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

本方案的主要目的是描述肾上腺功能，并研究糖皮质激素和盐皮质激素在血管加压药依赖性脓毒性休克期间的剂量依赖性作用。在美国，感染性休克每年造成约40万重症监护病房入院和20万死亡。识别和开发能够提高感染性休克患者生存率的治疗方法至关重要。 在过去的40年中，糖皮质激素（类固醇）已被研究作为脓毒症的治疗方法，结果各不相同。糖皮质激素几乎作用于体内所有细胞，对应激反应尤其重要。 它们增加了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，类固醇可能对生存有不良影响。这些不良反应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，这些早期试验招募了不同疾病严重程度的患者人群，从轻度脓毒症（即存在感染伴发烧、心动过速和正常血压）到严重脓毒性休克（即脓毒症伴低血压和器官灌注不足，需要血管加压药）来维持血压。 这种疾病严重程度的范围也可能部分解释了在早期临床试验中在一些患者中观察到的糖皮质激素的有害作用。 我们已经开发了一种镇静和通气的犬金黄色葡萄球菌细菌性肺炎模型，模拟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数小时内仍需要持续的血管加压药。已发现1.5 x 109 cfu/kg的支气管内细菌负荷导致约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。 这种脓毒症的临床代表性模型将使我们能够更好地理解脓毒症休克中肾上腺功能的生理学，并确定1）在脓毒症期间肾上腺功能如何随时间变化，与类固醇治疗无关; 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;糖皮质激素和盐皮质激素对血管加压素依赖性感染性休克存活和休克逆转的作用机制。 我们已完成本研究的初始方案。前2部分研究了在清醒、镇静和通气动物中，类固醇治疗对ACTH刺激试验（目前用于确定患者是否应接受类固醇治疗）反应中皮质醇释放的影响。 这些数据表明，肾上腺功能受到镇静，类固醇治疗和以前的压力。这份手稿已经完成，将在一个月内提交出版。研究的第三部分迄今为止表明，它是类固醇的盐皮质激素成分，而不是糖皮质激素成分，具有有益的生存效果。目前正在分析这些数据，并应在未来4-6个月内以手稿形式提交。

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 manuscript is completed and will be submitted for publication within a month. 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.