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.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Figures

Figure 1. Flow of Patients Through the Study

At the time of enrollment, patients were randomized to lorazepam or placebo. All enrolled patients immediately began a standardized regimen with haloperidol 2 mg every 4 hours intravenously and 2 mg every hour as needed for agitation. Because of the fluctuating nature of delirium, the Richmond Agitation-Sedation Scale score of each patient was monitored every 2 hours until the patient’s score was 1 or more and required rescue medication per the judgment of the bedside nurse. Once the dose of haloperidol was increased and standardized, 27 of 90 randomized patients (30%) did not develop further agitation until death or discharge and thus did not require the study medication.

Figure 2. Change in Richmond Agitation-Sedation Scale (RASS) Over the First 8 Hours After Treatment

A, Time 0 indicates immediately before treatment administration. Error bars indicate 95% CIs. Both treatments were associated with significant reduction in the mean RASS score within the first 30 minutes of treatment. RASS score remained relatively stable for both groups over the 8-hour observation period. Lorazepam + haloperidol was associated with a significantly greater reduction in RASS score than placebo + haloperidol at 8 hours (P < .001, 2-sided Wilcoxon rank sum test). B, A larger proportion of patients had hyperactivity (RASS score, 1 to 4) in the placebo + haloperidol group at both 30 minutes and 8 hours (P = .001 for both time points). In contrast, a larger proportion of patients had sedation in the lorazepam group (RASS score, −3 to −5). The 2-sided Fisher exact test was used to compare the 3 categories of RASS scores between groups.