胡翠 趙孝文 鮑峻峻 丁浩 徐張巍 劉曉昌 梅俏 許建明

內(nèi)鏡逆行胰膽管造影術(shù)(ERCP)最常見和最嚴(yán)重的并發(fā)癥是術(shù)后胰腺炎(post-ERCP pancreatitis，PEP)，發(fā)生率為1%～10%[1-2]，高?；颊甙l(fā)生率可達(dá)30%[3-5]。因此，預(yù)防PEP是臨床研究的熱點(diǎn)問題。研究表明，非甾體類抗炎藥(NSAIDs)具有預(yù)防PEP的臨床療效[6]。Elmunzer等[7]和Dai等[8]的薈萃分析亦證實(shí)NSAIDs能降低PEP發(fā)生率。NSAIDs是通過促進(jìn)NSAID激活基因(NSAID activated gene，NAG-1)的表達(dá)發(fā)揮抗炎作用。近年有研究證實(shí)，雙氯芬酸鈉同樣具有預(yù)防PEP發(fā)生的作用[9]。本研究應(yīng)用雙氯芬酸鈉防治PEP，觀察患者血清NAG-1水平的變化，探討其作用機(jī)制。

一、材料和方法

1．研究對(duì)象：收集2012年9月至2013年10月安徽醫(yī)科大學(xué)第一附屬醫(yī)院消化內(nèi)科行ERCP治療的住院患者。入選標(biāo)準(zhǔn)：年齡>18歲，未合并心、肺、肝、腎疾病及凝血功能障礙，無(wú)NSAIDs藥物禁忌證，術(shù)前未使用NSAIDs，術(shù)前影像學(xué)及血清學(xué)證實(shí)未合并胰腺炎。試驗(yàn)經(jīng)醫(yī)院倫理委員會(huì)批準(zhǔn)，入選病例術(shù)前均簽署知情同意書。按完全隨機(jī)法分為雙氯芬酸鈉組和對(duì)照組，ERCP術(shù)后按常規(guī)處理，雙氯芬酸鈉組術(shù)后立即肌內(nèi)注射奧爾芬(含雙氯芬酸鈉75 mg)1支。

2．PEP診斷標(biāo)準(zhǔn)：ERCP術(shù)后有新出現(xiàn)或者加重的腹痛，術(shù)后24 h血淀粉酶升高至少3倍，可診斷為PEP，單純淀粉酶升高患者則為高淀粉酶血癥。

3．血清淀粉酶活性、NAG-1水平檢測(cè)：術(shù)前及術(shù)后3、24 h采集空腹靜脈血2 ml，3 000 r/min離心15 min，分離血漿，置-80℃冰箱內(nèi)保存待測(cè)。采用全自動(dòng)生化檢測(cè)儀測(cè)定血清淀粉酶活性，采用ELISA法檢測(cè)血清NAG-1水平。

二、結(jié)果

1．一般情況：共納入120例患者，其中男性56例，女性64例，年齡21～80歲，平均57歲。雙氯芬酸鈉組和對(duì)照組各60例，兩組患者在年齡、性別、吸煙史、飲酒史和病因方面具有可比性。

2．兩組患者術(shù)前、術(shù)后血清淀粉酶活性的變化及PEP發(fā)生率：兩組患者術(shù)前淀粉酶活性差異無(wú)統(tǒng)計(jì)學(xué)意義，術(shù)后3、24 h，雙氯芬酸鈉組患者血清淀粉酶活性均顯著低于同時(shí)間點(diǎn)對(duì)照組(t值分別為2.06、2.03，P值均<0.05，表1)。兩組患者共16例(13.3%)發(fā)生PEP，其中雙氯芬酸鈉組4例(6.7%)，對(duì)照組12例(20.0%)，兩組PEP發(fā)生率的差異有統(tǒng)計(jì)學(xué)意義(χ2=4.62，P=0.03)。

表1 兩組患者ERCP術(shù)前、術(shù)后淀粉酶活性的比較

3．兩組患者術(shù)前、術(shù)后血清NAG-1水平的變化：對(duì)照組患者術(shù)前、術(shù)后血清NAG-1水平無(wú)顯著變化。雙氯芬酸鈉組患者術(shù)前血清NAG-1水平與對(duì)照組的差異無(wú)統(tǒng)計(jì)學(xué)意義；術(shù)后3 h的NAG-1水平較術(shù)前顯著升高(F=4.30，P=0.04)，也較同時(shí)間點(diǎn)對(duì)照組顯著升高(t=2.54，P=0.01)；術(shù)后24 h的NAG-1水平較術(shù)后3 h時(shí)顯著下降(P=0.00)，且恢復(fù)到術(shù)前水平(P=0.54。表2)。

表2 兩組患者ERCP術(shù)前、術(shù)后血清NAG-1水平的變化

討論P(yáng)EP是ERCP術(shù)后最常見和最嚴(yán)重的并發(fā)癥之一，如何預(yù)防PEP成為臨床難題。國(guó)內(nèi)外對(duì)防治PEP的藥物[1]進(jìn)行了大量研究，如奧曲肽[10]、別嘌呤醇[11]、肝素[12]等。研究證實(shí)，NSAIDs可以預(yù)防PEP的發(fā)生[6]。NSAIDs預(yù)防PEP的機(jī)制尚不完全清楚，可能是通過抑制前列腺素的合成和阻斷胰腺炎的炎癥級(jí)聯(lián)反應(yīng)來預(yù)防PEP的發(fā)生[13]。M?kel?等[14]研究發(fā)現(xiàn)，NSAIDs可抑制重癥急性胰腺炎患者血清PLA2活性及中性粒細(xì)胞/內(nèi)皮細(xì)胞的黏附。Simon等[15]研究表明，NSAIDs可通過抑制中性粒細(xì)胞活化，減輕PEP的炎癥程度。

Senol等[16]研究發(fā)現(xiàn)，ERCP術(shù)后立即肌內(nèi)注射75 mg雙氯酚酸鈉，PEP發(fā)生率及術(shù)后4、8、24 h血淀粉酶值與對(duì)照組相比無(wú)顯著差別，但對(duì)未合并Oddi括約肌功能障礙的患者，雙氯酚酸鈉可顯著降低其PEP發(fā)生率。Murray等[17]研究表明，ERCP術(shù)后立即直腸給予雙氯芬酸，PEP發(fā)生率顯著降低(6.36%比15.5%)。本研究結(jié)果顯示，給予雙氯芬酸鈉的患者術(shù)后血淀粉酶活性顯著下降，PEP的發(fā)生率也顯著下降，提示ERCP術(shù)后立即注射雙氯芬酸鈉可以預(yù)防PEP的發(fā)生。

NAG-1是TGF-β超家族的重要成員之一，是從吲哚美辛處理的結(jié)腸癌細(xì)胞中通過PCR消減雜交技術(shù)獲取，可通過抑制環(huán)氧化物酶途徑抑制結(jié)腸腫瘤的進(jìn)展。NAG-1在炎癥發(fā)生過程中表達(dá)增加[18]，可以降低脂多糖引起的炎癥反應(yīng)[19]，同時(shí)，通過降低巨噬細(xì)胞TNF-α的分泌水平，發(fā)揮顯著抗炎作用[20]。NSAIDs對(duì)NAG-1的表達(dá)具有重要影響[21-22]。

本研究結(jié)果顯示，雙氯芬酸鈉組術(shù)后血清NAG-1水平顯著高于對(duì)照組，表明雙氯芬酸鈉可通過誘導(dǎo)NAG-1的表達(dá)，從而減輕炎癥反應(yīng)。

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