藥物預(yù)防應(yīng)激性潰瘍的系統(tǒng)綜述

邢曉璇，白向榮，褚燕琦，閆素英

藥物預(yù)防應(yīng)激性潰瘍的系統(tǒng)綜述

邢曉璇，白向榮，褚燕琦，閆素英*

目的 綜述應(yīng)激性潰瘍出血(Stress ulcer bleeding，SUB)的發(fā)生率、危險因素和預(yù)防方案的有效性、安全性和經(jīng)濟性，為臨床合理制定SUB預(yù)防方案提供依據(jù)。方法 以“預(yù)防應(yīng)激性潰瘍”、“出血”、“危險因素”、“成本”、“stress ulcer prophylaxis”、“bleeding”、“risk factor”、“cost”為關(guān)鍵詞，計算機檢索MEDLINE、EMbase、Cochrane (Central)、CNKI、CBM、VIP、Wanfang，提取總結(jié)相關(guān)數(shù)據(jù)。結(jié)果 腸內(nèi)營養(yǎng)是SUB的保護因素。PPI和H2RA關(guān)于預(yù)防SUB療效的研究結(jié)論并不一致。3項RCT研究結(jié)果均顯示，在預(yù)防臨床大出血方面，PPI并非優(yōu)于H2RA。同時，2項回顧性研究表明，PPI在預(yù)防臨床大出血方面不如H2RA。4項Meta分析均認(rèn)為，PPI與肺炎發(fā)生有關(guān)(OR：1.04～1.92)。5項Meta分析均認(rèn)為，PPI能增加腸道感染的風(fēng)險，尤其是難辨梭菌感染(OR：1.69～3.33)。3項研究對比了PPI和H2RA預(yù)防SUB的成本-效益分析。結(jié)果顯示，在預(yù)防SUB時，腸內(nèi)奧美拉唑最優(yōu)；在預(yù)防SUB和并發(fā)癥時，PPI最優(yōu)；在PPI組和H2RA組死亡率相同時，H2RA預(yù)防SUB成本低于PPI。結(jié)論 危重患者使用抑酸藥預(yù)防SUB前應(yīng)先進行風(fēng)險因素評估。鑒于臨床大出血發(fā)生率低，臨床醫(yī)生應(yīng)考量預(yù)防SUB用藥的必要性、安全性及經(jīng)濟性。

預(yù)防應(yīng)激性潰瘍；出血；質(zhì)子泵抑制劑；成本-效益

0 引言

應(yīng)激性潰瘍(Stress ulcer，SU)一般是指嚴(yán)重創(chuàng)傷、感染、休克等應(yīng)激情況下繼發(fā)的胃十二指腸等黏膜發(fā)生糜爛、潰瘍，嚴(yán)重者可導(dǎo)致應(yīng)激性潰瘍出血(Stress ulcer bleeding，SUB)，多發(fā)生于重癥監(jiān)護室患者中[1]。ICU患者SU發(fā)生率為75%～100%，胃潛血的發(fā)生率為5%～25%[2]，而臨床大出血(Clinical important bleeding，CIB)發(fā)生率非常低。2015年1項最新研究顯示，CIB的發(fā)生率僅為2.6%[3]。因不能排除ICU中的消化道出血患者在入住ICU前是否已有胃腸道疾病，故真實CIB發(fā)生率可能會更低。

抑酸藥包括PPI和H2RA，預(yù)防SUB應(yīng)維持胃內(nèi)pH>4，而PPI抑制胃酸能力優(yōu)于H2RA，故PPI使用量逐年上升。2013年一項研究表明，70%的ICU患者都使用PPI，而2002年和1998年分別為23%和3%[4-6]。最新一項多國多中心研究顯示，66% (64/97)的ICU將PPI作為首選藥，其他ICU將H2RA作為首選藥[7]。抑酸藥(尤其是PPI)長期應(yīng)用可能增加肺炎、難辨梭菌感染、低鎂血癥等并發(fā)癥的風(fēng)險[8-10]。考慮到臨床大出血發(fā)生率低，本文將分別討論SUB的發(fā)生率、危險因素，以及預(yù)防SUB用藥的必要性、安全性及經(jīng)濟性，為臨床合理預(yù)防SUB提供理論依據(jù)。

