假单胞菌与呼吸机相关性肺炎诊断及预防策略探讨-黎毅敏

Cliquez et modifiez le titre,Cliquez pour modifier les styles du texte du masque,Deuxime niveau,Troisime niveau,Quatrime niveau,Cinquime niveau,*,假单胞菌与呼吸机相关性肺炎诊断及预防策略探讨,广州医学院 第一临床学院,广州呼吸疾病研究所,英东广州危重症监护医学中心,黎毅敏,医院获得性肺炎和呼吸机相关肺炎,(VAP),医院获得性肺炎指住院48小时以后发生的肺炎，呼吸机相关性肺炎(,VAP),指接受机械通气(,MV)48,小时或以后发生的肺炎,早发,VAP,：指机械通气后4天内发生,晚发,VAP,：认为5天或者更后发生,VAP,（Langer,1987,；,ATS,1995,),接受机械通气的患者发生肺炎的风险增加621倍,VAP,发病机制,机体呼吸道与全身防御机制受损,机械通气时病原菌侵入和定植呼吸道的方式,口咽部定植菌的“误吸”,胃肠内细菌的逆行,吸入带菌气溶胶,气管导管和医疗操作如吸痰,高强度致病菌,医院获得性肺炎的发病机制,假单胞呼吸机相关肺炎,(PA,VAP),主要的危险因素,:,气管内插管,患者的危重状态,医院和,ICU,内细菌的定植,独立的危险因素：年龄、基础疾病、免疫抑制、昏迷,VAP,常见的危险因素,血浆白蛋白水平,年龄, 60 yrs,ARDS, COPD,昏迷,烧伤,创伤,多器官衰竭,/,功能紊乱,大量的胃内容返流误吸,胃,/,气管细菌的定植,Chastre J, Fagon J-Y AJRCCM 2002,肌松剂、持续的镇静, 4,单位的血液制品,MV (? intubation) 2 d,经常更换呼吸机管道,重新插管,鼻胃管,仰卧位,曾经,+/-,抗生素,宿主方面的因素,干预因素,ICU,患者,VAP,的发生率与粗死亡率比较,作者 年份,病例数 发生率,%,诊断方法 死亡率,%,Salata 1987 51 41,临床活检,76,Craven 1986 233 21,临床,55,Langer 1989 724 23,临床,44,Fagon 1989 567 9,保护毛刷,71,Kerver 1987 39 67,临床,30,Driks 1987 130 18,临床,56,Torres 1990 322 24,临床保护毛刷,33,Baker 1996 514 5,保护毛刷,/,灌洗,24,Kollef 1993 277 16,临床,37,Fagon 1996 1118 28,保护毛刷,/,灌洗,53,Timsit 1996 387 15,保护毛刷,/,灌洗,57,Cook 1998 1014 18,临床,-,保护毛刷,/,灌洗,24,Tejada 2001 103 22,保护毛刷,44,ICU,患者的医院获得性肺炎,医院获得性肺炎的发生率,10%,3-21 x,（如接受,MV,）,VAP,发生率,8-67%,一般为,20-28%,VAP ARDS,患者发生率,死亡率：,2-3 x VAP than without,G, 杆菌的肺炎的预后比,G+,球菌感染更差,因假单胞菌感染引起的,VAP,死亡率,30%,Chastre J, Fagon J-Y AJRCCM,Garau J.,Curr Opin Infect Dis 16:135143,Etiology of VAP as documented by bronchoscopic techniques in 24 studies for a total of 1689 episodes and 2490 pathogens,PathogenFrequency%,Pseudomonas,Acinetobacter spp.,Stenotrophomonas maltophilia,Enterobacteriaceae,Haemophilus spp,.,Staphylococcus aureus,Streptococcus pneumoniae,Coagulase,Neisseria spp,Jean Chastre Am J Respir Crit Care Med 165, 2002,2003,年广州呼研所细菌监测结果,革兰氏阴性杆菌,杆 菌,总株数,百分率,铜,绿假单胞菌,334 39.3,嗜麦芽单胞菌,107 12.6,鲍曼不动菌,83 9.8,克雷伯菌属,65 6.8,产硷杆菌属,56 6.5,2003,年广州呼研所细菌监测结果,革兰氏阳性球菌,球 菌,总株数,百分率,金黄色葡球菌,96 23.2,凝阴葡球菌,86 20.7,他莫拉氏菌,83 20.0,草绿链球菌属,57 13.7,链球菌属,56 13.5,2003,年英东,-,广州重症监护中心,VAP,患者监测（,PSB/BAL),细 菌,总株数,百分率,铜绿假单胞,嗜麦芽单胞菌,金黄色葡球菌,凝阴葡球菌,36 6.9,鲍曼不动菌,41 7.9,2003,年英东,-,广州重症监护中心,G-,杆菌监测结果,2003,年英东,-,广州重症监护中心,G+,球菌监测结果,MRSA 89.8% (53/59),的诊断,临床诊断的,VAP,常常只有,50,左右得到细菌学的证实,Fagon,Am Rev Respir Dis 139,1989,Tejada,Crit Care Med 28, 2000,And 8 