黃秋綺，張慶國，徐世元

(南方醫(yī)科大學(xué)珠江醫(yī)院 麻醉科，廣東 廣州 510280)

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糖尿病患者局麻藥敏感性的研究進(jìn)展

黃秋綺，張慶國，徐世元Δ

(南方醫(yī)科大學(xué)珠江醫(yī)院 麻醉科，廣東 廣州 510280)

局麻藥具有神經(jīng)毒性作用，可導(dǎo)致患者出現(xiàn)暫時(shí)性甚至是永久性的感覺和運(yùn)動(dòng)功能障礙，而區(qū)域神經(jīng)阻滯是糖尿病患者四肢及下腹部手術(shù)時(shí)常用的麻醉方法，局麻藥在其身上廣泛應(yīng)用。但是糖尿病患者對(duì)局麻藥的敏感性尚未明確。本文將就此問題進(jìn)行探討，展開綜述。

局麻藥；糖尿?。簧窠?jīng)毒性；蛛網(wǎng)膜下腔阻滯

隨著患病率的逐年上升，糖尿病人群日漸龐大。而相對(duì)于非糖尿病患者，糖尿病患者面對(duì)著更高的手術(shù)比率[1]，更大的手術(shù)風(fēng)險(xiǎn)。為了避免全身麻醉可能帶來的心肺相關(guān)并發(fā)癥以及胰島素抵抗作用[2]，減少血糖波動(dòng)，麻醉醫(yī)生更多地選擇了區(qū)域神經(jīng)阻滯作為糖尿病患者四肢及下腹部手術(shù)的麻醉方法。然而，盡管局麻藥的臨床應(yīng)用已有一百多年的歷史，但對(duì)于其在糖尿病患者的應(yīng)用，還認(rèn)識(shí)不足。所有局麻藥在高濃度時(shí)均具有神經(jīng)毒性[3]，甚至臨床常規(guī)濃度時(shí)也有潛在毒性[4]，但糖尿病患者對(duì)局麻藥的神經(jīng)毒性是否更敏感仍不能確定。

1 糖尿病患者、動(dòng)物局麻藥神經(jīng)毒性的相關(guān)研究

1.1 臨床研究 在臨床上，椎管內(nèi)阻滯引起的嚴(yán)重神經(jīng)系統(tǒng)并發(fā)癥很少見。Moen等[4]報(bào)道，151,000例椎管內(nèi)麻醉后出現(xiàn)嚴(yán)重神經(jīng)系統(tǒng)并發(fā)癥127例(0.008%)。Brull等[5]對(duì)32個(gè)研究進(jìn)行統(tǒng)計(jì)分析，蛛網(wǎng)膜下腔阻滯和硬膜外阻滯后神經(jīng)并發(fā)癥的發(fā)生率分別為0.04%和0.002%。然而，Hebl等[6]回顧性調(diào)查發(fā)現(xiàn)，合并周圍感覺運(yùn)動(dòng)神經(jīng)病變或糖尿病性神經(jīng)病的患者接受椎管內(nèi)麻醉或鎮(zhèn)痛后發(fā)生嚴(yán)重神經(jīng)功能障礙的風(fēng)險(xiǎn)為0.4%，遠(yuǎn)高于普通人群。而近年來，也有個(gè)案[7-12]報(bào)道術(shù)前合并糖尿病神經(jīng)病變的患者應(yīng)用常規(guī)劑量的局麻藥區(qū)域神經(jīng)阻滯后，神經(jīng)系統(tǒng)功能惡化。這提示，術(shù)前已存在的神經(jīng)系統(tǒng)疾病，尤其是糖尿病周圍神經(jīng)病變，可能是術(shù)后神經(jīng)損傷的重要危險(xiǎn)因素[13]。

有學(xué)者[14]回顧發(fā)現(xiàn)，以感覺異常為標(biāo)志，糖尿病患者鎖骨上臂叢神經(jīng)阻滯的成功率高于非糖尿病患者。另外，Echevarria等[15]對(duì)糖尿病患者予0.5%等比重布比卡因行蛛網(wǎng)膜下腔阻滯，發(fā)現(xiàn)感覺、運(yùn)動(dòng)起效時(shí)間較非糖尿病患者縮短，持續(xù)時(shí)間相對(duì)延長。Cuvillon等[16]的前瞻性研究發(fā)現(xiàn)，2型糖尿病患者與非糖尿病患者相比，坐骨神經(jīng)阻滯的感覺、運(yùn)動(dòng)阻滯持續(xù)時(shí)間均顯著延長。而Sertoz等[17]則發(fā)現(xiàn)相比控制良好的糖尿病患者，血糖控制不佳的糖尿病患者坐骨神經(jīng)阻滯的阻滯持續(xù)時(shí)間有所延長。不過，以上研究都觀察到糖尿病患者局麻藥的神經(jīng)阻滯時(shí)效延長，但并沒有觀察到局麻藥的神經(jīng)毒性損傷癥狀。

