Evaluation of Delirium in Critically Ill Patients Prescribed Melatonin or Ramelteon

Abstract

Background:

An impaired sleep-wake cycle may be one factor that affects the development of delirium in critically ill patients. Several small studies suggest that exogenous melatonin or ramelteon may decrease the incidence and/or duration of delirium.

Objective:

To compare the effect of prophylactic administration of melatonin, ramelteon, or no melatonin receptor agonist on the development of delirium in the intensive care unit (ICU).

Methods:

This was a single-center, retrospective, observational cohort study of nondelirious patients in the ICU who received melatonin, ramelteon, or no melatonin receptor agonist. The primary end point was the incidence of delirium. Secondary end points included assessments of daily level of sedation and daily utilization of antipsychotic, sedative, and opioid agents.

Results:

No difference was observed in the incidence of delirium among the melatonin, ramelteon, and placebo cohorts (18.7% vs 14.3% vs 13.8%; P = 0.77). A difference was observed in the rate of agitation and sedation among the 3 groups, with the greatest observed in the melatonin cohort. Additionally, there was a difference in the use of propofol, dexmedetomidine, and opioids. Overall, there was no difference in clinical outcomes, including duration of mechanical ventilation and ICU or hospital length of stay.

Conclusion and Relevance:

Therapy with melatonin, ramelteon, and no melatonin receptor agonist resulted in similar rates of delirium in a mixed ICU population. Despite significant differences in agitation, sedation, and medication utilization, there was no differences in the clinical outcomes evaluated.

Keywords

melatonin ramelteon delirium intensive care unit agitation sedation

Introduction

Delirium is a commonly recognized problem in the critically ill population, affecting up to 80% of mechanically ventilated patients.^1,2 It is characterized by an acute onset and fluctuation in level of consciousness, cognition, and attention that can be further described as “hyperactive,” “hypoactive,” or a combination of both.³ The development of delirium in the critically ill has been associated with prolonged intensive care unit (ICU) and hospital length of stay (LOS), increased mortality, and long-term cognitive impairment.^4-8 The cause of delirium is often multifactorial, and the fundamental management strategy is prevention, which includes avoiding known risk factors for delirium.¹

An impaired sleep-wake cycle may be one factor that affects the development of delirium in the ICU.⁹ Common environmental (eg, noise, lack of natural light, patient care activities) and physiological factors (eg, critical illness, pain, medications, anxiety) can contribute to the disruption of natural circadian rhythms, including sleep.¹⁰ Several studies have demonstrated abnormal circadian patterns of melatonin secretion in critically ill patients, and 2 randomized, placebo-controlled trials of exogenous melatonin in the ICU suggest improved sleep quality with nightly melatonin administration.^11-16 Given the potentially beneficial role of melatonin receptor agonists in the regulation of sleep patterns, there is a growing interest in evaluating the role of these agents on the outcome of delirium.¹⁷ Small randomized and retrospective observational studies have demonstrated variable effects on delirium and ICU LOS with the use of ramelteon or melatonin in ICU patients.^18-22

Melatonin and ramelteon are attractive pharmacological agents for the prevention of delirium in high-risk populations because of the limited adverse effects associated with their use. Whereas both agents interact with the MT1 and MT2 receptors to exert their effect, it is unknown whether they produce equivalent outcomes on sleep and/or delirium, and previous studies have not sought to answer this question. The primary objective of this study was to compare the incidence of delirium in critically ill patients who received melatonin, ramelteon, or no melatonin receptor agonist.

Materials and Methods

Settings and Participants

We conducted a retrospective, observational cohort study of nondelirious critically ill patients receiving ramelteon, melatonin, or a nonmelatonin receptor agonist sleep aid at Brigham and Women’s Hospital, a tertiary, academic medical center with 793 inpatient beds, including 9 inpatient ICUs. The study design was approved by the Mass General Brigham Institutional Review Board (IRB #2016P002728 and #2020P003421).