other studies,Bacteriological confirmation of clinically suspected VAP,Author Clinically Bacteriological,Suspected VAP confirmation,(n)(n)%,Fagon842732,Croce1364634,Rodriguez1104541,Luna1326549,Bonten1387252,Kollef1306046,Sanchez513671,Ruiz764255,Fagon2049044,Tejada1032322,VAP,的诊断的三个基本参考因素,肺部感染的系统判断,胸部影像学上新出现或原来的渗出病灶增加,肺间质感染的细菌学证据,Andrews C P, Chest 1981;80,t 38,3 C,WBC 1,2 X 1,0,9,/,m,l,脓性气管分泌物,影像学异常表现,敏感性,69%,，特异性,75%,（尸检病理）,T,orres A. Am J Respir Crit Care Med 1994;149,临床诊断标准,24,个,ARDS,机械通气病人,回顾性研究,病理证实肺炎,: 14,病人,临床诊断肺炎,:,敏感性,: 64%,特异性,: 80%,Andrews et al. Chest 81,临床诊断标准问题,临床肺部感染评分,Clinical Pulmonary Infection Score,（,CPIS,）,* temperature C, 36.5 and 38.5 and 39 or 4,000 and 500 = + 1 point,* tracheal secretions,absence,of tracheal secretions = 0 point,presence of tracheal secretions = 1 point + purulent secretions = + 1 point,* PaO2/FiO2, mmHg, 240 or ARDS = 1 point, 240 and no evidence of ARDS = 0 point,* pulmonary radiography,no infiltrate = 0 point,diffused (or patchy) infiltrate = 1 point,localized infiltrate = 2 points,* culture of TA (semiquantitative : 0,1,2 or 3 +),pathogenic bacteria cultured 1 = 1 point + same bacteria,on Gram stain 1 + = + 1 point,Pugin et al. ARRD 91,与肺泡灌洗（,BAL）,比较,: CPIS 6,敏感性,: 93 %,特异性,: 100 %,Pugin et al. ARRD 91,临床诊断标准,Clinical Pulmonary Infection Score,临床诊断标准,Clinical Pulmonary Infection Score,modified,Singh et al.,后又增加了一个指标：,肺部,X,片阴影,如肺部,X,片阴影无进展或变化，则,CPIS=0,如有异常（除去心功能不全和,ARDS）， = 2,第一天计算前,5,个指标：体温、白细胞、气管吸出物、氧和情况和,X,片，第三天计算全部,7,个指标，如,CPIS,大于,6,则提示,VAP,Singh N, Am J Respir Crit Care med 162, 2000,改良,CPIS,评分系统,Luna: Crit,CPIS,预测,VAP,患者预后的价值,Luna CM et al. Crit Care Med 31(3):676-82 March 2003,治疗反应差,治疗反应好,病死率,Luna Carlos,：等对,6,个中心的患者进行评分,其中,472,例机械通气患者有,VAP,的临床证据,但仅,63,例经,BAL,或血培养得到证实,.,结果,:,CPIS,从,VAP-3,天升高,31,例幸存者经治疗后下降,32,例死亡者无降低,Luna Carlos,et al. Criti Care Med, 2003,31(3):676-682,CIPS,评分系统的作用,Muriel Fartoukh,等对,79,例疑诊肺炎患者进行,CPIS,评分,并以,BAL,定量培养作参考对照,结果： 敏感性,:60%,特异性,:,59%,Fartoukh M, et al: Am J Respir Crit Care Med 2003;168:173-179,Neus,等对,25,例疑诊肺炎的危重患者进行,CPIS,评分,并在,患者死亡后取肺组织作定量培养作参考标准,结果： 敏感性,:77%,特异性,:44%,Neus et al. Thorax, 1999; 54:867-873,临床肺部感染评分（,CPIS,）,对初期的筛选有用,有助于指导临床治疗,评分为,1-10,分,判断标准,:,6,分,敏感性及特异性均不甚理想,PSBBAL ATCombCPIS,seuil =10,3,10,4,10,4,10,5,10,6,10,3,6,Torrs,AJRCCM 94,36,/50,50,/45,- - - -,Marquette AJRCCM 