The Effect of Glucocorticoids in a Sedated and Ventilated Model of Canine Sepsis

糖皮质激素在犬脓毒症镇静通气模型中的作用

• 批准号: 7593077
• 负责人: Charles Natanson
• 金额: $ 27.98万
• 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/7593077
• 关键词: Accounting; Admission activity; Adrenal Glands; Adverse effects; Animals; Bacterial Pneumonia; Blood Pressure; Canis familiaris; Cardiovascular system; Catecholamines; Cells; Cessation of life; Clinical; Clinical Trials; Conscious; Corticotropin; Data; Dose; Enrollment; Fever; Functional disorder; Glucocorticoids; Goals; Hour; Hydrocortisone; Hypotension; Immune; Immunosuppression; Infection; Inflammatory Response; Intensive Care Units; Manuscripts; Mineralocorticoids; Modeling; Organ; Outcome; Patients; Physiology; Population; Process; Protocols documentation; Range; Resuscitation; Risk; Sedation procedure; Sepsis; Septic Shock; Severity of illness; Shock; Simulate; Staphylococcus aureus; Steroid therapy; Steroids; Tachycardia; Testing; Time; United States; Vasoconstrictor Agents; Writing; biological adaptation to stress; hypothalamic-pituitary-adrenal axis; improved; mortality; response; secondary infection; stressor; 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 initial protocol of this study. The first 2 parts investigated the effect of steroid treatment on cortisol release in response to ACTH stimulation tests (presently used to determine whether patients should be treated with steroids) in conscious and sedated and ventilated animals. This data showed that adrenal function is effected by sedation, steriod treatment and previous stressors. This data is in the process of being analyzed and a manuscript should be written in the next 1-2 months. The third part of the study has thus far shown that it is the mineralocorticoid component of steroids, not the glucocorticoid component that has a beneficial survvival effect. This data is currently being analyzed and should be presented in a manuscript in the next 4-6 months.

该协议的主要目标是表征肾上腺功能并研究糖皮质激素和盐皮质激素在血管加压药依赖性败血性休克期间的剂量依赖性效应。在美国，每年约有 40 万人因感染性休克入住重症监护室，并导致 20 万人死亡。确定和开发能够提高感染性休克患者生存率的疗法至关重要。 过去 40 年来，人们一直在研究糖皮质激素（类固醇）作为脓毒症的治疗方法，但结果各不相同。糖皮质激素几乎作用于体内所有细胞，其作用对应激反应尤其重要。 它们增加儿茶酚胺的合成和作用，从而增加心血管收缩力和血压。 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。这些有害影响可能是由于类固醇治疗的免疫抑制作用增加了继发感染的风险。然而，这些早期试验招募的患者群体的疾病严重程度各不相同，从轻度脓毒症（即存在感染并伴有发烧、心动过速和血压正常）到严重脓毒症休克（即脓毒症伴低血压和需要血管加压药维持血压的器官灌注不足）。 这种疾病严重程度的范围也可能部分解释了早期临床试验中一些患者中发现的糖皮质激素的有害作用。 我们开发了一种犬金黄色葡萄球菌细菌性肺炎的镇静和通气模型，模拟临床败血症期间发生的许多病理生理变化。 最重要的是，尽管进行了容量复苏，这些动物在细菌性肺炎发作后数小时内仍需要持续的血管加压药。已发现支气管内细菌负荷为 1.5 x 109 cfu/kg 会导致约 60-70% 的死亡率。这个死亡率范围将使我们能够确定类固醇治疗在败血症期间是否有益。 这种具有临床代表性的脓毒症模型将使我们能够更好地了解脓毒症休克中肾上腺功能的生理学，并确定：1）脓毒症期间肾上腺功能如何随时间变化，独立于类固醇治疗； 2）肾上腺功能与总皮质醇和游离皮质醇水平之间的关系，以及下丘脑-垂体-肾上腺轴功能障碍和结果的更复杂的测试； 3）糖皮质激素和盐皮质激素对血管加压药依赖性感染性休克期间生存和休克逆转的机制。 我们已经完成了这项研究的初步方案。前两部分研究了类固醇治疗对清醒、镇静和通气动物的 ACTH 刺激试验（目前用于确定患者是否应该接受类固醇治疗）皮质醇释放的影响。 该数据表明，肾上腺功能受到镇静、类固醇治疗和先前压力源的影响。该数据正在分析中，预计将在未来 1-2​​ 个月内撰写手稿。迄今为止，该研究的第三部分表明，具有有益生存作用的是类固醇的盐皮质激素成分，而不是糖皮质激素成分。目前正在分析这些数据，并将在未来 4-6 个月内以手稿形式呈现。