亞甲藍(lán)對(duì)老年非心臟手術(shù)患者術(shù)后認(rèn)知功能障礙及術(shù)后譫妄的影響

蔡嘉靖，邵思銘，鄭艷雅，金資源，徐振東，聶文夫，熊俊成

·藥物研究·

亞甲藍(lán)對(duì)老年非心臟手術(shù)患者術(shù)后認(rèn)知功能障礙及術(shù)后譫妄的影響

蔡嘉靖，邵思銘，鄭艷雅，金資源，徐振東，聶文夫，熊俊成

溫州市人民醫(yī)院麻醉科，浙江溫州 325000

評(píng)價(jià)亞甲藍(lán)預(yù)防老年非心臟手術(shù)患者術(shù)后認(rèn)知功能障礙（postoperative cognitive dysfunction，POCD）及術(shù)后譫妄（postoperative delirium，POD）的安全性及有效性。選取2021年9月至2022年7月在溫州市人民醫(yī)院進(jìn)行全身麻醉下非心臟手術(shù)的240名老年患者，采用隨機(jī)數(shù)字表法分為亞甲藍(lán)組（=120）和對(duì)照組（=120）。亞甲藍(lán)組患者在插管后靜脈輸注2mg/kg的亞甲藍(lán)，對(duì)照組輸注等量生理鹽水。使用簡(jiǎn)易精神狀態(tài)量表（mini-mental state examination，MMSE）和蒙特利爾認(rèn)知評(píng)估（Montreal cognitive assessment，MoCA）評(píng)估兩組的POCD發(fā)病率。POD的診斷與評(píng)估則采用意識(shí)模糊評(píng)估量表（confusion assessment method，CAM）及譫妄評(píng)定量表-98修訂版（delirium rating scale，DRS-R-98）。比較兩組患者術(shù)前和術(shù)后24h中樞神經(jīng)特異蛋白（S100 calcium-binding protein β，S100-β）、超氧化物歧化酶（superoxide dismutase，SOD）、神經(jīng)元特異性烯醇化酶（neuron specific enolase，NSE）和同型半胱氨酸（homocysteine，Hcy）水平。亞甲藍(lán)組的POCD發(fā)病率顯著低于對(duì)照組（<0.05）。術(shù)前1d和術(shù)后7d，兩組MMSE和MoCA評(píng)分比較，差異均無(wú)統(tǒng)計(jì)學(xué)意義（>0.05），亞甲藍(lán)組的POD發(fā)病率顯著低于對(duì)照組（<0.05），兩組POD亞型情況比較，差異無(wú)統(tǒng)計(jì)學(xué)意義（＞0.05）。亞甲藍(lán)組的DRS-R-98得分顯著低于對(duì)照組（<0.05）；術(shù)前兩組患者血清中S100β、NSE、SOD和Hcy水平比較，差異均無(wú)統(tǒng)計(jì)學(xué)意義（>0.05）。亞甲藍(lán)組術(shù)后24h血清中的S-100β和NSE水平顯著低于對(duì)照組（<0.05），血清SOD和Hcy水平比較，差異均無(wú)統(tǒng)計(jì)學(xué)意義（>0.05）。術(shù)中輸注亞甲藍(lán)可降低非心臟手術(shù)老年患者POCD和POD的發(fā)生率，可用于臨床普及應(yīng)用。

