李青松，滕曉生

(臺(tái)州市中心醫(yī)院 消化內(nèi)科，浙江 臺(tái)州 318000)

吲哚美辛對(duì)50歲以下患者十二指腸乳頭小切開聯(lián)合球囊擴(kuò)張取石術(shù)后胰腺炎的預(yù)防作用

李青松Δ，滕曉生

(臺(tái)州市中心醫(yī)院 消化內(nèi)科，浙江 臺(tái)州 318000)

目的 研究吲哚美辛術(shù)前直腸給藥對(duì)50歲以下患者十二指腸乳頭小切開聯(lián)合球囊擴(kuò)張取石術(shù)后胰腺炎的預(yù)防作用。方法 選取患有膽總管結(jié)石50歲以下患者202例，隨機(jī)分為2組，其中治療組101例術(shù)前予以吲哚美辛直腸給藥，對(duì)照組101例予以安慰劑術(shù)前給藥，2組均行十二指腸乳頭小切開聯(lián)合球囊擴(kuò)張取石術(shù)。術(shù)后監(jiān)測(cè)患者腹痛NRS評(píng)分、淀粉酶、胰腺炎、住院時(shí)間等情況。并統(tǒng)計(jì)患者出現(xiàn)燒心、皮疹、消化道出血的情況。結(jié)果 對(duì)照組術(shù)后24 h疼痛NRS評(píng)分(0.634±1.027)分，治療組術(shù)后24 h疼痛NRS評(píng)分(0.327±0.763)分；對(duì)照組術(shù)后24 h淀粉酶為(185.38±160.60)U/L，治療組術(shù)后24 h淀粉酶(116.87±113.97)U/L；對(duì)照組術(shù)后發(fā)生胰腺炎11例(10.89%)，治療組術(shù)后發(fā)生胰腺炎3例(2.97%)；對(duì)照組術(shù)后住院時(shí)間(7.29±2.71)d，治療組術(shù)后住院時(shí)間(6.42±2.11)d；2組疼痛NRS評(píng)分、淀粉酶、胰腺炎發(fā)病率、術(shù)后住院時(shí)間差異具有統(tǒng)計(jì)學(xué)意義(P<0.05)。2組術(shù)后出現(xiàn)燒心、皮疹、消化道出血情況差異經(jīng)分析無統(tǒng)計(jì)學(xué)意義。結(jié)論 吲哚美辛術(shù)前直腸給藥能夠有效預(yù)防50歲以下患者十二指腸乳頭小切開聯(lián)合球囊擴(kuò)張取石術(shù)后的胰腺炎，并且具有較好的安全性。

吲哚美辛；術(shù)后胰腺炎；十二指腸乳頭小切開；球囊擴(kuò)張；50歲以下

隨著醫(yī)學(xué)水平的發(fā)展，內(nèi)鏡下逆行胰膽管造影(endoscopic retrograde cholangiopancreatography，ERCP)已經(jīng)由單純的診斷技術(shù)發(fā)展成為治療胰腺和膽道疾病的微創(chuàng)治療方法。在這一過程中，許多學(xué)者發(fā)現(xiàn)，術(shù)后胰腺炎是ERCP最常見的早期并發(fā)癥之一[1]。尤其是女性患者、年輕患者、既往胰腺炎病史患者及膽道病情復(fù)雜的患者更容易發(fā)生ERCP術(shù)后胰腺炎(post-endoscopic retrograde cholangiopancreatography pancreatitis，PEP)。對(duì)膽總管結(jié)石的治療，國(guó)外有學(xué)者推薦采取十二指腸乳頭小切開聯(lián)合球囊擴(kuò)張取石的方法[2]。但球囊擴(kuò)張容易合并胰腺炎，有學(xué)者認(rèn)為，球囊擴(kuò)張?jiān)黾恿撕喜⑿g(shù)后胰腺炎的風(fēng)險(xiǎn)[3]。因此，地患者采取十二指腸乳頭小切開聯(lián)合球囊擴(kuò)張取石術(shù)，對(duì)術(shù)后胰腺炎的預(yù)防尤為重要。而國(guó)外已經(jīng)有學(xué)者報(bào)道，術(shù)前應(yīng)用非甾體類消炎藥有助于預(yù)防胰腺炎，但仍存在一定爭(zhēng)議。有文獻(xiàn)報(bào)道，100 mg的吲哚美辛栓術(shù)前塞肛，未能有效預(yù)防ERCP術(shù)后胰腺炎[4]。但是Murray等[5]對(duì)ERCP術(shù)前使用雙氯芬酸組和安慰劑組進(jìn)行對(duì)照，發(fā)現(xiàn)非甾體類抗炎藥的術(shù)前應(yīng)用能夠有效降低術(shù)后胰腺炎的發(fā)生。Inamdar 等[6]也報(bào)道直腸吲哚美辛對(duì)具有術(shù)后胰腺炎高危因素的患者有保護(hù)作用。本研究對(duì)采用術(shù)前吲哚美辛直腸給藥的患者和安慰劑直腸給藥的患者進(jìn)行比較，分析吲哚美辛直腸給藥對(duì)50歲以下患者十二指腸乳頭小切開聯(lián)合球囊擴(kuò)張取石術(shù)后胰腺炎的預(yù)防作用。

