右旋美托咪定對(duì)心臟外科病人術(shù)后譫妄發(fā)生率的影響-PLOS

右美托咪定與心臟手術(shù)后譫妄/Dexmedetomidineanddeliriumaftercardiacsurgery右美托咪定與心臟手術(shù)后譫妄/Dexmedetomidineanddeliriumaftercardiacsurgery（版本號(hào)V2.0；版本日期2014-09-10/Version:2.0;Dateofversion:September10,2014）#.方案實(shí)施：藥品分發(fā)：由研究協(xié)調(diào)員根據(jù)試驗(yàn)入組編號(hào)選擇藥物，即藥物編碼與入組患者的隨機(jī)編號(hào)一致，并在CRF表中記錄該編碼。藥品使用：兩組試驗(yàn)藥物均用生理鹽水稀釋至50ml（右美托咪定濃度為4g/ml）。在麻醉誘導(dǎo)前，右美托咪定組以[0.9xkg]ml/h速度靜脈輸注試驗(yàn)藥物10min（相當(dāng)于在10min內(nèi)泵入0.6g/k的美托咪定），繼以[0.1xkg]ml/h速度靜脈輸注至術(shù)畢（相當(dāng)于干預(yù)組以0.4g/kg/h速度輸注右美托咪定），術(shù)后干預(yù)組病人繼續(xù)以0.025xkgml/h速度輸注右美托咪定（相當(dāng)于0.1g/kg/）直至停止機(jī)械通氣；對(duì)照組則以相同的速度輸注生理鹽水至停止機(jī)械通氣。麻醉管理：手術(shù)當(dāng)日根據(jù)病人情況可給相應(yīng)的術(shù)前藥，但避免使用東莨菪堿和長托寧。患者入室，常規(guī)吸氧，監(jiān)護(hù)五導(dǎo)聯(lián)心電圖、脈氧飽和度、有創(chuàng)動(dòng)脈血壓、BIS、中心靜脈壓和/或肺動(dòng)脈壓、鼻咽溫、尿量。根據(jù)臨床需要決定是否使用心排量監(jiān)測設(shè)備或經(jīng)食道超聲。麻醉誘導(dǎo)采用靜脈麻醉誘導(dǎo)法，藥物包括咪達(dá)唑侖、依托咪酯、舒芬太尼、丙泊酚等，麻醉維持采用舒芬太尼、丙泊酚、七氟烷吸入等，保證BIS在40-60之間。除試驗(yàn)藥物外不使用右美托咪定。術(shù)中根據(jù)血流動(dòng)力學(xué)監(jiān)測情況調(diào)整輸液量和輸液速度，維持血流動(dòng)力學(xué)穩(wěn)定。術(shù)后患者常規(guī)入心外科監(jiān)護(hù)室繼續(xù)治療。術(shù)后鎮(zhèn)痛采用阿片類靜脈注射/輸注，或其他口服鎮(zhèn)痛藥；術(shù)后鎮(zhèn)靜采用以丙泊酚為基礎(chǔ)的靜脈鎮(zhèn)靜策略，維持RASS鎮(zhèn)靜評(píng)分在-2~1之間。必要時(shí)可靜脈注射咪達(dá)唑侖。譫妄的處理：一旦診斷術(shù)后譫妄，應(yīng)積極的處理。需從去除誘因、支持療法、藥物干預(yù)三方面入手。去除誘因的措施有：停用可能引起譫妄的藥物、糾正水電解質(zhì)平衡等。支持療法包括：優(yōu)質(zhì)護(hù)理（再定向、認(rèn)知刺激、早期活動(dòng)、視聽幫助）、恰當(dāng)?shù)臒崃亢蜖I養(yǎng)供應(yīng)、糾正患者的睡眠-覺醒周期紊亂、家庭成員床旁陪同等。對(duì)于躁動(dòng)型譫妄，可給予氟哌啶醇靜脈注射（首次負(fù)荷量0.5-2mg，15-20min后可重復(fù)，直至癥狀控制，其后可根據(jù)需要每4-6小時(shí)靜脈給予負(fù)荷量的半量），持續(xù)數(shù)日。用藥期間應(yīng)注意監(jiān)測QT間期及有無錐體外系癥狀。必要時(shí)咨詢精神科醫(yī)師。.資料收集研究者在試驗(yàn)開始前統(tǒng)一經(jīng)過數(shù)據(jù)收集及結(jié)局評(píng)估有關(guān)的培訓(xùn)。術(shù)前：采集人口學(xué)資料，包括姓名、性別、出生日期、文化程度、受教育年限、體重系數(shù)等；術(shù)前診斷，合并疾病，最近一個(gè)月內(nèi)的用藥情況，既往手術(shù)史及麻醉史等；計(jì)算Charlson合并癥指數(shù)分值；輔助檢查：主要化驗(yàn)結(jié)果［血/尿/便常規(guī)、血生化全項(xiàng)（肌酐、肌鈣蛋白）、凝血功能等］，心電圖、心臟超聲、胸片等；簡明智力狀態(tài)檢查量表（MMSE）評(píng)分；醫(yī)院焦慮/抑郁量表（HospitalAnxietyandDepressionScale,HAD）評(píng)分;巴氏指數(shù)（BarthelIndex），評(píng)價(jià)日常生活活動(dòng)能力；譫妄評(píng)估（CAM法）；血清樣本：術(shù)前留取血液樣本2管各2-3ml，置于專用采血管，并離心分離出血清樣品，-80C深低溫保存，分別進(jìn)行血中s100p、NeutrophilGelatinaseAssociatedLipocalin例6八1）水平的測定。術(shù)中記錄手術(shù)時(shí)間、手術(shù)名稱，麻醉時(shí)間、麻醉藥物總用量，術(shù)中出血量、輸血量、液體出入量及其他各種藥物的使用情況；術(shù)后血清樣本：分別于術(shù)后6h及術(shù)后48h抽取血樣2管各2-3ml，置于專用采血管，并離心分離出血清樣品，-80C深低溫保存。對(duì)術(shù)后6h血清樣本進(jìn)行NeutrophilGelatinaseAssociatedLipocalin網(wǎng)6八1）水平的測定、對(duì)術(shù)后48h血清樣本進(jìn)行s1000蛋白水平的測定；術(shù)后入ICU后24小時(shí)內(nèi)的最差A(yù)PACHEII評(píng)分；譫妄評(píng)估：術(shù)后第1-5天每天1次，插管病人采用CAM-ICU、非插管病人采用CAM法對(duì)進(jìn)行譫妄評(píng)估；疼痛評(píng)分：術(shù)后第1-5天每天上午8-10點(diǎn)用NRS法（0二完全無痛，10=最嚴(yán)重疼痛）評(píng)估患者靜息狀態(tài)及咳嗽時(shí)的疼痛評(píng)分；主觀睡眠質(zhì)量評(píng)分：術(shù)后1-5天每天上午8-10采用NRS法（0二睡眠最好，10=睡眠最差）進(jìn)行睡眠質(zhì)量評(píng)分；認(rèn)知功能評(píng)估：術(shù)后第6天用MMSE法，在術(shù)后1月用TICS法進(jìn)行認(rèn)知功能評(píng)估；術(shù)后1-5天用藥（原發(fā)疾病所需藥物，鎮(zhèn)靜、鎮(zhèn)痛、抗膽堿藥以及糖皮質(zhì)激素）情況及監(jiān)護(hù)室出入量情況；術(shù)后機(jī)械通氣時(shí)間、ICU停留時(shí)間、住院天數(shù);。