1 資料與方法

1.1 文獻(xiàn)檢索 由2名研究員獨立檢索國內(nèi)外研究。以“應(yīng)激性潰瘍預(yù)防”、“出血”、“危險因素”、“成本”、“stress ulcer prophylaxis”、“bleeding”、“risk factor”、“cost”為關(guān)鍵詞，計算機檢索Cochrane圖書館臨床對照試驗數(shù)據(jù)庫、MEDLINE光盤數(shù)據(jù)庫、EMbase光盤數(shù)據(jù)庫、Cochrane (Central)數(shù)據(jù)庫、中國知網(wǎng)中國期刊全文數(shù)據(jù)庫(CNKI)、中國生物醫(yī)學(xué)文獻(xiàn)數(shù)據(jù)庫(CBM)、中國科技期刊全文數(shù)據(jù)庫(VIP)、萬方數(shù)字化期刊全文數(shù)據(jù)庫(Wanfang Data)，檢索時限均為建庫至2016年4月。

1.2 文獻(xiàn)篩選與資料提取 研究篩選檢索收集的文獻(xiàn)，納入所有與SUP相關(guān)的原始研究、系統(tǒng)評價和臨床指南。閱讀全文后提取總結(jié)相關(guān)數(shù)據(jù)。

2 結(jié)果

2.1 CIB的高危因素 危重患者因生理應(yīng)激導(dǎo)致黏膜防御機制破壞和黏膜缺血，發(fā)生應(yīng)激性潰瘍，并有出現(xiàn)CIB的風(fēng)險[11]。一項多中心前瞻性研究顯示，機械通氣(>48 h)和凝血障礙是CIB的獨立高危因素。近期一項多國家多中心研究共評估1 034例ICU發(fā)生CIB的危險因素[7]，結(jié)果顯示，以下因素與CIB相關(guān)(用OR、95%CI表示)：至少3個合并癥(8.9，2.7～28.8)，肝功能不全(7.6，3.3～17.6)，腎臟替代治療(6.9，2.7～17.5)，合并凝血障礙 (4.2，1.7～10.2)，器官衰竭評分高 (1.4，1.2～1.5)。其他的危險因素包括：脊髓損傷、顱腦損傷(GGCS評分≤10)、嚴(yán)重?zé)齻?、菌血癥、部分肝切除、肝腎移植、多發(fā)外傷(ISS≥16)、酒精濫用、HP感染、ICU>1周、明顯潛血≥6 d和大劑量糖皮質(zhì)激素[12-15]。

2.2 預(yù)防SUB的措施

2.2.1 腸內(nèi)營養(yǎng) 一項比較雷尼替丁和硫糖鋁預(yù)防SUB的RCT結(jié)果顯示，腸內(nèi)營養(yǎng)為預(yù)防出血的保護因素(RR=0.30，95%CI：0.13～0.67)[4]。腸內(nèi)營養(yǎng)可誘導(dǎo)胃黏液分泌，改善黏液血流[16-17]。近年來腸內(nèi)營養(yǎng)用于預(yù)防SUB的地位逐漸上升[18-19]。2010年一項比較H2RA預(yù)防SUB的Meta分析顯示，使用腸內(nèi)營養(yǎng)的H2RA組預(yù)防用藥能降低出血風(fēng)險，而使用腸內(nèi)營養(yǎng)的H2RA組則不會降低出血風(fēng)險[20]。

2.2.2 抑酸藥 2014年一項比較抑酸藥和安慰劑預(yù)防危重患者SUB的Meta分析中(其中實驗組為H2RA的20篇，為PPI的僅2篇)，結(jié)果顯示，使用抑酸藥預(yù)防SUB有統(tǒng)計學(xué)意義(RR=0.44，95%CI：0.28～0.68)，但是實驗序貫分析后，無統(tǒng)計學(xué)意義(調(diào)整后95%CI：0.18～1.11)[21]。由于納入的均為高偏倚風(fēng)險的RCT，故此結(jié)論有待商榷。

