1. 戴啟明 醫師 實證醫學報告

2. 實證醫學五大步驟 A. 整理出一個可以回答的問題 (Asking an answerable question) B. 尋找文獻證據 (Tracking down the best evidence) C. 嚴格評讀文獻 (Critical appraisal) D. 應用於病人身上 (Integrating the appraisal with clinical expertise & patients' preference) E. 對於過程進行稽核 (Auditing performance in step 1-4) ( 實證醫學 : 臨床流行病學方法之應用 邱文達, 陳杰峰 2004)

3. EBM worksheet 1.Clinical scenario 2.Background knowledge 3.Question by PICO 4.Search strategy 5.Search outcome 6.Citations 7.Evidence appraisal 8.Conclusion 9.Plain-language explanation Step A Step B Step C Step D

4. 建構完整的臨床問題 詢問與臨床決策或行動有關的特殊知識 包含四個必要成分 :  病人和 / 或問題 (Patient)  介入 ( 或暴露 ) (Intervention)  比較，如果有關的話 (Comparison)  臨床結果，如果有關的話應包括時間 (Outcome) PICO ( 實證醫學 : 臨床實踐與教學指引 Sharon E. Straus 等原作 陳杰峰, 王慈蜂編譯 2007 )

5. 1. Clinical scenario 王先生， 45 歲男性，從昨天開始解黑便，胃鏡檢查發現 胃部有一個潰瘍且已有血塊覆蓋，內視鏡治療只能注 射 diluted epinephrine ，故建議氫離子阻斷劑 (PPI) 治療 ，但是要用多少劑量 ?1 支,2 支,5 支 ……

6. 特徵再出血率 ForrestIActive bleeding IaActive pulsation90% IbActive oozing30% ForrestIIBleeding stigmata IIaVisible vessel50% IIbClot20% IIcBlack base<5% ForrestIIINo bleeding signs Clear ulcer base<5% 2.Background knowledge

7. Role of acid in haemostasis Impairs clot formation – Impairs platelet aggregation and causes disaggregation Accelerates clot lysis ­ Predominantly acid-stimulated pepsin May impair integrity of mucus/bicarbonate barrier => 胃內 PH 重要 !!

8. pH Matters Intragastric pH>3: Correlated with DU healing1 Intragastric pH>4: Correlated with healing of gastric ulcer 2 & erosive esophagits 3 Intragastric pH>6: Correlated with clot formation 4,5 & prevention of ulcer rebleeding 1 Johnes DB et al. Gut 1987; 28:1120-7 2 Bell NJV et al. Digestion 1992; 51(suppl 1): 59-67 3 Howden CW et al. Aliment Pharmacol Ther 1990; 4:25-33 4 Green FJ et al. Gastroenterology 1978; 74:38-43 5 Patchett SE et al. Gut 1989; 30:1704-7

9. Bolus Followed by Bolus Julapalli V et al. Dig Dis Sci 2005; 50:1185-93

10. Median pH profiles in eight healthy subjects after receiving an intravenous infusion of 80 mg of pantoprazole followed by 8 mg/hr as a constant infusion Julapalli V et al. Dig Dis Sci 2005; 50:1185- 93 5vials qd

11. 3. Question by PICO P (Patient)P (Patient) : 王先生， 45 歲男性，從昨天開始解黑便，胃鏡檢查 發現胃部有一個潰瘍且已有血塊覆蓋 I (Intervention)I (Intervention) : Pantoprazole ( 40mg/vial) 2 or 5 vials qd Bolus or constant infusion C (Comparison)C (Comparison) : 1 vial qd, iv bolus O (Outcome)O (Outcome) : 潰瘍再出血，開刀或死亡的機會

12. 4. Search strategy-1  Search Cochrane Database Syst Rev for ulcer bleeding and proton-pump inhibitor  One review article found, but irrelevant

13. 4. Search strategy-2  Search PubMed for ulcer bleeding and proton-pump inhibitor -- 390 papers found Limits: English,human,meta-analysis,RCT -- 52 papers found Limits: English,human,meta-analysis, -- 19 papers found

15. 英國 Oxford Center 證據應用等級 LevelTherapy/Prevention, Aetilogy/Harm 1 a 將隨機對照臨床研究 (Randomized Clinical Trial, RCT) 以系統性評論 (systemic review, SR) 後的結果。 b 具有嚴格的信賴區間的個別 RCT 研究。 c 無論使用何種研究方法，但其研究結果為完全正面、完全負面或完全無效果 (all or none) 的研究結果。 2 a 將同質性的世代研究 (cohort studies) 以系統性評論的結果。 b 個別世代研究或是質量較不足的 RCT 研究。 c 以多數結果為基礎的研究，及生態學的研究 ("Outcomes" research; ecological studies) 。 3 a 將同質的個案對照研究 (case control studies) 以系統性評論後的結果。 b 個別的個案對照研究 (individual case control study) 。 4 病例統計報告，以及質量較不足的個案對照研究。 5 未經嚴謹評估的意見，或者基礎生理學、一般實驗室研究及必要原則。 (Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998)

