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: 9339110
• 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/9339110
• 关键词: Abdomen; Acetates; Acute; Admission activity; Adrenal Cortex Hormones; Adrenal Glands; Adrenal gland hypofunction; Affect; Agonist; Aldosterone; Amiloride; Apical; Biological Preservation; Bladder; Blood Pressure; Canis familiaris; Cardiovascular system; Cell membrane; Cessation of life; Clinical; Colon; Critical Illness; Dehydration; Deoxycorticosterone; Development; Distal; Distal convoluted renal tubule structure; Diuretics; Duct (organ) structure; Endocrine Glands; Ensure; Epithelial; Failure; Fluid Balance; Functional disorder; Glucocorticoids; Hemostatic function; Hormones; Hydrochlorothiazide; Hydrocortisone; Hypotension; Immunologics; Infection; Intensive Care Units; Kidney; Lung; Maintenance; Measures; Metabolic; Mineralocorticoids; Modeling; Operative Surgical Procedures; Organ; Outcome; Patients; Physiological; Physiology; Play; Pneumonia; Potassium; Prophylactic treatment; Protocols documentation; Publishing; Regulation; Research Personnel; Role; Salivary; Sepsis; Septic Shock; Series; Severities; Shock; Sodium; Sodium Channel; Sodium Chloride; Staphylococcus aureus; Steroid therapy; Stress; Sweat Glands; Testing; Time; United States; Vasoconstrictor Agents; Water; blood pressure reduction; drug development; epithelial Na+ channel; high risk; hypothalamic-pituitary-adrenal axis; improved; lead acetate; research study; response; therapy development

The adrenal glands are endocrine glands which produce both glucocorticoid and mineralocorticoid hormones in response to critical illness. The primary glucocorticoid hormone is cortisol, whereas the primary mineralocorticoid hormone is aldosterone. Cortisol has important cardiovascular, metabolic, immunologic, and hemostatic functions. In comparison, aldosterone is important in salt and water regulation and therefore critical to the maintenance of intravascular volume and blood pressure. Acute adrenal insufficiency is the failure of the adrenal gland to respond appropriately to physiologic stress, such as infection. The clinical presentation of acute adrenal insufficiency is due to insufficient mineralocorticoid activity rather than inadequate glucocorticoid activity. As such, critically ill patients with acute adrenal insufficiency can present with low blood pressure and severe dehydration. Thus, it has been hypothesized that mineralocorticoid deficiency may contribute to the development and severity of septic shock. Although many researchers have studied the importance of glucocorticoid activity in septic shock, the importance of mineralocorticoid activity and aldosterone in septic shock remains unclear. Aldosterone is produced in the adrenal gland and causes increased renal sodium reabsorption via the activity of an amiloride-sensitive epithelial sodium (Na) channel (ENaC). Increased reabsorption of sodium leads to expansion of intravascular volume and increased blood pressure. Amiloride is a potassium sparing diuretic that blocks ENaC thereby inhibiting sodium reabsorption in the late distal convoluted tubules, connecting tubules, and collecting ducts in the kidney. Hydrochlorothiazide (HCT), a well described diuretic, will be used in conjunction with amiloride to ensure maximal effect on eNaC function. ENaC is expressed on the apical plasma membrane of many organs including the kidneys, lungs, urinary bladder, distal colon, sweat glands, and salivary ducts.1 For the purpose of this protocol, we will concentrate on the importance of ENaC in the kidneys and the lungs Using a canine model of septic shock, our lab has previously conducted experiments suggesting mineralocorticoid activity via aldosterone may be important to the pathophysiology of septic shock. We demonstrated that administration of desoxycorticosterone acetate (DOCA), a selective mineralocorticoid with physiologic effects similar to aldosterone given 72h before the onset of sepsis, led to a more rapid reversal of shock and improved survival. The direct effect on sodium reabsorption or ENaC activity was not measured in these experiments but these results suggest that the administration of DOCA leads to increased renal sodium reabsorption and preservation of intravascular volume resulting in less severe shock and improved survival. As a basic physiologic question, this study will expand our understanding of sodium channels in the kidney and lung and the role mineralocorticoids plays in managing fluid balance during critical illness. This study will also show how the expression of these channels can be influenced to improve survival. From a clinical perspective, if prophylactic treatment is shown to improve survival this would immediately benefit patients subject to high risk for infection surgical procedures, ie, abdominal. In addition, these results will define which components of the sodium channel could be targeted for drug development. This series of studies investigates the independent roles of glucocorticoids and mineralocorticoids in a sedated and ventilated model of sepsis. We began by defining normal adrenal function during sepsis in an ICU setting (Sweeney, JID 2010). We then determined the efficacy of selective corticosteroid agonists during sepsis (Hicks CCM 2012) and the role of corticosteroids on bacterial clearance (Hicks ICM 2012). We then investigated the Hypothalamic-Pituitary-Adrenal Axis in Lethal Canine Staphylococcus aureus Pneumonia (Corts-Puch AJP, 2014). The current study will expand our understanding of the mechanisms behind water handling and how survival is affected during critical illness

