ARDS患者應(yīng)用糖皮質(zhì)激素的再評價課件

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1、Cliquez pour modifier le style du titre,Cliquez pour modifier les styles du texte du masque,Deuxime niveau,Troisime niveau,Quatrime niveau,Cinquime niveau,*,ARDS,患者應(yīng)用糖皮質(zhì)激素的再評價,2010,年,04,月,提綱：,ARDS,的病理生理機制,ARDS,與糖皮質(zhì)激素,小結(jié),定 義,急性呼吸衰竭：急性發(fā)病，進(jìn)行性加重；,胸片顯示：雙肺呈斑片狀或毛玻璃樣改變；,PaO,2,/FiO,2, 200 mmHg,（,不管,PE,E,P,水平

2、,）；,無左心房壓力增高的臨床證據(jù)。,發(fā)病機制,局部炎癥反應(yīng),肺內(nèi)炎性介質(zhì)和抗炎介質(zhì)的平衡失調(diào),系統(tǒng)性炎癥反應(yīng)綜合征和代償性抗炎癥反應(yīng)綜合征（,SIRS/CARS,）失衡階段,發(fā)病機制,ALI/ARDS,中炎性反應(yīng)調(diào)節(jié)的研究進(jìn)展,1,、,Toll,樣受體,4 (TLR-4):,Janardhan,K S, et al. Toll like receptor-4 expression in,lipopolysaccharide,induced lung inflammation.,Histol,Histopathol, 2006,21.,Baumgarten,G, et al. Role of

3、Toll-like receptor 4 for the pathogenesis of acute lung,injuryin,Gram-negative sepsis.,Eur,J,Anaesthesiol, 2006,23.,2,、過氧化物酶體增生物激活受體,(PPAR):,Genovese T, et al. Role of endogenous and exogenous,ligands,for the,peroxisome,Proliferator,-activated receptor alpha in the development of,bleomycin,-induced

4、lung injury. Shock , 2005,24.,Cuzzocrea,S, et al. The role of the,peroxisome,proliferator,-activated receptor-alpha (PPAR-alpha) in the regulation of acute inflammation. J,Leukoc,Biol,2006,79.,發(fā)病機制,ALI/ARDS,中炎性反應(yīng)調(diào)節(jié)的研究進(jìn)展（,II,）,3,、煙堿乙酰膽堿受體,-,7(NAR-,7):,Hamano R , et al. Stimulation of alpha7 nicotinic

5、 acetylcholine receptor inhibits CD14 and the toll-like receptor-4 expression in human monocytes. Shock , 2006 , 26.,4,、,高遷移率族蛋白,(,HMGB,),-,1,:,Ren,D, et al. Role of inducible nitric oxide,synthase,expressed by alveolar macrophages in high mobility group box 1-induced acute lung injury.,Inflamm,Res

6、, 2006 ,55 .,Silva E, et al. HMGB1 and LPS,induced,distinct patterns of gene expression and activation in,neutrophils,from patients,with sepsis,-,induced acute lung,injury. ICM, 2007,33.,發(fā)病機制,ALI/ARDS,中炎性反應(yīng)調(diào)節(jié)的研究進(jìn)展（,III,）,5,、,補體5a,(,C5a,),：,Guo R F, Ward P A. Role of C5a in inflammatory responses. An

7、nu Rev Immunol , 2005 , 23,。,6,、,巨噬細(xì)胞遷移抑制因子 （MIF）,:,Gao L , et al. Macrophage migration inhibitory factor in acute lung injury: expression , biomarker ,and associations. Transl Res, 2007 , 150.,7,、鈣離子通道：,Lee C, Xu D Z, Feketeova E, et al. Calcium entry inhibition during resuscitation from shock atte

8、nuates inflammatory lung injury. Shock , 2008 , 30.,主要病理特征：,肺廣泛性充血水腫和肺泡內(nèi)透明膜形成并伴有肺間質(zhì)纖維化,大體觀：肺內(nèi)病,變呈不均一分布。,主要病理生理：,肺順應(yīng)性降低（,baby lung,）、肺內(nèi)分流增加及通氣,/,血流比值失衡,ARDS,與糖皮質(zhì)激素現(xiàn)狀,ARDS,患者的死亡率居高不下，包括在病程的后期合并院內(nèi)獲得性感染和肺組織纖維化所致死亡率增加；,糖皮質(zhì)激素因其對炎癥介質(zhì)的抑制一直在,ARDS,患者的治療被寄予厚望,糖皮質(zhì)激素 抗炎 逆轉(zhuǎn),ALI/ARDS,？,ARDS,與糖皮質(zhì)激素,在理化因素所致的,ARDS,患者

9、中，,激素已被證實是有效的。,ARDS,與糖皮質(zhì)激素,早期、短程、足量靜脈使用地塞米松,0.30.5mg/kg,每日,2,次,共,35d,。,ARDS,與糖皮質(zhì)激素,ARDS,與糖皮質(zhì)激素,ARDS,與糖皮質(zhì)激素,糖皮質(zhì)激素與感染性,ALI/ARDS,？,在某些特定病因所致的,ARDS,患者中，激素已被證實是有效的：,-,卡氏肺孢子蟲肺炎,Masur et al N Engl J Med 1990, 323: 1500-1504,-,嗜酸性粒細(xì)胞肺炎,Allen Am J Respir Crit Care Med 1994,，,150:1423-1438,-,脂肪栓塞,Schonfeld An