術(shù)后認(rèn)知功能障礙；術(shù)后譫妄；亞甲藍(lán)；高齡患者

術(shù)后認(rèn)知功能障礙（postoperative cognitive dysfunction，POCD）及術(shù)后譫妄（postoperative delirium，POD）是老年患者圍手術(shù)期常見(jiàn)的神經(jīng)系統(tǒng)并發(fā)癥，POCD臨床表現(xiàn)為學(xué)習(xí)和記憶力下降、定向力的障礙及社會(huì)活動(dòng)能力減退，POD表現(xiàn)為起病急、病程波動(dòng)大、術(shù)后注意力不集中、思維紊亂及意識(shí)改變等[1]。短期內(nèi)POCD及POD可增加患者的并發(fā)癥發(fā)生率、死亡率及住院費(fèi)用，而長(zhǎng)期來(lái)看，POCD與POD可能增加患者患阿爾茨海默病的風(fēng)險(xiǎn)甚至致殘[2-3]。但目前臨床上尚無(wú)有效、安全的預(yù)防和治療方法。研究顯示亞甲藍(lán)具有顯著的線(xiàn)粒體保護(hù)作用[4]，對(duì)于阿爾茨海默病及帕金森病等神經(jīng)退行性疾病有神經(jīng)及認(rèn)知保護(hù)效應(yīng)[5-6]。但亞甲藍(lán)作為一種強(qiáng)有力的單胺氧化酶抑制劑（monoamine oxidase inhibitors，MAOI），可能會(huì)導(dǎo)致患者出現(xiàn)血流動(dòng)力學(xué)不穩(wěn)定、心律不齊和血清素綜合征等并發(fā)癥。因此本研究對(duì)亞甲藍(lán)預(yù)防POCD和POD的安全性和有效性進(jìn)行了評(píng)估。

1 資料與方法

1.1 一般資料

選取2021年9月至2022年7月在溫州市人民醫(yī)院進(jìn)行全身麻醉下非心臟手術(shù)的240名老年患者，采用隨機(jī)數(shù)字表法分為亞甲藍(lán)組（=120）和對(duì)照組（=120）。納入標(biāo)準(zhǔn)：①年齡≥65歲；②擇期行全身麻醉下非心臟手術(shù)的患者。排除標(biāo)準(zhǔn)：①亞甲藍(lán)過(guò)敏；②蠶豆??；③近期服用選擇性5-羥色胺再攝取抑制劑或5-羥色胺-去甲腎上腺素再攝取抑制劑；④肝臟或腎臟功能異常；⑤術(shù)前簡(jiǎn)易精神狀態(tài)量表（mini-mental state examination，MMSE）評(píng)估顯示已存在認(rèn)知功能不全[7]。本研究經(jīng)溫州市人民醫(yī)院倫理委員會(huì)批準(zhǔn)（倫理審批號(hào)：KY-2019-078）?；颊邔?duì)本次研究充分知情理解，患者及家屬書(shū)面簽署知情同意書(shū)。

1.2 方法

所有患者均進(jìn)行全身麻醉插管。麻醉藥物選用芬太尼（生產(chǎn)單位：宜昌人福藥業(yè)有限責(zé)任公司，批準(zhǔn)文號(hào)：國(guó)藥準(zhǔn)字H42022076，規(guī)格：2ml:0.1mg）、瑞芬太尼（生產(chǎn)單位：宜昌人福藥業(yè)有限責(zé)任公司，批準(zhǔn)文號(hào)：國(guó)藥準(zhǔn)字H20030199，規(guī)格：2mg）、丙泊酚（生產(chǎn)廠商：Fresenius Kabi Austria GmbH；Fresenius Kabi AB，注冊(cè)證號(hào)：國(guó)藥準(zhǔn)字HJ20170306，規(guī)格：20ml:0.2g）、順式阿曲庫(kù)銨（生產(chǎn)單位：江蘇恒瑞醫(yī)藥股份有限公司，批準(zhǔn)文號(hào)：國(guó)藥準(zhǔn)字H20183042，規(guī)格：5ml:10mg）。本研究中禁止使用苯二氮?類(lèi)藥物及氯胺酮。在上述基礎(chǔ)上，亞甲藍(lán)組在患者完成誘導(dǎo)后泵注2mg/kg的亞甲藍(lán)稀釋液（生產(chǎn)單位：濟(jì)川藥業(yè)集團(tuán)有限公司，批準(zhǔn)文號(hào)：國(guó)藥準(zhǔn)字H32024828，規(guī)格：5ml:50mg）共50ml，持續(xù)時(shí)間1h。對(duì)照組給予等量生理鹽水。在患者術(shù)前（T0），開(kāi)始輸注亞甲藍(lán)（T1），輸注完畢（T2），手術(shù)結(jié)束后（T3）分別測(cè)量平均動(dòng)脈壓（mean artery pressure，MAP）。在患者M(jìn)AP低于65mmHg（1mmHg=0.133kPa）或較基線(xiàn)下降20%時(shí)使用血管活性藥物。

