愛愛醫(yī)資源-ICU患者血糖的控制 09-8-1

ICU患者血糖的監(jiān)測與管理中南醫(yī)院ICU李璐血糖的來源和去路血糖3.89～6.11CO2+H2O其他糖肝，肌糖原脂肪，氨基酸等肝糖原非糖物質(zhì)食物糖消化吸收分解糖異生氧化分解糖原合成磷酸戊糖途徑等脂類，氨基酸代謝血糖水平的調(diào)節(jié)升糖激素：胰高血糖素，腎上腺皮質(zhì)激素，腎上腺髓質(zhì)激素，生長激素，甲狀腺素，性激素，ＨＣＧ降糖激素：胰島素(體內(nèi)唯一降低血糖的激素)

胰島素與血糖胰腺胰島Ｂ細胞分泌對糖代謝的調(diào)節(jié)：促進組織細胞對葡萄糖的攝取和利用；加速葡萄糖合成為糖原，儲存于肝和肌肉；抑制糖異生；促進葡萄糖轉(zhuǎn)變?yōu)橹舅?，儲存于脂肪組織血糖水平異常糖代謝障礙→血糖水平紊亂一高血糖糖尿?。簍ype1，type2，特異型糖尿病，妊娠糖尿病應(yīng)激狀態(tài)下的高血糖狀態(tài)二低血糖應(yīng)激狀態(tài)下發(fā)生高血糖的原因反向調(diào)節(jié)激素產(chǎn)生增加誘發(fā)炎癥反應(yīng)的細胞因子產(chǎn)生增多，誘發(fā)胰島素抵抗外源性因素的作用進一步促使高血糖的發(fā)生（激素，含糖液體）高血糖高血糖的危害降低免疫功能和增加感染性并發(fā)癥，成為獨立因素影響危重癥預后長期慢性高血糖所致心腦腎血管損害，視網(wǎng)膜病變和神經(jīng)病變減慢傷口愈合高血糖毒性……ＩＣＵ患者血糖異常應(yīng)激狀態(tài)下的高血糖狀態(tài)合并胰島素抵抗分解代謝加速,糖異生作用加強激活機體神經(jīng)內(nèi)分泌系統(tǒng)致使代謝激素(兒茶酚胺、皮質(zhì)醇、胰高血糖素、生長激素)分泌異常細胞因子大量釋放和胰島素抵抗ICU患者高血糖的危害Hyperglycemiaoccursinupto90%ofcriticallyillpatientsandisassociatedwithincreasedmorbidityandmortalityinvirtuallyallsubgroupsofintensivecareunit(ICU)patients.

超過90％的危重病人會發(fā)生高血糖，并且會增加幾乎所有亞組ICU患者的發(fā)病率和死亡率

最佳目標血糖水平？是否血糖水平在正常范圍內(nèi)就能降低死亡率？什么樣的血糖水平可使ICU患者獲益最大？血糖控制史上的“里程碑”2009年2008年2001年NICESUGAR研究SurvivingSepsisCampaign強化血糖控制血糖控制--強化胰島素治療前瞻性隨機對照試驗外科ICU機械通氣成人患者1548例隨機分為：強化胰島素治療組傳統(tǒng)治療組強化胰島素治療組維持血糖80~110mg/dL(4.4~6.1mmol/L)傳統(tǒng)治療組血糖高于215mg/dL(12mmol/L)輸注胰島素維持在180~200mg/dL(10~11mmol/L).Intensiveinsulintherapyinthecriticallyillpatients(危重患者的強化胰島素治療)VandenBergheG,etal.NEnglJMed2001;345:1359–1367.血糖控制--強化胰島素治療平均跟蹤23天結(jié)局強化胰島素傳統(tǒng)治療ICU死亡5%8%住院死亡7%11%ICU留住5天以上11%16%機械通氣14天以上8%12%需血濾/透析腎衰5%8%血行感染4%8%危重病多發(fā)性神經(jīng)病29%52%血糖控制--強化胰島素治療VandenBergheG,etal:Intensiveinsulintherapyinthecriticallyillpatients.NEnglJMed2001;345:1359–1367.入住后天數(shù)入院后天數(shù)住院生存率

ICU生存率血糖控制--強化胰島素治療隨后分析表明，盡管將血糖控制在80~110mg/dL(4.4~6.1mmol/L)最佳但是與高血糖比較，目標為血糖＜150mg/dL(8.3mmol/L)也能改善預后

