Delirium has been defined as an acute impairment of attention and overall cognitive function in hospitalized patients (1). In critically ill patients, delirium is associated with increased morbidity and mortality, and may also increase the length of stay in critically ill patients (2–7). Delirium is especially common in intensive care unit (ICU) patients, with such a wide range of occurrence reported in the literature (11%-80%) (6, 8–10). Importantly, most medications currently available clinically are not effective for delirium and there is a lack of evidence-based medicine in the treatment of this disorder.

Melatonin, a serotonin-derived hormone secreted by the pineal gland, is a powerful free radical scavenger and antioxidant with a broad spectrum (11) that easily crosses the blood-brain barrier in large, non-toxic doses (12). It plays a major role in sleep regulation and circadian rhythm management (13, 14). Melatonin has anti-inflammatory and immunomodulatory properties and may have neuroprotective effects in brain injury, encephalopathy and neurodegenerative diseases (15–19).

Melatonin supplementation may prevent delirium. To date, there were many clinical trials of melatonin or melatonin agonists to prevent delirium (20–29). Due to the heterogeneity of experimental methods and patients, results between clinical trials are conflicting and it is difficult to draw firm conclusions. In light of recently published large randomized clinical trials (30), we conducted a comprehensive systematic review and meta-analysis to summarize the available evidence and provide more reliable quantitative results as a basis for delirium prevention and clinical treatment in critically ill patients.

Six articles were analyzed, and a total of 2374 patients participated in the study, with 1207 patients receiving melatonin and 1167 patients receiving placebo. After the heterogeneity test, I² = 74%>50%, and the P=0.002<0.1 of the Q test, suggested a strong heterogeneity between the selected studies, selecting random effects for meta-analysis, while continuing to investigate the reasons of the heterogeneity. Based on the data of this study, the source of heterogeneity was highly suspected to be inconsistent reasons for patients’ admission to the ICU, and subgroup analysis will be conducted according to the type of ICU. In terms of the type of ICU, patients were divided into two subgroups: general intensive care unit (GICU) group and cardiovascular care unit (CCU) group according to the reasons for their admission to the ICU. For the overall six articles, random effects were selected for me-ta-analysis and the results were shown in Figure 3 . The results of the meta-analysis showed that melatonin did not reduce the incidence of delirium in ICU patients (Random-effects model: OR, 0.71; 95% CI, 0.46 to 1.12; p=0.14; I² = 74%).

Three articles were analyzed regarding 28-day/30-day all-cause mortality. A total of 1635 patients were included in the studies, of whom 815 received melatonin treatment and 820 received placebo treatment ( Figure 7 ). All-cause mortality was similar between the two groups, and no heterogeneity was observed (Fixed-effects model: OR, 0.85; 95% CI, 0.66 to 1.09; p=0.20; I² = 0%).

Four articles were analyzed with respect to length of ICU stay. A total of 1580 patients were included in the studies, of whom 811 received melatonin treatment and 769 received placebo treatment. Because the heterogeneity was considerable (I² = 76%), we used a random-effects model ( Figure 8 ). Length of ICU stay was similar between the two groups (Random-effects model: MD, 0.33; 95% CI, -0.53 to 1.18; p=0.45; I² = 76%).

Six articles were analyzed with respect to length of ICU stay. A total of 2374 patients were included in the studies, of whom 1207 received melatonin treatment and 1167 received placebo treatment. Because the heterogeneity was considerable (I² = 85%), we used a random-effects model ( Figure 9 ). Length of hospital stay was similar between the two groups (Random-effects model: MD, 0.51; 95% CI, -1.17 to 2.19; p=0.55; I² = 85%)

Critical illness has been considered a risk factor for the development of delirium, which is associated with increased mortality, prolonged ICU stay, and long-term cognitive decline and poor functional recovery in patients (36, 37). Therefore, any potential benefit of melatonin may be more pronounced in critically ill patients (6, 15, 38). Melatonin is an endogenous hormone secreted by the pineal gland that regulates circadian rhythms (39), and current studies in vitro and in animal models have demonstrated the potential anti-inflammatory and antioxidant characteristics of melatonin, suggesting that its use in critically ill patients may have multiple benefits (40, 41).

