药物预防应激性溃疡的系统综述

邢晓璇，白向荣，褚燕琦，闫素英

药物预防应激性溃疡的系统综述

邢晓璇，白向荣，褚燕琦，闫素英*

目的 综述应激性溃疡出血(Stress ulcer bleeding，SUB)的发生率、危险因素和预防方案的有效性、安全性和经济性，为临床合理制定SUB预防方案提供依据。方法 以“预防应激性溃疡”、“出血”、“危险因素”、“成本”、“stress ulcer prophylaxis”、“bleeding”、“risk factor”、“cost”为关键词，计算机检索MEDLINE、EMbase、Cochrane (Central)、CNKI、CBM、VIP、Wanfang，提取总结相关数据。结果 肠内营养是SUB的保护因素。PPI和H2RA关于预防SUB疗效的研究结论并不一致。3项RCT研究结果均显示，在预防临床大出血方面，PPI并非优于H2RA。同时，2项回顾性研究表明，PPI在预防临床大出血方面不如H2RA。4项Meta分析均认为，PPI与肺炎发生有关(OR：1.04～1.92)。5项Meta分析均认为，PPI能增加肠道感染的风险，尤其是难辨梭菌感染(OR：1.69～3.33)。3项研究对比了PPI和H2RA预防SUB的成本-效益分析。结果显示，在预防SUB时，肠内奥美拉唑最优；在预防SUB和并发症时，PPI最优；在PPI组和H2RA组死亡率相同时，H2RA预防SUB成本低于PPI。结论 危重患者使用抑酸药预防SUB前应先进行风险因素评估。鉴于临床大出血发生率低，临床医生应考量预防SUB用药的必要性、安全性及经济性。

预防应激性溃疡；出血；质子泵抑制剂；成本-效益

0 引言

应激性溃疡(Stress ulcer，SU)一般是指严重创伤、感染、休克等应激情况下继发的胃十二指肠等黏膜发生糜烂、溃疡，严重者可导致应激性溃疡出血(Stress ulcer bleeding，SUB)，多发生于重症监护室患者中[1]。ICU患者SU发生率为75%～100%，胃潜血的发生率为5%～25%[2]，而临床大出血(Clinical important bleeding，CIB)发生率非常低。2015年1项最新研究显示，CIB的发生率仅为2.6%[3]。因不能排除ICU中的消化道出血患者在入住ICU前是否已有胃肠道疾病，故真实CIB发生率可能会更低。

抑酸药包括PPI和H2RA，预防SUB应维持胃内pH>4，而PPI抑制胃酸能力优于H2RA，故PPI使用量逐年上升。2013年一项研究表明，70%的ICU患者都使用PPI，而2002年和1998年分别为23%和3%[4-6]。最新一项多国多中心研究显示，66% (64/97)的ICU将PPI作为首选药，其他ICU将H2RA作为首选药[7]。抑酸药(尤其是PPI)长期应用可能增加肺炎、难辨梭菌感染、低镁血症等并发症的风险[8-10]。考虑到临床大出血发生率低，本文将分别讨论SUB的发生率、危险因素，以及预防SUB用药的必要性、安全性及经济性，为临床合理预防SUB提供理论依据。

1 资料与方法

1.1 文献检索 由2名研究员独立检索国内外研究。以“应激性溃疡预防”、“出血”、“危险因素”、“成本”、“stress ulcer prophylaxis”、“bleeding”、“risk factor”、“cost”为关键词，计算机检索Cochrane图书馆临床对照试验数据库、MEDLINE光盘数据库、EMbase光盘数据库、Cochrane (Central)数据库、中国知网中国期刊全文数据库(CNKI)、中国生物医学文献数据库(CBM)、中国科技期刊全文数据库(VIP)、万方数字化期刊全文数据库(Wanfang Data)，检索时限均为建库至2016年4月。

1.2 文献筛选与资料提取 研究筛选检索收集的文献，纳入所有与SUP相关的原始研究、系统评价和临床指南。阅读全文后提取总结相关数据。

2 结果

2.1 CIB的高危因素 危重患者因生理应激导致黏膜防御机制破坏和黏膜缺血，发生应激性溃疡，并有出现CIB的风险[11]。一项多中心前瞻性研究显示，机械通气(>48 h)和凝血障碍是CIB的独立高危因素。近期一项多国家多中心研究共评估1 034例ICU发生CIB的危险因素[7]，结果显示，以下因素与CIB相关(用OR、95%CI表示)：至少3个合并症(8.9，2.7～28.8)，肝功能不全(7.6，3.3～17.6)，肾脏替代治疗(6.9，2.7～17.5)，合并凝血障碍 (4.2，1.7～10.2)，器官衰竭评分高 (1.4，1.2～1.5)。其他的危险因素包括：脊髓损伤、颅脑损伤(GGCS评分≤10)、严重烧伤、菌血症、部分肝切除、肝肾移植、多发外伤(ISS≥16)、酒精滥用、HP感染、ICU>1周、明显潜血≥6 d和大剂量糖皮质激素[12-15]。

