Evaluation and Treatment of Skeletal Muscle Weakness in Critically Ill Patients

危重病人骨骼肌无力的评估和治疗

• 批准号: 7831192
• 负责人: GERALD S. SUPINSKI
• 金额: $ 48.09万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7831192
• 关键词: Acetylcysteine; Acids; Acute Disease; Adrenal Cortex Hormones; Animal Disease Models; Animal Model; Anterior; Arts; Attenuated; Basic Science; Bilateral; Blood gas; Breathing; Clinical; Critical Illness; Development; Diagnosis; Drug Design; Evaluation; Evolution; Functional disorder; Goals; Hospitalization; Human; Hyperglycemia; Hypophosphatemia; Incidence; Institution; Intensive Care Units; Laboratories; Learning; Length of Stay; Limb structure; Magnetism; Measures; Mechanical ventilation; Mechanics; Muscle; Muscle Weakness; Muscle function; Outcome; Outcome Measure; Patients; Pharmaceutical Preparations; Physiological; Physiology; Placebos; Principal Investigator; Process; Randomized; Reporting; Respiratory Diaphragm; Respiratory Failure; Respiratory Mechanics; Respiratory Muscles; Respiratory System; Risk; Scientist; Sepsis; Severities; Skeletal Muscle; Structure of phrenic nerve; Testing; Time; Translating; United States National Institutes of Health; Work; base; cohort; cost; improved; indexing; mortality; muscle strength; patient population; pressure; prevent; research study; respiratory

DESCRIPTION (provided by applicant): Challenge Topic: 04-HL-108; Improving clinical outcomes in critically ill patients with respiratory failure. Over the past two decades a great deal has been learned about the basic physiology of the breathing muscles and a number of pathophysiological conditions, including sepsis, have been shown to rapidly produce severe respiratory muscle dysfunction in animal models of disease. Importantly, these basic science studies have identified a number of pharmacological agents that appear capable of largely preventing or reversing the development of respiratory muscle dysfunction in animal models of disease. Unfortunately, virtually none of these discoveries have been translated into clinical usage. In fact, it is not even clear which hospitalized patients have respiratory muscle dysfunction, how severe their dysfunction is, and when this dysfunction develops during hospitalization. Based on our own observations, however, we believe severe respiratory muscle weakness develops in a large percentage of critically ill patients. If so, administration of drugs designed to prevent the development of skeletal muscle weakness in this patient population should have a major impact on patient outcomes, reducing the need for respiratory support, shortening the duration of ICU and hospital stay, and ultimately, improving mortality. The purpose of the present proposal is to investigate these issues in detail, to test our central hypothesis that respiratory muscle contractile dysfunction is a major contributor to respiratory failure in critically ill patients, and to translate drug treatments for respiratory muscle dysfunction from the basic science laboratory to the intensive care unit. Aim 1 will systematically evaluate respiratory muscle strength in a large cohort of MICU patients using a state-of-the-art nonvolitional measure of diaphragmatic function, namely assessment of the transdiaphragmatic twitch pressure elicited during bilateral phrenic nerve magnetic stimulation (twitch Pdi). Aim 2 will test the hypothesis that the development of skeletal muscle weakness in critically ill MICU patients can be attenuated by administration of two pharmacological agents (N-acetylcysteine and eicosopentanoic acid). We will compare skeletal muscle force and other outcome measures (duration of mechanical ventilation, duration of ICU and hospital stay) in patients at risk for respiratory muscle weakness randomized to receive either placebo, N- acetylcysteine (NAC), eicosopentanoic acid (EPA), or a combination of NAC and EPA. These experiments will provide the first comprehensive, objective evaluation of the incidence, severity, and evolution of respiratory and limb skeletal muscle dysfunction in critically ill patients. In addition, we will determine if it is possible to prevent the development of skeletal muscle weakness in critically ill patients via administration of two drugs (N-acetylcysteine and eicosopentanoic acid) previously shown in basic science studies to prevent respiratory muscle weakness in animal models of critical illness.

描述（由申请人提供）： 挑战主题：04-HL-108；改善呼吸衰竭危重患者的临床结果。在过去的二十年中，人们对呼吸肌的基本生理学有了很多了解，并且包括脓毒症在内的许多病理生理学状况已被证明可以在疾病动物模型中迅速产生严重的呼吸肌功能障碍。重要的是，这些基础科学研究已经确定了许多药物制剂，它们似乎能够在很大程度上预防或逆转疾病动物模型中呼吸肌功能障碍的发展。不幸的是，实际上这些发现都没有转化为临床应用。事实上，甚至不清楚哪些住院患者患有呼吸肌功能障碍、其功能障碍有多严重、以及这种功能障碍在住院期间何时出现。然而，根据我们自己的观察，我们认为很大一部分危重患者会出现严重的呼吸肌无力。如果是这样，使用旨在预防该患者群体出现骨骼肌无力的药物应该会对患者的治疗结果产生重大影响，减少对呼吸支持的需求，缩短 ICU 和住院时间，并最终提高死亡率。本提案的目的是详细研究这些问题，检验我们的中心假设，即呼吸肌收缩功能障碍是危重患者呼吸衰竭的主要原因，并从基础科学实验室转化呼吸肌收缩功能障碍的药物治疗到重症监护室。目标 1 将使用最先进的膈肌功能非意志测量方法，系统地评估一大群 MICU 患者的呼吸肌力量，即评估双侧膈神经磁刺激（抽搐 Pdi）期间引起的跨膈抽搐压力。目标 2 将检验以下假设：使用两种药物（N-乙酰半胱氨酸和二十碳五酸）可以减轻重症 MICU 患者骨骼肌无力的发展。我们将比较有呼吸肌无力风险的患者的骨骼肌力量和其他结果指标（机械通气持续时间、ICU 持续时间和住院时间），这些患者随机接受安慰剂、N-乙酰半胱氨酸 (NAC)、二十碳五酸 (EPA)、或 NAC 和 EPA 的组合。这些实验将对危重患者呼吸和四肢骨骼肌功能障碍的发生率、严重程度和演变提供首次全面、客观的评估。此外，我们将确定是否可以通过使用两种药物（N-乙酰半胱氨酸和二十碳五酸）来预防危重患者骨骼肌无力的发展，这两种药物先前在基础科学研究中显示可以预防动物模型中的呼吸肌无力。危重疾病。