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ERCP術(shù)后胰腺炎的最新研究進(jìn)展

錢陽(yáng)陽(yáng)趙朕華廖專李兆申

200433上海，第二軍醫(yī)大學(xué)長(zhǎng)海醫(yī)院消化內(nèi)科

內(nèi)鏡下逆行胰膽管造影術(shù)(ERCP)是膽胰疾病一項(xiàng)重要的診斷與治療技術(shù)，具有診斷確切、療效好、創(chuàng)傷小、不良反應(yīng)少及費(fèi)用低等優(yōu)點(diǎn)。但其作為有創(chuàng)操作，術(shù)后有一定并發(fā)癥，包括ERCP術(shù)后胰腺炎(post-ERCP pancreatitis, PEP)、出血、感染等，其中，PEP是最常見、最嚴(yán)重的并發(fā)癥，一旦并發(fā)重癥胰腺炎，患者的生命會(huì)受到嚴(yán)重威脅。為了有效預(yù)防PEP，國(guó)內(nèi)外學(xué)者對(duì)其發(fā)病機(jī)制、危險(xiǎn)因素及防治措施等方面進(jìn)行了廣泛而深入的研究。迄今為止，直腸給予非甾體類抗炎藥及胰管支架置入的效果是比較明確的，但仍未有效解決這一世界性的難題。本文就PEP的定義、發(fā)生率、危險(xiǎn)因素尤其是預(yù)防治療的最新研究作一綜述。

一、ERCP術(shù)后胰腺炎的概況

眾所周知，早在1991年Cotton等[1]專家即提出了PEP的共識(shí)定義：ERCP術(shù)后出現(xiàn)急性胰腺炎相關(guān)的臨床癥狀，包括新出現(xiàn)的或加重的腹部疼痛，伴有術(shù)后24 h血清淀粉酶超過正常上限的3倍，并且需住院一天以上。依據(jù)患者的住院時(shí)間長(zhǎng)短及其治療措施，可將PEP的嚴(yán)重程度分為輕型、中型和重型。

目前PEP的診斷采用的是臨床定義，包括：(1)典型腹痛癥狀；(2)ERCP術(shù)后24 h血清淀粉酶、脂肪酶超過正常上限的3倍；(3)CT提示胰腺炎。只要符合以上3個(gè)指標(biāo)中的任意兩項(xiàng)，臨床即可診斷為PEP。Artifon等[2]收集了300例ERCP患者術(shù)后的血清淀粉酶、脂肪酶和腹部CT的相關(guān)資料，比較了臨床定義和共識(shí)定義，認(rèn)為共識(shí)定義低估了PEP的發(fā)生率，不能發(fā)現(xiàn)所有的PEP，而臨床定義則能更有效地診斷PEP。

盡管PEP的研究得到廣泛開展，但其發(fā)生率卻并未得到有效的下降。Kochar等[3]對(duì)1977年至2012年間的108個(gè)隨機(jī)對(duì)照試驗(yàn)(RCT)中13 296例患者PEP的發(fā)生率、嚴(yán)重度及死亡率進(jìn)行系統(tǒng)回顧，發(fā)現(xiàn)PEP的總發(fā)生率是9.7%(表1)。

PEP的發(fā)病機(jī)制復(fù)雜，但不管源頭是什么，其過程都存在一條共同通路，即產(chǎn)生級(jí)聯(lián)反應(yīng)導(dǎo)致蛋白水解酶過早激活，胰腺組織自我消化，腺泡分泌受損，從而產(chǎn)生PEP的臨床癥狀[4-5]。

表1　13 296例PEP的發(fā)生率、嚴(yán)重度及死亡率(%)

注：SOD：Oddi括約肌功能障礙

二、PEP的危險(xiǎn)因素

既往已有很多研究探討過PEP發(fā)生的危險(xiǎn)因素，其中一些已取得相當(dāng)?shù)墓沧R(shí)，這些危險(xiǎn)因素主要可分為患者相關(guān)性和操作相關(guān)性。

