新光医院感染科败血症标准作业流程28132.pptx
新光醫院感染科敗血症標準作業流程新光醫院感染科敗血症標準作業流程severe sepsis and septic shock新光醫院感染科黃建賢SEPSISDEFINITIONS microbesmicrobes involves a involves a rapidly amplifying rapidly amplifying polyphony of signals polyphony of signals and responses that and responses that may spreadmay spread beyond beyond the invaded tissue.the invaded tissue.1.敗血症的定義敗血症的定義1.1.敗血症的定義敗血症的定義敗血症的定義敗血症的定義1.11.1宿主因微生物感染大量繁殖並造而造成全身性症狀，宿主因微生物感染大量繁殖並造而造成全身性症狀，臨床上可表現出發燒，低體溫，寒顫，呼吸加速，心臨床上可表現出發燒，低體溫，寒顫，呼吸加速，心搏加速，宿主因為微生物的侵犯而表現出搏加速，宿主因為微生物的侵犯而表現出”系統性發系統性發炎反應症候群炎反應症候群”(systemic inflammatory response”(systemic inflammatory response syndromesyndrome，SIRS)SIRS)1.2”1.2”系統性發炎反應症候群系統性發炎反應症候群”定義為包函下列或兩者以定義為包函下列或兩者以上上1.2.1 1.2.1 體溫體溫3838度度C C以上或以上或3636度度C C以下以下1.2.2 1.2.2 心跳速度超越每分鐘心跳速度超越每分鐘9090下下1.2.3 1.2.3 呼吸速率超越每分鐘呼吸速率超越每分鐘2020下下1.2.4 1.2.4 血液中白血球大於每毫升血液中白血球大於每毫升1200012000或小於每毫升或小於每毫升40004000或含百分之或含百分之1010以上之不成熟白血球以上之不成熟白血球(bands)(bands)ETIOLOGYgram-negativegram-negative and and gram-gram-positive bacteriapositive bacteria fungi,fungi,mycobacteria,mycobacteria,rickettsiae,rickettsiae,viruses,viruses,or protozoansor protozoansPositive blood cultures:Positive blood cultures:30 to 6030 to 60%of patients with%of patients with sepsissepsis 60 to 8060 to 80%of patients with%of patients with septic septic shockshockSepsisDefinitions Used to Describethe Condition of Septic PatientsBacteremiaSystemic inflammatoryresponse syndrome(SIRS)SepsisSevere sepsisSeptic shockMultiple-organ dysfunctionsyndrome(MODS)Presence of bacteria in bloodFever,tachypnea,tachycardia,leukocytosis/leukopeniaSIRS has a proven or suspectedmicrobial etiologySepsis with 1 signs of organdysfunctionSepsis with hypotension or needfor vasopressorDysfunction of 1 organEpidemiology of Sepsis in theUnited States from 1979-2000N Engl J Med 2003;348:1546-54.EPIDEMIOLOGY2/3:2/3:in hospitalized patients.in hospitalized patients.Risk FactorsRisk Factors to to GNB bacteremiaGNB bacteremia diabetes mellitusdiabetes mellitus lymphoproliferative diseaseslymphoproliferative diseases cirrhosis of the livercirrhosis of the liver burnsburns invasive procedures or devicesinvasive procedures or devices drugs that cause neutropeniadrugs that cause neutropeniaEPIDEMIOLOGYRisk factors for GPC bacteremia vascular catheters,vascular catheters,indwelling mechanical devices,indwelling mechanical devices,burns,burns,intravenous drug injection.intravenous drug injection.Fungemia:immunosuppressed patients immunosuppressed patients neutropenianeutropenia broad-spectrum