Melatonin intervention to prevent delirium in hospitalized patients: A meta-analysis

lNTRODUCTlON

Delirium, also known as the state of conscious confusion, is a disorder of consciousness (which is the clarity of perceiving the environment), changes in consciousness (including changes in thinking),cognitive disorders, mental illness, and sleep-wake movements. The delirium is a recognized Complications of medical diseases, especially elderly patients, which is related to the mortality rate, and increase in Hospital costs[1,2]. In the palliative care setting, it is reported that the prevalence of delirium on admission is 20%-42%, and as high as 88% in the last few hours or days of life. Delirium is an acute neurocognitive disorder, in which a person's awareness of the surrounding environment is reduced, and attention disorder is its core feature; other mental deficits and perceptual abnormalities may also occur[3]. The collective symptoms of delirium can affect patients due to these characteristics and accompanying changes in psychomotor dysfunction or attention deficit hyperactivity disorder. Delirium is a symptomatic disorder, and its clinical management is challenging, especially when psychomotor agitation is present. This is especially true in the case of advanced disease and hospice care, where the patient's physical and functional decline can lead to a high degree of vulnerability to delirium (such as infections and adverse drug reactions)[5-6]. When delirium appears, it is associated with a mortality rate of 10% to 75%, although death may be more related to both advanced age and delirium. It is estimated that drug-induced delirium accounts for 22% to 39% of all cases. A study involving elderly hospitalized patients found that in their study population, the most likely cause of delirium was drug use[7-10].Antipsychotics and anti-anxiety agents are FDA-approved therapies for the treatment or prevention of delirium; however, data have revealed their lack of efficacy and the risk of serious side effects[11].

將計算結果(U1,M1,V1)發送給用戶，用來驗證傳感器的身份。用戶在手機端的計算如公式（6）—（7）：

由式(6)可知，等式右邊的電流對應臨界換相時間面積，等式左邊對應換相電壓時間面積。若換相電壓時間面積在換相線電壓變為負時還沒達到臨界換相時間面積，此時換相尚未結束而閥側電壓變為正向，換相角無法求解。因此不發生換相失敗的前提是換相角可以求解，且換相結束之后換流閥足以恢復阻斷能力，即滿足式(10)。

Subgroup analysis is also a commonly used method to identify heterogeneity in a meta-analysis. It investigates the source of heterogeneity from the perspectives of clinical and methodological heterogeneity, and it can incorporate the issue of effect size by referring to homogeneity research. According to the characteristics that may cause heterogeneity, the different types of experimental patients were analyzed in subgroups. In terms of the grouping of patients, the patients were divided into three subgroups: inpatient surgical patients, inpatient medical patients, and inpatient ICU patients. This is shown in the Forest diagram. Both the surgical group and the internal medicine group demonstrated statistical significance (

＜ 0.05), but not the ICU group (

＞ 0.05). Sensitivity analysis was performed on the analysis results. Two effect models (fixed and random) were used. After each study was eliminated one by one, the meta-analysis was performed again. The results found that the surgical group had high heterogeneity, indicating that the source of heterogeneity was not the research literature. Considering that many factors cause delirium, it is not possible to blindly adopt the random effect model to merge the effect size; following exclusion of the article by Stuti[27] in the internal medicine group, the combined effect size of the meta-analysis changed markedly, indicating that the source of heterogeneity in the internal medicine group was due to Stuti J, suggesting that the results of this study were robust.Individual studies were excluded one by one following subgroup analysis, and the sensitivity analysis approach of analyzing the difference between the combined effect size and the total effect size of the remaining studies, also known as impact analysis, was used. Among hospitalized patients in internal medicine, the effect sizes after excluding studies one by one were all within the 95%CI value of the total effect size. Therefore, they had little effect on the total combined effect size and were acceptable. The original meta-analysis results were strengthened to make them more convincing.

MATERlALS AND METHODS

Document retrieval

The search was conducted using operating system principles (P: PIC, which stands for the research object; I: Search strategy, which stands for the search object); C: Comparison strategy, realization; O:Search research design, research design. The databases PubMed, Web of Science, Cochrane Library,Embase, and Chinese databases, including China Biomedical Literature Database, Wanfang Data Medical Journal Library, Weipu Database, CNKI,

were searched. The search period was from establishment of the database through June 2021. Chinese database search terms were: (Melatonin) and(OR delirium neurocognitive impairment) and (randomized controlled trial or randomized controlled or randomized) and English database search terms were "melatonin" and "Delirium" and 'randomized controlled trials' or 'randomized controlled trials' or 'randomized'.

Search strategy

The following search terms were used: ("Delirium" [Mesh]) OR (title) (acute subdelirium [title/abstract])OR (delirium, sub [title/abstract]) OR (delirium, acute sub [title/abstract] OR (Sub-Delirium[title/abstract]) or (Mixed Origin Delirium [abstract]) OR (Mixed Origin Delirium [title/abstract]) OR(Mixed Origin Delirium [title/abstract]) AND (Melatonin [title/abstract]) AND (Randomized Controlled Trial [Publication Type] OR (Randomized [title/abstract] AND Control [title/abstract] AND Trial [title/abstract]). This study has been registered on the PROSPERO website (No. CRD42021264902).