1．患者相關(guān)性：(1)性別：女性比男性更容易發(fā)生PEP。女性是PEP的危險(xiǎn)因素比較明確[6]。不過也有研究表明SOD本身就會(huì)增加PEP的風(fēng)險(xiǎn)，而女性SOD的發(fā)生率較男性高[7]。(2)胰腺炎病史：Chen等[8]研究發(fā)現(xiàn)既往發(fā)生過胰腺炎的患者發(fā)生PEP的概率是5.46%，而對(duì)照組則為3.21%(P<0.01)，既往發(fā)生有PEP的患者再次發(fā)生PEP的概率是17.82%，對(duì)照組僅為5.03%(P<0.01)。這可能與胰腺長(zhǎng)期分泌不暢，胰腺萎縮和胰酶減少有關(guān)。(3)SOD：這是PEP的一個(gè)確定的危險(xiǎn)因素[9]。發(fā)病機(jī)制可能為各種因素致使括約肌痙攣及水腫導(dǎo)致胰管引流不暢，放置胰管支架可降低 PEP發(fā)生率。(4)年齡：目前年齡的因素還不明確。有些專家認(rèn)為年齡(>60歲)是一個(gè)重要的保護(hù)因素，隨著年齡的增長(zhǎng)，胰腺外分泌功能越來越差，這也能解釋為什么年老的患者PEP的發(fā)生率低。Finkelmeier等[10]發(fā)現(xiàn)80歲以上的患者PEP發(fā)生率顯著低于其他組，但20～39歲的年齡是一個(gè)危險(xiǎn)因素。(5)其他因素：黃疸、高血壓等均可增加PEP的發(fā)生率，壺腹周圍憩室、膽總管結(jié)石等是否為高危因素尚存在爭(zhēng)議。

2．技術(shù)相關(guān)性：(1)插管困難：插管困難包括插管的時(shí)間及插管的次數(shù)[11]。反復(fù)多次的插管容易造成 Oddi括約肌痙攣與乳頭水腫,導(dǎo)絲引導(dǎo)插管可能造成乳頭部損傷，導(dǎo)致胰液引流不暢及胰腺炎的發(fā)生。(2)內(nèi)鏡下十二指腸乳頭括約肌切開術(shù)(EST)：關(guān)于EST是否為危險(xiǎn)因素尚有爭(zhēng)議。Akashi等[12]認(rèn)為EST使周圍組織水腫從而阻塞胰管引起PEP，但在許多研究中，EST并非危險(xiǎn)因素。理論上講，EST降低了胰管開口的張力，所以，PEP的發(fā)生很大程度上取決于操作者的技巧[13]。(3)胰管顯影：造影劑進(jìn)入胰管使胰管顯影也是導(dǎo)致PEP的危險(xiǎn)因素之一。Kakutani等[14]通過單變量和多變量分析均發(fā)現(xiàn)胰管造影是胰腺炎的一大危險(xiǎn)因素(P<0.001;OR= 5.55;95%CI2.98～10.33)。(4)預(yù)切開：乳頭預(yù)切開可能導(dǎo)致乳頭水腫，胰管開口阻塞。Ding等[6]的薈萃分析結(jié)果表明乳頭預(yù)切開的患者PEP發(fā)生的概率為對(duì)照組的兩倍多。不過，以前有研究表明局部切開乳頭的頂部會(huì)使PEP的發(fā)生率降低[15]。(5)其他因素：長(zhǎng)時(shí)間操作會(huì)增加PEP的發(fā)生率，內(nèi)鏡下鼻膽管引流、內(nèi)鏡下膽道置管等是否增加PEP的風(fēng)險(xiǎn)仍需更多研究加以證明。

三、PEP的防治措施

1．藥物預(yù)防：目前臨床PEP預(yù)防用藥主要包括抗炎藥物、減少胰酶分泌的藥物、蛋白酶抑制劑、降低Oddi括約肌壓力的藥物等。2010年歐洲胃腸鏡協(xié)會(huì)指南依據(jù)5個(gè)RCT結(jié)果，推薦經(jīng)直腸給予非甾體類藥物預(yù)防PEP[16]。

抗炎藥物包括非甾體類抗炎藥(NSAIDs)、類固醇、IL-10、別嘌呤醇、己酮可可堿、利培酮、阿瑞匹坦等。NSAIDs的研究是最多的?；贜ASIDs有效、低價(jià)、安全、分布廣等特點(diǎn)，NSAIDs經(jīng)直腸給藥是現(xiàn)今唯一臨床指南推薦的PEP預(yù)防用藥[17]。NSAIDs能預(yù)防PEP的原因在于它能夠抑制急性胰腺炎發(fā)病機(jī)制中的相關(guān)通路，包括磷脂酶A2的激活，前列腺素合成增加及中性粒細(xì)胞-內(nèi)皮細(xì)胞黏附[18]。Sun等[19]對(duì)7篇RCT的1 846例患者進(jìn)行了薈萃分析，結(jié)果顯示NSAIDs經(jīng)直腸給藥能顯著降低PEP的發(fā)生率，減輕PEP的嚴(yán)重程度及ERCP術(shù)后2 h的血清淀粉酶。Li等[20]的薈萃分析則表明NSAIDs能有效降低PEP的發(fā)生率，而對(duì)減輕PEP的嚴(yán)重程度沒有統(tǒng)計(jì)學(xué)意義。NSAIDs藥物中研究最多的當(dāng)屬雙氯芬酸和吲哚美辛。研究表明，ERCP術(shù)前或術(shù)后直腸給予吲哚美辛能顯著降低PEP的發(fā)生率[21]，且這一作用對(duì)高?；虻臀EP患者均有效[22]。Patai等[23]的隨機(jī)對(duì)照研究發(fā)現(xiàn)直腸給予100 mg吲哚美辛顯著降低了PEP的發(fā)生率，尤其是對(duì)于插管困難及高危PEP的患者。Yoshihara等[24]對(duì)比了直腸給予不同劑量的雙氯芬酸后PEP的發(fā)生率，發(fā)現(xiàn)50 mg的效果優(yōu)于25 mg。但肌內(nèi)注射雙氯芬酸是否能降低PEP的發(fā)生率仍有爭(zhēng)議[25]。

