肝硬化合併腹水的病人使用氫離子幫浦阻斷劑發生自發性細菌性腹膜炎的風險

The Risk of Spontaneous Bacterial Peritonitis Caused by Proton Pump Inhibitors in Cirrhotic Patients with Ascites

李冠廷(Kuan-Ting Lee)

指導教授 ： 張榮叁

高雄醫學大學/藥學院/臨床藥學研究所/碩士(2013年)

摘要

背景及目的：
在肝硬化合併腹水的病人中，自發性細菌性腹膜炎是很常見且具高死亡率的併發症。文獻記載氫離子幫浦阻斷劑可能會造成腸道內細菌的過度生長及轉位，進而增加自發性細菌性腹膜炎的風險，但未有確切的結論。本研究目的為探討肝硬化合併腹水的病人使用氫離子幫浦阻斷劑是否會增加自發性細菌性腹膜炎的風險。

方法：
（1） 系統性回顧及統合分析：本研究以系統性的方式搜尋PubMed、MEDLINE、Cochrane Library、Web of Science、相關文章的參考文獻以及主要的胃腸科學會摘要。在沒有語言限制下，以關鍵字（包含氫離子幫浦阻斷劑、肝硬化及自發性細菌性腹膜炎等）進行搜尋。收納文章的品質，分別以Carter’s評分系統及Newcastle-Ottawa Scale （NOS）評分系統來評估。最後使用隨機效應模式（random effects model）執行統合分析。
（2） 世代研究：利用「2000年全民健康保險承保抽樣歸人檔」執行一個以族群為基礎的全國性世代研究。本研究收納2001年到2009年間的肝硬化新診斷腹水的病人，一共1,837位。每位病人的追蹤時間以28天為單位分段處理，只要有接受1次氫離子幫浦阻斷劑處方即被定義為氫離子幫浦阻斷劑使用者，並以疾病診斷碼及處置碼定義自發性細菌性腹膜炎。以Time-varying的Cox廻歸分析計算病人得到自發性細菌性腹膜炎的風險比（hazard ratios，HRs）。

結果：
（1）系統性回顧及統合分析：經篩選後獲得3篇世代研究及6篇病例對照研究，一共4,804人納入統合分析，結果顯示，使用氫離子幫浦阻斷劑和自發性細菌性腹膜炎有顯著相關（OR=2.53, 95% CI: 1.35-4.75），但是異質性很高（I2=90%）。在高研究品質的次族群分析中，氫離子幫浦阻斷劑和自發性細菌性腹膜炎仍然有顯著相關，而且異質性也下降（I2=27%）。我們使用3種方法去評估出版偏差（publication bias），但結果並沒有一致性。
（2）世代研究：在多變項分析中，使用氫離子幫浦阻斷劑，每處方7個DDDs（defined daily doses）會顯著增加自發性細菌性腹膜炎的風險（HR=1.168, 95% CI: 1.131-1.207），另外，胃腸道出血7天內（HR=1.861, 95% CI: 1.131-3.063）及8-14天內（HR=5.747, 95% CI: 2.391-13.809），以及內視鏡檢查7天內（HR=8.251, 95% CI: 5.733-11.873)皆為自發性細菌性腹膜炎的獨立危險因子。

結論：
肝硬化合併腹水的病人，在使用氫離子幫浦阻斷劑、或於14天內發生胃腸道出血或於7天內進行內視鏡檢查等事件，皆會顯著地增加自發性細菌性腹膜炎的風險。

關鍵字

肝硬化 ； 腹水 ； 氫離子幫浦阻斷劑 ； 自發性細菌性腹膜炎

並列摘要

BACKGROUND and AIM:
Spontaneous bacterial peritonitis (SBP) is a frequent and serious complication of cirrhotic patients with ascites. Proton pump inhibitors (PPIs) may cause intestinal bacterial overgrowth and translocation, therefore, increase the risk of developing SBP. The aim of the study was to determine whether PPIs use would increase the risk of SBP in cirrhotic patients with ascites.

METHODS:
(1) Systematic review and meta-analysis of observational studies: We systematically searched related articles in PubMed, MEDLINE, Cochrane Library, Web of Science, in their references lists, and abstracts in major gastroenterology meetings with the key words of PPIs, liver cirrhosis, and SBP. There was no language restriction. Two scoring systems, i.e., Carter’s scoring system and Newcastle-Ottawa Scale (NOS), were used to assess the quality of included studies. Random effects model was used for meta-analysis.
(2) Population-based cohort study: We conducted a nationwide, population-based cohort study based on the data of Taiwan Longitudinal Health Insurance Database 2000 (LHID2000). Study cohort consisted of all cirrhotic patients with ascites from 2001 to 2009. Overall, there were 1,837 patients identified. Patients who had been prescribed at least one dose of PPIs would be defined as PPI-user during a 28-day window. SBP was confirmed by both ICD-9-CM code and procedure code. Time-varying Cox models were used to estimate adjusted HR of SBP.

RESULTS:
(1) Systematic review and meta-analysis of observational studies: The pooled analysis of 3 retrospective cohort studies and 6 case-control studies, totally including 4,804 patients, found a significant association between PPIs use and the development of SBP (OR=2.53, 95% CI: 1.35-4.75). The heterogeneity was high (I2=90%). In the subgroup analysis of high quality studies, the result also showed a significant association, and the heterogeneity became lower (I2=27%). Three methods were applied to evaluate the publication bias, but the results were not consistent.
(2) Population-based cohort study: On the multivariate analysis, cirrhotic patients with ascites who had PPIs use (per 7 defined daily doses, DDDs) had a higher risk of developing SBP (HR=1.168, 95% CI: 1.131-1.207). Besides, GI bleeding with 7 days (HR=1.861, 95% CI: 1.131-3.063) and within 8-14 days (HR=5.747, 95% CI: 2.391-13.809), and endoscopic exam within 7 days (HR=8.251, 95% CI: 5.733-11.873) were also independent risk factors for the development of SBP.

CONCLUSIONS:
PPIs use, as well as GI bleeding within 14 days, and having endoscopic exam within 7 days, were independent risk factors of the development of SBP in cirrhotic patients with ascites.

並列關鍵字

liver cirrhosis ； ascites ； proton pump inhibitors ； spontaneous bacterial peritonitis

參考文獻

1. Wiest R, Krag A, Gerbes A. Spontaneous bacterial peritonitis: recent guidelines and beyond. Gut 2012;61:297-310.

2. Runyon BA. Management of adult patients with ascites due to cirrhosis: an update. Hepatology 2009;49:2087-107.

3. Bonnel AR, Bunchorntavakul C, Reddy KR. Immune dysfunction and infections in patients with cirrhosis. Clin Gastroenterol Hepatol 2011;9:727-38.

4. Siple JF, Morey JM, Gutman TE, Weinberg KL, Collins PD. Proton pump inhibitor use and association with spontaneous bacterial peritonitis in patients with cirrhosis and ascites. Ann Pharmacother 2012;46:1413-8.

5. Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol 2012;107:1011-9.