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1、PCT临床应用指导抗生素治疗,浙江省人民医院ICU 孙仁华,内容,PCT特点、应用指导抗生素治疗,PCT,PCT是降钙素无激素活性的前肽物质，116个氨基酸组成的糖蛋白，分子质量约13 ku，由甲状腺C细胞合成 ，生理情况下血浓度0.1 ng/mL。严重细菌、真菌和寄生虫感染且有全身表现时，血清PCT含量升高,不受激素应用的影响。3-6小时即可检测到，8-24小时达高峰，半衰期20-24小时。病毒感染或非感染性致病原炎症反应(SIRS)，PCT含量不升高或仅轻中度升高,非特异性PCT诱因-可能的假阳性结果包括:手术创伤、多处创伤：在手术后的前两天出生48小时以內的新生儿免疫刺激药物 (OKT3
2、,TNFa,IL-2.)严重烧伤血液透析中暑,PCT略微增加感染早期 ( 6-12 小時后重新检测!)之前进行过有效的抗生素治疗非典型性肺炎(肺炎支原体、肺炎衣原体)局部感染,PCT的局限性,PCT的影响因素,受以下因素影响 * 甲状腺功能 是功能性甲状腺髓样癌的肿瘤标志物* 肾功能 严重肾功能受损者中水平较高不受以下因素影响* 类固醇药物* 自身免疫性疾病* 年龄、性別* 免疫功能低下状态:肝硬化、HIV感染,PCT的应用,诊断、鉴别诊断细菌感染判断感染的严重程度及预后指导抗生素的治疗,PCT与真菌感染,Candida (念珠菌) 念珠菌相关的脓毒症并没有显现出一致性的上升Aspergill
3、osis (曲霉菌) PCT 会延迟上升 第一天 平均 1.5 ng/ml,重症医学杂志.2006;32:1577-83,菌血症,念珠菌血症,其他病原体感染中的PCT水平,在一次内毒素刺激的人体试验中不同的生物标志物的动力学变化,Reinhart K, et al. Crit Care Clin 2006;22;503-519,在监测方面，PCT有着明显的优势!,PCT与其他炎症反应因子,在对感染程度严重性的判断上，PCT比IL-6、IL-8能更好的区分脓毒症、严重脓毒症、脓毒性休克，有着更好的分析效果,Impact of guiding ATB duration by PCT levels
4、on ATB consumption in pts with severe sepsis and no proven source and pathogen.,在脓毒症患者进入ICU当天，进行血清降钙素原（PCT）、白介素6（IL-6）和白介素8（IL-8）的检测结果进行的比较分析Use of Procalcitonin level as part of a decision tree to discontinue antibiotics when started empirically in the ICU in hemodynamically stable patients with no
5、 site of infection identified,All kind of hospitalized patients12 studies,AUC PCT AUC CRP (p 0.05),PCT 集合的灵敏度：88 集合的特异性：81CRP 集合的灵敏度：75 集合的特异性：67,PCT与其他炎症反应因子,PCT,IL-6,CRP,PCT比传统的CRP、IL-6等炎性指标，有着更好的ROC曲线下分布面积，体现出更具优势的诊断灵敏度和特异性,Mller et al., CCM 2000,lactates,Muller et al.,Circulation 2004,在感染性心内膜炎的早
6、期诊断上，PCT体现出比CRP更好的诊断灵敏度和特异性,1-,细菌感染严重程度判断,在感染疾病的发展过程中，PCT随着严重程度的不同（局部感染、脓毒血症、严重脓毒血症、脓毒性休克），呈现由低到高的浓度变化,PCT血中浓度与病程发展呈正相关对于感染程度及器官机能障碍的严重性进行准确的判断,E.J. Giamarellos-Bourboulis et al.,Jan 07 . Sept. 2008 .,Mortality Rate in Patients with Sepsis.(The Hellenic Sepsis Study Group) Outside ICU: - PCT 0.12 ng
7、/ml: Mortality rate 19.5%Inside ICU: - PCT 0.53 ng/ml: Mortality rate 45.1%,报警值: 所有数值 1.0ng/ml, 从第一天高于 1.0ng/ml时开始计算非报警值:从第一天高于 1.0ng/ml时开始减少,并以后数值均 1.0ng),Jensen et al., Crit Care Med, 2006,PCT浓度变化与ICU脓毒症患者生存率的关系,指导抗生素治疗,是否需要抗生素处方？评估抗生素治疗成功与否？什么时候停抗生素 ?,抗生素治疗每延迟1小时，死亡率上升7%,Kumar et al., CCM 2006,D.