Prior to May 2017, ramelteon was the only approved melatonin receptor agonist on hospital formulary. In May 2017, melatonin replaced ramelteon on formulary at our institution. Using a report generated from the electronic medical record (EMR), a convenience sample was used to identify patients in the medical, surgical, cardiac, and cardiothoracic surgical ICUs receiving ramelteon during the period February 2017 to April 2017 and patients receiving melatonin during the period May 2017 to July 2017. To represent a placebo group, we identified patients in the ICUs listed above that were ordered for mirtazapine and/or trazodone during the period May 2017 to July 2017.

In the melatonin and ramelteon cohorts, patients were included in the analysis if they received at least 1 dose of scheduled melatonin or ramelteon in the ICU and were not delirious in the 48 hours prior to receiving the first dose, as defined by a positive Confusion Assessment Method for the ICU (CAM-ICU) score. In the placebo cohort, patients were included in the analysis if they were not delirious in the 48 hours prior to ICU admission and/or within the first 24 hours of ICU admission. Patients in the placebo cohort may have received one-time doses of melatonin or ramelteon but were excluded if they met inclusion criteria for the other melatonin or ramelteon cohorts. Patients were excluded if they had a history of severe cognitive or neurodegenerative disease or severe structural brain injury, were receiving melatonin, ramelteon, or antipsychotics prior to admission, or were considered to be in active alcohol withdrawal. Patients with a period of >72 hours between melatonin or ramelteon doses were also excluded in those respective cohorts.

Outcomes and Data Collection

A review of the EMR was conducted to collect baseline patient demographics, admission diagnosis, and medication use within the prior 24 hours of receiving melatonin or ramelteon, or within the first 24 hours of ICU admission for the placebo group. Severity of illness was assessed using the Sequential Organ Failure Assessment (SOFA) score at ICU admission. For the melatonin and ramelteon groups, patients were evaluated for 72 hours after the last dose of study medication or up to day of ICU discharge. For the placebo group, patients were evaluated up to ICU discharge.

The primary end point was the incidence of delirium, defined as a positive CAM-ICU assessment during the follow-up period as defined above. Secondary end points included assessments of daily level of sedation defined by the Richmond Agitation-Sedation Scale (RASS) and daily utilization of antipsychotic, sedative, and opioid agents. Total daily doses (TDDs) of opioids are expressed in fentanyl equivalents (100 µg intravenous [IV] fentanyl = 1.5 mg IV hydromorphone = 10 mg IV morphine), and benzodiazepines are expressed in midazolam equivalents (1 mg IV lorazepam = 2 mg IV midazolam).²³ Agitation was defined as a RASS ≥ +1; moderate sedation was defined as RASS −2 to −3; and deep sedation was defined as RASS −4 to −5. Other secondary end points included the time to delirium, duration of delirium, and percentage of days with delirium in the subgroup of patients that developed delirium. Clinical outcomes evaluated included duration of mechanical ventilation, ICU LOS, hospital LOS, and whether the patient was discharged from the ICU or from the hospital with melatonin or ramelteon.

Assessment and documentation of CAM-ICU and RASS was carried out by the ICU nurse at least every 8 hours (or more frequently if the patient was mechanically ventilated) per institutional guidelines. Vital signs are collected every hour during ICU admission. Additionally, nurses and physicians are advised to practice standard guideline-directed ICU care, which includes daily spontaneous awakening trials, spontaneous breathing trials, early mobility, and nonpharmacological delirium prevention and management strategies.¹

Statistical Analysis

Continuous parametric data were presented as mean ± SD, and nonparametric data as median (interquartile range). Continuous data were compared using the 1-way ANOVA test (parametric) or the Kruskal-Wallis test (nonparametric) when applicable. Nominal data were presented as frequencies and percentages and were compared using the χ² test. All tests were 2-tailed, and a P value less than 0.05 was used to represent statistical significance.

Results

A total of 478 patients were identified as having received at least 1 dose of melatonin or ramelteon, or having been ordered for mirtazapine and/or trazodone during admission in the ICU, of which 320 were excluded from the analysis (see Figure 1). Most patients were excluded because they were delirious prior to receiving any dose of melatonin or ramelteon or within the first 24 hours of ICU admission in the placebo group. Of the remaining 158 patients included in this analysis, 75 patients received melatonin, 56 received ramelteon, and 27 represented the placebo cohort.

