臺灣博碩士論文加值系統

背景
急性上消化道出血成因大多是急性消化性潰瘍出血。針對高危險性出血潰瘍病兆，內視鏡止血術，已被證實可預防潰瘍再出血、減低需緊急開刀手術的風險、降低住院日數。經內視鏡止血療法後，高劑量輔助性氫離子幫浦抑制劑治療已被證實可降低再出血率，然而氫離子幫浦抑制劑的劑量是否影響再出血率仍有爭議。此外氫離子幫浦抑制劑及內視鏡止血術廣泛的應用下，潰瘍再出血危險因子尚缺乏相關資料。

目的
評估內視鏡止血治療後，氫離子幫浦抑制劑的劑量是否會影響再出血率、手術比率、輸血量、住院日數、三十天死亡率，以及患者的臨床表現、內視鏡表現及既有疾病、非類固醇消炎止痛劑，幽門螺旋桿菌狀況、CYP2C19基因型是否和再出血相關。

方法
針對201位高風險出血性潰瘍患者，以內視鏡進行腎上腺素注射及熱探子熱凝止血治療後，依氫離子幫浦抑制劑劑量不同，隨機分派成高劑量組（pantoprazole八十毫克快速靜脈注射後，以每小時八毫克速率靜脈注射）或標準劑量組（每日pantoprazole靜脈注射四十毫克）共七十二小時。七十二小時後給予口服pantoprazole每天四十毫克，共二十七天。試驗期間給予必要之輸血及其他治療，並監測是否再出血。

結果
100位病患進入高劑量組，101位病患進入標準劑量。高劑量組組有6位(6.2%, 95% C.I: 1.3% ~ 11.1%)，而標準劑量有5位(5.2%, 95% C.I: 0.6% ~ 11.1%) 在內視鏡治療後三十天內再出血 (p=0.77)。高劑量組平均輸血量為2.9 ± 6.2單位，標準劑量組平均輸血量為1.6 ± 2.1單位(P = 0.046)。住院天數在五天內的病患，高劑量組的病患有55位(56.7%)，標準劑量組有57位(59.3%)，p=0.70。高劑量組中有一位病患接受血管栓塞術止血 (0 vs. 1, p=0.32)。高劑量組中有3位(3.1%)在三十天內死亡，而標準劑量組有1位(1%)在三十天內死亡(p=0.32)。利用逐步Cox迴歸分析顯示透析、吐血、慢性阻塞性肺病為再出血的獨立危險因子（危險比：37.15、10.07、9.12，95% 信賴區間：6.76～204.14、2.07～49.01、1.66～50.00）。幽門螺旋桿菌感染者較不容易發生再出血（危險比：0.20，95% 信賴區間：0.04～0.94）。

結論
出血性潰瘍經合併兩種內視鏡止血術後，標準劑量pantoprazole靜脈輸注預防再出血的效果和高劑量pantoprazole靜脈輸注相當。透析、慢性阻塞性肺病、吐血以及幽門螺旋桿菌陰性的潰瘍為內視鏡治療後再出血之獨立危險因子。

Background
Acute peptic ulcer bleeding remains the most common cause of acute upper gastrointestinal bleeding. Endoscopic hemostasis has been documented to be effective in decreasing rebleeding, need for surgery, and decreasing hospitalization days. Studies showed a high dose intravenous proton pump inhibitor infusion after endoscopic hemostasis reduced recurrent ulcer bleeding. It was controversial whether an adjuvantive use of standard-dose proton pump inhibitor therapy after endoscopic therapy had similar benefit. In addition, few literatures discussed risk factors of recurrent bleeding in the era of endoscopic therapy and proton pump inhibitors

Methods
Patients with actively bleeding ulcers or ulcers with non-bleeding visible vessel were treated with epinephrine injection and thermal coagulation, and randomized to receive intravenous PPIs according to a high-dose regimen (pantoprazole 80 mg bolus followed by 8 mg/h as continuous infusion for 72 h) or a standard-dose regimen (pantolprazole 40 mg bolus daily for 72 h). After 72 hours, all patients were given 40 mg pantoprazole daily orally for 27 days. The primary end point was recurrent bleeding within 30days after endoscopy.