1.2 相關(guān)的動(dòng)物實(shí)驗(yàn)研究 最早在1992年，Kalichmann和Calcutt[18]就曾報(bào)道，長時(shí)間或高濃度的普魯卡因和利多卡因?qū)μ悄虿∈蟮淖巧窠?jīng)有強(qiáng)毒性，可以導(dǎo)致神經(jīng)纖維水腫、軸索變性和脫髓鞘，糖尿病鼠局麻藥的神經(jīng)毒性和隨后神經(jīng)損傷的風(fēng)險(xiǎn)增加。2010年，Kroin等[19]予糖尿病鼠0.5%羅哌卡因坐骨神經(jīng)阻滯后其坐骨神經(jīng)產(chǎn)生軸索變性及髓鞘改變。而2年后，Kroin[20]發(fā)現(xiàn)，鞘內(nèi)注射0.75%布比卡因或者2%利多卡因(加或不加腎上腺素)后，阻滯持續(xù)時(shí)間較非糖尿病鼠延長，但是并沒有在脊髓、神經(jīng)根及背根神經(jīng)節(jié)發(fā)現(xiàn)組織病理上較非糖尿病模型更有意義的損傷。同一年，他們又發(fā)現(xiàn)，持續(xù)控制血糖的糖尿病鼠坐骨神經(jīng)阻滯的持續(xù)時(shí)間與非糖尿病鼠相似，較無控制血糖的糖尿病鼠縮短，但急性的血糖控制并不能縮短阻滯時(shí)間。這與Sertoz等[17]的臨床研究結(jié)果相一致，提示糖尿病患者局麻藥阻滯時(shí)間的延長與長時(shí)間的高血糖狀態(tài)相關(guān)。Lirk等[22]則發(fā)現(xiàn)2%利多卡因坐骨神經(jīng)阻滯(體內(nèi))后,阻滯前存在的亞臨床神經(jīng)病變導(dǎo)致阻滯持續(xù)時(shí)間的延長，但未能觀察到毒性損傷顯著的增加。

2 糖尿病影響局麻藥阻滯時(shí)效的可能機(jī)制

無論是否伴有神經(jīng)損傷癥狀，以上研究都發(fā)現(xiàn)糖尿病患者、動(dòng)物區(qū)域神經(jīng)阻滯后，較非糖尿病患者、動(dòng)物的阻滯時(shí)間延長。有學(xué)者將此歸因于糖尿病動(dòng)物及患者的神經(jīng)細(xì)胞可能對(duì)局麻藥有更高的敏感性。其原因可能有以下幾點(diǎn)。

2.1 雙重?cái)D壓效應(yīng)假說 雙重?cái)D壓效應(yīng)[6](double-crush phenomenon，DCH)，即已存在神經(jīng)損傷的患者，在另一點(diǎn)暴露于二次刺激時(shí)可能更易感。二次刺激包括各種毒性(如局麻藥神經(jīng)毒性)，機(jī)械性(如穿刺針或?qū)Ч芤鸬膭?chuàng)傷)，缺血性(如腎上腺素導(dǎo)致的血管收縮)危險(xiǎn)因素，而這些往往與區(qū)域神經(jīng)阻滯相關(guān)。糖尿病患者的神經(jīng)細(xì)胞本已處于慢性缺血、缺氧環(huán)境中[18]，神經(jīng)損傷可能已存在或潛在，其對(duì)局麻藥神經(jīng)毒性的耐受力顯著下降。糖尿病患者早中期已存在脊髓及周圍神經(jīng)的微循環(huán)障礙，而局麻藥可使血管發(fā)生持續(xù)性收縮，導(dǎo)致神經(jīng)缺血而發(fā)生損傷。與非糖尿病患者相比，糖尿病患者的神經(jīng)細(xì)胞對(duì)缺血更易感[23]，更易受損。而且糖尿病所致的神經(jīng)細(xì)胞軸索變性與神經(jīng)細(xì)胞對(duì)局麻藥的敏感性的改變密切相關(guān)[24]。糖尿病神經(jīng)病變的程度越重，其對(duì)局麻藥的敏感性可能就越大。持續(xù)的高血糖狀態(tài)會(huì)加重糖尿病患者神經(jīng)的損傷，而感覺神經(jīng)傳導(dǎo)的改善跟糖化血紅蛋白水平的下降有關(guān)[25]。據(jù)Sertoz等[17]發(fā)現(xiàn)，相比控制良好的糖尿病患者，血糖控制不佳的糖尿病患者坐骨神經(jīng)阻滯的持續(xù)時(shí)間延長，這可能與血糖控制不佳導(dǎo)致神經(jīng)纖維脫髓鞘，感覺、運(yùn)動(dòng)傳導(dǎo)速度下降有關(guān)。不過，也有學(xué)者[9,26]對(duì)DCH假說持懷疑態(tài)度，認(rèn)為其未能得到更多的研究證實(shí)，而且糖尿病周圍神經(jīng)病變相關(guān)的循環(huán)、代謝機(jī)制非常復(fù)雜，不能僅以DCH這一假說解釋糖尿病患者對(duì)局麻藥的敏感性增加。這個(gè)假說仍需要更多的實(shí)驗(yàn)及臨床研究來證實(shí)。

