Premedication effect of melatonin on propofol induction dose for anesthesia,anxiety,orientation and sedation after abdominal surgery:a double-blinded randomized trial

Afsaneh Norouzi,Shahin Fateh,Hesameddin Modir, ,Alireza Kamali,Leila Akrami

1 Department of Anesthesiology and Critical Care,Arak University of Medical Sciences,Arak,Iran

2 Department of surgery,Arak University of Medical Sciences,Arak,Iran

Abstract

Key words:abdominal surgery; anesthesia; induction; melatonin; premedication; propofol

INTRODUCTION

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone naturally produced in the brain,secreted by the pineal gland,1whose receptors are found throughout the central nervous system and other body tissues.2,3It is known to be an effective hormone in sleep disorders,4,5anxiety,and pain,as well as an anti-infl ammatory antioxidant,6used as a premedication.3,6,7

相对于政府一元独大的管理模式，多元主体合作共治的最大特点，在于它可以把多元主体置于社会治理系统之中，实现多元主体的优势互补，克服多元主体各自的局限，实现社会治理系统的整体优化。而从新时代构建共建共治共享格局的要求讲，它可以解决社会治理领域社会组织和公众参与发展不平衡、不充分问题，最大限度地激发社会组织活力和公众参与热情，促进社会进步，减少社会治理成本。

吃火锅也要讲究营养均衡，而且火锅更易达到食物多样化，更容易做到营养均衡。肉类可选择羊肉片、牛肉片、鸡肉片等品种；蔬菜可选择清爽可口的白菜、冬瓜、生菜及油菜、油麦菜、茼蒿等蔬菜。蔬菜中的纤维素可帮助打扫肠道中黏附的脂肪和蛋白质废物，还能减少脂肪和胆固醇的吸收。豆制品可选择豆腐、豆浆。主食可选择杂面条等。

Melatonin interacts with multiple receptors,including opioidergic,benzodiazepinergic,muscarinic,nicotinic,serotonergic,α1- and α2-adrenergic,and melatonergic receptors found in the spinal cord in the central nervous system.3,8Premedication reduces the need for anesthetic induction agents during surgery.7,9Melatonin,an effective hypnotic drug,is revealed to have the effect on both the onset and maintenance of sleep,10while it is known as a natural hypnotic agent whose actions are activated by MT1 and MT2 receptors and a yetunclarified physiologic mechanism underlying the analgesic actions of melatonin.7,9

Several studies have been focused on the effects of various premedication on the induction and maintenance propofol dose in the human body.11A dose range of melatonin premedication is used to provide sedation and analgesia without cognitive impairment and psychomotor skills,and without any increase in recovery time.5,12Past studies have proven that melatonin is effective in the premedication of adults and children.13-15Anderson et al.'s review7which explored 24 clinical trials and 1749 participants suggested that melatonin decreases anxiety and pain,as compared to placebo.They performed three studies on anesthetic induction dose which reduced anesthetic dose but did not affect sevofl urane dose.7While Turkistani et al.'s study16suggested that melatonin 3 or 5 mg is recommended to reduce propofol dose to achieve bispectral index (BIS) 45,another which conducted on BIS and reducing the dose of anesthetic drugs by Evagelidis et al.'s study17focused on the effect of melatonin premedication on the reduced administration of sevofl urane guided by BIS monitoring,reporting no effect on the reduction of anesthetic dose.

Lophocolea heterophylla（Schrad.）Dumort.刘胜祥等（1999）；马俊改（2006）；赵文浪等（2002）

However,there are few quantitative studies addressing melatonin premedication for reducing the dose of anesthetic agent used during surgery,16,19whereas in Naguib et al.'s trial,1945 patients undergoing various surgeries received melatonin 100 minutes prior to surgery and only sufficed for eyelash refl ex and verbal command,but in the present study we intended to perform,BIS was also used.Contrarily,the studies are limited and cannot be generalized to the entire community,while not considering all in each case,and the subject still needs to be reviewed.Thus,we designed a study to compare the effect of melatoninversusplacebo as the premedication on propofol induction dose for anesthesia in abdominal surgeries in Arak,Iran.

