# Melatonin and delirium in the intensive care units: a systematic review and meta-analysis of randomized controlled trials

Inès Lakbar, Daniele Poole, Louis Delamarre, Gérald Chanques, Joris Pensier, Clément Monet, Fouad Belafia, Mathieu Capdevila, Audrey de Jong, Samir Jaber

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To cite this version:

Inès Lakbar, Daniele Poole, Louis Delamarre, Gérald Chanques, Joris Pensier, et al., Melatonin and delirium in the intensive care units: a systematic review and meta-analysis of randomized controlled trials. Intensive Care Medicine, 2025, 51, pp.2079-2092. 10.1007/s00134-025-08143-1. hal-05300744

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# Melatonin and delirium in the intensive care units: a systematic review and meta-analysis of randomized controlled trials

Inès Lakbar<sup># 1 2</sup>, Daniele Poole<sup># 3</sup>, Louis Delamarre<sup>4</sup>, Gérald Chanques<sup>5</sup>, Joris Pensier<sup>5</sup>, Clément Monet<sup>5</sup>, Fouad Belafia<sup>5</sup>, Mathieu Capdevila<sup>5</sup>, Audrey De Jong<sup>5</sup>, Samir Jaber<sup>5</sup>

<sup>1</sup> Department of Anesthesia and Intensive Care Unit, Regional University Hospital of Montpellier, St-Eloi Hospital, University of Montpellier, PhyMedExp, INSERM U1046, CNRS UMR, 9214, Montpellier Cedex 5, France. ines.lakbar@chu-montpellier.fr.

<sup>2</sup> Département d'Anesthésie-Réanimation B (DAR B), Montpellier, France. ines.lakbar@chu-montpellier.fr.

<sup>3</sup> Departmental Operative Unit of Pain Therapy, S. Martino Hospital, Belluno, Italy.

<sup>4</sup> Department of Anesthesia and Intensive Care Unit, Regional University Hospital of Montpellier, Gui De Chauliac, Montpellier, France.

<sup>5</sup> Department of Anesthesia and Intensive Care Unit, Regional University Hospital of Montpellier, St-Eloi Hospital, University of Montpellier, PhyMedExp, INSERM U1046, CNRS UMR, 9214, Montpellier Cedex 5, France.

<sup>#</sup> Contributed equally.

**\*Correspondence:**

ines.lakbar@chu-montpellier.fr

4 Département d'Anesthésie-Réanimation B (DAR B), Montpellier, France
# Abstract

**Background:**

Delirium is frequent in critically ill patients and is associated with increased mortality. Discrepancies were found in the results of recent randomized controlled trials (RCTs) regarding the effect of melatonin to prevent delirium onset in critically ill patients.

**Methods:**

We searched MEDLINE, Embase, and Web of Science from inception to 5 July 2025 for RCTs evaluating melatonin in critically ill patients. The primary outcome was the incidence of delirium. The main secondary outcome was mortality. We generated pooled risk ratios (RR). To base our conclusions on the highest quality of evidence, our primary analysis was based only on the trials with low to moderate risk of bias for each outcome. A secondary analysis was conducted, including all the trials. The study was registered with PROSPERO (CRD420251041661).

**Findings:**

Our primary analysis was based on six RCTs with 2209 patients and did not show any difference in the incidence of delirium attributable to the treatment with melatonin (RR 0.89, [95% confidence interval (CI) 0.73-1.09]). This result was consistent with the secondary analysis including thirteen RCTs with 2830 patients (RR 0.86, [95% CI 0.70-1.04]). No association was found between mortality and melatonin in the primary (seven RCTs, 2165 patients, RR 0.87, [95% CI 0.73-1.02]) and secondary (8 RCTs, 2396 patients, RR 0.92, [95% CI 0.79-1.06]) analyses.

**Interpretation:**

The results suggest that compared to placebo, melatonin does not reduce delirium incidence in critically ill patients. Similarly, no effect was observed on mortality.
# Introduction

Delirium is a prevalent complication among critically ill patients, occurring in up to 80% of those admitted to intensive care units (ICUs) [1]. In ICU settings, delirium is more frequent among patients receiving invasive mechanical ventilation compared with those who are not ventilated. In the postoperative setting, the prevalence of delirium varies depending on the type of surgery and the need for ventilation, with the highest rates consistently observed after cardiac surgery with cardiopulmonary bypass [1–3]. It is associated with significant adverse outcomes, including increased early and longterm mortality, elevated healthcare costs, and cognitive and functional impairments in survivors [4, 5]. Critically ill patients are particularly susceptible, as delirium may exacerbate pre-existing organ dysfunction, notably respiratory failure, by complicating ventilator weaning and prolonging the duration of mechanical ventilation [6–8].