生長(zhǎng)抑素及其類似物奧曲肽能通過直接減少消化酶的合成釋放，以及間接抑制胰泌素和膽囊收縮素的生成來抑制胰腺外分泌功能[26]，降低血漿氨基酸的濃度，同時(shí)還有抗炎和細(xì)胞保護(hù)的作用，但其用于預(yù)防PEP的療效尚待確定。Omata等[27]的薈萃分析顯示生長(zhǎng)抑素和大劑量的奧曲肽能降低PEP，且胰腺導(dǎo)管內(nèi)注射生長(zhǎng)抑素、膽囊括約肌切開術(shù)、12 h大劑量靜脈滴注或靜脈推注等情況下療效更好。Concepcion-Martin等[28]的隨機(jī)雙盲試驗(yàn)則發(fā)現(xiàn)靜脈內(nèi)大劑量給予生長(zhǎng)抑素，隨后短時(shí)間輸注生長(zhǎng)抑素并不能降低PEP的發(fā)生率。Bai等[29]進(jìn)行的多中心隨機(jī)對(duì)照研究表明生長(zhǎng)抑素(ERCP術(shù)前250 μg靜脈注射，術(shù)后250 μg/h靜脈滴注11 h)對(duì)于PEP的預(yù)防及ERCP術(shù)后的高淀粉酶血癥都是有益的。Zhao等[30]的臨床研究表明ERCP術(shù)前給予生長(zhǎng)抑素對(duì)于高危而非低危PEP患者有益，若術(shù)后給藥則沒有預(yù)防PEP的作用。由此看來，生長(zhǎng)抑素及其類似物奧曲肽的給藥時(shí)機(jī)、劑量、方式等都會(huì)對(duì)預(yù)防PEP的療效產(chǎn)生影響，故如何提高其效用尚需進(jìn)一步研究。

蛋白酶抑制劑阻斷了胰蛋白酶的活化，而胰酶的內(nèi)激活是PEP發(fā)生的關(guān)鍵步驟。這類藥物有加貝酯、肝素、烏司他丁、萘莫司他、硫酸鎂等。甲磺酸萘莫司他是一種低分子量蛋白酶抑制劑，它能夠阻斷胰蛋白酶、激肽緩釋酶、補(bǔ)體成分1、凝血酶等絲氨酸蛋白酶的活化。Park等[31]對(duì)608例ERCP患者進(jìn)行的RCT證實(shí)甲磺酸萘莫司他(20 mg或50 mg)對(duì)PEP的預(yù)防是有效的，然而，對(duì)于PEP的高?；颊?，加大藥物的劑量沒有顯示出更好的預(yù)防效果。最新的薈萃分析顯示，甲磺酸萘莫司他降低了高危和低?；颊逷EP的發(fā)生率，且輕度和中度PEP的發(fā)生率均有顯著降低，但重度PEP發(fā)生率并無(wú)改善，且插管困難及ERCP術(shù)后高淀粉酶血癥發(fā)生率也未下降[32]。肝素、加貝酯、硫酸鎂等的預(yù)防效果尚待進(jìn)一步證實(shí)[33-36]。