95,58,/89,47,/100,67,/75,67,/75,53,/87,-,Chastre AJRCCM 95,82,/89,91,/78 - - - - -,Papazian AJRCCM 95,33,/95,50,/95,72,/80,56,/95,44,/100,67,/80,72,/85,临床诊断标准与病理结果相比较的研究,敏感性,/,特异性,VAP,的诊断方法,有创诊断和无创诊断方法的矛盾,通过常规吸痰或盲目小灌洗对气管分泌物进行采样，尽管能够分离出致病菌，但同时也能够得到更多的污染细菌,支气管肺泡灌洗,(BAL),或保护性毛刷技术(,PSB),能够提供更为准确的资料，帮助医生决定是否停用经验性抗生素，或将广谱抗生素改为窄谱,VAP,的微生物学病原学诊断,无创方式,气道内吸痰：定量,/,半定量,有创方式,保护性毛刷（,PSB,）,支气管肺泡灌洗（,BAL,）,肺组织活检培养,(,可能金标准,),开胸活检,Papazian et al. Anesthesiology 98,ARDS,病人,4,年,37,例活检,床边,: 25,病人,手术室,: 12,病人,活检前,活检后,PaO2 /FiO2*,120 47 152 60,PEEP cmH20,10 3 10 3,VAP,病原诊断方法,临床诊断：症状 体征,CIPS,无创方法：,ETA,经气道吸引：定量,/,半定量培养, 10,6,7,cfu/ml,有创的方法：,PSB,：, 10,3,cfu/ml,BAL/Mini,BAL: 10,4,cfu/ml,开胸肺活检,: “,可能” 金标准,有创检查,vs.,无创检查技术对,VAP,的影响,Ruiz,M,。,AJRCCM Vol 162. pp 119125, 2000,VAP,患者（,ATS,，,1995,，,2001,）,76,例患者,(Group 1,无创技术经气管吸痰, n=39,Group 2,有创检查, n= 37,PSB = 8 PSB/+BAL = 29).,Non= tracheobronchial aspirates TBAS,Invasive= bronchoscopically retrieved protected,specimen brush PSB and,bronchoalveolar lavage BAL.,GENERAL CHARACTERISTICS OF THE STUDY POPULATION AND OUTCOME,MORTALITY RATES IN BOTH GROUPS AND DIFFERENT SUBGROUPS OF BOTH GROUPS,结 论,Current evidence supports noninvasive microbial investigation as the principal approach to microbial investigation in suspected VAP,.,有创检查技术在,VAP,诊疗中的价值,Andrew FS,，,et al. Crit Care Med 2005;33:46-53,比较有创检查技术对用药的影响：,1996,2003,年,678,项研究中,4,项随机研究,n= 628 pts,5,项描述性研究,n= 635 pts,Table 1.,Characteristics of the randomized studies of diagnostic strategies,Table 2.,Antibiotics and outcomes in randomized studies of diagnostic strategies,Figure 1.,Invasive strategies for the diagnosis of ventilator-associated pneumonia and their impact on mortality,Figure 3.,Impact of invasive strategies for the diagnosis of ventilator-associated pneumonia on alterations in antibiotic management.,Figure 4.,Changes in antibiotic prescribing based on invasive testing: observational studies,.,FOB,有创检查与临床诊断,VAP,对预后的影响,结 论,仍然缺乏系统和大规模的临床研究,有创检查技术降低,VAP,的死亡率,X,影响,VAP,应用抗生素的选择,其他的实验室诊断方法,炎症介质的测定：,TNFa,、,IL,1,、,6,内毒素的测定,(GNB),：,NBL/BAL,n=64 pts,59 BALs and 92 NBLs,P G Flanagan,J. Clin. Pathol,2001;54;107-110,Type III secretory proteins,：,6 x,n=108 pts, 动物模型,Roy-Burman A,J Infect Dis 2001; 183:17671774,.,有关,PA,在,ET,VAP,患者中的定植,Intensive Care Med (2004) 30:17681775,脉冲凝胶电泳,N,=72 pts 1067 