antimicrobial therapybroad-spectrum antimicrobial therapy TPNTPN Intestinal perforationIntestinal perforationPATHOPHYSIOLOGYEndotoxinGram negative bacilliLipopolysaccharide(LPS,also called endotoxin)PATHOPHYSIOLOGYMicrobial signalsGram positive cocciGram positive coccipeptidoglycanpeptidoglycan and and lipoteichoic acidslipoteichoic acids extracellular enzymesextracellular enzymes敗血症的症狀敗血症的症狀Fever or hypothermia(low body temperature)Fever or hypothermia(low body temperature)Hyperventilation Hyperventilation Chills Chills Shaking Shaking Warm skin Warm skin Skin rash Skin rash Rapid heart beat Rapid heart beat Confusion or delirium Confusion or delirium Decreased urine output Decreased urine output CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONSS/S:S/S:fever,chills,tachycardia,tachypnea,altered mental fever,chills,tachycardia,tachypnea,altered mental status,and hypotension.status,and hypotension.afebrile afebrile common in neonates,in elderly patients common in neonates,in elderly patients and in persons with uremia or alcoholism.and in persons with uremia or alcoholism.CLINICAL MANIFESTATIONSLlaboratory finding:Llaboratory finding:C-reactive proteinC-reactive protein fibrinogenfibrinogen complement componentscomplement components transferrintransferrin inhibits albumin synthesis inhibits albumin synthesis Leukocytosis,left shiftLeukocytosis,left shiftLABORATORY FINDINGSEarly sepsis Early sepsis leukocytosis with a left shiftleukocytosis with a left shift Respiratory alkalosisRespiratory alkalosis ThrombocytopeniaThrombocytopenia HyperbilirubinemiaHyperbilirubinemia proteinuria.proteinuria.neutrophils may contain toxic granulations,Dohle neutrophils may contain toxic granulations,Dohle bodies,or cytoplasmic vacuolesbodies,or cytoplasmic vacuolesLABORATORY FINDINGSProgressing of sepsis:Progressing of sepsis:thrombocytopenia worsens thrombocytopenia worsens prolongation of the thrombin timeprolongation of the thrombin time decreased fibrinogendecreased fibrinogen presence of D-dimers,suggesting DIC)presence of D-dimers,suggesting DIC)Azotemia,hyperbilirubinemia become prominentAzotemia,hyperbilirubinemia become prominent Elevated GOT GPTElevated GOT GPTLABORATORY FINDINGSProgressing sepsis:Progressing sepsis:hyperventilation induces hyperventilation induces respiratory alkalosisrespiratory alkalosis.accumulation of lactate,accumulation of lactate,metabolic acidosismetabolic acidosis(with increased anion gap)(with increased anion gap)hyperglycemiahyperglycemia,severe