Figure 1.

Inclusion and exclusion flowsheet.

Baseline patient characteristics are presented in Table 1. Patient characteristics were similar across the 3 cohorts, except for differences in critical care unit, admission diagnosis, and recent medication use. A greater proportion of patients in the placebo group were admitted to the medical ICU and had greater baseline use of sedative agents, benzodiazepines, and propofol. Overall, a large proportion of patients in the melatonin and ramelteon groups were admitted to a surgical ICU, with primary admission diagnosis of surgery or trauma, whereas the distribution of admission diagnoses was more balanced in the placebo group.

Table 1.

Patient Baseline Characteristics.^a

Characteristic	Melatonin (n = 75)	Ramelteon (n = 56)	Placebo (n = 27)
Age, mean (SD)	65.3 (15.8)	65.8 (14.6)	60.7 (18.4)
Male	46 (61.3)	33 (58.9)	15 (55.6)
BMI, mean (SD)	29.4 (7.9)	26.7 (6.6)	27.1 (4.9)
Mechanical ventilation	32 (42.7)	21 (37.5)	8 (29.6)
SOFA score, median (IQR)
ICU admission	4 (1-7)	4 (1-7)	4 (3-5.5)
Critical care unit
Medical ICU^b	9 (12.0)	12 (21.4)	10 (37.0)
Surgical ICU	19 (25.3)	10 (17.9)	7 (25.9)
Thoracic surgery ICU	6 (8.0)	5 (8.9)	1 (3.7)
Cardiac surgery ICU	23 (30.7)	12 (21.4)	4 (14.8)
Cardiac ICU	18 (24.0)	17 (30.4)	5 (18.5)
Admission diagnosis
Surgery/trauma^c	40 (53.3)	29 (51.8)	7 (25.9)
Sepsis/infection	4 (5.3)	4 (7.1)	4 (14.8)
Respiratory failure	4 (5.3)	10 (17.9)	4 (14.8)
Heart failure/ACS^d	17 (22.7)	3 (5.4)	5 (18.5)
Other^e	10 (13.3)	10 (17.9)	7 (25.9)
Medication use prior 24 hours
Benzodiazepines^f	21 (28.0)	10 (17.9)	13 (48.1)
Opioids	54 (72.0)	36 (64.3)	17 (63.0)
Propofol^g	10 (13.3)	8 (14.3)	10 (37.0)
Dexmedetomidine	7 (9.3)	3 (5.4)	3 (11.1)
Corticosteroids	12 (16.0)	15 (26.8)	4 (14.8)
Anticholinergic agents	8 (10.7)	2 (3.6)	4 (14.8)

Abbreviations: ACS, acute coronary syndrome; BMI, body mass index; ICU, intensive care unit; IQR, interquartile range; SOFA, Sequential Organ Failure Assessment.

Data presented as n (%), unless otherwise indicated.

P = 0.018.

P = 0.040.

P = 0.025.

Other admission diagnoses included electrolyte imbalances, hypersensitivity reaction, arrhythmia, hyperglycemic emergencies, bleeding, sickle cell pain crisis, venous thromboembolism, and atrial fibrillation.

P = 0.016.

P = 0.015.

The median doses of melatonin and ramelteon were 3 and 8 mg, respectively. In the placebo group, 18 (66.7%) patients received at least 1 dose of trazodone, 3 (11.1%) mirtazapine, 4 (14.8%) ramelteon, and 2 (7.4%) melatonin during ICU admission. In the melatonin and ramelteon groups, there was no difference in the median time from ICU admission to first dose of melatonin receptor agonist (2 vs 2 days; P = 0.83) or the median number of doses received in the ICU (2 vs 3 doses; P = 0.29).

For the primary end point of incidence of delirium, 14 (18.7%) patients developed delirium in the melatonin group versus 8 (14.3%) patients in the ramelteon group and 4 (13.8%) patients in the placebo group, which was not statistically significant (P = 0.77; see Table 2).

