淺談加速康復外科模式下術前口服碳水化合物在結直腸外科中的應用及可能機制

王治國

?青年專家論壇?

淺談加速康復外科模式下術前口服碳水化合物在結直腸外科中的應用及可能機制

王治國

王治國副教授，碩士研究生導師，上海第二軍醫大學附屬長征醫院結直腸肛門外科副主任醫師。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。在國內較早開展了加速康復外科技術在結直腸外科中的應用，獲上海市醫學科技獎二等獎1項、中華醫學科技獎三等獎1項。主持及參與國家自然科學基金及上海市科委基金等課題多項。在《Br J Surg》《Ann Surg Oncol》《J Surg Res》等雜志發表學術論文多篇。學術任職：中國醫師協會肛腸醫師分會肛門部疾病專業委員會委員；中國康復技術轉化及發展促進會精準醫學與腫瘤康復專業委員會委員；上海市中西醫結合學會圍手術期專業委員會委員及中國臨床腫瘤學會（CSCO）會員。

加速康復外科（ERAS）是指在圍手術期采用多模式處理措施以提高臨床預后。結直腸手術創傷導致機體產生一系列生理和心理應激，最終發生術后胰島素抵抗。術后胰島素抵抗是結直腸癌手術引發代謝反應的中心環節，它可增加術后并發癥發生率和死亡率，其早期糾正與預后直接相關。術前口服碳水化合物方法可以改善結直腸外科手術術后機體的胰島素抵抗，是重要的術前代謝調控方法之一。

結直腸腫瘤； 外科手術； 術前口服； 胰島素抵抗； 加速康復外科

加速康復外科（enhanced recovery after surgery，ERAS）理念最早由丹麥Henrik Kehlet教授在1997年提出，其后在歐洲和美國得到了進一步的發展［1］。2005年歐洲營養和代謝委員會完整地提出了ERAS圍手術期多模式的整體管理方案。目前ERAS已經在多個臨床領域得到廣泛應用，其中結直腸外科是應用較早也是最成功的領域。

ERAS理念基于高水平的循證醫學證據，是循證醫學在外科臨床應用的具體體現，其核心是減少手術創傷及應激。近年來，隨著前瞻性隨機對照試驗為主體的循證醫學觀念普及和廣泛應用，越來越多的外科曾經奉為經典的臨床決策也因缺乏足夠的循證醫學證據而使得其存在的合理性和必要性越來越受到質疑，術前禁食就是其一。

一、術前禁食對代謝的不利影響

自20世紀早期Mendelson等［2］提出的術前胃排空可以減少麻醉后酸性胃內容物的反流和誤吸等并發癥的發生率以來，擇期手術患者術前禁食一直是很多醫院的常規處理方法，近年來因缺乏循證醫學證據支持而受到越來越多的質疑。首先，術前攝入固態食物會增加麻醉意外的發生率，但尚無循證醫學證據證實術前口服低滲或者等滲液體有類似風險［3-5］。事實上諸多研究均證實術前2 h飲用諸如水、茶、咖啡及果汁等純液體對患者來說是安全的，并不會增加麻醉時患者胃內液體容積或酸度［6-10］。此外，盡管術前禁食符合人類固有的晝夜生物節律，對胃腸手術患者還有減少術前胃腸負擔和術后感染發生的可能，但禁食可對機體代謝產生嚴重影響。健康個體禁食6～8 h可足以發生顯著的胰島素抵抗［4］，而結直腸癌患者術前一般禁食時間長達12～16 h，這足以消耗患者體內全部的肝糖原儲備而造成可直接利用的能源耗竭［11］，可見，術前禁食對手術患者本身就是一個額外的應激，加上術后對能量需求增大，這些代謝變化極不利于患者應對手術應激［12］，從而對臨床預后產生較為嚴重影響［13］。術前禁食以及手術所引發的一系列代謝改變，理論上來上說都和胰島素的作用下降有關，其核心就是術后胰島素抵抗（insulin resistance，IR）［14］。

二、術后胰島素抵抗及改善方法

擇期結直腸外科手術和燒傷、車禍外傷及膿毒癥等應激一樣，都可導致機體的分解代謝反應并產生胰島素抵抗。術后胰島素抵抗是由于手術創傷后機體對胰島素的敏感性下降，導致體內胰島素作用減弱并代償性引起胰島素分泌增加，同時伴有血糖增高，形成和Ⅱ型糖尿病相類似的代謝狀態。這種代謝改變雖然可以在一定程度上保證循環穩定，使得腦細胞、紅細胞等獲得充分的代謝底物供應，但胰島素抵抗引發的高糖血癥同時會損傷腎、肝等器官功能，增加術后諸如感染等并發癥的發生率和死亡率［15-16］，并與患者術后康復速度密切相關。常規的開放性腹部手術術后胰島素抵抗的高峰發生在術后當天，持續約3～4周左右。當前術后胰島素抵抗程度作為預測術后住院時間長短的獨立影響因子的觀點已被廣泛接受［17］。