The pathophysiology of delirium in ICU patients is multifactorial, involving predisposing factors such as advanced age, severity of acute illness, and exposure to sedative medications, notably benzodiazepines and opioids [9, 10]. Moreover, disturbances in circadian rhythm and sleep architecture, which are regulated by endogenous melatonin secretion, have been recognized as pivotal contributors in the pathogenesis of delirium [6]. In critically ill patients, serum melatonin levels are decreased among patients with delirium compared to those without delirium [11]. Furthermore, melatonin exhibits anti-inflammatory and immunomodulatory properties that can potentially protect the brain from injury in cases of encephalopathy, acute brain injury, and chronic neurodegenerative disorders [12, 13]. The objective of this meta-analysis was to aggregate results from randomized controlled trials investigating the effect of melatonin on delirium in critically ill patients. We hypothesized that melatonin would have no significant effect on the incidence of delirium.

# Methods

The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) recommendations [14, 15] and was registered in the PROSPERO database prior to the study initiation (CRD 420251041661).

## PICO question

In adult patients hospitalized in intensive care units (ICUs) (Population), does the administration of melatonin (any dosage or route) (Intervention) compared with placebo (Comparator) result in a lower incidence of delirium (Outcome)?

## Search strategy

We systematically searched PubMed, Embase and Web of Science databases from inception until July 5, 2025, for randomized controlled trials (RCTs) evaluating melatonin administered during the intensive care unit stay in adult patients (≥ 18 years). No language restrictions were applied. In brief, we used keywords as exact phrases and subject headings according to
database syntaxes. The full search strategy is described in electronic supplementary material
1.

Eligibility and inclusion/exclusion criteria

We intended to include papers describing randomized controlled trials only. Observational studies may provide supportive information when adjusted analyses are performed, but their results cannot be reliably pooled because statistical models and covariates differ across studies, and unadjusted outcome data would introduce major confounding. Therefore, only RCTs were included as the most reliable source of evidence. Observational studies, cohorts, case reports, animal models, and special populations (children, pregnant women) were excluded. We used author definitions for delirium. For the primary analysis, only studies that adhered to guideline-compliant delirium assessment practices were retained [2]. Studies were excluded if the incidence of delirium was zero in both the melatonin and placebo groups.

Paper selection

The titles and abstracts of all records were screened independently and in duplicate by two of the authors (IL, LD) using the Rayyan software tool [16]. The papers selected were downloaded in full, and they were reviewed independently and in duplicate by the same two authors to verify fulfillment of inclusion criteria. The reference lists of relevant articles were searched for additional potentially pertinent articles (i.e., snowballing method). All articles rated discrepantly by the two screening authors in the Rayyan software were reviewed and discussed one by one by both authors and subsequently included only if both authors agreed on eligibility. In each stage, disagreements were resolved by a third author (SJ). We planned to contact the corresponding authors of the screened studies in case questions arose regarding eligibility or data presentation, but no such issues arose.

Data extraction

Two authors (IL, DP) extracted the data in duplicate using a standardized data extraction
form. Discrepancies in the extracted data were adjudicated by consensus or a third author
when needed (SJ). The data extracted included study characteristics (e.g., source country,
study type, single/multicenter), patient demographics (age, sex), medical background,
treatments (melatonin route and dosage), and outcomes. The final version of the database was
validated by all the investigators involved in data collection (IL, DP, LD) and is available as
electronic supplementary material 2.

Assessment of risk of bias

Risk of bias was assessed for the primary outcome in each trial through a sequential process
(Methodology in electronic supplementary material 3). First (step 1), we evaluated reporting
quality according to the CONSORT statement [17]. Trials with reporting judged insufficient
for quality assessment were excluded from the primary analysis. Second (step 2), we assessed
the risk of bias using the Cochrane RoB2 tool [18], complemented by selected items from the
GRADE framework (step 3) to capture additional methodological features (see Methodology,
e-Table 1 in electronic supplementary material 3) [19]. Trials at high risk of bias were excluded from the primary analysis. Then (step 4), we examined the presence of small trial bias. This was defined when the total sample size was < 100 patients and the absolute risk difference in delirium incidence between groups exceeded 10% [20–26]. The choice of this 10% threshold was informed by prior randomized trials comparing haloperidol with placebo for delirium prevention, which reported absolute risk reductions ranging from 0 to 8% [27, 28], as well as by a metaanalysis reporting a 2% reduction [29]. Finally (step 5), we calculated the fragility index as a marker of robustness. This index corresponds to the number of outcome events that would need to overturn statistical significance [30]. Based on values reported in prior reviews of RCTs published in major medical journals [30–32], we set a threshold of ≤ 2 for exclusion from the primary analysis. A schematic diagram summarizing these steps and the criteria required for inclusion in the primary analysis is reported in Methodology in electronic supplementary material 3.