肾上腺是内分泌腺体，可响应危害疾病，从而产生糖皮质激素和矿物皮质激素。 原发性糖皮质激素是皮质醇，而原代矿物皮质激素是醛固酮。 皮质醇具有重要的心血管，代谢，免疫学和止血功能。 相比之下，醛固酮在盐和水调节中很重要，因此对于维持血管内体积和血压至关重要。急性肾上腺功能不全是肾上腺无法对生理胁迫（例如感染）做出适当反应。急性肾上腺功能不全的临床表现是由于盐皮质激素活性不足而不是糖皮质激素活性不足所致。 因此，患有急性肾上腺功能不全的重症患者可能会出现低血压和严重脱水。 因此，已经假设矿物皮质激素缺乏可能有助于败血性休克的发育和严重程度。尽管许多研究人员研究了糖皮质激素活性在败血性休克中的重要性，但矿物皮质激素活性和醛固酮在败血性休克中的重要性尚不清楚。 醛固酮是在肾上腺中产生的，并通过艾米洛德敏感的上皮钠（NA）通道（ENAC）的活性导致肾脏钠的重吸收增加。钠的重吸收增加导致血管内体积的扩张和血压升高。 Amiloride是一种保留钾的利尿剂，可阻断ENAC，从而抑制晚期远端曲折小管，连接小管和在肾脏中收集管道的钠重吸收。氢氯噻嗪（HCT）是一种良好描述的利尿剂，将与Amiloride结合使用，以确保对ENAC功能的最大作用。 ENAC在许多器官的顶端质膜上表达 使用败血性休克的犬模型，我们的实验室先前已经进行了实验，表明通过醛固酮进行矿物皮质激素活性可能对败血性休克的病理生理可能很重要。我们证明了乙酸脱氧皮质酮（DOCA）是一种选择性矿物皮质激素，其生理作用类似于败血症发作之前72H的醛固酮，导致休克的快速逆转和改善的存活率。在这些实验中未测量对钠重吸收或ENAC活性的直接影响，但是这些结果表明，DOCA的给药会导致肾脏钠的重吸收增加并保留血管内体积，从而减少严重的休克和改善的生存率。 作为一个基本的生理问题，这项研究将扩展我们对肾脏和肺中钠通道的理解，以及矿物皮质激素在危重疾病期间管理液体平衡方面的作用。这项研究还将表明如何影响这些通道的表达以提高生存率。从临床角度来看，如果证明预防性治疗可以提高生存率，这将立即使受感染手术程序高风险的患者受益，即腹部。此外，这些结果将定义钠通道的哪些组成部分可以针对药物开发。 这一系列研究调查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。我们首先在ICU环境中定义败血症期间正常的肾上腺功能（Sweeney，Jid，2010年）。然后，我们确定了选择性皮质类固醇激动剂在败血症期间的疗效（Hicks CCM 2012）和皮质类固醇在细菌清除率上的作用（Hicks ICM 2012）。然后，我们研究了致命犬葡萄球菌金黄色葡萄球菌中的下丘脑 - 垂体 - 肾上腺轴（Corts-Puch AJP，2014年）。当前的研究将扩大我们对水处理背后机制的理解以及在危害疾病期间如何影响生存

项目成果

Defining normal adrenal function testing in the intensive care unit setting: a canine study.

定义重症监护病房环境中的正常肾上腺功能测试：一项犬类研究。

• DOI: 10.1097/ccm.0b013e3181cb0a25
• 发表时间: 2010
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Sweeney,DanielA;Natanson,Charles;Banks,StevenM;Solomon,StevenB;Behrend,EllenN
• 通讯作者: Behrend,EllenN