ERCP术后胰腺炎的危险因素及预防措施

经内镜逆行胰胆管造影(ERCP)具有创伤小、恢复快及可重复操作等优点，已成为治疗胆胰疾病的一线治疗方法，但ERCP术后并发症限制了其广泛推广，主要包括ERCP术后急性胰腺炎(PEP)、出血、穿孔及感染等，其中PEP是较严重、较常见的并发症，不但增加了患者的痛苦和经济负担，一旦发生重症PEP甚至可危及生命。目前对PEP危险因素的研究较多，结论尚不统一，且缺乏标准规范的预防措施。本文就近年来PEP的危险因素及预防措施的研究进展作一综述。

1 PEP的总体发病情况

PEP的总体发生率较高，由于不同地区医生的ERCP操作经验及熟练程度不同，PEP的发生率存在一定差异。Kochar等[1]对1977年至2012年的108项随机对照试验(RCT)中的13 269例患者的PEP发生率、严重程度、病死率进行回顾性分析，结果显示PEP总体发生率为9.7%，多次插管、胰管显影、Oddi括约肌功能障碍(SOD)及女性等高危患者的PEP发生率达14.7%；重症PEP发生率和病死率分别为0.5%、0.7%；对亚洲地区4 203例患者的32项RCT亚组分析显示，PEP发生率为9.9%，北美和欧洲地区的PEP发生率分别为13.0%、8.4%。

2 PEP的危险因素

2.1 患者相关的危险因素

有学者认为女性易发生PEP，这是由于女性的SOD发病率较高，而SOD易引起PEP。一项纳入32 381例患者的大样本系统性回顾性分析表明，女性是PEP的危险因素(OR=1.24，P<0.01)，SOD患者的PEP发生率(9.74%)比非SOD患者(3.37%)明显升高(P<0.01)[2]。Iorgulescu等[3]的临床回顾性研究显示女性及SOD是PEP的危险因素。但另一项纳入2 715例患者的临床回顾性研究显示，女性及SOD均与PEP的发生无关[4]。Christensen等[5]提出高龄是PEP的保护因素，年轻人群的PEP发生率较高；但有研究表明年龄<40岁与PEP发生无关[4]。Freeman等[6]认为性别和年龄为其他危险因素创造了条件，女性、SOD对PEP的独立影响需多中心大样本研究进一步证实。既往胰腺炎病史对PEP的影响尚无定论，Iorgulescu等[3]认为慢性胰腺炎是PEP的保护因素，可能与胰腺分泌功能减退相关；但有研究表明既往慢性胰腺炎病史是PEP的危险因素，无论是否与ERCP相关的既往急性胰腺炎病史均是PEP的危险因素[2]。此外，还有研究报道酗酒和长期抽烟是PEP的危险因素[7]。

2.2 操作相关的危险因素

研究证实胰管显影是发生PEP的独立危险因素，且进入胰管的造影剂剂量与PEP发生率呈正相关[8]，胰管残留造影剂及术后持续腹痛3 h是重症PEP的危险因素，须引起足够重视[9]。此外，有研究报道意外胰管插管是PEP的独立危险因素，需要积极预防[10]。

内镜下十二指肠乳头球囊扩张可以避免十二指肠乳头括约肌切开的出血风险并保留Oddi括约肌功能，在ERCP操作中广泛应用。Jang等[11]报道球囊扩张并不会提升PEP发生率；不充分的球囊扩张可提升PEP发生率，充分的球囊扩张是PEP的保护因素[12]；Attam等[13]和Heo等[14]认为根据胆管结石大小行充分的球囊扩张不会提升PEP发生率；但Tsujino等[15]认为适当降低压力、减少压迫时间的改良球囊压迫法能降低PEP发生率。

正确的监测分析方法是获得准确结果的关键因素之一。每一种监测分析方法的灵敏度和准确度要能满足要求，方法成熟，抗干扰能力强，操作简便。在常规监测中，分光光度法用得较多，可测定多种金属和非金属离子或化合物；原子吸收法主要用于多种微量、痕量金属元素的测定；容量法主要用于DO、COD、BOD5等的测定。审核时主要关注一些新监测标准和方法有没有进行及时更新。

