The impact of anesthetic selection on sepsis outcome and its mechanism

 描述(申请人提供)：这项名为“麻醉药物选择对脓毒症结局的影响及其机制”的研究旨在研究日常使用的麻醉药物对脓毒症病理生理学的影响。尽管对脓毒症的病理生理学进行了广泛的研究，并在全球范围内启动了以方案为导向的脓毒症治疗，但脓毒症的死亡率仍然很高，约为20%-30%。感染源控制是脓毒症管理的基本原则之一。脓毒症患者，特别是腹部脓毒症患者，经常在紧急或紧急的情况下接受全身麻醉下的源头控制程序。儿科患者经常需要全身麻醉，甚至需要进行影像检查以确定感染源。尽管有关于麻醉剂对免疫系统的潜在影响的报道 在体外功能方面，缺乏对其体内意义和潜在机制的研究。我们先前报道了常用的麻醉药异氟醚、七氟醚和异丙酚在体外对免疫细胞上的关键黏附分子LFA-1和Mac-1有不同的影响。在这个项目中，我们假设这些麻醉药通过对LFA-1和Mac-1的不同影响而对脓毒症的结局有不同的影响。为了验证这一假设，我们将使用多菌腹部脓毒症小鼠模型，对三种常见麻醉药异氟醚、七氟醚和异丙酚进行研究。在目标1中，我们将确定LFA-1和Mac-1的作用以及麻醉药在中性粒细胞募集中的影响。在目标2中，我们将确定LFA-1和Mac-1的作用以及麻醉剂对中性粒细胞细菌吞噬的影响。在目标3中，我们将确定这些麻醉药对结局、全身细菌负荷和全身组织损伤的影响。此外，我们还将评估麻醉药是否会直接影响细菌的分布和生长。在我们拟议的研究中，麻醉药对免疫学影响的表征将提供对脓毒症的麻醉作用的深入了解，并引导麻醉提供者重新考虑如何对脓毒症患者进行麻醉。

 DESCRIPTION (provided by applicant): The proposed research titled "The impact of anesthetic selection on sepsis outcome and its mechanism" is to study the impact of daily used anesthetic drugs on sepsis pathophysiology. Despite extensive research on sepsis pathophysiology, and initiation of protocol-driven sepsis management worldwide, the mortalities of sepsis continue to be high at around 20-30%. One of the cardinal tenets of sepsis management is infection source control. Patients suffering from sepsis, particularly abdominal sepsis often undergo source control procedures under general anesthesia on an emergent or urgent basis. Pediatric patients often require general anesthesia even for imaging studies to identify the source of infection. Despite the reports of potential effects of anesthetics on immune functions in vitro, there is a paucity of research investigating the in vivo significance and underlying mechanisms. We previously reported that the commonly used anesthetics isoflurane, sevoflurane and propofol differently affected critical adhesion molecules LFA-1 and Mac-1 on immune cells in vitro. In this project we hypothesize that these anesthetics have different impacts on sepsis outcome via their differential effects on LFA-1 and Mac-1. To test this hypothesis, we will perform the study of the three common anesthetic drugs isoflurane, sevoflurane and propofol, using polymicrobial abdominal sepsis model in mice. In Aim 1, we will determine the role of LFA-1 and Mac-1 and the impact of anesthetics in neutrophil recruitment. In Aim 2, we will determine the role of LFA-1 and Mac-1 and the impact of anesthetics in neutrophil bacterial phagocytosis. In Aim 3, we will determine the impact of these anesthetics on outcome, systemic bacterial loads and systemic tissue injury. In addition, we will evaluate if anesthetics affect bacterial profiles and growth directly. The characterization of immunological impact by anesthetics in our proposed study will provide the in- depth insight of anesthetic effects on sepsis pathophysiology and lead anesthesia providers to reconsider how to anesthetize patients suffering from sepsis.