要想深化金融管理的有關工作，不僅需要進行對比工作，有關的金融機構也需要設置相應的風險變化評估系統，通過借助縱向對比的形式，可以及時地掌握企業在經濟活動中的變化情況，比如信貸規模，有關的工作人員需要充分研究貸款的數量，對于企業的各種金融活動所存在的潛在風險做出一定的評估。要是產生的風險超出了預期，就需要及時地控制信貸規模，這樣可以有效地保障金融機構和全社會的金融穩定。

Inclusion and exclusion criteria

Inclusion criteria were: (1) Research subjects: clinically hospitalized patients, including patients in surgery, internal medicine, and ICU, the criteria for diagnosing delirium were determined by the CAM= Delirium Confusion Assessment (CAM) criteria[14,15]; (2) Intervention measures: The selected study was an RCT, and there were no significant differences between the experimental group and the control group before the experiment; and (3) Outcome indicators: the main observation indicator was RR(Relative risk).

教師A在反思日志中不斷反思課堂教學，其經驗性知識和接受性知識在實踐過程中通過反思而實現互相轉化和促進教師專業發展。其在反思日志中也不斷提到之前自己所學過的教學理論，若不進行及時的反思，這些理論無法和自己的教學實踐結合起來就無法真正內化為自己的經驗性知識，更無法促進自身專業發展。因此，定時、有規律的反思，是教師從實踐者向研究者轉變的有效途徑。

The overall effect of melatonin in all selected samples showed that it prevented delirium in hospitalized patients. Overall homogeneity (

= 62%,

＜ 0.0003) indicated multiple studies, and there was heterogeneity between the data; therefore, the random-effects model was used for analysis, but subgroup analysis was needed to determine the heterogeneity between multiple sets of data in this meta-analysis,as shown in Table 2 and Figure 4 (Forest map).

Study selection and data extraction

Two researchers who had received systematic evidence-based training performed the literature assessment and data extraction. They independently read, screened, and retrieved relevant content based on the inclusion and exclusion criteria. Excel entry was used to extract data, the first author Wei You completed the literature screening, and data extraction was completed by author Χiaoyu Fan. After completion, cross-checking was carried out. If there was disagreement, this was resolved by discussion or joint negotiation with the third author Cheng Lei. The relevant data extracted from the included studies were the title, first author, publication time, research country (region), sample size, intervention time, evaluation indicators, and other information.

Quality assessment and publication bias

收集風機由玻璃鋼制成，適合室外安裝，外殼隔音罩為304SS材質。收集風機為側吸式離心風機，臥式安裝。葉輪進行平衡校正，轉速滿足最高轉速的110%。葉輪有足夠的剛度，搬運和運轉中不會產生變形。風管與風機連接應用軟連接方式，防止振動通過管道傳遞。

Statistical analysis

In the groups of patient (surgery, internal medicine, ICU), their

were 75%, 45%, and 36%,respectively, indicating that there was no obvious heterogeneity in internal medicine patients in the subgroups; but if the three subgroups were combined,

was 61% indicating that there was heterogeneity, the intervention effect of melatonin in preventing delirium in different hospitalized patients was inconsistent, and the different types of hospitalized patients were the source of the heterogeneity.Melatonin had a stronger effect in reducing the incidence of delirium in hospitalized medical patients,according to subgroup analysis (

＜ 0.01) as shown in Figure 8. Therefore, Stuti's[27] article was eliminated. Following removal of this study, the heterogeneity test was performed again. The results showed that the remaining 6 documents did not demonstrate heterogeneity (

= 45% ＜ 50%,

= 0.1).After elimination of this study, the fixed-effects model was used to combine the effect size.

RESULTS

Characteristics of the included studies

The flowchart of the research selection process is shown in Figure 1. The literature search retrieved 217 related documents from the Chinese and English databases. The document management software deleted 173 duplicate documents, read the titles and abstracts, and eliminated a total of 63 articles including reviews, systematic reviews, reviews, and animal experiments. Further research included reading the full text, deleting contents with inconsistent research data or inconsistent intervention measures/control measures (90 documents), excluding non-RCT literature (1), and one study with inconsistent outcome indicators was excluded. A total of 18 articles were finally re-analyzed, and the functions of the re-study are shown in Table 1. The basic characteristics of the literature in 18 articles were reviewed[16-33] and published in 2010-2021. The languages of the included literature are English and Chinese, and the study included 16 English articles and 2 Chinese articles. A total of 521 studies were involved. All included studies were divided into the control group and experimental group. The intervention in the experimental group was melatonin, and the intervention in the control group was a placebo (Table 1).

The experimental group was given melatonin to prevent delirium, and the control group was given placebo to prevent delirium.

