術(shù)后認(rèn)知功能障礙的危險(xiǎn)因素及預(yù)防

蘇文良，王丹風(fēng) 綜述 田毅 審校

(中南大學(xué)湘雅?？卺t(yī)院麻醉科，海南 ?？?570100)

術(shù)后認(rèn)知功能障礙的危險(xiǎn)因素及預(yù)防

蘇文良，王丹風(fēng) 綜述 田毅 審校

(中南大學(xué)湘雅?？卺t(yī)院麻醉科，海南 ?？?570100)

術(shù)后認(rèn)知功能障礙(POCD)是麻醉與手術(shù)后出現(xiàn)的一種中樞神經(jīng)系統(tǒng)疾病，其在臨床中尤其是老年患者中并非少見，由于POCD可對患者生活質(zhì)量造成嚴(yán)重影響，給個(gè)人、家庭、社會帶來巨大負(fù)擔(dān)。近年來，POCD的危險(xiǎn)因素及預(yù)防倍受關(guān)注，研究成果為臨床預(yù)測、預(yù)防、治療提供新的思路。

術(shù)后認(rèn)知功能障礙；危險(xiǎn)因素；預(yù)防

術(shù)后認(rèn)知功能障礙(POCD)是麻醉、手術(shù)后中樞神經(jīng)系統(tǒng)的并發(fā)癥之一，是老年人術(shù)后常見的嚴(yán)重并發(fā)癥，即便發(fā)生輕微的認(rèn)知功能損傷，也會對老年患者的生活質(zhì)量造成嚴(yán)重影響，且與阿爾茲海默病和過早死亡有關(guān)。POCD不僅嚴(yán)重影響患者運(yùn)動功能、日常生活能力的恢復(fù)，更直接影響患者社會適應(yīng)能力，給患者重返社會帶來困難。已成為圍術(shù)期管理的重點(diǎn)和難點(diǎn)。了解臨床相關(guān)危險(xiǎn)因素的研究現(xiàn)狀對POCD的臨床工作具有重要的指導(dǎo)意義。

1 POCD的特點(diǎn)及發(fā)病率

POCD是術(shù)前無精神障礙的患者在術(shù)后出現(xiàn)的中樞神經(jīng)系統(tǒng)并發(fā)癥，表現(xiàn)為定向、思維、記憶、注意力、自知力等認(rèn)知能力的改變，其不會在術(shù)前和術(shù)后的短時(shí)間內(nèi)發(fā)病，特點(diǎn)為長期穩(wěn)定的認(rèn)知功能的可逆損害，病程可持續(xù)到術(shù)后數(shù)月[1]，與譫妄、阿爾茲海默病相混淆。術(shù)后譫妄常表現(xiàn)為外科手術(shù)后精神狀態(tài)的急劇變化，注意力不集中、意識水平降低超過24 h。術(shù)后譫妄在年輕和老年患者均可發(fā)生，其中老年患者的發(fā)病率更高。與POCD相比，譫妄的臨床表現(xiàn)多為精神方面，常見癥狀為短期內(nèi)注意力分散、感覺能力下降、認(rèn)知功能下降等，術(shù)后譫妄精神錯(cuò)亂大多發(fā)生于手術(shù)后1～7 d，通常具有可逆性并常伴有嚴(yán)重的全身癥狀如心動過速、多汗、過度通氣等。POCD因具有進(jìn)行性認(rèn)知功能受損的特點(diǎn)而易于與術(shù)后譫妄相鑒別。而阿爾茲海默病為一種慢性的、不可逆的進(jìn)行性疾病，主要發(fā)患者群為老年人，往往在術(shù)前和麻醉前已經(jīng)發(fā)病，手術(shù)和麻醉可加重此病。記憶障礙是阿爾茲海默病的特征之一，患者解決問題、決策、判斷和定向的能力常受損傷。此外，阿爾茲海默病也常伴有人格改變。

Evered等[2]分析表明，術(shù)后7 d，接受全髖置換手術(shù)(THR)的患者POCD的發(fā)病率為17%，冠脈旁路搭橋術(shù)(CABG)后POCD的發(fā)病率為43%；術(shù)后3個(gè)月，鎮(zhèn)靜狀態(tài)下冠脈造影術(shù)后的發(fā)病率為21%，CABG術(shù)后發(fā)病率為16%，THR術(shù)后發(fā)病率為16%。

