寿松涛-危重患者内分泌代谢变化

天津医科大学总医院天津医科大学总医院急救中心寿松涛寿松涛1应激和神经内分泌免疫系统内分泌系统在危重症中变化2内分泌系统在危重症中变化危患变化34危重患者HPA变化64危重患者HPT轴变化应激性高血糖与危重症65应激性高血糖与危重症分泌在危重症中的变化6HG分泌在危重症中的变化7HPG轴在危重症中的变化神经-内分泌-免疫神经内分泌免疫`1928年，Scherrer发现硬骨鱼的下丘脑具有内分泌细胞的特征，随后对多种动物的研究也得到了相似的结果。`1955年，Harris和Green基于神经解剖、神经生理学的研究成果，提出了“下丘脑可能分泌某些激素样物质，参与并调控垂体激素的合成与分泌功能”的假设激素的合成与分泌功能”的假设。`70～80年代，直到相继从下丘脑组织中分离、纯化出了促甲状腺激素释放激素(TRH)促性腺激素释放激素(GnRH)生长激腺激素释放激素(TRH)、促性腺激素释放激素(GnRH)、生长激素释放激素(GHRH)、生长抑素(SS)和促肾上腺皮质激素释放激素(CRH)等肽类激素证实了上述的假设。由此认识到了神经、内分泌两个系统，在功能上实质上是一个相互依存的整体。`临床上很早就已经发现了内分泌系统中的肾上腺皮质所分泌的糖皮质激素对治疗大多数自身免疫病有效说明糖皮质激的糖皮质激素对治疗大多数自身免疫病有效，说明糖皮质激素和性激素与免疫系统存在着直接或间接的联系。`五十年代以后，由于中枢毁损方法在神经生理学研究中的应用，发现某些中枢神经核团或区域参与对机体免疫功能的调节，如可改变外周血中单核细胞吞噬能力及循环血中抗体深节，如可改变外周血中单核细胞吞噬能力及循环血中抗体深度等。`1972年苏联学者Korneva等发现机体接受抗原刺激后脑内`1972年苏联学者Korneva等发现机体接受抗原刺激后，脑内某些区域神经元放电发生改变。瑞士学者Besedovsky等实验也得到类似结果。`这些结果表明：看似独立存在的神经、内分泌和免疫三大系统，实际上是一个有着广泛的内在联系的有机整体，它们组成神经-内分泌-免疫网络，共同调节机体内环境的平衡与稳定。其中某一环节的疾病，必然会影响到另外两个环节功能的正常发挥。神经-内分泌-免疫调节网络的概念神经内分泌免疫调节网络的概念1应激和神经内分泌免疫系统内分泌系统在危重症中变化2内分泌系统在危重症中变化危患变化34危重患者HPA变化64危重患者HPT轴变化应激性高血糖与危重症65应激性高血糖与危重症分泌在危重症中的变化6HG分泌在危重症中的变化7HPG轴在危重症中的变化人体主要的内分泌腺和激素：调节机体代谢、发育，维持内环境MLTTRH、GnRH、GHIH、GHRH、CRH、RPF、GH、PRL、TSH、ACTH、FSH、LHMLT、、、PIF、ADH、OTFSH、LHT4、T3、CTPTHthymosin甲状旁腺皮质激素,E,NEInsulinglocagonE2、P、relaxinT、inhibin内分泌激素的调节模式内分泌激素的调节模式外界刺激神经中枢神经中枢释放激素释放抑制激素短反馈超短反馈下丘脑释放激素释放抑制激素短反馈腺垂体腺垂体长反馈长反馈靶腺靶腺激素`AdrenalInsufficiencyy`HyperglycemiaandInsulinResistance`EuthyroidSickSyndrome`EuthyroidSickSyndrome`Cataboliceventsassociatedwithgrowthhormone-insulingrowthfactor-1axis内分泌系统在危重症不同阶段变化特点VandenBergheGetal.JCEM1998;83:1827-1834©1998byEndocrineSociety内分泌紊乱与危重症患者疾病严重程度相关EndocrineIndexAPACHEII危重患者内分泌功能紊乱危重患者内分泌功能紊乱有重要临床意义RthllPMtlCitCMd237883RothwellPMetal.CritCareMed23:78–83下丘脑-垂体-肾上腺(HPA)轴STRESS:PhysicalstressImmunesystem:alteredHypothalamusyEmotionalstressHypoglycemiaColdexposurePainCRHMuscle:NetlossofaminoAnteriorPituitaryGlandPainCRHPosteriorPituitaryGlandNetlossofaminoAcids(glucose)Liver:(-)ACTHLiver:Deaminationofproteinsintoaminoacids,gluconeogenesisAdrenalsCatecholamines,etcGlucocorticoids,gluconeogenesisFatCells:FreefattyacidmobilizationKidneymobilizationHeartrate:IncreasedIncreasedHPA轴激活具有重要生理意义分解分解合成血糖蛋白HPA轴激活代谢重要器官供能游离皮质醇升高内皮完整血浆皮质醇循环维持循环稳定允许作用浆皮质醇稳膜减轻组织损伤炎症细胞聚集促炎因子抑炎因子炎症广泛抑炎抑炎因子CritCareMed2008;36:1937–1949EndocrinolMetabClinNAm2006;35:823–838HPAAlterationDuringCriticalIllnessHPAAlterationDuringCriticalIllnessClassicalregulatorsoftheaxiscontinuetobeoperableincriticallyillpatientsbutwithsignificantalterations:◦Hypothalamichormones◦ACTHVasopressin