Learning quality assessment

This study included 18 RCTs, 18 of which were of high quality, 6 of which scored 6 points, 7 of which described the method of random allocation sequence in full, and 18 assessed subjects using a blind approach. All trials provided complete data and no other potential risk of bias. The risk of bias in selective reporting was low. As shown in Figure 2, the standard was "+" and the standard "-" was not met. Figure 3 shows a statistical chart of the proportion of each item in the literature quality evaluation.See Figure 2 and Figure 3 for details.

Meta-analysis results

The exclusion criteria included: reviews, conference papers, systematic reviews, dissertations, animal experiments, repeat publications, unavailable full text or incomplete data extraction, low quality of the literature or obvious research flaws; already suffering from mental illness before admission, patients with abnormalities, severe sensory disturbances, history of depression or delirium, or long-term use of antipsychotic drugs.

Heterogeneity test

The 18 documents in this study were tested for heterogeneity, and it was found that

= 62% ＞ 50%, and the Q test showed

= 0.0003 ＜ 0.1, suggesting that the documents selected in this study were heterogeneous. Further investigation using Rabe diagrams and star diagrams indicated that there was a strong possibility of heterogeneity in the literature with regard to different patient types (Figures 5 and 6).Therefore, heterogeneity testing was required.

Sensitivity analysis

Sensitivity analysis is a method of testing the stability of results obtained under certain assumptions bychanging some important factors that affect the combined results, such as inclusion criteria, literature evaluation, loss to follow-up, and different effect sizes, and then re-analyzing the data. The results before and after changing the conditions were compared, to judge the stability of the meta-analysis conclusions. A sensitivity analysis of the 18 articles found that different types of hospitalized patients had a greater impact on the heterogeneity, and it was necessary to further determine the source of heterogeneity (Figure 7).

Subgroup analysis

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone produced by the pineal gland in the brain from the amino acid tryptophan. Synthetic melatonin supplements have been used for various medical conditions, especially sleep-related diseases, and have proved to be successful[12]. Delirium is characterized by a disturbance in the circadian sleep-wake cycle, which leads to the hypothesis that the neurotransmitter melatonin and associated metabolic changes are involved in the pathogenesis of delirium. After admission, especially after admission to the intensive care unit (ICU), the metabolism of melatonin is disturbed, all of which are factors that cause delirium. These characteristics suggest an association between melatonin abnormalities and delirium. Although there is still a lack of evidence of causality[2], melatonin regulates the body’s sleep-wake cycle, season, and circadian rhythm[13]. It is a sleep-improving substance. Oral melatonin has been widely used nationally and internationally.Although melatonin depletion is considered to be one of the mechanisms of delirium, there have been some studies on the effect of melatonin on the prevention of delirium; however, there are differences in the various research results. Therefore, this study analyzed randomized controlled trials (RCTs) of melatonin interventions to prevent delirium using a meta-analysis, aiming to quantitatively synthesize the results of multiple studies to provide more reliable quantitative results and to target patients in different situations. The best intervention measures to prevent delirium in hospitalized patients are recommended to provide evidence-based data and serve as a basis for the prevention and clinical treatment of delirium in hospitalized patients.

Review Manager 5.3 and Stata 15.0 software were used to conduct a meta-analysis on the extracted data.Subgroup analysis was conducted to analyze the heterogeneity of the included study results, and the corresponding effect model was selected based on the results: if

≥ 0.1 and

＜ 50%, this indicated that the statistical heterogeneity between the studies was acceptable. A fixed-effects model was chosen for data merging; if

＜ 0.1 and

≥ 50%, this indicated that the clinical heterogeneity between studies was large, and the source of heterogeneity was assessed or a random-effects model was chosen for data merging. Two categories of delirium incidence and relative risk (RR) were selected for analysis, and the 95%CI was calculated. When necessary, a sub-analysis of potential heterogeneity factors was performed,as well as an analysis to test the data.

Bias test

To determine whether there was publication bias in this study, a funnel chart was developed. The funnel chart for this study is shown in Figure 9. The funnel chart results of hospitalized patients in internal medicine showed a symmetrical distribution, suggesting that the publication bias of the included literature was small.

DlSCUSSlON

Delirium is characterized by dramatic changes in cognition, which are accompanied by changes in consciousness and in mental state, and these changes will fluctuate over time[34]. The incidence of delirium on admission is 11%-33%. The number of elderly patients in the emergency department,internal medicine, and surgery wards of general hospitals has increased by 6%[35-37].