infection may precipitate,severe infection may precipitate diabetic ketoacidosis(DKA)diabetic ketoacidosis(DKA)Multiple organ dysfunction syndromeMOF:Dysfunction or failure of multiple organsDysfunction or failure of multiple organsreflecting widespread vascular endothelial reflecting widespread vascular endothelial injuryinjuryassociated with high fatality rates.associated with high fatality rates.Mortality and morbidity correlate with the Mortality and morbidity correlate with the number number of organs affected.of organs affected.DIAGNOSISS/S-Progressing sepsis tachypnea,tachypnea,tachycardia,tachycardia,altered mental status,altered mental status,The septic response can be quite variableThe septic response can be quite variablesystemic inflammatory response syndrome systemic inflammatory response syndrome SIRSSIRSDIAGNOSISDefinitive diagnosisDefinitive diagnosis isolation of the microorganism from blood or a local isolation of the microorganism from blood or a local infected site infected site Grams stainGrams stain culture of the primary site of infection.culture of the primary site of infection.TREATMENTSepsis may be fatal quickly.Sepsis may be fatal quickly.Successful managementSuccessful management urgent measures to treat the local urgent measures to treat the local site of infectionsite of infection,hemodynamic and respiratory supporthemodynamic and respiratory support eliminate the eliminate the offending microorganismoffending microorganism Therapy of acidosis and DIC,other complicationsTherapy of acidosis and DIC,other complicationsTREATMENTOutcome Outcome influenced by the patients influenced by the patients underlying diseaseunderlying disease aggressively treated.aggressively treated.Antimicrobial agents Antimicrobial agents PROGNOSISMortality:More than 25%1/3 within the first 48 h mortality can occur 14 or more days later.Late deaths poorly controlled infectionpoorly controlled infectioncomplications of intensive carecomplications of intensive caremultiple organs failuremultiple organs failure2.敗血症初期之緊急處理敗血症初期之緊急處理2.1 2.1 敗血症最初七小時之緊急處理措施著眼於恢敗血症最初七小時之緊急處理措施著眼於恢復因敗血症所引起的低血流灌注，恢復組織復因敗血症所引起的低血流灌注，恢復組織功能，應包含以下所有之緊急處理功能，應包含以下所有之緊急處理2.1.1 2.1.1 中心靜脈壓維持中心靜脈壓維持8-12mmHg8-12mmHg2.1.2 2.1.2 平均動脈壓維持大於等於平均動脈壓維持大於等於65 mmHg65 mmHg2.1.3 2.1.3 小便量維持大於等於每小時每公斤體重小便量維持大於等於每小時每公斤體重0.50.5毫升毫升2.1.4 2.1.4 中心靜脈氧飽含量維持大於等於中心靜脈氧飽含量維持大於等於70702.