Division of Palliative Care, Department of Medicine, University of Ottawa, 43 Bruyère Street, Ottawa, ON, K1N 5C8, Canada.
Bruyère Research Institute, Ottawa, Canada.
BMC Palliat Care. 2020 Oct 21;19(1):163. doi: 10.1186/s12904-020-00669-z.
Delirium is highly problematic in palliative care (PC). Preliminary data indicate a potential role for melatonin to prevent delirium, but no randomized controlled trials (RCTs) are reported in PC.
Patients aged ≥18 years, with advanced cancer, admitted to an inpatient Palliative Care Unit (PCU), having a Palliative Performance Scale rating ≥ 30%, and for whom consent was obtained, were included in the study. Patients with delirium on admission were excluded. The main study objectives were to assess the feasibility issues of conducting a double-blind RCT of exogenous melatonin to prevent delirium in PC: recruitment, retention, procedural acceptability, appropriateness of outcome measures, and preliminary efficacy and safety data. Study participants were randomized in a double-blind, parallel designed study to receive daily melatonin 3 mg or placebo orally at 21:00 over 28 days or less if incident delirium, death, discharge or withdrawal occurred earlier. Delirium was diagnosed using the Confusion Assessment Method. Efficacy endpoints in the melatonin and placebo groups were compared using time-to-event analysis: days from study entry to onset of incident delirium.
Over 16 months, 60/616 (9.7%; 95% CI: 7.5-12.4%) screened subjects were enrolled. The respective melatonin (n = 30) vs placebo (n = 30) outcomes were: incident delirium in 11/30 (36.7%; 95%CI: 19.9-56.1%) vs 10/30 (33%; 95% CI: 17.3-52.8%); early discharge (6 vs 5); withdrawal (6 vs 3); death (0 vs 1); and 7 (23%) vs 11 (37%) reached the 28-day end point. The 25th percentile time-to-event were 9 and 18 days (log rank, χ = 0.62, p = 0.43) in melatonin and placebo groups, respectively. No serious trial medication-related adverse effects occurred and the core study procedures were acceptable. Compared to those who remained delirium-free during their study participation, those who developed delirium (n = 21) had poorer functional (p = 0.036) and cognitive performance (p = 0.013), and in particular, poorer attentional capacity (p = 0.003) at study entry.
A larger double-blind RCT is feasible, but both subject accrual and withdrawal rates signal a need for multisite collaboration. The apparent trend for shorter time to incident delirium in the melatonin group bodes for careful monitoring in a larger trial.
Registered on July 21st 2014 with ClinicalTrials.gov : NCT02200172 .
谵妄在姑息治疗（PC）中是一个非常严重的问题。初步数据表明，褪黑素在预防谵妄方面可能有一定作用，但在 PC 中没有报道随机对照试验（RCT）。
纳入年龄≥18 岁、患有晚期癌症、入住姑息治疗病房（PCU）、姑息治疗表现量表评分≥30%、并获得同意的患者。入院时出现谵妄的患者被排除在外。主要研究目的是评估在姑息治疗中进行外源性褪黑素预防谵妄的双盲 RCT 的可行性问题：招募、保留、程序可接受性、适当的结局测量指标以及初步的疗效和安全性数据。研究参与者按照双盲、平行设计进行随机分组，每天晚上 9 点口服褪黑素 3mg 或安慰剂，共 28 天，或更早出现谵妄、死亡、出院或退出。采用意识混乱评估方法诊断谵妄。使用时间到事件分析比较褪黑素组和安慰剂组的疗效终点：从研究入组到出现新发谵妄的天数。
在 16 个月的时间里，对 616 名（97%；95%CI：7.5-12.4%）筛查对象进行了筛选，其中 60 名（9.7%；95%CI：7.5-12.4%）入组。褪黑素（n=30）和安慰剂（n=30）的结果分别为：新发谵妄 11 例（36.7%；95%CI：19.9-56.1%）vs. 10 例（33%；95%CI：17.3-52.8%）；早期出院（6 例 vs. 5 例）；退出（6 例 vs. 3 例）；死亡（0 例 vs. 1 例）；28 天终点 7 例（23%）vs. 11 例（37%）。褪黑素组和安慰剂组的 25%分位数时间到事件分别为 9 天和 18 天（对数秩检验，χ=0.62，p=0.43）。没有发生严重的试验药物相关不良事件，核心研究程序是可以接受的。与研究期间保持无谵妄的患者相比，出现谵妄（n=21）的患者的功能（p=0.036）和认知表现（p=0.013）更差，尤其是注意力能力（p=0.003）在研究入组时更差。
更大规模的双盲 RCT 是可行的，但患者的入组率和退出率都表明需要多中心合作。褪黑素组出现新发谵妄的时间似乎更短，这需要在更大规模的试验中进行仔细监测。
2014 年 7 月 21 日在 ClinicalTrials.gov 注册：NCT02200172。