Recognizing the arbitrariness of these criteria, we performed prespecified sensitivity analyses applying alternative thresholds (5% and 15% for small trial bias; ≤ 1, ≤ 3, and ≤ 5 for the fragility index). Studies with simple randomization reporting exactly balanced groups (difference ≤ 2 patients per arm) were also rated down, as allocation concealment could not be considered ensured, particularly in the absence of blinding [33]. Finally, risk of bias was assessed separately for mortality and for other outcomes, since only mortality was assumed not to be influenced by blinding.

## Outcomes

The main study outcome was the incidence of delirium at any given point. We used authors’ definitions for delirium. Mortality was the main secondary outcome. Other prespecified secondary outcomes included delirium severity, adverse events, duration of mechanical ventilation, and ICU length of stay.

## Primary and secondary analyses

For the primary outcome (delirium incidence) and the main secondary outcome (mortality), we predefined two analytical strata. The primary analysis included studies with robust methodology, as determined by the stepwise risk-of-bias assessment described above. The secondary analysis included all eligible studies, irrespective of methodological limitations. In line with guideline recommendations, only studies that adhered to validated and guideline-compliant delirium assessment practices were retained in the primary analysis for the delirium outcome [2].

## Certainty of evidence

The certainty of the body of evidence for the delirium incidence outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [34]. Summary of findings tables were generated separately for the primary and secondary analyses to reflect differences in study selection and underlying risk of bias.
## Statistical analysis

The studies combined in the meta-analysis were considered to have sufficient clinical homogeneity. Nevertheless, we anticipated potential sources of heterogeneity related to trial methodology, patient populations, and dosing strategies. Therefore, all analyses were conducted with random-effects models, and sensitivity analyses were performed (see below). We used relative risks as the outcome measure for dichotomous variables and mean differences for continuous variables.

Statistical heterogeneity (i.e., chance variation between studies) was investigated with the nonparametric Cochran's *Q* test and the I2 statistic estimate [35] together with its confidence intervals [36]. Even in the presence of a statistically significant Cochran's *Q* test, if the I2 confidence interval ranged between low (< 25%) and high (> 50%) values of statistical heterogeneity, the results of the analyses were considered inconclusive. We also used interaction tests to compare subgroups.

We used double-*p* plots to visually evaluate the matched contribution of heterogeneity and overall results to *p* values [37]. The plot compares *p* values provided by meta-analyses performed excluding one trial at a time, allowing us to identify studies that are critical in determining statistical significance for heterogeneity and overall results. We conducted this analysis on the subset of studies included in the primary analysis and on the entire set of trials. When single outlier trials were crucial in determining statistical significance, especially for overall results, a critical reassessment of those studies was performed to make sure that clinical and methodological homogeneity assumptions were matched.

Exploratory sensitivity analyses were also performed to test the robustness of the findings. These included stratification by protocol cumulative dose, meta-regression with cumulative dose entered as a continuous covariate, and exclusion of trials conducted exclusively in surgical ICUs.

We used trial sequential analysis (TSA) to assess the risk of random errors due to sparse data and multiple testing of accumulating data, and to calculate the required information size for delirium incidence. To determine the control event rate required for boundary estimation, the incidence of delirium in the control group was pooled using both fixed-effect and random effects models. The resulting cumulative incidence of fixed effects was used for all TSA calculations. For TSA calculations, we set the following parameters: alpha error 0.05, beta error 0.20, event incidence in the control arm 0.37 (the pooled incidence meta-analyzing all the studies using a common-effect model, e-Fig. 1), and an absolute risk reduction of 0.10.

All *p* values were two-tailed. *p* values less than 0.05 were considered statistically significant.

