1 實證暨流病中心評核結果： 日期： 2011/02/28 ■ Satisfactory: (■ 第一次通過 ) Very good Search Strategy 只限於 systematic, 過於 簡略會擔心有遺漏最新研究證據的可能 (2007 年之後的研究不包括在內） 若有修訂或進一步更新，歡迎將新檔案 到本中心。

神經科 實 證 期 刊 閱 讀 報 告 EBM-style Journal Reading 報告人：張凱茗 指導臨床教師：莊介森 日期： 地點：神經科醫研室

3 Clinical Scenario （臨床情境） 53y/o male admitted due to frequent posture change related dizziness. Loss of consciousness and left hemiparesis on 2010/12/8 Brain CT: Subarachnoid hemorrhage over right frontotemopral regions Transfer to NCU on the same day

4 Background knowledge Oral nimodipine reduce poor outcome (death or dependency) related to aneurysmal SAH (Class I, Level of Evidence A). The number needed to treat (NNT) with nimodipine to prevent one poor outcome was 13 (95% CI 8-30). 60 mg orally Q4H started within 4 days * 3 weeks Pract Neurol 2009; 9: 195–209 Stroke. 2009;40:

5 Background knowlege Nimodipine is effective in the prevention of ischaemic complications after haemorrhage Possible mechanisms include (1)Neuroprotection via reduction of calcium- dependent excitotoxicity, (2)Diminished platelet aggregation, (3)Dilation of small arteries not visible on angiograms, (4)Inhibition of ischemia triggered by red blood cell products.

6 Clinical Uncertainty → PICO 問題 Can Nimodipine reduce poor outcome in tramatic subarachnoid hemorrahge patient?

7 臨床個案的 PICO Patient / Problem Adult patient with tramatic subarachnoid hemorrahge Intervention Nimodipine Comparison Placebo Outcome Death/severe disability Type of Question: therapy

8 Search Terms & Strategy: （搜尋關鍵字與策略） 資料庫： PubMed 搜尋日期： 2011/01/05 搜尋關鍵字與策略：  systematic[sb] AND (traumatic subarachnoid hemorrhage and nimodipine)

9 Best available evidence: （挑選可獲得之最佳研究證據） Citation/s: Effect of nimodipine on outcome in patients with traumatic subarachnoid haemorrhage: a systematic review Lancet Neurol 2006; 5: 1029–32 Lead author's name : Mervyn D I Vergouwen

10 Evidence about this problem HIT 1  no reduction in poor outcome HIT-2  trend of beneficial effect 1996 HIT-3  RR reduction 55% Cochrane review 2003  pooled odds ratio for death was 0.59 (95%CI ); 0.67 for OR of poor outcome 未發表 HIT-4  significant increase in poor outcome in nimodipine-treated patients.

11 The Study: （研究效度） - 1 Search strategy and selection criteria of studies Systematically searched the electronic PubMed and EMBASE databases up to 2006 Randomised controlled studies investigating the effect of the calcium antagonist nimodipine in patients with head injury were included, irrespective of dose, route of administration, and duration of treatment.

12 The Study: （研究效度） - 2 Glasgow outcome scale was measured 6 months after head injury Outcome definition: Poor=death, vegetative state, or severe disability Favourable=moderate disability and good recovery Secondary outcome=mortality Jadad scale as predictor for quality of trails: All trials scoring 1 or 2 points for randomisation were included

13 The Study: （研究效度） - 3 Statistical analysis: Intention-to-treat principle and processed in Review Manager 4.2 Odds ratios for poor outcome were calculated with a random-effects model because of possible heterogeneity Level of Evidence: Ia

14 The Study: （研究效度） - 3 本篇文獻的 PICO (T) Patient / Problem Patient with traumatic subarachnoid hemorrhage Intervention Nimodipine Comparison Placebo Outcome Death, vegetative state, or severe disability Time All trails until 2006

15 The Evidence: （研究重要結果） - 1 Four trials was found in EMBASE and Pubmed Investigators of HIT 1 and 2 and study by Pillai were contacted for additional data; HIT3, only published data were available Principal investigator of HIT 4 granted us permission to analyse and publish the results of HIT 4, which were described in a table of the pooled outcome scores of all patients of all four HITs.