Results
We enrolled 201 patients, 100 patients in the high-dose group and 101 patients in standard-dose group. Bleeding recurred within 30 days in 6 patients (6.2%, 95% CI 1.3% – 11.1%) in the high-dose group, as compared with 5 patients (5.2%, 95% CI 0.6% – 9.7%) in the standard-dose group (P=0.77). Mean units of blood transfused were 2.9 ± 6.2 in the high-dose and 1.6 ± 2.2 in the standard-dose group (P = 0.05). The duration of hospital stay was ≦ 5 days for 55 (56.7%) and 57 patients (59.3%) in the high- and standard-dose groups (P = 0.70). There were fewer surgical interventions or transcatheter arterial embolization in the standard- versus high-dose group (0 vs 1, P = 0.32). Three (3.1%) patients in the high-dose group and 1 (1%) patients died within 30 days after endoscopy (P = 0.32). The stepwise Cox regression analysis showed dialysis, hematemesis, chronic obstructive pulmonary disease (hazard ratio: 37.15, 10.07, 9.12, 95% confidence interval (CI): 6.76 - 204.14, 2.07 – 49.01, 1.66 – 50.00, respectively) were independent risk factors for recurrent bleeding and Helicobacter pylori (H. pylori) infection was associated with lower risk of recurrent bleeding (hazard ratio: 0.20, 95% CI: 0.04 – 0.94).

Conclusions
Following combined endoscopic hemostasis of bleeding ulcers, standard-dose pantoprazole infusion is as effective as a high-dose regimen in reducing the risk of recurrent bleeding. Dialysis, hematemesis, chronic obstructive pulmonary disease, and H. pylori negative ulcer, but no proton pump inhibitor dosage, are independent factors for recurrent bleeding.

目錄
國立臺灣大學碩士學位論文 口試委員會審定書 I
誌謝 II
中文摘要 III
ABSTRACT V
第一章 緒論 1
一、 消化性潰瘍及消化性潰瘍出血 1
二、 消化性潰瘍出血流行病學上的變遷 1
三、 消化性潰瘍出血的治療 3
（一） 內視鏡診斷及治療 3
（二） 藥物治療 5
四、 急性消化性潰瘍再出血之危險因子 7
五、 研究假說與特定目的 10
第二章 研究方法與材料 12
一、 研究對象與收入研究條件 12
二、 排除條件 12
三、 內視鏡治療止血 13
四、 幽門桿菌感染的判定 13
五、 CYTOCHROME P450 2C19基因型判定 13
（一） 萃取去氧核醣核酸 (DNA)之方式 13
（二） CYP2C19 第四及第五個表現序列的基因型 (Genotype) 之測定 15
六、 PANTOPRAZOLE的治療 17
七、 再出血之判定 18
八、 治療意願分析法（INTENTION-TO-TREAT ANALYSIS）和計劃性分析法（PER-PROTOCOL ANALYSIS） 18
九、 統計方法 19
（一） 統計模式設定 19
（二） 樣本數估計 19
（三） 資料分析方法 19
（四） 統計軟體 20
第三章 研究結果 21
一、 研究對像 21
二、 使用高劑量與低劑量靜脈輸注PANTOPRAZOLE對治療結果的影響 21
（一） 兩組患者的基本背景資料 21
（二） 兩組患者72小時內、7日內、30日內再 出血率的比較 22
（三） 兩組患者接受手術或血管栓塞術率的比較 22
（四） 兩組患者輸血量、住院天術的比較 22
（五） 兩組患者死亡率的比較 23
三、 內視鏡治療合併靜脈輸注PANTOPRAZOLE治療後30天內再出血之危險因子 23
第四章 討論 24
一、 討論 24
二、 研究限制 27
第五章 結論與未來展望 29
一、 結論 29
二、 展望 29
參考文獻 32
附錄 49