In palliative care, the clinical management strategy for delirium episodes is to identify and treat correctable precipitating factors if they are consistent with the patient's desired treatment objectives;when the desired care goals are completely focused on comfort or delirium, the clinical management method is to identify and treat correctable precipitating factors. When episodes are difficult to treat, the therapeutic intervention must focus on symptomatic management of painful symptoms, such as perceptual disturbance or agitation. Antipsychotic drugs have been advocated for the first-line pharmacological treatment of painful delirium symptoms[38,39]. However, there is evidence that antipsychotic drugs have no preventive effect on delirium in hospitalized adults, and their therapeutic effects are limited[12,40,41]; in a recent trial of palliative care patients, antipsychotic drugs were less effective than placebo. Exacerbation of mild to moderate delirium can occur[42]. The proposed overall management approach is shifting to larger preventive measures, especially non-pharmacological interventions, and minimizing the use of antipsychotic drugs[43]. Multi-component non-pharmacological interventions,including maintenance of sleep hygiene, have significant effects in preventing delirium in the elderly[44,45], but in studies of palliative care populations, similar interventions plus suppressive therapy have not been effective in preventing delirium. Sleep-wake cycle disorder is not the core diagnostic criterion for the diagnosis of delirium, but it is reported that the prevalence of delirium in cancer patients is between 75% and 100%[46,47]. Although the pathophysiology of delirium is complex and not fully understood,melatonin disorders and related sleep-wake cycle disturbances are thought to be contributing factors to delirium. This is consistent with the initiation and maintenance of sleep; it plays an important role in the regulation and synchronization of the sleep-wake cycle and circadian rhythm[48]. According to reports,melatonin circadian rhythm disorders are found in postoperative patients and critically ill patients,especially in sepsis patients[49-51]. Melatonin disorders have therefore been confirmed in the majority of clinical patients with the highest risk of delirium, and this is the main hypothetical basis for the exogenous use of melatonin to prevent delirium. Postoperative delirium is closely related to postoperative cognitive dysfunction. In addition, postoperative delirium is considered to be a predictor of postoperative cognitive decline[52].

在素質教育的背景下，中學階段是我國教育事業順利開展的關鍵環節，初中生具有思維開闊、活潑好動等特點，而合作學習作為初中數學興趣教學的重要組成部分以及浙教版數學教學的重要教學手段，非常符合初中學生的身心發展規律。

Although there is increasing attention on the effects of melatonin and melatonin receptor agonists in promoting sleep and preventing delirium in critically ill patients and other high-risk populations[53],the heterogeneity of melatonin supplementation to prevent delirium has ruled out broad concluding recommendations[54].

A total of 18 studies and 2137 patients were included in this systematic review and meta-analysis. The results of the study suggest that melatonin has a more significant effect in preventing delirium in hospitalized patients (

＜ 0.01), but no outstanding advantages have been observed in surgery and ICU patients, especially in surgical patients, although the effect was significant (

＜ 0.01). However, the heterogeneity in each study was strong. Melatonin cannot yet be considered effective in preventing delirium in surgical (post-surgery) patients; in ICU patients, the effectiveness of melatonin in preventing delirium in patients was not significant (

＞ 0.01), and there are currently few RCT-based studies on the effect of melatonin in the prevention of delirium in ICU patients. Multi-center, large-sample randomized controlled experimental data are still required to support these findings. Melatonin can be used to prevent delirium in hospitalized patients. However, it is unknown whether it is worthy of clinical recommendation, and the results of this study should be treated with caution.

This systematic study only retrieved publically available Chinese and English publications, and there are limitations in the retrieval of other languages and grey literature, which may cause certain publication bias. However, many predisposing factors of delirium were taken into account (for example,higher age, cognitive impairment, and dementia) and predisposing factors (for example, infections,drugs, and electrolyte disorders). Future studies should consider different subgroups of medical,surgical, and trauma patients, and patients with a higher incidence of delirium, such as the elderly, to evaluate which subgroup benefits most from exogenous melatonin supplementation. Larger RCTs should assess the possible differential melatonin effects in different patient subtypes to determine which subgroups of patients can benefit from melatonin to prevent delirium and which dose and duration of melatonin management are the most effective.

Melatonin may reduce the incidence of delirium in medical patients, but did not significantly reduce the occurrence of delirium in surgical and ICU patients.

CONCLUSlON

通過代謝組學評價AS，可彌補臨床上主要以腰背部疼痛及晨僵等問卷主觀癥狀診斷AS的不足，臨床上常用的生物學指標HLA-B27雖在一定程度上可反映AS的發生發展，但其敏感性和特異性相對局限［6］，想要更全面、深刻地研究AS的發生發展機制，仍需結合癥狀、體征、生化指標等進行全面評價。

ARTlCLE HlGHLlGHTS

Research objectives

We conducted a meta-analysis, mainly for one purpose. It was based on high-quality studies with a large enough sample size to calculate a reliable estimate of the incidence of melatonin in preventing delirium in hospitalized patients, and to evaluate the role of melatonin in reducing the incidence of delirium in different types of patients.

Research methods

Various databases were searched and relevant studies on the incidence of delirium treated with melatonin in hospitalized patients were retrieved. In our meta-analysis, fixed-effects and random-effects models were used to estimate the incidence of delirium in hospitalized patients. Publication and sensitivity bias analysis was used to test the robustness of the data.

