吲哚美辛對內(nèi)鏡下逆行性胰膽管造影術(shù)后胰腺炎的預防

錢建清 戴建軍 王衛(wèi)軍 徐曉丹

·論著·

吲哚美辛對內(nèi)鏡下逆行性胰膽管造影術(shù)后胰腺炎的預防

錢建清 戴建軍 王衛(wèi)軍 徐曉丹

目的探討吲哚美辛對內(nèi)鏡下逆行性胰膽管造影術(shù)后胰腺炎(PEP)的預防作用。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)前影像學及血清學證實未合并胰腺炎者。采用前瞻性隨機對照病例研究方法分為吲哚美辛組和對照組。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。并對診斷PEP的患者于術(shù)后72 h進行APACHEⅡ評分。結(jié)果2004年至2010年共入選348例患者，其中吲哚美辛組182例，對照組166例。吲哚美辛組術(shù)后發(fā)生PEP 6例(3.3%)，對照組14例(8.4%)，兩組差異具有統(tǒng)計學意義(P<0.05)。吲哚美辛組發(fā)生PEP者的APACHEⅡ評分為4.3±1.3，對照組為7.4±1.7，兩組差異具有統(tǒng)計學意義(P<0.05)。但兩組高胰淀粉酶血癥的發(fā)生率無統(tǒng)計學差異(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防術(shù)后胰腺炎是有效的，同時可以降低胰腺炎的嚴重程度。

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]。目前報道的用于預防PEP的藥物主要包括生長抑素、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，國外有多項隨機對照臨床研究(randomized clinical trial, RCT)[7-12]顯示非甾體類抗炎藥(non-steroidal anti-inflammatory drugs, NSAIDs)在預防PEP中可能有很好的應用前景?，F(xiàn)將我院應用NSAID的資料報道如下。

材料和方法

一、臨床資料

對本院內(nèi)鏡中心2004年至2010年進行EST取石的患者進行篩選。入選標準：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)前影像學及血清學證實未合并胰腺炎。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

采用前瞻性隨機對照病例分析。入選患者按完全隨機法分為吲哚美辛組和對照組。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，我們采用標準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)因素對實驗結(jié)果產(chǎn)生偏倚。

三、PEP診斷

PEP的診斷基于Cotton等[14]統(tǒng)一標準：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《美國胰腺炎診治指南》[15]，對診斷PEP的患者，于術(shù)后72 h進行APACHEⅡ評分，評估PEP的嚴重程度。

四、統(tǒng)計學處理

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，對照組166例，兩組患者的基本情況均無統(tǒng)計學差異(表1)。

表1 吲哚美辛組與對照組基本情況比較

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)計學意義(P<0.05)。吲哚美辛組發(fā)生PEP者的APACHEⅡ評分為4.3±1.3，對照組為7.4±1.7，兩組差異具有統(tǒng)計學意義(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)計學意義(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)活性及中性粒細胞、內(nèi)皮細胞的附著，從而減少中性粒細胞在損傷組織的積聚和活化，繼而抑制伴隨中性粒細胞的一系列炎癥反應,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，在急性胰腺炎的炎癥級聯(lián)反應初期起重要作用。此后，部分學者開始探討NSAIDs用于預防PEP的可行性。我國浙江醫(yī)科大學的Dai等[17]薈萃分析了截至2009年全球發(fā)表的4項關(guān)于應用NSAIDs預防PEP的高質(zhì)量RCT，結(jié)果顯示NSAIDs預防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，為臨床廣泛應用的NSAIDs藥物。為了探尋NSAIDs對PEP的影響，我們嚴格控制入選標準，剔除可能影響病情轉(zhuǎn)歸的因素。本結(jié)果顯示，直腸應用吲哚美辛可有效預防PEP的發(fā)生，與國外報道基本一致[7-12]。Zheng等[18]將PEP按照Cotton標準[14]分為輕、中、重度,分級統(tǒng)計分析結(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)。本研究對發(fā)生PEP的患者進行APACHEⅡ評分，結(jié)果吲哚美辛組發(fā)生PEP的嚴重程度亦顯著較對照組輕。而且，所有應用吲哚美辛的患者無一出現(xiàn)藥物不良反應，提示NSAIDs藥物預防PEP是安全、有效的。

NSAIDs使用方便，價格便宜，投入效益比明顯。雖然目前的研究認為吲哚美辛直腸給藥預防PEP具有良好的應用前景，但我們?nèi)杂性S多疑慮需要解決，比如給藥的時機，術(shù)前給藥或者術(shù)后給藥是否會對結(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)。

[1] Adler DG,Baron TH,Davira RE,et al.ASGE guideline：the role of ERCP in disease of biliaty tract and the Pancreas.Gastrointest Endose,2005,62,1-8.