1 資料與方法

1.1 一般資料 選取2012年3月～2016年5月在臺(tái)州市中心醫(yī)院消化內(nèi)科治療的膽總管結(jié)石患者202例。其中女性114例，男性88例，有高血壓、糖尿病、血脂異常、病毒性肝炎等合并癥者51例，無上述合并癥者151例。既往有胰腺炎病史者34例。將患者隨機(jī)分為治療組和對(duì)照組，每組各101例。2組在性別比例、年齡、高血壓等合并癥、既往病史、術(shù)前膽紅素水平、術(shù)前淀粉酶水平等方面的差異無統(tǒng)計(jì)學(xué)意義。本研究經(jīng)患者知情并簽署知情同意書，經(jīng)本院倫理委員會(huì)審核批準(zhǔn)。

納入標(biāo)準(zhǔn)：經(jīng)腹部CT或MRCP確診膽總管結(jié)石，年齡在50歲以下，18歲以上。排除標(biāo)準(zhǔn)：不同意參加本項(xiàng)研究；年齡<18歲；妊娠、哺乳的女性患者；對(duì)阿司匹林、吲哚美辛或其他非甾體類抗炎藥過敏；近期(4w內(nèi))[7]有消化道出血；慢性胰腺炎；合并壺腹部腫瘤或膽道惡性狹窄患者；入院時(shí)淀粉酶高或合并急性胰腺炎患者。

1.2 方法

1.2.1 治療方法：治療組術(shù)前予以吲哚美辛栓(湖北東信藥業(yè)有限公司，國(guó)藥準(zhǔn)字H42021462)100 mg，術(shù)前半小時(shí)直腸給藥。對(duì)照組予以甘油栓，術(shù)前半小時(shí)直腸給藥[7-8]。常規(guī)進(jìn)行術(shù)前準(zhǔn)備。采用奧林巴斯電子十二直腸鏡以及相關(guān)治療設(shè)備。進(jìn)鏡至十二指腸降部，尋及十二指腸乳頭后，以切開刀及導(dǎo)絲嘗試選擇性膽管插管，插管成功后注入造影劑。以切開刀行十二指腸乳頭小切開，切開長(zhǎng)度不超過乳頭的1/3[9]，再以乳頭擴(kuò)張球囊行十二指腸乳頭擴(kuò)張術(shù)，球囊直徑選大小和膽總管結(jié)石直徑相仿但不超過膽總管下段直徑者，直徑范圍在10～18 mm左右。在X線監(jiān)視下行十二指腸乳頭擴(kuò)張，球囊內(nèi)加壓至球囊影腰部凹陷基本消失，并持續(xù)60 s，間隔半分鐘后再次重復(fù)上述球囊擴(kuò)張步驟。擴(kuò)張完成后采用取石網(wǎng)籃取石，部分結(jié)石過大者，予以碎石網(wǎng)籃行碎石術(shù)，再予以去除結(jié)石。術(shù)后常規(guī)留置鼻膽管引流膽汁并予以0.9%氯化鈉溶液沖洗膽道。所有操作均由本院同一位高年制熟練操作ERCP的醫(yī)師完成。

