Response to Beta2-Agonists in Acute Severe Asthma

描述（由申请人提供）： 博士Nicola Hanania是贝勒医学院的成人肺病学家和医学助理教授。候选人的长期目标是在哮喘方面发展独立的研究事业。拟议的K-23奖项的职业发展计划包括，通过临床科学家培训计划（K-30）进行高级教学培训，获得临床研究硕士学位，来自多学科科学咨询委员会和导师的正式指导，以及独立进行前瞻性临床研究，调查急性重度哮喘成人对β 2受体激动剂的反应。 急性哮喘的初始管理传统上包括吸入短效β 2受体激动剂沙丁胺醇的重复剂量给药。 然而，超过30%的哮喘急性发作患者对沙丁胺醇没有初步反应。这种不良反应可能是由于沙丁胺醇是一种“弱”激动剂（具有较低的内在功效（激活β 2受体的能力））。 根据对β 2-肾上腺素能受体的实验室研究和候选人的初步数据，在某些情况下使用具有高内在疗效的“强效”β 2-激动剂可能具有治疗优势。 一种这样的情况是急性严重哮喘，其中β 2受体通常由于患者在寻求医疗帮助之前频繁使用补救β 2受体激动剂而脱敏，或者可能由于急性发作期间释放的炎性介质的存在而在功能上被拮抗。 传统上，急性哮喘对β 2受体激动剂的反应是通过第一秒用力呼气量（FEV 1）的变化来确定的，该变化使用深吸气（DI）之前的用力呼气动作来测量。 然而，这种DI操作可抑制中度至重度气道阻塞患者的支气管扩张反应。 确定支气管扩张剂反应的更灵敏的方法可能是在潮式呼吸时测量呼气气流，避免DI动作（部分呼气流量）。 急性重度哮喘患者由于潮气呼吸时呼气气流受限而出现症状。 因此，在这种情况下，反映潮气呼吸水平气流的部分呼气流量的变化可能比FEV的变化更好地与症状改善相关。因此，拟议研究的目的是：（1）评价β 2-受体激动剂内在疗效在确定支气管扩张剂和对这些药物的症状反应中的作用，（2）比较FEV 1和部分呼气流量对β 2-激动剂的反应，（3）确定部分呼气流量的变化是否比FEV 1的变化更好地指示症状改善。

DESCRIPTION (provided by applicant): Dr. Nicola Hanania is an adult pulmonologist and Assistant Professor of Medicine at Baylor College of Medicine. The candidate's long-term goal is to develop an independent research career in asthma. The career development plan of the proposed K-23 award includes, advanced didactic training through the Clinical Scientist Training Program (K-30) leading to a Masters degree in Clinical Investigations, formal mentoring from a multidisciplinary scientific advisory committee and mentors and, independently conducting a prospective clinical study investigating the response to beta2-agonists in adults with acute severe asthma. The initial management of acute asthma traditionally includes the administration of repeated doses of the inhaled short-acting beta2-agonist, albuterol. However, more than 30% of patients with asthma exacerbation fail to show an initial response to albuterol. This poor response may result from the fact that albuterol is a "weak" agonist (has a low intrinsic efficacy (ability to activate the beta2-receptor). Based on laboratory studies on beta2-adrenergic receptors and on the candidate's pilot data, there may be a therapeutic advantage in using a "strong" beta2-agonist with high intrinsic efficacy in some situations. One such situation is acute severe asthma where the beta2-receptor is often desensitized by the patient's frequent use of rescue beta2-agonists prior to seeking medical help or may be functionally antagonized by the presence of inflammatory mediators released during an acute attack. The response to beta2-agonists in acute asthma is traditionally determined by the change in the forced expiratory volume in the first second (FEV1,) measured using a forced expiratory maneuver preceded by deep inhalation (DI). However, this DI maneuver can dampen the bronchodilator response in patients with moderate to severe airway obstruction. A more sensitive method of determining bronchodilator response may be the measurement of expiratory airflow at tidal breath avoiding the DI maneuver (partial expiratory flow). Patients with acute severe asthma are symptomatic because of limitation in their expiratory airflow during tidal breath. Thus, changes in partial expiratory flow, which reflect airflow at the level of tidal breath, may correlate better with symptom improvement in this situation than changes in FEV Therefore, the aims of the proposed study are to: (1) to evaluate the role of intrinsic efficacy of beta2- agonists in determining the bronchodilator and symptomatic responses to these medications, (2) to compare the FEV1 and partial expiratory flow responses to beta2-agonist and, (3) to determine whether changes in partial expiratory flow are better indicators of symptom improvement than changes in FEV1.