新冠肺炎“炎癥風暴”是近期公眾關注的諸多熱點話題之一;所謂“炎癥風暴”即全身炎癥反應綜合征(SIRS),人體的炎癥因子,不僅可以殺掉病毒,也會給自身造成損害,某些新冠患者后期可能突然啟動了一個“炎癥風暴”,結果導致各個器官的功能衰竭。那么應該如何應對“炎癥風暴”呢?中南大學湘雅醫學院林韶輝博士撰文“有效針對新冠肺炎的“炎癥風暴”——Omega-3多不飽和脂肪酸”,表達了自己的一些觀點,或許會給大家一些思考和啟發。
一、新冠肺炎專家說
1. 武漢金銀潭醫院:上海中山醫院重癥醫學科副主任鐘鳴醫生(2020年1月24到達武漢),2020年2月3日,南方人物周刊對鐘醫生進行獨家專訪,提到救治初期,所面臨的困難之中,有的新冠患者后期可能突然啟動了一個“炎癥風暴”,這種炎癥風暴導致了各個器官的功能衰竭,一旦進入這個狀態,我們的治療很難把它拉回來。
2. 武漢大學中南醫院:《美國醫學會雜志》2月7日在線發布了武漢大學中南醫院重癥監護室(ICU)主任彭志勇博士領銜的一項回顧性分析,研究團隊認為,新冠肺炎致死的三大主要機制:
中性粒細胞增多,與細胞因子風暴有關;
D-二聚體升高反映凝血激活,提示持續的炎癥反應;
血尿素升高提示急性腎損傷,這是感染、休克和缺氧的綜合結果。
3. 種種跡象表明,這些重癥患者中發生了不可逆轉的“炎癥風暴”。而一旦患者發生“炎癥風暴”,糖皮質激素是對抗炎癥風暴的武器之一,可以給免疫系統“滅火”,減輕機體損傷。不過,糖皮質激素是一把“雙刃劍”。一方面它可以減輕炎癥反應,有利于改善缺氧、呼吸窘迫癥狀;但長期大劑量使用也可能引發諸多不良反應。不少經過大劑量激素治療的“非典”患者,都留下了如股骨頭壞死等嚴重后遺癥。
二、“炎癥風暴”與Omega-3多不飽和脂肪酸
3. Omega-3 PUFA對抗炎癥反應的作用機制
圖1. 長鏈不飽和脂肪酸代謝示意圖
4. 多種文獻證明,為了減少患者還可能發生爆發性炎癥反應,使用高純度的 Omega-3 PUFA制劑,可以減低炎癥風暴的發生風險。具體表現
4.1 Omega-3 PUFA富集于細胞膜,參與炎癥反應調控過程,減少炎性細胞產生促炎性細胞因子;
Omega-3 PUFA富集于細胞膜,提高細胞膜EPA和DHA脂肪酸的比例[11, 12],影響胞內信號傳導,抑制炎癥相關的轉錄因子NF-kappa B的轉錄活性[13, 14],從而減少促炎性細胞因子TNF-alpha、IL-6 和IL-8等的表達[15]。
花生四烯酸類脂質經一系列酶催化產生促炎癥調節作用的前列腺素(PGE2)和白三烯B4等。這些促炎性介質進而可激活中性粒細胞、巨噬細胞,刺激炎癥細胞因子TNF-α、IL-1、IL-2、IL-8和干擾素(Interferon, IFN)等釋放增多。Omega-3和Omega-6兩類 PUFA競爭相同的脂肪酸代謝酶(Elovl5和FADS2)系統[16-18],從而干擾促炎性介質的生成。
EPA和DHA經代謝產生消散素(Resolvins)和保護素(Protections)。實驗研究證實,消散素和保護素在關節炎[19]、結腸炎[20]、哮喘[21, 22]等多種炎性疾病中發揮重要的抗炎作用[23, 24] 。例如,resolvin E1,resolvin D1和protectin D1能抑制浸潤性中性粒細胞的細胞遷移,從而減輕局部炎癥[24]。此外,resolvin D1和protectin D1還能抑制TNF-α and IL-1β的產生,從而減弱炎癥反應[25, 26]。
5. Omega-3 PUFA緩解炎癥的具體臨床獲益
5.1 C反應蛋白等炎癥指標顯著下降,血紅蛋白和白細胞、血小板等細胞類群總量顯著上升。
表1. ICU患者使用Omega-3 PUFA帶來的生理指標和臨床指標獲益
5.2 敗血癥狀明顯下降,治療用抗生素使用時間縮短,全身炎癥反應綜合征減少,器官功能障礙后遺癥發生率減少,死亡率下降;
美國田納西大學附屬醫院和西班牙多所醫院的臨床研究表明,對于重癥創傷患者和膿毒癥患者等ICU患者,每天1~3克Omega-3 PUFA營養液可以有效降低菌血癥、敗血癥并發癥發生(下降14%[29]~35%[30]),明顯降低治療用抗生素使用時間和腹腔內膿腫發生率[30]。而使用更高Omega-3 PUFA含量(4克以上)的營養液后,創傷病人全身炎癥反應綜合征發生人數顯著下降[27];膿毒癥、敗血癥患者的器官功能障礙發生率減少達到43%[31],死亡率顯著下降13.1%[29]~19.4%[31]。
表2. 創傷患者和敗血癥患者使用Omega-3 PUFA的臨床獲益
5.3 改善氧合狀態,減少呼吸機使用,縮短ICU監護時間;
6.2 生物利用度高,保證體內有效富集。
6.3 添加中鏈甘油三酯(MCTs),促進Omega-3 PUFA快速細胞富集,為重癥患者的癥狀緩解贏得時間。添加MCT的Omega-3脂肪乳的體內富集時間更短(術后第六天即檢測到病患血清磷脂和紅細胞細胞膜中的EPA和DHA顯著升高)[35],激發免疫更強(第六天起外周血細胞釋放的白三烯B5含量已增長約2倍)[36];
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