Table 2.

Primary and Secondary End Points.^a

End point	Melatonin (n = 75)	Ramelteon (n = 56)	Placebo (n = 27)	P value
Primary
Incidence of delirium	14 (18.7)	8 (14.3)	4 (13.8)	0.774
Secondary
RASS assessment
Total assessments per day, median (IQR)	6 (4-8)	5 (4-7)	5 (3-6)	<0.001
Agitation, RASS ≥ +1	292 (12.9)	348 (7.7)	67 (9.3)	<0.001
Moderate sedation, RASS −2 to −3	302 (13.3)	44 (3.8)	48 (6.7)	<0.001
Deep sedation, RASS ≤ −4	165 (7.3)	16 (1.4)	30 (4.2)	<0.001
Days of medication administered, ICU days (%)
Propofol	40 (11.5)	9 (4.5)	17 (12.5)	0.017
Dexmedetomidine	33 (9.5)	4 (2.0)	4 (14.8)	<0.001
Benzodiazepines	88 (25.4)	34 (16.8)	51 (2.9)	0.05
Opioids	251 (72.3)	109 (54.0)	90 (66.2)	<0.001
Antipsychotic agent	51 (14.7)	17 (8.4)	13 (9.6)	0.061
Total daily dose, median (IQR)
Opioids,^b µg	181.7 (77.5-475)	100 (50-176.7)	296.5 (100-901.3)	<0.001
Benzodiazepines,^c mg	2 (1.5-6)	2.5 (1.25-10)	4 (2-2.75)	0.727
Antipsychotic agents
Haloperidol, mg	4 (2.5-5)	0	3.5 (2.25-4.25)	0.261
Olanzapine, mg	5 (3.75-7.5)	2.5 (2.5-6.25)	0	0.269
Quetiapine, mg	68.75 (25-100)	50 (37.5-93.75)	12.5 (12.5-25)	<0.001

Abbreviations: ICU, intensive care unit; IQR, interquartile range; RASS, Richmond Agitation-Sedation Scale.

Data presented as n (%), unless otherwise indicated.

Presented in fentanyl equivalents.

Presented in midazolam equivalents.

For the secondary end points, a difference was observed in the rate of agitation and sedation among the 3 groups, with numerically greater rates of both agitation and sedation in the melatonin group compared with the ramelteon and placebo groups (see Table 2). Additionally, there was a difference in the use of propofol, dexmedetomidine, and opioids (see Table 2). Patients in the melatonin group had a greater proportion of days requiring dexmedetomidine and opioids compared with the ramelteon and placebo groups, and the melatonin and placebo groups had a greater proportion of days requiring propofol compared with the ramelteon group. There was no difference observed in the use of benzodiazepines or antipsychotic agents among the 3 groups. The median TDD of opioid agents was also different across the 3 groups, with the greatest TDD observed in the placebo group, followed by the melatonin and ramelteon groups (296.5 vs 181.7 vs 100 µg; P < 0.001). There was no difference in the TDD of the other sedative agents (see Table 2).

In the overall population, there was no difference in the duration of mechanical ventilation, ICU LOS, hospital LOS, and in-hospital mortality (see Table 3). Approximately 74% of patients were continued on melatonin or ramelteon following ICU discharge, and approximately 20% of patients were continued following hospital discharge (see Table 3).

Table 3.

Clinical Outcomes.^a

	Melatonin (n = 75)	Ramelteon (n = 56)	Placebo (n = 27)	P value
Duration of mechanical ventilation, days, median (IQR)	1 (0-2)	0 (0-1)	0 (0-3.6)	0.104
ICU length of stay, days, median (IQR)	5 (3-8)	5 (4-6.3)	3 (3-6)	0.094
Hospital length of stay, days, median (IQR)	11 (8-22.5)	10 (8-15)	8 (6-15)	0.082
Discharged from ICU with melatonin receptor agonist	58 (77.3)	39 (69.6)	—	0.321
Discharged from hospital with melatonin receptor agonist	15 (20.0)	12 (21.4)	—	0.842
Hospital mortality	7 (9.3)	8 (14.3)	2 (7.4)	0.549

Abbreviations: ICU, intensive care unit; IQR, interquartile range.