1.2.2 觀察指標(biāo)：記錄術(shù)中嘗試插管的次數(shù)以及操作時(shí)間；術(shù)后24 h評(píng)估患者疼痛程度，記錄疼痛數(shù)字模擬量表(numeric rating scales，NRS)評(píng)分，并檢測(cè)患者血淀粉酶水平；參照COTTON標(biāo)準(zhǔn)[10]判斷是否發(fā)生術(shù)后胰腺炎；記錄并統(tǒng)計(jì)患者術(shù)后住院天數(shù)。

2 結(jié)果

2.1 2組患者一般資料比較 2組患者性別、年齡、合并其他疾病情況、既往胰腺炎病史情況差異無統(tǒng)計(jì)學(xué)意義，2組術(shù)前膽紅素及淀粉酶水平差異無統(tǒng)計(jì)學(xué)意義。見表1。

表1 2組患者一般資料比較Tab.1 Comparison of general information between two groups

2.2 2組操作因素對(duì)比 2組患者術(shù)中嘗試插管次數(shù)、操作時(shí)間及碎石例數(shù)差異無統(tǒng)計(jì)學(xué)意義。見表2。

表2 2組患者嘗試插管次數(shù)、操作時(shí)間及碎石例數(shù)情況對(duì)比Tab.2 Comparison of intubation times, operation time and the number of cases of stone breaking between the two groups

2.3 2組術(shù)后疼痛、淀粉酶、胰腺炎發(fā)病例數(shù)、術(shù)后住院時(shí)間情況比較 治療組術(shù)后24 h NRS評(píng)分顯著低于對(duì)照組(P<0.05)；治療組術(shù)后24 h淀粉酶水平顯著低于對(duì)照組(P<0.05)；治療組術(shù)后發(fā)生胰腺炎3例(2.97%)，對(duì)照組術(shù)后發(fā)生胰腺炎11例(10.89%)，2組差異有統(tǒng)計(jì)學(xué)意義(P<0.05)；治療組術(shù)后住院時(shí)間明顯少于對(duì)照組(P<0.05)。見表3。

表3 2組術(shù)后疼痛、淀粉酶、胰腺炎發(fā)病例數(shù)、術(shù)后住院時(shí)間情況對(duì)比Tab.3 Comparison of NRS score, amylase, incidence of pancreatitis and hospitalization time between the two groups

*P<0.05，與對(duì)照組比較，compared with control group

2.4 2組術(shù)后藥物不良反應(yīng)對(duì)比治療組術(shù)后有12例(11.88%)患者出現(xiàn)燒心，2例(1.98%)患者出現(xiàn)皮疹，6例(5.94%)患者出現(xiàn)消化道出血，對(duì)照組術(shù)后有9例(8.91%)患者出現(xiàn)燒心，1例(0.99%)患者出現(xiàn)皮疹，3例(2.97%)患者出現(xiàn)消化道出血。2組差異無統(tǒng)計(jì)學(xué)意義。2組患者均未出現(xiàn)導(dǎo)致死亡的嚴(yán)重并發(fā)癥。

3 討論

內(nèi)鏡逆行胰膽管造影(ERCP)作為一種微創(chuàng)治療各種良性和惡性膽總管疾病的方法，目前被廣泛接受。而術(shù)后急性胰腺炎是其最常見的和嚴(yán)重的并發(fā)癥[7]。盡管技術(shù)進(jìn)步和內(nèi)鏡醫(yī)師技能提高，PEP發(fā)生率尚未大幅下降[11]。