SUBJECTS AND METHODS

In addition,no significant difference was found in orientation between both before melatonin administration and in recovery (P＞0.05),while it was statistically significant before anesthesia induction (P=0.44) and lower in the melatonin group before the induction.Though no significant difference was seen in orientation at the recovery time,it was higher in the melatonin group.In addition,there was no significant difference in the sedation between the two groups before melatonin administration (P＜0.05),before anesthesia induction (P=0.44) and recovery (P=0.049).A statistically significant difference was observed in propofol dose between both groups (P=0.002),whereas the dose was lower in the melatonin group than the placebo group (Table 5).

Figure 1:CONsolidated Standards of Reporting Trials (CONSORT) diagram showing the fl ow of participants throughout a randomized trial

The inclusion criteria included American Society of Anesthesiologists status I-II,age 15-55 years,non-emergency abdominal surgery,both genders,surgery time from 30 minutes to 1 hour and a half,body mass index＞19 to＜25 kg/m2,and non-use of narcotics during the previous week.Exclusion criteria were including lack of patient cooperation and use of benzodiazepine-derived drugs within the past 72 hours.

Subjects were randomized into two groups:melatonin group (n=44),sublingually administered 3 mg of melatonin (Webber,Naturals,Canada) dissolved in 3 mL of distilled water 50 minutes before surgery; and placebo group (n=44),administered placebo (3 mL of distilled water) 50 minutes before surgery.The treatment was implemented by an anesthesiologist resident who was blinded to drugs.A nurse anesthetist prepared anesthetics and provided them with the resident.Afterwards,the subjects were transferred to the operating room,while recording vital signs,including oxygen saturation (SaO2),and attaching the BIS monitor to him/her.The monitor electrodes were placed on three points:the middle of the forehead above the glabella,upper corner of the left eye,and left mastoid region.

Study conception:AN,SF,AK,LA; data collection:LA; data acquisition and analysis:HM; data interpretation:AN,AK; manuscript writing:HM.All authors approved the final version of the manuscript for publication.

Midazolam (Boroujerd Eksir Co,Broujerd,Iran) 0.2 mg/kg and fentanyl (Rasht Caspian Co.,Iran),2 μg/kg were injected into both groups,and then the induction of general anesthesia propofol Lipuro (B.Braun Medical) 1 mg/kg was started by the anesthesiologist resident and finally continued until the BIS reached 40.The total propofol dose was recorded to achieve the BIS to lose eyelash refl ex and to prevent response to verbal stimulation.Then atracurium (Rasht Caspian Co.,Iran) 0.5 mg/kg was injected and anesthesia continued by isofl urane,and nitrogen-oxygen (at 50:50),as well as and fentanyl injected at an appropriate dose for the time of surgery.

Anxiety,orientation and sedation were recorded before melatonin administration,before anesthesia induction and during recovery by the resident who then recorded mean arterial pressure (MAP),heart rate (HR),SaO2,and end-tidal carbon dioxide (EtCO2) before induction,every 10 minutes during and after surgery,and every 15 minutes after arrival in the recovery room until achieving a score of＞8 on the Aldrete scoring21when the monitoring device was attached to the end of a nasal mask.Visual Analogue Scale score was used to assess patients' anxiety17,18and then was completed by the resident.A 10 cm ruler was used to assess anxiety,in which zero stood for no anxiety and 10 stood for a severe anxiety.

Based on the results depicted in Table 5,no significant difference was seen in anxiety between both before melatonin administration (P=0.07),but it was significantly different between in both groups before the induction (P=0.013) and in recovery (P=0.034) and less in the melatonin group.

