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Preliminary Communication
September 19, 2017

Effect of Lorazepam With Haloperidol vs Haloperidol Alone on Agitated Delirium in Patients With Advanced Cancer Receiving Palliative CareA Randomized Clinical Trial

Author Affiliations
  • 1Department of Palliative Care, Rehabilitation and Integrative Medicine, MD Anderson Cancer Center, Houston, Texas
  • 2Department of Biostatistics, MD Anderson Cancer Center, Houston, Texas
  • 4Department of Investigational Pharmacy, MD Anderson Cancer Center, Houston, Texas
  • 5Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, New York
JAMA. 2017;318(11):1047-1056. doi:10.1001/jama.2017.11468
Key Points

Question  Is the combination of lorazepam + haloperidol superior to placebo + haloperidol in the treatment of persistent agitation in patients with delirium and advanced cancer?

Findings  In this randomized trial of 58 patients, the addition of lorazepam to haloperidol compared with haloperidol alone resulted in a significantly greater reduction in agitation at 8 hours (−4.1 vs −2.3 points on the 10-point Richmond Agitation Sedation Scale).

Meaning  The addition of lorazepam to haloperidol may provide superior control of agitation in patients with persistent delirium.

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

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