2.2 预防SUB的措施

2.2.1 肠内营养 一项比较雷尼替丁和硫糖铝预防SUB的RCT结果显示，肠内营养为预防出血的保护因素(RR=0.30，95%CI：0.13～0.67)[4]。肠内营养可诱导胃黏液分泌，改善黏液血流[16-17]。近年来肠内营养用于预防SUB的地位逐渐上升[18-19]。2010年一项比较H2RA预防SUB的Meta分析显示，使用肠内营养的H2RA组预防用药能降低出血风险，而使用肠内营养的H2RA组则不会降低出血风险[20]。

2.2.2 抑酸药 2014年一项比较抑酸药和安慰剂预防危重患者SUB的Meta分析中(其中实验组为H2RA的20篇，为PPI的仅2篇)，结果显示，使用抑酸药预防SUB有统计学意义(RR=0.44，95%CI：0.28～0.68)，但是实验序贯分析后，无统计学意义(调整后95%CI：0.18～1.11)[21]。由于纳入的均为高偏倚风险的RCT，故此结论有待商榷。

在比较PPI和H2RA预防SUB的RCTs中[22-35]，只有4个RCT将CIB作为主要终点指标，但各研究对CIB的定义不同，且样本量均相对偏小[22,26-28]。Levy等[27]在1997年发表第1个RCT (n=67)，结果显示，奥美拉唑组CIB的发生率(6%)低于雷尼替丁组(31%)。本研究显示，CIB发生率较高，可能是由于雷尼替丁组患者SU的高危因素多于奥美拉唑组(2.7/例 vs.1.9/例，P<0.05)，而高危因素多能增加CIB的发生率。一项外科ICU患者的大样本RCT (n=287)结果显示，奥美拉唑(1%，1/72)、法莫替丁(3%，2/71)、硫糖铝(4%，3/69)或安慰剂 (1%，1/75) 在CIB发生率方面无显著差异(P>0.05)[26]。2005年Conrad等[22]发表多中心、样本量最大(n=359)的RCT，结果显示，奥美拉唑(3.9%，7/178)与西咪替丁(5.5%，10/181)的CIB发生率比较差异无统计学意义。最新一项RCT结果显示，奥美拉唑和雷尼替丁的CIB发生率无显著差异(1.6% vs.5.9%，P<0.05)[28]。而2项大型回顾性队列研究结果均显示，PPI组CIB的发生率高于H2RA组(5.9% vs.2.1%，P<0.05)[36-37]。

多项Meta分析认为，抑酸药预防SUB的疗效优于抗酸药、硫糖铝[42-46]。4个比较PPI和H2RA预防SUB的Meta分析均认为，PPI预防出血效果优于H2RA[38-46]，但由于RCT偏倚风险不同、基线不一致，故不同偏倚风险的RCT合并分析可能导致结果的偏差。2012年一项Meta分析排除偏倚风险高的RCT，结果显示，PPI组与H2RA组在预防SUB方面差异无统计学意义(RR=0.60，95%CI：0.27～1.35，P=0.21)[39]。此外，纳入人群、SUP药物(剂量、途径、频次)、出血定义等因素会影响临床异质性，但并非所有Meta分析均对其进行解释。

3 抑酸药的安全性

3.1 肺炎 胃酸环境可通过杀灭细菌使其不能在胃肠道生长，而抑酸治疗后细菌会在胃肠道过度生长，导致呼吸道感染和肺炎的发生，PPI增加感染的风险还可能与其免疫调节作用有关[47-48]。

目前样本量最大的RCT表明，雷尼替丁组和硫糖铝组肺炎发生率无显著差异[49]。多项比较PPI和H2RA肺炎发生率的临床研究的结果显示，除1项小样本RCT和2项回顾性研究认为PPI肺炎发生率高于H2RA外[50-53]，其他研究均认为二者并无显著性差异[22-23,26,28,30-31]。4项关于抑酸药是否增加肺炎发生风险的系统评价和Meta分析中(其中2个研究抑酸药只涉及PPI并未纳入H2RA)，Lambert等[53-55]Meta分析显示，H2RA与肺炎发生无关，Eom等[56]认为，H2RA与肺炎发生有关，但4项研究均认为PPI与肺炎发生有关(OR=1.04～1.92)。Lambert等进一步分析PPI疗程，结果显示，肺炎发生风险只与初始PPI治疗的第1个月有关(OR=1.11，95%CI：0.90～1.38；OR=2.10，95%CI：1.39～3.16)，反而与药物的剂量和给药频次无关，这似乎与抑酸药导致肺炎的机制相悖。因此，有必要进一步调查或开展前瞻性研究，以明确PPI治疗与肺炎的关系。