Orientation scoring was based on:No orientation (0),orientation about place where patient is located (1),and orientation in both time and place (2).14The sedation scoring was as follows:Awake (1),drowsy (2),asleep,but arousable (3),and asleep and not arousable (4).14It should be noted that the data were measured by an anesthesiologist resident,unaware of the groupings,to double-blinded the study and then data were analyzed using descriptive and analytical statistics through SPSS 20 (IBM Corp.,Armonk,NY,USA).Independentt-test and chi-square test were used in data analysis.

RESULTS

This double-blinded clinical trial was conducted in abdominal surgery patients (n=88) admitted to the Arak Valiasr Hospital,who were randomly assigned to two groups with a minimum age of 24 years,a maximum age of 55 years,and a mean age of 43.97 ± 7.40 years.No significant difference was seen in age between two groups (P=0.568) who were matched for age.They showed no significant difference in gender (P=0.856) and were gender matched.

Table 1:Baseline characteristics of abdominal surgery patients

Based on the results in Table 2,a significant difference was found in MAP between the groups at 10,20 and 70 minutes,and recovery time (P＜0.05).The MAP level was lower in the melatonin group than in the placebo group at all times.Based on the below chart,the lowest MAP is related to the melatonin group,whereas MAP had also a sharp increase in the placebo group at the time of extubation,but is low in the melatonin group.Figure 1 shows the repeated measurement analysis for trend of MAP between two groups.Melatonin caused lower MAP in patients for all times.

Table 2:Comparison of mean arterial pressure (mmHg) between the patients in melatonin and placebo groups

Based on Table 3,no statistically significant difference was seen in HR between the two groups (P＜0.05).Though no statistically significant difference was between them,the HR was lower in the melatonin group.Moreover,the repeated measurement test showed that no difference was observed in HR,but it was lower in the melatonin group (P＞0.05).

他这安逸的小鹰巢值得留恋。墙根斜倚着的大镜子照着她的脚，踏在牡丹花丛中。是天方夜谭里的市场，才会无意中发现奇珍异宝。她把那粉红钻戒戴在手上侧过来侧过去地看，与她玫瑰红的指甲油一比，其实不过微红，也不太大，但是光头极足，亮闪闪的，异星一样，红得有种神秘感。可惜不过是舞台上的小道具，而且只用这么一会工夫，使人感到惆怅。

Table 3:Comparison of heart rate (beats/min) between the patients in melatonin and placebo groups

Based on Table 4,there was a significant difference in SaO2between the groups after recovery and the mean of SaO2was higher in melatonin than placebo group.But there was no significant between two groups in other time after operation.Figure 2 shows the trend of SaO2in two groups.Moreover,no significant difference was found in mean of EtCO2between groups (P＜0.05; Figure 3).

Table 4:Comparison of oxygen saturation (SaO2) (mmHg) between the patients in melatonin and placebo groups

2.2 送管过程 13例患儿中有2例在送管至5～6 cm时遇阻力，继续送管困难，先将导管退回至回血通畅处，助手将患儿头及上身竖起，使患儿呈坐位，操作者边推注生理盐水边送管，助手则沿血管走行在导管上方平行推送，协助送管，最终送至预定长度。

Table 5:Comparison of anxiety,orientation,sedation and propofol dose between the patients in melatonin and placebo groups

This is a double-blinded clinical trial in which abdominal surgery patients admitted to the Valiasr Hospital,Iran (n=88) were included after completing the informed consent form.The patients were informed about the objectives of study and signed the informed consent form.Moreover,the protocol of study was approved by the Ethical Committee of Arak University of Medical Sciences with IR.ARAKMU.REC.1395.432 code in July 2016.In addition,it was registered in Iranian Registry of Clinical Trials with IRCT20141209020258N98 in September 2016.The fl ow chart is shown in Figure 1.