在比較PPI和H2RA預(yù)防SUB的RCTs中[22-35]，只有4個RCT將CIB作為主要終點指標(biāo)，但各研究對CIB的定義不同，且樣本量均相對偏小[22,26-28]。Levy等[27]在1997年發(fā)表第1個RCT (n=67)，結(jié)果顯示，奧美拉唑組CIB的發(fā)生率(6%)低于雷尼替丁組(31%)。本研究顯示，CIB發(fā)生率較高，可能是由于雷尼替丁組患者SU的高危因素多于奧美拉唑組(2.7/例 vs.1.9/例，P<0.05)，而高危因素多能增加CIB的發(fā)生率。一項外科ICU患者的大樣本RCT (n=287)結(jié)果顯示，奧美拉唑(1%，1/72)、法莫替丁(3%，2/71)、硫糖鋁(4%，3/69)或安慰劑 (1%，1/75) 在CIB發(fā)生率方面無顯著差異(P>0.05)[26]。2005年Conrad等[22]發(fā)表多中心、樣本量最大(n=359)的RCT，結(jié)果顯示，奧美拉唑(3.9%，7/178)與西咪替丁(5.5%，10/181)的CIB發(fā)生率比較差異無統(tǒng)計學(xué)意義。最新一項RCT結(jié)果顯示，奧美拉唑和雷尼替丁的CIB發(fā)生率無顯著差異(1.6% vs.5.9%，P<0.05)[28]。而2項大型回顧性隊列研究結(jié)果均顯示，PPI組CIB的發(fā)生率高于H2RA組(5.9% vs.2.1%，P<0.05)[36-37]。

多項Meta分析認(rèn)為，抑酸藥預(yù)防SUB的療效優(yōu)于抗酸藥、硫糖鋁[42-46]。4個比較PPI和H2RA預(yù)防SUB的Meta分析均認(rèn)為，PPI預(yù)防出血效果優(yōu)于H2RA[38-46]，但由于RCT偏倚風(fēng)險不同、基線不一致，故不同偏倚風(fēng)險的RCT合并分析可能導(dǎo)致結(jié)果的偏差。2012年一項Meta分析排除偏倚風(fēng)險高的RCT，結(jié)果顯示，PPI組與H2RA組在預(yù)防SUB方面差異無統(tǒng)計學(xué)意義(RR=0.60，95%CI：0.27～1.35，P=0.21)[39]。此外，納入人群、SUP藥物(劑量、途徑、頻次)、出血定義等因素會影響臨床異質(zhì)性，但并非所有Meta分析均對其進行解釋。

3 抑酸藥的安全性

3.1 肺炎 胃酸環(huán)境可通過殺滅細(xì)菌使其不能在胃腸道生長，而抑酸治療后細(xì)菌會在胃腸道過度生長，導(dǎo)致呼吸道感染和肺炎的發(fā)生，PPI增加感染的風(fēng)險還可能與其免疫調(diào)節(jié)作用有關(guān)[47-48]。

目前樣本量最大的RCT表明，雷尼替丁組和硫糖鋁組肺炎發(fā)生率無顯著差異[49]。多項比較PPI和H2RA肺炎發(fā)生率的臨床研究的結(jié)果顯示，除1項小樣本RCT和2項回顧性研究認(rèn)為PPI肺炎發(fā)生率高于H2RA外[50-53]，其他研究均認(rèn)為二者并無顯著性差異[22-23,26,28,30-31]。4項關(guān)于抑酸藥是否增加肺炎發(fā)生風(fēng)險的系統(tǒng)評價和Meta分析中(其中2個研究抑酸藥只涉及PPI并未納入H2RA)，Lambert等[53-55]Meta分析顯示，H2RA與肺炎發(fā)生無關(guān)，Eom等[56]認(rèn)為，H2RA與肺炎發(fā)生有關(guān)，但4項研究均認(rèn)為PPI與肺炎發(fā)生有關(guān)(OR=1.04～1.92)。Lambert等進一步分析PPI療程，結(jié)果顯示，肺炎發(fā)生風(fēng)險只與初始PPI治療的第1個月有關(guān)(OR=1.11，95%CI：0.90～1.38；OR=2.10，95%CI：1.39～3.16)，反而與藥物的劑量和給藥頻次無關(guān)，這似乎與抑酸藥導(dǎo)致肺炎的機制相悖。因此，有必要進一步調(diào)查或開展前瞻性研究，以明確PPI治療與肺炎的關(guān)系。