8、 Antimicrobial Therapy,We recommend that intravenous antimicrobial therapy be started as early as possible and within the first hour of recognition of septic shock (grade 1B) and severe sepsis without septic shock (grade 1C). Appropriate cultures should be obtained before initiating antibiotic thera
9、py but should not prevent prompt administration of antimicrobial therapy,D. Antimicrobial Therapy,We suggest the use of low procalcitonin levels or similar biomarkers might be useful to assist the clinician in the discontinuation of empiric antibiotics in patients who appeared septic, but have no su
10、bsequent evidence of infection (grade 2C).,Thirty-three studies fulfilled inclusion criteria (3,943 patients, 1,828 males, 922 females; mean age: 56.1 yrs;1,825 patients with sepsis, severe sepsis, or septic shock; 1,545 with only systemic inflammatory response syndrome); eight studies could not be
11、analyzed statistically. Global mortality rate was 29.3%,Global odds ratios for diagnosis of infection complicated by systemic inflammation were 15.7 for the 25 studies (2,966 patients) using procalcitonin (95% confidence interval, 9.127.1) and 5.4 for the 15 studies (1,322 patients) using C-reactive
12、 protein (95% confidence interval, 3.29.2).,Crit Care Med 2006; 34:19962003,Global diagnostic accuracy odds ratios for procalcitonin (PCT, circle, solid line) and C-reactiveprotein (CRP, triangle, dashed line); n 15 studies. OR, odds ratio; CI, confidence interval.,Summary receiver operating charact
13、eristics curves for procalcitonin (circle, solid line) and Creactive protein (triangle, dashed line), accordingto Moses and Littenberg model; n 15 studies,Lancet 2004; 363, 600-607,研究背景：在西方国家，下呼吸道感染(LRTI)是应用抗生素最常见的指征目前临床症状、体征以及常用的实验室检查，均无法准确分辨LRTI的病原体(细菌?病毒?) ，因此约75%的患者接受抗生素的治疗，尽管有时候是病毒感染针对细菌感染，PCT是
14、一个敏感性较高的生物学指标，它在一定程度上可以协助临床内科医师管理抗生素的使用,研究病例组成,标准组PCT指导组 Good clinical outcome 好的临床效果 97% 97%ATB prescribed 抗生素用率 83% 44%Duration of ATB treatment (d) 抗生素治疗天数 12.8 10.9ATB cost per patients (US$) 抗生素成本 202.5 96.3,两组临床结果比较,两组抗生素使用率比较,抗生素的使用及成本减少50（8344）,p = 0.03,p = 0.003,p 0.001,p 0.001,p = 0.003,针对
15、社区获得性肺炎（CAP）患者PCT指导临床抗生素的使用,如何确定何时停用抗生素的困难:*多达 40% 的CAP病人不出现发热*70%推测为细菌感染的CAP 病人鉴定不出致病细菌,结果表明：使用PCT指导抗生素的使用,其用药疗程由12天降至5天，缩短约 55，但其治疗效果不变,n=151 (标准组), n=151 PCT 指导组PCT 指导下，在病人到达医院当天，抗生素使用减少14%， (99% Vs 85%), 在整个疗程中，PCT指导组的疗程时间为5天，标准组为12 天两组的治疗结果相约 : 整体为 83%,减少抗生素的消耗，缩短治疗天数,Christ-Crain M et al. Am J
16、 Respir Crit Care Med. 2006 Apr 7,PCT指导ICU患者的抗生素治疗,Hochreiter et al., Anaesthesist 2008;57:571-577,标准: 如果临床感染的症状和体征改善- 并且PCT 1 ng/ml- 或者3天后PCT下降超过初始值 25-35% (1ng/ml)= 建议结束抗生素治疗,Hochreiter et al., Anaesthesist 2008;57:571-577,抗生素治疗时间: - PCT组：5.9 1.7 d- 对照组：7.9 0.5 d =无明显副作用.,5-8天就足够了吗？,PCT指导ICU患者的抗生素
17、治疗,Nobre et al, Am J Respir Crit Care Med. 2008;177(5):498-505,PCT指导抗生素治疗,Schuetz P et al, JAMA. 2009;302 (10):1059-1066,目的：监测血清PCT水平是否能在不增加严重并发症风险的情况下,最大程度地减少滥用抗生素对象：2006年10月-2008年3月瑞士6家医院的1359例严重LRTI患者设计：该研究是一项多中心、非劣性、随机控制研究将入选患者随机分为对照组和PCT指导治疗组(PCT组)对照组根据标准指南确定的抗生素治疗方案，PCT组则同时参考血清PCT水平终点：死亡、入ICU、