DISCUSSION

The results of the double-blinded clinical trial showed that MAP was lower in the melatonin group than that in another group at all times and did not have a sudden increase in the placebo group at the time of extubation,but low in the melatonin group,while no statistically significant difference was found in HR between both groups (P＜0.05),but HR was lower in the melatonin group.Based on the results,no significant difference was seen in SaO2(P＜0.05) and in EtCO2(P＞0.05) between both.Though anxiety was less in the melatonin group before anesthesia induction (P=0.013) and recovery (P=0.034),orientation was less in melatonin group than another before the induction (P=0.44).Though no significant difference was found in orientation at recovery time,it was higher in the melatonin group whose sedation was better before anesthesia induction (P=0.44) and recovery (P=0.049) and whose propofol dose used was lower than the placebo group (P=0.002).Here,we continue to explore some concerned studies:Anderson's results7were consistent with ours,whereby anxiety and pain were less in the melatonin group.Ionescu et al.'s study22aimed at assessing the effect of melatonin premedication in laparoscopic cholecystectomy suggested that sedation was lower in the melatonin group than that in midazolam and that melatonin can be successfully used as a premedication in cholecystectomy surgery.Their results were consistent with ours.Isik et al.23conducted an interventional study to compare melatonin and midazolam premedication in child anxiety,which was done in children undergoing dental treatment,showing that placebo,like melatonin,had no effect on the anxiety.Their results were not consistent with ours.This could be due to small sample size in each group in the Isik study and while the target group was children,adults (＞15 and＜55 years) were targeted in our study.

In the study by Turkistani et al.16addressing the effect of melatonin premedication and propofol dose for induction,45 patients undergoing different surgeries were enrolled and randomized into three groups:The former two groups were given melatonin 3 mg and 5 mg,respectively,as a premedication at 100 minutes before surgery,while no drug was administered to the third group.Afterwards,10 mg of propofol was given in the anesthetic process every 5 minutes to attain a BIS value of 45.Eye responses and eyelid refl exes were assessed and the total propofol dose was recorded,reporting the total dose for propofol 25 mg in the placebo group and 19.5 mg in melatonin 3 mg group and 20.9 mg in melatonin 5 mg group (P＜0.05).The anxiety was higher in the placebo group than that in the other groups.No significant difference was found in recovery time among all groups.Melatonin 3 mg or 5 mg is recommended to reduce propofol dose to reach the BIS value of 45.16Their results were consistent with ours.

Naguib et al.'s study19compared melatonin and midazolam as a premedication in adults,where 84 women received 0.5,1,and 2 mg/kg of midazolam,melatonin,and placebo,respectively,at 100 minutes before anesthesia.Sensation,anxiety,and orientation were then recorded at 10,30,60 and 90 minutes after premedication,and at 15,30,60 and 90 minutes in the recovery room.Subjects receiving midazolam and melatonin premedication showed a significant decrease in anxiety and sedation in the placebo group.Those who received midazolam 0.2 mg/kg had an increased level of sedation at 90 minutes after surgery,in comparison with those receiving melatonin 0.05 and 0.1 mg/kg at that time.Premedication with melatonin 0.05 mg resulted in less anxiety,lower sedation,and enhanced recovery.Their results were consistent with ours.

The sedation,anxiety and propofol dose used were found to be lower in the melatonin group than in the placebo group.Melatonin 3 mg is recommended to reduce propofol dose to achieve the BIS of 40.

3.4 果园管理水平不同，坐果率差别较大 树体管理水平较高的园（开花整齐一致）、管理粗放（树势差）的园、没有授粉树或授粉树少的园，受冻后坐果率较差。

Acknowledgements

We would like to thank the Clinical Research Development Center in the Valiasr Hospital for their guidance and the research deputy of Arak University of Medical Sciences for his assistance.

