李青松，滕晓生

(台州市中心医院 消化内科，浙江 台州 318000)

吲哚美辛对50岁以下患者十二指肠乳头小切开联合球囊扩张取石术后胰腺炎的预防作用

李青松Δ，滕晓生

(台州市中心医院 消化内科，浙江 台州 318000)

目的 研究吲哚美辛术前直肠给药对50岁以下患者十二指肠乳头小切开联合球囊扩张取石术后胰腺炎的预防作用。方法 选取患有胆总管结石50岁以下患者202例，随机分为2组，其中治疗组101例术前予以吲哚美辛直肠给药，对照组101例予以安慰剂术前给药，2组均行十二指肠乳头小切开联合球囊扩张取石术。术后监测患者腹痛NRS评分、淀粉酶、胰腺炎、住院时间等情况。并统计患者出现烧心、皮疹、消化道出血的情况。结果 对照组术后24 h疼痛NRS评分(0.634±1.027)分，治疗组术后24 h疼痛NRS评分(0.327±0.763)分；对照组术后24 h淀粉酶为(185.38±160.60)U/L，治疗组术后24 h淀粉酶(116.87±113.97)U/L；对照组术后发生胰腺炎11例(10.89%)，治疗组术后发生胰腺炎3例(2.97%)；对照组术后住院时间(7.29±2.71)d，治疗组术后住院时间(6.42±2.11)d；2组疼痛NRS评分、淀粉酶、胰腺炎发病率、术后住院时间差异具有统计学意义(P<0.05)。2组术后出现烧心、皮疹、消化道出血情况差异经分析无统计学意义。结论 吲哚美辛术前直肠给药能够有效预防50岁以下患者十二指肠乳头小切开联合球囊扩张取石术后的胰腺炎，并且具有较好的安全性。

吲哚美辛；术后胰腺炎；十二指肠乳头小切开；球囊扩张；50岁以下

随着医学水平的发展，内镜下逆行胰胆管造影(endoscopic retrograde cholangiopancreatography，ERCP)已经由单纯的诊断技术发展成为治疗胰腺和胆道疾病的微创治疗方法。在这一过程中，许多学者发现，术后胰腺炎是ERCP最常见的早期并发症之一[1]。尤其是女性患者、年轻患者、既往胰腺炎病史患者及胆道病情复杂的患者更容易发生ERCP术后胰腺炎(post-endoscopic retrograde cholangiopancreatography pancreatitis，PEP)。对胆总管结石的治疗，国外有学者推荐采取十二指肠乳头小切开联合球囊扩张取石的方法[2]。但球囊扩张容易合并胰腺炎，有学者认为，球囊扩张增加了合并术后胰腺炎的风险[3]。因此，地患者采取十二指肠乳头小切开联合球囊扩张取石术，对术后胰腺炎的预防尤为重要。而国外已经有学者报道，术前应用非甾体类消炎药有助于预防胰腺炎，但仍存在一定争议。有文献报道，100 mg的吲哚美辛栓术前塞肛，未能有效预防ERCP术后胰腺炎[4]。但是Murray等[5]对ERCP术前使用双氯芬酸组和安慰剂组进行对照，发现非甾体类抗炎药的术前应用能够有效降低术后胰腺炎的发生。Inamdar 等[6]也报道直肠吲哚美辛对具有术后胰腺炎高危因素的患者有保护作用。本研究对采用术前吲哚美辛直肠给药的患者和安慰剂直肠给药的患者进行比较，分析吲哚美辛直肠给药对50岁以下患者十二指肠乳头小切开联合球囊扩张取石术后胰腺炎的预防作用。

1 资料与方法

1.1 一般资料 选取2012年3月～2016年5月在台州市中心医院消化内科治疗的胆总管结石患者202例。其中女性114例，男性88例，有高血压、糖尿病、血脂异常、病毒性肝炎等合并症者51例，无上述合并症者151例。既往有胰腺炎病史者34例。将患者随机分为治疗组和对照组，每组各101例。2组在性别比例、年龄、高血压等合并症、既往病史、术前胆红素水平、术前淀粉酶水平等方面的差异无统计学意义。本研究经患者知情并签署知情同意书，经本院伦理委员会审核批准。

纳入标准：经腹部CT或MRCP确诊胆总管结石，年龄在50岁以下，18岁以上。排除标准：不同意参加本项研究；年龄<18岁；妊娠、哺乳的女性患者；对阿司匹林、吲哚美辛或其他非甾体类抗炎药过敏；近期(4w内)[7]有消化道出血；慢性胰腺炎；合并壶腹部肿瘤或胆道恶性狭窄患者；入院时淀粉酶高或合并急性胰腺炎患者。

