糖皮質(zhì)激素在膿毒癥中的應(yīng)用課件

糖皮質(zhì)激素在膿毒癥中的應(yīng)用浙江省中醫(yī)院ICU雷澍

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

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

應(yīng)用的新理論依據(jù)伴發(fā)相對腎4相對腎上腺皮質(zhì)功能不全周圍ＧＣ抵抗膿毒癥GC相對不足炎癥反應(yīng)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(yīng)過度循環(huán)衰竭病情外5相對腎上腺皮質(zhì)功能不全的發(fā)生機制ＴＮＦ-α及促皮質(zhì)素抑素抑制腎上腺功能并降低皮質(zhì)醇水平機體ＡＣＴＨ水平偏低活化的淋巴細胞產(chǎn)生ＡＣＴＨ片段干擾經(jīng)典ＡＣＴＨ的功能腎上腺皮質(zhì)血液灌注不足相對腎上腺皮質(zhì)功能不全的發(fā)生機制ＴＮＦ-α及促皮質(zhì)素抑素抑6糖皮質(zhì)激素在膿毒癥中的應(yīng)用課件7糖皮質(zhì)激素在膿毒癥中的應(yīng)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(zhì)功能不全的最佳定義為:快速ＡＣＴＨ刺激實驗時,皮質(zhì)醇增加幅度<9μｇ/ｄｌ。應(yīng)用此概念,嚴重膿毒癥時相對腎上腺皮質(zhì)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(zhì)醇水平較低的ACTH反應(yīng)高死亡率相對腎上腺功能不全較高的皮質(zhì)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(zhì)功能不全與ＧＣ抵抗的關(guān)系過度活化的ＨＤＲ炎癥介質(zhì)升高降低皮質(zhì)醇與ＧＲ的親和力炎癥部位皮質(zhì)醇濃度調(diào)節(jié)異常抑制ＣＲＨ和ＡＣＴＨ對垂體和腎上腺皮質(zhì)的刺激作用膿毒癥炎癥反應(yīng)進一步失衡相對腎上腺皮質(zhì)功能不全與ＧＣ抵抗的關(guān)系過度炎癥降低皮質(zhì)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(yīng)綜合征(ＳＩＲＳ),全部病例均獲好轉(zhuǎn)。該劑量與促腎上腺皮質(zhì)激素(ＡＣＴＨ)興奮試驗后健康人群皮質(zhì)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(jié)果。相對腎上腺功能不全16并不一致的治療結(jié)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(jié)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(zhì)激素在膿毒癥中的應(yīng)用浙江省中醫(yī)院ICU雷澍

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

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

應(yīng)用的新理論依據(jù)伴發(fā)相對腎23相對腎上腺皮質(zhì)功能不全周圍ＧＣ抵抗膿毒癥GC相對不足炎癥反應(yīng)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(yīng)過度循環(huán)衰竭病情外24相對腎上腺皮質(zhì)功能不全的發(fā)生機制ＴＮＦ-α及促皮質(zhì)素抑素抑制腎上腺功能并降低皮質(zhì)醇水平機體ＡＣＴＨ水平偏低活化的淋巴細胞產(chǎn)生ＡＣＴＨ片段干擾經(jīng)典ＡＣＴＨ的功能腎上腺皮質(zhì)血液灌注不足相對腎上腺皮質(zhì)功能不全的發(fā)生機制ＴＮＦ-α及促皮質(zhì)素抑素抑25糖皮質(zhì)激素在膿毒癥中的應(yīng)用課件26糖皮質(zhì)激素在膿毒癥中的應(yīng)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(zhì)功能不全的最佳定義為:快速ＡＣＴＨ刺激實驗時,皮質(zhì)醇增加幅度<9μｇ/ｄｌ。應(yīng)用此概念,嚴重膿毒癥時相對腎上腺皮質(zhì)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(zhì)醇水平較低的ACTH反應(yīng)高死亡率相對腎上腺功能不全較高的皮質(zhì)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(zhì)功能不全與ＧＣ抵抗的關(guān)系過度活化的ＨＤＲ炎癥介質(zhì)升高降低皮質(zhì)醇與ＧＲ的親和力炎癥部位皮質(zhì)醇濃度調(diào)節(jié)異常抑制ＣＲＨ和ＡＣＴＨ對垂體和腎上腺皮質(zhì)的刺激作用膿毒癥炎癥反應(yīng)進一步失衡相對腎上腺皮質(zhì)功能不全與ＧＣ抵抗的關(guān)系過度炎癥降低皮質(zhì)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(yīng)綜合征(ＳＩＲＳ),全部病例均獲好轉(zhuǎn)。該劑量與促腎上腺皮質(zhì)激素(ＡＣＴＨ)興奮試驗后健康人群皮質(zhì)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(jié)果。相對腎上腺功能不全35并不一致的治療結(jié)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