isolates,来源：水源、胃、口咽部、声门下的分泌物、气管和,直肠,结果：,54.2%(n=39),的患者有定植,气管：,30.5%.,10pts,插管时存在，,4pts VAP 4 2 days.,31pts,获得；,4 pts VAP 10 5 days,62.4%,水的样本可分离到,PA, PT1,PT2,8pts PA-VAP(BAL),50%,外源性,结论,插管患者,PA,感染不应忽略外源性的定植,有关影像学的诊断研究,Journal of Thoracic Imaging,17:,5357 2002,N,=28 patients PAP (,12 men, 16 women; mean age, 57 yrs),PA,VAP,的治疗原则,VAP,治疗最为关键的阶段是前3天，此时尚无法得到致病菌或药敏的检查结果。,Core organisms responsible for VAP and recommended antimicrobial therapy(1),Core OrganismsCore Antibiotics,Early-onset VAP, no risk factor,Enteric gram- (nonpseudomonal)Cephalosporin,Enterobacter spp.,Second generation,Escherichia coli,Nonpseudomona 3,rd,or,Klebsiella spp,.,B-lactam-B-lactamase,Proteus spp.,Inhibitor combination,Serratia marcescens,Haemophilus influenzae,If allergic to penicillin:,MSSA Fluoroquinolone,or,Streptococcus pneumoniae,Clindamycin +aztreonam,Adapted from the American Thoracic Society. Am J Respir Crit Care Med 153,1996,Core organisms responsible for VAP and recommended antimicrobial therapy(2),Core OrganismsCore Antibiotics,late-onset VAP,Core organisms plusAminoglycoside or,ciprofloxacin plus,Pseudomonas,Antipseudo penicillin,Acinetobacter baumanni,B-Lactam-,B-lactamase inhibitor,Ceftazidime,Imipenem,Aztreonam,Consider MRSA+Vancomycin,Adapted from the American Thoracic Society. Am J Respir Crit Care Med 153,1996,针对,VAP,错误的经验性抗生素治疗能够增加病死率,参考文献,病例数,病死率 （正确),病死率不正确),p-,值,Luna,50,37.5%,*,91.2%,*,p0.001,Lerma,430,16.2%,#,24.7%,#,p=0.039,Rello,113,15.6%,#,37%,#,p0.05,*总病死率, #,归因病死率,Luna CM et al Chest 111:676-85, 1997,Alvarez-Lerma F Intensive Care Med 22:387-94, 1996,Rello J et al Am J Resp Crit Care Med 156:196-200, 1997,VAP,致病菌与经验性抗生素治疗错误的比例,铜绿假单胞菌,MRSA,不动杆菌属,Kollef MH Clinical Inf Diseases 31 Suppl 4:131-8, Sept 2000,机械通气时间与既往抗生素治疗是多重耐药致病菌,VAP,的独立危险因素,多重耐药致病菌,N=22,MV 7,天,抗生素：否,N=12,MV 7,天,抗生素：是,N=17,MV, 7,天,抗生素：否,N=84,MV, 7,天,抗生素：是,铜绿假单胞菌,0,4(20%),2(6.3%),33(21.7%),鲍曼不动杆菌,0,1(5.0%),1(3.1%),20(13.2%),嗜麦芽窄食单胞菌,0,0,0,6(3.9%),MRSA,0,1(5.0%),1(3.1%),30(19.7%),Trouillet JL et al.Am J Respir Crit Care Med 157:531-39, 1998,抗生素治疗,作用,=,在感染部位细菌种植数量，依靠机体自身抗感染能力清除消灭病原体,哪些细菌,?,呼吸道感染,P. aeruginosa (30-35%),S. aureus (30-35%),Enterobacter (5-10%),Acinetobacter (5-10%),K. pneumoniae (3-5%),E. coli (3-5%),经验性抗生素治疗原则,取决于,什么病房,(,环境,),什么病人,是否免疫抑制,是否有感染性休克,是否前面用过抗生素,肾功能情况,经济情况,Mortality rates according to initial empiric