Preclinical and Clinical Investigations in Septic Shock

前言与目的：感染性休克是一种由严重、压倒性感染引起的高度致死性综合征。这种疾病是美国重症监护病房的主要死亡原因。尽管经过半个多世纪的科学研究，但导致这种综合征的潜在机制仍未完全清楚。 这些研究试图研究感染性休克的发病机制，并探索使用该综合征的大小模型、脓毒症患者和内毒素激发的正常志愿者的新治疗策略的可能性。 进度： 早期的研究集中在比较革兰氏阳性和革兰氏阴性生物的病理生理学，内毒素血症的作用，以及抗内毒素治疗的疗效，如类脂A类似物和抗体。 一氧化氮被认为是感染性休克的重要介质。非选择性一氧化氮合酶抑制剂有时是有毒的，永远不会有益。 研究发现，受到内毒素攻击的正常志愿者会释放更多的一氧化氮。虽然布洛芬阻止了内毒素诱导的一氧化氮产生的增加，但血压没有受到影响，这表明其他机制补偿了维持血管扩张的作用。 最近的研究发现，疾病的严重程度(死亡风险)会影响抗炎药在感染性休克中的治疗效果。 建议的工作进程： 感染性休克中常用的血管增压剂包括肾上腺素、去甲肾上腺素和加压素正在进行的比较生存研究。 感染性休克的淋巴细胞过继转移和主动脉内气囊反搏支持方案正在制定中。 验证和应用从功能基因组研究中获得的生物标志物和致病途径的信息。

Introduction and Objective: Septic shock is a highly lethal syndrome initiated by severe, overwhelming infection. This condition is the leading cause of death in Intensive Care Units in the U.S. The underlying mechanisms that cause this syndrome remain incompletely understood despite more than a half century of scientific investigation. These studies seek to examine septic shock pathogenesis and to explore the potential of novel therapeutic strategies using both small and large models of the syndrome, patients with sepsis, and normal volunteers challenged with endotoxin. progress: Early studies focused on pathophysiology comparing gram positive and gram negative organisms, the role of endotoxemia, and the efficacy of anti-endotoxin therapies such as lipid A analogs and antibodies. Nitric oxide was examined as an important mediator of septic shock. Non-selective nitric oxide synthase inhibitors were sometimes toxic and never beneficial. Normal volunteers challenged with endotoxin were found to release increased amounts of nitric oxide. Although ibuprofen blocked endotoxin-induced increases in nitric oxide production, blood pressure was unaffected, suggesting that other mechanisms compensated to maintain vasodilation. More recent work has found that severity of illness (risk of death) influences the therapeutic efficacy of anti-inflammatory agents in septic shock. Proposed Course of Work: Ongoing comparative survival study of commonly used vasopressors in septic shock including epinephrine, norepinephrine and vasopressin. Protocols under development for lymphocyte adoptive transfer, and intra-aortic balloon pump support in septic shock. Validate and apply information on biomarkers and pathogenic pathways obtained from functional genomic investigations.