Eduardo

PY - 2017/9/19

Y1 - 2017/9/19

N2 - IMPORTANCE: The use of benzodiazepines to control agitation in delirium in the last days of life is controversial. OBJECTIVE: To compare the effect of lorazepam vs placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium in the setting of advanced cancer. DESIGN, SETTING, AND PARTICIPANTS: Single-center, double-blind, parallel-group, randomized clinical trial conducted at an acute palliative care unit at MD Anderson Cancer Center, Texas, enrolling 93 patients with advanced cancer and agitated delirium despite scheduled haloperidol from February 11, 2014, to June 30, 2016, with data collection completed in October 2016. INTERVENTIONS: Lorazepam (3 mg) intravenously (n = 47) or placebo (n = 43) in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode. MAIN OUTCOMES AND MEASURES: The primary outcome was change in Richmond Agitation-Sedation Scale (RASS) score (range, −5 [unarousable] to 4 [very agitated or combative]) from baseline to 8 hours after treatment administration. Secondary end points were rescue neuroleptic use, delirium recall, comfort (perceived by caregivers and nurses), communication capacity, delirium severity, adverse effects, discharge outcomes, and overall survival. RESULTS: Among 90 randomized patients (mean age, 62 years; women, 42 [47%]), 58 (64%) received the study medication and 52 (90%) completed the trial. Lorazepam + haloperidol resulted in a significantly greater reduction of RASS score at 8 hours (−4.1 points) than placebo + haloperidol (−2.3 points) (mean difference, −1.9 points [95% CI, −2.8 to −0.9]; P < .001). The lorazepam + haloperidol group required less median rescue neuroleptics (2.0 mg) than the placebo + haloperidol group (4.0 mg) (median difference, −1.0 mg [95% CI, −2.0 to 0]; P = .009) and was perceived to be more comfortable by both blinded caregivers and nurses (caregivers: 84% for the lorazepam + haloperidol group vs 37% for the placebo + haloperidol group; mean difference, 47% [95% CI, 14% to 73%], P = .007; nurses: 77% for the lorazepam + haloperidol group vs 30% for the placebo + haloperidol group; mean difference, 47% [95% CI, 17% to 71%], P = .005). No significant between-group differences were found in delirium-related distress and survival. The most common adverse effect was hypokinesia (3 patients in the lorazepam + haloperidol group [19%] and 4 patients in the placebo + haloperidol group [27%]). CONCLUSIONS AND RELEVANCE: In this preliminary trial of hospitalized patients with agitated delirium in the setting of advanced cancer, the addition of lorazepam to haloperidol compared with haloperidol alone resulted in a significantly greater reduction in agitation at 8 hours. Further research is needed to assess generalizability and adverse effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01949662.

AB - IMPORTANCE: The use of benzodiazepines to control agitation in delirium in the last days of life is controversial. OBJECTIVE: To compare the effect of lorazepam vs placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium in the setting of advanced cancer. DESIGN, SETTING, AND PARTICIPANTS: Single-center, double-blind, parallel-group, randomized clinical trial conducted at an acute palliative care unit at MD Anderson Cancer Center, Texas, enrolling 93 patients with advanced cancer and agitated delirium despite scheduled haloperidol from February 11, 2014, to June 30, 2016, with data collection completed in October 2016. INTERVENTIONS: Lorazepam (3 mg) intravenously (n = 47) or placebo (n = 43) in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode. MAIN OUTCOMES AND MEASURES: The primary outcome was change in Richmond Agitation-Sedation Scale (RASS) score (range, −5 [unarousable] to 4 [very agitated or combative]) from baseline to 8 hours after treatment administration. Secondary end points were rescue neuroleptic use, delirium recall, comfort (perceived by caregivers and nurses), communication capacity, delirium severity, adverse effects, discharge outcomes, and overall survival. RESULTS: Among 90 randomized patients (mean age, 62 years; women, 42 [47%]), 58 (64%) received the study medication and 52 (90%) completed the trial. Lorazepam + haloperidol resulted in a significantly greater reduction of RASS score at 8 hours (−4.1 points) than placebo + haloperidol (−2.3 points) (mean difference, −1.9 points [95% CI, −2.8 to −0.9]; P < .001). The lorazepam + haloperidol group required less median rescue neuroleptics (2.0 mg) than the placebo + haloperidol group (4.0 mg) (median difference, −1.0 mg [95% CI, −2.0 to 0]; P = .009) and was perceived to be more comfortable by both blinded caregivers and nurses (caregivers: 84% for the lorazepam + haloperidol group vs 37% for the placebo + haloperidol group; mean difference, 47% [95% CI, 14% to 73%], P = .007; nurses: 77% for the lorazepam + haloperidol group vs 30% for the placebo + haloperidol group; mean difference, 47% [95% CI, 17% to 71%], P = .005). No significant between-group differences were found in delirium-related distress and survival. The most common adverse effect was hypokinesia (3 patients in the lorazepam + haloperidol group [19%] and 4 patients in the placebo + haloperidol group [27%]). CONCLUSIONS AND RELEVANCE: In this preliminary trial of hospitalized patients with agitated delirium in the setting of advanced cancer, the addition of lorazepam to haloperidol compared with haloperidol alone resulted in a significantly greater reduction in agitation at 8 hours. Further research is needed to assess generalizability and adverse effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01949662.

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