All analyses were performed using R software (R Core Team 2013, R Foundation for Statistical Computing, Vienna, Austria, URL (http://www.R-project.org/) with the package meta and metafor [38].
<table><caption>Table 1 Characteristics of the included studies</caption><thead><tr><th>Name year</th><th>Intervention</th><th>Control</th><th>Outcome measure</th></tr></thead><tbody><tr><td>Abbasi 2018<br>RCT<br>Iran<br>Single center<br>Medical-surgical ICU<br>GCS &lt; 8 excluded<br>N = 137</td><td>Melatonin 3 mg administered for 5 days</td><td>Placebo</td><td>Delirium assessed with CAM-ICU for 8 days<br>Guidelines compliant in terms of delirium definition</td></tr><tr><td>Bandyopadhyay 2024<br>RCT<br>India<br>Single center<br>Medical-surgical ICU<br>Comatose patients excluded<br>N = 108</td><td>Melatonin 3 mg for 7 days or until discharge</td><td>Placebo</td><td>New-onset delirium within 24 h assessed with CAM-ICU<br>Guidelines compliant in terms of delirium definition for secondary outcomes only</td></tr><tr><td>Bourne 2008<br>RCT<br>United Kingdom<br>Single center<br>General ICU<br>Neurological disease and SAS &lt; 4 excluded<br>N = 24</td><td>Melatonin 10 mg for 4 nights</td><td>Placebo</td><td>Delirium (for which no diagnostic method was reported) during the study period<br>Guidelines non-compliant in terms of delirium definition</td></tr><tr><td>Burry 2025<br>Three-arm feasibility RCT<br>Canada<br>Multi-center<br>Neurotrauma excluded<br>N = 70</td><td>Melatonin 0.5 or 2 mg for a maximum of 14 days or ICU discharge or death</td><td>Placebo</td><td>Delirium diagnosed by ICDSC score ≥ 4 (period of assessment<br>probably 14 days)<br>Guidelines compliant in terms of delirium definition</td></tr><tr><td>Gandolfi 2020<br>RCT<br>Brazil<br>Multi-center<br>Medical surgical ICUs<br>Seizures and neurological illness excluded<br>N = 203</td><td>Melatonin 10 mg for 7 days</td><td>Placebo</td><td>Delirium assessed with the delirium diagnosed by ICDSC score ≥ 4<br>Guidelines compliant in terms of delirium definition</td></tr><tr><td>Gupta 2022<br>RCT<br>India<br>Single center<br>Surgical ICU<br>No information on inclusion/exclusion criteria for neurologically injured patients<br>N = 140</td><td>Melatonin 5 mg until death or ICU discharge</td><td>Placebo</td><td>Delirium diagnosed with CAM-ICU (the period of assessment is likely the stay in the ICU)<br>Guidelines non-compliant in terms of delirium definition</td></tr><tr><td>Mekontso Dessap 2025<br>Multi-arm, multi-stage adaptive RCT<br>France<br>Multi-center<br>Mixed ICUs<br>TBI and patients who undergone neurosurgery excluded<br>N = 301</td><td>Melatonin 0.3 mg for 14 days</td><td>Placebo</td><td>Incidence of delirium measured with CAM-ICU within 14 days or death or ICU discharge<br>Guidelines compliant in terms of delirium definition</td></tr><tr><td>Naderli-Behdani 2022<br>RCT<br>Iran<br>Single center<br>General ICU<br>Patients with neurological injury included<br>N = 96</td><td>Melatonin 3 mg twice a day, for 3 days</td><td>Placebo</td><td>Delirium was assessed with the RASS within 7 days from randomization only in patients still in the ICU<br>Guidelines non-compliant in terms of delirium definition</td></tr><tr><td>Shi 2021<br>RCT<br>China<br>Single center<br>Cardiac ICU<br>Brain Injury and patients who undergone neurosurgery excluded<br>N = 297</td><td>Melatonin 3 mg/day within 7 days from onset of acute heart failure and administered for up to seven days thereafter</td><td>Placebo</td><td>Delirium measured by CAM or CAM-ICU criteria within 7 days<br>Guidelines compliant in terms of delirium definition</td></tr></tbody></table>
<table><caption>Table 1 (continued)</caption><thead><tr><th>Name year</th><th>intervention</th><th>Control</th><th>Outcome measure</th></tr></thead><tbody><tr><td>Vijayakumar 2016<br>RCT<br>India<br>Single center<br>Unclear type of ICU<br>Post cardiac arrest excluded<br>N=56</td><td>Melatonin 3 mg each night during ICU stay through nasogastric tube</td><td>Placebo</td><td>Delirium measured with CAM-ICU only in patients with RASS - 3 or more<br>Guidelines compliant in terms of delirium definition</td></tr><tr><td>Wibrow 2022<br>RCT<br>Australia<br>Multi-center<br>Unclear types of ICU<br>Persistent neurological impairment excluded<br>N=841</td><td>Melatonin 4 mg via nasogastric tube for 14 days</td><td>Placebo</td><td>Delirium measured by CAM-ICU criteria within 14 days or at ICU discharge if occurring earlier<br>Guidelines compliant in terms of delirium definition</td></tr><tr><td>Yin 2022<br>RCT<br>Iran<br>Single-center<br>Post CV-surgery ICU<br>Brain injury and patients who undergone neurosurgery or had seizures excluded<br>N=497</td><td>Melatonin 3 mg/day within 7 days from onset of AHF and administered for up to seven days thereafter</td><td>Placebo</td><td>Delirium measured by CAM or CAM-ICU criteria within 7 days<br>Guidelines compliant in terms of delirium definition</td></tr><tr><td>Zadeh 2021<br>RCT<br>Iran<br>Single-center<br>Post CV-surgery ICU<br>Neurological illness excluded<br>N=60</td><td>Melatonin 3 mg the evening before, the same day, the day after coronary bypass</td><td>Placebo</td><td>Delirium assessed by CAM-ICU on the first day after surgery<br>Guidelines non-compliant in terms of delirium definition</td></tr></tbody></table>