敗血症初期之緊急處理敗血症初期之緊急處理2.2 臨床檢驗2.2.12.2.1由周邊靜脈至少抽取由周邊靜脈至少抽取2 2至至3 3套血液培養後盡快給予抗生素治療套血液培養後盡快給予抗生素治療2.2.22.2.2盡快找尋可能之感染部位並取得檢體，如導管相關之感染，呼盡快找尋可能之感染部位並取得檢體，如導管相關之感染，呼吸器相關之肺炎等吸器相關之肺炎等2.2.32.2.3在抗生素使用前須取得可能感染部位之培養檢體，如尿液，腦在抗生素使用前須取得可能感染部位之培養檢體，如尿液，腦脊髓液，傷口，呼吸道檢體或其他部位之組織液脊髓液，傷口，呼吸道檢體或其他部位之組織液2.2.42.2.4必要時可作血清學檢查、檢測抗體及抗原或檢測尿液中退伍軍必要時可作血清學檢查、檢測抗體及抗原或檢測尿液中退伍軍人菌抗體人菌抗體2.敗血症初期之緊急處理敗血症初期之緊急處理2.2 2.2 臨床檢驗臨床檢驗2.2.52.2.5如有液狀檢體，可作染色鏡檢如葛蘭氏染色，抗酸菌染色等如有液狀檢體，可作染色鏡檢如葛蘭氏染色，抗酸菌染色等2.2.62.2.6軟組織感染時，除了做血液培養外，盡可能取得檢體做染色鏡檢軟組織感染時，除了做血液培養外，盡可能取得檢體做染色鏡檢2.2.72.2.7必要時可在主治醫師同意下對病灶施行超音波檢查，電腦斷層或核必要時可在主治醫師同意下對病灶施行超音波檢查，電腦斷層或核 磁共振檢查以確立病灶及嚴重程度磁共振檢查以確立病灶及嚴重程度2.2.82.2.8必要時可對病灶做抽吸或切片檢查以取得檢體必要時可對病灶做抽吸或切片檢查以取得檢體2.2.92.2.9如病灶有明顯積液、必要時可施以抽吸引流或外科治療如病灶有明顯積液、必要時可施以抽吸引流或外科治療 3.抗生素療法 3.13.1抗生素治療必須在取得適當檢體後盡快給予抗生素治療必須在取得適當檢體後盡快給予3.23.2當病患有嚴重敗血症或敗血性休克時，要盡速給予體液補充，除非當病患有嚴重敗血症或敗血性休克時，要盡速給予體液補充，除非有相當禁忌症有相當禁忌症(如急性肺水腫等如急性肺水腫等)3.33.3抗生素經驗療法必須依社區或院內感染，感染部位抗生素經驗療法必須依社區或院內感染，感染部位、菌種菌種、抗生素抗生素穿透能力及疾病人實際狀況來給予穿透能力及疾病人實際狀況來給予(參考本院每半年出版之菌種及抗參考本院每半年出版之菌種及抗生素敏感試驗表生素敏感試驗表)3.3.13.3.1抗生素治療以一種抗生素為原則抗生素治療以一種抗生素為原則3.3.23.3.2必要時可以合併抗生素使用以治療混合型感染或加強抗生素療效必要時可以合併抗生素使用以治療混合型感染或加強抗生素療效3.3.33.3.3抗生素之選擇依病人過去病史，過敏史，合併疾病，合併症及臨床抗抗生素之選擇依病人過去病史，過敏史，合併疾病，合併症及臨床抗生素敏感性做選擇生素敏感性做選擇3.抗生素療法3.43.4抗生素治療必須在使用抗生素治療必須在使用4848小時至小時至7272小時後重小時後重新評估新評估3.4.13.4.1依細菌培養及抗生素敏感性試驗之結果做調整依細菌培養及抗生素敏感性試驗之結果做調整3.4.23.4.2以窄效性抗生素為原則以窄效性抗生素為原則3.4.33.4.3為避免抗藥性產生，抗生素之選擇以低毒性及同為避免抗藥性產生，抗生素之選擇以低毒性及同類藥中價廉為原則類藥中價廉為原則3.4.43.4.4治療以治療以7-107-10天為原則，必要時可延長之天為原則，必要時可延長之3.4.53.4.5抗生素之使用及停用以培養結果及臨床醫師判定抗生素之使用及停用以培養結果及臨床醫師判定為原則為原則4 控制病源控制病源4.14.1臨床上所有敗血症病患均盡量查出並除去感染源臨床上所有敗血症病患均盡量查出並除去感染源4.1.14.1.1必要時以引流、清創或外科手術行之必要時以引流、清創或外科手術行之4.1.24.1.2病患有外科手術需求時，必須在完成初步急救並病患有外科手術需求時，必須在完成初步急救並解釋病情之後、在家屬同意下、盡速施行之解釋病情之後、在家屬同意下、盡速施行之5 輸液治療輸液治療5.15.1輸液治療包括自然血漿，人工血漿及一般輸液輸液治療包括自然血漿，人工血漿及一般輸液5.1.15.1.1人工輸液較血漿易出現水份積蓄及水腫人工輸液較血漿易出現水份積蓄及水腫5.1.25.1.2輸液速度以每輸液速度以每3030分鐘輸人工輸液分鐘輸人工輸液300300至至10001000毫升、或血漿毫升、或血漿以每以每3030分鐘分鐘300300至至500500毫升為主毫升為主5.1.35.1.3輸液速度及輸液量以臨床反應、血壓及尿液量做調整輸液速度及輸液量以臨床反應、血壓及尿液量做調整5.1.45.1.4密切監視病患以避免出現肺水腫及其他併發症密切監視病患以避免出現肺水腫及其他併發症5.2 5.2 個人體液需求量依個體及疾病狀況不同依臨床狀況做個人體液需求量依個體及疾病狀況不同依臨床狀況做調整調整6 血管收縮劑血管收縮劑6.1 6.1 當病患經輸液治療後仍無法維持適當的血壓及組織灌流時當病患經輸液治療後仍無法維持適當的血壓及組織灌流時得使用血管收縮劑治療得使用血管收縮劑治療6.2 6.2 當低血壓足以危及生命時，血管收縮劑得以和輸液治療同當低血壓足以危及生命時，血管收縮劑得以和輸液治療同時給予時給予6.3 Nor-epinephrine6.3 Nor-epinephrine或或dopaminedopamine須以中心靜脈方式給予須以中心靜脈方式給予6.4 6.4 使用血管收縮劑病患得施行動脈血壓監測使用血管收縮劑病患得施行動脈血壓監測6.5 Nor-epinephrine6.5 Nor-epinephrine起始劑量以起始劑量以0.010.01至至0.04 units/0.04 units/分為原則分為原則6.6 Cardiac index6.6 Cardiac index在在在在2.5 L.min-1.m22.5 L.min-1.m2以下者不宜使用血管收以下者不宜使用血管收以下者不宜使用血管收以下者不宜使用血管收縮劑縮劑縮劑縮劑 7 升壓劑升壓劑(Dobutamine)7.1 7.1 病患在經適當輸液治療後仍無法維持正常之病患在經適當輸液治療後仍無法維持正常之輸出量時得以使用升壓劑，必要時得合併血管輸出量時得以使用升壓劑，必要時得合併血管收縮劑使用收縮劑使用8 