In a small single-center randomized trial reported in The Lancet Oncology, David Hui, MD, MS, MSc, and colleagues found that increasing haloperidol dose, rotating to chlorpromazine, and combining haloperidol and chlorpromazine each appeared to improve refractory agitation in patients with terminal delirium.
David Hui, MD, MS, MSc
Study Details
The double-blind trial included 45 patients with refractory agitation, despite treatment with low-dose haloperidol, at the palliative and supportive care unit at The University of Texas MD Anderson Cancer Center. Patients were randomly assigned between July 2017 and July 2019 to receive intravenous haloperidol dose escalation at 2 mg every 4 hours (n = 15), neuroleptic rotation with chlorpromazine at 25 mg every 4 hours (n = 16), or combined haloperidol at 1 mg and chlorpromazine at 12.5 mg every 4 hours (n = 14) until death or discharge. Rescue doses identical to the scheduled doses were administered at inception and then hourly as needed.
Outcomes were assessed using the Richmond Agitation Sedation Scale (RASS). RASS uses a 10-point scale of −5 to 4: 0 indicates that the patient is alert and calm, negative numbers indicate increasing sedation, and positive numbers indicate increasing agitation. The primary outcome was change in RASS score from time 0 to 24 hours in the modified intent-to-treat population, consisting of the patient completing 24 hours of treatment.
Key Findings
Among all patients, RASS score decreased significantly by 30 minutes after administration in the haloperidol escalation group (mean change = –2.6, 95% confidence interval [CI] = –3.6 to –1.6), the chlorpromazine rotation group (mean change = –2.4, 95% CI = –3.0 to –1.8), and the combination group (mean change = –2.1, 95% CI = –3.0 to –1.3). No significant differences among groups were observed (P = .86)
The modified intent-to-treat population consisted of 10 patients in the haloperidol escalation group, 11 in the chlorpromazine rotation group, and 10 in the combination group. RASS score at 24 hours remained significantly decreased from baseline in the escalation group (mean change = –3.6, 95% CI = –5.0 to –2.2), the chlorpromazine rotation group (mean change = –3.3, 95% CI = –4.4 to –2.2), and the combination group (mean change = –3.0, 95% CI = –4.6 to –1.4), with no significant differences observed among groups (P = .71).
The most common serious toxicity was hypotension, occurring in 40% of the escalation group, 31% of the rotation group, and 21% of the combination group. No dose reductions were required due to adverse events. One patient in the combination group discontinued treatment due to grade 3 akathisia, which was considered possibly related to treatment. No treatment-related deaths were reported.
The investigators concluded, “Our data provide preliminary evidence that the three strategies of neuroleptics might reduce agitation in patients with terminal agitation. These findings are in the context of the single-center design, small sample size, and lack of a placebo-only group.”
Dr. Hui, of the Department of Palliative Care, Rehabilitation & Integrative Medicine, The University of Texas MD Anderson Cancer Center, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the National Institute of Nursing Research. For full disclosures of the study authors, visit thelancet.com.