2 POCD的危險(xiǎn)因素

2.1 術(shù)前因素與POCD POCD的術(shù)前危險(xiǎn)因素包括年齡、術(shù)前認(rèn)知障礙(未診斷輕度認(rèn)知功能障礙、血管性癡呆、阿爾茲海默病或其他癡呆)、腦功能受損、CABG手術(shù)史、肺部疾病、酗酒、電解質(zhì)紊亂(藥物所致或因脫水)、精神藥物、代謝性疾病、術(shù)前譫妄等，其中高齡更是獨(dú)立危險(xiǎn)因素[3-13]。相關(guān)研究表明，糖化血紅蛋白(HbA1c)升高可明顯增加POCD的患病風(fēng)險(xiǎn)[13]，麻醉前給予咪達(dá)唑侖可加重POCD，而山莨菪堿對POCD沒有明顯影響[14]。Hovens等[15]研究了術(shù)前潛在感染對手術(shù)炎癥期大鼠認(rèn)知功能的影響，結(jié)果表明，術(shù)前潛在感染可加重術(shù)后炎癥反應(yīng)和認(rèn)知功能障礙；積極糾正術(shù)前感染等危險(xiǎn)因素可大大降低POCD的發(fā)病率。

2.2 術(shù)中危險(xiǎn)因素 術(shù)中低血壓、缺氧、栓塞、藥物和術(shù)中感染已被證實(shí)為導(dǎo)致POCD的危險(xiǎn)因素。

2.2.1 麻醉因素 局部麻醉藥物與全身麻醉藥物均可參與術(shù)后長期認(rèn)知功能障礙的形成[16-17]。陳瑩瑩等[18]研究表明，羥考酮用于結(jié)腸鏡診療術(shù)時(shí)，患者術(shù)后早期POCD的發(fā)病率相對高于芬太尼和氫嗎啡酮。一些研究結(jié)果表明，七氟烷麻醉可增加POCD的發(fā)病率，并且幼兒期七氟烷暴露史會增加遠(yuǎn)期POCD的發(fā)生風(fēng)險(xiǎn)[19-20]。但Evered等[2]的研究結(jié)果不只支持麻醉與POCD的相關(guān)性。現(xiàn)有大樣本研究均認(rèn)為麻醉方式的選擇對認(rèn)知結(jié)果沒有影響。

2.2.2 血壓 多項(xiàng)研究分析了心臟手術(shù)中低血壓和認(rèn)知能力下降之間的關(guān)系。結(jié)果表明，大腦在麻醉過程中代謝需求降低，低血壓多不會引起腦組織灌注不足；然而，低血壓會因減弱栓子清除能力，而影響腦血流自動調(diào)節(jié)的效率。Gold等[21]研究結(jié)果指出，體外循環(huán)(CPB)期間，維持相對較低的平均動脈壓(45～60 mmHg，1 mmHg=0.133 kPa)時(shí)，腦卒中發(fā)病率為7.2%，而相對較高的平均動脈壓(80～110 mmHg)時(shí)，腦卒中發(fā)病率為2.4%。術(shù)后6個(gè)月隨訪結(jié)果表明，兩者神經(jīng)功能下降患者的比例分別為11%和12%。Siepe等[22]研究發(fā)現(xiàn)，接受CABG的患者CPB期間在腦氧飽和度相似情況下，平均動脈壓在60～70 mmHg的患者POCD發(fā)病率遠(yuǎn)高于維持平均動脈壓80～90 mmHg的患者?？傮w而言，現(xiàn)有研究似乎支持手術(shù)過程中持維持一個(gè)足夠高的平均動脈血壓對保護(hù)腦灌注是非常重要的。