Inconclusion,theuseofexogenousinsulintomaintainbloodglucoseatalevelnohigherthan110mgperdeciliterreducedmorbidityandmortalityamongcriticallyillpatientsinthesurgicalintensivecareunit,regardlessofwhethertheyhadahistoryofdiabetes無論有無糖尿病病史，應(yīng)用胰島素將血糖水平控制在110mg/dL以下能降低外科ICU患者死亡率VandenBergheG,etal:Intensiveinsulintherapyinthecriticallyillpatients.NEnglJMed2001;345:1359–1367.2008SurvivingSepsisCampaign:Internationalguidelines

formanagementofseveresepsisandsepticshock

1.Werecommendthat,followinginitialstabilization,patientswithseveresepsisandhyperglycemiawhoareadmittedtotheICUreceiveIVinsulintherapytoreducebloodglucoselevels(Grade1B).2.Wesuggestuseofavalidatedprotocolforinsulindoseadjustmentsandtargetingglucoselevelstothe<150mg/dlrange(Grade2C).3.Werecommendthatallpatientsreceivingintravenousinsulinreceiveaglucosecaloriesourceandthatbloodglucosevaluesbemonitoredevery1–2hoursuntilglucosevaluesandinsulininfusionratesarestableandthenevery4hoursthereafter(Grade1C).4.Werecommendthatlowglucoselevelsobtainedwithpoint-of-caretestingofcapillarybloodbeinterpretedwithcaution,assuchmeasurementsmayoverestimatearterialbloodorplasmaglucosevalues(Grade1B).2008SurvivingSepsisCampaign:Internationalguidelines

formanagementofseveresepsisandsepticshock

1.Werecommendthat,followinginitialstabilization,patientswithseveresepsisandhyperglycemiawhoareadmittedtotheICUreceiveIVinsulintherapytoreducebloodglucoselevels(Grade1B)我們建議，初步穩(wěn)定后，發(fā)生高血糖的嚴重膿毒癥的ICU患者應(yīng)接受靜脈胰島素治療來降低血糖水平

(Grade1B)2.Wesuggestuseofavalidatedprotocolforinsulindoseadjustmentsandtargetingglucoselevelstothe<150mg/dlrange(8.3mmol/L)(Grade2C)我們建議使用有效的方案來調(diào)整胰島素劑量，目標血糖水平為<150mg/dl(8.3mmol/L)(Grade2C)2008SurvivingSepsisCampaign:Internationalguidelines

formanagementofseveresepsisandsepticshock

3.Werecommendthatallpatientsreceivingintravenousinsulinreceiveaglucosecaloriesourceandthatbloodglucosevaluesbemonitoredevery1–2hoursuntilglucosevaluesandinsulininfusionratesarestableandthenevery4hoursthereafter(Grade1C)我們建議，所有接受靜脈注射胰島素患者應(yīng)接受葡萄糖為熱量來源，并且每1-2小時監(jiān)測血糖值，直到血糖水平和胰島素輸注率穩(wěn)定后每4小時監(jiān)測血糖值(Grade1C)2008SurvivingSepsisCampaign:Internationalguidelines

formanagementofseveresepsisandsepticshock

4.Werecommendthatlowglucoselevelsobtainedwithpoint-of-caretestingofcapillarybloodbeinterpretedwithcaution,assuchmeasurementsmayoverestimatearterialbloodorplasmaglucosevalues(Grade1B)由手指血糖測得的低血糖水平應(yīng)持謹慎態(tài)度，因為這種測量獲得的數(shù)值可能高于動脈血或血清值(Grade1B)2008SurvivingSepsisCampaign:Internationalguidelines

formanagementofseveresepsisandsepticshock

Cancontrollingbloodsugarlevelsinthe

ICUsaveyourlife?

TueMar24,2009

LandmarkstudiespublishedinNewEnglandJournalofMedicineandCMAJ（CanadianMedicalAssociationJournal）

ThisisthequestionateamofcriticalcarephysicianresearchersatVGHsetouttoanswerseveralyearsago.TheirworkispublishedtodayintheNewEnglandJournalofMedicineandCanadianMedicalAssociationJournal(CMAJ).Theresultscallforanurgentreviewofinternationalclinicalguidelines.LtoR:InvestigatorDr.VinayDhingradiscussestheSUGARstudywithresearchco-ordinatorsSusanLogieandLaurieSmithalongwithCanadianprojectmanagerDeniseFoster.