3.2 腸道感染 5項Meta分析均認(rèn)為PPI能增加腸道感染的風(fēng)險，尤其是難辨梭菌感染(C difficile infections，CID)(OR=1.69～3.33)[57-61]。難辨梭菌是革蘭陽性厭氧菌，是腹瀉的常見致病菌。多項研究發(fā)現(xiàn)，抑酸藥(尤其是PPI)是CID的一項危險因素[62-64]。

3.3 血小板減少 關(guān)于H2RA導(dǎo)致血小板減少的報道僅限于病例報道和回顧性病例系列研究[65-66]，機制可能與直接抑制骨髓和半抗原的形成有關(guān)，但由于半抗原的形成可能需要數(shù)天，若使用H2RA后短時間內(nèi)即出現(xiàn)血小板減少癥，則很可能與H2RA無關(guān)[67]。

3.4 PPI與慢性腎病 一項最新回顧性研究分析了加拿大退伍軍人事務(wù)所5年的數(shù)據(jù)，結(jié)果顯示，服用PPI的患者比服用H2RA的患者更容易出現(xiàn)腎功能下降，且慢性腎臟疾病的發(fā)生風(fēng)險升高28%[68]。另一項大型隊列研究，除了證實上述結(jié)論，還提出2次/d較1次/d的風(fēng)險更高[69]。

此外，也有文獻(xiàn)報道PPI和骨折、維生素B12缺乏、癌癥風(fēng)險、癡呆等存在相關(guān)性，但由于目前尚無循證等級高的研究，故仍需日后的前瞻性隨機對照研究、隊列研究等證實這些觀點的可靠性。

4 SUP的藥物經(jīng)濟學(xué)

盡管抑酸藥的費用只占到ICU總費用的很小一部分，但是抑酸藥的過度預(yù)防使用和其可能導(dǎo)致的不良事件強調(diào)了經(jīng)濟學(xué)評估的重要性。3項研究對比了PPI和H2RA預(yù)防SUB的成本效益分析。第1個研究比較不同PPI、法莫替丁和硫糖鋁預(yù)防SUB的成本-效果，結(jié)果顯示，腸內(nèi)奧美拉唑最優(yōu)(為避免出血每人$12 391)[70]。第2個研究比較PPI和H2RA預(yù)防SUB且避免發(fā)生肺炎所需成本[71]，PPI最優(yōu)(為避免并發(fā)癥每人$58 700 vs. $63 920)。第3個研究結(jié)果顯示，PPI組和H2RA組死亡率均為3.8%，但使用H2RA預(yù)防SUB成本低于PPI($6 707 vs. $7 802)，故H2RA最優(yōu)[72]。

經(jīng)濟學(xué)研究結(jié)果不一致的可能原因如下：①終點指標(biāo)不同，第1項研究為出血，第2項研究為出血、肺炎，第3項研究為死亡、出血、肺炎和CDI。②終點指標(biāo)(出血、肺炎、CDI)的發(fā)生率和其治療成本不同。例如，第2項研究評估PPI、H2RA的出血率分別為1.3%和6.6%，肺炎的發(fā)生率均為10.3%。而第3項研究PPI、H2RA的出血率分別為1.5%和4.1%，肺炎發(fā)生率分別為23.5%和19.1%。這兩項研究都將肺炎作為影響結(jié)果的主要因素，故成本-效益分析主要由肺炎發(fā)生風(fēng)險和其治療成本決定。

綜上所述，危重患者使用抑酸藥預(yù)防SUB前應(yīng)先進行風(fēng)險因素評估。鑒于臨床大出血發(fā)生率低，臨床醫(yī)生應(yīng)考量預(yù)防SUB用藥的必要性、安全性及經(jīng)濟性。

[1] 林金鋒.應(yīng)激性潰瘍預(yù)防性治療的研究進展[J].中國急救醫(yī)學(xué),2014,34(5):468-472.