深栽造林用到的乌柳枝干春季截取母树上生长健壮的1～3年生萌生粗壮枝，插干大头直径在2～4cm。选择无机械损伤，无抽条干缩，无畸形，无弯曲和无病虫害的枝条。剪除枝条全部的抽条，剪取枝条中部作插干，插干长约110～120cm。

Author contributions

高校作为科技和人才的重要结合点，在积累智力资本、提高科技水平、建设创新型国家中具有重要地位，而创新能力的提升已经成为高等教育发展的迫切需要。

他被吓得激灵一哆嗦，手掌触电般地缩了回来。他的心“咚咚”地跳着，满面通红地扭头望向门口，正瞧见青萝那张气势汹汹的脸。

Conflicts of interest

There is no confl ict of interest.

Financial support

张华军：一个优秀的教师一定是一个很精彩、很生动的人，如果说他是一个很痛苦、很扭曲或者很冷漠、很顽固的人，课堂就不可能精彩。一个思维固化的人会等着世界接纳他，而不是主动认识世界。同时，当我们过多地放大自己的感受和认识时，会得出错误的观察，按照我们的感受、情绪去理解别人，所以我们的观察可能是不对的。

The study was supported by a grant from Arak University of Medical Sciences,Arak,Iran.

Institutional review board statement

Melatonin-mediated analgesic effects may be involved in two melatonin receptors,γ-aminobutyric acid receptor,and opioid receptors.5,7,18Melatonin can increase β-endorphins levels in the receptor MT2 in spinal cord and is effective as a premedication due to the sedative,hypnotic,analgesic,anti-infl ammatory,anti-oxidative and chronobiotic properties.18The review has revealed that melatonin is effective as a premedication in adults,but with controversial anesthetic effects.18Premedication with sublingually and orally administered melatonin (0.05,0.1,or 0.2 mg/kg) has been proven to reduce anxiety and to provide problem-free sedation in surgery and psychomotor skill test,or a negative impact on the quality of recovery.14,19Ismail and Mowafi20studied the effect of orally administered melatonin 10 mg as a premedication at 90 minutes before cataract surgery and found that it provided better operating conditions,including decreased intraocular pressure and enhanced analgesia,and it was also effective in reducing the pain caused by injuries.

Biostatistics statement

Declaration of patient consent

The authors certify that they have obtained patients or their legal guardians consent forms.In the form,patients or their legal guardians have given their consent for the patients' images and other clinical information to be reported in the journal.The patients or their legal guardians understand that the patients' names and initials not be published and due efforts will be made to conceal their identity,but anonymity cannot be guaranteed.

Reporting statement

The writing and editing of the article was performed in accordance with the CONsolidated Standards of Reporting Trials (CONSORT) Statement.

根据京东平台所提供信息观看短视频的人群45岁以下居多，占据所以短视频用户的85%，其中35岁以下占据60%以上，26-35岁占据又43.1%。从职业身份分析白领和一般职员占据了58%。不同行业的短视频生存周期也不同，活跃人群有区别，短视频的出现加快了个性化发展的路途，通过短视频，用户可以更快的明白商家是否还满足自己的个性化需求。商家的个性化标准定义也将越来越精准。

The protocol of study was approved by the Ethical Committee of Arak University of Medical Sciences with IR.ARAKMU.REC.1395.432 code in July 2016.In addition,it was registered in Iranian Registry of Clinical Trials with IRCT20141209020258N98 in September 2016.

The statistical methods of this study were reviewed by the biostatistician of Arak University of Medical Sciences,Iran.

个人与历史的互动：《历史人》的事件性 …………………………………………………………… 奚 茜（4.84）

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清代是中国古典园林发展成就最大也是最后一个时期，清代皇家园林则是中国皇家园林的巅峰。清代皇家园林从康熙年间兴起，至乾隆时期达到高潮，主要分布于北京西北郊和承德等地，分为宫城园林和离宫园林两类。⑤宫城园林包括西苑三海、景山以及紫禁城内的御花园、建福宫花园、慈宁宫花园和宁寿宫花园(即乾隆花园)6处;离宫园林包括北京西北郊的三山五园、南郊的南苑、承德的避暑山庄和蓟县的静寄山庄等8处。

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