控制血糖水平能拯救ICU患者的生命嗎？發(fā)表在新英格蘭和HCAMJ雜志上研究的里程碑NICESUGAR研究：Background背景Aparallel-group,randomized,controlledtrialinvolvingadultmedicalandsurgicalpatientsadmittedtotheICUsof42hospitals:38academictertiarycarehospitalsand4communityhospitalsInvolving42hospitalsfromfourcountriesandtwocontinentsOfthe6104patientswhounderwentrandomization,3054wereassignedtoundergointensivecontroland3050toundergoconventionalcontrol

大樣本，隨機，對照試驗42家醫(yī)院的外科和內(nèi)科成人ICU患者，38學院的三級保健醫(yī)院，4個社區(qū)醫(yī)院四個國家和兩個大洲

6104例隨機分成2組，強化胰島素治療組3054例和傳統(tǒng)治療組3050例

NICESUGAR研究：Twotargetrangesgroups強化胰島素治療組theintensive(i.e.,tight)control目標血糖水平81~108mg/dL(4.5~6.0mmol/L)傳統(tǒng)治療組theconventionalcontrol目標血糖水平180mg/dL(10.0mmol/L)及以下方法Controlofbloodglucosewasachievedwiththeuseofanintravenousinfusionofinsulininsaline.靜脈注射胰島素控制血糖Inthegroupofpatientsassignedtoundergoconventionalglucosecontrol,insulinwasadministeredifthebloodglucoselevelexceeded180mgperdeciliter(10.0mmolperliter);insulinadministrationwasreducedandthendiscontinuedifthebloodglucoseleveldroppedbelow144mgperdeciliter(8.0mmolperliter).在傳統(tǒng)治療組如果血糖水平超過10.0mmol/L;應(yīng)用胰島素。如果血糖水平低于8.0mmol/L胰島素用量減少，然后停止NICESUGAR研究：結(jié)論經(jīng)過總計6030例患者的校驗，強化血糖控制在81-108mg/dl者的所有主要或次要考察指標都顯著差于常規(guī)治療組（血糖述評180mg/dl）

強化血糖控制組90天病死率明顯升高(27.5%vs.24.9%,p=0.02，根據(jù)危險因素進行校正后病死率仍有顯著差異

；

強化血糖控制組存活時間縮短(HR1.11,95%CI1.01–1.23,p=0.04，強化血糖控制組死于心血管病因的比例更高)；強化血糖控制組發(fā)生嚴重低血糖的患者比例明顯升高(6.8%vs.0.5%,OR14.7,95%CI9.0–25.9,p<0.001)

；同時，強化血糖控制組在90天內(nèi)ICU住院日及總住院日；新發(fā)單一或多器官功能衰竭患者比例；機械通氣時間，腎臟替代時間，血培養(yǎng)陽性率和輸血比例等諸多方面也沒有顯示出和常規(guī)治療組之間的差異。

死亡率和生存時間Ninetydaysafterrandomization,829of3010patients(27.5%)intheintensive-controlgrouphaddied,ascomparedwith751of3012patients(24.9%)intheconventional-controlgroup隨機分組后90天，強化胰島素治療組3010例中的829例（27.5％）死亡，而傳統(tǒng)治療組3012例中的751例（24.9％）死亡

Themediansurvivaltimewaslowerintheintensive-controlgroupthanintheconventional-controlgroup平均生存時間強化胰島素治療組低于傳統(tǒng)治療組90天存活率Theprobabilityofsurvival,whichat90dayswasgreaterintheconventional-controlgroupthanintheintensive-controlgroup(hazardratio,1.11;95%confidenceinterval,1.01to1.23;P=0.03).90天存活率強化胰島素組高于傳統(tǒng)治療組ICU留住時間Duringthe90-daystudyperiod,therewasnosignificantdifferencebetweenthetwogroupsinthemedianlengthofstayintheICU在90天的研究期間，2組ICU平均留住時間沒有顯著差異器官功能衰竭，機械通氣時間和

