王治國(guó)

?青年專家論壇?

淺談加速康復(fù)外科模式下術(shù)前口服碳水化合物在結(jié)直腸外科中的應(yīng)用及可能機(jī)制

王治國(guó)

王治國(guó)副教授，碩士研究生導(dǎo)師，上海第二軍醫(yī)大學(xué)附屬長(zhǎng)征醫(yī)院結(jié)直腸肛門外科副主任醫(yī)師。主要從事大腸癌的外科綜合治療以及肛門部疾病的外科治療。在國(guó)內(nèi)較早開展了加速康復(fù)外科技術(shù)在結(jié)直腸外科中的應(yīng)用，獲上海市醫(yī)學(xué)科技獎(jiǎng)二等獎(jiǎng)1項(xiàng)、中華醫(yī)學(xué)科技獎(jiǎng)三等獎(jiǎng)1項(xiàng)。主持及參與國(guó)家自然科學(xué)基金及上海市科委基金等課題多項(xiàng)。在《Br J Surg》《Ann Surg Oncol》《J Surg Res》等雜志發(fā)表學(xué)術(shù)論文多篇。學(xué)術(shù)任職：中國(guó)醫(yī)師協(xié)會(huì)肛腸醫(yī)師分會(huì)肛門部疾病專業(yè)委員會(huì)委員；中國(guó)康復(fù)技術(shù)轉(zhuǎn)化及發(fā)展促進(jìn)會(huì)精準(zhǔn)醫(yī)學(xué)與腫瘤康復(fù)專業(yè)委員會(huì)委員；上海市中西醫(yī)結(jié)合學(xué)會(huì)圍手術(shù)期專業(yè)委員會(huì)委員及中國(guó)臨床腫瘤學(xué)會(huì)（CSCO）會(huì)員。

加速康復(fù)外科（ERAS）是指在圍手術(shù)期采用多模式處理措施以提高臨床預(yù)后。結(jié)直腸手術(shù)創(chuàng)傷導(dǎo)致機(jī)體產(chǎn)生一系列生理和心理應(yīng)激，最終發(fā)生術(shù)后胰島素抵抗。術(shù)后胰島素抵抗是結(jié)直腸癌手術(shù)引發(fā)代謝反應(yīng)的中心環(huán)節(jié)，它可增加術(shù)后并發(fā)癥發(fā)生率和死亡率，其早期糾正與預(yù)后直接相關(guān)。術(shù)前口服碳水化合物方法可以改善結(jié)直腸外科手術(shù)術(shù)后機(jī)體的胰島素抵抗，是重要的術(shù)前代謝調(diào)控方法之一。

結(jié)直腸腫瘤； 外科手術(shù)； 術(shù)前口服； 胰島素抵抗； 加速康復(fù)外科

加速康復(fù)外科（enhanced recovery after surgery，ERAS）理念最早由丹麥Henrik Kehlet教授在1997年提出，其后在歐洲和美國(guó)得到了進(jìn)一步的發(fā)展［1］。2005年歐洲營(yíng)養(yǎng)和代謝委員會(huì)完整地提出了ERAS圍手術(shù)期多模式的整體管理方案。目前ERAS已經(jīng)在多個(gè)臨床領(lǐng)域得到廣泛應(yīng)用，其中結(jié)直腸外科是應(yīng)用較早也是最成功的領(lǐng)域。

ERAS理念基于高水平的循證醫(yī)學(xué)證據(jù)，是循證醫(yī)學(xué)在外科臨床應(yīng)用的具體體現(xiàn)，其核心是減少手術(shù)創(chuàng)傷及應(yīng)激。近年來(lái)，隨著前瞻性隨機(jī)對(duì)照試驗(yàn)為主體的循證醫(yī)學(xué)觀念普及和廣泛應(yīng)用，越來(lái)越多的外科曾經(jīng)奉為經(jīng)典的臨床決策也因缺乏足夠的循證醫(yī)學(xué)證據(jù)而使得其存在的合理性和必要性越來(lái)越受到質(zhì)疑，術(shù)前禁食就是其一。

