Vagus Nerve Stimulation Treatment for Asthmatic Bronchoconstriction

迷走神经刺激治疗哮喘性支气管收缩

• 批准号: 9488161
• 负责人: Mark Bates
• 金额: $ 14.92万
• 依托单位: PULSUS MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9488161
• 关键词: Accident and Emergency department; Adrenal Cortex Hormones; Air; American; Animals; Asthma; Blood Pressure; Body Temperature; Body Weight; Breathing; Bronchoconstriction; Cannulas; Carotid Arteries; Cavia; Cervical; Cessation of life; Classification; Clinical; Clinical Trials; Data; Devices; Diabetes Mellitus; Dyspnea; Economic Inflation; Electrodes; Emergency department visit; Enrollment; Epilepsy; FDA approved; Goals; Grant; Guinea; Hand; Health; Heart Rate; Heating; Hospitalization; Human; Hunger; Implant; Individual; Intractable Epilepsy; Investigation; Left; Life; Link; Lipids; Lung; Measures; Medical; Mental Depression; Methods; Mineral Oil; Modeling; Morbidity - disease rate; Nocturnal Asthma; Obesity; Osteopenia; Ovalbumin; Paralysed; Patients; Pharmaceutical Preparations; Phase; Physical activity; Physicians; Population; Pressure Transducers; Pump; Quality of life; Refractory; Resistance; Respiratory System; Safety; Seizures; Severity of illness; Source Code; Structure of jugular vein; Succinylcholine; Symptoms; System; Target Populations; Testing; Tidal Volume; Urethane; Vagus nerve structure; Visit; asthmatic; cohort; constriction; cost; disabling symptom; early experience; efficacy study; experience; human study; improved; mortality; patient population; phase 1 study; pressure; prevent; response; time interval; treatment response; vagus nerve stimulation

Project Summary The Specific Aim of this proposal is to test the feasibility of using vagus nerve stimulation (VNS) for treating asthma related airway constriction that is refractory to current treatments. There are approximately 25 million people with asthma in the US. About 15% percent of these asthma sufferers experience early and late phase severe asthmatic bronchoconstriction that is refractory to current medication. These patients account for more than half of health related asthma costs and the majority of its mortality. This patient population accounts for 4,700 emergency department visits per day, 1,200 hospitalizations per day, and more than 3,300 deaths annually. There is currently no treatment for people who suffer from uncontrolled asthma. Other percutaneous devices have proven effective for blocking the early phase of asthma attacks that are refractory to current therapy in an ED setting; but there is currently no effective VNS device for outside of the ED setting. In addition, the efficacy of their device for blocking the later phase of the asthma response is unknown. The late phase occurs in 50% of individuals and may account for extended stand and returns to the ED. Our goal is to provide patients with VNS for on-demand treatment of both the early- and late-asthma responses in order to drastically improve quality of life, prevent death, and to obviate the need for visiting the ED.However, before evaluating our method in humans, we must first determine if VNS is effective for halting both the early and the late phase of asthma. In this Phase I study, we will achieve our Specific Aim by evaluating the efficacy of VNS for blocking both early and late asthma responses in an ovalbumin (OVA)- sensitized guinea pig model of asthma. Guinea pigs are anesthetized with urethane (1.8 g/kg i.p.). Heart rate and blood pressure are measured via a carotid artery cannula. Both jugular veins are also cannulated for administration of drugs. The left vagus nerve will be isolated and immersed in a pool of mineral oil, and bipolar cuff electrode will be placed around the left cervical vagus. Animal's body temperature will be maintained at 37C using a heating blanket. Animals are paralyzed with succinylcholine (10 ml/kg/min, i.v.) and ventilated (tidal volume 1 ml/100 g body weight at 100 breaths per minute) via a tracheal cannula (using a constant volume pump, Harvard Apparatus Co, South Natick, MA). Bronchoconstriction (measured as an increase in pulmonary inflation pressure (Ppi) via a pressure transducer on a sidearm of the tracheal cannula) will be measured at stated time intervals after ovalbumin inhalation. Test of Feasibility: We must observe ≥ 35% (mean) reduction of max respiratory system resistance when OVA is combined with VNS in comparison to sham VNS. This value was chosen because it is both directly related to previously demonstrated pulmonary pressure change in guinea pigs and predictive of later clinically meaningful responses in humans.

项目摘要 本提案的具体目的是测试使用迷走神经刺激（VNS）进行 治疗与哮喘相关的气道收缩，这是目前治疗方法难以解决的问题。大约有25所 在美国有100万哮喘患者。大约15%的这些哮喘患者经历早期和晚期 严重哮喘性支气管收缩期，目前的药物治疗无效。这些患者占 超过一半的健康相关哮喘费用和大部分死亡率。这个病人群体占 每天有4,700人急诊，1,200人住院，3,300多人死亡 每年。目前还没有治疗患有不受控制的哮喘的人。 其他经皮装置已被证明可有效阻断哮喘发作的早期阶段， 在艾德环境中对当前治疗难治;但目前没有有效的VNS器械用于 艾德设置。此外，他们的装置阻断哮喘反应后期的功效是 未知晚期阶段发生在50%的个体中，可能是延长的林分，并返回到 ED.我们的目标是为早期和晚期哮喘患者提供VNS按需治疗 为了大幅度提高生活质量，防止死亡，并考虑到访问的必要性， 艾德。然而，在评估我们的方法在人类中的应用之前，我们必须首先确定VNS是否有效地用于停止 哮喘的早期和晚期阶段。在第一阶段研究中，我们将通过以下方式实现我们的具体目标： 评估VNS阻断卵清蛋白（OVA）中早期和晚期哮喘反应的功效- 致敏豚鼠哮喘模型。 用氨基甲酸乙酯（1.8 g/kg i. p.）麻醉豚鼠。测量心率和血压 通过颈动脉插管两个颈静脉也被插管用于给药。左迷走 将神经分离并浸入矿物油池中，并将双极袖状电极放置在神经周围。 左颈迷走神经使用加热毯将动物体温维持在37 ℃。动物 用琥珀酰胆碱（10 ml/kg/min，i. v.）和通气（潮气量1 ml/100 g体重，100 每分钟呼吸次数）通过气管插管（使用恒定体积泵，哈佛仪器公司，南 Natick，MA）。支气管收缩（测量为肺充气压（Ppi）的增加， 气管插管侧臂上的压力传感器）将在 卵清蛋白吸入 可行性测试：我们必须观察到最大呼吸系统阻力降低≥ 35%（平均值） 与假VNS相比，当OVA与VNS联合使用时。之所以选择此值，是因为它既是 与先前证明的豚鼠肺压变化直接相关，并预测了随后的 临床上有意义的反应。