◦ACTHVasopressin◦Inflammatorycytokines:IL-1,IL-6,TNF-αmodulatorsofHPAmodulatorsofHPAfunctionfunction,,◦ANSfunctionfunctionAnesthesiology(1993)77:426–431DuringanInflammatoryProcess◦Cytokinesstimulate/maintainglucocorticoidCytokinesstimulate/maintainglucocorticoidproductiontohighlevels◦IL-6isoneofthemostimportantcytokines◦IL-6receptors:pituitarycorticotrophs&adrenalcorticalcellsJCEM(1993)7716901694JCEM(1993)77:1690–1694Neuroendocrinology(1997)66:54–62ClinEndocrinol(Oxf)(2004)60:29–35`ACTHandcortisolresponsivenesstoexogenousCRHisenhancedduringcriticalenhancedduringcriticalillnessesArginineVasopressin`ACTH=dominantfactorEndothelinAtrialNatriureticFactorstimulatingcortisolsecretionthroughoutthecriticalillness→otherAtrialNatriureticFactor(ANF)VarietyofCytokinescriticalillness→otherfactorsplayasignificantmodulatinginfluenceonVarietyofCytokines(IL-6)gtheaxisJInflamm(1996)47:39–51`aninflammationinducedrestraintoftheHPAaxis(areversibleofHPAaxis))`S/Sx:Vertigo,Depression,Fatigue,Nausea,Abdominalpain,HemodynamicInstability,UnexplainedFever,Hyponatremia,Hypoglycemia,andEosinophiliaPaulEetalCritCareMed200836:19371949PaulE,etal.CritCareMed,2008,36:1937-194974%33%18%AnnaneD,etal.JAMA.2000;283:1038-1045.`Acutephaseofillness→cortisollevelsproportionatetodegreeofstress`Cortisollevels:majorsurgeryvssepsis⇒SIMILARELEVATION`Cortisollevels:majorsurgeryvssepsis⇒SIMILARELEVATION`Cortisolelevationsinsepsis:-widerange?don’tcorrelatewithAPACHE-?dontcorrelatewithAPACHE-highestlevels→highestmortality`SepsisvsTraumapatients:-similarcortisolelevation-M-MIFmarkedlyhigherin:xSepsisxSepsis,xProgressiontoARDS,xPatientswhodidn’tsurviveGldhhhll`GlucocorticoidresistantpatientshavehigherlevelsJCEM(2001)86:2811–2816()IntensiveCareMed(2001)27:1584-1591ClinEndocrinol(2004)60:29-35.IdSCtilIncreasedSerumCortisol(freecortisollevel)•IncreasedsteroidproductionStressImpairedhepatocellular•DecreasedsteroidclearancefunctionImpairedhepaticbloodflowclearanceImpairedrenal/thyroidfunction`Adrenalinsufficiencycanbedifficulttoydiagnoseincriticallyillpatientsunlesscluesfrompatients’priorclinicalhistoryareconsideredinthatcontext:consideredinthatcontext:◦priorhistoryofunexplainedfatigue◦arthralgiasg◦intakeofmedicationsknowntosuppresstheHPAaxisoralparenteralInhaledGLUCOCORTICOIDdermalintraarticularRU486KETOCONAZOLEETOMIDATE`Nostrictbiochemicalcriteriadefiningnormalserum`NostrictbiochemicalcriteriadefiningnormalserumcortisolorACTHlevels`Relativeadrenalinsufficiency:Basalcortisollevel935`Relativeadrenalinsufficiency:Basalcort