另眼看镇静调节重症病人的交感兴奋性与炎症免疫反应2015

另眼看镇静:调节重症病人的交感兴奋性与免疫反应,南京大学医学院南京军区总医院重症中心全军普通外科研究所 SICU 李维勤,Contents,Nature Immunology 2006,脓毒症是什么？,感染,急性器官衰竭,脓毒症,Contents,Propofol - Antioxidant effect,抑制脂质过氧化,减少缺血再灌注损伤,减少ROS相关的组织炎症、损伤,Antioxidant effect,Propofol - immunosuppressant effects,LPS,动物实验 sepsis、ALI体外实验,LPS,iNOS,NO,Possible mechanism,March 2011 Volume 6,TNF-、IL-1、IL-8、IL-12、IL-6,iNOS,TLR4,细菌产物LPS,February 2011 | Volume 6,GABAA receptor 2 subunit expression in human monocytes,propofol /硫喷妥钠,action on GABAA receptors,inhibits normal monocyte behaviour. (chemotaxis and phagocytosis),increase the risk of infection in critically ill patients,a potential solution：monocyte GABAA receptors are insensitive to diazepam,Propofol,抑制中性粒、巨噬细胞吞噬Staphylococcus aureus 和 Escherichia coli,A therapeutic application for attenuation of sterile inflammation,however, in the presence of infection the impaired clearance of bacteria may prove a significant problem,丙泊酚乳剂：,脂肪乳可能参与免疫抑制,长时间使用,高甘油三脂血症,代酸,A water-soluble preparation (Aquavan, fospropofol disodium, MGI Pharma) will soon be available.,Contents,Benzodiazepines,动物、体外实验,抑制LPS诱导的COX2、iNOS、IkB-a降解、NF-kB 转录活性、p38MAPK磷酸化、过氧化物、TNFa、IL-6,抑制中性粒、巨噬细胞氧爆发、吞噬金葡菌能力,抑制分叶白细胞的吞噬作用、粘附、趋化,抑制肥大细胞趋向作用、释放颗粒物质,The peripheral benzodiazepine receptor in immune cells,May be detrimental with benzodiazepines increasing mortality from infections in animals,Immunosuppressant,Benzodiazepine use as a risk factor for complicated community-acquired lower respiratory tract infection,Contents,a2-Adrenoceptor agonistsDexmedetomidine,减少Sleep deprivation,Immune responses,Autonomic nervous system,NE,central-acting alpha-2 agonistsinhibit noradrenergic neurotransmission have a strong sedative component secondary to sympathetic inhibition,Go Back,The electroencephalogram and pattern of cerebral blood flow show greater similarity to natural sleep with dexmedetomidine than with benzodiazepines.,In vitro and in vivo study of DEX,SEPSIS,Cytokine storm,Apoptosis of B and T lymphocytes,A hypo-inflammatory phase,Exaggerated Inflammatory response,DEX promote macrophage phagocytosis and bactericidal killing,Decreased mortality from infection,IL-6 decreased in the Dexmedetomidine group,Only DEX suppressed the expression of TNF-, IL-1, and IL-6; both agents improved oxygenation,2007,28天死亡率、ICU住院时间无差别,A particular class of sedative be preferred when sedating the septic patient ？,no or at least not yet.,Animal models of sedatives in sepsis,Adrenergic catecholamines，vasopressors,Other immunomodulating therapies,? Clinical data is lacking,Contents,Opioid,体外实验、动物模型,抑制分裂素诱导的淋巴细胞增殖,抑制NK细胞毒性,抑制巨噬细胞吞噬、迁移功能,抑制IL-2、IFN、TNF、NO浓度,Immunosuppressant,Be beneficial in septic patients ？ no published data support this hypothesis,Acute exposure to opioids,抑制组织巨噬细胞吞噬细菌,Chronic exposure to opioids 与免疫系统的相关性不如acute expose,Opioids withdraw 动物实验：免疫抑制增强、时间延长,Possible mechanism,1.a direct interaction on the immune system,Location of opioid receptors on immunocytes,These suppressive effects are blocked by naloxone,Sympathic nervous system,2.Central opioid receptors,Hypothalamic-pituitary-adrenal axis,激活,Suppress immune function,Contents,ICU-acquired infection,Prospective data collection lasting 6 months in 71 Italian adult ICUs. 9,493 consecutive patients,47% ICU-acquired pneumonia,37% ICU-acquired bloodstream infection,11.4% an ICU-acquired infection,Others,A Cohort, multiple-center, observational study.,SETTING: 198 ICU in 24 European countries.,PATIENTS: All new adult admissions to a participating ICU between May 1 and 15, 2002.,3,147 patients, 12% had an ICU-acquired sepsis.,Sedation and ICU-acquired infection,DesignProspective descriptive study conducted over a 2-yr period,SettingFive ICU in a university-affiliated medical center with level I trauma status.,PatientsEach of the 360 adult patients participated for 4 days.,the inclusion criteria were：mechanical ventilation and tube feedings.,Preliminary identification of risk factors associated with pneumonia in tube-fed patients,determined by multivariate stepwise logistic regression.,ICU-acquired infection as a sideeffect of sedation-Pathophysiology,1.Pronlongation of exposure to risk factors for infection,5.Immunomodulatory effect of sedation:gastrointestinal motility disturbances,3.Microcirculatory effects of sedation,4.Intestinal effects of sedation,2.Microaspiration:Impaired tubular esophageal motility,Increased exposure to invasive procedures,Prolonged stay in the ICU,The major risk factor for VAP, bloodstream infection, and urinary tract infection,Duration of MV ： a well-known risk factor for VAP,Possible solution,1.Daily interruption of continuous sedation,2.Nurse