錢建清 戴建軍 王衛(wèi)軍 徐曉丹

·論著·

吲哚美辛對(duì)內(nèi)鏡下逆行性胰膽管造影術(shù)后胰腺炎的預(yù)防

錢建清 戴建軍 王衛(wèi)軍 徐曉丹

目的探討吲哚美辛對(duì)內(nèi)鏡下逆行性胰膽管造影術(shù)后胰腺炎(PEP)的預(yù)防作用。方法從需行內(nèi)鏡下十二指腸乳頭括約肌切開術(shù)(EST)的患者中選擇年齡18～75歲，未合并有心、肺、肝、腎疾病及凝血功能障礙等手術(shù)高危因素，未合并惡性疾病，無非甾體類抗炎(NSAIDs)藥物禁忌證，術(shù)前影像學(xué)及血清學(xué)證實(shí)未合并胰腺炎者。采用前瞻性隨機(jī)對(duì)照病例研究方法分為吲哚美辛組和對(duì)照組。吲哚美辛組患者術(shù)后0.5 h使用吲哚美辛100 mg肛塞，對(duì)照組給予安慰劑。以術(shù)后出現(xiàn)持續(xù)性的胰腺炎相關(guān)臨床癥狀伴有術(shù)后24 h血清淀粉酶值超過正常上限3倍、需住院1 d以上者診斷為PEP。并對(duì)診斷PEP的患者于術(shù)后72 h進(jìn)行APACHEⅡ評(píng)分。結(jié)果2004年至2010年共入選348例患者，其中吲哚美辛組182例，對(duì)照組166例。吲哚美辛組術(shù)后發(fā)生PEP 6例(3.3%)，對(duì)照組14例(8.4%)，兩組差異具有統(tǒng)計(jì)學(xué)意義(P<0.05)。吲哚美辛組發(fā)生PEP者的APACHEⅡ評(píng)分為4.3±1.3，對(duì)照組為7.4±1.7，兩組差異具有統(tǒng)計(jì)學(xué)意義(P<0.05)。但兩組高胰淀粉酶血癥的發(fā)生率無統(tǒng)計(jì)學(xué)差異(9.3%比10.8%，P>0.05)。結(jié)論內(nèi)鏡下乳頭括約肌切開取石術(shù)后使用吲哚美辛肛栓預(yù)防術(shù)后胰腺炎是有效的，同時(shí)可以降低胰腺炎的嚴(yán)重程度。

括約肌切開術(shù)，內(nèi)窺鏡； ERCP術(shù)后胰腺炎； 非甾類抗炎劑； 病例對(duì)照研究

內(nèi)鏡下逆行性胰膽管造影(ERCP)加十二指腸乳頭括約肌切開(EST)是目前治療膽總管結(jié)石安全、有效的一線治療手段[1]。EST取石術(shù)后嚴(yán)重并發(fā)癥主要包括出血、穿孔、結(jié)石嵌頓、急性胰腺炎等，其中以ERCP術(shù)后胰腺炎(post-ERCP pancreatitis, PEP)最為常見[2]，其發(fā)生率為1.3%～8.6%[3-5]。目前報(bào)道的用于預(yù)防PEP的藥物主要包括生長(zhǎng)抑素、硝酸甘油、蛋白酶抑制劑等[6],但效果均不能令人滿意。近年來，國(guó)外有多項(xiàng)隨機(jī)對(duì)照臨床研究(randomized clinical trial, RCT)[7-12]顯示非甾體類抗炎藥(non-steroidal anti-inflammatory drugs, NSAIDs)在預(yù)防PEP中可能有很好的應(yīng)用前景?，F(xiàn)將我院應(yīng)用NSAID的資料報(bào)道如下。

材料和方法

一、臨床資料

對(duì)本院內(nèi)鏡中心2004年至2010年進(jìn)行EST取石的患者進(jìn)行篩選。入選標(biāo)準(zhǔn)：年齡18～75歲；未合并有心、肺、肝、腎疾病及凝血功能障礙等手術(shù)高危因素；未合并惡性疾?。粺oNSAIDs藥物禁忌證；術(shù)前影像學(xué)及血清學(xué)證實(shí)未合并胰腺炎。造影及手術(shù)操作由具有10年以上ERCP操作經(jīng)驗(yàn)的同一操作組的內(nèi)鏡醫(yī)師完成；術(shù)后未留置鼻膽管。

