Neuroleptic Rotation for Terminal Agitation in Patients with Cancer and Delirium at an Acute Palliative Care Unit: A Single-Centre, Parallel-Group, Double-Blind, Randomised Clinical Trial

Background: The role of neuroleptics for terminal agitated delirium is controversial. We assessed the effect of 3 neuroleptic strategies on refractory agitation in cancer patients with terminal delirium. Methods: In this single-centre, double-blind, parallel group randomised trial, patients with advanced cancer, age≥18, admitted to a Palliative Care unit with refractory agitation despite low dose haloperidol were randomised to haloperidol dose escalation 2 mg intravenously every 4 hours; neuroleptic rotation with chlorpromazine 25 mg intravenously every 4 hours; or combined haloperidol 1 mg and chlorpromazine 12.5 mg intravenously every 4 hours until death or discharge. Rescue doses identical to the scheduled doses were administered at inception then hourly as needed. Permuted block randomization (block size=six, 1:1:1) was conducted, stratified by baseline Richmond Agitation Sedation Scale (RASS) scores. Research staff, clinicians, patients and caregivers were blinded. The primary outcome was change in RASS from time 0 to 24 hours. Comparisons among group was conducted with modified intention-to-treat analysis. This completed study is registered with Clinicaltrials.gov, NCT03021486. Findings: Between 7/5/2017 and 7/1/2019, 68 patients were enrolled and 45 received the blinded study interventions (escalation n=15, rotation n=16, combination n=14). RASS decreased significantly within 30 minutes and remained low at 24 hours in the escalation group (number analyzed, mean RASS change between 0 and 24 h [95%CI]: n=10, −3·6 [−5,−2·2]), rotation group (n=11, −3·3 [−4·4,−2·2]) and combination group (n=10, −3.0 [−4·6,−1·4]), with no difference among groups (P=0·71). The most common serious toxicity was hypotension (escalation n=6 [40%], rotation n=5 [31%], combination n=3 [21%]); there were no treatment-related deaths. Interpretation: Our data provided preliminary evidence that the 3 strategies of neuroleptics may reduce agitation in patients with terminal agitation. These findings should be put in context of the single-centre design, small sample size and lack of a placebo-only group. the the level our study the use preliminary for in on This double-blind, double dummy trial examines a clinically relevant primary (i.e. in a unique Our study also used high doses of neuroleptics (e.g. haloperidol starting at 12 mg/day and up to 48 mg/day at dose level 4). We used relatively high doses of in this study despite multiple measures including repeated trial of lower doses of haloperidol (≤8 mg/day) and the time sensitivity of the situation. We found that repeated administration of high dose haloperidol and/or chlorpromazine was associated with a rapid reduction of restlessness assessed by in addition to overall impression of control and by both caregivers and nurses. Unlike deep palliative few in this study were sedated with of −5. the suggests that neuroleptics have a limited effect on the duration of delirium delirium severity, our study highlights they may have a pharmacologic effect on reducing agitation. This beneficial effect is of clinical significance, in the terminal agitation setting in which palliation is of paramount importance.