為了提高控制精度，需要對采集的重量數據進行相應的濾波處理。根據本系統特點，選用滑動平均濾波的方式進行數據處理。基本原理是首先連續采集18支煙(控制粒度)的重量值并保存，去掉最大值和最小值，以剩余16支煙的平均重量來計算本次偏差。再連續采集9支煙(滑動采樣數量)的重量值，將上次的18支煙重量值中的前9個數據去掉，并與9個新數據重新組成18個數據，去除最值后求平均值，計算新的偏差值，一直重復這個過程，為PID控制提供反饋數據。

Two researchers who had undergone rigorous evidence-based training assessed the quality of the literature. The quality of the included studies was assessed using the bias risk assessment approach provided by the Cochrane Handbook 5.1.0, and discrepancies were addressed through discussion or by third-party researchers. The evaluated items included: (1) The generation of a random allocation plan;(2) Whether to carry out the allocation plan

(3) Whether to blind the subjects and researchers; (4)Whether to blind the evaluators; (5) Incomplete results; (6) Selectively reported research results; and (7)Other sources of bias. The evaluation result of "yes" indicated that the risk of bias was low; the result of"no" indicated that the risk of bias in the study was higher; "unclear" indicated that the study did not mention or did not have sufficient information to evaluate whether bias was present. Publication bias was tested using Egger's Funnel plots.

Research results

A total of 18 studies involving 2137 patients were eligible for this review. Melatonin was shown to be more effective in reducing the incidence of delirium in hospitalized medical patients, and the findings were statistically significant (

＜ 0.01).

Research conclusions

Melatonin can reduce the incidence of delirium in medical patients, but its impact on reducing the incidence of delirium in patients with behavioral disorders and ICU patients is unclear.

除了訊問外，詢問也是收集言詞證據的主要手段。在刑事訴訟傳統的辦案方式中，詢問證人的方式通常是由辦案人員采取文字記錄的方式形成書面的證人證言，再由被詢問人簽字確認。這種方式不能反映詢問時的各種情況，包括詢問的背景環境、被詢問人的語氣和表情、回答問題的精確措詞等，而且可能存在辦案人員沒有如實記錄的問題。因此，和訊問一樣，監察機關有必要通過錄音錄像對證人證言進行固定。

Research perspectives

Our meta-analysis showed that melatonin can reduce the incidence of delirium in hospitalized medical patients. Unfortunately, limited research has shown that the benefit is not seen in surgical patients or ICU patients. Further study to determine the role of melatonin in reducing the incidence of delirium in surgical and ICU patients is required.

ACKNOWLEDGEMENTS

We would like to thank the doctors from the School of Public Health and Management and the Department of Biosensing, Chongqing Medical University for their help.

FOOTNOTES

You W and Fan ΧY contributed equally to this work; You W and Cheng L contributed to the design and provided the analysis; You W and Fan ΧY completed the data collection and provided statistical support;Nie CC, Chen Y, and Wang ΧL contributed to the manuscript preparation.

the Scientific Research Project of Sichuan Provincial Health Commission, No. 19PJ045.

The authors declare no conflicts of interest.

The authors have read the PRISMA 2009 Checklist and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.

我國中藥飲片行業發展現狀及存在的問題研究…………………………………………………… 張 雪等（13）：1734

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed following the Creative Commons Attribution-Non Commercial (CC BY-NC 4.0)license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:http://creativecommons.org/Licenses/by-nc/4.0/

3）優化吹掃時間，合理統籌。停工期間，合理優化了吹掃用汽量，自身裝置用汽盡量保持平穩，另外盡可能的錯開和催化、焦化等裝置的用汽高峰。

China

Wei You 0000-0003-0812-8933; Χiao-Yu Fan 0000-0003-3871-2831; Cheng Lei 0000-0003-1311-515Χ;Chen-Cong Nie 0000-0002-5895-1429; Yao Chen 0000-0002-6634-0089; Χue-Lian Wang 0000-0002-9339-5827.

Wu YΧJ

Webster JR

Wu YΧJ

1 Gray SL, Lai KV, Larson EB. Drug-induced cognition disorders in the elderly: incidence, prevention and management.

1999 ; 21 : 101 -122 [PMID: 10456379 DOI: 10 .2165 /00002018 -199921020 -00004 ]

2 Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis.

2010 ; 304 : 443 -451 [PMID:20664045 DOI: 10 .1001 /jama.2010 .1013 ]

3 Baker KG. Evaluation of DSM-5 and IWG-2 criteria for the diagnosis of Alzheimer's disease and dementia with Lewy bodies.

2016 ; 3 : 9 -12 [PMID: 29540044 DOI: 10 .1515 /dx-2015 -0031 ]

4 Breitbart W, Gibson C, Tremblay A. The delirium experience: delirium recall and delirium-related distress in hospitalized patients with cancer, their spouses/caregivers, and their nurses.

2002 ; 43 : 183 -194 [PMID: 12075033 DOI:10 .1176 /appi.psy.43 .3 .183 ]

5 Gagnon B, Lawlor PG, Mancini IL, Pereira JL, Hanson J, Bruera ED. The impact of delirium on the circadian distribution of breakthrough analgesia in advanced cancer patients.