Definition of delirium is considered compliant to guidelines if it follows both the European definition of postoperative delirium and the PADIS definition [2, 12, 67]

ICU intensive care unit, GCS Glasgow Coma Scale, SAS Sedation Agitation Scale, TBI traumatic brain injury, CAM confusion assessment method, CAM-ICU confusion assessment method-intensive care unit, RASS Richmond Agitation and Sedation Scale, ICDSC Intensive Care Delirium Screening Checklist, CV cardiovascular

<figure><img src="image_3.png" /><figcaption>Fig. 1 Flowchart of the included studies. ICU Intensive care unit</figcaption></figure>
# Results

A total of 1238 studies were identified and screened, of which 13 provided data eligible for inclusion in the metaanalysis [39–51], encompassing 2830 patients (1417 patients allocated to melatonin and 1413 allocated to placebo) (Fig. 1). Six studies including 1110 and 1099 patients in the melatonin and placebo arms respectively, were included in the primary analysis [42, 45–48, 51].

## Included studies

All included studies were randomized controlled trials; one was available only in abstract form from a conference proceeding [49]. The trials were conducted across multiple continents, including Europe, North America, Asia, and South America (Europe $n = 2$, North America $n = 1$, Iran $n = 3$, China $n = 2$, India $n = 3$, Brazil $n = 1$, and Australia $n = 1$).

## Risk of bias

One study was excluded from the primary analysis because methodological reporting was insufficient according to the CONSORT checklist, preventing a reliable quality assessment (Methodology in electronic supplementary material 3) [49]. As for the primary outcome (delirium incidence), the risk of bias assessment using the RoB 2 tool [18] showed that four studies [39, 40, 44, 50] were at high risk of bias and the other eight studies [41–43, 45–48, 51] were either at low risk of bias or showed some concerns (electronic supplementary material 4.A).

The quality of evidence provided by two studies (Bourne and Zadeh [41, 43]) among the eight trials with low risk of bias according to RoB2 was rated down because of small trial bias. Therefore, these two studies were included in the secondary analysis only. No RCT matched the fragility index criteria for exclusion from the primary analysis (electronic supplementary material 4.A). The results of the risk of bias assessment for the mortality outcome are reported in electronic supplementary material 4.B.

## Primary outcome

Thirteen randomized controlled trials including a total of 2,830 patients (1,417 receiving melatonin and 1,413 receiving placebo) reported the incidence of delirium. Nine out of 13 studies [39, 40, 43–46, 48, 49, 51] used the confusion assessment method for the intensive care unit (CAM-ICU) [52] as a tool to diagnose delirium, 2 studies [42, 47] used the Intensive Care Delirium Screening Checklist (ICDSC), 1 study [50] reported using the Richmond Agitation Sedation Scale (RASS), and another one [41] did not mention the diagnosis tool used (Table 1).
The pooled analysis showed no effect of melatonin on delirium incidence. The primary and secondary analyses were consistent in their results with relative risk (RR) of 0.89 [95% confidence interval (CI) 0.73–1.09] and 0.86 [95% CI 0.70–1.04], respectively.