一、術(shù)前禁食對(duì)代謝的不利影響

自20世紀(jì)早期Mendelson等［2］提出的術(shù)前胃排空可以減少麻醉后酸性胃內(nèi)容物的反流和誤吸等并發(fā)癥的發(fā)生率以來(lái)，擇期手術(shù)患者術(shù)前禁食一直是很多醫(yī)院的常規(guī)處理方法，近年來(lái)因缺乏循證醫(yī)學(xué)證據(jù)支持而受到越來(lái)越多的質(zhì)疑。首先，術(shù)前攝入固態(tài)食物會(huì)增加麻醉意外的發(fā)生率，但尚無(wú)循證醫(yī)學(xué)證據(jù)證實(shí)術(shù)前口服低滲或者等滲液體有類似風(fēng)險(xiǎn)［3-5］。事實(shí)上諸多研究均證實(shí)術(shù)前2 h飲用諸如水、茶、咖啡及果汁等純液體對(duì)患者來(lái)說(shuō)是安全的，并不會(huì)增加麻醉時(shí)患者胃內(nèi)液體容積或酸度［6-10］。此外，盡管術(shù)前禁食符合人類固有的晝夜生物節(jié)律，對(duì)胃腸手術(shù)患者還有減少術(shù)前胃腸負(fù)擔(dān)和術(shù)后感染發(fā)生的可能，但禁食可對(duì)機(jī)體代謝產(chǎn)生嚴(yán)重影響。健康個(gè)體禁食6～8 h可足以發(fā)生顯著的胰島素抵抗［4］，而結(jié)直腸癌患者術(shù)前一般禁食時(shí)間長(zhǎng)達(dá)12～16 h，這足以消耗患者體內(nèi)全部的肝糖原儲(chǔ)備而造成可直接利用的能源耗竭［11］，可見(jiàn)，術(shù)前禁食對(duì)手術(shù)患者本身就是一個(gè)額外的應(yīng)激，加上術(shù)后對(duì)能量需求增大，這些代謝變化極不利于患者應(yīng)對(duì)手術(shù)應(yīng)激［12］，從而對(duì)臨床預(yù)后產(chǎn)生較為嚴(yán)重影響［13］。術(shù)前禁食以及手術(shù)所引發(fā)的一系列代謝改變，理論上來(lái)上說(shuō)都和胰島素的作用下降有關(guān)，其核心就是術(shù)后胰島素抵抗（insulin resistance，IR）［14］。

二、術(shù)后胰島素抵抗及改善方法

擇期結(jié)直腸外科手術(shù)和燒傷、車禍外傷及膿毒癥等應(yīng)激一樣，都可導(dǎo)致機(jī)體的分解代謝反應(yīng)并產(chǎn)生胰島素抵抗。術(shù)后胰島素抵抗是由于手術(shù)創(chuàng)傷后機(jī)體對(duì)胰島素的敏感性下降，導(dǎo)致體內(nèi)胰島素作用減弱并代償性引起胰島素分泌增加，同時(shí)伴有血糖增高，形成和Ⅱ型糖尿病相類似的代謝狀態(tài)。這種代謝改變雖然可以在一定程度上保證循環(huán)穩(wěn)定，使得腦細(xì)胞、紅細(xì)胞等獲得充分的代謝底物供應(yīng)，但胰島素抵抗引發(fā)的高糖血癥同時(shí)會(huì)損傷腎、肝等器官功能，增加術(shù)后諸如感染等并發(fā)癥的發(fā)生率和死亡率［15-16］，并與患者術(shù)后康復(fù)速度密切相關(guān)。常規(guī)的開放性腹部手術(shù)術(shù)后胰島素抵抗的高峰發(fā)生在術(shù)后當(dāng)天，持續(xù)約3～4周左右。當(dāng)前術(shù)后胰島素抵抗程度作為預(yù)測(cè)術(shù)后住院時(shí)間長(zhǎng)短的獨(dú)立影響因子的觀點(diǎn)已被廣泛接受［17］。