[2] Alhazzani W,Alshahrani M,Moayyedi P,et al.Stress ulcer prophylaxis in critically ill patients:review of the evidence[J].Pol Arch Med Wewn,2012,122(3):107-114.

[3] Krag M,Perner A,Wetterslev J,et al.Prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients[J].Intensive Care Med,2015,41(5):833-845.

[4] Barletta JF,Kanji S,MacLaren R,et al.Pharmacoepidemiology of stress ulcer prophylaxis in the United States and Canada[J].J Crit Care,2014,29(6):955-960.

[5] Daley RJ,Rebuck JA,Welage LS,et al.Prevention of stress ulceration:current trends in critical care[J].Crit Care Med,2004,32(10):2008-2013.

[6] Erstad BL,Barletta JF,Jacobi J,et al.Survey of stress ulcer prophylaxis[J].Crit Care,1999,3(6):145-149.

[7] Krag M,Perner A,Wetterslev J,et al.Stress ulcer prophylaxis in the intensive care unit:an international survey of 97 units in 11 countries[J].Acta Anaesthesiol Scand,2015,59(5):576-585.

[8] Barletta JF,El-Ibiary SY,Davis LE,et al.Proton pump inhibitors and the risk for hospital-acquired clostridium difficile infection[J].Mayo Clin Proc,2013,88(10):1085-1090.

[9] Barletta JF,Sclar DA.Proton pump inhibitors increase the risk for hospital-acquired Clostridium difficile infection in critically ill patients[J].Crit Care,2014,18(6):714.

[10]朱珠,蔡樂.質(zhì)子泵抑制劑的安全性與合理應(yīng)用[J].藥物不良反應(yīng)雜志,2005,7(2):81-90.

[11]MacLaren R.A review of stress ulcer prophylaxis[J].J Pharm Pract,2002,15:147-157.

[12]ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis.ASHP commission on therapeutics and approved by the ASHP Board of Directors on November 14,1998[J].Am J Health Syst Pharm,1999,56(4):347-379.

[13]Ellison RT,Perez-Perez G,Welsh CH,et al.Risk factors for upper gastrointestinal bleeding in intensive care unit patients:role of helicobacter pylori.Federal Hyperimmune Immunoglobulin Therapy Study Group[J].Crit Care Med,1996,24(12):1974-1981.

[14]Guillamondegui OD,Gunter OL,Bonadies JA,et al.Practice management guidelines for stress ulcer prophylaxis,2008.https://www.east.org.[2015-8-25]

[15]Cook D,Heyland D,Griffith L,et al.Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical ventilation.Canadian Critical Care Trials Group[J].Crit Care Med,1999,27(12):2812-2817.

[16]Kles KA,Wellig MA,Tappenden KA.Luminal nutrient sex acerbate intestinal hypoxia in the hypoperfused jejunum[J].JPEN J Parenter Enteral Nutr,2001,25(5):246-253.

[17]Smith JS,Karlstadt R,Blatcher,et al.Gastric pH from NPO to enteral-fed period with intermittent intravenous (IV) pantoprazole (P) vs continuously infused cimetidine (C)[J].Am J Gastroenterol,2002,97:S47.

[18]Hurt RT,Frazier TH,McClave SA,et al.Stress prophylaxis in intensive care unit patients and the role of enteral nutrition[J].J Parenter Enteral Nutr,2012,36(6):721-731.

[19]Marik PE.Stress ulcer prophylaxis in the new millennium[J].ICU Director,2010,1:12-16.