動物實驗證實在應激開始前進行代謝調控可改善預后。例如，在失血［5，19］、內毒素［20］應激下大鼠的喂食組存活率較饑餓組顯著增加。國外的相關臨床研究亦表明，手術時的代謝狀態對后繼的代謝反應有著顯著的影響。對擬行全髖關節置換術的患者而言，如果術前使用外源性胰島素靜脈維持血糖在正常水平，表明機體對葡萄糖的攝取以及對代謝底物的利用接近正常水平［21］，這些患者術后可不發生胰島素抵抗；而術后在ICU治療的外科患者［3］，相對于傳統的胰島素治療（當血糖濃度超過215 mg/dL時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）可顯著減少并發癥發生率和死亡率。此外，對于那些需在ICU治療5天以上的重癥患者來說，嚴格的胰島素治療所帶來的臨床獲益是非常顯著的，可以降低47.5%的死亡率，尤其對于那些有明確膿毒敗血癥導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，術前采用代謝調控干預以改善術后胰島素抵抗可以顯著改善臨床預后。早期改善代謝狀態的方法是術前當晚以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荷又能提供足夠的能量。術前當晚靜脈注射葡萄糖代替傳統的禁食可以使得腹部大手術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下增加65%［23］，并可改善術后的氮平衡［24］；還可以減少心臟手術患者的死亡率和術后住院時間［25-26］。然而這種方法需在輸注高滲糖的同時輸注胰島素，還需頻繁監測血糖濃度，使其臨床應用受到限制，但這些缺點可以通過口服法克服。術前口服碳水化合物是重要的術前代謝調控方法之一，國內外一些相關臨床研究均證實術前口服碳水化合物可以改善術后的胰島素抵抗［12，27-29］，但具體機理仍未明確。

三、術前口服碳水化合物的方法

術前兩小時飲用諸如水、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說并不適合用于術前的治療。Nygren等［12］的研究證實術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創性的給藥方法，這是擇期手術病人在術前給予碳水化合物溶液口服的循證依據。目前常用的術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。服用方法有術前晚服用800 ml聯合術前2～3小時服用400 ml或者僅術前2～3小時服用400 ml兩種，而動物和臨床實驗均證實這兩種方法對于改善結直腸手術術后胰島素抵抗的程度差異無統計學意義［51-52］。

四、術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，胃內液體的排空速度隨滲透壓增加而降低［33-37］。研究發現，健康受試者口服單糖溶液會導致胃排空時間延長［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間明顯縮短［39-41］。擇期結直腸手術患者術前焦慮等不適感的增加并不會影響胃排空［12，27，42］，他們術前口服400 ml碳水化合物溶液后達到安全的胃內殘留量的時間和健康個體一樣約需90 min［12，43-44］。Sherif等［50］的Meta分析納入21個研究共1 685例手術患者，并未發現口服碳水化合物或安慰劑導致術中及術后發生肺部相關并發癥的情況。可見，術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險［12，45］。

五、術前口服碳水化合物的有效性

應激是指機體對于能危及或打破穩態平衡的刺激的反應，而ERAS的核心是減少手術創傷應激以及圍手術期的其他各種應激。在研究術前口服碳水化合物的有效性時首先應關注受試者的主觀舒適度（well-being），其次再觀測由此引發的機體代謝的改變［12］。術前口服碳水化合物可以改善術前禁食帶來的不適應激，如不同程度的減輕患者術前［12，27，46］和術后［47］的口渴感、饑餓感和焦慮感。其次，術前口服碳水化合物可以刺激胰島素釋放，促進β細胞分泌胰島素并改善胰島素敏感性，減輕術后的分解代謝，改善機體氮平衡，減少術后機體瘦組織群丟失，從而改善胰島素抵抗［27，48］。此外，術前口服碳水化合物可以縮短結直腸術后患者的住院時間［49］。由于術后胰島素抵抗程度作為一個決定術后住院時間長短（length of postoperative hospital stay，LOS）的獨立影響因子觀點已被廣泛接受［14］，所以術前口服碳水化合物縮短術后住院時間可視為其有效減輕術后胰島素抵抗的一個有力的循證醫學證據。

六、術前口服碳水化合物改善術后胰島素抵抗的可能機制

已知的唯一由氨基酸調控的信號分子［60-62］。而在所有的氨基酸中，亮氨酸是調控mTOR的最可能的激活劑［63］。Duchêne等［64］研究提示，哺乳動物中結構和功能均相對保守的AKT、TOR及p70S6K等激酶均可在禁食后再喂食和胰島素作用時被活化。Bigot等［65］也證實，在禁食16 h后重新喂食或輸注胰島素（1 U/Kg）可以上調骨骼肌中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S6的磷酸化［64］。Obata等［66］采用穩定性同位素示蹤技術證實腹部手術術中輸入葡萄糖可以增加機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。我們團隊的隨機對照研究發現術前口服碳水化合物可以增強結直腸癌患者術后即時胰島素作用的信號轉導路徑上的關鍵酶（PTK，PI3K和AKT）的表達和活性，增加了手術后的胰島素敏感性，促進外周組織中GluT4的轉位，從而增加外周組織對葡萄糖的利用，最終改善術后胰島素抵抗的信號通路假說［27］，并在進一步的研究中指出這種作用可能是通過影響體內亮氨酸代謝和調控PI3K/AKT/mTOR通路來實現的［67］。

綜上所述，術前口服碳水化合物是以循證醫學為基礎，結合近年對手術創傷應激后患者生理和心理變化的最新認識而開展的一種不法常可的術前處理辦法。術前口服碳水化合物并未增加結直腸手術術中和術后并發癥，相反，它可通過減少手術引起的生理和心理應激，減輕術后不適，更重要的是減輕術后胰島素抵抗來提高臨床預后。當前在結直腸外科領域開展ERAS已經取得很大成功，術前口服碳水化合物作為ERAS模式中一種重要的代謝調控方法，其安全性和有效性已被越來越多的循證醫學證據所證實，是結直腸外科圍手術期處理措施發展的重要環節和必然選擇。目前它的具體機制仍未完全闡明，因此進一步闡明術前口服碳水化合物改善術后胰島素抵抗的機制是臨床診治術后胰島素抵抗、提高患者臨床預后的必由之路。

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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

國家自然基金青年基金資助項目（No.81000845）

200003 上海第二軍醫大學附屬長征醫院結直腸肛門外科

王治國，Email：seraph.wzg@126.com

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