Neuroleptic strategies for terminal agitation in patients with cancer and delirium at an acute palliative care unit: a single-centre, double-blind, parallel-group, randomised trial

Abstract

Background: The role of neuroleptics for terminal agitated delirium is controversial. We assessed the effect of three neuroleptic strategies on refractory agitation in patients with cancer with terminal delirium.

Methods: In this single-centre, double-blind, parallel-group, randomised trial, patients with advanced cancer, aged at least 18 years, admitted to the palliative and supportive care unit at the University of Texas MD Anderson Cancer Center (Houston, TX, USA), with refractory agitation, despite low-dose haloperidol, were randomly assigned to receive intravenous haloperidol dose escalation at 2 mg every 4 h, neuroleptic rotation with chlorpromazine at 25 mg every 4 h, or combined haloperidol at 1 mg and chlorpromazine at 12·5 mg every 4 h, until death or discharge. Rescue doses identical to the scheduled doses were administered at inception, and then hourly as needed. Permuted block randomisation (block size six; 1:1:1) was done, stratified by baseline Richmond Agitation Sedation Scale (RASS) scores. Research staff, clinicians, patients, and caregivers were masked to group assignment. The primary outcome was change in RASS score from time 0 to 24 h. Comparisons among group were done by modified intention-to-treat analysis. This completed study is registered with ClinicalTrials.gov, NCT03021486.

Findings: Between July 5, 2017, and July 1, 2019, 998 patients were screened for eligibility, with 68 being enrolled and randomly assigned to treatment; 45 received the masked study interventions (escalation n=15, rotation n=16, combination n=14). RASS score decreased significantly within 30 min and remained low at 24 h in the escalation group (n=10, mean RASS score change between 0 h and 24 h -3·6 [95% CI -5·0 to -2·2]), rotation group (n=11, -3·3 [-4·4 to -2·2]), and combination group (n=10, -3·0 [-4·6 to -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 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-centre design, small sample size, and lack of a placebo-only group.

Funding: National Institute of Nursing Research.

Figure 1.. Participant Flow Diagram.

At the time of enrollment, patients were randomised to haloperidol dose escalation, neuroleptic rotation or combination therapy. All enrolled patients were immediately started on a standardized regimen with haloperidol 2 mg every 6 hours intravenously and 2 mg every 1 hour as needed for agitation. Because of the fluctuating nature of delirium, we monitored patients’ RASS every 2 hours until it was at least +1 and required rescue medication in the bedside nurse’s judgement. 23/68 (34%) patients did not develop further agitation until death, discharge or dropout while on open label phase, and thus did not require the study medication.

Figure 2.. Change in Richmond Agitation Sedation Scale over the first 24 Hours after Study Medication Administration.

The mean RASS scores (data markers) are plotted for each study group starting at time 0 (i.e. immediately before blinded study medication administration) over the next 24 hours, with error bars indicating standard error.