Delirium represents a form of acute brain dysfunction that predicts excess death and long-term cognitive impairment in critically ill patients . For many years we have wondered whether pharmacological doses of would help prevent the onset or mitigate the duration of this calamity in the lives of our sickest patients.
Data is growing to help us find answers. Melatonin is a pleiotropic neurohormone produced by the pineal gland during hours of darkness. Understanding of the pineal gland and the biological effects of melatonin has evolved from its historical conceptualization as the "soothing organ" and "seat of the soul" to knowledge of its fundamental role in regulating circadian rhythm.
Melatonin is synthesized from tryptophan through a sequence of enzymatic reactions. The rate-limiting enzyme is N-acetyltransferase (AA-NAT) whose synthesis is promoted by darkness with its activity modulated by the suprachiasmatic nucleus in the hypothalamus.
Darkness stimulates the pineal gland to secrete melatonin with peak concentrations of ~100 pg/mL between 02:00 and 04:00 h, while strong light suppresses production.
Melatonin works as a hypnotic by accelerating sleep onset and improving sleep maintenance and efficiency. Unlike other hypnotics, melatonin does not cause significant changes in sleep architecture, has no hangover effects or potential for abuse, nor has it been associated with delirium. Although sleep-wake cycle disturbances are not a diagnostic criterion for delirium, they are incorporated into delirium assessment tools with studies indicating that sleep disturbances are present in 75% of patients with delirium. Alterations in the circadian pattern of melatonin secretion have been described in various critically ill populations.
Advances in our understanding of the association of delirium and the devastating outcomes of critically ill patients have fueled the fury of prevention trials with pharmacological and non-pharmacological interventions and, more recently, these include melatonin or melatonin receptor agonists. and sleep strategies (e.g., reducing noise or light).
Purpose
Delirium is common in critically ill patients, highly distressing to patients and families, and is associated with increased morbidity and mortality. The results of studies on the preventive use of melatonin in various patient groups have produced mixed results.
The objective of this study was to determine whether the administration of melatonin reduces the prevalence of delirium in critically ill patients.
Methods
Multicenter, randomized, placebo-controlled, double-blind trial in 12 Australian ICUs recruiting patients from July 2016 to September 2019.
Patients at least 18 years old who required ICU admission with an expected length of stay (LOS) greater than 72 h; enrolled within 48 hours of admission to the ICU.
Indistinguishable liquid melatonin (4 mg; n = 419) or placebo (n = 422) was administered enterally at 9:00 p.m. for 14 consecutive nights or until ICU discharge.
The primary outcome was the proportion of delirium-free assessments, as a marker of delirium prevalence, within 14 days or before ICU discharge.
Delirium was assessed twice daily using the Confusion Assessment Method for ICU (CAM-ICU) score.
Secondary outcomes included sleep quality and quantity, hospital and ICU length of stay, and in-hospital and 90-day mortality.
Results
A total of 847 patients were randomized into the study with 841 included in the data analysis. Baseline characteristics of the participants were similar.
- There was no significant difference in the average proportion of delirium-free assessments per patient between the melatonin and placebo groups (79.2 vs 80% respectively, p = 0.547).
- There were no significant differences in secondary outcomes, including ICU stay (median: 5 vs 5 days, p = 0.135), hospital stay (median: 14 vs 12 days, p = 0.135), mortality at any time point, even at 90 days (15.5 vs 15.6% p = 0.948), nor in the quantity or quality of sleep.
- No serious adverse events were reported in either group.
Conclusion
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Main message
In this multicenter randomized trial involving 847 critically ill patients, the proportion of assessments without delirium was 79.2% in the melatonin group and 80% in the placebo group, a nonsignificant difference. Early use of melatonin for patients admitted to intensive care units did not reduce delirium compared with placebo.
From the editorial
We often think that simple things will solve complicated problems in the ICU; They rarely do. Importantly, we have not yet found a single prophylactic drug that targets a specific pathway to consistently prevent delirium.
What we do know is that bundled interventions (i.e., ABCDEF bundles ) reduce the risk of delirium and show us that multifaceted approaches are likely key.
One of the important next steps in delirium research may include studies investigating specific pharmacological interventions, such as melatonin, to restore layered sleep in addition to bundled interventions that have been shown to be successful. These studies should not only focus on the burden of delirium in the ICU, but also other clinically relevant outcomes, including cognitive impairments, anxiety and depression, and sleep disorders frequently seen in ICU survivors. .