腎臟替代療法Thenumberofpatientsinwhomnewsingleormultipleorganfailuresdevelopedweresimilarwithintensiveandconventionalglucosecontrol(P=0.11)新發(fā)生的單個或多器官功能衰竭，2組相似Therewasnosignificantdifferencebetweenthetwogroupsinthenumbersofdaysofmechanicalventilationandrenalreplacementtherapy機械通氣時間和腎臟替代療法沒有顯著差異subgroupanalysesWithrespectto90-daymortality,subgroupanalysessuggestednosignificantdifference90天死亡率亞組間沒有顯著差異亞組死亡率P值手術(shù)/非手術(shù)0.1糖尿病0.6Severesepsis0.93外傷0.07使用皮質(zhì)激素0.0690天死亡率0.02最佳目標血糖水平Inthislarge,international,randomizedtrial,wefoundthatintensiveglucosecontrolincreasedmortalityamongadultsintheICU:abloodglucosetargetof180mg(10.0mmolorlessperliter)orlessperdeciliterresultedinlowermortalitythandidatargetof81to108mgperdeciliter(4.5to6.0mmolperliter).這次大樣本國際隨機實驗顯示：在ICU患者強化胰島素治療增加死亡率，與4.5-6mmol/dl的目標血糖水平相比，10mmol/dl及以下的血糖水平能降低死亡率Onthebasisofourresults,wedonotrecommenduseofthelowertargetincriticallyilladults.推建目標血糖水平為10mmol/dl及以下severalquestions?Header為什么時隔僅僅8年，同樣的強化血糖控制竟然有完全顛倒的兩種結(jié)果？Vandenberge的魯紋研究和NICESUGAR研究之間結(jié)論為何出現(xiàn)如此顯著差異NICE-SUGAR研究同樣對監(jiān)護醫(yī)學領(lǐng)域始終在熱捧的Bundle策略的推廣和國際指南的制定有何影響？200920082001IntensiveinsulintherapySSCguidelinesNICESUGAR相關(guān)述評（一）March26,2009美國內(nèi)分泌協(xié)會Finally,therushtodeploydifficultandresource-intensiveprotocolsinICU’smaybeprematureuntilthereisabetterunderstandingofthereasonsthattheNICE-SUGARresultsdiffersomarkedlyfromthoseofanearlierstudybyVandenBergheetal.

在明確原因之前，貿(mào)然推動復雜且消耗資源的規(guī)章指南還為時尚早

WebelievephysiciansshouldindividuallytailortheirapproachtoglycemiccontrolintheirICUpatients,perhapstargetingglucosevaluesbetween144-180mg/dl,untilwebetterunderstandthereasonsforthesesomewhatcounterintuitivefindings

在未闡明各項強化血糖控制研究結(jié)論為何出現(xiàn)如此顯著差異之前，危重病血糖控制的目標還是訂在144-180mg/dl是合適

TheEndocrineSocietyStatementtoProvidersontheReportPublishedintheNewEnglandJournalofMedicineonNICE-SUGARMarch26,2009mayoclinicproceedings

梅奧臨床學報澳大利亞和日本學者的聯(lián)合述評

魯紋大學vandenberge第一次強化血糖控制研究存在的問題，例如非雙盲;主要病種限于心外科患者;轉(zhuǎn)入ICU后每日靜脈糖量200-300g以及24小時內(nèi)即開始PN\EN或混合喂養(yǎng)等非常規(guī)治療，對照組術(shù)后病死率是澳大利亞的2倍；病死率如果未經(jīng)校準可下降42%，這是任何治療都無法達到的，低血糖的風險等

Atthattime,wechosenottohighlightevenmoresourcesofconcern,suchastheintrinsiclimitationsofsingle-centerstudies,whichmakethemunsuitableforlevelIevidence單中心的研究提供不了一級證據(jù)WhatIsaNICE-SUGARforPatientsintheIntensiveCareUnit?相關(guān)述評（二）ANUMBEROFSERIOUSLIMITATIONS否定了強化胰島素治療，肯定NICE-SUGARtrialthesecondlargestrandomizedstudysample(toourknowledge)inthehistoryofcriticalcaremedicine,itwouldclearlyprovidelevelIevidencetoguidecliniciansintheirdecisionmakingatthebedside

NICESUGAR研究為臨床醫(yī)生的工作提供了一級證據(jù)Thisdetrimentalintensiveinsulintherapy(IIT)mortalityeffectintheNICE-SUGARtrialoccurredinallsubgroups,includingsurgicalpatients.Assuch,whenconsideringadiversepopulationofICUpatients,theIITexpresshassurelycometoitslaststop（強化血糖可以休矣?。?SeveralquestionswillbeaskedWhydidtheNICE-SUGARtrialshowsuchadifferentoutcomefromthefirstLeuvenstudy?WhyandhowdidIITcauseincreasedmortality?HowshouldwetreathyperglycemiainpatientsintheICU?問題是為何研究結(jié)論大相徑庭，強化血糖又是如何增加病死率的，今后我們?nèi)绾沃委烮CU內(nèi)的高血糖？WethinkitisimportanttoemphasizethatthefindingsofNICE-SUGARdonotjustifyneglectingglycemiccontrol

不過需要強調(diào)不要因為NICE-SUGAR今后就忽視血糖的控制

WhatIsaNICE-SUGARforPatientsintheIntensiveCareUnit?Donottreathyperglycemiaunlesstheglucoselevelincreaseshigherthan180mg/dL;