二、方法

采用前瞻性隨機(jī)對(duì)照病例分析。入選患者按完全隨機(jī)法分為吲哚美辛組和對(duì)照組。吲哚美辛組患者術(shù)后0.5 h常規(guī)使用100 mg吲哚美辛肛塞；對(duì)照組患者術(shù)后0.5 h使用安慰劑。為避免治療相關(guān)混雜因素的影響，我們采用標(biāo)準(zhǔn)ERCP+EST取石術(shù)[13]，術(shù)中造影劑15%泛影葡胺使用量控制在50 ml以內(nèi)，且無胰管顯影，ERCP術(shù)后未植入膽、胰管支架，未留置鼻膽管；術(shù)后均采用相同的治療方案，即術(shù)后禁食，并使用奧美拉唑、奧曲肽、奧硝唑及環(huán)丙沙星治療，以期最大限度減少治療相關(guān)因素對(duì)實(shí)驗(yàn)結(jié)果產(chǎn)生偏倚。

三、PEP診斷

PEP的診斷基于Cotton等[14]統(tǒng)一標(biāo)準(zhǔn)：ERCP術(shù)后出現(xiàn)持續(xù)性的胰腺炎相關(guān)的臨床癥狀(如新出現(xiàn)或加重的腹部疼痛)伴有術(shù)后24 h血清淀粉酶值超過正常上限的3倍,需住院1 d以上者診斷為PEP， 若只有血、尿淀粉酶升高，則診斷為術(shù)后高淀粉酶血癥。根據(jù)2006年發(fā)表的《美國(guó)胰腺炎診治指南》[15]，對(duì)診斷PEP的患者，于術(shù)后72 h進(jìn)行APACHEⅡ評(píng)分，評(píng)估PEP的嚴(yán)重程度。

四、統(tǒng)計(jì)學(xué)處理

結(jié) 果

2004年至2010年期間本中心共行EST取石術(shù)878例，符合條件并入選的患者共348例，其中男212例，女136例，平均年齡51歲；吲哚美辛組182例，對(duì)照組166例，兩組患者的基本情況均無統(tǒng)計(jì)學(xué)差異(表1)。

表1 吲哚美辛組與對(duì)照組基本情況比較

吲哚美辛組中有6例(3.3%)患者發(fā)生PEP，對(duì)照組中有14例(8.4%)發(fā)生PEP，兩組術(shù)后PEP發(fā)生率差異具有統(tǒng)計(jì)學(xué)意義(P<0.05)。吲哚美辛組發(fā)生PEP者的APACHEⅡ評(píng)分為4.3±1.3，對(duì)照組為7.4±1.7，兩組差異具有統(tǒng)計(jì)學(xué)意義(P<0.05)。吲哚美辛組中17例(9.3%)術(shù)后發(fā)生高淀粉酶血癥，對(duì)照組中18例(10.8%)術(shù)后發(fā)生高淀粉酶血癥，兩組差異無統(tǒng)計(jì)學(xué)意義(P>0.05)。

討 論

NSAIDs是一類具有環(huán)氧合酶(COX)抑制活性的藥物，對(duì)COX-1、COX-2均有抑制作用，臨床廣泛用于抗炎、鎮(zhèn)痛及退熱等病癥。1997年，Makela等[16]首次報(bào)道NSAIDs能有效抑制重癥胰腺炎患者血清的磷脂酶A2(PLA2)活性及中性粒細(xì)胞、內(nèi)皮細(xì)胞的附著，從而減少中性粒細(xì)胞在損傷組織的積聚和活化，繼而抑制伴隨中性粒細(xì)胞的一系列炎癥反應(yīng),包括環(huán)磷酸腺苷的合成、過氧化物酶的產(chǎn)生、溶酶體酶的釋放等，減輕炎癥反應(yīng)，在急性胰腺炎的炎癥級(jí)聯(lián)反應(yīng)初期起重要作用。此后，部分學(xué)者開始探討NSAIDs用于預(yù)防PEP的可行性。我國(guó)浙江醫(yī)科大學(xué)的Dai等[17]薈萃分析了截至2009年全球發(fā)表的4項(xiàng)關(guān)于應(yīng)用NSAIDs預(yù)防PEP的高質(zhì)量RCT，結(jié)果顯示NSAIDs預(yù)防PEP是值得臨床推薦的。