19. Meta-analysis: proton-pump inhibition in high-risk patients with acute peptic ulcer bleeding. Aliment Pharmacol Ther. 2005 Mar 15;21(6):677-86 METHODS: MEDLINE was used to identify randomized trials (01/1990-04/2003) that assessed the efficacy of pharmacological treatments for patients with bleeding peptic ulcers exhibiting high-risk stigmata (Forrest Ia-IIb). Three groups of treatment were assessed: proton-pump inhibitors given as high-dose bolus followed by intravenous constant infusion (40-80 mg and at least 6 mg/h), high-dose oral proton-pump inhibitors (at least twice the standard dosage), non-high-dose proton-pump inhibitors (other proton-pump inhibitors dosing schedules) Mixed-effect models were used to determine rate differences between treatment and control groups. 6. Citations

20. Non-high-dose proton-pump inhibitor regimens 20–40 mg bolus every 3–6 h 40 mg bolus followed by 80 mg/day continuous infusion 40 mg q12 h for 3 days 80 mg bolus followed by 40 mg q12 40 mg q12 h for 2 days followed by 40 mg/day oral

21. Results: -- high-dose bolus followed by intravenous constant infusion =>significantly decreases ulcer rebleeding, surgery and mortality -- high-dose oral proton-pump inhibitors => reduced rebleeding but not surgery or mortality -- non-high-dose proton-pump inhibitors =>reduced rebleeding, surgery and mortality

22. 8. Conclusion PPIs: (vs. placebo) intravenous 80 mg bolus and then 8 mg/h 可最有效維持胃內 PH 值 >6 ，有助於血塊 的形成，降低再出血率，手術和死亡率 較低劑量的 PPIs 也可能有效 但 40mg qd or bid vs. high-dose ??

23. Appropriate use of intravenous proton pump inhibitors in the management of bleeding peptic ulcer Julapalli V et al. Dig Dis Sci 2005; 50:1185-93

24. 9. Plain-language explanation 對於潰瘍有再出血的高危險患者，氫離子 阻斷劑的使用應以高劑量為最有效 Pantoprazole ( 40mg/vial) intravenous 80 mg bolus and then 8mg/h 至於 40mg qd or bid 是否足夠可能要進一 步研究

25. Policy or practice change 1 amp qd iv 可能不夠的，應增加劑量 健保 ?

26. 謝謝大家 !!

28. 6. Citations Low-dose intravenous pantoprazole for optimal inhibition of gastric acid in Korean patients. J Gastroenterol Hepatol. 2007 Sep;22(9):1429-34 BACKGROUND AND AIM: Proton-pump inhibitor (PPI) therapy for bleeding ulcers is more efficacious in Asian patients than in non-Asian patients. The aim of this study was to evaluate the efficacy of various doses of pantoprazole on intragastric acidity in Korean patients. METHODS: A prospective randomized study was conducted in 52 patients either with bleeding peptic ulcers after successful endotherapy or who received endoscopic mucosal resection for gastric neoplasms. Patients were randomized into two doses of intravenous pantoprazole: 40 mg q.d. and 40 mg b.i.d. We compared these results with our preliminary study utilizing high-dose pantoprazole (80 mg + 8 mg/h). The potential contribution of CYP2C19 genetic polymorphisms and the presence of Helicobacter pylori were also assessed. RESULTS: Pantoprazole 40 mg b.i.d. and high-dose pantoprazole demonstrated better inhibition of intragastric acid than pantoprazole q.d. (P < 0.05). The pantoprazole 40 mg q.d. group exhibited significant variations in acid inhibition correlating with CYP2C19 genotype. Median 24 h pH values did not differ significantly between the pantoprazole b.i.d. and high-dose pantoprazole groups, regardless of H. pylori infection status. A median intragastric pH < 6.0 was observed in only three of 28 patients in the 40 mg b.i.d. group; these three patients were extensive metabolizers. CONCLUSION: A 40 mg b.i.d. dose of pantoprazole is sufficient to maintain pH > 6.0 in Korean patients, except for patients with extensive metabolizing CYP2C19 genotypes.