Delirium affects a large percentage of intensive care unit (ICU) patients. This acute fluctuating disturbance in consciousness, cognition, and perception is often accompanied by a deranged circadian rhythm. The development of delirium has been associated with increases in hospital length of stay, costs, complications, and mortality. Healthcare providers use a variety of prevention and treatment strategies, including nonpharmacologic approaches such as environmental optimization, and pharmacologic approaches, including antipsychotics, alpha-2 agonists, and sedatives. Recent studies suggest that melatonin can prevent delirium; however, little data exists on melatonin use in critically ill patients.
Nishikimi et al (Crit Care Med. 2018;46:1099-1105) studied the effects of ramelteon, a selective melatonin receptor agonist with 3 to 6 times greater affinity for melatonin receptors. This single-center, randomized, triple-blind, placebo-controlled trial was performed in both medical and surgical ICUs in an academic hospital. The primary outcome was ICU length of stay. Secondary outcomes included mortality and the occurrence and duration of delirium in the ICU. Patients older than 20 years were randomized to receive either ramelteon, 8 mg/day at 8:00 p.m., or placebo. Randomization was stratified according to age (older or younger than 60 years), Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) score (above or below 30), and intubation status. Patients were excluded if they were already receiving ramelteon, had a known sensitivity to ramelteon, or refused consent. The trial drug was continued until ICU discharge.
A total of 88 patients were randomized and included in the intention-to-treat analysis. The primary end point of ICU length of stay was 4.56 days in the ramelteon group and 5.86 days in the placebo group (p = 0.086). A multivariate analysis adjusting for patient characteristics showed statistically significant reduction in ICU length of stay. Secondary end points of delirium occurrence (24.4% vs. 46.5%, p = 0.044) and duration of delirium (0.78 days vs. 1.4 days, p = 0.048) were statistically significant in favor of ramelteon. The was no difference in mortality (6.7% vs 7.5%, p = 0.99), and no adverse events were attributed to ramelteon.
Although the results were promising, this study has limitations. The initial calculation to detect a one-day reduction in ICU stay for the ramelteon group with at least 80% statistical power was calculated as 182 patients. This study is underpowered, randomizing only 88 patients. The patient characteristics between groups were grossly similar; however, the ramelteon group had a slightly higher proportion of men and subjects with dementia, sepsis, and history of heavy alcohol use, perhaps masking some of the benefits of ramelteon. The usual limitations of a small randomized controlled trial from a single academic center certainly limit generalizability.
Despite these limitations, Nishikimi et al showed that melatonin agonists may play a role in decreasing ICU length of stay in critically ill patients and may also decrease the incidence and duration of delirium in this population. Given the relative low cost of ramelteon compared to the cost of an additional day in the ICU, it may be advantageous to institute prophylactic use, especially considering the adverse effect profile (no adverse events were noted in this study). More studies are needed that address these limitations, and indeed some have already been conducted, with a multicenter feasibility trial in Canada by Burry et al (BMJ Open. 2017;7:e015420), and the multicenter Pro-MEDIC randomized controlled trial (Martinez F, et al. Trials. 2017;18:4).
Coauthors of this installment of Concise Critical Appraisal:
Daniel Eraso, MD, is a clinical assistant professor of emergency medicine at the University of Florida College of Medicine – Jacksonville.
Brian J. Wright, MD, MPH, is a clinical assistant professor and the program director for the Advanced Resuscitation Training Program in the Department of Emergency Medicine at Stony Brook Medicine. Dr. Wright is an editor of Concise Critical Appraisal.