圖目錄
圖 一、消化性潰瘍出血徵兆的內視鏡分類及再出血機率 37
圖 二、血小板凝集與酸鹼值關係 38
圖 三、不同氫離子幫浦抑制劑劑量對胃內酸鹼值的影響 39
圖 四、STUDY FLOW DIAGRAM 40
圖 五、CYP2C19 GENOTYPING 41
圖 六、. KAPLAN-MEIER ESTIMATE OF THE CUMULATIVE PERCENTAGE OF PATIENTS FREE FROM RECURRENT BLEEDING WITHIN 30 DAYS AFTER ENDOSCOPIC TREATMENT. 42

表目錄
TABLE 1. BASELINE DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF THE INTENTION-TO-TREAT GROUPS 43
TABLE 2. ENDOSCOPIC FINDINGS AT BASELINE IN THE INTENTION-TO-TREAT GROUPS 45
TABLE 3 OUTCOMES AFTER ENDOSCOPIC THERAPY 46
TABLE 4. SUMMARY OF CASES WITH RECURRENT BLEEDING 47
TABLE 5. INDEPENDENT RISK FACTORS FOR 30-DAY RECURRENT BLEEDING IN PATIENTS WITH HIGH RISK BLEEDING PEPTIC ULCER, DETERMINED BY STEPWISE COX EGRESSION ANALYSIS 48