18、发生并发症以及30天内复发感染需要抗生素治疗,入选患者流程图,Phillip Schuetz, et al. JAMA, 2009(302)10:1059-1066,PCT组与对照组抗生素使用比较,PCT组抗生素使用时间低于对照组,PCT组的总体抗生素使用水平比对照组平均低25.7%38.7%,研究后列入时间(天),Phillip Schuetz, et al. JAMA, 2009(302)10:1059-1066,Primary outcomes included the duration of antibiotic therapy for the first episode of inf
19、ection and 28-day mortality. Secondary outcomes included length of ICU stay, length of hospitalisation, antibiotic-free days within the first 28 days of hospitalisation, recurrences, and superinfections,2,199 patients were included in the trials, of which 1,098 were assigned to thePCT-guided treatme
20、nt arm and 1,101 were assigned to the control group.,antibiotics were discontinued when PCT was lower than a value that ranged from 0.5 to 1 ng/ml.,. Intensive Care Med 2012,Duration of antibiotic therapy for the first episode of infection was reduced in favour of PCT-guided treatment pooled weighte
21、d mean difference (WMD) = -3.15 days, random effects model, 95 % confidence interval (CI) -4.36 to -1.95, P0.001.,Matthaiou DK et al. Intensive Care Med 2012,Matthaiou DK et al. Intensive Care Med 2012,Matthaiou DK et al. Intensive Care Med 2012,Matthaiou DK et al. Intensive Care Med 2012,Secondary
22、outcomes,The length of ICU stay were provided in six out of seven of the included RCTs . There was no difference in length of ICU stayThe length of hospitalisation were provided in three of seven of the included RCTs . There was no difference in length of hospitalisation,Secondary outcomes,Antibioti
23、c-free days within the first 28 days of hospitalisation were provided in three out of seven of the included RCTs . There was an increase in antibiotic-free days within the first 28 days of hospitalisation in favour of the PCT-guided treatment arm with a pooled WMD of 3.08 days (P = 0.71, I2 = 0 %, F
24、EM: 95 % CI 2.064.10, P0.001).,Secondary outcomes,Recurrences were provided in three of seven of the included RCTs . There was no difference in recurrencesSuperinfections were provided in three out of seven of the included RCTs . There was no difference in superinfections,脓毒症患者抗生素有治疗效果判断,(n=109),F.
25、Stber, University Bonn, Lecture at ISICEM, Brussels 2001,通过PCT浓度的变化，提示抗生素治疗的成功与否,随着患者对抗生素治疗的响应，引起了PCT血中浓度水平的典型变化过程,持续升高的PCT水平，提示比较差的预后（程度加重，死亡）,连续的监测PCT血中浓度 可以更好的评估患者的预后,严重外伤导致脓毒血症患者，生存者,PCT呈快速下降趋势，预示着成功的治疗效果（感染控制、存活）,连续的监测PCT血中浓度 可以更好的评估患者的预后,临床应用,如果PCT非常低： 严重细菌感染的可能性不大 抗生素应用是有问题的 (0.1ng/ml, 0.3ng/
26、ml) PCT越高 越有可能是败血症 越有抗生素应用的指正如果PCT下降，炎症控制； 如果不是，炎症继续,建议第3天:“更改或不更改抗生素”如果PCT下降: 不更改抗生素治疗！如果PCT 不下降: 更改抗生素治疗 !,建议第5天到第7天：第7天抗生素选择的基本原则：“要么停止，要么更改！”1.停止治疗 - 感染的临床体征消失- PCT显着下降或低于0.1 ng/ml. 2. 更改抗生素疗法- 如果PCT没有下降（PCT 0.5 ng/ml 或 60% ）- 临床资料显示有感染迹象残留- 如果病人有高风险（免疫抑制，. .）,PCTbest performing biomarker for bacterial infection/sepsis,细菌感染后快速升高,细菌感染时高的灵敏度和特异性,感染的严重程度,快速反映抗生素的治疗效果,总结,早期诊断,改善细菌感染/脓毒症的诊断准确性,疾病严重程度及预后评估,指导抗生素的治疗,Thank you!,