Response to Beta2-Agonists in Acute Severe Asthma

描述(由申请人提供)： 尼古拉·哈纳尼亚博士是贝勒医学院的成人肺病专家和医学助理教授。候选人的长期目标是发展哮喘的独立研究事业。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)获得临床研究硕士学位的高级教学培训，多学科科学咨询委员会和导师的正式指导，以及独立开展一项前瞻性临床研究，调查患有急性严重哮喘的成年人对β2激动剂的反应。 传统上，急性哮喘的初始治疗包括反复给药吸入短效β-受体激动剂沙丁胺醇。然而，超过30%的哮喘急性发作患者对沙丁胺醇没有表现出初步反应。这种不良反应可能是由于沙丁胺醇是一种“弱”激动剂(具有较低的内在疗效(激活β2受体的能力))。根据对β2-肾上腺素能受体的实验室研究和候选人的试点数据，在某些情况下使用具有高内在疗效的“强大的”β2-激动剂可能具有治疗优势。一种这样的情况是急性重症哮喘，患者在寻求医疗帮助之前频繁使用救援β2受体激动剂，往往会使β2受体失去敏感性，或者在急性发作期间释放的炎症介质的存在会在功能上产生拮抗作用。急性哮喘患者对β2受体激动剂的反应传统上是由第一秒用力呼气量(FEV1)的变化决定的，测量方法是在用力呼气动作之前进行深吸气(DI)。 然而，在中度到重度呼吸道阻塞的患者中，这种DI手法可能会抑制支气管扩张剂的反应。确定支气管扩张剂反应的一种更灵敏的方法可能是测量潮气时的呼气气流，避免DI动作(部分呼气流量)。急性重症哮喘患者由于潮气呼吸时呼气气流受限而出现症状。因此，反映潮气呼吸水平气流的部分呼气流量的变化可能比FEV的变化与这种情况下的症状改善更相关。因此，拟议的研究的目的是：(1)评估Beta2-激动剂的内在疗效在确定这些药物的支气管扩张剂和症状反应方面的作用，(2)比较FEV1和部分呼气流量对Beta2-激动剂的反应，以及(3)确定部分呼气流量的变化是否比FEV1的变化更能反映症状的改善。

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.