Sepsis年前瞻

1、内内 容容Sepsis 概述概述Sepsis 治疗进展与反思治疗进展与反思Sepsis 2005的预期进展的预期进展启启 示示Living tissue Living tissue broking downbroking downPepsisPepsisSepsisSepsis1822-1895 1827-1912 1812-1865 PasteurListerSemmelweis 历史的回顾历史的回顾800/10万万100年间美国感染性疾病的死亡率变迁年间美国感染性疾病的死亡率变迁Incidence 82.7/10万万 240.4/10万万Mortality 27.8% 17.9%1979-

2、2000年年 美国美国Sepsis 的流行病调查的流行病调查80/10万万1.Davies A et al. Abstract 581. 14th Annual Congress of the European Society of Intensive Care Medicine, Geneva, Switzerland, 30 September-3 October 20012.Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis

3、of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:13031310EndotheliumNeutrophilMonocyteIL-6IL-1TNF- IL-6Inflammatory Responseto InfectionThrombotic Responseto InfectionFibrinolytic Responseto InfectionTAFIPAI-1SuppressedfibrinolysisFactor VIIIaTissue FactorCOAGULATION CASCA

4、DEFactor VaTHROMBINFibrinFibrin clotTissue FactorOrganismsSepsis with 1 sign of organ failureCardiovascular (refractory hypotension)RenalRespiratoryHepaticHematologicCNSMetabolic acidosis0%10%20%30%40%50%60%70%80%90%OneTwoThreeFourFivePROWESSVincentData from PROWESS (placebo arm). Eli Lilly, Data on

5、 File and Vincent JL, et al. Crit Care Med 1998;21:1793-800.*Four or more dysfunctional organs*指标指标标准标准已明确或疑似的感染已明确或疑似的感染a, 并伴有下列某些征象并伴有下列某些征象:(1) 一般指标一般指标发热发热 （中心体温（中心体温 38.3 ）、低温）、低温 (中心体温中心体温 90 次次/m in 或大于不同年龄段正常心率范围或大于不同年龄段正常心率范围2 个标准差个标准差气促气促 30 次次/分分意识改变意识改变明显水肿或液体正平衡明显水肿或液体正平衡( 20 m l/kg 超过超

6、过24 h)高糖血症高糖血症(血糖血糖 7.7 mmo l/L 或或120 mg/d l) 而无糖尿病史而无糖尿病史(2) 炎症反应参数炎症反应参数白细胞计数白细胞计数 12109/L 或白细胞计数或白细胞计数 10%血浆血浆C 反应蛋白反应蛋白 正常值正常值2个标准差个标准差前降钙素前降钙素 正常值正常值2个标准差个标准差(3) 血流动力学参数血流动力学参数收缩压收缩压 90 mm Hg , 平均动脉压平均动脉压 40 mm Hg混合静脉血氧饱和度混合静脉血氧饱和度 0.70b心排指数心排指数 3.5 L/m in/m2 (4) 器官功能障碍指标器官功能障碍指标低氧血症低氧血症(PaO2/F

7、iO2 300 mm Hg)急性少尿急性少尿(尿量尿量 1.5 或活化部分凝血激酶时间或活化部分凝血激酶时间 60 s)腹胀腹胀(肠鸣音消失肠鸣音消失)血小板减少症血小板减少症(血小板计数血小板计数 40 mg/L 或或70 mmo l/L(5) 组织灌流参数组织灌流参数高乳酸血症高乳酸血症( 3 mmo l/L )毛细血管再充盈时间延长或皮肤出现花斑毛细血管再充盈时间延长或皮肤出现花斑Sepsis 概述概述Sepsis 治疗进展与反思治疗进展与反思Sepsis 2005的预期进展的预期进展启启 示示SAFE Trial 亚组亚组28天死亡率分析天死亡率分析 （no/Tatal no）白蛋白组

8、白蛋白组生理盐水组生理盐水组RR (95% CI)P值值Severe Sepsis185/603 (30.7)217/615 (35.3)0.87 (0.74-1.02)0.09ARDS24/61 (39.3)28/66 (42.4)0.93 (0.61-1.41)0.72Trauma81/596 (13.6)59/590 (10.0)1.36 (0.99-1.86)0.06traumatic brain injury59/241 (24.5)38/251（15.1）1.62 (1.12-2.34)0.0091.The SAFE Study Investigators A Comparison

9、 of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit. N Engl J Med 2004;350:2247-56.2. Fan E, Stewart TE. Albumin in critical care: SAFE, but worth its salt? Critical Care 2004, 8 EndotheliumNeutrophilMonocyteIL-6IL-1TNF- IL-6Activated Protein CInactivationInactivationInactivati