1.3 觀察指標(biāo)

在術(shù)前1d、術(shù)后7d采用MMSE和蒙特利爾認(rèn)知評(píng)估（Montreal cognitive assessment，MoCA）評(píng)價(jià)患者認(rèn)知功能，兩表術(shù)后得分較術(shù)前均下降≥1分標(biāo)準(zhǔn)差，診斷為POCD[8-9]。采用用意識(shí)模糊評(píng)估量表（confusion assessment method，CAM）診斷術(shù)后譫妄，在術(shù)后7d內(nèi)或直到患者出院，每天進(jìn)行CAM量表評(píng)估[10]。CAM評(píng)估包括4個(gè)方面：①意識(shí)狀態(tài)急性改變或波動(dòng)；②注意力不集中；③思維紊亂；④意識(shí)水平改變。同時(shí)具備①②以及③或④中的1項(xiàng)即為譫妄。根據(jù)譫妄評(píng)定量表-98修訂版（delirium rating scale，DRS-R-98）得分判斷譫妄的嚴(yán)重程度[11]。在術(shù)前及術(shù)后24h采集患者空腹靜脈血，3000轉(zhuǎn)/min，離心15min，取上清液并分裝，–20℃保存。通過(guò)酶聯(lián)免疫吸附法（購(gòu)自杭州迪安生物技術(shù)有限公司）檢測(cè)血清中樞神經(jīng)特異蛋白（S100 calcium-binding protein β，S100-β）、超氧化物歧化酶（superoxide dismutase，SOD）、神經(jīng)元特異性烯醇化酶（neuron specific enolase，NSE）和同型半胱氨酸（homocysteine，Hcy）水平。

1.4 統(tǒng)計(jì)學(xué)方法

2 結(jié)果

2.1 兩組患者臨床資料比較

兩組的性別、年齡、體質(zhì)量指數(shù)（body mass index，BMI）、美國(guó)麻醉醫(yī)師協(xié)會(huì)分級(jí)（American Society of Anesthesiologists，ASA）等比較，差異均無(wú)統(tǒng)計(jì)學(xué)意義（>0.05）。亞甲藍(lán)組在T2的MAP顯著高于對(duì)照組（<0.05），亞甲藍(lán)組在術(shù)中使用去甲腎上腺素（noradrenalin，NA）的患者數(shù)量和用量均顯著少于對(duì)照組（<0.05），見(jiàn)表1。

2.2 兩組患者術(shù)后認(rèn)知功能情況比較

兩組各有117例受試者完成術(shù)后隨訪。亞甲藍(lán)組的POCD發(fā)病率顯著低于對(duì)照組（<0.05）。術(shù)前1d和術(shù)后7d，兩組MMSE和MoCA評(píng)分比較，差異無(wú)統(tǒng)計(jì)學(xué)意義（>0.05），見(jiàn)表2。

表1 兩組患者臨床資料比較

注：1mmHg=0.133kPa

表2 兩組患者術(shù)后認(rèn)知情況比較

2.3 兩組患者術(shù)后譫妄情況比較

亞甲藍(lán)組的POD發(fā)病率顯著低于對(duì)照組（<0.05），亞甲藍(lán)組中有POD患者6例，其中高活動(dòng)型4例，低活動(dòng)型1例，混合型1例；對(duì)照組中有POD患者15例，其中高活動(dòng)型9例，低活動(dòng)型5例，混合型1例。兩組POD亞型情況比較，差異無(wú)統(tǒng)計(jì)學(xué)意義（=0.897，=0.842）。亞甲藍(lán)組的DRS-R-98得分顯著低于對(duì)照組（<0.05），見(jiàn)表3。