[20]Marik PE,Vasu T,Hirani A,et al.Stress ulcer prophylaxis in the new millennium:a systematic review and meta-analysis[J].Crit Care Med,2010,38(11):2222-2228.

[21]Krag M,Perner A,Wetterslev J,et al.Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients.A systematic review of randomized clinical trials with meta-analysis and trial sequential analysis[J].Intensive Care Med,2014,40(1):11-22.

[22]Conrad SA,Gabrielli A,Margolis B,et al.Randomized,double-blind comparison of immediate-release omeprazole oral suspension versus intravenous cimetidine for the prevention of upper gastrointestinal bleeding in critically ill patients[J].Crit Care Med,2005,33(4):760-765.

[23]Azevedo J,Soares M,Silva G.Prevention of stress ulcer bleeding in high risk patients.Comparison of three drugs[J].Gastrenterol Endosc Dig,2000,19:239-244.

[24]Bashar FR,Manuchehrian N,Mahmoudabadi M,et al.Effects of ranitidine and pantoprazole on ventilator-associated pneumonia:a randomized double-blind clinical trial[J].Tanaffos,2013,12(2):16-21.

[25]Brophy GM,Brackbill ML,Bidwell KL,et al.Prospective,randomized comparison of lansoprazole suspension,and intermittent intravenous famotidine on gastric pH and acid production in critically ill neurosurgical patients[J].Neurocrit Care,2010,13(2):176-181.

[26]Kantorova I,Svoboda P,Scheer P,et al.Stress ulcer prophylaxis in critically ill patients:a randomized controlled trial[J].Hepatogastroenterology,2004,51(57):757-761.

[27]Levy MJ,Seelig CB,Robinson NJ,et al.Comparison of omeprazole and ranitidine for stress ulcer prophylaxis[J].Dig Dis Sci,1997,42(6):1255-1259.

[28]Solouki M,Marashian S,Kouchak M.Comparison between the preventive effects of ranitidine and omeprazole on upper gastrointestinal bleeding among ICU patients[J].Tanaffos,2009,8:37-42.

[29]Hata M,Shiono M,Sekino H,et al.Prospective randomized trial for optimal prophylactic treatment of the upper gastrointestinal complications after open heart surgery[J].Circ J,2005,69(3):331-334.

[30]Lee TH,Hung FM,Yang LH.Comparison of the efficacy of esomeprazole and famotidine against stress ulcers in a neurosurgical intensive care unit[J].Adv Dig Med,2014,1:50-53.

[31]Liu BL,Li B,Zhang X,et al.A randomized controlled study comparing omeprazole and cimetidine for the prophylaxis of stress-related upper gastrointestinal bleeding in patients with intracerebral hemorrhage[J].J Neurosurg,2013,118(1):115-120.

[32]Pan X,Xhang W,Li Z.The preventive effects of rabeprazole on upper gastrointestinal tract hemorrhage in patients with severe acute pancreatitis[J].Chin J Gastroenterol,2004,9:30-32.

[33]Powell H,Morgan M,Li S.Inhibition of gastric acid secretion in the intensive care unit after coronary artery bypass graft[J].Theor Surg,1993,8:125-130.

[34]Solouki M,Mar′ashian SM,Koochak M,et al.Ventilator-associated pneumonia among ICU patients receiving mechanical ventilation and prophylaxis of gastrointestinal bleeding[J].Iran J Clin Infect Dis,2009,4:177-180.

[35]Somberg L,Morris J,Fantus R,et al.Intermittent intravenous pantoprazole and continuous cimetidine infusion:effect on gastric pH control in critically ill patients at risk of developing stress-related mucosal disease[J].J Trauma,2008,64(5):1202-1210.

[36]Krag M,Perner A,Wetterslev J,et al.Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients.A systematic review of randomised clinical trials with meta-analysis and trial sequential analysis[J].Intensive Care Med,2014,40(1):11-22.

[37]MacLaren R,Reynolds PM,Allen RR.Histamine-2 receptor antagonists vs proton pump inhibitors on gastrointestinal tract hemorrhage and infectious complications in the intensive care unit[J].JAMA Intern Med,2014,174(4):564-574.

