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

肾上腺是一种内分泌腺，它产生糖皮质激素和盐皮质激素以应对危重疾病。 主要的糖皮质激素是皮质醇，而主要的盐皮质激素是醛固酮。 皮质醇具有重要的心血管、代谢、免疫和止血功能。 相比之下，醛固酮在盐和水调节中是重要的，因此对维持血管内容量和血压至关重要。急性肾上腺功能不全是肾上腺对生理应激（如感染）的反应不佳。急性肾上腺皮质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。 因此，急性肾上腺功能不全的危重患者可能会出现低血压和严重脱水。 因此，有人推测盐皮质激素缺乏可能导致脓毒性休克的发展和严重程度。虽然许多研究者已经研究了糖皮质激素活性在感染性休克中的重要性，但盐皮质激素活性和醛固酮在感染性休克中的重要性仍不清楚。 醛固酮在肾上腺中产生，并通过阿米洛利敏感性上皮钠（Na）通道（ENaC）的活性引起肾钠重吸收增加。钠重吸收增加导致血管内容量扩张和血压升高。 阿米洛利是一种保钾利尿剂，可阻断ENaC，从而抑制肾脏中的晚期远曲小管、连接小管和集合管中的钠重吸收。氢氯噻嗪（HCT）是一种充分描述的利尿剂，将与阿米洛利联合使用，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，包括肾、肺、膀胱、远端结肠、汗腺和唾液管。1为了本方案的目的，我们将集中讨论ENaC在肾和肺中的重要性 我们的实验室以前用感染性休克的犬模型进行的实验表明，盐皮质激素通过醛固酮的活性可能对感染性休克的病理生理学很重要。我们证明，给予醋酸脱氧皮质酮（DOCA），一种选择性盐皮质激素，其生理作用类似于脓毒症发作前72小时给予的醛固酮，可更快地逆转休克并提高生存率。在这些实验中未测量对钠重吸收或ENaC活性的直接影响，但这些结果表明DOCA给药导致肾钠重吸收增加和血管内容量保留，导致休克严重程度降低和存活率提高。 作为一个基本的生理问题，这项研究将扩大我们对肾脏和肺中钠通道的理解，以及盐皮质激素在危重病期间管理液体平衡中的作用。这项研究还将显示如何影响这些通道的表达以提高生存率。从临床的角度来看，如果预防性治疗显示出提高生存率，这将立即使感染外科手术（即腹部）风险高的患者受益。此外，这些结果将确定钠通道的哪些组分可以作为药物开发的目标。 这一系列的研究探讨了糖皮质激素和盐皮质激素在镇静和通气的脓毒症模型中的独立作用。我们首先定义了ICU环境中脓毒症期间的正常肾上腺功能（Sweeney，JID 2010）。然后，我们确定了脓毒症期间选择性皮质类固醇激动剂的疗效（Hicks CCM 2012）和皮质类固醇对细菌清除的作用（Hicks ICM 2012）。然后，我们研究了致死性犬金黄色葡萄球菌肺炎的下丘脑-肾上腺-肾上腺轴（Corts-Puch AJP，2014）。目前的研究将扩大我们对水处理背后的机制以及危重病期间生存率如何受到影响的理解

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