糖皮质激素在脓毒症中的应用

糖皮质激素在脓毒症中的应用浙江省中医院ICU雷澍体内的作用•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ＧＣ抵抗GC相对不足相对肾上腺皮质功能不全周围ＧＣ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ＴＮＦ-α及促皮质素抑素抑制肾上腺功能并降低皮质醇水平机体ＡＣＴＨ水平偏低活化的淋巴细胞产生ＡＣＴＨ片段干扰经典ＡＣＴＨ的功能肾上腺皮质血液灌注不足周围ＧＣ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(ＧＲ)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ＡＣＴＨ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ＡＣＴＨ刺激实验时，皮质醇增加幅度9μｇ/ｄｌ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ＡＣＴＨ试验后血皮质醇低于690nmol/L（24.2ug/dl)FeaturessuggestingcorticosteroidinsufficiencySymptomsWeaknessandfatigueAnorexia,nausea,vomitingAbdominalpainMyalgiaorarthralgiaPosturaldizzinessCravingforsaltHeadachesMemoryimpairmentDepressionFindingsonphysicalexaminationIncreasedpigmentationHypotension(postural)TachycardiaFeverDecreasedbodyhairVitiligoFeaturesofhypopituitarismAmenorrheaIntoleranceofcoldClinicalproblemsHemodynamicinstabilityHyperdynamic(common)Hypodynamic(rare)OngoinginflammationwithnoobvioussourceMutiple-organdysfunctionHypoglycemiaLaboratoryfindingsHyponatremiaHyperkalemiaHypoglycemiaEosinophiliaElevatedthyrotropinlevels相对肾上腺功能不全和周围ＧＣ抵抗的发生率•相对肾上腺功能不全:基于ＲＡＩ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ＧＣ抵抗:?相对肾上腺功能不全Lancet.1991,RothwellPM,septicshock,13/32（41%）,riselessthan250nmol/l(9ug/dl)tocorticotropinIntensiveCareMed.1994,MoranJL,septicshock,22/33(67%),riselessthan200nmol/ltocorticotropinIntensiveCareMed.1995,BouachourG,septicshock,1/40(2.5%),basalcortisollevelbelow10micrograms/dl;responsetotheACTHstimulationtestbelow18micrograms/dlExpClinEndocrinolDiabetes.1997,AygenB,sepsis,16.3%,riselessthan250nmol/l(9ug/dl)tocorticotropinJAMA.2002,DjillaliAnnane,septicshock,229/299(77%),riselessthan250nmol/l(9ug/dl)tocorticotropin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ＡＣＴＨ刺激实验时,皮质醇增加幅度9μｇ/ｄｌ。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%,28ｄ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ACTHtestpost-corticotropinplasmacortisollevels18µg/dLtrueprimaryorsecondaryadrenalinsufficiency1.post-corticotropinplasmacortisollevels18µg/dL2.anincreaseinplasmacortisollevel9µg/dLRelativeAdrenalInsufficiency相对肾上腺皮质功能不全与ＧＣ抵抗的关系过度活化的ＨＤＲ炎症介质升高降低皮质醇与ＧＲ的亲和力炎症部位皮质醇浓度调节异常抑制ＣＲＨ和ＡＣＴＨ对垂体和肾上腺皮质的刺激作用脓毒症炎症反应进一步失衡相对肾上腺功能不全•1994年,Briegel等第1次报道12例外科严重脓毒症及感染性休克病例,持续滴注小剂量ＨＣ(10ｍｇ/ｈ)能减轻全身炎症反应综合征(ＳＩＲＳ),全部病例均获好转。该剂量与促肾上腺皮质激素(ＡＣＴＨ)兴奋试验后健康人群皮质醇最大理论分泌速率相当。其后,至少有8篇英文文献得出了类似的结果。并不一致的治疗结果CritCareMed1998,BollaertPE,Prospective,randomized,double-blind,placebo-controlledstudy,Forty-onepatientswithsepticshock,post-corticotropincortisolplasmaconcentrationof18µg/dL(excludingadrenalinsufficiency)hydrocortisone(100mgi.v.threetimesdailyfor5days),asignificantimprovementinhemodynamicsandabeneficialeffectonsurvival.ThesebeneficialeffectsdonotappearrelatedtoadrenocorticalinsufficiencyCritCareMed.1999,BriegelJ,Prospective,randomized,double-blind,single-centerstudy,Fortypatientswithsepticshock,Hydrocortisonewasstartedwithaloadingdoseof100mggivenwithin30minsandfollowedbyacontinuousinfusionof0.18mg/kg/hr.Whensepticshockhadbeenreversed,thedoseofhydrocortisonewasreducedto0.08mg/kg/hr.Thisdosewaskeptconstantfor6days,reducedthetimetocessationofvasopressortherapyinhumansepticshock.Thiswasassociatedwithatrendtoearlierresolutionofsepsis-inducedorgandysfunctions.OverallshockreversalandmortalitywerenotsignificantlydifferentbetweenthegroupsJAMA.2002,DjillaliAnnane,Placebo-controlled,randomized,double-blind,parallel-grouptrialperformedin19intensivecareunitsinFrance.Threehundredadultpatientswithsepticshock,(50-mgintravenousbolusevery6hours)andfludrocortisone(50-µgtabletoncedaily)for7days,significantlyreducedtheriskofdeathinpatientswithsepticshockandrelativeadrenalinsufficiency,Therewasnosignificantdifferencebetweengroupsinresponders所有的脓毒性休克患者需要激素吗patientswhorespondednormallytocorticotropindisplayedatrendforhighermortalitywithhydrocortisonetherapy(61%vs53%intheplacebogroup).等待•新的循证医学依据：CORTICUS•我们自己的探索