2.2 異常的局麻藥吸收 糖尿病患者本身存在微血管功能障礙[27]，一方面其毛細(xì)血管基底膜增厚、血管內(nèi)皮細(xì)胞增生等可以減少局麻藥的吸收；另一方面糖尿病中后期微循環(huán)障礙時(shí)微血管內(nèi)血流減緩可減緩局麻藥的吸收；這2方面可導(dǎo)致一段時(shí)間內(nèi)局部組織保持相對(duì)更高的局麻藥濃度。Egleton等[28]發(fā)現(xiàn)鏈脲霉素誘導(dǎo)的高血糖小鼠的腦脊液代謝產(chǎn)物較普通小鼠減少，可能是糖尿病動(dòng)物腰段椎管內(nèi)腦脊液容量或者清除率的下降，相對(duì)增加了局部組織局麻藥的濃度。而局麻藥毒性對(duì)神經(jīng)的損傷呈濃度依賴性，藥物濃度越高，損傷程度越重。

2.3 其他機(jī)制 有學(xué)者認(rèn)為糖尿病患者神經(jīng)細(xì)胞離子平衡的破壞也是其對(duì)局麻藥敏感性增加的一個(gè)原因[16]。高血糖環(huán)境中，肌醇的攝取受到抑制，胞內(nèi)肌醇減少，從而導(dǎo)致Na+-K+-ATP酶活性下降[29]，使神經(jīng)細(xì)胞膜內(nèi)外Na+梯度下降，導(dǎo)致了神經(jīng)傳導(dǎo)速度的降低[30-31]。另外，還有學(xué)者[15]認(rèn)為糖尿病患者阻滯時(shí)效的延長可能跟術(shù)前其腦脊液的成份如葡萄糖等有關(guān)，通過改變了局麻藥在鞘內(nèi)的比重而增強(qiáng)阻滯作用。

綜上所述，糖尿病患者對(duì)局麻藥的敏感性增強(qiáng)這一理論仍有待更多的調(diào)查與研究。其可能是多途徑共同作用的結(jié)果，也可能還有其他的機(jī)制需要進(jìn)一步的發(fā)現(xiàn)探討。

3 糖尿病神經(jīng)病變與局麻藥神經(jīng)毒性損傷的共同通路

糖尿病周圍神經(jīng)病變和局麻藥神經(jīng)毒性的發(fā)生機(jī)制在氧化應(yīng)激、細(xì)胞內(nèi)鈣離子超載、細(xì)胞內(nèi)信號(hào)轉(zhuǎn)導(dǎo)等方面有相似之處。這也可能是糖尿病患者對(duì)局麻藥神經(jīng)毒性的敏感性增強(qiáng)的分子機(jī)制。

3.1 氧化應(yīng)激 高糖環(huán)境[32]和局麻藥[33]都可使活性氧族(reactive oxygen species，ROS)增加，引起線粒體功能障礙與內(nèi)質(zhì)網(wǎng)應(yīng)激(endoplasmic reticulum stress，ERS)，最終導(dǎo)致細(xì)胞的調(diào)亡[32-35]。

3.2 細(xì)胞內(nèi)鈣超載 高血糖可使N型Ca2+通道持續(xù)激活，Ca2+進(jìn)入突觸前神經(jīng)末梢，Ca2+持續(xù)失衡及線粒體功能障礙誘導(dǎo)軸突變性，細(xì)胞興奮性增加，神經(jīng)元自發(fā)傳遞神經(jīng)沖動(dòng)引起致痛性神經(jīng)遞質(zhì)釋放，從而導(dǎo)致糖尿病多發(fā)神經(jīng)病及痛性神經(jīng)病變的發(fā)生[36]。同樣，Gold等[37]發(fā)現(xiàn)局麻藥可引起細(xì)胞內(nèi)鈣離子濃度升高，且與神經(jīng)毒性作用相關(guān)，而在細(xì)胞外液中加入鈣選擇性螯合劑BAPTA使細(xì)胞外液鈣離子減少，則損傷的程度可明顯減輕。

