吲哚美辛对内镜下逆行性胰胆管造影术后胰腺炎的预防

钱建清 戴建军 王卫军 徐晓丹

·论著·

吲哚美辛对内镜下逆行性胰胆管造影术后胰腺炎的预防

钱建清 戴建军 王卫军 徐晓丹

目的探讨吲哚美辛对内镜下逆行性胰胆管造影术后胰腺炎(PEP)的预防作用。方法从需行内镜下十二指肠乳头括约肌切开术(EST)的患者中选择年龄18～75岁，未合并有心、肺、肝、肾疾病及凝血功能障碍等手术高危因素，未合并恶性疾病，无非甾体类抗炎(NSAIDs)药物禁忌证，术前影像学及血清学证实未合并胰腺炎者。采用前瞻性随机对照病例研究方法分为吲哚美辛组和对照组。吲哚美辛组患者术后0.5 h使用吲哚美辛100 mg肛塞，对照组给予安慰剂。以术后出现持续性的胰腺炎相关临床症状伴有术后24 h血清淀粉酶值超过正常上限3倍、需住院1 d以上者诊断为PEP。并对诊断PEP的患者于术后72 h进行APACHEⅡ评分。结果2004年至2010年共入选348例患者，其中吲哚美辛组182例，对照组166例。吲哚美辛组术后发生PEP 6例(3.3%)，对照组14例(8.4%)，两组差异具有统计学意义(P<0.05)。吲哚美辛组发生PEP者的APACHEⅡ评分为4.3±1.3，对照组为7.4±1.7，两组差异具有统计学意义(P<0.05)。但两组高胰淀粉酶血症的发生率无统计学差异(9.3%比10.8%，P>0.05)。结论内镜下乳头括约肌切开取石术后使用吲哚美辛肛栓预防术后胰腺炎是有效的，同时可以降低胰腺炎的严重程度。

括约肌切开术，内窥镜； ERCP术后胰腺炎； 非甾类抗炎剂； 病例对照研究

内镜下逆行性胰胆管造影(ERCP)加十二指肠乳头括约肌切开(EST)是目前治疗胆总管结石安全、有效的一线治疗手段[1]。EST取石术后严重并发症主要包括出血、穿孔、结石嵌顿、急性胰腺炎等，其中以ERCP术后胰腺炎(post-ERCP pancreatitis, PEP)最为常见[2]，其发生率为1.3%～8.6%[3-5]。目前报道的用于预防PEP的药物主要包括生长抑素、硝酸甘油、蛋白酶抑制剂等[6],但效果均不能令人满意。近年来，国外有多项随机对照临床研究(randomized clinical trial, RCT)[7-12]显示非甾体类抗炎药(non-steroidal anti-inflammatory drugs, NSAIDs)在预防PEP中可能有很好的应用前景。现将我院应用NSAID的资料报道如下。

材料和方法

一、临床资料

对本院内镜中心2004年至2010年进行EST取石的患者进行筛选。入选标准：年龄18～75岁；未合并有心、肺、肝、肾疾病及凝血功能障碍等手术高危因素；未合并恶性疾病；无NSAIDs药物禁忌证；术前影像学及血清学证实未合并胰腺炎。造影及手术操作由具有10年以上ERCP操作经验的同一操作组的内镜医师完成；术后未留置鼻胆管。

二、方法

采用前瞻性随机对照病例分析。入选患者按完全随机法分为吲哚美辛组和对照组。吲哚美辛组患者术后0.5 h常规使用100 mg吲哚美辛肛塞；对照组患者术后0.5 h使用安慰剂。为避免治疗相关混杂因素的影响，我们采用标准ERCP+EST取石术[13]，术中造影剂15%泛影葡胺使用量控制在50 ml以内，且无胰管显影，ERCP术后未植入胆、胰管支架，未留置鼻胆管；术后均采用相同的治疗方案，即术后禁食，并使用奥美拉唑、奥曲肽、奥硝唑及环丙沙星治疗，以期最大限度减少治疗相关因素对实验结果产生偏倚。

