糖皮质激素在脓毒症中的应用,体内的作用,对应激诱发的反应的反馈系统的活化，保证人体在防御机制方面不反应过度,应用的现状,2003年6月，SSC制定了新的脓毒症治疗指南：推荐对脓毒性休克静脉使用小剂量氢化可的松 50mg，q6h，连续7天(C级)；可以同时每日给予氟氢可的松 50ug ，鼻饲(E级)；避免氢化可的松300mg/d(A级).,应用的新理论依据,伴发相对肾上腺皮质功能不全,周围抵抗,GC相对不足,相对肾上腺 皮质功能不全,周围抵抗,脓毒症,GC相 对不足,炎症反应过度,循环衰竭,病情 加重,外源性GC,相对肾上腺皮质功能不全的发生机制,-及促皮质素抑素抑制肾上腺功能并降低皮质醇水平,机体水平偏低,活化的淋巴细胞产生片段干扰经典的功能,肾上腺皮质血液灌注不足,周围抵抗的发生机制,皮质醇向炎症部位转运障碍,糖皮质激素受体 ()数目减少和亲和力下降,炎症部位皮质醇浓度调节异常,如何确定存在相对肾上腺功能不全,以兴奋试验后皮质醇的升幅被削峰为特征,临床症状和体征是决定诊断的关键因素,快速刺激实验时，皮质醇增加幅度9/,若任意时间血皮质醇水平低于 552nmol/L（19.3ug/dl),相对肾上 腺功能不全,试验后血皮质醇低于 690nmol/L （24.2ug/dl),Features suggesting corticosteroid insufficiency,Symptoms Weakness and fatigue Anorexia, nausea, vomiting Abdominal pain Myalgia or arthralgia Postural dizziness Craving for salt Headaches Memory impairment Depression,Findings on physical examination Increased pigmentation Hypotension (postural) Tachycardia Fever Decreased body hair Vitiligo Features of hypopituitarism Amenorrhea Intolerance of cold,Clinical problems Hemodynamic instability Hyperdynamic (common) Hypodynamic (rare) Ongoing inflammation with no obvious source Mutiple-organ dysfunction Hypoglycemia,Laboratory findings Hyponatremia Hyperkalemia Hypoglycemia Eosinophilia Elevated thyrotropin levels,相对肾上腺功能不全和周围抵抗的发生率,相对肾上腺功能不全:基于的不同定义 ,脓毒症及感染性休克时 ,其发生率为 6.25% 75% 周围抵抗: ?,相对肾上腺功能不全,Lancet. 1991,Rothwell PM,septic shock,13/32（41%）,rise less than 250 nmol/l(9ug/dl) to corticotropin,Intensive Care Med. 1994, Moran JL, septic shock ,22/33(67%), rise less than 200 nmol/l to corticotropin,Intensive Care Med. 1995, Bouachour G, septic shock,1/40(2.5%),basal cortisol level below 10 micrograms/dl; response to the ACTH stimulation test below 18 micrograms/dl,Exp Clin Endocrinol Diabetes. 1997, Aygen B,sepsis, 16.3%, rise less than 250 nmol/l(9ug/dl) to corticotropin,JAMA. 2002, Djillali Annane, septic shock , 229/299(77%), rise less than 250 nmol/l(9ug/dl) to corticotropin,相对肾上腺功能不全,一项 由Annane 等完成的189例脓毒性休克患者的队列研究证实,相对肾上腺皮质功能不全的最佳定义为 :快速刺激实验时 ,皮质醇增加幅度 9/。应用此概念 ,严重脓毒症时相对肾上腺皮质功能不全发生率约 50% ,28的死亡率约75% 。,相对肾上腺功能不全,较高的皮质醇水平,较低的ACTH反应,高死亡率,区分相对肾上腺功能不全和肾上腺功能不全,ACTH test,post-corticotropin plasmacortisol levels 18 g/dL 2.an increase in plasmacortisol level 18 g/dL(excluding adrenal insufficiency) hydrocortisone (100 mg i.v. three times daily for 5 days) ,a significant improvement in hemodynamics and a beneficial effect on survival. Thesebeneficial effects do not appear related to adrenocortical insufficiency,Crit Care Med. 1999, Briegel J, Prospective, randomized, double-blind, single-center study, Forty patients with septic shock, Hydrocortisone was started with a loading dose of 100 mg given within 30 mins and followed by a continuous infusion of 0.18 mg/ kg/hr. When septic shockhad been reversed, the dose of hydrocortisone was reduced to 0.08 mg/kg/hr. This dosewas kept constant for 6 days, reduced the time to cessation of vasopressor therapyin human septic shock. This was associated with a trend to earlier resolution of sepsis-induced organdysfunctions. Overall shock reversal and mortality were not significantly different between the groups,JAMA. 2002, Djillali Annane, Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 intensive care units in France. Three hundred adult patients with septic shock,(50-mg intravenous bolus every 6 hours) and fludrocortisone (50-g tablet once daily) for 7 days,significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency,There was no significant difference between groups in responders,所有的脓毒性休克患者需要激素吗,patients who responded normally to corticotropin displayed a trendfor higher mortality with hydrocortisone therapy (61% vs 53% in the placebo group).,等 待,新的循证医学依据：CORTICUS 我们自己的探索,