術(shù)后30天內(nèi)各系統(tǒng)并發(fā)癥發(fā)生情況，如肺部并發(fā)癥、急性腎損傷、心腦血管事件、感染等。9.9.10術(shù)后30天的存活狀態(tài)（電話隨訪）。.結(jié)局指標(biāo)主要結(jié)局：術(shù)后前5天內(nèi)譫妄的發(fā)生率。次要結(jié)局：術(shù)后6天及30天的認(rèn)知功能評(píng)估；術(shù)后30天內(nèi)的非譫妄并發(fā)癥的發(fā)生率；術(shù)后30天的全因死亡率。其他結(jié)局：術(shù)后1-5天的NRS疼痛評(píng)分；術(shù)后1-5天的主觀睡眠質(zhì)量NRS評(píng)分；術(shù)后機(jī)械通氣時(shí)長；術(shù)后ICU停留時(shí)間及術(shù)后住院時(shí)間；術(shù)后30內(nèi)的再入院率。.不良事件及嚴(yán)重不良事件不良事件定義無論與藥物是否有關(guān)，凡是與研究中的任何醫(yī)療措施有關(guān)的、出現(xiàn)的非預(yù)期的、不利的醫(yī)學(xué)事件均為不良事件。一個(gè)不良事件可以是任何非預(yù)測的和不適宜的體征（包括異常的實(shí)驗(yàn)室檢查等）、癥狀或與使用產(chǎn)品相關(guān)的暫時(shí)性疾病。本試驗(yàn)預(yù)期的不良事件心動(dòng)過緩：心率＜45次/分，或較術(shù)前基礎(chǔ)水平下降超過30%并持續(xù)5min以上；低血壓：收縮壓＜80mmHg，或較術(shù)前基礎(chǔ)水平下降超過30%并持續(xù)5min以上；心動(dòng)過速：心率＞100次/分，或較術(shù)前基礎(chǔ)水平增加超過30%并持續(xù)5min以上；高血壓:收縮壓＞160mmHg，或較術(shù)前基礎(chǔ)水平增加超過30%并持續(xù)5min以上；低氧合：脈氧飽和度＜90%,或較基礎(chǔ)水平下降超過5%。不良事件的處理不良事件一旦出現(xiàn)，應(yīng)根據(jù)臨床醫(yī)療常規(guī)進(jìn)行治療，試驗(yàn)藥物的速度可根據(jù)需要作短暫或長期下調(diào)，如麻醉醫(yī)師或監(jiān)護(hù)室醫(yī)師認(rèn)為有必要，可終止試驗(yàn)藥物的輸注，但需要CRF表詳實(shí)記錄停藥時(shí)間及原因。常見處理包括：心動(dòng)過緩（靜脈注射阿托品或輸注異丙腎上腺素）；低血壓（容量治療及諸如麻黃堿、多巴胺、去甲腎上腺素等血管活性藥的使用）；心動(dòng)過速（靜脈使用艾司洛爾、阿替洛爾或地爾硫卓）；高血壓（靜脈使用硝普鈉、烏拉地爾、地爾硫卓等血管活性藥）；低氧合（增加吸入氧濃度或調(diào)整呼吸機(jī)參數(shù)以及胸部物理治療）。記錄任何發(fā)生的不良事件均應(yīng)記錄，包括種類、診斷時(shí)間、處理、持續(xù)時(shí)間、結(jié)局等。不良事件隨訪至消失或治療終結(jié)。嚴(yán)重不良事件定義嚴(yán)重不良事件是指非預(yù)期的導(dǎo)致病人死亡、危及病人生命、永久性傷殘或延長住院時(shí)間的其他嚴(yán)重情況的醫(yī)學(xué)事件。嚴(yán)重不良事件的處理如出現(xiàn)嚴(yán)重不良事件，除應(yīng)積極治療或搶救外，應(yīng)在獲知后24小時(shí)內(nèi)以電話或傳真形式通知臨床研究負(fù)責(zé)人和倫理委員會(huì)。如發(fā)生與治療相關(guān)的死亡事件，應(yīng)立即停止臨床試驗(yàn)，盡快上報(bào)倫理委員會(huì)，并詳細(xì)記錄和妥善保存有關(guān)資料。所有嚴(yán)重不良事件都應(yīng)當(dāng)追蹤，并及時(shí)記錄不良事件的出現(xiàn)、類別、發(fā)生時(shí)間、程度、持續(xù)時(shí)間及轉(zhuǎn)歸。直到得到妥善解決或病情穩(wěn)定。不良事件的監(jiān)測期限從實(shí)驗(yàn)藥物開始輸注至術(shù)后24h。但不良事件一旦發(fā)生，應(yīng)監(jiān)測至其消失或治療終結(jié)。.數(shù)據(jù)管理研究者根據(jù)受試者的原始觀察記錄，將數(shù)據(jù)及時(shí)、完整、正確的載入病例報(bào)告表；監(jiān)查員監(jiān)查試驗(yàn)的進(jìn)行是否遵循試驗(yàn)方案。病例報(bào)告表經(jīng)監(jiān)查員簽字后，及時(shí)送交臨床試驗(yàn)數(shù)據(jù)保管員；病例報(bào)告表在按要求完成數(shù)據(jù)錄入和核查后（一人錄入，另一人核查），按編號(hào)的順序歸檔保存。數(shù)據(jù)監(jiān)察由北京大學(xué)第一醫(yī)院臨床研究倫理委員會(huì)進(jìn)行。.統(tǒng)計(jì)學(xué)分析一般原則：計(jì)量資料根據(jù)數(shù)據(jù)分布的形態(tài)采用均值（標(biāo)準(zhǔn)差）或中位數(shù)（四分位間距）表示；計(jì)數(shù)資料用例數(shù)（百分比）表示。所有的統(tǒng)計(jì)檢驗(yàn)均采用雙側(cè)檢驗(yàn)，P值小于或等于0.05將被認(rèn)為所檢驗(yàn)的差別有統(tǒng)計(jì)意義。入組及完成情況：總結(jié)各中心入組及完成病例數(shù)，對(duì)兩組總脫落率將采用卡方檢驗(yàn)進(jìn)行比較。一般信息與基線特征：對(duì)患者的人口學(xué)信息、用藥史、合并其他疾病史等進(jìn)行統(tǒng)計(jì)描述。對(duì)于實(shí)驗(yàn)組與對(duì)照組的基線數(shù)據(jù)比較，計(jì)量資料采用采用成組t檢驗(yàn)/Wilcoxon秩和檢驗(yàn)，計(jì)數(shù)資料采用卡方檢驗(yàn)/Fisher精確檢驗(yàn)。.療效評(píng)價(jià)主要結(jié)局評(píng)價(jià)：對(duì)兩組術(shù)后5日內(nèi)各時(shí)間點(diǎn)的譫妄發(fā)生情況進(jìn)行統(tǒng)計(jì)描述。兩組譫妄發(fā)生率的比較采用卡方檢驗(yàn)。二元logistic回歸分析計(jì)算干預(yù)措施對(duì)術(shù)后譫妄發(fā)生率的危險(xiǎn)度及其95%可信區(qū)間。