The impact of anesthetic selection on sepsis outcome and its mechanism

 描述（由申请方提供）：拟开展的题为“麻醉剂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。尽管对脓毒症病理生理学进行了广泛的研究，并在全球范围内启动了方案驱动的脓毒症管理，但脓毒症的死亡率仍然很高，约为20- 30%。脓毒症管理的主要原则之一是感染源控制。患有脓毒症，特别是腹部脓毒症的患者通常在紧急或紧急基础上在全身麻醉下经历源控制程序。儿科患者通常需要全身麻醉，即使是用于成像研究以确定感染源。尽管有报告称麻醉剂对免疫系统的潜在影响， 虽然在体外发挥作用，但缺乏研究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剂异氟烷、七氟烷和丙泊酚在体外对免疫细胞上的关键粘附分子LFA-1和Mac-1的不同影响。在这个项目中，我们假设这些麻醉剂通过它们对LFA-1和Mac-1的不同作用对脓毒症结局具有不同的影响。为了验证这一假设，我们将使用多种微生物腹腔脓毒症模型在小鼠中进行三种常用麻醉药异氟烷、七氟烷和丙泊酚的研究。在目标1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募集的影响。在目的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作用的影响。在目标3中，我们将确定这些麻醉剂对结果、全身细菌负荷和全身组织损伤的影响。此外，我们还将评估麻醉剂是否直接影响细菌特征和生长。在我们拟议的研究中，麻醉剂对免疫影响的表征将提供麻醉剂对脓毒症病理生理学影响的深入见解，并引导麻醉提供者重新考虑如何麻醉脓毒症患者。

 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.