Study On The Role And Mechanisms Of Dexmedetomidine In Perioperative Patients And Chronic Moderate To Severe Insomnia Patients

BackgroundWith the increasing pace of life,the prevalence of chronic insomnia has been on the rise due to mental and long-term stress.However,treating chronic moderate to severe insomnia poses several challenges and difficulties.One common issue is the drug dependence and tolerance following treatment.Additionally,perioperative patients frequently experience sleep disorders,which negatively impact overall treatment and postoperative rehabilitation.Studies have shown that both perioperative patients and those with chronic insomnia exhibit similar sleep structure parameters,including reduced sleep efficiency,prolonged sleep onset latency,and significantly decreased deep sleep(N3).Previous research has demonstrated that Dexmedetomidine(Dex)can enhance postoperative sleep quality and alleviate anxiety in perioperative patients.However,there is limited research on the use of Dex for the treatment of chronic moderate to severe insomnia,especially regarding its objective impact on sleep structure in these patients.There is also a lack of clear and standardized treatment plans,criteria for evaluating efficacy,long-term follow-up data,and clear indications after treatment.Therefore,more clinical data is needed to support the understanding of the effects of Dex on sleep structure and long-term efficacy in patients with chronic moderate to severe insomnia.Insomnia frequently triggers or exacerbates anxiety,while individuals with anxiety commonly suffer from poor sleep quality and various sleep disorders,particularly insomnia.Hence,anxiety is closely intertwined with sleep quality and serves as a significant aspect in treating insomnia.Although several studies have demonstrated that Dex can improve anxiety,the precise mechanism remains unclear,necessitating additional theories to support the notion that Dex can improve both sleep quality and anxiety.ObjectiveThis study aims to investigate the impact of Dex on sleep structure in perioperative patients and patients with chronic moderate to severe insomnia during the perioperative period,as well as its long-term treatment effects on these patients.Additionally,the study seeks to explore the mechanisms through which Dex improves sleep and alleviates anxiety.Part Ⅰ.The Effects of Dex on sleep structure in perioperative patients: a Meta-analysisObjective: To investigate the effect of Dex on sleep structure in perioperative patients by meta-analysis.Methods: We conducted a comprehensive search in databases including PubMed,Embase,The Cochrane Library,Web of Science,China National Knowledge Infrastructure,VIP Chinese Biomedical Journal Database,and Wanfang Database.The search encompassed studies from the inception of these databases until December 31,2023,and was restricted to articles published in both Chinese and English languages.The inclusion criteria consisted of randomized controlled trials that evaluated postoperative Dex administration and utilized objective sleep monitoring.In this meta-analysis,we assessed various sleep parameters,including sleep efficiency,non-REM stage 1(N1),non-REM stage 2(N2),non-REM stage 3(N3),and rapid eye movement(REM)sleep.Results: Thirteen studies comprising a total of 811 participants were included in this analysis.Comparing the postoperative Dex administration group with the control group,it was found that Dex can enhance sleep efficiency,reduce the duration of N1 sleep,and increase the duration of N2 and N3 sleep(P < 0.05).However,no significant effect was observed on REM sleep(P > 0.05).Subgroup analysis revealed that Dex improved N2 and N3 sleep in postoperative patients,which may be attributed to the specific surgical method employed.Furthermore,Dex was found to improve sleep efficiency and N2 sleep in postoperative patients,potentially due to the method of Dex administration.Conclusions: Dex has been shown to enhance sleep efficiency,increase the proportion of deep sleep,and improve the sleep structure in postoperative patients.Part Ⅱ.The effects of Dex on sleep structure,sleep quality,and mood in patients with chronic moderate to severe insomniaTrial 1 The effects of Dex on sleep structure in patients with chronic moderate to severe insomniaObjective: The primary aim of this study is to investigate the effects of Dex on the sleep structure of patients with chronic moderate to severe insomnia.Specifically,the study aims to evaluate whether Dex can improve the objective sleep efficiency and increase the proportion of deep sleep in patients who have previously received oral hypnotic treatment without significant effectiveness.Methods: This study was a prospective,open-label,before-after study conducted at a single center.Enrollment took place from October 2021 to December 2023 at Tangdu hospital,targeting patients with chronic moderate to severe insomnia who had failed to respond to two or more hypnotic treatments.In the study,Dex was administered via intravenous pump injection every night for three consecutive nights.Using polysomnography(PSG),we monitored objective sleep structure parameters in patients to compare the differences in objective sleep efficiency,proportion of deep sleep(N3 sleep),and other sleep structure parameters before Dex treatment(baseline),during Dex treatment,and after discontinuation of Dex.Additionally,we observed patients’ heart rate,blood pressure,and adverse reactions during Dex treatment,and conducted psychomotor vigilance testing to evaluate the impact of Dex on alertness.Results: Compared to baseline,the application of Dex treatment significantly increased the objective sleep efficiency and N3 sleep(P < 0.05)in patients with chronic moderate-to-severe insomnia.It also led to an extension of total sleep time,a reduction in sleep latency,and a decrease in post-sleep arousal time and arousal index(P < 0.05).Additionally,N2 sleep