3.2 肠道感染 5项Meta分析均认为PPI能增加肠道感染的风险，尤其是难辨梭菌感染(C difficile infections，CID)(OR=1.69～3.33)[57-61]。难辨梭菌是革兰阳性厌氧菌，是腹泻的常见致病菌。多项研究发现，抑酸药(尤其是PPI)是CID的一项危险因素[62-64]。

3.3 血小板减少 关于H2RA导致血小板减少的报道仅限于病例报道和回顾性病例系列研究[65-66]，机制可能与直接抑制骨髓和半抗原的形成有关，但由于半抗原的形成可能需要数天，若使用H2RA后短时间内即出现血小板减少症，则很可能与H2RA无关[67]。

3.4 PPI与慢性肾病 一项最新回顾性研究分析了加拿大退伍军人事务所5年的数据，结果显示，服用PPI的患者比服用H2RA的患者更容易出现肾功能下降，且慢性肾脏疾病的发生风险升高28%[68]。另一项大型队列研究，除了证实上述结论，还提出2次/d较1次/d的风险更高[69]。

此外，也有文献报道PPI和骨折、维生素B12缺乏、癌症风险、痴呆等存在相关性，但由于目前尚无循证等级高的研究，故仍需日后的前瞻性随机对照研究、队列研究等证实这些观点的可靠性。

4 SUP的药物经济学

尽管抑酸药的费用只占到ICU总费用的很小一部分，但是抑酸药的过度预防使用和其可能导致的不良事件强调了经济学评估的重要性。3项研究对比了PPI和H2RA预防SUB的成本效益分析。第1个研究比较不同PPI、法莫替丁和硫糖铝预防SUB的成本-效果，结果显示，肠内奥美拉唑最优(为避免出血每人$12 391)[70]。第2个研究比较PPI和H2RA预防SUB且避免发生肺炎所需成本[71]，PPI最优(为避免并发症每人$58 700 vs. $63 920)。第3个研究结果显示，PPI组和H2RA组死亡率均为3.8%，但使用H2RA预防SUB成本低于PPI($6 707 vs. $7 802)，故H2RA最优[72]。

经济学研究结果不一致的可能原因如下：①终点指标不同，第1项研究为出血，第2项研究为出血、肺炎，第3项研究为死亡、出血、肺炎和CDI。②终点指标(出血、肺炎、CDI)的发生率和其治疗成本不同。例如，第2项研究评估PPI、H2RA的出血率分别为1.3%和6.6%，肺炎的发生率均为10.3%。而第3项研究PPI、H2RA的出血率分别为1.5%和4.1%，肺炎发生率分别为23.5%和19.1%。这两项研究都将肺炎作为影响结果的主要因素，故成本-效益分析主要由肺炎发生风险和其治疗成本决定。

综上所述，危重患者使用抑酸药预防SUB前应先进行风险因素评估。鉴于临床大出血发生率低，临床医生应考量预防SUB用药的必要性、安全性及经济性。

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A systematic review of drugs for stress ulcer prophylaxis

XING Xiao-xuan,BAI Xiang-rong,CHU Yan-qi,YAN Su-ying*

(Department of Pharmacy,Xuanwu Hospital of Capital Medical University,Beijing 100053,China)

Objective To review the incidence and risk factors of stress ulcer bleeding (SUB),and the effectiveness,safety and cost of the prophylaxis ,and provide a basis for the clinical rational development of SUB prophylaxis.Methods The clinical studies and systematic reviews were searched by Medline,Embase,Cochrane (Central),CNKI,CBM,VIP and Wanfang database with the key words of “stress ulcer prophylaxis”,“bleeding”,“risk factor” and “cost”,and the relevant data was extracted and summarized.Results Enteral nutrition was a protective factor for SUB.The conclusions of SUB between proton pump inhibitors (PPI) and histamine-2-receptor antagonist (H2RA) were not consistent.The results of 3 high-quality RCT all showed that PPI in the prevention of important clinical bleeding was not superior to H2RA,and the two retrospective cohort study results showed that the frequency of important clinical bleeding was higher than H2RA.Four systematic reviews showed a relation between pneumonia and PPI use (OR=1.04～1.92).Five Meta analysis reported a significant increased risk of enteric infections with PPI use,specifically the clostridium difficile (OR=1.69～3.33).There were three studies comparing the cost-effectiveness of PPI and H2RA.The most cost-effective profile was enteral omeprazole in preventing SUB,and PPI was best in preventing SUB and complications.The cost of H2RA in preventing SUB was lower than PPI.Conclusion SUB prophylaxis should be used after assessing the risk factors of the critically ill patients.In view of the low incidence of important clinical bleeding,clinicians should weigh the necessity,safety and economy of drugs in stress ulcer prophylaxis

Stress ulcer prophylaxis;Bleeding;Proton pump inhibitor;Cost-effectiveness

2016-08-17

首都医科大学宣武医院药剂科，北京 100053

*通信作者

10.14053/j.cnki.ppcr.201704029