三、PEP诊断

PEP的诊断基于Cotton等[14]统一标准：ERCP术后出现持续性的胰腺炎相关的临床症状(如新出现或加重的腹部疼痛)伴有术后24 h血清淀粉酶值超过正常上限的3倍,需住院1 d以上者诊断为PEP， 若只有血、尿淀粉酶升高，则诊断为术后高淀粉酶血症。根据2006年发表的《美国胰腺炎诊治指南》[15]，对诊断PEP的患者，于术后72 h进行APACHEⅡ评分，评估PEP的严重程度。

四、统计学处理

结 果

2004年至2010年期间本中心共行EST取石术878例，符合条件并入选的患者共348例，其中男212例，女136例，平均年龄51岁；吲哚美辛组182例，对照组166例，两组患者的基本情况均无统计学差异(表1)。

表1 吲哚美辛组与对照组基本情况比较

吲哚美辛组中有6例(3.3%)患者发生PEP，对照组中有14例(8.4%)发生PEP，两组术后PEP发生率差异具有统计学意义(P<0.05)。吲哚美辛组发生PEP者的APACHEⅡ评分为4.3±1.3，对照组为7.4±1.7，两组差异具有统计学意义(P<0.05)。吲哚美辛组中17例(9.3%)术后发生高淀粉酶血症，对照组中18例(10.8%)术后发生高淀粉酶血症，两组差异无统计学意义(P>0.05)。

讨 论

NSAIDs是一类具有环氧合酶(COX)抑制活性的药物，对COX-1、COX-2均有抑制作用，临床广泛用于抗炎、镇痛及退热等病症。1997年，Makela等[16]首次报道NSAIDs能有效抑制重症胰腺炎患者血清的磷脂酶A2(PLA2)活性及中性粒细胞、内皮细胞的附着，从而减少中性粒细胞在损伤组织的积聚和活化，继而抑制伴随中性粒细胞的一系列炎症反应,包括环磷酸腺苷的合成、过氧化物酶的产生、溶酶体酶的释放等，减轻炎症反应，在急性胰腺炎的炎症级联反应初期起重要作用。此后，部分学者开始探讨NSAIDs用于预防PEP的可行性。我国浙江医科大学的Dai等[17]荟萃分析了截至2009年全球发表的4项关于应用NSAIDs预防PEP的高质量RCT，结果显示NSAIDs预防PEP是值得临床推荐的。

吲哚美辛，又称消炎痛，是COX-1和COX-2的非选择性抑制剂，为临床广泛应用的NSAIDs药物。为了探寻NSAIDs对PEP的影响，我们严格控制入选标准，剔除可能影响病情转归的因素。本结果显示，直肠应用吲哚美辛可有效预防PEP的发生，与国外报道基本一致[7-12]。Zheng等[18]将PEP按照Cotton标准[14]分为轻、中、重度,分级统计分析结果提示，直肠给予NSAIDs可显著降低轻度PEP的发生(RR=0.40),可降低中度及重度PEP的发生(RR=0.13)。本研究对发生PEP的患者进行APACHEⅡ评分，结果吲哚美辛组发生PEP的严重程度亦显著较对照组轻。而且，所有应用吲哚美辛的患者无一出现药物不良反应，提示NSAIDs药物预防PEP是安全、有效的。

NSAIDs使用方便，价格便宜，投入效益比明显。虽然目前的研究认为吲哚美辛直肠给药预防PEP具有良好的应用前景，但我们仍有许多疑虑需要解决，比如给药的时机，术前给药或者术后给药是否会对结局有所影响，再如给药的方式，口服还是肛塞，以及药物种类和剂量的选择等等都是不能回避的问题，期待有更多、更高质量的研究提供更确切的证据。

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2011-06-17)

(本文编辑：屠振兴)

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，苏州大学附属常熟第一人民医院消化内科

徐晓丹，Email：xxd20@163.com