Effect of Lorazepam With Haloperidol vs Haloperidol Alone on Agitated Delirium in Patients With Advanced Cancer Receiving Palliative Care

Abstract

IMPORTANCEThe 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 RELEVANCEIn 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.

Olanzapine Versus Haloperidol for Treatment of Delirium in Patients with Advanced Cancer: A Phase III Randomized Clinical Trial

“…The 2018 European Society for Medical Oncology clinical practice guideline on delirium in adult cancer patients identified 15 studies, including three RCTs . Kim et al ( n = 32; 72% with a cancer diagnosis) compared risperidone with olanzapine over a 7‐day period .…”

“…There was no significant difference in either efficacy or adverse effects in this underpowered study. The second study by Hui et al ( n = 90; 100% with a cancer diagnosis) was a single‐center, double‐blind, parallel group RCT conducted in adult patients with advanced cancer, comparing the effect of lorazepam versus placebo as an adjuvant to haloperidol for persistent agitation (Richmond Agitation‐Sedation Scale [RASS] score of ≥ + 2) in patients with delirium (DSM‐IV‐TR criteria) . This study was designed to assess a different primary research objective than our RCT.…”

How far along the disease trajectory? An examination of the time-related patient characteristics in the palliative oncology literature

“…[31] However, our experience conducting studies in this population suggests that many patients and families were still willing to participate in clinical trials because they recognize the meaning in helping others through research. [32] In the last days to weeks of life, assessment of patient-reported outcome is particularly challenging, and clinicians often have to rely on surrogate reporting or clinician impression which may not be well validated. Because patients in the last weeks and days of life often experience significant distress and have unique care needs (e.g.…”

Geriatrics Literature 2017 Year in Review

“…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 …”

“…Hyperactive Delirium Near the End of Life, Lorazepam Plus Haloperidol Results in Greater Sedation than Haloperidol Alone 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 16. …”