The test for subgroup interaction between studies with robust methodology and those with methodological limitations yielded a $\chi^2$ value of 0.18 with a $p$ value of 0.67, indicating no statistically significant difference in treatment effect across these (Fig. 2).

Statistical heterogeneity was not statistically significant in the primary analysis ($I^2$ = 49% [95% CI 0–80%], $\tau^2$ = 0.0282, $p$ = 0.08), but significant in the secondary analysis ($I^2$ = 51% [95% CI 9–74%], $\tau^2$ = 0.0485, $p$ = 0.02). However, in both cases, the interpretation of heterogeneity remained inconclusive. The 95% confidence intervals around $I^2$ ranged from 0 to 80% in the primary analysis and from 0 to 81% in the secondary analysis, thus encompassing values that correspond to markedly different levels of heterogeneity (Fig. 2).

<figure><img src="image_4.png" /></figure>

In the primary analysis for the incidence of delirium, the double-p plot showed that exclusion of the Shi [45] or Yin [48] studies increased the $p$ value for the overall effect, while removal of the Wibrow study [46] decreased it. However, statistical significance was never reached in any scenario. Other studies had minimal influence. This led us to review the and trials more closely. Both had several reporting limitations (no mention of the expected delirium incidence in the control group, unclear expected risk reduction, and missing information on randomization block sizes) and analysis issues (patients lost to follow-up were still included in the intention-to-treat analysis). Still, these studies did not meet formal exclusion criteria for
the primary analysis. Because of these inconsistencies, we downgraded the certainty of evidence for the primary analysis. The p value for statistical heterogeneity was low, suggesting substantial heterogeneity. In the double-p plot, excluding any of the three studies (Shi [47], Yin [42] or Wibrow [40]) moderately increased the p value for heterogeneity, indicating a partial reduction in inconsistency when these trials were removed (electronic supplementary material 4.A).

In the secondary analysis for the incidence of delirium, the double-p plot revealed that the exclusion of the Nader-Behdani [50] study (which showed an increased risk with melatonin (RR 1.35)) led to a statistically significant overall effect. Of note, this study had been excluded from the primary analysis due to small study bias associated with a large harmful effect estimate (absolute risk increase of 12.5% with 96 patients enrolled, electronic supplementary material 4.A). Moreover, in this study, delirium was assessed using the Richmond Agitation Sedation Scale (RASS), which is not a validated diagnostic tool for delirium and could not be comparable with other tools such as the CAM-ICU.

Trial sequential analyses (TSA) were performed for both the primary and secondary analyses.

In the primary analysis, the cumulative Z-curve did not cross the monitoring boundaries for benefit or harm (alpha boundaries), but did cross the futility boundary (beta boundary), suggesting that further studies are unlikely to change the conclusion. The required information size adjusted for heterogeneity (HARIS) was estimated at 2,531 patients (electronic supplementary material 4.A).

In the secondary analysis, similar results were observed: the futility boundary was crossed, while alpha boundaries were not. The HARIS was estimated with 2,994 patients (electronic supplementary material 4.A).

## Secondary outcomes

Eight trials (n = 2,396 patients) were available for the analysis of mortality, after exclusion of studies not reporting mortality [41, 43], not specifying the time point [39, 49] or reporting no deaths [44]. Mortality was analyzed according to the reported time point (28-day or 30-day, hospital, or ICU mortality), with 28-day or 30-day mortality prioritized when multiple outcomes were available. The pooled analysis of 28- or 30-day mortality, the most clinically relevant and consistently reported endpoint, showed no significant effect of melatonin (RR 0.91 [95% CI 0.77–1.06], I2 = 0% [95% CI 0–85%], p = 0.23, Fig. 3, electronic supplementary material 4.B). Results were consistent when considering hospital or ICU mortality, with no signal of benefit in any subgroup. Overall pooled mortality likewise showed no significant association (RR 0.93 [95% CI 0.80–1.08], I2 = 0% [95% CI 0–71%], p = 0.32, Fig. 3, electronic supplementary material 4.B). One study was classified in the secondary analysis according to the risk-of-bias framework, but its exclusion did not materially change the findings.

Data on delirium severity could not be aggregated due to the limited number of studies (n = 2) reporting this outcome and the heterogeneity of assessment tools.