吲哚美辛，又稱消炎痛，是COX-1和COX-2的非選擇性抑制劑，為臨床廣泛應(yīng)用的NSAIDs藥物。為了探尋NSAIDs對(duì)PEP的影響，我們嚴(yán)格控制入選標(biāo)準(zhǔn)，剔除可能影響病情轉(zhuǎn)歸的因素。本結(jié)果顯示，直腸應(yīng)用吲哚美辛可有效預(yù)防PEP的發(fā)生，與國(guó)外報(bào)道基本一致[7-12]。Zheng等[18]將PEP按照Cotton標(biāo)準(zhǔn)[14]分為輕、中、重度,分級(jí)統(tǒng)計(jì)分析結(jié)果提示，直腸給予NSAIDs可顯著降低輕度PEP的發(fā)生(RR=0.40),可降低中度及重度PEP的發(fā)生(RR=0.13)。本研究對(duì)發(fā)生PEP的患者進(jìn)行APACHEⅡ評(píng)分，結(jié)果吲哚美辛組發(fā)生PEP的嚴(yán)重程度亦顯著較對(duì)照組輕。而且，所有應(yīng)用吲哚美辛的患者無一出現(xiàn)藥物不良反應(yīng)，提示NSAIDs藥物預(yù)防PEP是安全、有效的。

NSAIDs使用方便，價(jià)格便宜，投入效益比明顯。雖然目前的研究認(rèn)為吲哚美辛直腸給藥預(yù)防PEP具有良好的應(yīng)用前景，但我們?nèi)杂性S多疑慮需要解決，比如給藥的時(shí)機(jī)，術(shù)前給藥或者術(shù)后給藥是否會(huì)對(duì)結(jié)局有所影響，再如給藥的方式，口服還是肛塞，以及藥物種類和劑量的選擇等等都是不能回避的問題，期待有更多、更高質(zhì)量的研究提供更確切的證據(jù)。

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2011-06-17)

(本文編輯：屠振興)

EfficacyofrectallyadministeredindomethacinforthepreventionofpostERCPpancreatitis

QIANJian-qing,DAIJian-jun,WANGWei-jun,XUXiao-dan.

DepartmentofGastroenterology,ChangshuFirstPeople′sHospital,SuzhouUniversity,Changshu215500,China

XUXiao-dan,Email:xxd20@163.com

ObjectivesTo evaluate the efficacy of rectally administered indomethacin for the prevention of post-ERCP pancreatitis(PEP).MethodsAll eligible patients without high risk factors such as heart, lung, liver and kidney, coagulation dysfunction, without malignant disease and contraindication for NSAIDs, and pre-operative imaging study and lab test suggesting no pancreatitis, aged from 18～75 who underwent ERCP and EST were enrolled. In a randomized prospective trial, patients were randomized to receive a suppository containing indomethacin, 100 mg, or an identical placebo 30 minutes after ERCP. PEP was diagnosed when there was pancreatitis related clinical symptoms, and serum amylase was higher than 3 times of the normal values, and when the patient needed more than 1 day hospitalization. Patients with PEP were evaluated with APACHE Ⅱ score 72 hours after ERCP.ResultsDuring 2004～2010, a total of 348 patients were enrolled, of which 182

indomethacin and 166 received placebo. Six patients developed pancreatitis in the indomethacin group and 14 in the placebo group (3.3%vs. 8.4%,P<0.05), and the difference between the two group was statistically significant (P<0.05). In those patients with PEP, the APACHE Ⅱ scores in indomethacin group (4.3±1.3) were lower than that in the placebo group (7.4±1.7), and the difference between the two groups was statistically significant (P<0.05). The incidence of hyperamylasemia in both groups was not statistically significant (9.3%vs. 10.8%,P>0.05).ConclusionsThis trial shows that rectally administered indomethacin after ERCP and EST can effectively reduce the incidence and severity of PEP.

Sphincterotomy,endoscopic; post-ERCP pancreatitis; Non-steroidal anti-inflammatory agents; Case-control studies

10.3760/cma.j.issn.1674-1935.2011.05.007

215500 常熟，蘇州大學(xué)附屬常熟第一人民醫(yī)院消化內(nèi)科

徐曉丹，Email：xxd20@163.com