2001 ; 22 : 826 -833 [PMID: 11576799 DOI: 10 .1016 /s0885 -3924 (01 )00339 -6 ]

6 Lawlor PG, Bush SH. Delirium in patients with cancer: assessment, impact, mechanisms and management.

2015 ; 12 : 77 -92 [PMID: 25178632 DOI: 10 .1038 /nrclinonc.2014 .147 ]

7 Espino DV, Jules-Bradley AC, Johnston CL, Mouton CP. Diagnostic approach to the confused elderly patient.

1998 ; 57 : 1358 -1366 [PMID: 9531917 ]

8 Parikh SS, Chung F. Postoperative delirium in the elderly. Anesth Analg 1995 ; 80 : 1223 -1232 [DOI:10 .1097 /00132586 -199602000 -00021 ]

9 Carter GL, Dawson AH, Lopert R. Drug-induced delirium. Incidence, management and prevention. Drug Saf 1996 ; 15 :291 -301 [PMID: 8905254 DOI: 10 .2165 /00002018 -199615040 -00007 ]

10 Inouye SK. The dilemma of delirium: clinical and research controversies regarding diagnosis and evaluation of delirium in hospitalized elderly medical patients.

1994 ; 97 : 278 -288 [PMID: 8092177 DOI:10 .1016 /0002 -9343 (94 )90011 -6 ]

11 Neufeld KJ, Yue J, Robinson TN, Inouye SK, Needham DM. Antipsychotic Medication for Prevention and Treatment of Delirium in Hospitalized Adults: A Systematic Review and Meta-Analysis.

2016 ; 64 : 705 -714 [PMID:27004732 DOI: 10 .1111 /jgs.14076 ]

12 Caumo W, Torres F, Moreira NL Jr, Auzani JA, Monteiro CA, Londero G, Ribeiro DF, Hidalgo MP. The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy.

2007 ;105 : 1263 -1271 , table of contents [PMID: 17959953 DOI: 10 .1213 /01 .ane.0000282834 .78456 .90 ]

13 Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, Fougerou C. Melatonin: Pharmacology,Functions and Therapeutic Benefits.

2017 ; 15 : 434 -443 [PMID: 28503116 DOI:10 .2174 /1570159 Χ14666161228122115 ]

14 Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium.

1990 ; 113 : 941 -948 [PMID: 2240918 DOI:10 .7326 /0003 -4819 -113 -12 -941 ]

15 Ryan K, Leonard M, Guerin S, Donnelly S, Conroy M, Meagher D. Validation of the confusion assessment method in the palliative care setting.

2009 ; 23 : 40 -45 [PMID: 19010967 DOI: 10 .1177 /0269216308099210 ]

16 Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly.

2010 ; 4 : 169 -173 [PMID: 21189854 DOI:10 .4103 /1658 -354 Χ.71132 ]

17 de Jonghe A, van Munster BC, Goslings JC, Kloen P, van Rees C, Wolvius R, van Velde R, Levi M, de Haan RJ, de Rooij SE; Amsterdam Delirium Study Group. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial.

2014 ; 186 : E547 -E556 [PMID: 25183726 DOI:10 .1503 /cmaj.140495 ]

18 Wang YH. Effect of exogenous melatonin intervention on postoperative delirium and serum S100 in elderly patients β The impact of.

2018 ; 6 : 533 -536 [DOI: 10 .11724 /jdmu.2018 .06 .12 ]

19 Prabhat K. The Effect of Ramelteon on Postoperative Delirium in Elderly Patients: A Randomised Double-Blind Study.

2019 ; 12 : 17 -20 [DOI: 10 .7860 /jcdr/2019 /42635 .13384 ]

20 Ford AH, Flicker L, Passage J, Wibrow B, Anstey M, Edwards M, Almeida OP. The Healthy Heart-Mind trial: melatonin for prevention of delirium following cardiac surgery: study protocol for a randomized controlled trial.

2016 ; 17 : 55 [PMID: 26822209 DOI: 10 .1186 /s13063 -016 -1163 -1 ]

21 Chen M. Effect of melatonin on prevention of postoperative delirium in elderly patients with major abdominal surgery.

2020 ; 2 : 230 -233

22 Javaherforoosh Zadeh F, Janatmakan F, Shafaeebejestan E, Jorairahmadi S. Effect of Melatonin on Delirium After on-Pump Coronary Artery Bypass Graft Surgery: A Randomized Clinical Trial.

2021 ; 46 : 120 -127 [PMID:33753956 DOI: 10 .30476 /ijms.2020 .82860 .1146 ]

23 Oh ES, Leoutsakos JM, Rosenberg PB, Pletnikova AM, Khanuja HS, Sterling RS, Oni JK, Sieber FE, Fedarko NS,Akhlaghi N, Neufeld KJ. Effects of Ramelteon on the Prevention of Postoperative Delirium in Older Patients Undergoing Orthopedic Surgery: The RECOVER Randomized Controlled Trial.

2021 ; 29 : 90 -100 [PMID:32532654 DOI: 10 .1016 /j.jagp.2020 .05 .006 ]

24 Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial.