2.2.3 腦血流自動調(diào)節(jié) 對認(rèn)知能力的影響發(fā)揮作用的重要機(jī)制并非是平均動脈壓本身，而是大腦血流的自動調(diào)節(jié)(CA)以適應(yīng)血壓和氧飽和度的變化能力。調(diào)查心臟手術(shù)中CA適應(yīng)血壓的變化的研究發(fā)現(xiàn)，很大一部分POCD患者是由于難以通過自動調(diào)節(jié)維持術(shù)中腦血流[23]。Patel等[24]在兩項(xiàng)研究中發(fā)現(xiàn)術(shù)后6周認(rèn)知功能下降與CA能力下降有關(guān)。Newman等[25]通過215例患者CA的分析，指出CA的下降并不能解釋認(rèn)知功能障礙，而氧耗增加可能與認(rèn)知功能下降有關(guān)，即腦的氧供需失衡可能導(dǎo)致POCD。相關(guān)研究表明某些麻醉藥物可嚴(yán)重抑制腦血流的調(diào)節(jié)能力[26]。Goettel等[27]研究指出，術(shù)中的腦血流量自動調(diào)節(jié)功能受損并不能有效預(yù)測非心臟手術(shù)POCD的發(fā)生。但大多數(shù)研究似乎更傾向于支持CA對POCD的影響。

2.2.4 炎癥反應(yīng)與POCD 最近的證據(jù)表明，炎癥反應(yīng)可加劇老年人POCD的發(fā)病率，并且此作用隨老年人的年齡增長而增加。此學(xué)說雖可能解釋在老年人群的POCD高風(fēng)險(xiǎn)性，但并不能完全解釋不同老年人POCD不同發(fā)展結(jié)局。海馬作為大腦邊緣系統(tǒng)的重要組成部分，在學(xué)習(xí)、記憶以及情緒活動的調(diào)節(jié)中起重要作用，Hem等[28]通過對顱內(nèi)手術(shù)誘導(dǎo)海馬內(nèi)的炎癥反應(yīng)研究發(fā)現(xiàn)，海馬的炎癥反應(yīng)可能是POCD的重要危險(xiǎn)因素。Tang等[29]也證實(shí)了胰島素抵抗增加POCD的發(fā)生與炎癥因子的增加有關(guān)。Zhu等[30]研究發(fā)現(xiàn)圍手術(shù)期輸血超過3個(gè)單位紅細(xì)胞是老年患者全髖關(guān)節(jié)置換術(shù)后POCD的獨(dú)立危險(xiǎn)因素。同時(shí)，越來越多的證據(jù)表明，輸血治療往往改善生存，甚至可能導(dǎo)致不良后果。相關(guān)機(jī)制包括輸血與感染易感性增加、免疫致敏、輸血相關(guān)的肺損傷、加重應(yīng)激損傷、術(shù)后全身炎癥反應(yīng)等。

2.3 術(shù)后因素與POCD 術(shù)后疼痛可能是POCD發(fā)生的致病因素[31]。相比靜脈鎮(zhèn)痛，局麻藥物復(fù)合阿片類藥物的局部鎮(zhèn)痛效果更好，且可以有效減少POCD[32-33]。此外，在術(shù)后口服鎮(zhèn)痛藥患者的POCD發(fā)病率低于靜脈鎮(zhèn)痛的患者[34]。

3 POCD的預(yù)防及治療

POCD的病理生理機(jī)制尚不完全清楚，仍沒有公認(rèn)的有效干預(yù)措施以降低其發(fā)生率。在心臟外科手術(shù)中，七氟烷或地氟烷替代丙泊酚可減少早期POCD。七氟烷腦保護(hù)作用可減輕經(jīng)體外循環(huán)的心臟手術(shù)POCD[35-36]。且七氟烷可對不同器官的缺血性損傷進(jìn)行預(yù)處理，而且其可能的抗炎作用也可以防止POCD[37]。但至今仍沒有足夠的數(shù)據(jù)支持七氟烷或任何其他麻醉物可有效避免POCD。