increased while REM sleep decreased(P < 0.05).Compared to baseline,on the day of Dex treatment cessation,the objective sleep efficiency and N3 sleep increased again(P < 0.05).This also led to an extension of total sleep time,a reduction in sleep latency,and a decrease in post-sleep arousal time and arousal index(P < 0.05).Furthermore,N1 sleep(light sleep)decreased while REM sleep increased(P < 0.05).At the given therapeutic dose,Dex treatment had minimal effects on heart rate and blood pressure in patients,with no severe adverse reactions observed.Additionally,it did not affect alertness behavior in patients.Conclusions: Dex has demonstrated effectiveness in enhancing objective sleep efficiency and deep sleep proportions in patients with chronic moderate to severe insomnia.Furthermore,Dex treatment has been found to extend total sleep time,shorten the sleep latency,decrease wakefulness after sleep onset,and improve the overall structure of sleep.Importantly,these improvements in sleep quality do not impede the alertness levels of patients.Trial 2 A comparison of the sleep quality and mood therapeutic effects between Dex and conventional treatment in patients with chronic moderate to severe insomniaObjective: The study aimed to compare the differences in PSQI,ISI,HAMA,and HAMD scores between patients receiving Dex treatment and those receiving conventional treatment.Methods: This retrospective observational matched cohort study aimed to assess the effectiveness of Dex treatment compared to conventional treatment in patients with chronic moderate to severe insomnia.Patients from the same period as the previous prospective study were selected based on similar criteria.They were then divided into two groups,the conventional treatment group and the Dex treatment group,following different treatment protocols.To ensure comparability,the propensity score matching method was utilized to balance the baseline characteristics of patients in both groups.Comparative analysis was conducted to evaluate the differences in PSQI,ISI,HAMA,and HAMD scores between the two treatment groups at 1,3,and 6 months after treatment.Results: Compared with the conventional treatment group,the Dex treatment group had a significant reduction in PSQI,ISI and HAMA scores at 1,3 and 6 months(P < 0.05).Conclusions: Dex treatment is more effective than conventional treatment in improving sleep quality in patients diagnosed with chronic moderate to severe insomnia.It not only reduces the severity of insomnia but also effectively alleviates anxiety symptoms.Part Ⅲ.The molecular mechanism underlying the anxiety-reducing effects of Dex in sleep-deprived miceObjective: By utilizing a mouse model of sleep deprivation to mimic the sleep strcture observed in chronic insomnia patients as well as the anxiety triggered by insufficient sleep,our objective is to explore the molecular mechanism through which Dex ameliorates anxiety resulting from sleep deprivation.Methods: The effects of Sleep Deprivation(SD)model and Dex on the sleep structure of C57BL/6 male mice were investigated by analyzing the electroencephalogram(EEG)and electromyography(EMG)monitoring data.Open field test and elevated plus maze test were used to detect the emotional behavior of mice.Transcriptome sequencing analysis was performed in the prefrontal cortex of mice.Intraperitoneal injection of p38 inhibitor and Dex was used to verify that p38/MSK1/NFκB pathway played an important role in SD induced anxiety and Dex improved anxiety in SD mice.The protein expressions of p38,pp38,MSK1,p-MSK1,NFκBp65 and p-NFκBp65 were detected by immunofluorescence staining and Western Blot.The expression levels of IL-1β,IL-6,TNF-α,i NOS,COX-2 and other inflammatory mediators were detected by ELISA.The level of oxidative stress was detected by Superoxide dismutase(SOD)activity.High-resolution mass spectrometry was used to detect the effect of Dex application on neurotransmitters in the prefrontal cortex of SD mice.Immunofluorescence staining was used to observe the effect of Dex on the activation of cholinergic neurons in the prefrontal cortex of SD mice.Results: The effect of SD on sleep structure: compared with the control group,the SD group had increased wakefulness and decreased NREM sleep and REM sleep(P < 0.05).The behavioral test showed that the SD group spent less time in the target area than the control group in the open field and the elevated plus maze(P < 0.05).Transcriptome sequencing results showed that the SD model was closely related to inflammatory response and MAPK pathway.SD increased the expression of p-p38,p-MSK1 and p-NFκBp65 in mouse cortical microglia(P < 0.05),and the expression levels of IL-1β,IL-6,TNF-α,i NOS,COX-2 and other inflammatory mediators were increased(P < 0.05),decreased SOD activity(P < 0.05).SB203580 down-regulated the expression of p-p38,p-MSK1 and pNFκBp65 in mouse cortical microglia induced by SD(P < 0.05),decreased the expression of inflammatory mediators such as IL-1β,IL-6,TNF-α,i NOS and COX-2 induced by SD(P < 0.05),increased SOD activity(P < 0.05).Effects of Dex on sleep structure in SD mice:Dex reduced wakefulness(P < 0.05),increased NREM sleep(P< 0.05),decreased REM sleep(P < 0.05).Dex increased the secretion of acetylcholine(ACh)in the prefrontal cortex of SD mice and activated cholinergic neurons(P < 0.05).In addition,Dex increased the time of residence in the target area of SD mice in open field and elevated plus maze,and down-regulated the expression of p-p38,p-MSK1 and p-NFκBp65 in mice cortical microglia induced by SD(P < 0.05),decreased the secretion of inflammatory mediators such as IL-1β,IL-6,TNF-α,i NOS and COX-2 induced by SD(P < 0.05),increased SOD activity(P < 0.05).Conclusions: SD induced anxiety in mice is caused by cerebral cortex inflammatory responses.Dex can mitigate SD induced anxiety in mice by stimulating ACh secretion and suppressing the activation of the p38/MSK1/NFκB pathway in microglia.