16 HIT-1HIT-2HIT-3HIT-4Palli Total 病 人數 352 (257 有 CT) (15?) (577 for ITT) 97 驗證 CT 方式 4 observes check CT (Review committee) 原研究主持 人＋ review committee Committee cannot confirm 26 CT, still evaluate for ITT Review committee tSAH 病 人數 ( 實 驗 / 對照 ) 71 35/ / / / 確定有 SAH 37 18/19 Dose 1-2mg/h * 7 days 2mg/h*7-10 day +360mg PO ~21 days ? Loss of f/u ？ 2 ＝ 1074

17 The Evidence: （研究重要結果） - 2 Quality of methodology The median score was 3 (range 2–5). As all trials scored 1 or 2 points for randomisation, no studies were excluded. Randomization 1= 內文有描述，但不夠適當 Randomization 2= 內文有描述，且夠適當

18 The Evidence: （研究重要結果） - 3 Odds ratio 0·88 [95% CI 0·51–1·54]

19 The Evidence: （研究重要結果） - 4 Odds ratio 0·95 [95% CI 0·71–1·26]

20 Comment & Discussion: -1 The occurrence of poor outcome and mortality rates did not differ between patients treated with nimodipine and those treated with placebo. Contrast with those of the Cochrane review published in 2003.

21 Comment & Discussion: -2 本文與 2003 Cochrane 相異之處有三 Restudied the original data of HIT 1 so that mortality rates of HIT 1 could be included Obtain additional data from the HIT 4 study and included these data in the analysis of all patients with tSAH. (In 2003 Cochrane review HIT 4 data were only included in the overall analysis…) Included the results of Palli study.

22 Comment & Discussion: -3 為何 traumatic 和 aneurysm 對 nimodipine 反應 不同？ Nimodipine is probably only effective for secondary cerebral ischaemia In aSAH, secondary cerebral ischaemia can occur in the weeks after hemorrhage (decrease flow 75/65% blood flow in acute and subacute stage), but much less in tSAH(85/increase) Nimodipine exerts a fibrinolytic effect (decrease secondary vasospasm in aSAH, but increase bleeding in tSAH)

23 Comment & Discussion: -4 此 Paper 之缺點： The Jadad score of HIT 4 was based on a limited number of data. With the available data of HIT 4, the Jadad score was 2. The largest study in this systematic review probably had the lowest quality score.

24 回到臨床個案情境 Clinical bottom line 臨床決策底線 In patient with traumatic subarachnoid haemorrhage, nimodipine did not reduce the poor outcome and mortality.  證據等級 1a, 建議等級 A

25 References: Langham J, Goldfrad C, Teasdale G, Shaw D, Rowan K. Calcium channel blockers for acute traumatic brain injury. Cochrane Database Syst Rev 2003; 4: CD Fukuda T, Hasue M, Ito H. Does traumatic subarachnoid hemorrhage caused by diff use brain injury cause delayed ischemic brain damage? Comparison with subarachnoid hemorrhage caused by ruptured intracranial aneurysms. Neurosurgery 1998; 43: 1040–49. Gabriel J E Rinkel, Catharine J M Klijn. Prevention and treatment of medical and neurological complications in patients with aneurysmal subarachnoid haemorrhage Pract Neurol 2009; 9: 195–209 Joshua B. Bederson, Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage, Stroke 2009;40;

26 結 論 （標題 Title ） Nimodipine didn’t improve the outcome and mortality in patient with traumatic subarachnoid hemorrhage. Kill or Update By （下次更新日期） : Jan. 05, 2012

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