糾正心臟手術(shù)期間腦氧飽和度下降并不減少冠狀動脈旁路移植術(shù)患者POCD發(fā)生率，因?yàn)楦纳颇X氧合或改變麻醉的類型似乎對預(yù)防POCD并不是很有效，而神經(jīng)保護(hù)劑如利多卡因、他汀類對預(yù)防POCD更加有效[38]。研究表明，右美托咪定可抑制炎癥反應(yīng)。右美托咪定可降低膿毒血癥大鼠的血清中炎癥因子白細(xì)胞介素-6(IL-6)的水平，抑制炎性反應(yīng)[39]。Zhao等[40]證實(shí)右美托咪定可以抑制脂多糖誘導(dǎo)的腫瘤壞死因子-α、IL-6、白細(xì)胞介素-8、高遷移率族蛋白等炎性因子的產(chǎn)生。Qi等[41]認(rèn)為尼莫地平和7.5%高滲鹽水預(yù)處理對老年大鼠術(shù)后認(rèn)知功能均具有較好的保護(hù)作用，其與海馬神經(jīng)元凋亡的抑制有關(guān)。有研究發(fā)現(xiàn)烏司他丁治療早期POCD減少術(shù)后兩天IL-6和s100蛋白濃度是有效的[42-43]。Wu等[44]發(fā)現(xiàn)姜黃素可防止POCD，其機(jī)制可能是通過提高抗氧化酶的活性，腦源性神經(jīng)營養(yǎng)因子信號激活，中和膽堿能功能障礙。Lin等[45]認(rèn)為腦氧飽和度(rSO2)可作為POCD的重要預(yù)測指標(biāo)，使用rSO2監(jiān)測指導(dǎo)麻醉?？蓽p小腦缺血缺氧的潛在風(fēng)險(xiǎn)，可改善腦功能，降低POCD的發(fā)生率，縮短住院時(shí)間、PACU滯留時(shí)間。Ballard等[1]的研究結(jié)果表明術(shù)中監(jiān)測麻醉深度、rSO2可降低術(shù)后認(rèn)知功能障礙。

4 結(jié) 語

POCD的發(fā)病機(jī)制至今仍是未解的臨床問題，對于POCD的臨床診斷、認(rèn)知功能的測評、診斷的標(biāo)準(zhǔn)仍未統(tǒng)一，各研究中得出的數(shù)據(jù)結(jié)論仍具有不確定性，今后的研究需多學(xué)科、多因素綜合考量POCD的研究，以求對POCD早預(yù)防、早發(fā)現(xiàn)、早診斷、早治療。

[1]Ballard C,Jones E,Gauge N,et al.Optimised anaesthesia to reduce post operative cognitive decline(POCD)in older patients undergoing elective surgery,a randomised controlled trial[J].PLoS One,2012,7(6):e37410.

[2]Evered L,Scott DA,Silbert B,et al.Postoperative cognitive dysfunction is independent of type of surgery and anesthetic[J].Anesth Analg,2011,112(5):1179-1185.

[3] Sachdev PS,Valenzuela M.Brain and cognitive reserve[J].Am J Geriatr Psychiatry,2009,17(3):175-178.

[4]Moller JT,Cluitmans P,Rasmussen LS,et al.Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study.ISPOCD investigators.International Study of Post-Operative Cognitive Dysfunction[J].Lancet,1998,351(9106):857-861.

[5]Monk TG,Weldon BC,Garvan CW,et al.Predictors of cognitive dysfunction after major noncardiac surgery[J].Anesthesiology,2008,108(1):18-30.

[6]Silbert B,Evered L,Scott DA,et al.Preexisting cognitive impairment is associated with postoperative cognitive dysfunction after hip joint replacement surgery[J].Anesthesiology,2015,122(6):1224-1234.

[7]Willis SL,Schaie KW.Cognitive training and plasticity:theoretical perspective and methodological consequences[J].Restor Neurol Neurosci,2009,27(5):375-389.

[8]Arrowsmith JE,Grocott HP,Reves JG,et al.Central nervous system complications of cardiac surgery[J].Br J Anaesth,2000,84(3):378-393.

[9]Freter S,Dunbar M,Koller K,et al.Prevalence and characteristics of pre-operative delirium in hip fracture patients[J].Gerontology,2016,62(4):396-400.

[10]Gvozdenovi? L,Antanaskovi? A.History of alcohol abuse after major non-cardiac surgery and postoperative cognitive dysfunction[J].Eur J Intern Med,2015,26(9):e51.