Reporting of adverse events was inconsistent across studies and did not allow for meta-analysis. In most trials, either no adverse events were observed in either group, or the authors did not report on safety outcomes at all. Only a few studies described isolated events, including pruritus, headache, or postoperative neurological complications, with no clear
pattern or excess risk attributable to melatonin. No study reported a statistically significant increase in adverse events in the melatonin arm.

<figure><img src="image_5.png" /><figcaption>Fig. 3 Forest plot for the main secondary outcome study: mortality. RR risk ratio, CI confidence interval, T treatment (melatonin), C control</figcaption></figure>

Six RCTs reported data on the duration of mechanical ventilation (n = 1338 patients; 677 in the melatonin group and 661 in the control group). The pooled analysis showed no association between ventilation duration and melatonin administration when aggregating mean or median data as reported by authors (see electronic supplementary material 4.C).

Nine RCTs (n = 1338 patients; 677 in the melatonin group and 661 in the control group) reported ICU length of stay. The pooled analysis showed no significant difference between melatonin and placebo when aggregating mean or median data as reported by authors (see electronic supplementary material 4.C).

## Sensitivity analyses

Sensitivity analyses were performed to test the robustness of the primary findings across different methodological thresholds. When alternative fragility index cut-offs were applied (≤ 1, ≤ 3, and ≤ 5), the overall conclusions remained unchanged (Methodology in electronic supplementary material 3). Similarly, varying the definition of small trial bias by adopting alternative thresholds for the absolute risk reduction (5% and 15%) did not alter the results (Methodology in electronic supplementary material 3). In each case, the exclusion or reclassification of individual trials led to minor shifts in study grouping but no meaningful
modification of the pooled effect estimates as reported in the Methodology in electronic supplementary material 3.

In exploratory analyses, stratification by protocol cumulative dose (< 10 mg vs ≥ 10 mg) showed no significant interaction with treatment effect (electronic supplementary material 3). Likewise, meta-regression of delirium risk against cumulative dose did not identify a significant dose-response relationship (coefficient 0.006; *p* = 0.382; electronic supplementary material 3).

Finally, exclusion of trials conducted exclusively in surgical ICUs yielded results consistent with the primary analysis (RR 1.04 [95% CI 0.82–1.32], *I2* = 29% [95% CI 0–66%], *p* = 0.76) (electronic supplementary material 3).

## Certainty of the evidence

The results of the GRADE assessment for the incidence of delirium outcome are reported in Table 2. The overall certainty of evidence for the primary analysis was rated as low, owing to some concerns regarding inconsistency [53] and imprecision [54]. For the secondary analysis, the certainty was rated as very low, due to the presence of a serious risk of bias, inconsistency, and imprecision. For mortality, the certainty of evidence was rated as moderate in the primary analysis, due to serious imprecision. The secondary analysis, including only one additional small study, did not change the level of certainty (electronic supplementary material 4.B).

<table><caption>Table 2 Grade assessment of the meta-analysis (primary outcome)</caption><thead><tr><th colspan="10">Overall quality assessment</th></tr><tr><th>Outcome</th><th>N. of RCTs</th><th>Treatment, n</th><th>Control, n</th><th>RR [95% CI]</th><th>Risk of bias</th><th>Inconsistency</th><th>Indirectness</th><th>Imprecision</th><th>Publication bias</th><th>Quality</th><th>Analysts</th></tr></thead><tbody><tr><td>Delirium rate</td><td>6</td><td>1110</td><td>1099</td><td>0.89 [0.73–1.09]</td><td>No</td><td>Serious</td><td>No</td><td>Serious</td><td>No</td><td>++ ∞ Low</td><td>Not in favor</td><td>Primary</td></tr><tr><td>Delirium rate</td><td>13</td><td>1417</td><td>1413</td><td>0.86 [0.7–1.04]</td><td>Serious</td><td>Serious</td><td>No</td><td>Serious</td><td>No</td><td>+ ∞ ∞ Very low</td><td>Not in favor</td><td>Secondary</td></tr></tbody></table>

RCT randomized controlled trial, RR risk ratio, CI confidence interval

## Discussion

This meta-analysis does not support the efficacy of melatonin for preventing delirium in critically ill patients. The pooled effect estimate for delirium incidence was not statistically significant, both in the primary analysis restricted to high-quality studies and in the secondary analysis including all trials. Trial sequential analyses further indicated that additional data are unlikely to modify this conclusion. Similarly, no effect was observed on mortality, ICU length of stay, or duration of mechanical ventilation.

