乙醯半胱胺酸在接受體外循環的病人對急性腎傷害的保護效果

Effect of N-Acetylcysteine in protecting against acute renal insult in patients undergoing cardiopulmonary bypass

李紹榕(Shao-Jung Li)

指導教授 ： 王水深

國立臺灣大學/醫學院/臨床醫學研究所/碩士(2007年)

https://doi.org/10.6342/NTU.2007.02888

摘要

背景
病人接受心臟血管手術，在進行體外循環﹙cardiopulmonary bypass, CPB﹚的過程中，會經歷體內發炎反應遽增及血液循環改變；因此而導致的急性腎功能損傷，常常會延長病人的住院天數及增加醫療費用，甚至造成死亡率增加，尤其是對原先腎功能不全的病人影響更鉅。近來愈來愈多的國外學術研究指出，乙醯半胱胺酸（N-Acetylcysteine，NAC）可以降低顯影劑所引起的腎毒性，但是它對體外循環後的急性腎衰竭鮮少有相關的研究報告。
材料與方法
1. 凡在亞東醫院接受需體外循環之心臟血管手術病患即為本次研究的主要對象。實驗方法採隨機，雙盲，前瞻性設計，隨機決定接受NAC或安慰劑(Placebo，不含有效成分NAC之同劑型產品)。術前請病患簽署受試者同意書，並需記錄病人個人資料；在病患接受手術前一天開始由負責藥師隨機給予口服研究藥品，病患及醫師皆不知道服藥的種類；同時，在手術前12小時開始給予0.45% saline。在資料收集後，評估病患服用NAC對於體外循環誘發之腎衰竭的預防療效。根據病患接受手術前的腎功能(尿素氮/血清肌胺酸酐值，BUN/creatinine)為基準值，如果在接受手術後48小時內血清肌胺酸酐值（serum creatinine，Scr）增加0.5mg/dl或是上升25%以上，就視為體外循環造成的急性腎功能損傷。
研究對象排除條款：
洗腎病患（Dialyzed patients）
急性腎衰竭（Acute renal failure）
左心室射出率（left ventricular ejection fraction, LVEF）≦30%.
慢性阻塞性肺疾病急性發作或氣喘惡化（Acute exacerbation of chronic obstructive lung disease or asthma exacerbation）
NAC過敏
2. 樣本數：60名
3. 研究方法：
i. 收集個案的基本資料、手術過程、術後恢復期。需記錄病人姓名、年齡、性別、身高、體重、診斷、手術名稱、病史(高血壓、糖尿病、心臟衰竭、末梢血管疾病)、手術前12小時的BUN/Scr、手術前24小時內曾經使用的藥物(mannitol、diuretics、ACE-I、CCB、dopamine、theophylline...等會影響腎臟功能的藥物)。
ii. 資料收集：在病人被手術前12小時、手術當天、手術後48小時及第5天，抽血評估病人腎功能狀況。術前及術後24小時之cystatin C（Cys C）及β2 Microglobulin﹙β2m﹚也一起測量。
結果
總計有55位病患接受雙盲隨機分組試驗，29位接受NAC治療，26位接受Placebo；排除LVEF<30%的病患後，NAC治療組有28位，Placebo組有23位。單變數分析發現年齡、冠狀動脈繞道手術加上瓣膜手術、術前12小時BUN落在3rd tertile者、手術當天BUN及creatinine clearance、術前β2m及Cys C這幾個因子是有意義的。多變數分析僅有冠狀動脈繞道手術加上瓣膜手術有統計學上之趨勢，但未達統計學上有意義之程度(OR = 8.49; 95% CI: 0.82, 88.38, P value = 0.07) 。
若考慮樣本數過小之因素，另加計72位同時期未用藥之病患資料；這些人經比對Placebo組後因無統計學上之差異，加入Placebo組併計。去除其中LVEF<30%的病患之後計有89位Placebo組。所以第二個分析總計包括117位病患，當成cohort study，雖然統計上之效力可能會降低，不若雙盲隨機化、安慰劑控制之臨床試驗結果。兩組基本資料之描述性統計，並無統計學上之差異。單變數分析之結果，令人驚訝的是NAC治療會增加急性腎衰竭風險達2.62倍多(95% CI: 1.10, 6.27)。冠狀動脈繞道手術加上瓣膜手術相對於單做瓣膜手術者也有顯著風險達5.42倍多(95% CI: 2.16, 13.58)。糖尿病及高血壓也明顯增加急性腎臟傷害發生率。較高的術前12小時BUN，手術當天BUN、Creatinine、Creatinine clearance，及術前β2m高低也會增加風險。雖然沒有統計學上之意義，Reopen after surgery也會增加風險達3倍多。
在控制干擾因子之後，由多變數分析可看出NAC的relative risk (OR)為2.54 (95% CI: 0.82, 7.88; relative to placebo group)，雖然沒有統計學上之意義。此外，僅有冠狀動脈繞道手術加上瓣膜手術(OR = 4.02; 95% CI: 1.19, 13.64, 相對於單做瓣膜手術者)，術前β2m落在3rd tertile者(OR = 5.63; 95% CI: 1.01, 31.20, relative to the 1st tertile) 在兩組間有統計學上之意義。
結論
我們的數據與期望的結果顯示十分不同。由兩種分析看來，冠狀動脈繞道手術加上瓣膜手術、術前β2m落在3rd tertile者與結果有重要的相互關聯。但是在術前以抗氧化劑NAC處理者，當與安慰劑組相比較時反而會增加急性腎衰竭的危險；或許因為NAC保護腎的機制不同於CPB 引起的損害路徑，或不足以減少CPB 引起的損害。因為研究沒擁有足夠大的樣本數來反映出顯著的統計意義，無法斷言NAC對CPB 引起的腎的傷害保護的影響，但其趨勢值得未來做更多的研究。