動(dòng)物實(shí)驗(yàn)證實(shí)在應(yīng)激開始前進(jìn)行代謝調(diào)控可改善預(yù)后。例如，在失血［5，19］、內(nèi)毒素［20］應(yīng)激下大鼠的喂食組存活率較饑餓組顯著增加。國(guó)外的相關(guān)臨床研究亦表明，手術(shù)時(shí)的代謝狀態(tài)對(duì)后繼的代謝反應(yīng)有著顯著的影響。對(duì)擬行全髖關(guān)節(jié)置換術(shù)的患者而言，如果術(shù)前使用外源性胰島素靜脈維持血糖在正常水平，表明機(jī)體對(duì)葡萄糖的攝取以及對(duì)代謝底物的利用接近正常水平［21］，這些患者術(shù)后可不發(fā)生胰島素抵抗；而術(shù)后在ICU治療的外科患者［3］，相對(duì)于傳統(tǒng)的胰島素治療（當(dāng)血糖濃度超過(guò)215 mg/dL時(shí)輸注胰島素或者維持血糖180～200 mg/dL（10.0～11.1 mmol/L），如果用胰島素嚴(yán)格控制血糖在正常范圍80～110 mg/dL（4.4～6.1 mmol/L）可顯著減少并發(fā)癥發(fā)生率和死亡率。此外，對(duì)于那些需在ICU治療5天以上的重癥患者來(lái)說(shuō)，嚴(yán)格的胰島素治療所帶來(lái)的臨床獲益是非常顯著的，可以降低47.5%的死亡率，尤其對(duì)于那些有明確膿毒敗血癥導(dǎo)致的多器官功能衰竭的患者其死亡率降低更為明顯［3］。

可見(jiàn)，術(shù)前采用代謝調(diào)控干預(yù)以改善術(shù)后胰島素抵抗可以顯著改善臨床預(yù)后。早期改善代謝狀態(tài)的方法是術(shù)前當(dāng)晚以5 mg/（kg.min）的速率靜脈輸注一定量10%～20%的高滲糖［21-22］，這樣既可避免液體超負(fù)荷又能提供足夠的能量。術(shù)前當(dāng)晚靜脈注射葡萄糖代替?zhèn)鹘y(tǒng)的禁食可以使得腹部大手術(shù)后患者的胰島素抵抗程度減輕50%［22］，肝糖原含量較禁食狀態(tài)下增加65%［23］，并可改善術(shù)后的氮平衡［24］；還可以減少心臟手術(shù)患者的死亡率和術(shù)后住院時(shí)間［25-26］。然而這種方法需在輸注高滲糖的同時(shí)輸注胰島素，還需頻繁監(jiān)測(cè)血糖濃度，使其臨床應(yīng)用受到限制，但這些缺點(diǎn)可以通過(guò)口服法克服。術(shù)前口服碳水化合物是重要的術(shù)前代謝調(diào)控方法之一，國(guó)內(nèi)外一些相關(guān)臨床研究均證實(shí)術(shù)前口服碳水化合物可以改善術(shù)后的胰島素抵抗［12，27-29］，但具體機(jī)理仍未明確。

三、術(shù)前口服碳水化合物的方法

術(shù)前兩小時(shí)飲用諸如水、茶、咖啡及果汁等純液體雖然不影響胃排空，但其中只含極少量的能量，從改善代謝的角度來(lái)說(shuō)并不適合用于術(shù)前的治療。Nygren等［12］的研究證實(shí)術(shù)前口服一定配方的碳水化合物可以獲得和靜脈輸注高滲葡萄糖相似的效果，且與之相比是一種無(wú)創(chuàng)性的給藥方法，這是擇期手術(shù)病人在術(shù)前給予碳水化合物溶液口服的循證依據(jù)。目前常用的術(shù)前口服溶液多為麥芽糖——糊精制劑，如荷蘭Nutricia公司的PreOp（260 mOsm/kg）口服溶液。服用方法有術(shù)前晚服用800 ml聯(lián)合術(shù)前2～3小時(shí)服用400 ml或者僅術(shù)前2～3小時(shí)服用400 ml兩種，而動(dòng)物和臨床實(shí)驗(yàn)均證實(shí)這兩種方法對(duì)于改善結(jié)直腸手術(shù)術(shù)后胰島素抵抗的程度差異無(wú)統(tǒng)計(jì)學(xué)意義［51-52］。