表3 兩組患者術(shù)后譫妄情況比較

2.4 兩組患者手術(shù)前后血清S100β、NSE、SOD和Hcy水平比較

術(shù)前兩組患者血清中S100β、NSE、SOD和Hcy水平比較，差異均無(wú)統(tǒng)計(jì)學(xué)意義（>0.05）。亞甲藍(lán)組術(shù)后24h血清中的S-100β和NSE水平顯著低于對(duì)照組（<0.05），血清SOD和Hcy水平比較，差異均無(wú)統(tǒng)計(jì)學(xué)意義（>0.05），見(jiàn)表4。

3 討論

在接受非心臟手術(shù)的老年患者中，術(shù)后7d的POCD的發(fā)生率為17%～40%[12-13]，而POD的發(fā)生率約為30%[12]。本研究POCD和POD的發(fā)生率分別為18.8%和12.8%，處于較低的水平。究其原因，可能與研究中禁用了苯二氮?類(lèi)藥物和氯胺酮有關(guān)。有研究顯示苯二氮?類(lèi)藥物和氯胺酮有可能增加POCD和POD的發(fā)生率[14]。

線(xiàn)粒體是細(xì)胞內(nèi)能量代謝的中心，亞甲藍(lán)可通過(guò)促進(jìn)電子傳遞鏈上的電子運(yùn)輸，改善線(xiàn)粒體的功能，減少病理過(guò)程中的氧化應(yīng)激及炎癥因子生成，對(duì)血腦屏障的高滲透性和對(duì)神經(jīng)元的高親和力，被認(rèn)為是治療神經(jīng)退行性疾病的一種潛在的有效方法[15]。S-100β和NSE常被描述為神經(jīng)元損傷標(biāo)志物，當(dāng)手術(shù)因素引發(fā)神經(jīng)元損傷時(shí)，包括S100β和NSE在內(nèi)的各種蛋白質(zhì)會(huì)迅速釋放到血液中[7]。本研究中，亞甲藍(lán)組患者術(shù)后24h的血清S-100β和NSE水平顯著低于對(duì)照組，提示亞甲藍(lán)減少了神經(jīng)細(xì)胞的損傷。血清Hcy升高通常被認(rèn)為與各類(lèi)認(rèn)知障礙的發(fā)生、發(fā)展有關(guān)，但一項(xiàng)多中心試驗(yàn)顯示，在接受大手術(shù)的患者中，手術(shù)和麻醉后段時(shí)期內(nèi)患者血清Hcy水平并不會(huì)上升[16]，這與本研究中術(shù)后Hcy水平無(wú)明顯上升的結(jié)果一致，這表明術(shù)后短期內(nèi)POCD與血清Hcy水平無(wú)關(guān)。Deng等[17]發(fā)現(xiàn)，亞甲藍(lán)沒(méi)有調(diào)節(jié)老年患者術(shù)后外周SOD水平的效果，本研究結(jié)果也顯示圍手術(shù)期給予靜脈注射亞甲藍(lán)并沒(méi)有提示患者血清的SOD水平。

本研究結(jié)果顯示，亞甲藍(lán)組患者在T2時(shí)的MAP較對(duì)照組高4mmHg，而亞甲藍(lán)組術(shù)中使用NA的患者數(shù)量和用量均明顯低于對(duì)照組。一般認(rèn)為MAOI可以增加血管對(duì)兒茶酚胺的敏感性，亞甲藍(lán)作為一種強(qiáng)效MAOI，還被描述為一種兒茶酚胺保留劑，被用于治療血管痙攣綜合癥、敗血癥和各種難治性低血壓[18]。一項(xiàng)隊(duì)列研究顯示，給予心臟手術(shù)患者輸注亞甲藍(lán)可使MAP增加8mmHg[19]。另一項(xiàng)多中心隊(duì)列研究顯示術(shù)中低血壓與POD的發(fā)生率增加有關(guān)[20]。本研究使用血管活性藥物將兩組患者的術(shù)中MAP維持在正常范圍，但亞甲藍(lán)在減少POD發(fā)生率方面的作用可能與其穩(wěn)定血壓效果有關(guān)。