antibiotic therapy,Author,Crude Mortality Rates of patients Receiving,Inadequate AdequateP value,Alvarez34.9%(n=146)32.5%(n=284)NS,Rello,Kollef,Sanchez42.9%(n=14)25.0%(n=24)NS,Ruiz50.0%(n=18)39.3%(n=28)NS,Dupont60.7%(n=56)47.3%(n=55)NS,Jean Chastre AJRCCM,；,165, 2002,单药治疗或联合治疗,确诊呼吸道感染,P. aeruginosa, Acinetobacter, Enterobacter, Klebsiella :,联合治疗,-lactamine + aminoside,E. coli, SAOS, H. influenzae :,单药治疗,如无感染性休克,-lactamine,晚期,VAP,=,联合治疗,= B-lactamine + aminoside,猛击策略,=,快,狠,短,一次注射,高峰浓度, 3-5,天,喹喏酮,喹喏酮耐药,与,B-lactamines,交叉耐药,抗生素治疗：动物实验,经,Cipro,处理的鼠炎症反应,imipenem or cephalosporins,Chemotherapy 2001;47:421429,.,14,员环的大环内酯类：减少生物膜的形成 慢性感染，,CF,？,J,Antimicrob Chemother 2002;49:867870,imipenem, cefepime, ceftazidime, piperacillin/tazobactam, and aztreonam,可显著降低细菌在肺内的滴度,Antimicrob Agents Chemother 2002; 46:20322034,临床的建议：,缺乏,EBM,的证据,头孢类：,CTZ,，,CEP,碳氰霉烯类：,Imipenem vs. Meropenem,lac+ inh:,Piperacillin/tazobactam,-lactam + antipseudomonal fluoroquinolone,+,Aminoglycoside,VAP,的经验治疗,VAP,的预防,预防,VAP,的策略,(2),Marin H. Kollef,Crit Care Med 2004; 32:1396 1405,Recommendations for Strategies To Prevent VAP,Ann Intern Med.,2003;138:494-501,VAP,的预防策略（,3,）,Evidence-Based Clinical Practice Guideline for the Prevention ofVentilator-Associated Pneumonia,Ann Intern Med.,2004;141:305-313.,VAP,的预防,体位,持续吸痰护理,痰池引流,体位与,VAP,仰卧位是,VAP,一个独立的风险因素,半卧位（,45,o,）可减少,VAP,的发生率，,尤其在肠内营养患者,每天须大部分时间保持半卧位,Semirecumbency Reduces VAP,*,*,Drakulovic MB et al. Lancet 1999;354:1851-8,MICU and RICU patients,Study powered for 182 patients,Study stopped early,Positioning and VAP: Summary,Drakulovic MB,等多中心,:,86,例气管插管机械通气患者随机进行对照研究,两组 仰卧位,vs,半卧位,结果,:,半卧位组的,VAP,发生率明显减少,8% vs,Table 1.,Summary of Studies of Effect of Semi-Recumbent Positioning on Risk for Ventilator-Associated Pneumonia,and death,Ann Intern Med.,2003;138:494-501,.,持续吸痰护理,连续声门下吸痰（,CAS,）,减少气道内分泌物,需维持合适的气囊内压，减少口咽分泌物流入气道,有效的预防需：,减少口咽分泌物的数量及防止流入下呼吸道,改善口咽部细菌的致病性及其数量,提高宿主的抵抗力,痰池引流,有创通气时，人工气道气囊上形成痰池,痰池可渗入下呼吸道,细菌含量丰富,是,VAP,的一个风险因素,痰池引流可减少,VAP,的发生,Table 3.,Summary of Studies of Effect of Aspiration of Subglottic Secretions on Risk for VAP and Death,Intermittent Subglottic Secretion Drainage Reduces VAP Incidence,Smulders K et al. Chest 2002; 121:858-62,Probability of No VAP,Subglottic drainage,Control,小结：PAVAP,目前仍是临床医学工作者的难题,诊断：临床实验,病原学：,ETA,？,BAL,？,Biopsy,治疗：指南经验,期待：多中心的研究,谢谢各位！,