围术期糖皮质激素的基础与临床课件.ppt

1、围术期糖皮质激素应用的基础与临床Perioperative Glucocorticoid Application:from Basic Science to Clinical Trials病例报道：病例报道：Case Reports病例病例1：女，82岁，41kg,因摔倒后致右侧人工股骨粗隆区粉碎性骨折，需择期行人工股骨头置换术；术前合并T2DM、有高血压病史多年，不规则服用降压药，脑梗病史十余年，体质消瘦，内科药物控制尚可。麻醉方式：全身麻醉气管内插管，诱导与维持平稳；手术进展顺利，术中填充人工骨水泥时出现血压骤降、心动过速，SPO2下降；给予甲基强的松龙针剂80mg静注、去氧肾上腺素分次静

2、注，去甲肾上腺素与肾上腺素泵注，血流动力学仍难以维持稳定，全身大面积皮疹渐现。考虑：考虑：极罕见的严重骨水泥过敏反应，合并应激功能不全极罕见的严重骨水泥过敏反应，合并应激功能不全，遂给予氢化可的松给予氢化可的松150mg快速静滴后，有创血压回升至快速静滴后，有创血压回升至105/50mmHg,HR110次次/分，继续分，继续给予氢化可的松给予氢化可的松150mg静滴静滴、大剂量Ad 80ng/kgmin、NE120ng/kgmin泵注，维持MAP55 mmHg；手术结束后转ICU；次日清醒，出现急性肾功能衰竭，继续抗过敏、免疫调节、强心、利尿、床旁腹膜透析支持等综合性处理，术后3d脱机，继续透

3、析、激素支持治疗；30d后基本康复。病例病例2：成年男性，车祸后双下肢大面积撕脱伤清创、多发性肋骨骨折合并血气胸胸腔闭式引流术后，胸椎CT/MRI 示：T8T12压缩性骨折伴不完全截瘫，由外院转至我院。术前出现神志基本清醒，头颅CT/MRI未见明显异常。拟行手术：俯卧位椎管内探查减压，胸椎压缩性骨折复位内固定术。麻醉方式：有创血流动力学监测下静-吸全麻、慢诱导气管内插管；麻醉诱导与维持均平稳，术中生命体征平稳，椎管内减压前给予甲基强的松龙椎管内减压前给予甲基强的松龙500mg静注静注，术毕转PACU，半小时内拔除气管内导管、生命体征平稳，患者平静合作，转回普通病房，术后后1d病房继续静脉给予甲

4、基强的松龙病房继续静脉给予甲基强的松龙500mg，出现睡眠倒错，出现睡眠倒错，72h后渐出现意识障碍，注意后渐出现意识障碍，注意力与定向力异常表现力与定向力异常表现，请麻醉科会诊：麻醉科会诊：考虑系创伤后应激功能紊乱考虑系创伤后应激功能紊乱，给予氟哌利多给予氟哌利多2mg，q6h（用药用药24h后停药）后停药），症状缓解，拔除胸腔闭式引流，睡眠节律恢复至正常。患者一周后痊愈、轮椅平推出院。30d随访预后基本良好，无麻醉远期并发症。病例病例3：女性，83岁，行人工股骨头置换术，患者术前隐瞒病史，术中发生严重哮喘持术中发生严重哮喘持续状态续状态，给予：甲基强的松龙，给予：甲基强的松龙50mg静注静

5、注+氢考氢考150mg静滴静滴+布地奈德布地奈德/博利康尼雾化吸入，缓博利康尼雾化吸入，缓解解。问题：问题：围术期创伤后应激功能失调、生物节律围术期创伤后应激功能失调、生物节律改变与麻醉安全及危重症患者的管理改变与麻醉安全及危重症患者的管理原发性肾上腺皮质功能不全危及生命，多种内分泌激素不足继发性或三发性肾上腺皮质机能不全，糖皮质激素典型缺乏为什么围术期会出现各类生物节律的紊乱现象？流行病学流行病学病因病机病因病机临床表现临床表现疾病诊断疾病诊断 胰岛素激发试验胰岛素激发试验CRHCRH激发试验激发试验麻醉管理麻醉管理一、机体内稳态维持的主要应激激一、机体内稳态维持的主要应激激素素 糖皮质激素

6、糖皮质激素 下丘脑-腺垂体-肾上腺轴：hypothalamic-pituitary-adrenal（HPA）axis 糖皮质激素-糖皮质激素受体：glucocorticoid-activated GR11beta-hydroxysteroid dehydrogenase,11beta-HSD)二、糖皮质激素受体的结构三、糖皮质激素调节的信号转导途径Glucocorticoid activation of the membrane-associated GR regulates gap junction intercellular.四、糖皮质激素的生物学功能PTSD&GC五、糖皮质激素的药理学功

7、能（小结）1.1.调节糖、脂肪、和蛋白质的生物合成和代谢调节糖、脂肪、和蛋白质的生物合成和代谢2.2.抑制免疫应答抑制免疫应答3.3.抗炎提高机体对内毒素的耐受力抗炎提高机体对内毒素的耐受力4.4.抗毒抗毒5.5.抗休克抗休克6.6.刺激骨髓的造血功能刺激骨髓的造血功能7.7.提高中枢神经系统兴奋性提高中枢神经系统兴奋性 六、围术期应激性记忆受损与六、围术期应激性记忆受损与GR应激状态下，外源性系统给予大剂量糖皮质激素损害记忆的提取与巩固GC穿越血-脑屏障，影响HPA轴，参与PTSD的形成与发展七、糖皮质激素与急性肺损伤u糖皮质激素能有效纠正系统性炎症与部分逆转ALI/ARDS的病理生理紊乱u