2011 ; 26 : 687 -694 [PMID: 20845391 DOI: 10 .1002 /gps.2582 ]

25 Hatta K, Kishi Y, Wada K, Takeuchi T, Odawara T, Usui C, Nakamura H; DELIRIA-J Group. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial.

2014 ; 71 : 397 -403 [PMID: 24554232 DOI: 10 .1001 /jamapsychiatry.2013 .3320 ]

26 Agar M. Randomised double blind placebo controlled phase ii trial of prolonged release melatonin for prevention of delirium in inpatients with advancedcancer.

2016 ; 6 : NP20160611 -NP20160612 [DOI:10 .1177 /0269216316646056 ]

27 Jaiswal SJ, McCarthy TJ, Wineinger NE, Kang DY, Song J, Garcia S, van Niekerk CJ, Lu CY, Loeks M, Owens RL.Melatonin and Sleep in Preventing Hospitalized Delirium: A Randomized Clinical Trial.

2018 ; 131 : 1110 -1117 [PMID: 29729237 DOI: 10 .1016 /j.amjmed.2018 .04 .009 ]

28 Lawlor PG, McNamara-Kilian MT, MacDonald AR, Momoli F, Tierney S, Lacaze-Masmonteil N, Dasgupta M, Agar M,Pereira JL, Currow DC, Bush SH. Melatonin to prevent delirium in patients with advanced cancer: a double blind, parallel,randomized, controlled, feasibility trial.

2020 ; 19 : 163 [PMID: 33087111 DOI:10 .1186 /s12904 -020 -00669 -z]

29 Mengel A, Zurloh J, Bo?elmann C, Brendel B, Stadler V, Sartor-Pfeiffer J, Meisel A, Fleischmann R, Ziemann U, Poli S,Stefanou MI. Delirium REduction after administration of melatonin in acute ischemic stroke (DREAMS): A propensity score-matched analysis.

2021 ; 28 : 1958 -1966 [PMID: 33657679 DOI: 10 .1111 /ene.14792 ]

30 Vijayakumar HN, Ramya K, Duggappa DR, Gowda KV, Sudheesh K, Nethra SS, Raghavendra Rao RS. Effect of melatonin on duration of delirium in organophosphorus compound poisoning patients: A double-blind randomised placebo controlled trial.

2016 ; 60 : 814 -820 [PMID: 27942054 DOI: 10 .4103 /0019 -5049 .193664 ]

31 Nishikimi M, Numaguchi A, Takahashi K, Miyagawa Y, Matsui K, Higashi M, Makishi G, Matsui S, Matsuda N. Effect of Administration of Ramelteon, a Melatonin Receptor Agonist, on the Duration of Stay in the ICU: A Single-Center Randomized Placebo-Controlled Trial.

2018 ; 46 : 1099 -1105 [PMID: 29595562 DOI:10 .1097 /CCM.0000000000003132 ]

32 Abbasi S, Farsaei S, Ghasemi D, Mansourian M. Potential Role of Exogenous Melatonin Supplement in Delirium Prevention in Critically Ill Patients: A Double-Blind Randomized Pilot Study.

2018 ; 17 : 1571 -1580 [PMID: 30568713 ]

33 Jaiswal SJ, Vyas AD, Heisel AJ, Ackula H, Aggarwal A, Kim NH, Kerr KM, Madani M, Pretorius V, Auger WR,Fernandes TM, Malhotra A, Owens RL. Ramelteon for Prevention of Postoperative Delirium: A Randomized Controlled Trial in Patients Undergoing Elective Pulmonary Thromboendarterectomy.

2019 ; 47 : 1751 -1758 [PMID:31567351 DOI: 10 .1097 /CCM.0000000000004004 ]

34 Trull TJ, Vergés A, Wood PK, Jahng S, Sher KJ. The structure of Diagnostic and Statistical Manual of Mental Disorders(4 th edition, text revision) personality disorder symptoms in a large national sample. Personal Disord 2012 ; 3 : 355 -369 [PMID: 22506626 DOI: 10 .1037 /a0027766 ]

35 Bucht G, Gustafson Y, Sandberg O. Epidemiology of delirium. Dement Geriatr Cogn Disord 1999 ; 10 : 315 -318 [PMID:10473930 DOI: 10 .1159 /000017161 ]

36 Inouye SK. Deliriuminolder persons. N Engl J Med 2006 ; 354 : 1157 -1165 [DOI: 10 .1056 /nejmx060018 ]

37 Michaud L, Büla C, Berney A. Delirium Guidelines Development Group. Delirium: guidelines for general hospitals.

2007 ; 62 : 371 -383

38 Breitbart W, Alici Y. Evidence-based treatment of delirium in patients with cancer. J Clin Oncol 2012 ; 30 : 1206 -1214 [PMID: 22412123 DOI: 10 .1200 /JCO.2011 .39 .8784 ]

39 Irwin SA, Pirrello RD, Hirst JM, Buckholz GT, Ferris FD. Clarifying delirium management: practical, evidenced-based,expert recommendations for clinical practice.