綜上所述，術(shù)中輸注亞甲藍(lán)可降低非心臟手術(shù)老年患者POCD和POD的發(fā)生率，可用于臨床普及應(yīng)用。但本試驗(yàn)有幾個(gè)局限性。首先，本試驗(yàn)的樣本量是基于兩項(xiàng)臨床試驗(yàn)結(jié)果計(jì)算得出，未進(jìn)行預(yù)試驗(yàn)。其次，本試驗(yàn)是單中心試驗(yàn)，可靠程度不如多中心試驗(yàn)。而且本研究只在短期內(nèi)跟蹤了POCD的發(fā)生率，但POCD可能會(huì)長(zhǎng)期影響患者的認(rèn)知能力，同時(shí)也會(huì)影響患者的生活質(zhì)量和死亡率，未來(lái)應(yīng)進(jìn)行多中心臨床試驗(yàn)，并評(píng)估亞甲藍(lán)對(duì)POCD的長(zhǎng)期影響。

表4 兩組患者手術(shù)前后血清S100β、NSE、SOD和Hcy水平比較

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Effect of methylene blue on postoperative cognitive dysfunction and postoperative delirium in elderly patients undergoing non-cardiac surgery

Department of Anesthesiology, Wenzhou People’s Hospital, Wenzhou 325000, Zhejiang, China

Objective To evaluate the safety and efficacy of methylene blue for the prevention of postoperative cognitive dysfunction (POCD) and postoperative delirium (POD) in elderly non-cardiac surgery patients. Method A total of 240 elderly patients who underwent non-cardiac surgery under general anaesthesia in Wenzhou People’s Hospital from September 2021 to July 2022 were selected and divided into the methylene blue group (=120) and the control group (=120) according to the random number table method. Patients in the methylene blue group were infused with 2mg/kg of methylene blue intravenously after intubation, and the control group was infused with an equal amount of saline. The incidence of POCD was assessed using the mini-mental state examination (MMSE) and the Montreal cognitive assessment (MoCA). The diagnosis and assessment of POD were performed using the confusion assessment method (CAM) and the delirium rating scale-98-revised (DRS-R-98). The levels of S100 calcium-binding protein β (S100-β), superoxide dismutase (SOD), neuron specific enolase (NSE) and homocysteine (Hcy) were compared between the two groups before and 24 hours after surgery. Results The incidence of POCD in the methylene blue group was significantly lower than that in the control group (<0.05). The MMSE and MoCA scores of the two groups were not statistically significant when compared with those of the preoperative 1 days and postoperative 7 days (>0.05). The incidence rate of POD in the methylene blue group was significantly lower than that of the control group (<0.05), and the difference between the two groups in terms of the subtypes of POD was not statistically significant when compared with those of the control group (>0.05). The DRS-R-98 score of the methylene blue group was significantly lower than that of the control group (<0.05), and the differences in serum levels of S100β, NSE, SOD and Hcy between the two groups were not statistically significant when comparing the two groups before surgery (>0.05). The serum levels of S-100β and NSE in the methylene blue group were significantly lower than those in the control group at 24 hours postoperatively (<0.05), and no statistically significant differences were observed when comparing the serum levels of SOD and Hcy (>0.05). Conclusion Intraoperative infusion of methylene blue reduces the incidence of POCD and POD in elderly patients undergoing non-cardiac surgery and can be used for universal clinical application.

Postoperative cognitive dysfunction; Postoperative delirium; Methylene blue; Elderly patients

R614.2

A

10.3969/j.issn.1673-9701.2023.23.017

溫州市基礎(chǔ)性科研項(xiàng)目（Y20190114）

熊俊成，電子信箱：xjc040402@sina.com

（2022–10–10）

（2023–07–23）