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

该方案的主要目的是表征肾上腺功能，并研究血管加压剂依赖型败血症休克期间糖皮质激素和盐皮质激素的剂量依赖效应。在美国，感染性休克每年导致大约400,000名重症监护病房入院和200,000人死亡。确定和开发能够提高感染性休克患者存活率的治疗方法是至关重要的。 在过去的40年里，糖皮质激素(类固醇)一直被研究作为脓毒症的治疗方法，但结果各不相同。糖皮质激素作用于体内几乎所有的细胞，其作用对应激反应尤为重要。它们增加儿茶酚胺的合成和作用，从而增加心血管收缩能力和血压。糖皮质激素也调节免疫和炎症反应。使用大剂量糖皮质激素抑制过度炎症反应的初步临床试验表明，类固醇可能对生存有不利影响。这些有害的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，这些早期试验纳入了病情严重程度不同的患者群体，从轻度脓毒症(存在感染伴发热、心动过速和正常血压)到严重败血症休克(即败血症伴低血压和需要血管升压剂维持血压的器官低灌流)。疾病严重程度的这种范围也可能在一定程度上解释了早期临床试验中一些患者使用糖皮质激素的有害影响。 我们已经开发了一种镇静和通风的犬金黄色葡萄球菌细菌性肺炎模型，它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，尽管进行了容量复苏，但这些动物在细菌性肺炎发作后的几个小时内就产生了持续的血管升压剂需求。已发现，支气管内细菌负荷为1.5x109cfu/kg可导致约60%-70%的死亡率。这个死亡率范围将使我们能够确定在脓毒症期间使用类固醇治疗是否有益。这一具有临床代表性的脓毒症模型将使我们更好地了解感染性休克时肾上腺功能的生理学，并确定1)脓毒症期间肾上腺功能是如何随时间变化的，独立于类固醇治疗的；2)肾上腺功能与总皮质醇和游离皮质醇水平的关系以及更复杂的下丘脑-垂体-肾上腺轴功能障碍和预后的测试；3)糖皮质激素和盐皮质激素对血管升压剂依赖型败血症休克患者存活和休克逆转的机制。 我们已经完成了目前的一系列研究，调查糖皮质激素和盐皮质激素在镇静和通风的脓毒症模型中的独立作用。一篇关于脓毒症期间肾上腺功能的论文已经发表。描述选择性皮质类固醇激动剂在脓毒症期间的疗效的第二篇论文也已经发表。第三篇描述皮质类固醇在细菌清除中的作用的论文已经被接受。另外两份手稿应在未来12个月内完成。

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. A second paper describing the efficacy of selective corticosteroid agonists during sepsis has also been published. A third paper describing the role of corticosteroids on bacterial clearance has been accepted. Two additional manuscripts should be completed in the next 12 months.