類固醇類固醇8.1 8.1 休克病患在適當補充輸液，使用血管升壓劑後，仍無法休克病患在適當補充輸液，使用血管升壓劑後，仍無法維持正常血壓時得以使用類固醇維持正常血壓時得以使用類固醇8.2 8.2 劑量以每天劑量以每天hydrocortisone200hydrocortisone200至至300300毫克，分毫克，分3 3至至4 4次給次給予，使用予，使用7 7天為原則天為原則、必要時得延長之必要時得延長之8.3 8.3 病患在檢測病患在檢測ATCHATCH前得以使用前得以使用dexamethasonedexamethasone取代取代hydrocortisonehydrocortisone以免影響血中以免影響血中cortisolcortisol濃度檢測值濃度檢測值8.4 8.4 敗血症病患未合併休克時，不建議使用類固醇敗血症病患未合併休克時，不建議使用類固醇9 人類活性人類活性C蛋白使用蛋白使用9.1 9.1 高死亡率之多重器官衰竭高死亡率之多重器官衰竭高死亡率之多重器官衰竭高死亡率之多重器官衰竭、敗血性休克敗血性休克敗血性休克敗血性休克、成成成成人呼吸窘迫症病患，無出血傾向時人呼吸窘迫症病患，無出血傾向時人呼吸窘迫症病患，無出血傾向時人呼吸窘迫症病患，無出血傾向時、APACHEII score=25APACHEII score=25、在主治醫師同意下得在主治醫師同意下得在主治醫師同意下得在主治醫師同意下得以使用人類活性以使用人類活性以使用人類活性以使用人類活性C C蛋白蛋白蛋白蛋白(rhAPC)(rhAPC)10 血類製劑 10.1 10.1 無特殊禁忌症之敗血症病患在血色素無特殊禁忌症之敗血症病患在血色素7.0g/dl7.0g/dl以下時得以以下時得以輸血輸血10.2 10.2 輸血目標值為血色素輸血目標值為血色素7.07.0至至9.0g/dl9.0g/dl10.3 10.3 病患無明顯出血時病患無明顯出血時、不建議以冷凍新鮮血漿來改善血液不建議以冷凍新鮮血漿來改善血液中之凝血值中之凝血值10.410.4不論有無出血現象，嚴重敗血症病患得以輸用血小板以不論有無出血現象，嚴重敗血症病患得以輸用血小板以維持血小板值在維持血小板值在5000/mm35000/mm3以上以上(510-9/L)(510-9/L)11 呼吸器使用呼吸器使用11.1 11.1 呼吸器使用依本院呼吸器使用原則，及成人呼吸器使用依本院呼吸器使用原則，及成人呼吸窘迫症呼吸器使用原則行之呼吸窘迫症呼吸器使用原則行之12 鎮靜劑麻醉藥品及肌肉鬆弛劑使用鎮靜劑麻醉藥品及肌肉鬆弛劑使用12.1 12.1 嚴重敗血症病患合併呼吸衰竭及呼吸器使用時嚴重敗血症病患合併呼吸衰竭及呼吸器使用時、得依得依本院藥物使用規範使用鎮靜劑麻醉藥物及肌肉鬆弛劑本院藥物使用規範使用鎮靜劑麻醉藥物及肌肉鬆弛劑12.2 12.2 必要時得以會診麻醉科必要時得以會診麻醉科、以進行藥物調整及避免藥物以進行藥物調整及避免藥物副作用副作用13 血中葡萄糖控制血中葡萄糖控制13.1 13.1 敗血症病患須嚴密監測並控制血糖敗血症病患須嚴密監測並控制血糖13.2 13.2 血中葡萄糖控制以血中葡萄糖控制以200 mg/dl200 mg/dl以下為原則以下為原則(有嚴格監有嚴格監測時得控制在測時得控制在140 mg/dl140 mg/dl以下以下)13.3 13.3 必要時得以使用胰島素取代口服降血糖藥控制血糖必要時得以使用胰島素取代口服降血糖藥控制血糖14 碳酸鹽治療碳酸鹽治療14.1 14.1 碳酸鹽治療得以使用於敗血症合併血流灌注所引起之酸中碳酸鹽治療得以使用於敗血症合併血流灌注所引起之酸中毒毒14.2 14.2 碳酸鹽治療酸中毒以碳酸鹽治療酸中毒以pHpH值值7.37.3以下為原則以下為原則14.3 14.3 嚴重敗血症病患得使用低劑量肝素或低分子量肝素預防深嚴重敗血症病患得使用低劑量肝素或低分子量肝素預防深部靜脈血栓形成部靜脈血栓形成14.4 14.4 病患有出血傾向或其他禁忌症時應避免使用肝素病患有出血傾向或其他禁忌症時應避免使用肝素15 預防壓力性腸胃道潰瘍預防壓力性腸胃道潰瘍15.1 15.1 所有敗血症病患均應預防壓力性潰瘍之產生所有敗血症病患均應預防壓力性潰瘍之產生15.2 15.2 以使用以使用H2 receptorH2 receptor抑制劑為原則，有禁忌抑制劑為原則，有禁忌症或不適用者除外症或不適用者除外16 褥瘡之預防褥瘡之預防16.1 16.1 敗血症合併活動能力降低之病患敗血症合併活動能力降低之病患、應預防褥瘡之產生應預防褥瘡之產生16.2 16.2 臨床上依預防褥瘡形成臨床技術手冊行之臨床上依預防褥瘡形成臨床技術手冊行之16.3 16.3 褥瘡之治療褥瘡之治療、必要時可給予抗生素及施行清創手術必要時可給予抗生素及施行清創手術Epidemiology of Sepsis in theUnited States from 1979-2000N Engl J Med 2003;348:1546-54.Causative OrganismsGram-positive bacteria 52.1%Gram-negative bacteria 37.6%polymicrobial infections 4.7%anaerobes 1.0%fungi 4.6%Specific organisms causing sepsis were recorded in51%of all discharge records over the 22-year period.Antimicrobial Agents in theManagement of SepsisCrit Care Med 2004;32:858-73.Two blood culture-one percutaneous-one from each