[11]Messerotti Benvenuti S,Patron E,Zanatta P,et al.Preexisting cognitive status is associated with reduced behavioral functional capacity in patients 3 months after cardiac surgery:an extension study[J].Gen Hosp Psychiatry,2014,36(4):368-374.

[12]Saleh AJ,Tang GX,Hadi SM,et al.Preoperative cognitive intervention reduces cognitive dysfunction in elderly patients after gastrointestinal surgery:a randomized controlled trial[J].Med Sci Monit,2015,21(1):798-805.

[13]Feinkohl I,Winterer G,Pischon T.Diabetes is associated with risk of postoperative cognitive dysfunction:A meta-analysis[J].Diabetes Metab Res Rev,2017,33(2):116-119.

[14]王瓏,張惠曼,王宏,等.麻醉前給予不同藥物對小鼠術(shù)后認(rèn)知功能的影響[J].中國臨床研究,2017,30(2):251-253.

[15]Hovens IB,van Leeuwen BL,Nyakas C,et al.Prior infection exacerbates postoperative cognitive dysfunction in aged rats[J].Am J Physiol Regul Integr Comp Physiol,2015,309(2):R148-R159.

[16]Newman S,Stygall J,Hirani S,et al.Postoperative cognitive dysfunction after noncardiac surgery:a systematic review[J].Anesthesiology,2007,106(3):572-590.

[17]Yin J,Wang SL.The effects of general anaesthesia on memory in children:a comparison between propofol and sevoflurane[J].Anaesthesia,2014,69(2):118-123.

[18]陳瑩瑩,張宗澤,劉漢興,等.氫嗎啡酮或羥考酮復(fù)合丙泊酚對結(jié)腸鏡診療術(shù)后患者認(rèn)知功能的影響[J].貴州醫(yī)科大學(xué)學(xué)報(bào),2017,42(2):194-197.

[19]Zheng JW,Meng B,Li XY,et al.NF-kappaB/P65 signaling pathway:a potential therapeutic target in postoperative cognitive dysfunction after sevoflurane anesthesia[J].Eur Rev Med Pharmacol Sci,2017,21(2):394-407.

[20]Zhu Y,Wang Y,Yao R,et al.Enhanced neuroinflammation mediated by DNA methylation of the glucocorticoid receptor triggers cognitive dysfunction after sevoflurane anesthesia in adult rats subjected to maternal separation during the neonatal period[J].J Neuroinflammation,2017,14(1):6-7.

[21]Gold JP,Charlson ME,Williams-Russo P,et al.Improvement of outcomes after coronary artery bypass A randomized trial comparing intraoperative high versus low mean arterial pressure[J].J Thorac Cardiovasc Surg,1995,110(5):1302-1311.

[22]Siepe M,Pfeiffer T,Gieringer A,et al.Increased systemic perfusion pressure during cardiopulmonary bypass is associated with less early postoperative cognitive dysfunction and delirium[J].Eur J Cardiothorac Surg,2011,40(1):200-207.

[23]Ono M,Joshi B,Brady K,et al.Risks for impaired cerebral autoregulation during cardiopulmonary bypass and postoperative stroke[J].Br JAnaesth,2012,109(3):391-398.

[24]Patel N,Minhas JS,Chung EM.Risk factors associated with cognitive decline after cardiac surgery:A systematic review[J].Cardiovasc Psychiatry Neurol,2015,18(15):1-12.

[25]Newman MF,Croughwell ND,Blumenthal JA,et al.Effect of aging on cerebral autoregulation during cardiopulmonary bypass Association with postoperative cognitive dysfunction [J].Circulation,1994,90(5 Pt 2):II243-249.

[26]Tanaka T,Kai S,Koyama T,et al.General anesthetics inhibit erythropoietin induction under hypoxic conditions in the mouse brain[J].PloS one,2011,6(12):e29378.

[27]Goettel N,Burkhart CS,Rossi A,et al.Associations between impaired cerebral blood flow autoregulation,cerebral oxygenation,and biomarkers ofbrain injury and postoperative cognitive dysfunction in elderly patients after major noncardiac surgery[J].AnesthAnalg,2017,124(3):934-942.

[28]Hem S,Albite R,Loresi M,et al.Pathological changes of the hippocampus and cognitive dysfunction following frontal lobe surgery in a rat model[J].Acta Neurochir(Wien),2016,158(11):2163-2171.