非甾体类抗炎药(NSAID)经直肠给药(50 mg或100 mg)是目前临床指南唯一推荐的PEP预防用药[21]，NSAID通过减少前列腺素合成、抑制磷脂酶A2激活及中性粒细胞与内皮细胞的黏附作用来预防PEP。自2003年Murray等[22]首次报道NSAID能有效预防PEP发生后，学者们对不同剂型、用药时间和给药方式进行了一系列研究。Yang等[23]对包含3 989例用ERCP治疗的患者的12项RCT进行荟萃分析，结果显示术前或术后、不同剂型的NSAID直肠给药对预防PEP均有效。de Quadros等[24]的随机双盲对照试验显示，静脉给予酪洛芬对PEP无保护作用，直肠给药被普遍认可。目前NSAID对不同危险分层患者预防PEP的有效性的认识不一。Hou等[25]及Puig等[26]的荟萃分析显示，直肠给予吲哚美辛对各级风险水平的患者均有效。He等[27]、Inamdar等[28]及Wan等[29]认为吲哚美辛对PEP的预防作用对高危患者有效，对普通患者无明显优势；Barkin等[30]认为ERCP的风险受诸多因素共同影响，高低风险难以清晰界定，建议常规给予吲哚美辛预防PEP。近年来日本学者提出胰管支架对SOD患者没有保护作用，也推荐常规使用吲哚美辛预防PEP[31]。Choksi等[32]的研究显示直肠给予吲哚美辛能降低置管失败引起的PEP发生率，建议常规直肠给予吲哚美辛。Patai等[33]对吲哚美辛的安全性进行评估，结果显示其不会提升30 d内抗凝治疗患者的胆道括约肌切开术后出血率及心血管病死率，其预防PEP安全可靠。

以生长抑素为主的胰酶抑制剂对PEP是否有保护作用仍存在争议。一项纳入570例患者的临床研究显示，不同时期使用生长抑素可明显降低ERCP术后高淀粉酶血症及PEP的发生率，且术前、术后持续用药对其预防作用更佳[34]。另一项荟萃分析认为术前、术后大剂量、长时间使用生长抑素(0.5 mg/h，持续24 h)仅能减少高淀粉酶血症的发生，对PEP无影响[35]。一项前瞻性双盲对照试验显示生长抑素联合双氯芬酸钠能有效减低PEP发生率[36]，但该试验仅将生长抑素与双氯芬酸钠联合作为试验组，不能排除NSAID发挥主要作用的可能。Bai等[37]的荟萃分析显示无足够证据表明奥曲肽能预防PEP，另一项有关奥曲肽使用剂量的荟萃分析显示，只有足量奥曲肽(≥0.5 mg)才能降低PEP发生率[38]。

Freeman等[6]的多中心回顾性研究显示，PEP发生率并不因十二指肠乳头括约肌切开而升高，而是与医生的操作技术及对胰腺组织的损伤相关。Cennamo等[16]对6项随机对照试验中的966例患者进行统计学分析，结果显示由经验丰富的内镜医师操作，十二指肠乳头括约肌预切开与持续尝试的插管的成功率相仿，且预切开Oddi括约肌能降低PEP发生率，也不会增加其他并发症。Gong等[17]的研究结果支持上述结论，但Navaneethan等[18]的研究显示早期预切开Oddi括约肌对PEP发生率没有影响。因此，预切开Oddi括约肌对PEP发生率的影响尚需进一步临床研究。

以曹妃甸港集团各应用系统为基础，把曹妃甸港集团各个应用系统的功能、个性化的业务，关键核心数据综合加工利用，建设一套综合性的服务管理系统，为曹妃甸港集团各层次、各岗位提供统一入口、统一操作、统一界面、统一管理的系统服务平台，主动把信息推送到集团人员面前，提升服务水平与效率。

目前Katsinelos等[4]和Aronson等[19]认为插管困难不是PEP的危险因素，而插管的次数与PEP的发生密切相关。Aronson等[19]认为反复插管导致的十二指肠乳头及胰管括约肌损伤是引发PEP及高淀粉酶血症的原因之一。Vandervoort等[20]对1 223例患者进行分析，发现插管少于5次者的PEP发生率为3.3%，插管多于20次者的PEP发生率高达14.9%(P<0.000 1)。

3 PEP的预防措施

3.1 药物预防

金枝是乡下女人，她还看不清那人是假意同情，她轻轻受了“可怜”字眼的感动，她心有些波荡，停在门口，想说一句感谢的话，但是她不懂说什么，终于走了！她听道旁大水壶的笛子在耳边叫，面包作坊门前取面包的车子停在道边，俄国老太太花红的头巾驰过她。

