Melatonin and Its Analogs for Prevention of Post-cardiac Surgery Delirium: A Systematic Review and Meta-Analysis.

Background: The effectiveness of melatonin and its analogs in preventing postoperative delirium (POD) following cardiac surgery is controversial. The purpose of this systematic review and meta-analysis was to confirm the benefits of melatonin and its analogs on delirium prevention in adults who underwent cardiac surgery. Methods: We systematically searched the PubMed, Cochrane Library, Web of Science, Embase, and EBSCOhost databases, the last search was performed in October 2021 and repeated before publication. The controlled studies were included if investigated the impact of melatonin and its analogs on POD in adults who underwent cardiac surgery. The primary outcome was the incidence of delirium. The Stata statistical software 17.0 was used to perform this study. Results: This meta-analysis included eight randomized controlled trials (RCTs) and two cohort studies with a total of 1,714 patients. The results showed that melatonin and ramelteon administration were associated with a significantly lower incidence of POD in adults who underwent cardiac surgery (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.29-0.74; P = 0.001). The subgroup analyses confirmed that melatonin 3 mg (OR, 0.37; 95% CI, 0.18-0.76; P = 0.007) and 5 mg (OR, 0.34; 95% CI, 0.21-0.56; P < 0.001) significantly reduced the incidence of POD. Conclusion: Melatonin at dosages of 5 and 3 mg considerably decreased the risk of delirium in adults who underwent cardiac surgery, according to our results. Cautious interpretation of our results is important owing to the modest number of studies included in this meta-analysis and the heterogeneity among them. Systematic Review Registration: PROSPERO registration number: CRD42021246984.

Suvorexant with or without ramelteon to prevent delirium: a systematic review and meta-analysis.

Delirium is a common and serious neurobehavioral syndrome, associated with prolonged hospital stays, and increased morbidity and mortality. As it remains unclear whether suvorexant with or without ramelteon prevents delirium in elderly hospitalized patients, we conducted a systematic review and meta-analysis to evaluate, searching the PubMed, Cochrane Library, Web of Science, EMBASE, and EBSCOhost databases for all randomized controlled trials (RCTs), case-control studies, and cohort studies that investigated the effects of suvorexant with or without ramelteon on delirium in adult hospitalized patients. The primary outcome was the incidence of delirium. Two randomized controlled trials, 7 cohort studies and 2 case-control studies involving 2594 patients were included in this meta-analysis. The results showed that both suvorexant alone (odds ratio (OR) = 0.30, 95% confidence interval (CI): 0.14-0.65, P = 0.002) and suvorexant with ramelteon (OR = 0.39, 95% CI 0.23-0.65, P = 0.0003) reduced the incidence of delirium in adult hospitalized patients. Six studies involved the use of benzodiazepines; subgroup analysis performed separately in the suvorexant alone and suvorexant with ramelteon groups indicated that when benzodiazepine was administered, suvorexant with ramelteon was effective at reducing the incidence of delirium (OR = 0.53, 95% CI 0.37-0.74, P = 0.0002), but no significant difference was observed for suvorexant alone (OR = 0.40, 95% CI 0.11-1.53, P = 0.18). The current literature thus supports the effectiveness of suvorexant with or without ramelteon for delirium prevention, although suvorexant alone failed to significantly reduce the incidence of delirium when benzodiazepine was administered. The present study was limited by the significant heterogeneity among the included studies, and caution should be exercised when interpreting the results. This study was registered in the PROSPERO database (CRD4202017964).

Melatonin Attenuates Sepsis-Induced Small-Intestine Injury by Upregulating SIRT3-Mediated Oxidative-Stress Inhibition, Mitochondrial Protection, and Autophagy Induction.

Melatonin reportedly alleviates sepsis-induced multi-organ injury by inducing autophagy and activating class III deacetylase Sirtuin family members (SIRT1-7). However, whether melatonin attenuates small-intestine injury along with the precise underlying mechanism remain to be elucidated. To investigate this, we employed cecal ligation and puncture (CLP)- or endotoxemia-induced sepsis mouse models and confirmed that melatonin treatment significantly prolonged the survival time of mice and ameliorated multiple-organ injury (lung/liver/kidney/small intestine) following sepsis. Melatonin partially protected the intestinal barrier function and restored SIRT1 and SIRT3 activity/protein expression in the small intestine. Mechanistically, melatonin treatment enhanced NF-κB deacetylation and subsequently reduced the inflammatory response and decreased the TNF-α, IL-6, and IL-10 serum levels; these effects were abolished by SIRT1 inhibition with the selective blocker, Ex527. Correspondingly, melatonin treatment triggered SOD2 deacetylation and increased SOD2 activity and subsequently reduced oxidative stress; this amelioration of oxidative stress by melatonin was blocked by the SIRT3-selective inhibitor, 3-TYP, and was independent of SIRT1. We confirmed this mechanistic effect in a CLP-induced sepsis model of intestinal SIRT3 conditional-knockout mice, and found that melatonin preserved mitochondrial function and induced autophagy of small-intestine epithelial cells; these effects were dependent on SIRT3 activation. This study has shown, to the best of our knowledge, for the first time that melatonin alleviates sepsis-induced small-intestine injury, at least partially, by upregulating SIRT3-mediated oxidative-stress inhibition, mitochondrial-function protection, and autophagy induction.

Melatonin and its analogues for the prevention of postoperative delirium: A systematic review and meta-analysis.

It remains unclear whether melatonin and its analogues prevent postoperative delirium (POD). Therefore, we conducted a systematic review and meta-analysis to evaluate the effect of melatonin and its analogues on POD prevention. PubMed, Cochrane Library, Web of Science, Embase and CINAHL databases were searched. Primary outcome was the incidence of POD. Six randomized controlled trials, 2 cohort studies and 1 case-control study were included in this meta-analysis. Results showed that melatonin and its analogue ramelteon decreased the incidence of POD in the entire adult surgical population (odds ratio [OR] = 0.45, 95% confidence interval [CI] 0.24-0.84, P = .01). When administered at a higher dose (5 mg), melatonin was effective in reducing the POD incidence (OR = 0.32, 95% CI 0.20-0.52, P < .00001). Melatonin administered less than 5 elimination half-lives before the surgery significantly reduced the POD incidence (OR = 0.31, 95% CI 0.19-0.49, P < .00001). Current literature supports the effectiveness of melatonin and its analogue ramelteon in POD prevention. However, the present study was limited by the significant heterogeneity of the included studies. More studies are needed to ascertain the preventive effect of melatonin and its analogues on the incidence of delirium after cardiac and noncardiac surgeries.