10、onPrevention of activationActivated Protein CInflammatory Responseto InfectionThrombotic Responseto InfectionFibrinolytic Responseto InfectionTAFIPAI-1SuppressedfibrinolysisActivatedProtein CReductionof RollingInhibitionInhibitionActivated Protein CFactor VIIIaTissue FactorCOAGULATION CASCADEFactor

11、VaTHROMBINFibrinFibrin clotTissue FactorOrganismsBernard GR, Vincent JL, Laterre PF, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-70905101520253035PlaceboDrotrecogin Alfa (Activated)In-Hospital28-Dayp = 0.005p = 0.023Percent Morta

12、lity24.7%30.8%29.4%34.6%Bernard GR, Vincent JL, Laterre PF, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-7090.00.10.20.30.40.501m2m3mMortality RatePlaceboXigrisMonths from Start of Infusion Log rank P = 0.001Bernard GR, Vincent JL

13、, Laterre PF, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709020406080100120PlaceboDrotrecogin alfa (activated)RespiratoryFailureRefractorySepticShockSepsis-RelatedMulti-OrganFailure1029646632846Number of Deaths051015202530Study

14、DrugInfusion Period28-DayStudy PeriodDrotrecogin alfa (activated)Bleeding EventsSerious Bleeding EventsPlaceboBleeding Events18.8%24.9%2.4%3.5%10.8%1.0%17.7%2.0%p0.001p 34 g/dl or increase 9 g/dl Plasma cortisol level 15 g/dl or increase 9 g/dlAnnane D, Sebille V, Charpentier C, et al. Effect of tre

15、atment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 862-71.Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 28

16、8: 862-71.Bennett, 196396 (54)98 (32)0.65 (0.50-0.84)Klastersky, 197146 (24)39 (22)1.10 (0.69-1.75)Schumer, 197686 (9)86 (33)1.45 (0.69-1.73)Thompson,197628 (22)32 (25)0.98 (0.37-2.59)Lucas,198423 (5)25 (5)0.98 (0.7-1.31)Spung, 198443 (33)16 (11)0.74 (0.29-1.89)Bone, 1987191 (65)190 (48)0.88 (0.78-1

17、.01)VA, 1987112 (23)111 (24)1.01 (0.89-1.16)Luce, 198838 (22)37 (20)0.92 (0.55-1.53)Bollaert, 199822 (7)19 (12)1.85 (1.01-3.40)Brlegel, 199920 (3)20 (4)1.06 (0.80-1.42)Yildiz, 200220 (8)20 (12)1.50 (0.79-2.83)Annane, 2002150 (82)149 (91)1.17 (0.89-1.52)Summary All study (n=13)875 (357)842 (339)1.01

18、(0.94-1.09) Pre-1989 studies663 (257)634 (220)0.97 (0.89-1.04) Post-1997 studies 212 (100)208 (119)1.23 (1.01-1.50)2004 NIH 之之Meta-Analysis of Steroids on Survival and Shock during Sepsis0.611.00.370.221.652.724.48No effectBenefitHarm（ CORTICUS/ESICM）2005 Sprung and colleagues 800-patients trial, ca

19、lled CORTICUS Hypothesis that hydrocortisone (50 mg intravenously 4 times daily for 5 days, then tapered over 6 days) will reduce 28-day mortality by 10% in patients with septic shock whose cortisol levels do not increase by more than 248 mmol/L in response to corticotropin stimulation. Analyze the

20、effects of low-dose corticosteroids on responders to corticotropin. Compare total and free cortisol levels at baseline and after stimulation in their patients. Evaluate the effects of this agent in all patients regardless of their response to corticotropin stimulation. Annane D, Briegel J, Sprung CL

21、. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003;348:2157-9. EditorialPhysicians Should Administer Low-Dose Corticosteroids Selectively to Septic Patients until an Ongoing Trial Is CompletedLuce JM. Ann Intern Med. 2004;141:70-72. Rivers E, Nguyen B, Havstad S, et al. Early

22、 goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001, 345:1368-13772001年，年，Rivers1等提出在脓毒性休克等提出在脓毒性休克发病发病6h内，使治疗目标达到内，使治疗目标达到CVP812mmHg，MAP65mmHg，尿量至，尿量至少少0.5ml/（kgh），以及中心静脉血），以及中心静脉血氧饱和度氧饱和度70%等。等。接受接受EGDT的病人在的病人在6h内的输血输液内的输血输液量和多巴酚丁胺使用量均大于常规治量和多巴酚丁胺使用量均大于常规治疗者，在疗者，在772h的输血输液量和用药的输血输液量和用药量均少于常规治疗者，已达到的目标量均少于常规治