Yin B, Ye T, Liu X, Wan R, Gu L, Zong G. Effects of melatonin for delirium in elderly acute heart failure patients: a randomized, single-center, double-blind, and placebo-controlled trial. Heart Surg Forum. 2022;25(1):E037-E041.
To explore the benefits of melatonin for the prevention of delirium after acute heart failure in hospitalized elderly patients
Low-dose melatonin therapy can reduce the incidence of delirium, as well as decrease the length of hospitalization stay and cost for elderly patients, in acute heart failure.
Randomized, double-blind, placebo-controlled trial at a single center
The study enrolled patients aged more than 60 years in Jiangsu, China, who were admitted to the intensive care unit (ICU) for acute heart failure.
Investigators assessed 584 patients between October 2015 and October 2019. A computer-generated randomization sequence in a 1:1 ratio was used to randomly assign patients melatonin or placebo.
A total of 497 patients were randomly assigned to receive either placebo (n=249) or melatonin (n=248).
In the placebo group, 143 participants were male and 106 participants were female. In the melatonin group, 152 participants were male and 96 were female. Average age in the placebo group was 68.5 +/- 7.1. In the melatonin group, average age was 69.1 +/- 7.5.
Participants received 3 mg/day of either melatonin or placebo for 7 days, within 7 days after acute heart failure. Of note, the study provides no information on the placebo’s ingredients.
Study Parameters Assessed
Investigators assessed the incidence of delirium twice daily with the Confusion Assessment Method during the first 7 days. They performed analyses by using intention-to-treat and safety populations. The final follow-up occurred 30 days after acute heart failure.
In addition, investigators assessed 30-day all-cause mortality, length of stay in the ICU, and occurrence of nondelirium complications and hospital costs as secondary measures.
The primary outcome the study was designed to assess was the incidence of delirium.
The incidence of delirium was significantly lower in the melatonin group than in the placebo group (27.0% vs 36.9%, P=0.021). Regarding safety, the occurrence of rhabdomyolysis and abnormal hepatic function did not differ between the 2 groups.
The 30-day, all-cause mortality rate of the melatonin group was 38.1% (90/236), while that of the placebo group was 44.7% (109/244), with no significant statistical difference (P=0.146).
The mean length of stay in the melatonin group was 18.1 days, compared to 19.8 days in the placebo group, with a statistically significant difference between the 2 groups (P=0.01). The average hospitalization cost of the melatonin group was $5,850, which was less than the $6,470 of the placebo control group. This was statistically significant (P=0.01).
The current study suggests that acute melatonin treatment can reduce the incidence of delirium for elderly patients with acute heart failure. It also can reduce the duration of hospital stays and hospitalization costs. Melatonin therapy was determined to be safe for ICU elderly patients.
Study funding came from the Top Talent Support Program for Young and Middle-Aged People of Wuxi Health Committee.
Practice Implications & Limitations
Delirium is a challenging neuropsychiatric condition defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, as a disturbance of consciousness and a change in cognition that develops over a short period of time with fluctuations of status.1 Delirium is common in the ICU setting where it is associated with longer hospital stays,2 increased hospital costs,3 and increased mortality.4
Melatonin is an endogenous hormone synthesized from tryptophan and is an important regulator of circadian rhythm. Melatonin is normally released in the evening when stressors are low and there is less light exposure.5 There has been a theory that supplementation of melatonin in the hospital setting, to help mimic circadian rhythm, may prevent delirium in patients at risk.6 In addition, patients with high risk of delirium may have lower levels of melatonin.7
In this study, melatonin at a 3-mg dosage given for 7 days was found to decrease the incidence of delirium in elderly patients after acute heart failure, as well as lower both the length of time and cost of the hospital stay.8 This is significant, as patients with heart failure may be especially predisposed to delirium, with one study finding an incidence as high as 1 in 3 patients.9 In that same study, patients with delirium had a higher incidence of noncardiovascular death (P=0.046) and worsening heart failure (P<0.001) during hospitalization. Among patients who survived at discharge, the incidence of all-cause death, cardiovascular death, and noncardiovascular death after discharge was significantly higher in patients with delirium than in those without.9
The study under review did not show a statistically significant difference in 30-day, all-cause mortality. However, a limitation of the study was that it did not consider other clinical factors, such as time of endotracheal intubation.8 Importantly, the authors do not specify when during the day patients received melatonin, so it is unclear whether dosing was in sync with circadian rhythm. In addition, they received only 1 daily dose of melatonin (3 mg) and only for 7 days.
The content of melatonin between lots of the same product varied by as much as 465%.”
