Highlights
– A comprehensive meta-analysis of 13 randomized controlled trials finds no benefit for melatonin in delirium prevention.
– Primary analysis restricted to low-to-moderate risk of bias studies confirms no significant reduction in delirium incidence (RR 0.89).
– Melatonin administration does not influence mortality rates among critically ill patients, suggesting a limited role for this hormone in acute recovery.
Introduction: The Burden of Delirium in Critical Care
Delirium, characterized by acute brain dysfunction with fluctuating levels of consciousness and impaired attention, remains a formidable challenge in the Intensive Care Unit (ICU). It affects up to 80 percent of mechanically ventilated patients and is independently associated with increased mortality, prolonged hospital stays, and long-term cognitive impairment. The pathophysiology of delirium is multifactorial, involving neuroinflammation, oxidative stress, and profound disruptions in the circadian rhythm. Given the high clinical burden and the lack of effective pharmacological treatments once delirium is established, prevention has become the cornerstone of management. Among various potential agents, melatonin—an endogenous hormone that regulates the sleep-wake cycle—has emerged as a candidate for delirium prophylaxis due to its chronobiotic, antioxidant, and anti-inflammatory properties. However, clinical trials have yielded conflicting results, leading to uncertainty in international guidelines.
Study Design and Methodology
To address this clinical uncertainty, Lakbar and colleagues conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). The researchers performed an exhaustive search of MEDLINE, Embase, and Web of Science from their inception through July 5, 2025. The study was registered with PROSPERO (CRD420251041661).
The primary outcome of interest was the incidence of delirium in critically ill patients. The main secondary outcome was mortality. To ensure the highest level of evidence, the investigators performed a primary analysis restricted to trials with a low to moderate risk of bias. A secondary analysis was also conducted, incorporating all eligible trials regardless of bias risk to provide a broader overview of the existing literature. Pooled risk ratios (RR) with 95 percent confidence intervals (CI) were calculated to quantify the effect of melatonin compared to placebo or standard care.
Key Findings: No Significant Impact on Delirium or Survival
The results of this meta-analysis provide a clear, albeit negative, answer regarding the efficacy of melatonin in the ICU setting.
Delirium Incidence
In the primary analysis, which included six high-quality RCTs comprising 2,209 patients, there was no statistically significant difference in the incidence of delirium between patients receiving melatonin and those receiving a placebo (RR 0.89; 95% CI 0.73-1.09). This finding suggests that melatonin does not provide a protective effect against the onset of delirium in a general ICU population. The secondary analysis, which expanded the pool to 13 RCTs and 2,830 patients, yielded consistent results (RR 0.86; 95% CI 0.70-1.04), further reinforcing the lack of efficacy across varying study qualities.
Mortality and Safety
Secondary outcomes focused on patient survival. The primary analysis of seven RCTs involving 2,165 patients found no association between melatonin use and mortality (RR 0.87; 95% CI 0.73-1.02). The secondary analysis of eight RCTs involving 2,396 patients confirmed this (RR 0.92; 95% CI 0.79-1.06). While melatonin was generally well-tolerated, it offered no survival advantage to critically ill patients.
Expert Commentary: Interpreting the Discrepancies
The lack of efficacy observed in this meta-analysis stands in contrast to some earlier, smaller trials that suggested a potential benefit. Several factors may explain these discrepancies and provide insights into why melatonin might fail in the intensive care environment.
First, the dosage and timing of melatonin administration vary significantly across studies, ranging from 1 mg to 10 mg. It is possible that the optimal dose for restoring circadian rhythms in the hyper-inflammatory state of critical illness has not yet been identified. Furthermore, the bioavailability of oral melatonin is notoriously low and variable, which may be further compromised in ICU patients with gastrointestinal dysmotility.
Second, the multifactorial nature of delirium means that a single pharmacological intervention is unlikely to be a panacea. While melatonin addresses circadian disruption, it may not sufficiently counteract other drivers such as sedation depth, metabolic derangements, or the psychological stress of the ICU environment. This highlights the importance of the ABCDEF (Assess, Prevent, and Manage Pain; Both Spontaneous Awakening and Breathing Trials; Choice of Analgesia and Sedation; Delirium Monitoring and Management; Early Mobility; Family Engagement) bundle, which emphasizes non-pharmacological interventions.
Third, patient heterogeneity remains a significant hurdle. Subgroups of patients, such as those with specific surgical backgrounds or pre-existing sleep disorders, might still benefit from melatonin, but these nuances are often lost in large meta-analyses of heterogeneous ICU populations.
The results is similar to the article: Melatonin in the ICU Does Not Translate to Reduced Delirium Incidence
Conclusion and Future Directions
The findings by Lakbar et al. suggest that melatonin should not be routinely used for the prevention of delirium in critically ill patients. The evidence from high-quality RCTs consistently shows no significant reduction in delirium incidence or mortality. While melatonin remains a safe and relatively inexpensive supplement, its clinical utility in the acute phase of critical illness appears limited.
Future research should perhaps shift focus from general prophylaxis to targeted interventions in specific patient phenotypes or investigate the role of more potent melatonin receptor agonists, such as ramelteon, which may offer better bioavailability and receptor affinity. Until then, clinicians should prioritize evidence-based, non-pharmacological strategies—such as early mobilization, sleep hygiene, and minimizing benzodiazepine use—to mitigate the risk of delirium in their patients.
References
Lakbar I, Poole D, Delamarre L, Chanques G, Pensier J, Monet C, Belafia F, Capdevila M, De Jong A, Jaber S. Melatonin and delirium in the intensive care units: a systematic review and meta-analysis of randomized controlled trials. Intensive Care Med. 2025 Nov;51(11):2079-2092. doi: 10.1007/s00134-025-08143-1 IF: 21.2 Q1 . Epub 2025 Oct 6. PMID: 41051561 IF: 21.2 Q1 .