次要結(jié)局評(píng)價(jià)術(shù)后6天及30天的認(rèn)知功能評(píng)價(jià)：組間采用t檢驗(yàn)或Wilcoxon秩和檢驗(yàn)；術(shù)后非譫妄并發(fā)癥發(fā)生率：根據(jù)數(shù)據(jù)形態(tài)，組間采用卡方檢驗(yàn)、連續(xù)校正的卡方檢驗(yàn)或Fisher精確概率檢驗(yàn)；術(shù)后30天全因死亡率：采用Kaplan-Meier生存分析，組間差異用對(duì)數(shù)秩檢驗(yàn)；其他結(jié)局評(píng)價(jià)：術(shù)后1-5天疼痛及睡眠質(zhì)量評(píng)分：組間采用Wilcoxon秩和檢驗(yàn)；術(shù)后機(jī)械通氣時(shí)間、ICU停留時(shí)間、術(shù)后住院時(shí)間；根據(jù)數(shù)據(jù)形態(tài)，采用獨(dú)立樣本t檢驗(yàn)或Wilcoxon秩和檢驗(yàn)；術(shù)后30天再入院率：根據(jù)數(shù)據(jù)形態(tài)，組間采用卡方檢驗(yàn)、連續(xù)校正的卡方檢驗(yàn)或Fisher精確概率檢驗(yàn)；14．質(zhì)量控制研究開始前向研究人員和醫(yī)務(wù)人員詳細(xì)解釋研究方案。研究期間必須必須嚴(yán)格遵循研究方案；研究人員應(yīng)完整、詳細(xì)、準(zhǔn)確的填寫病例報(bào)告表。臨床試驗(yàn)中所有觀察到的結(jié)果和異常發(fā)現(xiàn)，均應(yīng)及時(shí)加以認(rèn)真核實(shí)、記錄，保證數(shù)據(jù)的可靠性；試驗(yàn)中各種檢查項(xiàng)目所使用的各種儀器設(shè)備，均應(yīng)有嚴(yán)格的質(zhì)量標(biāo)準(zhǔn)，并確保正常工作；統(tǒng)計(jì)分析由專業(yè)生物統(tǒng)計(jì)學(xué)的人員完成；所有結(jié)論應(yīng)基于原始數(shù)據(jù)得出。15倫理學(xué)要求遵循赫爾辛基宣言和中國有關(guān)臨床試驗(yàn)管理規(guī)范進(jìn)行臨床試驗(yàn)。在試驗(yàn)開始之前，由臨床研究倫理委員會(huì)批準(zhǔn)試驗(yàn)方案后方可實(shí)施臨床試驗(yàn)；術(shù)前研究人員到病房向符合篩選條件的患者或/及其委托人充分說明本研究的研究目的、方法及其可能帶來的益處和危害，并詳細(xì)解答患者及家屬的疑問，給予其充分的考慮時(shí)間，在完全自愿的前提下請(qǐng)患者或/及其委托人簽署知情同意書。對(duì)術(shù)前已明確存在癡呆等神經(jīng)精神疾病或無自主行為能力的患者，應(yīng)具備委托人簽字。知情同意書作為研究文件保存；所有與研究相關(guān)的個(gè)人信息均屬保密資料，不允許拷貝。除參與本臨床研究的研究人員、倫理委員會(huì)、研究單位相關(guān)管理部門外，不得向其他任何人、任何單位透露。16資料保存研究者、申辦者應(yīng)當(dāng)按照GCP要求對(duì)臨床試驗(yàn)的文件和資料進(jìn)行妥善保存。17預(yù)期進(jìn)度臨床試驗(yàn)觀察期：12-24個(gè)月。主要包括入選患者的篩選、入選、治療及隨訪；數(shù)據(jù)處理和資料總結(jié)期：6-12個(gè)月。主要對(duì)臨床試驗(yàn)所得資料進(jìn)行統(tǒng)計(jì)學(xué)處理、資料的總結(jié)。18．References:AssociationAP:DiagnosticAndStatisticalManualOfMentalDisorders.4thEd(DSM-IV).;1994.GroenJA,BanayanD,GuptaS,XuS,BhaleraoS:Treatmentofdeliriumfollowingcardiacsurgery.JCardSurg2012,27(5):589-593.KosterS,HensensAG,SchuurmansMJ,vanderPalenJ:Consequencesofdeliriumaftercardiacoperations.ANNTHORACSURG2012,93(3):705-711.JodatiA,SafaieN,RaoofiM,GhorbaniL,RanjbarF,NoorazarG,MosharkeshM:Prevalenceandriskfactorsofpostoperativedeliriuminpatientsundergoingopenheartsurgeryinnorthwestofiran.JCardiovascThoracRes2013,5(3):97-99.BrownCH:DeliriuminthecardiacsurgicalICU.CurrOpinAnaesthesiol2014,27(2):117-122.LeslieDL,InouyeSK:Theimportanceofdelirium:economicandsocietalcosts.JAMGERIATRSOC2011,59Suppl2:S241-S243.MilbrandtEB,DeppenS,HarrisonPL,ShintaniAK,SperoffT,StilesRA,TrumanB,BernardGR,DittusRS,ElyEW:Costsassociatedwithdeliriuminmechanicallyventilatedpatients.CRITCAREMED2004,32(4):955-962.KosterS,HensensAG,vanderPalenJ:Thelong-termcognitiveandfunctionaloutcomesofpostoperativedeliriumaftercardiacsurgery.ANNTHORACSURG2009,87(5):1469-1474.LoponenP,LutherM,WistbackaJO,NissinenJ,SintonenH,HuhtalaH,TarkkaMR:Postoperativedeliriumandhealthrelatedqualityoflifeaftercoronaryarterybypassgrafting.SCANDCARDIOVASCJ2008,42(5):337-344.MartinBJ,ButhKJ,AroraRC,BaskettRJ:Delirium:acauseforconcernbeyondtheimmediatepostoperativeperiod.ANNTHORACSURG2012,93(4):1114-1120.GottesmanRF,GregaMA,BaileyMM,PhamLD,ZegerSL,BaumgartnerWA,SelnesOA,McKhannGM:Deliriumaftercoronaryarterybypassgraftsurgeryandlatemortality.ANNNEUROL2010,67(3):338-344.ChanMT,ChengBC,LeeTM,GinT:BIS-guidedanesthesiadecreasespostoperativedeliriumandcognitivedecline.JNeurosurgAnesthesiol2013,25(1):33-42.RadtkeFM,FranckM,LendnerJ,KrugerS,WerneckeKD,SpiesCD:Monitoringdepthofanaesthesiainarandomizedtrialdecreasestherateofpostoperativedeliriumbutnotpostoperativecognitivedysfunction.BrJAnaesth2013,110Suppl1:i98-i105.PlaschkeK,FichtenkammP,SchrammC,HauthS,MartinE,VerchM,KarckM,KopitzJ:Earlypostoperativedeliriumafteropen-heartcardiacsurgeryisassociatedwithdecreasedbispectralEEGandincreasedcortisolandinterleukin-6.IntensiveCareMed2010,36(12):2081-2089.CerejeiraJ,BatistaP,NogueiraV,Vaz-SerraA,Mukaetova-LadinskaEB:Thestressresponsetosurgeryandpostoperativedelirium:evidenceofhypothalamic-pituitary-adrenalaxishyperresponsivenessanddecreasedsuppressionoftheGH/IGF-1Axis.JGeriatrPsychiatryNeurol2013,26(3):185-194.TanMC,FeldeA,KuskowskiM,WardH,KellyRF,AdabagAS,DyskenM:Incidenceandpredictorsofpost-cardiotomydelirium.AmJGeriatrPsychiatry2008,16(7):575-583.KosarCM,TabloskiPA,TravisonTG,JonesRN,SchmittEM,PuelleMR,InloesJB,SaczynskiJS,MarcantonioER,MeagherDetal:EFFECTOFPREOPERATIVEPAINANDDEPRESSIVESY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elderlypatientsaftercardiacsurgery:Amulticenter,

randomized,double-blind,placebo-controlledtrialStudyprotocolStudyDrug:dexmedetomidinehydrochlorideforinjectionPrincipalInvestigator:Dong-XinWang,MD,PhDStudyDesign:Dong-XinWang,MD,PhD;XueLi,MD;Li-HuanLi,MD,PhDandDaqingMa,MD,PhD,FRCANameofInstitute:DepartmentofAnesthesiologyandCriticalCareMedicine(Dong-XinWang,MD,PhDandXueLi,MD),PekingUniversityFirstHospital,Beijing100034,China;DepartmentofAnesthesiology(Li-HuanLi,MD,PhD),FuwaiHospital,NationalCenterforCardiovascularDiseases,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing100037,China;andSectionofAnaesthetics,PainManagementandIntensiveCare(DaqingMa,MD,PhD,FRCA),DepartmentofSurgeryandCancer,ImperialCollegeLondon,ChelseaandWestminsterHospital,London,UK.Version:2.0Dateofversion:September10,2014AbstractBackgroundRetrospectivestudiesshowedthatforpatientsundergoingcardiacsurgery,useofdexmedetomidineduringtheperioperativeperiodwasassociatedwithdecreasedriskofdelirium.However,evidencesfromprospectiverandomizedcontrolledtrialsarestilllacking.ObjectivesToinvestigatethehypothesisthatdexmedetomidine,whenusedasanadjunctivedrugduringbothgeneralanesthesiaandpostoperativesedation,woulddecreasetheincidenceofdeliriuminelderlypatientsaftercardiacsurgery.StudydesignThisisatwo-center,perspective,randomized,double-blind,placebo-controlledtrial.SettingTwotertiaryhospitals(PekingUniversityFirstHospitalandBeijingFuwaiHospital)inBeijing.PatientsTwohundredandeightyfourelderlypatients(age60years)whoarescheduledtoundergocoronaryarterybypassgraftand/orvalvesurgery.InterventionForpatientsinthedexmedetomidine(DEX)group,aloadingdosedexmedetomidinewillbeadministered10minutesbeforeanesthesia(0.6g/gin10minutes),followedbyacontinuousinfusionatarateof0.4g/kg/huntiltheendofsurgery.ftersurgery,theinfusionratewillbedecreasedto0.1g/kg/huntiltheendofmechanicalventilation;Forpatientsinthecontrol(CTRL)group,normalsalinewillbeadministeredinthesamerateandvolumeasthatintheDEXgroup.PrimaryoutcomeTheincidenceofdeliriumduringthefirst5daysaftersurgery.Predicteddurationofthestudy2-3years.TrialregistrationThestudyisregisteredwithClinicalT,numberNCT02267538.BackgroundDeliriumisanacutementalsyndromecharacterizedbydisturbanceofconsciousness,attention,cognitionandperceptionthatdevelopsoverashortperiodoftime(usuallyhourstodays)andtendingtofluctuateduringthecourseoftheday[1].Itisacommoncomplicationinelderlypatientsaftercardiacsurgery,withreportedincidencerangingfrom3%to47%[2].Theoccurrenceofpostoperativedelirium(POD)isassociatedwithworseoutcomes,includingprolongedlengthofstayintheICUandhospital[3,4],increasedmorbidity[5],andhighmedicalcarecosts[6,7].Moreover,prolongeddeliriumisassociatedwithworselong-termoutcomes,includingcompromisedcognitivefunction[8],loweredlifequality[9],andelevatedmortality[10,11].ThecausesofPODaremultifactorialandmayincludedeepanesthesia[12,13],severesurgicalstress[14,15],intensepostoperativepain[16,17],highdoseopioidanalgesia[18,19],prolongedmechanicalventilation[20,21],andsleepdisturbancesaftersurgery[22,23].Theoretically,measuresthatdecreasesanestheticconsumption(butmaintainsadequateanesthesiadepth),alleviatessurgicalstressresponse,improvespostoperativeanalgesia,reducesopioidandsedativerequirement,andpromotessleepqualitywillbeabletodecreasetheincidenceofPOD.Dexmedetomidineisahighlyselectivea2adrenoreceptoragonistthatprovidessympatholytic,sedative,andanalgesiceffects.Ithasbeenincreasinglyusedduringclinicalanesthesiaandpostoperativesedation[24].Studiesshowedthat,whenusedasanadjunctivedrugduringgeneralanesthesia,dexmedetomidinedecreasedtheconsumptionofanestheticsandopioidsandsuppressedtheseverityofstressresponse[25-27];whenusedduringthepostoperativeperiod,dexmedetomidinedecreasedtherequirementofothersedativesandanalgesics,improvedthequalityofanalgesiaandsleep,andreducedtheincidenceofdelirium[28-31].Retrospectivestudiesshowedthatforpatientsundergoingcardiacsurgery,useofdexmedetomidineduringtheperioperativeperiodwasassociatedwithdecreasedriskofdelirium,non-deliriumcomplicationsandone-yearmortalityaftersurgery[31-33].However,clinicalevidencesfromprospectiverandomizedcontrolledtrialsarestilllacking.Wehypothesizethat,forpatientsundergoingcardiacsurgery,useofdexmedetomidineasanadjuvantduringgeneralanesthesiaandpostoperativesedationmayreducetheincidenceofpostoperativedelirium,possiblybydecreasingtheconsumptionofgeneralanesthetics,relievingtheseverityofstressresponse,improvingpostoperativesleep,andsuppressingthedegreeofinflammation.PurposeofthestudyToinvestigatetheeffectsofdexmedetomidine,whenusedasanadjunctivedrugduringgeneralanesthesiaandpostoperativesedation,ontheincidenceofdelirium,therecoveryofcognitivefunction,theoccurrenceofcomplications,andthe30-daymortalityinelderlypatientsaftercardiacsurgery.RecruitmentofparticipantsPotentialparticipantswillbescreenedthedaybeforesurgeryor,forthosewhowillundergosurgeryonMonday,onFridaybeforesurgery.InclusioncriteriaElderlypatients(ageabove60years);Scheduledtoundergocoronaryarterybypassgraftand/orvalvesurgery.ExclusioncriteriaPatientswhomeetanyofthefollowingcriteriawillbeexcluded:Refusetoparticipate;Previoushistoryofschizophrenia,epilepsyorParkinsondisease;Unabletocompletepreoperativeassessmentduetoseveredementia,languagebarrierorend-stagedisease;Previoushistoryoffunctionalneurosurgeryorbraininjury;Preoperativesicksinussyndrome,severebradycardia(HR<50bpm),second-degreeoraboveatrioventricularblockwithoutpacemaker;Severehepaticinsufficiency(Child-PughgradesC);Severerenalinsufficiency(requirementofrenalreplacementtherapy);Anyotherconditionsthatareconsideredunsuitableforstudyparticipation.CriteriaofdropoutWithdrawnconsentsbytheparticipantsthemselves;Losstofollow-up;Orderedtoexitbytheinvestigatorsorattendingphysicians(occurrenceofsevereadverseeventsorseverecomplications);Casesofunmaskedblindness.Fordropoutcases,thedetailedreasonswillberecordedandtheprimarytherapeuticeffectsrecordedinthelasttimewillberegardedasthefinalresults.TheCaseReportForms(CRFs)ofthesecaseswillbepreservedforfuturereference.CriteriaofrejectionEnrolledcaseswhomeetanyofthefollowingcriteriawillbeexcludedfromfurtherperprotocolanalysis.Studydrugisnotadministered;Nostudyrecord;Unabletoevaluatetheeffectivenessandsafetybecauseoftheuseofanyprohibiteddrugs.Forrejectedcases,thedetailedreasonswillberecordedandCRFswillbepreservedforreference.Theresultsofthesecaseswillbeexcludedforfurtheranalysisoftherapeuticeffects.CriteriaofstudyinterruptionStudywillbeinterruptedinthefollowingsituations:Severesafetyproblemoccurredduringthestudy;Seriousmistakefoundintheprotocol;Fundormanagementproblemoftheinvestigators;Studycancelledbytheadministrativeauthority.Studyinterruptionmaytransientorpermanent.AllrecordedCRFswillbepreservedforreferenceincaseofstudyinterruption.StudyDesignThisisadouble-center,perspective,randomized,double-blind,placebocontrolledclinicaltrialwithtwoparallelarms;ItiscoordinatedbytheDepartmentofAnesthesiologyandCriticalCareMedicineofPekingUniversityFirstHospital;ThestudywillbeconductedinPekingUniversityFirstHospitalandBeijingFuwaiHospital.SampleSizeEstimationStudiesshowedthattheincidenceofpostoperativedeliriumincardiacsurgerypatientsvariedfrom3%to47%[2].Accordingtotheresultsofourpreviousstudy,weassumethattheincidenceofdeliriumis30%inthecontrolgroup.Arecentlymeta-analysisshowedthat,dexmedetomidinecanreducetheincidenceofdeliriumby63%(RR0.36,95%CI0.21-0.64)whenusedaspostoperativesedation[34].Weconservativelyassumethatdeliriumwillbereducedby50%inthedexmedetomidinegroupinthisstudy,i.e.,15%.Withsignificanceandpowersetat0.05(two-sided)and80%respectively,thesamplesizerequiredtodetectthisdifferenceis236patients.Takingintoaccounta20%loss-to-followuprate,weplantoenroll284patients.SamplesizecalculationisperformedwiththePASS11software(NCSS,LLC,Kaysville,Utah).Randomization,blindingandunmaskofblindingRandomizationAbiostatisticianwhodoesnotparticipateindatamanagementandstatisticalanalysiswillgeneraterandomnumbersina1:1ratiousingtheSASstatisticalpackageversion9.3(SASInstitute,Cary,NC,USA).Randomizationwillbestratifiedbycenters;Studydrugs(dexmedetomidinechloride200^g/2mLandnormalsaline2mL)willbeprovidedasclearaqueoussolutionsinthesame3mLbottles.Apharmacistwhodoesnotparticipateintherestofthestudywillencodethestudydrugsaccordingtotherandomizationsequence;Therandomizationresultswillbesealedinsequentiallynumberedlettersandstoredatthesiteofinvestigationuntiltheendofthestudy.BlindingAstudycoordinatorwillbeassignedtodistributethestudydrugsaccordingtothesequenceofrecruitedpatients,andtocoordinatebetweeninvestigators;Foreachrecruitedpatient,ananesthesiologistwillbeassignedforanesthesiamanagementandintraoperativedatacollection;Foreachrecruitedpatient,aninvestigator/nursewillbeassignedforstudydrugadministration;Postoperativefollow-upanddeliriumassessmentwillbeperformedbyinvestigatorswhohavebeentrainedpriortothestudy;Theanesthesiologistandtheinvestigatordonotknowtheresultstheycollectedeachother;Allsyringesandinjectionpumpsusedforstudydrugadministrationweresameinexternalappearance.UnmaskofblindingAftereachtrialpatient’sstudyiscompletedandalldataareinputtedintothedatabaseandcheckedwithoutmistakes,thedatabasewillbelockedupandtheblindnesswillbeunmasked.Thedatabasewillthenbesenttoabiostatisticianforstatisticalanalysis.InterventionandanesthesiamanagementDistributionofstudydrugsEachoftherecruitedpatientswillbeassignedanumberaccordingtothesequenceofrecruitment;Astudycoordinatorwilldistributethestudydrugsaccordingtothenumberofpatientrecruitment,i.e.,thenumberofrecruitmentwillbethesameofthenumberofstudydrugs;Thenumberofrecruitment/studydrugswillberecordedintheCRFbytheinvestigator.AdministrationofstudydrugsStudydrugswillbedilutedwithnormalsalineto50ml(fordexmedetomidinechloride,thefinalconcentrationis41g/mL);Studydruginfusionwillbeginatleast10minutesbeforeanesthesiainductionatarateof[0.9xkg]ml/hfor10minutes(i.e.,0.6pg/kgin10minutesfordexmedetomidine),thenatarateof[0.1xkg]ml/h(i.e.,0.4pg/kg/hfordexmedetomidine)untiltheendofsurgery.Aftersurgery,studydrugwillbeinfusedatarateof[0.025xkg]ml/h(i.e.,0.1pg/kg/hfordexmedetomidine)untiltheendofmechanicalventilation.AnesthesiamanagementPremedicationmaybeadministeredbeforeanesthesiaaccordingtopatients’condition;Intraoperativemonitoringincludeselectrocardiogram,pulseoxygensaturation,invasivearterialpressure,centralvenouspressure,nasopharyngealtemperature,bispectralindex(BIS),andurineoutput.Othercardiacmonitoring(thermodilutioncardiacoutput,transesophagealechocardiography,etc.)willbeperformedwhennecessary;Anesthesiawillbeinducedwithmidazolam,etomidate,sufentanil,andpropofol;andwillbemaintainedwithsufentanilinfusion,combinedwithpropofolinfusionand/orsevofluraneinhalation.BISwillbemaintainedbetween40and60;Duringsurgery,hemodynamicswillbemanagedbyadjustingfluidinfusionandusinginotropicand/orvasoactivedrugs;Patientswillbetransferredtotheintensivecareunit(ICU)aftersurgery;Patient-controlledintravenousanalgesia(withopioids)willbeprovidedwheneverpossible.Forpatientswhorequireadditionalanalgesia,opioidsorotheranalgesicswillbeadministeredeitherintravenouslyororally.Forpatientswhorequiresedation(formechanicalventilation),propofolintravenousinfusionwasthefirstchoice,thetargetRichmondAgitationSedationScale(RASS)isbetween-2and+1.Midazolamwillbeadministeredwhennecessary.ProhibitedmedicationPenehyclidineandscopolamineareprohibited;Open-lableddexmedetomidineisnotallowed.ManagementofdeliriumPrecipitatingfactors(usuallymultipleprecipitatingfactorsexist)shouldbeidentifiedandcorrectedormanaged;Supportivecareincludingreorientation,cognitivestimulation,earlymobilization,hearingorvisionaids,sleep-promotion,andnutritionsupplyshouldbeadministeredforalldeliriouspatients.Familymembersshouldbeincludedinthesupportivecareofdeliriouspatients;Pharmacologicaltreatmentisonlyreservedforpatientswithsevereagitation(RASSof+3orhigher).Haloperidol(0.5to2mg)willbeinjectedintravenously,repeatedwhennecessaryevery15to20minutesuntilcontrolofagitation.Formaintenancetreatment,halfoftheloadingdosewillbeadministeredevery4to6hours.Thetreatmentcanlastforseveraldays.QTinternalandextrapyramidalsymptomswillbemonitoredduringhaloperidoltherapy.Psychiatristswillbeconsultedwhennecessary.DatacollectionInvestigatorsperformingdatacollectionandassessmentwillbetrainedandqualifiedbeforethestudy.PreoperativedataDemographicdata,includinggender,height,weight,dateofbirth,education,etc.,willbecollected;Preoperativediagnosis,comorbidity(CharlsonComorbidityIndex),historyofmedication(especiallywithinonemonth),historyofpreviousanesthesiaandsurgerywillbecollected;Resultsofprimaryexamination,suchaselectrocardiogram,echocardiogram,hematologicalandbiochemicaltestresults,willbecollected;CognitivefunctionwillbeassessedwithMini-MentalStateExamination(MMSE);AnxietyanddepressionwillbeassessedwithHospitalAnxietyandDepressionScale;ActivityofdailylivingwillbeassessedwithBarthelIndex;DeliriumwillbeassessedwithConfusionAssessmentMethod(CAM);Bloodsamplewillbecollected.Serumwillbeseparatedbycentrifugationandstoredataprofoundhypothermicrefrigeratorof-80℃forthemeasurementofneutrophilgelatinaseassociatedlipocalin(NGAL)andS100Bprotein.IntraoperativedataDurationofanesthesia,typeanddoseofdrugsusedduringanesthesia;Fluidbalanceandtransfusionofbloodproducts;Typeanddurationofsurgery.PostoperativedataBloodsampleswillbecollectedat6and48hoursaftersurgery.Serumwillbeseparatedbycentrifugationandstoredataprofoundhypothermicrefrigeratorof-80℃forthemeasurementofNGAL(6hr)andS100pprotein(48hr);TheworstAcutePhysiologyandChronicHealthEvaluationII(APACHEII)scoreduringthefirst24hoursaftersurgerywillberecorded;Deliriumwillbeassesseddailyduringpostoperativedays1to5(8:00-10:00am).PatientswithendotrachealintubationwillbeassessedwiththeConfusionAssessmentMethodfortheICU(CAM-ICU);patientswithoutendotracheal