These findings should be interpreted in light of the 2025 PADIS guideline update [12], which recommended the use of melatonin to prevent ICU delirium. This recommendation was based on a meta-analysis conducted by the guideline panel, which combined studies of markedly heterogeneous quality, patient populations, and interventions, including trials that initiated melatonin prior to elective surgery, trials using structurally unrelated agents such as remolten,
and several small single-center studies at high risk of bias [12]. Despite the acknowledged low
certainty of evidence and substantial clinical heterogeneity, a preventive effect was suggested.
In contrast, our meta-analysis prioritized methodological rigor and incorporated the most
recent high-quality RCT by Mekontso Dessap et al. [51]. These differences in methodology
likely account for the divergent conclusions. When restricted to studies at low risk of bias, the
pooled effect was entirely neutral. Moreover, trial sequential analysis suggested that the
cumulative evidence is likely sufficient to exclude a clinically meaningful benefit.

Taken together, these results do not support the use of melatonin for the prevention of delirium in critically ill adults, albeit with low certainty of evidence. Future trials, if pursued, should carefully consider methodological rigor and patient selection, and several trials are still ongoing, addressing the treatment of delirium itself (NCT03438526, NCT05713877) through melatonin administration.

Other pharmacological strategies may warrant further investigation for the prevention of delirium in critically ill patients. These include alpha-2 adrenergic agonists such as dexmedetomidine or clonidine, which have shown promising effects on sleep architecture and delirium burden [55-57], as well as antipsychotics including haloperidol [58], despite mixed evidence regarding their preventive efficacy. Future trials should probably incorporate rigorous delirium phenotyping and long-term outcomes to better delineate the populations most likely to benefit.

This meta-analysis also has limitations that should be acknowledged. First, we did not assess the effect of melatonin on sleep quality, which was one of the supporting arguments cited in the PADIS guideline. While sleep disruption is a potential mediator of ICU delirium, the available evidence linking melatonin to improved sleep in the ICU remains sparse, inconsistent, and often derived from small trials with limited external validity [59, 60]. Second, although we attempted to address clinical and methodological heterogeneity through prespecified subgroup and sensitivity analyses, some degree of residual heterogeneity is likely unavoidable in a literature spanning diverse populations (notably patients with severe mental illness [61-63]), interventions (melatonin route, dosage, and administration), and outcome definitions. In addition, the extent to which non-pharmacological prevention strategies were implemented in participating centers was not consistently reported, precluding any assessment of their potential contribution to heterogeneity. Third, we could not perform individual patient data (IPD) meta-analysis, which might have allowed more granular exploration of effect modifiers, including baseline delirium risk [64], organ dysfunction severity [65], sedation strategies [66] and duration of melatonin exposure.

Conclusion

In conclusion, current evidence does not support the use of melatonin to prevent ICU delirium. While recent high-quality trials have not demonstrated efficacy, additional research may be needed to further clarify whether specific patient subgroups, dosing strategies, or clinical contexts could still benefit from melatonin.
**Author contributions**

Data collection: IL, DP, LD. Study design: IL, DP, ADJ, SJ. Data analysis: DP, IL, LD, JP.

Data interpretation: IL, DP, LD, JP, ADJ, SJ. Writing: IL, DP, ADJ, SJ. Overall manuscript review: IL, DP, LD, GC, JP, CM, FB, MC, ADJ, SJ.

**Funding**

None.

**Availability of data and materials**

Available and included in the supplemental material.

**Declarations**

**Conflicts of interest**

SJ is the Editor in Chief of Intensive Care Medicine. He has not taken part in the review or selection process of this article. SJ received consultant fees from Mindray, Fisher-Paykel, Baxter, Fresenius, Medtronic, and Drager. AdJ received fees for presentations from Sanofi, Medtronic, and Viatris. IL received fees from presentations from Viatris and AOP Health. No other potential conflict of interest relevant to this article was reported.

**Ethics approval and consent to participate**

Not applicable.

**Consent for publication**

Not applicable.

**Conflict of interest statement**

Declarations. Conflicts of interest: SJ is the Editor in Chief of Intensive Care Medicine. He has not taken part in the review or selection process of this article. SJ received consultant fees from Mindray, Fisher-Paykel, Baxter, Fresenius, Medtronic, and Drager. AdJ received fees for presentations from Sanofi, Medtronic, and Viatris. IL received fees from presentations from Viatris and AOP Health. No other potential conflict of interest relevant to this article was reported. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable.
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