1.2 方法

1.2.1 治疗方法：治疗组术前予以吲哚美辛栓(湖北东信药业有限公司，国药准字H42021462)100 mg，术前半小时直肠给药。对照组予以甘油栓，术前半小时直肠给药[7-8]。常规进行术前准备。采用奥林巴斯电子十二直肠镜以及相关治疗设备。进镜至十二指肠降部，寻及十二指肠乳头后，以切开刀及导丝尝试选择性胆管插管，插管成功后注入造影剂。以切开刀行十二指肠乳头小切开，切开长度不超过乳头的1/3[9]，再以乳头扩张球囊行十二指肠乳头扩张术，球囊直径选大小和胆总管结石直径相仿但不超过胆总管下段直径者，直径范围在10～18 mm左右。在X线监视下行十二指肠乳头扩张，球囊内加压至球囊影腰部凹陷基本消失，并持续60 s，间隔半分钟后再次重复上述球囊扩张步骤。扩张完成后采用取石网篮取石，部分结石过大者，予以碎石网篮行碎石术，再予以去除结石。术后常规留置鼻胆管引流胆汁并予以0.9%氯化钠溶液冲洗胆道。所有操作均由本院同一位高年制熟练操作ERCP的医师完成。

1.2.2 观察指标：记录术中尝试插管的次数以及操作时间；术后24 h评估患者疼痛程度，记录疼痛数字模拟量表(numeric rating scales，NRS)评分，并检测患者血淀粉酶水平；参照COTTON标准[10]判断是否发生术后胰腺炎；记录并统计患者术后住院天数。

2 结果

2.1 2组患者一般资料比较 2组患者性别、年龄、合并其他疾病情况、既往胰腺炎病史情况差异无统计学意义，2组术前胆红素及淀粉酶水平差异无统计学意义。见表1。

表1 2组患者一般资料比较Tab.1 Comparison of general information between two groups

2.2 2组操作因素对比 2组患者术中尝试插管次数、操作时间及碎石例数差异无统计学意义。见表2。

表2 2组患者尝试插管次数、操作时间及碎石例数情况对比Tab.2 Comparison of intubation times, operation time and the number of cases of stone breaking between the two groups

2.3 2组术后疼痛、淀粉酶、胰腺炎发病例数、术后住院时间情况比较 治疗组术后24 h NRS评分显著低于对照组(P<0.05)；治疗组术后24 h淀粉酶水平显著低于对照组(P<0.05)；治疗组术后发生胰腺炎3例(2.97%)，对照组术后发生胰腺炎11例(10.89%)，2组差异有统计学意义(P<0.05)；治疗组术后住院时间明显少于对照组(P<0.05)。见表3。

表3 2组术后疼痛、淀粉酶、胰腺炎发病例数、术后住院时间情况对比Tab.3 Comparison of NRS score, amylase, incidence of pancreatitis and hospitalization time between the two groups

*P<0.05，与对照组比较，compared with control group

2.4 2组术后药物不良反应对比治疗组术后有12例(11.88%)患者出现烧心，2例(1.98%)患者出现皮疹，6例(5.94%)患者出现消化道出血，对照组术后有9例(8.91%)患者出现烧心，1例(0.99%)患者出现皮疹，3例(2.97%)患者出现消化道出血。2组差异无统计学意义。2组患者均未出现导致死亡的严重并发症。

3 讨论

内镜逆行胰胆管造影(ERCP)作为一种微创治疗各种良性和恶性胆总管疾病的方法，目前被广泛接受。而术后急性胰腺炎是其最常见的和严重的并发症[7]。尽管技术进步和内镜医师技能提高，PEP发生率尚未大幅下降[11]。

许多学者都在探索如何通过药物预防ERCP术后胰腺炎。尽管有大量文献提到一些药物对预防术后胰腺炎有效，但尚未得到广泛的承认[12]。 在多种药物中，有学者发现非甾体类消炎药术前应用能够在一定程度上预防ERCP术后胰腺炎的发生。非甾体类消炎药能够通过调节多种炎症介质在急性胰腺炎中的初始炎症级联反应的关键作用，包括花生四烯酸和血小板活化因子，来抑制ERCP术后胰腺炎的发生[13-15]。有学者对双氯芬酸直肠给药和安慰剂直肠给药进行对比，发现双氯芬酸组术后胰腺炎的发生率为3.9%(2 / 51)，安慰剂组为18.9%(10 / 53)[8]。Elmunzer等[16]也对非甾体抗炎药直肠应用预防ERCP术后胰腺炎进行了一项多中心、随机、对照、双盲临床试验，证实由于其良好的安全性，价格低廉，容易获得，非甾体类抗炎药是ERCP术后胰腺炎最好的药物预防方法。

