糖皮質激素在膿毒癥中的應用課件

糖皮質激素在膿毒癥中的應用浙江省中醫(yī)院ICU雷澍

糖皮質激素在膿毒癥中的應用1體內的作用對應激誘發(fā)的反應的反饋系統(tǒng)的活化，保證人體在防御機制方面不反應過度體內的作用2

應用的現(xiàn)狀

2003年6月，SSC制定了新的膿毒癥治療指南：推薦對膿毒性休克靜脈使用小劑量氫化可的松50mg，q6h，連續(xù)7天(C級)；可以同時每日給予氟氫可的松50ug，鼻飼(E級)；避免氫化可的松>300mg/d(A級).

3

應用的新理論依據(jù)伴發(fā)相對腎上腺皮質功能不全周圍ＧＣ抵抗GC相對不足

應用的新理論依據(jù)伴發(fā)相對腎4相對腎上腺皮質功能不全周圍ＧＣ抵抗膿毒癥GC相對不足炎癥反應過度循環(huán)衰竭病情加重外源性GC相對腎上腺周圍ＧＣ抵抗膿毒癥GC相炎癥反應過度循環(huán)衰竭病情外5相對腎上腺皮質功能不全的發(fā)生機制ＴＮＦ-α及促皮質素抑素抑制腎上腺功能并降低皮質醇水平機體ＡＣＴＨ水平偏低活化的淋巴細胞產生ＡＣＴＨ片段干擾經典ＡＣＴＨ的功能腎上腺皮質血液灌注不足相對腎上腺皮質功能不全的發(fā)生機制ＴＮＦ-α及促皮質素抑素抑6糖皮質激素在膿毒癥中的應用課件7糖皮質激素在膿毒癥中的應用課件8FeaturessuggestingcorticosteroidinsufficiencySymptomsWeaknessandfatigueAnorexia,nausea,vomitingAbdominalpainMyalgiaorarthralgiaPosturaldizzinessCravingforsaltHeadachesMemoryimpairmentDepressionFindingsonphysicalexaminationIncreasedpigmentationHypotension(postural)TachycardiaFeverDecreasedbodyhairVitiligoFeaturesofhypopituitarismAmenorrheaIntoleranceofcoldClinicalproblemsHemodynamicinstabilityHyperdynamic(common)Hypodynamic(rare)OngoinginflammationwithnoobvioussourceMutiple-organdysfunctionHypoglycemiaLaboratoryfindingsHyponatremiaHyperkalemiaHypoglycemiaEosinophiliaElevatedthyrotropinlevelsFeaturessuggestingcorticoste9相對腎上腺功能不全和周圍ＧＣ抵抗的發(fā)生率相對腎上腺功能不全:基于ＲＡＩ的不同定義,膿毒癥及感染性休克時,其發(fā)生率為6.25%～75%周圍ＧＣ抵抗:?相對腎上腺功能不全和周圍ＧＣ抵抗的發(fā)生率10相對腎上腺功能不全Lancet.1991,RothwellPM,septicshock,13/32（41%）,riselessthan250nmol/l(9ug/dl)tocorticotropin

IntensiveCareMed.1994,MoranJL,septicshock,22/33(67%),

riselessthan200nmol/ltocorticotropin

IntensiveCareMed.1995,BouachourG,

septicshock,1/40(2.5%),basalcortisollevelbelow10micrograms/dl;responsetotheACTHstimulationtestbelow18micrograms/dl

ExpClinEndocrinolDiabetes.1997,AygenB,sepsis,16.3%,

riselessthan250nmol/l(9ug/dl)tocorticotropin

JAMA.

2002,DjillaliAnnane,

septicshock,229/299(77%),

riselessthan250nmol/l(9ug/dl)tocorticotropin

相對腎上腺功能不全Lancet.11相對腎上腺功能不全一項由Annane等完成的189例膿毒性休克患者的隊列研究證實,相對腎上腺皮質功能不全的最佳定義為:快速ＡＣＴＨ刺激實驗時,皮質醇增加幅度<9μｇ/ｄｌ。應用此概念,嚴重膿毒癥時相對腎上腺皮質功能不全發(fā)生率約50%,28ｄ的死亡率約75%。相對腎上腺功能不全12相對腎上腺功能不全較高的皮質醇水平較低的ACTH反應高死亡率相對腎上腺功能不全較高的皮質醇水平較低13區(qū)分相對腎上腺功能不全和腎上腺功能不全ACTHtestpost-corticotropinplasmacortisollevels<18μg/dLtrueprimaryorsecondaryadrenalinsufficiency

