The Effect of glucocorticoids and mineralocorticoids in a Sedated and Ventilated Model of Canine Sepsis

糖皮质激素和盐皮质激素在犬脓毒症镇静通气模型中的作用

• 批准号: 8952822
• 负责人: Charles Natanson
• 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/8952822
• 关键词: Accounting; Admission activity; Adrenal Cortex Hormones; Adrenal Glands; Adverse effects; Agonist; Animals; Bacterial Pneumonia; Blood Pressure; Canis familiaris; Cardiovascular system; Catecholamines; Cells; Cessation of life; Clinical; Clinical Trials; Dose; Enrollment; Fever; Functional disorder; Glucocorticoids; Goals; Hour; Hydrocortisone; Hypotension; Immune response; Immunosuppression; Infection; Inflammatory Response; Intensive Care Units; Mineralocorticoids; Modeling; Organ; Outcome; Paper; Patients; Physiology; Pneumonia; Protocols documentation; Publications; Publishing; Resuscitation; Risk; Role; Sepsis; Septic Shock; Series; Severity of illness; Shock; Simulate; Staphylococcus aureus; Steroid therapy; Steroids; Tachycardia; Testing; Time; United States; Vasoconstrictor Agents; biological adaptation to stress; hypoperfusion; hypothalamic-pituitary-adrenal axis; improved; mortality; patient population; secondary infection; therapy development

The primary goal of this protocol is to characterize adrenal function and to investigate the dose-dependent effects of glucocorticoids and mineralocortoids during vasopressor dependent septic shock. Septic shock is responsible for approximately 400,000 intensive care unit admissions and 200,000 deaths each year in the United States. The identification and development of therapies that can improve survival in patients with septic shock is essential. Glucocorticoids (steroids) have been investigated as a therapy for sepsis over the last 40 years with variable results. Glucocorticoids act on nearly all cells in the body, with effects that are especially important to the stress response. They increase the synthesis and action of catecholamines which increase cardiovascular contractility and blood pressure. Glucocorticoids also modulate the immune and inflammatory responses. Initial clinical trials using high dose glucocorticoids to suppress an excessive inflammatory response demonstrated that steroids may have adverse effects on survival. These harmful effects may have been due to the increased risk for secondary infections with the immunosuppressive effects of steroid therapy. However, these early trials enrolled a patient population with varying levels of severity of illness from mild sepsis i.e. presence of infection with fever, tachycardia, and normal blood pressure, to severe septic shock, i.e. sepsis with hypotension and organ hypoperfusion requiring vasopressors to maintain blood pressure. This range in severity of illness may also, in part, account for the harmful effects of glucocorticoids seen in some patients in the early clinical trials. We have developed a sedated and ventilated model of canine Staphylococcus aureus bacterial pneumonia that simulates many of the pathophysiologic changes occurring during clinical sepsis. Most importantly, despite volume resuscitation, these animals develop a persistent vasopressor requirement within hours of the onset of bacterial pneumonia. An intra-bronchial bacterial load of 1.5 x 109 cfu/kg has been found to result in about a 60-70% mortality. This mortality range will allow us to determine if treatment with steroids is beneficial during sepsis. This clinically representative model of sepsis will allow us to better understand the physiology of adrenal function in septic shock and to determine 1) how adrenal function changes over time during sepsis, independent of steroid therapy; 2) the relationship between adrenal function and total and free cortisol levels as well as more sophisticated tests of the hypothalamic-pituitary-adrenal axis dysfunction and outcome; and 3) the mechanism of glucocorticoids and mineralocorticoids on survival and shock reversal during vasopressor-dependent septic shock. We have completed the current series of studies investigating the independent roles of glucocorticoids and mineralocorticoids in a sedated and ventilated model of sepsis. One paper has been published on adrenal function during sepsis (Sweeney, JID 2010). Two additional papers describing the efficacy of selective corticosteroid agonists during sepsis (Hicks CCM 2012) and the role of corticosteroids on bacterial clearance (Hicks ICM 2012) have also been published. Another paper describing the Hypothalamic-Pituitary-Adrenal Axis in Lethal Canine Staphylococcus aureus Pneumonia has been accepted for publication.

该方案的主要目的是表征肾上腺功能并研究加速器依赖性败血性休克期间糖皮质激素和矿物皮质类固醇的剂量依赖性作用。在美国，败血性冲击造成约40万重症监护病房的入院和200,000人死亡。可以鉴定和开发可以改善败血性休克患者生存的疗法。 在过去的40年中，糖皮质激素（类固醇）已作为败血症的疗法进行了研究，结果可变。糖皮质激素作用于体内几乎所有细胞，其作用对压力反应尤为重要。 它们增加了儿茶酚胺的合成和作用，从而增加了心血管收缩性和血压。 糖皮质激素还调节免疫和炎症反应。 使用高剂量糖皮质激素抑制过度炎症反应的初步临床试验表明，类固醇可能对生存产生不利影响。这些有害作用可能是由于继发性感染的风险增加，并具有类固醇治疗的免疫抑制作用。然而，这些早期试验招募了一个患者人群，患者人群的疾病严重程度不同，来自轻度败血症，即发烧，心动过速和正常血压感染，以至于严重的败血性休克，即败血症，败血症患有低血压和器官灌注不足，需要加压剂维持血压。 这种疾病严重程度的范围也可能部分原因是在早期临床试验中某些患者中糖皮质激素的有害作用。 我们已经开发了一种镇静和通风模型的金黄色葡萄球菌细菌性肺炎，该模型模拟了临床脓毒症期间发生的许多病理生理变化。 最重要的是，尽管体积复苏了，但这些动物在细菌肺炎发作后数小时内提出了持续的加压剂需求。已经发现，总体内细菌载荷为1.5 x 109 CFU/kg，导致约60-70％的死亡率。该死亡率范围将使我们能够确定败血症期间用类固醇的治疗是否有益。 这种脓毒症的临床代表性模型将使我们能够更好地了解败血性休克中肾上腺功能的生理，并确定1）脓毒症期间肾上腺功能随时间的变化，与类固醇治疗无关； 2）肾上腺功能与总皮质醇水平以及对下丘脑 - 垂体 - 肾上腺轴功能障碍和结果的更复杂的测试之间的关系； 3）糖皮质激素和矿物皮质激素在加速器依赖性败血性休克期间生存和休克逆转的机制。 我们已经完成了当前研究的一系列研究，研究了糖皮质激素和矿物皮质激素在脓毒症的镇静和通风模型中的独立作用。败血症期间已经发表了一篇关于肾上腺功能的论文（Sweeney，Jid，2010年）。另外两篇描述了败血症中选择性皮质类固醇激动剂的功效的论文（Hicks CCM 2012）以及皮质类固醇在细菌清除率上的作用（Hicks ICM 2012）。一篇描述致命犬葡萄球菌金黄色葡萄球菌肺炎中下丘脑 - 垂体 - 肾上腺轴的论文已被接受进行发表。