Data presented as n (%), unless otherwise indicated.

In the subgroup of patients who developed delirium, there was no difference in the proportion of ICU days with delirium among the melatonin, ramelteon, and placebo groups (42.9% vs 36.1% vs 40.5%; P = 0.77) or the rate of agitation (17.2% vs 13.2% vs 15.2%; P = 0.25). A difference was observed in the proportion of days requiring dexmedetomidine and antipsychotic agents across the 3 groups, with the greatest use of dexmedetomidine (23.2% vs 8.3% vs 5.4%; P < 0.001) and antipsychotics (36.6% vs 5.6% vs 27%; P = 0.002) in the melatonin group compared with the ramelteon and placebo groups, respectively. Additionally, a difference was found in ICU LOS across the groups (8 days placebo vs 7 days melatonin vs 4.5 days ramelteon; P = 0.028). However, there was no difference in the median time to delirium (3.5 days placebo vs 2.5 days melatonin vs 1.5 days ramelteon; P = 0.24) or the median duration of delirium (3 days placebo vs 1 day melatonin vs 1 day ramelteon; P = 0.61).

Discussion

In this single-center, retrospective evaluation of ramelteon and melatonin in the ICU, we found no difference in the incidence of delirium among the cohorts of patients who received ramelteon, melatonin, or no melatonin receptor agonist. To our knowledge, this is the first study to compare melatonin and ramelteon in the ICU population, and the results suggest that melatonin, ramelteon, and therapy without a melatonin receptor agonist have similar effects on the rate of delirium.

Critical illness has consistently been found to be a risk factor for delirium, with sleep disturbances in the ICU being one of the contributory factors. The 2018 update to the Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in the ICU have been expanded to address sleep disturbances in this population because of the potential association with delirium and other negative outcomes.¹ However, because of the low-quality evidence available, the guidelines make no recommendations regarding the use of melatonin and melatonin receptor agonists to improve sleep quality.

Melatonin is an endogenous hormone secreted by the pineal gland that regulates circadian rhythms, including the sleep-wake cycle through its interaction with the MT1 and MT2 receptors.²⁴ Additionally, animal and in vitro models have demonstrated potential antioxidant and anti-inflammatory properties which suggests that melatonin may have multiple benefits when used in a critically ill population.^25,26 Melatonin has been available as a dietary supplement for decades, but in 2005, the United States Food and Drug Administration (FDA) approved ramelteon, a synthetic melatonin receptor agonist with high affinity for MT1 and MT2 receptors, for insomnia characterized by difficulty falling asleep.²⁷

A growing area of research is focusing on the role of melatonin or ramelteon in patients at high risk of developing delirium, which include those with increased age, critical illness, mechanical ventilation, trauma, and emergency surgery.²⁸ Results from previous studies in both ICU and non-ICU populations have been conflicting.^18-22,29-32 Furthermore, a recent meta-analysis of 16 randomized controlled trials examining the role of prophylactic melatonin or ramelteon in hospitalized patients found no difference in the incidence of delirium compared with placebo.³³ Similarly, our analysis did not show a significant difference in the incidence of delirium in the melatonin, ramelteon, or placebo groups.

Three previous trials have demonstrated a significant decrease in the incidence of delirium with the use of prophylactic melatonin or ramelteon in the ICU.^18-20 In these trials, the rate of delirium ranged from 3.0% to 24.4% in the treatment groups compared with 24.3% to 46.5% in the control groups.^18-20 The incidence of delirium in our current study is consistent with that in previous studies—18.7% in the melatonin group, 14.3% in the ramelteon group, and 13.8% in the placebo group—despite some differences in patient populations. The randomized trial by Hatta et al¹⁸ included a mixed population of both ICU and acute care elderly patients, but in the final population, only one-third were ICU patients. The second trial by Nishikimi et al¹⁹ consisted of an entirely medical population. The retrospective trial by Baumgarter et al²⁰ included a mixed ICU population, with approximately one-third being cardiac and two-thirds medical/surgical ICU patients, of whom approximately 57% of patients required emergent surgery. Our cohorts consisted of solely critically ill patients and was well-balanced between medical and surgical ICU admissions. Approximately 40% of our population required mechanical ventilation during their ICU admission, which was also consistent with the populations in the Nishikimi et al and Baumgarter et al trials. Of note, our analysis described patients who received melatonin and ramelteon for average durations (2 and 3 days, respectively), which may have been shorter than that in other studies.²⁰