(2002). "Non-variceal upper gastrointestinal haemorrhage: guidelines." Gut 51 Suppl 4: iv1-6.
Andersson, T., C. G. Regardh, et al. (1992). "Polymorphic hydroxylation of S-mephenytoin and omeprazole metabolism in Caucasian and Chinese subjects." Pharmacogenetics 2(1): 25-31.
Andriulli, A., S. Loperfido, et al. (2008). "High- versus low-dose proton pump inhibitors after endoscopic hemostasis in patients with peptic ulcer bleeding: a multicentre, randomized study." Am J Gastroenterol 103(12): 3011-3018.
Barkun, A., M. Bardou, et al. (2003). "Consensus recommendations for managing patients with nonvariceal upper gastrointestinal bleeding." Ann Intern Med 139(10): 843-857.
Barkun, A. N., M. Bardou, et al. (2010). "International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding." Ann Intern Med 152(2): 101-113.
Chan, W. H., L. W. Khin, et al. (2011). "Randomized controlled trial of standard versus high-dose intravenous omeprazole after endoscopic therapy in high-risk patients with acute peptic ulcer bleeding." Br J Surg 98(5): 640-644.
Cheng, H. C., W. L. Chang, et al. (2009). "Seven-day intravenous low-dose omeprazole infusion reduces peptic ulcer rebleeding for patients with comorbidities." Gastrointest Endosc 70(3): 433-439.
Cheng, H. C., A. W. Kao, et al. (2005). "The efficacy of high- and low-dose intravenous omeprazole in preventing rebleeding for patients with bleeding peptic ulcers and comorbid illnesses." Dig Dis Sci 50(7): 1194-1201.
Cheung, J., A. Yu, et al. (2010). "Peptic ulcer bleeding outcomes adversely affected by end-stage renal disease." Gastrointest Endosc 71(1): 44-49.
Chiu, P. W., E. K. Ng, et al. (2009). "Predicting mortality in patients with bleeding peptic ulcers after therapeutic endoscopy." Clin Gastroenterol Hepatol 7(3): 311-316; quiz 253.
Choi, K. D., N. Kim, et al. (2009). "Optimal dose of intravenous pantoprazole in patients with peptic ulcer bleeding requiring endoscopic hemostasis in Korea." J Gastroenterol Hepatol 24(10): 1617-1624.
de Morais, S. M., J. A. Goldstein, et al. (1995). "Genetic analysis of the S-mephenytoin polymorphism in a Chinese population." Clin Pharmacol Ther 58(4): 404-411.
Furuta, T., K. Ohashi, et al. (1998). "Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer." Ann Intern Med 129(12): 1027-1030.
Hearnshaw, S. A., R. F. Logan, et al. (2011). "Acute upper gastrointestinal bleeding in the UK: patient characteristics, diagnoses and outcomes in the 2007 UK audit." Gut.
Hung, L. C., J. Y. Ching, et al. (2005). "Long-term outcome of Helicobacter pylori-negative idiopathic bleeding ulcers: a prospective cohort study." Gastroenterology 128(7): 1845-1850.
Hung, W. K., V. K. Li, et al. (2007). "Randomized trial comparing pantoprazole infusion, bolus and no treatment on gastric pH and recurrent bleeding in peptic ulcers." ANZ J Surg 77(8): 677-681.
Kellow, J. E., Z. Tao, et al. (1986). "Ventilatory function in chronic peptic ulcer. A controlled study of ventilatory function in patients with gastric and duodenal ulcer." Gastroenterology 91(3): 590-595.
Klotz, U., M. Schwab, et al. (2004). "CYP2C19 polymorphism and proton pump inhibitors." Basic Clin Pharmacol Toxicol 95(1): 2-8.
Kupfer, A. and R. Preisig (1984). "Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man." Eur J Clin Pharmacol 26(6): 753-759.
Labenz, J., U. Peitz, et al. (1997). "Efficacy of primed infusions with high dose ranitidine and omeprazole to maintain high intragastric pH in patients with peptic ulcer bleeding: a prospective randomised controlled study." Gut 40(1): 36-41.
Laine, L. and W. L. Peterson (1994). "Bleeding peptic ulcer." N Engl J Med 331(11): 717-727.
Laine, L., A. Shah, et al. (2008). "Intragastric pH with oral vs intravenous bolus plus infusion proton-pump inhibitor therapy in patients with bleeding ulcers." Gastroenterology 134(7): 1836-1841.
Lam, S. K., M. Hasan, et al. (1980). "Comparison of maximal acid output and gastrin response to meals in Chinese and Scottish normal and duodenal ulcer subjects." Gut 21(4): 324-328.
Lee, Y. C., J. T. Lin, et al. (2007). "Influence of cytochrome P450 2C19 genetic polymorphism and dosage of rabeprazole on accuracy of proton-pump inhibitor testing in Chinese patients with gastroesophageal reflux disease." J Gastroenterol Hepatol 22(8): 1286-1292.
Leontiadis, G. I., L. McIntyre, et al. (2004). "Proton pump inhibitor treatment for acute peptic ulcer bleeding." Cochrane Database Syst Rev(3): CD002094.
Lewis, J. D., W. B. Bilker, et al. (2002). "Hospitalization and mortality rates from peptic ulcer disease and GI bleeding in the 1990s: relationship to sales of nonsteroidal anti-inflammatory drugs and acid suppression medications." Am J Gastroenterol 97(10): 2540-2549.
Li, Z. S., X. B. Zhan, et al. (2007). "Effect of esomeprazole and rabeprazole on intragastric pH in healthy Chinese: an open, randomized crossover trial." J Gastroenterol Hepatol 22(6): 815-820.
Lin, H. J., W. C. Lo, et al. (2006). "Role of intravenous omeprazole in patients with high-risk peptic ulcer bleeding after successful endoscopic epinephrine injection: a prospective randomized comparative trial." Am J Gastroenterol 101(3): 500-505.
Loperfido, S., V. Baldo, et al. (2009). "Changing trends in acute upper-GI bleeding: a population-based study." Gastrointest Endosc 70(2): 212-224.
Marmo, R., G. Rotondano, et al. (2007). "Dual therapy versus monotherapy in the endoscopic treatment of high-risk bleeding ulcers: a meta-analysis of controlled trials." Am J Gastroenterol 102(2): 279-289; quiz 469.
Monson, R. R. (1970). "Duodenal ulcer as a second disease." Gastroenterology 59(5): 712-716.
Ohmann, C., M. Imhof, et al. (2005). "Time-trends in the epidemiology of peptic ulcer bleeding." Scand J Gastroenterol 40(8): 914-920.
Rockall, T. A., R. F. Logan, et al. (1995). "Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. Steering Committee and members of the National Audit of Acute Upper Gastrointestinal Haemorrhage." BMJ 311(6999): 222-226.
Rockall, T. A., R. F. Logan, et al. (1996). "Risk assessment after acute upper gastrointestinal haemorrhage." Gut 38(3): 316-321.
Shepherd, A. M., W. K. Stewart, et al. (1973). "Peptic ulceration in chronic renal failure." Lancet 1(7816): 1357-1359.
Silverstein, F. E., D. A. Gilbert, et al. (1981). "The national ASGE survey on upper gastrointestinal bleeding. I. Study design and baseline data." Gastrointest Endosc 27(2): 73-79.
Simon-Rudler, M., J. Massard, et al. (2007). "Continuous infusion of high-dose omeprazole is more effective than standard-dose omeprazole in patients with high-risk peptic ulcer bleeding: a retrospective study." Aliment Pharmacol Ther 25(8): 949-954.
Siringo, S., A. K. Burroughs, et al. (1995). "Peptic ulcer and its course in cirrhosis: an endoscopic and clinical prospective study." J Hepatol 22(6): 633-641.
Sonnenberg, A. and J. E. Everhart (1997). "Health impact of peptic ulcer in the United States." Am J Gastroenterol 92(4): 614-620.
Sung, J. J., K. K. Tsoi, et al. (2010). "Causes of mortality in patients with peptic ulcer bleeding: a prospective cohort study of 10,428 cases." Am J Gastroenterol 105(1): 84-89.
Swain, C. P., D. W. Storey, et al. (1986). "Nature of the bleeding vessel in recurrently bleeding gastric ulcers." Gastroenterology 90(3): 595-608.
Targownik, L. E. and A. Nabalamba (2006). "Trends in management and outcomes of acute nonvariceal upper gastrointestinal bleeding: 1993-2003." Clin Gastroenterol Hepatol 4(12): 1459-1466.
Tseng, G. Y. and H. J. Lin (2010). "Peptic ulcer bleeding outcomes adversely affected by end-stage renal disease." Gastrointest Endosc 71(7): 1333-1334; author reply 1334.
Tseng, P. H., Y. C. Lee, et al. (2009). "A comparative study of proton-pump inhibitor tests for Chinese reflux patients in relation to the CYP2C19 genotypes." J Clin Gastroenterol 43(10): 920-925.
Udd, M., P. Miettinen, et al. (2001). "Regular-dose versus high-dose omeprazole in peptic ulcer bleeding - A prospective randomized double-blind study." Scandinavian Journal of Gastroenterology 36(12): 1332-1338.
van Herwaarden, M. A., M. Samsom, et al. (1999). "The effect of Helicobacter pylori eradication on intragastric pH during dosing with lansoprazole or ranitidine." Aliment Pharmacol Ther 13(6): 731-740.
Vergara, M., X. Calvet, et al. (2007). "Epinephrine injection versus epinephrine injection and a second endoscopic method in high risk bleeding ulcers." Cochrane Database Syst Rev(2): CD005584.
Viviane, A. and B. N. Alan (2008). "Estimates of costs of hospital stay for variceal and nonvariceal upper gastrointestinal bleeding in the United States." Value Health 11(1): 1-3.
Wang, C. H., M. H. Ma, et al. (2010). "High-dose vs non-high-dose proton pump inhibitors after endoscopic treatment in patients with bleeding peptic ulcer: a systematic review and meta-analysis of randomized controlled trials." Arch Intern Med 170(9): 751-758.
Wong, G. L., V. W. Wong, et al. (2009). "High incidence of mortality and recurrent bleeding in patients with Helicobacter pylori-negative idiopathic bleeding ulcers." Gastroenterology 137(2): 525-531.
Wu, C. Y., M. S. Wu, et al. (2011). "Long-term peptic ulcer rebleeding risk estimation in patients undergoing haemodialysis: a 10-year nationwide cohort study." Gut 60(8): 1038-1042.
Yavorski, R. T., R. K. Wong, et al. (1995). "Analysis of 3,294 cases of upper gastrointestinal bleeding in military medical facilities." Am J Gastroenterol 90(4): 568-573.
Yuksel, I., H. Ataseven, et al. (2008). "Intermittent versus continuous pantoprazole infusion in peptic ulcer bleeding: a prospective randomized study." Digestion 78(1): 39-43.
Zaragoza, A. M., J. M. Tenias, et al. (2008). "Prognostic factors in gastrointestinal bleeding due to peptic ulcer: construction of a predictive model." J Clin Gastroenterol 42(7): 786-790.