四、術(shù)前口服碳水化合物的安全性

在已知的影響胃排空的因素中，液體的量是最主要的［30-33］；其次是液體的組成，胃內(nèi)液體的排空速度隨滲透壓增加而降低［33-37］。研究發(fā)現(xiàn)，健康受試者口服單糖溶液會(huì)導(dǎo)致胃排空時(shí)間延長(zhǎng)［35，38］；如果用多聚糖代替單糖以降低滲透壓則碳水化合物的胃排空時(shí)間明顯縮短［39-41］。擇期結(jié)直腸手術(shù)患者術(shù)前焦慮等不適感的增加并不會(huì)影響胃排空［12，27，42］，他們術(shù)前口服400 ml碳水化合物溶液后達(dá)到安全的胃內(nèi)殘留量的時(shí)間和健康個(gè)體一樣約需90 min［12，43-44］。Sherif等［50］的Meta分析納入21個(gè)研究共1 685例手術(shù)患者，并未發(fā)現(xiàn)口服碳水化合物或安慰劑導(dǎo)致術(shù)中及術(shù)后發(fā)生肺部相關(guān)并發(fā)癥的情況?？梢?jiàn)，術(shù)前口服碳水化合物是安全的。需要指出的是，那些能提供相同的能量而含有脂肪、蛋白或單糖的溶液卻可以延遲胃排空從而增加麻醉誤吸的風(fēng)險(xiǎn)［12，45］。

五、術(shù)前口服碳水化合物的有效性

應(yīng)激是指機(jī)體對(duì)于能危及或打破穩(wěn)態(tài)平衡的刺激的反應(yīng)，而ERAS的核心是減少手術(shù)創(chuàng)傷應(yīng)激以及圍手術(shù)期的其他各種應(yīng)激。在研究術(shù)前口服碳水化合物的有效性時(shí)首先應(yīng)關(guān)注受試者的主觀舒適度（well-being），其次再觀測(cè)由此引發(fā)的機(jī)體代謝的改變［12］。術(shù)前口服碳水化合物可以改善術(shù)前禁食帶來(lái)的不適應(yīng)激，如不同程度的減輕患者術(shù)前［12，27，46］和術(shù)后［47］的口渴感、饑餓感和焦慮感。其次，術(shù)前口服碳水化合物可以刺激胰島素釋放，促進(jìn)β細(xì)胞分泌胰島素并改善胰島素敏感性，減輕術(shù)后的分解代謝，改善機(jī)體氮平衡，減少術(shù)后機(jī)體瘦組織群丟失，從而改善胰島素抵抗［27，48］。此外，術(shù)前口服碳水化合物可以縮短結(jié)直腸術(shù)后患者的住院時(shí)間［49］。由于術(shù)后胰島素抵抗程度作為一個(gè)決定術(shù)后住院時(shí)間長(zhǎng)短（length of postoperative hospital stay，LOS）的獨(dú)立影響因子觀點(diǎn)已被廣泛接受［14］，所以術(shù)前口服碳水化合物縮短術(shù)后住院時(shí)間可視為其有效減輕術(shù)后胰島素抵抗的一個(gè)有力的循證醫(yī)學(xué)證據(jù)。