許多學(xué)者都在探索如何通過藥物預(yù)防ERCP術(shù)后胰腺炎。盡管有大量文獻(xiàn)提到一些藥物對(duì)預(yù)防術(shù)后胰腺炎有效，但尚未得到廣泛的承認(rèn)[12]。 在多種藥物中，有學(xué)者發(fā)現(xiàn)非甾體類消炎藥術(shù)前應(yīng)用能夠在一定程度上預(yù)防ERCP術(shù)后胰腺炎的發(fā)生。非甾體類消炎藥能夠通過調(diào)節(jié)多種炎癥介質(zhì)在急性胰腺炎中的初始炎癥級(jí)聯(lián)反應(yīng)的關(guān)鍵作用，包括花生四烯酸和血小板活化因子，來抑制ERCP術(shù)后胰腺炎的發(fā)生[13-15]。有學(xué)者對(duì)雙氯芬酸直腸給藥和安慰劑直腸給藥進(jìn)行對(duì)比，發(fā)現(xiàn)雙氯芬酸組術(shù)后胰腺炎的發(fā)生率為3.9%(2 / 51)，安慰劑組為18.9%(10 / 53)[8]。Elmunzer等[16]也對(duì)非甾體抗炎藥直腸應(yīng)用預(yù)防ERCP術(shù)后胰腺炎進(jìn)行了一項(xiàng)多中心、隨機(jī)、對(duì)照、雙盲臨床試驗(yàn)，證實(shí)由于其良好的安全性，價(jià)格低廉，容易獲得，非甾體類抗炎藥是ERCP術(shù)后胰腺炎最好的藥物預(yù)防方法。

然而，對(duì)于ERCP術(shù)后胰腺炎來說，針對(duì)高危人群進(jìn)行預(yù)防尤為重要，這類人群主要有女性、年輕、既往有胰腺炎病史，以及膽道疾病復(fù)雜的患者。其中50歲以下年輕患者屬于高危人群之一[17]。針對(duì)這一人群的ERCP術(shù)后胰腺炎的預(yù)防，目前已經(jīng)有較多的報(bào)道，但針對(duì)目前許多學(xué)者推薦采取的十二指腸乳頭小切開聯(lián)合球囊擴(kuò)張取石術(shù)，采用非甾體類抗炎藥進(jìn)行術(shù)后胰腺炎預(yù)防的報(bào)道較少。

為了針對(duì)性地進(jìn)行分析，本研究對(duì)術(shù)前研究對(duì)象的性別、年齡、既往病史中相關(guān)因素、術(shù)前淀粉酶水平等進(jìn)行了統(tǒng)計(jì)，排除了其他高危因素導(dǎo)致術(shù)后胰腺炎發(fā)病率異常的影響。對(duì)于ERCP術(shù)后胰腺炎而言，術(shù)中的操作因素也直接影響術(shù)后胰腺炎的發(fā)病率。因此，本研究盡可能地去除2組操作的不同因素，對(duì)照分析了2組操作時(shí)間、嘗試插管次數(shù)等操作因素，排除了術(shù)中一些因素對(duì)術(shù)后胰腺炎發(fā)生率的影響。研究結(jié)果表明，以吲哚美辛為代表的非甾體類藥物直腸給藥能夠有效預(yù)防50歲以下患者十二指腸乳頭小切開聯(lián)合球囊擴(kuò)張取石術(shù)的術(shù)后胰腺炎的發(fā)生。

除了非甾體類消炎藥之外，還有其他一些方法能夠降低ERCP術(shù)后胰腺炎的發(fā)生。胰管支架置入術(shù)是預(yù)防ERCP術(shù)后胰腺炎的一種方法。它的有效性被多位學(xué)者報(bào)道[18-19]。十二指腸乳頭早期預(yù)切開也是預(yù)防ERCP術(shù)后胰腺炎的方法[20]。然而和術(shù)前應(yīng)用非甾體類消炎藥對(duì)比，后者具有更經(jīng)濟(jì)、更安全的特點(diǎn)。

本研究對(duì)術(shù)后非甾體類抗炎藥可能導(dǎo)致的常見不良反應(yīng)進(jìn)行了對(duì)比，沒有顯著性差異。提示ERCP術(shù)前常規(guī)劑量的吲哚美辛直腸給藥，具有良好的安全性。這一點(diǎn)和許多學(xué)者的報(bào)道一致[20]。

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(編校：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，碩士，主治醫(yī)師，研究方向：肝膽胰疾病診療，E-mail：liqingsong-1983@163.com。

R575.7

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