10、n Intern Med 1983, 99 (4) :438-443,),-,閉塞型毛細(xì)支氣管炎,Jantz Am J Respir Crit Care Med 1999,，,160:1079-1100,病毒性肺炎,? (,曾經(jīng)在,SARS,患者中廣泛應(yīng)用，但是,),Loletta Lancet 2003 ;361:1615-17,ARDS,與糖皮質(zhì)激素,ARDS,前期：激素能夠預(yù)防,ARDS?,Weigelt,研究顯示：激素治療組,ARDS,發(fā)病率明顯增加！,ARDS,發(fā)病率,C,組,P,組,ARDS,發(fā)病率,C,組,P,組,ARDS,發(fā)病率,C,組,P,組,ARDS,前期：死亡率,早期使用

11、激素并不改善患者預(yù)后；,Bone,研究顯示，早期使用激素增加,ARDS,患者死亡率。,p=0,004,死亡率,C,組,P,組,ARDS,死亡率,C,組,P,組,死亡率,C,組,P,組,C,組,P,組,ARDS,持續(xù)時間,激素不能縮短,ARDS,的持續(xù)時間！,P=0,005,ARDS,治愈率,C,組,P,組,C,組,P,組,ARDS,治療時間,ARDS,中、晚期,降低巨噬細(xì)胞膠原酶活性（使,型和,型膠原纖維蛋白的沉積增多）,降低纖維增生,促進(jìn),2,型肺泡上皮細(xì)胞的生成,可能有效的機制：,ARDS,中、晚期,病例,開始使用激的時間（天）,甲強龍劑量,病情改善的時間,療程（天）,Ashbaugh,1

12、985,10,12 ( 6-22 ),4-8 mg/kg/d,In 15 d,2,4 ( 1-4),51 (22-108),Hooper,1991,26,11( 4-40),4-8 mg/kg/d,In 3-4 d,4-7,38 (14-150),Meduri,1994,25,15+/- 8,2-3 mg/kg/d,直至拔管,_,36,Biffl,1995,6,16 ( 12- 26),1-2 mg/kg/6h,3,4 (1-7),21 (13-42),上述前瞻非隨機研究表明,:,激素能降低死亡率,激素使用,1,周內(nèi)改善肺通氣,ARDS,中、晚期,Mduri,J.A.M.A 1998;280:

13、159-165,前瞻、隨機、雙盲,多中心,(4),研究對象：,24,例,ARDS,患者，經(jīng),7,天常規(guī)治療肺部損傷評分（,LIS,）無明顯好轉(zhuǎn),分組,: 16,例為甲強龍組, 8,例為,placebo,組,經(jīng)過,10,天治療。若患者,LIS,無好轉(zhuǎn)（下降,1,分），則將該患者調(diào)整到另一治療組,劑量與療程,:,1-14,天,: 2 mg/kg/d; 15-21,天,: 1mg/kg/d; 22-28,天,: 0,5mg/kg/d; 29-30,天,: 0,25mg/kg/d; 31-32,天,:0,125 mg/kg/d,Meduri JAMA 1998:,激素治療第,10,天,肺通氣參數(shù)明顯好

14、轉(zhuǎn),機械通時間,死亡率,C,組,P,組,n,16,*,8,Pa02/Fi02,262,*,148,MODS,0,7,*,1,8,LIS,1,7,*,3,LIS,下降,1 (n,),16,*,2,機械通氣時間,(j),11,5,*,23,拔管,(,n),7,*,0,C,組,P,組,死亡率,0%,*,62%,院內(nèi)死亡率,12%,*,62%,ARDS,所致死亡,0 / 2,5 /5,Mduri JAMA 1998:,研究提前終止,激素組患者疾病嚴(yán)重程度,(,膿毒癥,肺損傷評分,多器官功能衰竭評分,),低于對照組,激素組感染發(fā)生率增加,1,8,倍,NIH ARDS net 2006:,PaO2/FiO

15、27d) of ARDS,Persistent ARDS: excessive fibroproliferation, ongoing inflammation - prolonged MV, and a substantial risk of death.,multicenter, randomized controlled trial,Pats with persistent ARDS (,day,7,-,28 after the onset of ARDS,), n=180,Methylprednisolone 2mg/kg, 0.5 mg/kg q6h for14d, 0.5 mg/k

16、g q12h for 7 days, and then tapering of the dose.,Groups:,Randomization within 713 Days after ARDS Onset,Randomization within 1428 Days after ARDS Onset,180-Day mortality according to baseline BAL,procollagen,peptide type III,level(PCPIII,),Median,N Engl J Med 2006;354:1671-84,糖皮質(zhì)激素明顯改善呼吸和循環(huán)功能,P=0.0

17、4,P=0.02,P=0.02,Outcome vs Steroid at ARDS onset 7-13d vs 14d,Tang et al. Crit Care Med,：,2009,Tang et al. Crit Care Med,：,2009,死亡率：,Tang et al. Crit Care Med,：,2009,機械通氣與住院時間：,小 結(jié),理化因素所致,ARDS,患者應(yīng)早期、足量、短程使用激素；,ARDS,早期（,7,天）使用激素，可能可以改善患者肺通氣功能，降低死亡率。,普遍使用劑量：甲基強的松龍,2mg/kg/day in 5days,是否使用激素？使用時機？療程？劑量？,仍需進(jìn)一步研究。,