硝酸甘油(GTN)對(duì)降低Oddi括約肌的壓力、減少其收縮有顯著作用。但是，評(píng)估GTN能否降低PEP的相關(guān)臨床試驗(yàn)卻沒有得到一個(gè)確切的答案。Chen等[37]的薈萃分析證實(shí)預(yù)防性使用GTN能顯著降低PEP的發(fā)生率但對(duì)插管成功率無(wú)益。Ding等[38]對(duì)12篇RCT的薈萃分析也證實(shí)預(yù)防性使用GTN能降低PEP的發(fā)生率及術(shù)后高淀粉酶血癥，但是GTN對(duì)于緩解PEP及幫助插管收效甚微。他們的結(jié)果還顯示，舌下給藥相對(duì)于局部用藥、經(jīng)皮給藥及靜脈給藥效果更好，發(fā)生一過性低血壓和頭痛等主要不良反應(yīng)的概率也更小。其他降低Oddi括約肌壓力的藥物如腎上腺素、磷酸二酯酶等的效果仍有待進(jìn)一步證實(shí)[16,39]。

2．機(jī)械預(yù)防：(1)導(dǎo)絲輔助插管：如何在進(jìn)行膽管插管的同時(shí)又能降低損傷，減少PEP的發(fā)生是廣泛開展的一項(xiàng)研究。導(dǎo)絲輔助膽管插管已經(jīng)被多次證明能提高膽道插管的成功率，但能否降低PEP的發(fā)生尚待進(jìn)一步證實(shí)。既往的研究證明，導(dǎo)絲輔助插管并未減少PEP的發(fā)生率或增加插管成功率[40]。而最新的臨床試驗(yàn)[41]及薈萃分析[42]卻得到了截然相反的結(jié)論。造成這一差別的可能原因一方面是操作者的技巧，另一方面可能是導(dǎo)絲輔助插管有多種實(shí)施方法。無(wú)論如何，就現(xiàn)有的研究來看，導(dǎo)絲輔助插管仍應(yīng)提倡。(2)置入胰管支架：術(shù)中置入臨時(shí)胰管支架可有效地避免術(shù)后十二指腸乳頭水腫、Oddi括約肌痙攣導(dǎo)致的胰管引流障礙，促進(jìn)胰液的引流，近年來大量研究著眼于置入胰管支架來預(yù)防PEP。Freeman等[43]教授認(rèn)為對(duì)于PEP的高危患者，胰管支架應(yīng)該成為一個(gè)標(biāo)準(zhǔn)性的預(yù)防措施。一些臨床研究已經(jīng)證實(shí)胰管支架置入能降低高?；颊呋蚴遣骞芾щy、預(yù)切開等操作導(dǎo)致的PEP發(fā)生率和嚴(yán)重程度[44-47]，但如果支架置入失敗，患者發(fā)生PEP的風(fēng)險(xiǎn)反而會(huì)增高。所以，需要接受胰管支架植入術(shù)的患者，醫(yī)師的經(jīng)驗(yàn)值及支架的材質(zhì)、內(nèi)徑、長(zhǎng)度、形狀等方面都會(huì)影響其對(duì)PEP的預(yù)防效果[48]。以往的薈萃分析僅說明胰管支架置入對(duì)輕、中度或重度PEP有預(yù)防作用，但最新的研究首次闡明了其對(duì)不同程度的PEP均有有效的預(yù)防作用，且PEP總的發(fā)生率下降了12%[49]。Afghani等[50]比較了5 F和3 F支架的效果，與3F支架相比，5 F支架對(duì)PEP高?；颊叩念A(yù)防作用更好，且不同類型的5F支架預(yù)防效果均比3 F支架好，顯示預(yù)防PEP方面，支架的直徑可能比類型更有意義。盡管置入胰管支架對(duì)PEP的預(yù)防作用已得到確切證實(shí)，但仍有諸多問題有待商榷。(3)其他：已知ERCP術(shù)中反復(fù)插管后行針狀刀括約肌切開術(shù)(NKS)會(huì)增加PEP發(fā)生的風(fēng)險(xiǎn)，但最新研究發(fā)現(xiàn)，插管次數(shù)增加是PEP的危險(xiǎn)因素，但單獨(dú)的NKS不會(huì)增加其風(fēng)險(xiǎn)，且經(jīng)驗(yàn)豐富的醫(yī)師行ERCP還能降低PEP的風(fēng)險(xiǎn)[51]。Yang等[52]的臨床試驗(yàn)證實(shí)內(nèi)鏡下鼻膽管引流(ENBD)顯著降低了術(shù)后高淀粉酶血癥的發(fā)生，并減少了內(nèi)鏡下括約肌切開術(shù)(EST)患者的住院時(shí)間，但未顯著降低PEP的發(fā)生率。

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(本文編輯：呂芳萍)

DOI:10.3760/cma.j.issn.1674-1935.2016.03.017

通信作者：李兆申，Email: zhaoshen-li@hotmail.com

(收稿日期：2015-09-23)