Our findings suggest that melatonin did not observe a significant advantage in preventing delirium in critically ill patients, but there was a high degree of heterogeneity between studies. In particular, the advantage of melatonin in preventing delirium was not significant in GICU, but in CCU, melatonin was shown to reduce the incidence of delirium, so based on the current findings, it cannot yet be assumed that melatonin is effective in preventing delirium in ICU patients. Although differences in disease severity may attenuate the beneficial effects of melatonin, current treatment options for delirium supported by valid evidence-based medical evidence are limited to preventive strategies with nonpharmacological interventions, such as early activity, light and noise reduction, sleep management, and involving relatives when appropriate (29, 42–44). The recent multicenter randomized controlled trial conducted by De Jonghe A in the Nether-lands for elderly patients with hip fracture also proved that melatonin treatment did not reduce the incidence of delirium (23). This is also consistent with our findings. There are still few studies on melatonin prevention of delirium in critically ill patients, and larger, multicenter randomized controlled studies are needed to support these findings, so the results of this study should be treated with caution.

There may be many reasons for the differences in the effects of melatonin due to different types of ICU, and the specific molecular mechanism of melatonin’s preventive effect on delirium in CCU patients may be closely related to its improvement of vascular endothelial cell function, anti-vasospasm, anti-neuronal apoptosis, improvement of cerebral perfusion, and reduction of microthrombosis (45). Current relevant basic studies have shown that the non-selective opening of the mitochondrial permeability transition pore in mitochondria and the overproduction of reactive oxygen species are important factors promoting heart disease and cardiac dysfunction, and melatonin can improve isoprenaline-hydrochloride-induced heart failure related to mitochondrial dysfunction (46). In addition, Wang J et al. showed that renal ischemia-reperfusion injury can attenuate cardiac diastolic function by increasing cardiomyocyte death and enhancing the inflammatory response, while also disrupting cardiomyocyte energy metabolism, causing calcium overload, and impairing mitochondrial function. In contrast, melatonin reduces cytoplasmic and mitochondrial calcium overload, while melatonin preconditioning attenuates cardiac damage mediated by renal ischemia-reperfusion injury by maintaining myocardial diastolic function and reducing myocardial cell death (47). On the other hand, in GICU, the condition of critically ill patients is relatively complex and the disease types are diverse, and the relatively complex sedative and analgesic regimens used in this group of patients as well as the use of some antipsychotics may alter neurotransmitter levels and subsequently cause direct damage to brain-related functions (48), while it is unclear whether the mixture of these drugs may affect the effectiveness of melatonin.

We completed this meta-analysis under the strict guidance of PRISMA (49), but our analysis still has some limitations. First, the different types of delirium (hyperactive, hypoactive, or mixed delirium) were not distinguished in the study. Second, the CAM-ICU score is only a screening tool and is not the gold standard for delirium diagnosis, and scores are performed by ICU nurses at different levels and may be under-estimated in some studies. Third, melatonin is not regulated in some countries, and therefore the quality of the product may vary depending on the manufacturer, which may lead to differences in the absorption of melatonin in different studies. Fourth, in some studies the authors did not directly provide means and standard deviations for continuous data, so estimated means and standard deviations were used in the analysis of relevant data. Nevertheless, our meta-analysis still had a high level of evidence, the majority of the included studies were randomized controlled trials, and most of the included studies were published in the last five years with comprehensive records of outcome indicators, which significantly increased the credibility of our results.

Our study of published trials indicates that melatonin reduced the incidence of delirium in CCU patients, but did not significantly reduce the incidence of delirium in GICU patients. The role of melatonin in reducing the incidence of delirium in ICU patients requires further study.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Conceptualization, YY, YD, XW and JS; methodology, YY and YD; software, YD and WZ; validation, LW, GW and WZ; formal analysis, XW and YY; investigation, GW, JY and QB; resources, WZ; data curation, YY and YD; writing—original draft preparation, YD and YY; writing—review and editing, LW, XW and JS; visualization, JY and QB; supervision, XW and JS; project administration, XW; funding acquisition, JS. All authors have read and agreed to the published version of the manuscript.