[29]Tang N,Jiang R,Wang X,et al.Insulin resistance plays a potential role in postoperative cognitive dysfunction in patients following cardiac valve surgery[J].Brain Res,2017,1657:377-382.

[30]Zhu S,Ji M,Gao D,et al.Association between perioperative blood transfusion and early postoperative cognitive dysfunction in aged patients following total hip replacement surgery[J].Ups J Med Sci,2014,119(3):262-267.

[31]Lynch EP,Lazor MA,Gellis JE,et al.The impact of postoperative pain on the development of postoperative delirium[J].Anesth Analg,1998,86(4):781-785.

[32]Morrison RS,Magaziner J,Gilbert M,et al.Relationship between pain and opioid analgesics on the development of delirium following hip fracture[J].J GerontolABiol Sci Med Sci,2003,58(1):76-81.

[33]Odor PM,Chis Ster I,Wilkinson I.Effect of admission fascia iliaca compartment blocks on post-operative abbreviated mental test scores in elderly fractured neck of femur patients:a retrospective cohort study[J].BMCAnesthesiology,2017,17(1):2.

[34]Wang Y,Sands LP,Vaurio L,et al.The effects of postoperative pain and its management on postoperative cognitive dysfunction[J].Am J Geriatr Psychiatry,2007,15(1):50-59.

[35]Royse CF,Andrews DT,Newman SN,et al.The influence of propofol or desflurane on postoperative cognitive dysfunction in patients undergoing coronary artery bypass surgery[J].Anaesthesia,2011,66(6):455-464.

[36]Kadoi Y.Sevoflurane anesthesia did not affect postoperative cognitive dysfunction in patients undergoing coronary artery bypass graft surgery[J].JAnesth,2007,21(3):330-335.

[37]Schoen J,Husemann L,Tiemeyer C,et al.Cognitive function after sevoflurane-vs propofol-based anaesthesia for on-pump cardiac surgery:a randomized controlled trial[J].Br J Anaesth,2011,106(6):840-850.

[38]Slater JP,Guarino T,Stack J,et al.Cerebral oxygen desaturation predicts cognitive decline and longer hospital stay after cardiac surgery[J].Ann Thorac Surg,2009,87(1):36-44.

[39]Yang CL,Tsai PS.Effects of dexmedetomidine on regulating pulmonary inflammation in a rat model of ventilator-induced lung injury[J].ActaAnaesthesiol Taiwan,2008,46(4):151-159.

[40]Zhao WX,Zhang JH,Cao JB,et al.Acetaminophen attenuates lipopolysaccharide-induced cognitive impairment through antioxidant activity[J].J Neuroinflammation,2017,14(1):17.

[41]Qi Z,Tianbao Y,Yanan L et al.Pre-treatment with nimodipine and 7.5%hypertonic saline protects aged rats against postoperative cognitive dysfunction via inhibiting hippocampal neuronal apoptosis[J].Behav Brain Res,2017,321(5):1-7.

[42]Lv ZT,Huang JM,Zhang JM,et al.Effect of ulinastatin in the treatment of postperative cognitive dysfunction:review of current literature[J].Biomed Res Int,2016,2016:2571080.

[43]Wang KY,Yang QY,Tang P,et al.Effects of ulinastatin on early postoperative cognitive function after one-lung ventilation surgery in elderly patients receiving neoadjuvant chemotherapy[J].Metab Brain Dis,2017,32(2):427-435.

[44]Wu X,Chen H,Huang C,et al.Curcumin attenuates surgery-induced cognitive dysfunction in aged mice[J].Metab Brain Dis,2017,32(2):789-798.

[45]Lin R,Zhang F,Xue Q,et al.Accuracy of regional cerebral oxygen saturation in predicting postoperative cognitive dysfunction after total hip arthroplasty[J].JArthroplasty,2013,28(3):494-497.

R619

A

1003—6350（2017）23—3896—04

10.3969/j.issn.1003-6350.2017.23.036

海南省科技廳項(xiàng)目（編號：KJHZ2014-20）

田毅。E-mail：13876826960@126.com

2017-04-17)