vascularaccess 48 hrs-microbial and clinical data-narrow-spectrum antibiotics-non-infectious cause identified-prevent resistance,reduce toxicity and reduce cost-one or more drugs active against likely bacterial or fungal pathogens-consider microbial susceptibility patternsEvaluate patient for afocused infectionReassess antimicrobialregimen at 48-72 hrsBegin IV antibiotics withinthe first hr of recognitionof severe sepsisNorepinephrine 4 mg/4 ml/amp(diluted by D5W)-0.033.3 g/kg/min(2200 g/kg/hr)Epinephrine 1 mg/1 ml/amp-0.060.47 g/kg/min(3.630 g/kg/hr)Dopamine 200 mg/5 ml/amp-255 g/kg/min(0.123.3 mg/kg/hr)Dobutamine 250 mg/20 ml/amp-228 g/kg/min(0.121.68 mg/kg/hr)Vasopressin 20 U/1 ml/amp-0.010.04 U/min(0.62.4 U/hr)Crit Care Med 2004;32:1928-48.Vasopressor and InotropicsRole of Corticosteroid in theManagement of Septic ShockCrit Care Med 2004;32:858-73.Treat patients who still require vasopressors despitefluid replacement with hydrocortisone 200-300 mg/dayfor 7 days divided in 3-4 doses or by continuousinfusion(Grade C)High dose of corticosteroids(300 mg/day)shouldNOT be used in severe sepsis or septic shock.(Grade A)Crit Care Med 2004;32:858-73.Role of Corticosteroid in theManagement of Septic ShockIn the absence of shock,corticosteroids should NOTbe administrated for the treatment of sepsis(Grade E)The use of ACTH stimulation test to identify responders(9 g/ml increase in cortisol 30-60 mins post-ACTHadministration)and to continue therapy is optional.Should NOT wait for ACTH stimulation results toadminister corticosteroids(Grade E)Mechanical Ventilation ofSepsis-induced ALI/ARDSCrit Care Med 2004;32:858-73.High tidal volume that are coupled with high plateaupressures should be avoided in ALI/ARDS.-reduce tidal volume over 1-2 hrs to 6 ml/kg predicted body weight-maintain inspiratory plateau pressure 30 cmH2O-maintain SaO2/SpO2 88-95%-anticipated PEEP settings at various FiO2 requirementsFiO2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0PEEP 5 5 8 8 8 10 10 12 14 14 14 16 18 20-24(Grade B)Intensive Insulin in CriticalIll PatientsCrit Care Med 2004;32:858-73.After initial stabilization of patients with severe sepsis-maintain glucose 150 mg/dl by continuous infusion of insulin-monitor blood glucose every 30-60 mins and then q4h(Grade D)In patients with severe sepsis,a strategy of glycemiccontrol should include a nutrition protocol with thepreferential use of the enteral route.(Grade E)Intensive Insulin in CriticalIll PatientsN Engl J Med 2006;354:449-61.-p