關鍵字

體外循環 ； 乙醯半胱胺酸 ； 急性腎傷害 ； 雙盲隨機試驗 ； 血清肌胺酸酐

並列摘要

Background
Reactive oxygen species have been shown to cause contrast-induced nephrotoxicity (CIN). According to the previous studies, the N-acetylcysteine (NAC) has been proved to be advantageous in the avoidance of CIN. We developed this study to evaluate the efficacy of the antioxidant NAC in limiting the renal injury after the cardiovascular surgery with cardiopulmonary bypass (CPB).
Materials and methods
All patients who would receive a cardiac surgery with cardiopulmonary bypass were included in this study. The patients were randomly assigned to receive either NAC (600 mg orally twice daily for 4 doses) with 0.45% saline intravenously, before and after cardiopulmonary bypass, or placebo with 0.45% saline. Serum creatinine and blood urea nitrogen were measured before, 48 h and 5 days after the operation procedure. Besides, cystatin C (Cys C) and β2-microglobulin (β2m) were measured just before and after the operation procedure.
Results
A total of 55 patients were recruited in this randomized clinical trial. Among them, 29 subjects were randomly assigned to the intervention group of NAC. After excluding the cases with left ventricular ejection fraction（LVEF）less than 30%, there were 28 subjects in the experiment group with intervention and 23 in the control group (placebo). No particular difference was found in the baseline comparison results. In univariate analyses, elevated risks of acute renal insult were detected for age, CABG plus valve procedure, 3rd tertile of BUN level (12 hours before surgery), BUN and creatinine clearance levels on surgery day, β2m and Cys C levels right before surgery. Unfortunately, only a borderline significance was identified for the procedure of CABG plus valve (OR = 8.49; 95% CI: 0.82, 88.38, p value = 0.07) in multivariate analysis.
Because of small sample size and difficulty on statistical analysis, we recruited another cohort into placebo control group for further analysis. A total of 117 patients were recruited in the further analysis. No any significantly statistical difference was detected in the baseline comparisons before intervention. In univariate analysis, amazingly, NAC treatment before surgery increased the risk of acute renal insult by 2.62 folds (95% CI: 1.10, 6.27). Subjects who underwent CABG plus valve procedure had a remarkable OR of 5.42 (95% CI: 2.16, 13.58), relative to the ones with valve procedure only. Also, patients with diabetes and hypertension had significantly elevated risk of outcome incidence. Meanwhile, higher BUN level 12 hours before surgery, BUN, serum creatinine, creatinine clearance levels on the surgery day, andβ2m level right before surgery showed remarkably altered risk of acute renal insult. Although not significant, reopen after surgery might dramatically raise the risk of outcome by approximate three folds. In multivariate analysis, the relative risk (OR) of NAC, after controlling confounders, was 2.54 folds (95% CI: 0.82, 7.88; relative to placebo group) without statistical significance. Besides, only the significance of CABG plus valve procedure, (OR = 4.02; 95% CI: 1.19, 13.64, relative to the ones with mere valve procedure), and 3rd tertile of β2m level before surgery (OR = 5.63; 95% CI: 1.01, 31.20, relative to the 1st tertile) remained significant.
Conclusion
NAC cannot protect the renal damage during CPB. CABG plus valve procedure and higher β2m level before surgery (2.83~41.05, upper limit of normal is 2.4 mg/L for both, males and females) are 2 independent risk factor for risk of renal injury.

並列關鍵字

N-acetylcysteine ； cardiopulmonary bypass ； renal injury ； randomized clinical trial ； cystatin C ； β2-microglobulin

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