[38]Alhazzani W,Alenezi F,Jaeschke RZ,et al.Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients:a systematic review and meta-analysis[J].Crit Care Med,2013,41(3):693-705.

[39]Barkun AN,Bardou M,Pham CQ,et al.Proton pump inhibitors vs.histamine 2 receptor antagonists for stress-related mucosal bleeding prophylaxis in critically ill patients:a meta-analysis[J].Am J Gastroenterol,2012,107(4):507-520,quiz 521.

[40]Lin PC,Chang CH,Hsu PI,et al.The efficacy and safety of proton pump inhibitors vs histamine-2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients:a meta-analysis[J].Crit Care Med,2010,38(4):1197-1205.

[41]Pongprasobchai S,Kridkratoke S,Nopmaneejumruslers C.Proton pump inhibitors for the prevention of stress-related mucosal disease in critically-ill patients:a meta-analysis[J].J Med Assoc Thai,2009,92(5):632-637.

[42]Lacroix J,Infante-Rivard C,Jenicek M,et al.Prophylaxis of upper gastrointestinal bleeding in intensive care units:a meta-analysis[J].Crit Care Med,1989,17(9):862-869.

[43]Cook DJ,Witt LG,Cook RJ,et al.Stress ulcer prophylaxis in the critically ill:a meta-analysis[J].Am J Med,1991,91(5):519-527.

[44]Cook DJ,Reeve BK,Scholes LC.Histamine-2-receptor antagonists and antacids in the critically ill population:stress ulceration versus nosocomial pneumonia[J].Infect Control Hosp Epidemiol,1994,15(7):437-442.

[45]Cook DJ,Reeve BK,Guyatt GH,et al.Stress ulcer prophylaxis in critically ill patients:resolving discordant meta-analyses[J].JAMA,1996,275(4):308-314.

[46]Tryba M.Sucralfate versus antacids or H2-antagonists for stress ulcer prophylaxis:a meta-analysis on efficacy and pneumonia rate[J].Crit Care Med,1991,19(7):942-949.

[47]Yoshida N,Yoshikawa T,Tanaka Y,et al.A new mechanism for anti-inflammatory actions of proton pump inhibitors--inhibitory effects on neutrophil-endothelial cell interactions[J].Aliment Pharmacol Ther,2000,14(Suppl 1):74-81.

[48]Zedtwitz-Liebenstein K,Wenisch C,Patruta S,et al.Omeprazole treatment diminishes intra-and extracellular neutrophil reactive oxygen production and bactericidal activity[J].Crit Care Med,2002,30(5):1118-1122.

[49]Cook D,Guyatt G,Marshall J,et al.A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation.Canadian Critical Care Trials Group[J].N Engl J Med,1998,338(12):791-797.

[50]Bashar FR,Manuchehrian N,Mahmoudabadi M,et al.Effects of ranitidine and pantoprazole on ventilator-associated pneumonia:a randomized double-blind clinical trial[J].Tanaffos,2013,12(2):16-21.

[51]Bateman BT,Bykov K,Choudhry NK,et al.Type of stress ulcer prophylaxis and risk of nosocomial pneumonia in cardiac surgical patients:cohort study[J].BMJ,2013,347:f5416.

[52]Herzig SJ,Howell MD,Ngo LH,et al.Acid-suppressive medication use and the risk for hospital-acquired pneumonia[J].JAMA,2009,301(20):2120-2128.

[53]Lambert AA,Lam JO,Paik JJ,et al.Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy:a systematic review and meta-analysis[J].PLoS One,2015,10(6):e0128004.

[54]Johnstone J,Nerenberg K,Loeb M.Meta-analysis:proton pump inhibitor use and the risk of community-acquired pneumonia[J].Aliment Pharmacol Ther,2010,31(11):1165-1177.

[55]Giuliano C,Wilhelm SM,Kale-Pradhan PB.Are proton pump inhibitors associated with the development of community-acquired pneumonia?A meta-analysis[J].Expert Rev Clin Pharmacol,2012,5(3):337-344.