Interestingly, there was a difference in the incidence of both agitation (RASS ≥ +1) and sedation (RASS < −1) among the 3 cohorts, with the largest proportion of patients in the melatonin group. Additionally, patients who received melatonin were administered dexmedetomidine, benzodiazepines, propofol, and opioids on a greater percentage of ICU days and received an increased TDD of opioids compared with patients in the ramelteon group. The previous ICU studies have not demonstrated any difference in concomitant medication use between melatonin or ramelteon compared with control groups.^18,20 This may reflect a more critically ill patient population in the melatonin group of our study; however, SOFA scores were similar between the 2 groups. Although not statistically significant across the 3 cohorts, patients in the melatonin group had a trend toward more days where they required antipsychotic agents. However, there was no difference in ICU LOS or duration of mechanical ventilation in the overall patient population. In the subgroup of patients who developed delirium, there was no difference in the time to delirium or duration of delirium. The increased use of opioids and sedatives in the melatonin group may have affected our primary outcome of incidence of delirium because of the increased incidence of delirium associated with these medications.¹ It remains unclear why patients in the melatonin group in this study had higher sedative and opioid use; this remains an area where future research is warranted.

Our study suggests that the rate of delirium may be similar with melatonin, ramelteon, or therapy without a melatonin receptor agonist. Despite the conflicting evidence available in the literature, many institutions continue to use melatonin receptor agonists attempting to optimize sleep and/or delirium. Ramelteon is significantly more expensive than melatonin, with the average wholesale price of $15.56 per 8-mg tablet of ramelteon as against $0.15 per 3-mg tablet of melatonin. However, one concern regarding melatonin is the possible variation in quality and consistency between the different manufacturers because dietary supplements are not regulated by the United States FDA in the same way as other prescription and over-the-counter medications, including ramelteon. A second concern is a lack of consensus in the dosing of melatonin in previous studies. However, in our study, a median dose of 3 mg of melatonin resulted in no difference in the outcome of delirium compared with FDA-labeled dosing of 8 mg of ramelteon.

There were several limitations noted with this study. First, it was a single-center retrospective study. Although our sample size was similar to if not larger than most studies evaluating these agents in the ICU, our study was not adequately powered to detect any differences between cohorts. Second, the retrospective, single-center study design may limit the generalizability of the results outside our institution because sedation practices and medication dosing and administration were ultimately at the discretion of the ordering provider. The retrospective design also limited data collection to the documentation in the EMR, which made it difficult to evaluate sleep as a clinical outcome and to identify other delirium risk factors. Additionally, delirium and sedation scores may be over- or underreported in critically ill patients.³⁴ Third, it remains unclear if the possible benefits of melatonin and melatonin agonists are directly linked or separate from their role in sleep. Finally, because of the low event rate, it was not feasible to perform further statistical analysis to control for confounding variables, such as the increased use of sedatives and opioids seen in the melatonin group. Ultimately, a larger study is needed to control for these confounding variables.

Conclusion and Relevance

In summary, the rate of delirium in ICU patients receiving melatonin, ramelteon, or neither agent was similar in this retrospective, observational study. Our results add to the growing body of literature on the use of these agents in the prevention of delirium. Larger randomized studies are needed to further assess the optimal dose and timing of melatonin administration as well as its overall role in the prevention of delirium and sleep disorders.

Footnotes

Authors’ Note

This work was performed at Brigham and Women’s Hospital, Boston, MA.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Natasha Romero

Kenneth E. Lupi

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