六、術(shù)前口服碳水化合物改善術(shù)后胰島素抵抗的可能機(jī)制

已知的唯一由氨基酸調(diào)控的信號(hào)分子［60-62］。而在所有的氨基酸中，亮氨酸是調(diào)控mTOR的最可能的激活劑［63］。Duchêne等［64］研究提示，哺乳動(dòng)物中結(jié)構(gòu)和功能均相對(duì)保守的AKT、TOR及p70S6K等激酶均可在禁食后再喂食和胰島素作用時(shí)被活化。Bigot等［65］也證實(shí)，在禁食16 h后重新喂食或輸注胰島素（1 U/Kg）可以上調(diào)骨骼肌中p70S6K的活性，并可以顯著增加p70S6K的上游諸如PKB/AKT、TOR的磷酸化和／或激酶活性和下游靶標(biāo)S6的磷酸化［64］。Obata等［66］采用穩(wěn)定性同位素示蹤技術(shù)證實(shí)腹部手術(shù)術(shù)中輸入葡萄糖可以增加機(jī)體能直接利用的底物丙氨酸以及丙酮酸鹽，而亮氨酸以及異亮氨酸的濃度顯著降低。我們團(tuán)隊(duì)的隨機(jī)對(duì)照研究發(fā)現(xiàn)術(shù)前口服碳水化合物可以增強(qiáng)結(jié)直腸癌患者術(shù)后即時(shí)胰島素作用的信號(hào)轉(zhuǎn)導(dǎo)路徑上的關(guān)鍵酶（PTK，PI3K和AKT）的表達(dá)和活性，增加了手術(shù)后的胰島素敏感性，促進(jìn)外周組織中GluT4的轉(zhuǎn)位，從而增加外周組織對(duì)葡萄糖的利用，最終改善術(shù)后胰島素抵抗的信號(hào)通路假說(shuō)［27］，并在進(jìn)一步的研究中指出這種作用可能是通過(guò)影響體內(nèi)亮氨酸代謝和調(diào)控PI3K/AKT/mTOR通路來(lái)實(shí)現(xiàn)的［67］。

綜上所述，術(shù)前口服碳水化合物是以循證醫(yī)學(xué)為基礎(chǔ)，結(jié)合近年對(duì)手術(shù)創(chuàng)傷應(yīng)激后患者生理和心理變化的最新認(rèn)識(shí)而開展的一種不法?？傻男g(shù)前處理辦法。術(shù)前口服碳水化合物并未增加結(jié)直腸手術(shù)術(shù)中和術(shù)后并發(fā)癥，相反，它可通過(guò)減少手術(shù)引起的生理和心理應(yīng)激，減輕術(shù)后不適，更重要的是減輕術(shù)后胰島素抵抗來(lái)提高臨床預(yù)后。當(dāng)前在結(jié)直腸外科領(lǐng)域開展ERAS已經(jīng)取得很大成功，術(shù)前口服碳水化合物作為ERAS模式中一種重要的代謝調(diào)控方法，其安全性和有效性已被越來(lái)越多的循證醫(yī)學(xué)證據(jù)所證實(shí)，是結(jié)直腸外科圍手術(shù)期處理措施發(fā)展的重要環(huán)節(jié)和必然選擇。目前它的具體機(jī)制仍未完全闡明，因此進(jìn)一步闡明術(shù)前口服碳水化合物改善術(shù)后胰島素抵抗的機(jī)制是臨床診治術(shù)后胰島素抵抗、提高患者臨床預(yù)后的必由之路。

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Analysis of the application and potential mechanism about the preoperative oral carbohydrate in colorectal surgery for ERAS mode

Wang Zhiguo. Department of Colorectal & Anal Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, Shanghai 200003, China
Corresponding author: Wang Zhiguo, Email: seraph.wzg@126.com

Enhanced recovery after surgery (ERAS) represents a multimodal approach to improve the outcomes of medical treatment and care. Colorectal surgery initiates a series of physiological and psychological stress processes in the body, inducing transient insulin resistance. Insulin resistance is a central metabolic response to surgery and it has been shown to increase morbidity and mortality after surgery. Thus its early detection and remedy would directly lead to great improvement of outcomes. Preoperative intake of oral carbohydrates for ERAS has resulted in attenuating the development of postoperative insulin resistance and being one of the important methods of preoperative metabolic regulation in colorectal surgery.

Colorectal neoplasms; Surgical procedures, operative; Preoperative oral; Insulin resistance; Enhanced recovery after surgery

2016-12-27）

（本文編輯：楊明）

10.3877/cma.j.issn.2095-3224.2017.01.004

國(guó)家自然基金青年基金資助項(xiàng)目（No.81000845）

200003 上海第二軍醫(yī)大學(xué)附屬長(zhǎng)征醫(yī)院結(jié)直腸肛門外科

王治國(guó)，Email：seraph.wzg@126.com

王治國(guó).淺談加速康復(fù)外科模式下術(shù)前口服碳水化合物在結(jié)直腸外科中的應(yīng)用及可能機(jī)制[J/CD].中華結(jié)直腸疾病電子雜志, 2017, 6(1): 15-20.