3.3 細(xì)胞分裂素活化蛋白激酶系統(tǒng) 細(xì)胞分裂素活化蛋白激酶(p38 mitogen-activated protein kinases，p38 MAPKs)系統(tǒng)的激活，也是糖尿病神經(jīng)病變及局麻藥神經(jīng)毒性損傷的一條共同通路[13]。Lirk等[38]研究發(fā)現(xiàn)，臨床常規(guī)濃度的利多卡因能誘導(dǎo)p38MAPK 通路的活化，通過激活p38 MAPK系統(tǒng)啟動(dòng)了細(xì)胞凋亡，而聯(lián)合應(yīng)用p38MAPK拮抗劑SB203580能明顯減輕這種作用。而研究發(fā)現(xiàn)高糖環(huán)境可激活MAPK家族中的c-Jun N-末端激酶(c-Jun N terminal kinases /stress activated protein kinases，JNKs/SAPKs)和p38，p38抑制物可抑制小鼠背跟神經(jīng)節(jié)中p38的激活和核轉(zhuǎn)錄[39]，并可以觀察到糖尿病早期的神經(jīng)功能障礙的進(jìn)展被減慢。

4 未來的研究趨勢

糖尿病患者應(yīng)用局麻藥后神經(jīng)損傷風(fēng)險(xiǎn)較常人增大這一觀點(diǎn)已得到一定的認(rèn)可，但由于缺乏大規(guī)模、多中心的研究，仍需要進(jìn)一步證實(shí)。而這一現(xiàn)象的機(jī)制，需要更多研究去發(fā)現(xiàn)、探討。未來可針對(duì)糖尿病患者建立局麻藥的劑量與效應(yīng)關(guān)系，分析風(fēng)險(xiǎn)獲益比以找到其最安全、適合的用法。有學(xué)者[40]以較低劑量的局麻藥(0.25%布比卡因)給糖尿病腎病患者行神經(jīng)阻滯，可達(dá)到足夠手術(shù)要求的麻醉效果。那么，糖尿病患者應(yīng)用相對(duì)更低劑量或濃度的局麻藥即可達(dá)到預(yù)想的麻醉效果，也可減少出現(xiàn)神經(jīng)損傷或加重神經(jīng)病變的風(fēng)險(xiǎn)。還有，可通過聯(lián)合使用輔助用藥以減少局麻藥的用量，從而降低其局麻藥神經(jīng)毒性損傷的風(fēng)險(xiǎn)。另一方面，基礎(chǔ)研究發(fā)現(xiàn)p38 MAPK抑制劑的應(yīng)用可以減弱糖尿病神經(jīng)病變[39]及局麻藥神經(jīng)毒性損傷[38]的程度。找到抑制其通路而起保護(hù)作用的藥物是值得研究的方向和期待的前景。

5 總結(jié)與展望

據(jù)目前的研究數(shù)據(jù)，糖尿病患者發(fā)生局麻藥相關(guān)神經(jīng)并發(fā)癥的風(fēng)險(xiǎn)較小。但是，糖尿病患者對(duì)局麻藥的敏感性可能較非糖尿病患者增強(qiáng)。盡管這一觀點(diǎn)仍存在爭議，但提醒麻醉醫(yī)生對(duì)糖尿病患者實(shí)施區(qū)域阻滯麻醉前，要評(píng)估其神經(jīng)系統(tǒng)功能，權(quán)衡利弊，不能忽視糖尿病對(duì)局麻藥阻滯時(shí)效的影響以及神經(jīng)損傷的風(fēng)險(xiǎn)，并盡量避免使用加重局麻藥毒性的配伍及輔助用藥。期待更多的臨床證據(jù)能為本研究提供糖尿病患者安全的局麻藥使用標(biāo)準(zhǔn)，以及神經(jīng)毒性損傷的預(yù)防措施，給患者提供完善而安全的阻滯效果。

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(編校：王冬梅)

Review of sensitivity of diabetics to local anesthetics

HUANG Qiu-qi, ZHANG Qing-guo, XU Shi-yuanΔ

(Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou 510280, China)

Local anesthetics have neurotoxicity, which can lead to temporary or permanent sensory and motor dysfunction.And regional anesthesia is commonly used in diabetics undergoing limbs or lower abdominal surgery, so that local anesthetics were widely used in them. However local anesthetics sensitivity in patients with diabetics is not yet clear.In this paper, we will discuss the problem and make a summary.

local anesthetics; diabetes; neurotoxicity; spinal anesthesia

廣東省科技計(jì)劃項(xiàng)目(2012B031800264)

黃秋綺，女，博士在讀，研究方向：局麻藥神經(jīng)毒性，E-mail：terence0417@qq.com；徐世元，通訊作者，男，博士，主任醫(yī)師，博士生導(dǎo)師，研究方向：局麻藥神經(jīng)毒性，E-mail：xushiyuan355@163.com。

R587.1

A

1005-1678(2015)06-0165-04