[2] 許曉倩，張文俊，李兆申.ERCP術(shù)后胰腺炎.胰腺病學,2003,3:243-247.

[3] Colton JB,Curran CC. Quality indicators, including complications, of ERCP in a community setting: a prospective study. Gastrointest Endosc,2009,70: 457-67.

[4] Wang P, Li ZS, Liu F,et al. Risk factors for ERCP-related complications: a prospective multicenter study. Am J Gastroenterol,2009,104:31-40.

[5] Sherman S,Ruffolo TA,Hawes RH,et al.Complications of endoscopic sphincterotomy:a prospective serieswith emphasis on the increased risk associated with sphincter of Oddi dysfunction and non-dilated bile ducts.Gastroenterology,1991,101:1068-1075.

[6] 陳小微，吳建勝，洪萬東.硝酸甘油預防ERCP術(shù)后胰腺炎的薈萃分析.中華胰腺病雜志,2010，10：206-208.

[7] Murray B, Carter R, Imrie C,et al.Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography. Gastroenterology, 2003,124: 1786-1791.

[8] Sotoudehmanesh R, Khatibian M, Kolahdoozan S,et al.Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP. Am J Gastroenterol, 2007, 102: 978-983.

[9] Montao Loza A,Rodriguez Lomli X,Garcia Correa JE,et al.Effect of the administration of rectal indomethacin on amylase serum levels af ter endoscopic retrograde cholangiopancreatography, and its impact on the development of secondary pancreatitis episodes.Rev Esp Enferm Dig, 2007, 99: 330-336.

[10] Cheon YK, Cho KB, Watkins JL,et al.Efficacy of diclofenac in the prevention of post-ERCP pancreatitis in predominantly high-risk patients: a randomized double-blind prospective trial. Gastrointest Endosc, 2007, 66: 1126-1132.

[11] Khoshbaten M, Khorram H, Madad L,et al.Role of diclofenac in reducing post-endoscopic retrograde cholangiopancreato-graphypancreatitis. J Gastroenterol Hepatol, 2008,23: e11-e16.

[12] Senol A, Sari tas U, Demirkan H. Efficacy of intramuscular diclofenac and fluid replacement in prevention of post-ERCP pancreatitis. World J Gastroenterol, 2009,15: 3999-4004.

[13] 李兆申，許國銘. ERCP基本技術(shù)與臨床應用. 濟南市：山東科學技術(shù)出版社, 2001：82-99.

[14] Cotton PB,Lehman G,Vennes J,et al.Endoscopic sphincterotomycomplications and their management: an attempt at consensus.Gastrointest Endosc,1991,37:383-393.

[15] Banks PA,Freeman ML.Practice guidelines in acute pancreatitis. Am J Gastroenterol,2006,101:2379-2400.

[16] Makela A, Kuusi T, Schroder T,et al.Inhibition of serum phospholipase-A2 in acute pancreatitis by pharmacological agents in vitro. Scand J Clin Lab Invest, 1997, 57: 401-407.

[17] Dai HF, Wang XW, Zhao K,et al.Role of nonsteroidal anti-inflammatory drugs in the prevention of post-ERCP pancreatitis: a meta-analysis. Hepatobiliary Pancreat Dis Int, 2009, 8: 11-16.

[18] Zheng MH, Xia HH, Chen YP,et al.Rectal administration of NSAIDs in the prevent ion of post-ERCP pancreatitis: a complementary meta-analysis. Gut, 2008, 57: 1632-1633.

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，蘇州大學附屬常熟第一人民醫(yī)院消化內(nèi)科

徐曉丹，Email：xxd20@163.com