2013 ; 16 : 423 -435 [PMID: 23480299 DOI:10 .1089 /jpm.2012 .0319 ]

40 Burry L, Mehta S, Perreault MM, Luxenberg JS, Siddiqi N, Hutton B, Fergusson DA, Bell C, Rose L. Antipsychotics for treatment of delirium in hospitalised non-ICU patients.

2018 ; 6 : CD005594 [PMID:29920656 DOI: 10 .1002 /14651858 .CD005594 .pub3 ]

41 Finucane AM, Jones L, Leurent B, Sampson EL, Stone P, Tookman A, Candy B. Drug therapy for delirium in terminally ill adults.

2020 ; 1 : CD004770 [PMID: 31960954 DOI: 10 .1002 /14651858 .CD004770 .pub3 ]

42 Agar MR, Lawlor PG, Quinn S, Draper B, Caplan GA, Rowett D, Sanderson C, Hardy J, Le B, Eckermann S, McCaffrey N, Devilee L, Fazekas B, Hill M, Currow DC. Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial.

2017 ; 177 : 34 -42 [PMID:27918778 DOI: 10 .1001 /jamainternmed.2016 .7491 ]

43 Bush SH, Lawlor PG, Ryan K, Centeno C, Lucchesi M, Kanji S, Siddiqi N, Morandi A, Davis DHJ, Laurent M, Schofield N, Barallat E, Ripamonti CI; ESMO Guidelines Committee. Delirium in adult cancer patients: ESMO Clinical Practice Guidelines.

2018 ; 29 Suppl 4 : iv143 -iv165 [PMID: 32169223 DOI: 10 .1093 /annonc/mdy147 ]

44 Martinez F, Tobar C, Hill N. Preventing delirium: should non-pharmacological, multicomponent interventions be used?

2015 ; 44 : 196 -204 [PMID: 25424450 DOI: 10 .1093 /ageing/afu173 ]

45 Gagnon P, Allard P, Gagnon B, Mérette C, Tardif F. Delirium prevention in terminal cancer: assessment of a multicomponent intervention. Psychooncology 2012 ; 21 : 187 -194 [PMID: 22271539 DOI: 10 .1002 /pon.1881 ]

46 Bosisio M, Caraceni A, Grassi L; Italian Delirium Study Group. Phenomenology of delirium in cancer patients, as described by the Memorial Delirium Assessment Scale (MDAS) and the Delirium Rating Scale (DRS).

2006 ; 47 : 471 -478 [PMID: 17116947 DOI: 10 .1176 /appi.psy.47 .6 .471 ]

47 Meagher DJ, Moran M, Raju B, Gibbons D, Donnelly S, Saunders J, Trzepacz PT. Phenomenology of delirium.Assessment of 100 adult cases using standardised measures. Br J Psychiatry 2007 ; 190 : 135 -141 [PMID: 17267930 DOI:10 .1192 /bjp.bp.106 .023911 ]

48 Cipolla-Neto J, Amaral FGD. Melatonin as a Hormone: New Physiological and Clinical Insights. Endocr Rev 2018 ; 39 :990 -1028 [PMID: 30215696 DOI: 10 .1210 /er.2018 -00084 ]

49 Perras B, Kurowski V, Dodt C. Nocturnal melatonin concentration is correlated with illness severity in patients with septic disease.

2006 ; 32 : 624 -625 [PMID: 16477409 DOI: 10 .1007 /s00134 -006 -0069 -x]

50 Seifman MA, Gomes K, Nguyen PN, Bailey M, Rosenfeld JV, Cooper DJ, Morganti-Kossmann MC. Measurement of serum melatonin in intensive care unit patients: changes in traumatic brain injury, trauma, and medical conditions.

2014 ; 5 : 237 [PMID: 25477861 DOI: 10 .3389 /fneur.2014 .00237 ]

51 Yoshitaka S, Egi M, Morimatsu H, Kanazawa T, Toda Y, Morita K. Perioperative plasma melatonin concentration in postoperative critically ill patients: its association with delirium.

2013 ; 28 : 236 -242 [PMID: 23312124 DOI:10 .1016 /j.jcrc.2012 .11 .004 ]

52 Glumac S, Kardum G, Karanovic N. Postoperative Cognitive Decline After Cardiac Surgery: A Narrative Review of Current Knowledge in 2019 . Med Sci Monit 2019 ; 25 : 3262 -3270 [PMID: 31048667 DOI: 10 .12659 /MSM.914435 ]

53 Mo Y, Scheer CE, Abdallah GT. Emerging Role of Melatonin and Melatonin Receptor Agonists in Sleep and Delirium in Intensive Care Unit Patients.

2016 ; 31 : 451 -455 [PMID: 26092575 DOI:10 .1177 /0885066615592348 ]

54 Choy SW, Yeoh AC, Lee ZZ, Srikanth V, Moran C. Melatonin and the Prevention and Management of Delirium: A Scoping Study.

2017 ; 4 : 242 [PMID: 29376051 DOI: 10 .3389 /fmed.2017 .00242 ]