然而，对于ERCP术后胰腺炎来说，针对高危人群进行预防尤为重要，这类人群主要有女性、年轻、既往有胰腺炎病史，以及胆道疾病复杂的患者。其中50岁以下年轻患者属于高危人群之一[17]。针对这一人群的ERCP术后胰腺炎的预防，目前已经有较多的报道，但针对目前许多学者推荐采取的十二指肠乳头小切开联合球囊扩张取石术，采用非甾体类抗炎药进行术后胰腺炎预防的报道较少。

为了针对性地进行分析，本研究对术前研究对象的性别、年龄、既往病史中相关因素、术前淀粉酶水平等进行了统计，排除了其他高危因素导致术后胰腺炎发病率异常的影响。对于ERCP术后胰腺炎而言，术中的操作因素也直接影响术后胰腺炎的发病率。因此，本研究尽可能地去除2组操作的不同因素，对照分析了2组操作时间、尝试插管次数等操作因素，排除了术中一些因素对术后胰腺炎发生率的影响。研究结果表明，以吲哚美辛为代表的非甾体类药物直肠给药能够有效预防50岁以下患者十二指肠乳头小切开联合球囊扩张取石术的术后胰腺炎的发生。

除了非甾体类消炎药之外，还有其他一些方法能够降低ERCP术后胰腺炎的发生。胰管支架置入术是预防ERCP术后胰腺炎的一种方法。它的有效性被多位学者报道[18-19]。十二指肠乳头早期预切开也是预防ERCP术后胰腺炎的方法[20]。然而和术前应用非甾体类消炎药对比，后者具有更经济、更安全的特点。

本研究对术后非甾体类抗炎药可能导致的常见不良反应进行了对比，没有显著性差异。提示ERCP术前常规剂量的吲哚美辛直肠给药，具有良好的安全性。这一点和许多学者的报道一致[20]。

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(编校：席大力)

Indomethacin preventing post-ERCP pancreatitis in patients aged under 50 years undergoing sEST combined with EPBD of choledocholithiasis

LI Qing-songΔ, TENG Xiao-sheng

(Department of Gastroenterology, Taizhou Central Hospital, Taizhou 318000, China)

ObjectiveTo study the effect of indomethacin preventing post-ERCP pancreatitis(PEP) on the patients younger than 50 years undergoing small endoscopic sphincterotomy (sEST) combined with endoscopic papillary balloon dilation(EPBD) in the treatment of choledocholithiasis.Methods202 patients younger than 50 years with choledocholithiasis were divided into two groups, 101 patients in treatment group before surgery were rectal administrated with indometacin, 101 patients in control group were administered with placebo, all patients underwent sEST combined with EPBD in the treatment of choledocholithiasis. After operation,the abdominal pain NRS score, amylase, incidence of pancreatitis and hospitalization time were recorded, and the rates of heartburn, rash, gastrointestinal bleeding were recorded.ResultsIn the treatment group, pain NRS score 24 hours after operation was(0.327±0.763), amylase 24 hours after operation was (116.87±113.97) U/L, there were 3 cases of postoperative pancreatitis(2.97%) in the treatment group,and the postoperative hospitalization time was (6.42±2.11) days.In the control group, pain NRS score 24 hours after operation was (0.634±1.027), amylase 24 hours after operation was (185.38±160.60) U/L, there were 11 cases of postoperative pancreatitis (10.89%) in the control group, and the postoperative hospitalization time were (7.29±2.71) days.The differences of NRS pain score, amylase, incidence of pancreatitis, postoperative hospitalization time between these two groups were statistically significant (P<0.05). The differences of the rates of postoperative heartburn, rash, gastrointestinal bleeding between these two groups were not statistically significant.ConclusionIndomethacin rectal administration can prevent post-ERCP pancreatitis(PEP)on the patients who undergoing sEST combined with EPBD in the treatment of choledocholithiasis,and this administration is quite security.

indomethacin; post-ERCP pancreatitis(PEP); small endoscopic sphincterotomy (sEST); endoscopic papillary balloon dilation(EPBD); aged under 50 years

10.3969/j.issn.1005-1678.2016.11.034

李青松，通信作者，男，硕士，主治医师，研究方向：肝胆胰疾病诊疗，E-mail：liqingsong-1983@163.com。

R575.7

B