紫趾综合征的确诊需作受累器官的组织学样本检查，可在直径为100μm～200μm的小动脉血管的管腔内见到胆固醇晶体，镜下可见胆固醇晶体溶解并出现针状裂缝[4]。

3.2 内镜预防

导丝引导插管能提高插管的成功率，但对PEP发生率的影响尚有争议。Adler等[39]对822例患者进行病例分析，提出导丝引导插管在深胆管插管中成功率为97%，PEP发生率仅为1%，对降低PEP发生率效果明显。但Savadkoohi等[40]却提出有否导丝引导插管的患者PEP发生率相似。Tse等[41]的荟萃分析仍推荐导丝引导插管作为预防插管困难导致的术后高淀粉酶血症及PEP的一线方法。目前对双导丝引导插管的优势观点不一。一项多中心对照试验显示双导丝引导插管的患者PEP发生率较单导丝引导插管者明显升高(17%比8%)[42]；另一项回顾性临床研究却显示双导丝与单导丝引导插管的患者的PEP发生率无明显差异(5.8%比6.1%)[43]；一项前瞻性随机对照试验提示胰管置管能明显降低双导丝引导插管患者的PEP发生率[44]。另有研究推荐应用内镜超声引导插管来提高多次插管、SOD及胰管显影等高危患者的插管成功率，从而降低PEP发生率[45]。

放置胰管支架能降低PEP发生率已被多项临床研究证实。一项纳入10个RCT共1 175例ERCP患者的荟萃分析结果显示，胰管置管不仅能降低PEP发生率，还能缓解PEP的严重程度[46]。Olsson等[47]对43 595例ERCP患者进行分析，结果显示预防性胰管置管能明显降低PEP发生率，并且直径>5 Fr、长度>5 cm的胰管支架的预防效果更好。需要注意的是，虽然胰管支架能降低PEP及化脓性胆管炎的发生率，但不能促进已发生的PEP恢复[48]，且胰管置管失败可明显提升PEP发生率[49]。放置胰管支架技术难度较大，因此由经验丰富的内镜医生选择性地熟练放置胰管支架至关重要。有研究报道双导丝引导插管、胰管插管>3次、腺泡显影、女性、SOD、年龄<50岁及多次插管等的高风险患者可使用胰管支架预防PEP。对于高危患者，Freeman[50]推荐胰管置管24 h。

3.3 其他预防方法

随着研究的深入，目前学者们认为操作者的经验和水平与PEP发生率有相关性[4]。一项纳入1 200例ERCP患者的临床回顾性研究分析显示，操作者的熟练程度低以及操作时间长是PEP的危险因素[51]。另一项纳入2 715例接受ERCP术患者的单中心临床研究也表明，经验丰富的操作者能减少患者及操作相关的并发症[4]。液体复苏对PEP也有一定保护作用，DiMagno等[52]和Elmunzer[53]的研究显示补液能降低酸中毒引起的胰酶激活，从而降低PEP发生率，围手术期体液复苏能减轻PEP的严重程度。Wu等[54]的荟萃分析结果显示，积极补液对降低PEP发生率、减轻PEP严重程度、降低高淀粉酶血症发生率、减轻术后疼痛及缩短住院时间均有帮助。Zhang等[55]的荟萃分析显示，采用乳酸林格氏液积极补液以预防PEP是安全、有效的方法。目前具体补液方案尚未明确，需更多临床研究进一步探讨。ERCP术后饮食管理对预防PEP也有帮助，Ferreira等[56]认为ERCP术后当日应禁食或清淡饮食，针对不同风险进行相应的饮食管理，能降低PEP发生率及PEP的严重程度。

4 结语

综上所述，各种引起胰腺受损、胰液引流障碍的因素都可引发PEP，各因素间是否存在交互作用有待进一步研究明确。目前NSAID经直肠给药及放置胰管支架预防PEP的疗效已明确，医生的操作经验和技术水平也不容忽视，要采取尽量避开胰腺操作、减少胰腺分泌、充分引流胰液等措施预防PEP。此外，要严格把握适应证，避免不必要的ERCP，围手术期的体液、饮食管理也有一定预防作用。

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