8、盲目增加糖皮质激素用量并不能改善ALI/ARDS的病理生理进程Glucocorticoid Treatment in Acute Lung Injury and Acute Respiratory Distress SyndromeReview ArticleCritical Care Clinics,Volume 27,Issue 3,July 2011,Pages 589-607Paul E.Marik,G.Umberto Meduri,Patricia R.M.Rocco,Djillali AnnaneExperimental and clinical evidence show a s

9、trong association between dysregulated systemic inflammation and progression of acute respiratory distress syndrome(ARDS).This article reviews eight controlled studies evaluating corticosteroid treatment initiated before day 14 of ARDS.Available data provide a consistent strong level of evidence for

10、 improving outcomes.Treatment was also associated with a markedly reduced risk of death.This low-cost highly effective therapy is well-known,and has a low-risk profile when secondary prevention measures are implemented.The authors recommend prolonged methylprednisolone at 1 mg/kg/d initially in earl

11、y ARDS,increasing to 2 mg/kg/d after 7 to 9 days of no improvement.八、糖皮质激素全身用药的利弊抑制下丘脑抑制下丘脑-垂体垂体-肾上腺素（肾上腺素（HPAHPA）轴：肾上腺萎缩）轴：肾上腺萎缩肾脏：水钠潴留肾脏：水钠潴留代谢：代谢：T2DMT2DMCNSCNS：行为、认知与情绪改变行为、认知与情绪改变循环：高血压、循环：高血压、消化：应激性溃疡消化：应激性溃疡骨骼肌肉系统：骨折、肌肉萎缩骨骼肌肉系统：骨折、肌肉萎缩眼科：青光眼、白内障眼科：青光眼、白内障ICS1.5mg/d,ICS1.5mg/d,同样引起全身性副作用！同样引起全

12、身性副作用！主要因素：经口服吸收，肝首过消除！主要因素：经口服吸收，肝首过消除！九、围术期吸入糖皮质激素的可行性早在上世纪早在上世纪8080年代年代,吸入用布地奈德混悬液（吸入用布地奈德混悬液（普米克令舒普米克令舒），试用于治疗支气管），试用于治疗支气管哮喘等气道高反应性疾病哮喘等气道高反应性疾病；在口服布地奈德类固醇类药物治疗不适合时，吸入在口服布地奈德类固醇类药物治疗不适合时，吸入普米克令舒普米克令舒与与0.9%0.9%生理盐水和生理盐水和特布他林、沙丁胺醇、色甘酸钠或异丙托溴铵溶液混合吸入使用，取得良好的临特布他林、沙丁胺醇、色甘酸钠或异丙托溴铵溶液混合吸入使用，取得良好的临床效应；床效

13、应；肝功能不全可能会影响到皮质类固醇的消除。肝功能不全可能会影响到皮质类固醇的消除。Proof of concept for next-generation nanoparticle drugs in humans.Chrastina A,Massey KA Schnitzer JE.Overcoming in vivo barriers to targeted nanodelivery.Wiley Interdiscip.Rev.Nanomedicine Nanobiotechnol.,3(2011),pp.421437Sheridan C.Proof of concept for next

14、-generation nanoparticle drugs in humansNat.Biotechnol.,30(2012),pp.471473九、围术期吸入糖皮质激素的可行性十、吸入糖皮质激素治疗呼吸道炎症性疾病1.肺炎2.哮喘3.COPD4.过敏性鼻炎BackgroundThe incidence of pediatric asthma has increased dramatically over the past few decades,with approximately 5%of American children affected by the disease.Objecti

15、vesTo compare the efficacy and safety of once-daily budesonide Turbuhaler with placebo in asthmatic children previously treated with orally inhaled corticosteroids.MethodsThis randomized,double-blind,placebo-controlled,multicenter(17 centers)study included 274 male and female children(aged 6 to 17 y

16、ears)with a history of asthma for at least the previous 6 months.Patients received placebo or budesonide Turbuhaler(200 g or 400 g)once daily for 12 weeks.Efficacy variables included mean changes from baseline in forced expiratory volume in 1 second(FEV1),am and pm peak expiratory flow rates(PEFRs),

17、nighttime and daytime asthma symptom severity scores,patient discontinuations,use of 2-agonists as breakthrough medication,forced vital capacity(FVC),and midexpiratory flow rate between 25%and 75%of FVC(FEF25%-75%).Safety was evaluated by adverse events,physical examinations,vital signs,and laborato

18、ry tests.ResultsBaseline characteristics were comparable among treatment groups.Percentage of predicted FEV1 at baseline was 76.6 6.9 for placebo,77.5 7.1,and 77.0 7.8 for the budesonide Turbuhaler 200 g and 400 g groups,respectively.Significantly(P 0.024)more placebo patients(24%)discontinued treat

19、ment because of disease deterioration or no improvement than budesonide Turbuhaler 200 g(11%)or 400 g patients(10%).Patients receiving budesonide Turbuhaler experienced significant improvements in FEV1 compared with patients receiving placebo(P 0.015).Significant(P 0.041)improvements over placebo al

20、so were observed in am and pm PEFRs,FVC,FEF25%-75%,nighttime and daytime asthma symptoms,and amount of 2-agonist used in both budesonide Turbuhaler groups.Adverse events were generally mild or moderate in intensity and similar among treatment groups.ConclusionsOnce-daily budesonide Turbuhaler is effective and safe in children with persistent asthma previously maintained on at least twice-daily dosing regimens of inhaled corticosteroids.十一、吸入糖皮质激素治疗在儿科患者中应用的安全性评估