1.post-corticotropinplasmacortisollevels>18μg/dL2.anincreaseinplasmacortisollevel<9μg/dL

RelativeAdrenalInsufficiency區(qū)分相對腎上腺功能不全和腎上腺功能不全ACTHtest14相對腎上腺皮質功能不全與ＧＣ抵抗的關系過度活化的ＨＤＲ炎癥介質升高降低皮質醇與ＧＲ的親和力炎癥部位皮質醇濃度調節(jié)異常抑制ＣＲＨ和ＡＣＴＨ對垂體和腎上腺皮質的刺激作用膿毒癥炎癥反應進一步失衡相對腎上腺皮質功能不全與ＧＣ抵抗的關系過度炎癥降低皮質醇與Ｇ15相對腎上腺功能不全1994年,Briegel等第1次報道12例外科嚴重膿毒癥及感染性休克病例,持續(xù)滴注小劑量ＨＣ(10ｍｇ/ｈ)能減輕全身炎癥反應綜合征(ＳＩＲＳ),全部病例均獲好轉。該劑量與促腎上腺皮質激素(ＡＣＴＨ)興奮試驗后健康人群皮質醇最大理論分泌速率相當。其后,至少有8篇英文文獻得出了類似的結果。相對腎上腺功能不全16并不一致的治療結果CritCareMed1998,BollaertPE,Prospective,randomized,double-blind,placebo-controlledstudy,Forty-onepatientswithsepticshock,post-corticotropincortisolplasmaconcentrationof>18μg/dL(excludingadrenalinsufficiency)

hydrocortisone(100mgi.v.threetimesdailyfor5days),asignificantimprovementinhemodynamicsandabeneficialeffectonsurvival.Thesebeneficialeffectsdonotappearrelatedtoadrenocorticalinsufficiency

CritCareMed.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

并不一致的治療結果Cri17所有的膿毒性休克患者需要激素嗎patientswhorespondednormallytocorticotropindisplayedatrendforhighermortalitywithhydrocortisonetherapy(61%vs53%

intheplacebogroup).所有的膿毒性休克患者需要激素嗎patientswh18等待新的循證醫(yī)學依據(jù)：CORTICUS我們自己的探索等待新的循證醫(yī)學依19

糖皮質激素在膿毒癥中的應用浙江省中醫(yī)院ICU雷澍

糖皮質激素在膿毒癥中的應用20體內的作用對應激誘發(fā)的反應的反饋系統(tǒng)的活化，保證人體在防御機制方面不反應過度體內的作用21

應用的現(xiàn)狀

2003年6月，SSC制定了新的膿毒癥治療指南：推薦對膿毒性休克靜脈使用小劑量氫化可的松50mg，q6h，連續(xù)7天(C級)；可以同時每日給予氟氫可的松50ug，鼻飼(E級)；避免氫化可的松>300mg/d(A級).

22

應用的新理論依據(jù)伴發(fā)相對腎上腺皮質功能不全周圍ＧＣ抵抗GC相對不足

應用的新理論依據(jù)伴發(fā)相對腎23相對腎上腺皮質功能不全周圍ＧＣ抵抗膿毒癥GC相對不足炎癥反應過度循環(huán)衰竭病情加重外源性GC相對腎上腺周圍ＧＣ抵抗膿毒癥GC相炎癥反應過度循環(huán)衰竭病情外24相對腎上腺皮質功能不全的發(fā)生機制ＴＮＦ-α及促皮質素抑素抑制腎上腺功能并降低皮質醇水平機體ＡＣＴＨ水平偏低活化的淋巴細胞產生ＡＣＴＨ片段干擾經典ＡＣＴＨ的功能腎上腺皮質血液灌注不足相對腎上腺皮質功能不全的發(fā)生機制ＴＮＦ-α及促皮質素抑素抑25糖皮質激素在膿毒癥中的應用課件26糖皮質激素在膿毒癥中的應用課件27FeaturessuggestingcorticosteroidinsufficiencySymptomsWeaknessandfatigueAnorexia,nausea,vomitingAbdominalpainMyalgiaorarthralgiaPosturaldizzinessCravingforsaltHeadachesMemoryimpairmentDepressionFindingsonphysicalexaminationIncreasedpigmentationHypotension(postural)TachycardiaFeverDecreasedbodyhairVitiligoFeaturesofhypopituitarismAmenorrheaIntoleranceofcoldClinicalproblemsHemodynamicinstabilityHyperdynamic(common)Hypodynamic(rare)OngoinginflammationwithnoobvioussourceMutiple-organdysfunctionHypoglycemiaLaboratoryfindingsHyponatremiaHyperkalemiaHypoglycemiaEosinophiliaElevatedthyrotropinlevelsFeaturessuggestingcorticoste28相對腎上腺功能不全和周圍ＧＣ抵抗的發(fā)生率相對腎上腺功能不全:基于ＲＡＩ的不同定義,膿毒癥及感染性休克時,其發(fā)生率為6.25%～75%周圍ＧＣ抵抗:?相對腎上腺功能不全和周圍ＧＣ抵抗的發(fā)生率29相對腎上腺功能不全Lancet.1991,RothwellPM,septicshock,13/32（41%）,riselessthan250nmol/l(9ug/dl)tocorticotropin

IntensiveCareMed.1994,MoranJL,septicshock,22/33(67%),

riselessthan200nmol/ltocorticotropin

IntensiveCareMed.1995,BouachourG,

septicshock,1/40(2.5%),basalcortisollevelbelow10micrograms/dl;responsetotheACTHstimulationtestbelow18micrograms/dl

ExpClinEndocrinolDiabetes.1997,AygenB,sepsis,16.3%,

riselessthan250nmol/l(9ug/dl)tocorticotropin

JAMA.

2002,DjillaliAnnane,

septicshock,229/299(77%),

riselessthan250nmol/l(9ug/dl)tocorticotropin

相對腎上腺功能不全Lancet.30相對腎上腺功能不全一項由Annane等完成的189例膿毒性休克患者的隊列研究證實,相對腎上腺皮質功能不全的最佳定義為:快速ＡＣＴＨ刺激實驗時,皮質醇增加幅度<9μｇ/ｄｌ。應用此概念,嚴重膿毒癥時相對腎上腺皮質功能不全發(fā)生率約50%,28ｄ的死亡率約75%。相對腎上腺功能不全31相對腎上腺功能不全較高的皮質醇水平較低的ACTH反應高死亡率相對腎上腺功能不全較高的皮質醇水平較低32區(qū)分相對腎上腺功能不全和腎上腺功能不全ACTHtestpost-corticotropinplasmacortisollevels<18μg/dLtrueprimaryorsecondaryadrenalinsufficiency

1.post-corticotropinplasmacortisollevels>18μg/dL2.anincreaseinplasmacortisollevel<9μg/dL

RelativeAdrenalInsufficiency區(qū)分相對腎上腺功能不全和腎上腺功能不全ACTHtest33相對腎上腺皮質功能不全與ＧＣ抵抗的關系過度活化的ＨＤＲ炎癥介質升高降低皮質醇與ＧＲ的親和力炎癥部位皮質醇濃度調節(jié)異常抑制ＣＲＨ和ＡＣＴＨ對垂體和腎上腺皮質的刺激作用膿毒癥炎癥反應進一步失衡相對腎上腺皮質功能不全與ＧＣ抵抗的關系過度炎癥降低皮質醇與Ｇ34相對腎上腺功能不全1994年,Briegel等第1次報道12例外科嚴重膿毒癥及感染性休克病例,持續(xù)滴注小劑量ＨＣ(10ｍｇ/ｈ)能減輕全身炎癥反應綜合征(ＳＩＲＳ),全部病例均獲好轉。該劑量與促腎上腺皮質激素(ＡＣＴＨ)興奮試驗后健康人群皮質醇最大理論分泌速率相當。其后,至少有8篇英文文獻得出了類似的結果。相對腎上腺功能不全35并不一致的治療結果CritCareMed1998,BollaertPE,Prospective,randomized,double-blind,placebo-controlledstudy,Forty-onepatientswithsepticshock,post-corticotropincortisolplasmaconcentrationof>18μg/dL(excludingadrenalinsufficiency)

hydrocortisone(100mgi.v.threetimesdailyfor5days),asignificantimprovementinhemodynamicsandabeneficialeffectonsurvival.Thesebeneficialeffectsdonotappearrelatedtoadrenocorticalinsufficiency

CritCareMed.1999,BriegelJ,

Prospective,randomized,double-blind,single-centerstudy,Fortypatientswithsepticshock,Hydrocortisonewasstartedwithaloadingdoseof100mggivenwithin30minsandfollowedbyacontinuousinfusionof0.18mg/kg/hr.Whensepticshockhadbeenreversed,thedoseofhydrocortisonewasreducedto0.08mg/kg/hr.Thisdosewaskeptconstantfor6days,reducedthetimetocessationofvasopressortherap