[56]Eom CS,Jeon CY,Lim JW,et al.Use of acid-suppressive drugs and risk of pneumonia:a systematic review and meta-analysis[J].CMAJ,2011,183(3):310-319.

[57]Kwok CS,Yeong JK,Loke YK.Meta-analysis:risk of fractures with acid-suppressing medication[J].Bone,2011,48(4):768-776.

[58]Shukla S,Shukla A,Guha S,et al.Use of proton pump inhibitors and risk of Clostridium difficile-associated diarrhea:a meta-analysis[J].Gastroenterology,2010,138(5):S-209.

[59]Janarthanan S,Ditah I,Adler DG,et al.Clostridium difficile-associated diarrhea and proton pump inhibitor therapy:a meta-analysis[J].Am J Gastroenterol,2012,107(7):1001-1010.

[60]Deshpande A,Pant C,Pasupuleti V,et al.Association between proton pump inhibitor therapy and Clostridium difficile infection in a meta-analysis[J].Clin Gastroenterol Hepatol,2012,10(3):225-233.

[61]Leonard J,Marshall JK,Moayyedi P.Systematic review of the risk of enteric infection in patients taking acid suppression[J].Am J Gastroenterol,2007,102(9):2047-2056,quiz 2057.

[62]MacLaren R,Reynolds PM,Allen RR.Histamine-2 receptor antagonists vs proton pump inhibitors on gastrointestinal tract hemorrhage and infectious complications in the intensive care unit[J].JAMA Intern Med,2014,174(4):564-574.

[63]Buendgens L,Bruensing J,Matthes M,et al.Administration of proton pump inhibitors in critically ill medical patients is associated with increased risk of developing Clostridium difficile-associated diarrhea[J].J Crit Care,2014,29(4):696.e11-e15.

[64]Barletta JF,Sclar DA.Proton pump inhibitors increase the risk for hospital-acquired Clostridium difficile infection in critically ill patients[J].Crit Care,2014,18(6):714.

[65]Papadopoulos J,Cooper B,Kane-Gill S,et al.Drug-induced complications in the critically ill patient:a guide for recognition and treatment[M].Mount Prospect:Society of Critical Care Medicine,2012:295-328.

[66]Wade EE,Rebuck JA,Healey MA,et al.H(2) antagonist-induced thrombocytopenia:is this a real phenomenon[J].Intensive Care Med,2002,28(4):459-465.

[67]MacLaren R,Kassel LE,Kiser TH,et al.Proton pump inhibitors and histamine-2 receptor antagonists in the intensive care setting:focus on therapeutic and adverse events[J].Expert Opin Drug Saf,2015,14(2):269-280.

[68]Arora P,Gupta A,Golzy M,et al.Proton pump inhibitors are associated with increased risk of development of chronic kidney disease[J].BMC Nephrol,2016,17(1):112.

[69]Fusaro M,Noale M,Tripepi G,et al.Long-term proton pump inhibitor use is associated with vascular calcification in chronic kidney disease:a cross-sectional study using propensity score analysis[J].Drug Saf,2013,36(8):635-642.

[70]Udeh BL,Udeh C,MBBS,et al.Cost-effectiveness of stress ulcer prophylaxis:role of proton pump inhibitors[J].Am J Manag Care,2010,(2):304-312.

[71]Barkun AN,Adam V,Martel M,et al.Cost-effectiveness analysis:stress ulcer bleeding prophylaxis with proton pump inhibitors,H2 receptor antagonists[J].Value Health,2013,16(1):14-22.

[72]MacLaren R,Campbell J.Cost-effectiveness of histamine receptor-2 antagonist versus proton pump inhibitor for stress ulcer prophylaxis in critically ill patients[J].Crit Care Med,2014,42(4):809-815.

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

首都醫(yī)科大學(xué)宣武醫(yī)院藥劑科，北京 100053

*通信作者

10.14053/j.cnki.ppcr.201704029