Preclinical and Clinical Investigations in Septic Shock

感染性休克的临床前和临床研究

• 批准号: 6825426
• 负责人: ROBERT L DANNER
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6825426
• 关键词: biomarker; blood disorder chemotherapy; clinical chemistry; clinical research; drug screening /evaluation; endotoxins; epinephrine; human subject; norepinephrine; pathologic process; septic shock; septicemia; vasoconstrictors; vasopressins

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.

简介和目的：感染性休克是一种由严重、压倒性感染引发的高度致命的综合征。这种情况是美国重症监护病房死亡的主要原因。尽管经过半个多世纪的科学研究，导致这种综合征的潜在机制仍未完全了解。 这些研究旨在检查感染性休克的发病机制，并利用小型和大型的综合征模型、脓毒症患者和受到内毒素挑战的正常志愿者来探索新的治疗策略的潜力。 进步： 早期研究主要集中在比较革兰氏阳性菌和革兰氏阴性菌的病理生理学、内毒素血症的作用以及脂质 A 类似物和抗体等抗内毒素疗法的功效。 一氧化氮被检查为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有毒且无益。 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。尽管布洛芬可以阻止内毒素诱导的一氧化氮生成增加，但血压不受影响，这表明其他机制可以补偿以维持血管舒张。 最近的研究发现，疾病的严重程度（死亡风险）会影响抗炎药物对感染性休克的治疗效果。 拟议的工作过程： 正在进行的败血性休克常用升压药（包括肾上腺素、去甲肾上腺素和升压素）的比较生存研究。 正在开发淋巴细胞过继转移和主动脉内球囊反搏泵支持感染性休克的方案。 验证并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。