The molecular basis for why melatonin decreases the incidence of delirium in this patient population may be secondary to its antivasospasm effects, as well as improvements in cerebral perfusion and sleep quality.10 In addition, excessive generation of reactive oxygen species in mitochondria is considered a factor in cardiac dysfunction.11 Of note, melatonin has been shown in preclinical research to improve mitochondrial dysfunction associated with heart failure via melatonin’s ability to scavenge free radical species and maintain optimal mitochondrial membrane function.11
One practical consideration is whether this is applicable to hospitalized patients in general who may be at risk for delirium. We know that up to 25% of patients who are hospitalized may develop delirium, and this risk increases to more than 50% in the geriatric population.12 Hospitalized patients often have disruption in their circadian rhythm due to the noise and light disruptions, as well as the stress of the experience.13 Disruption of sleep and circadian rhythm has been found to be a risk factor for the development of delirium.14
A recent review article examined 1 meta-analysis, 5 RCTs, and 1 observational study looking at acutely medically ill and perioperative elderly inpatients receiving melatonin for delirium prevention.13 The results of the review were conflicting, with some of the studies showing a benefit (eg, those taking melatonin having reduced incidence of delirium) and others showing no benefit.13 The studies were not as well designed as the acute heart failure study, due to heterogenicity in the patient populations, including indication for admission and comorbidities, and the studies’ relatively small sample sizes, as well as the lack of power to detect the effect of melatonin in these populations.13
Curiously, another systematic review and meta-analysis explored the effect of melatonin and the prescription melatonin agonist, ramelteon, on delirium prevention in adult hospitalized patients. It included 14 studies with 1,712 participants. Melatonin and ramelteon significantly reduced delirium incidence with a risk reduction of 49% in surgical patients and 34% in ICU patients (P=0.009). Researchers found a nonsignificant reduction in incidence in medical patients receiving melatonin.15 The patients who received melatonin/ramelteon experienced improvement in sleep quality and required lower sedative administration. However, melatonin/ramelteon did not reduce delirium duration, length of hospital stay, length of ICU stay, or mortality. Hallucinations, nightmares, and gastrointestinal distress were prevalent in the melatonin group.15
Where does this leave integrative practitioners on whether to advise the use of melatonin for patients at risk for delirium? The answer is that it depends on the patient, particularly the reason they may be at risk for delirium, and what, if any, their previous experience with melatonin was like, as well as the dose and the quality of the melatonin product.
From the studies above, one could extrapolate that melatonin might be most beneficial for prevention of delirium for patients after acute heart failure,8 in the perioperative setting, and in the ICU.15 The studies ranged in dosing, but most frequently gave either 3 mg or 5 mg at bedtime. Whether or not that is the most effective dose for delirium remains to be seen. To date there are no dose-escalation studies for inpatients for delirium prevention.
Patients can have adverse reactions to melatonin. A recent systematic review indicated that the most frequent adverse effects were daytime sleepiness, headache, other sleep-related adverse events, dizziness, and hypothermia.16 Very few side effects reported were serious. Other adverse effects included agitation, fatigue, mood swings, nightmares, skin irritation, and palpitations. Most side effects either resolved spontaneously within a few days with no adjustment in melatonin, or immediately upon withdrawal of treatment. Melatonin was generally regarded as safe and well-tolerated.16
Quality issues for melatonin products are a serious concern. As melatonin use has skyrocketed and the global market for melatonin has significantly increased, risk for alterations in melatonin products has risen, particularly actual melatonin content and presence of contaminants in melatonin supplements.17 In a 2017 systematic analysis of melatonin products, melatonin content varied from −83% to +478% of label claim amounts, and 70% of products had melatonin concentration ≤10% of what the label claimed. The content of melatonin between lots of the same product varied by as much as 465%.18 The least-variable products were those that contained the simplest mix of ingredients, generally oral or sublingual tablets with melatonin added to a filler of silica or cellulose derivatives.17 Roughly 25% of melatonin products analyzed contained serotonin, some at potentially significant doses.17 Serotonin could cause negative effects, such as serotonin syndrome, in patients taking SSRI medications (selective serotonin reuptake inhibitors used as antidepressants).
The wide variability in potency of products labeled with the same milligram amount may be a confounding factor in the variability of the study outcomes on melatonin efficacy, particularly for reducing incidence of delirium. The potency variability may also account for patients experiencing differing effects on sleep and adverse effects as well. Careful consideration of quality should be used in recommending brands of melatonin to patients. Ideally, patients should use products that undergo third-party testing and adhere to good manufacturing processes.
In conclusion, melatonin is worth trying for patients at risk for delirium. Given the benefits of improving sleep and circadian rhythm on hospitalized patients as well as its safety profile, melatonin should be more routinely considered in the inpatient setting.