1st Tier Drugs+Theophylline in Pediatric Severe Asthma

描述(申请人提供)：哮喘是影响近1500万儿童的最常见的儿童慢性病，也是美国儿童住院的最常见原因，每年近50万人。哮喘持续状态的标准一级治疗包括持续雾化吸入沙丁胺醇、定期静脉注射糖皮质激素和计量吸入异丙托品。虽然这种药物组合对大多数哮喘儿童是有益的，但有些儿童需要包括机械通气在内的辅助治疗。以前，茶碱和各种同系物被用作哮喘的一线治疗，无论是慢性哮喘还是哮喘持续状态。然而，雾化(32-激动剂)的引入在很大程度上取代了它的使用。除了已知的支气管扩张作用外，茶碱还表现出有别于类固醇的抗炎活性。最近已经证明，患有哮喘状态的危重儿童在常规的一级哮喘治疗的基础上持续输注氨茶碱可能会受益，如上所述。这种方法似乎与定量哮喘评分的更快解析、脉搏血氧饱和度和呼吸频率的更快正常化以及与小气道阻塞相关的肺活量变量的加速改善有关。来自西雅图儿童医院的先前数据表明，避免对哮喘状态患者进行机械通气的安全性和经济效益，以及(重新)探索除(32-激动剂)以外的药物类别的潜在好处是有必要的。因此，拟议的多机构、随机、双盲、安慰剂对照试验将进一步调查在PICU收治的危重儿童哮喘持续状态的标准一级治疗之外，静脉注射茶碱的潜在益处。研究的主要终点将在连续雾化沙丁胺醇停止后至少4小时内达到0-2的稳定儿童哮喘严重程度评分，这是在进入儿科重症监护病房后每两小时进行一次评估。这项研究的第二个具体目标包括比较服用安慰剂和氨茶碱的受试者在以下方面的情况：呼吸急促和低氧血症的缓解；与呼吸道阻塞有关的肺活量变量的改善；标准治疗失败的发生率；反映呼吸道炎症的生物标志物的变化；不良影响的发生率；PICU住院时间/达到非危重状态的时间；以及PICU出院后24-48小时的后续患者满意度调查。密切监测血清茶碱水平将有助于将目标浓度降至14.3微克/毫升范围，特别是避免 已知的不良事件与高茶碱水平有关。总之，这项拟议的研究将严格检查与静脉注射氨茶碱有关的潜在治疗益处，这些不良事件可能会增加与标准一级治疗哮喘危重儿童相关的不良事件。

DESCRIPTION (provided by applicant): Asthma is the most common childhood chronic disease affecting nearly 15 million children, and represents the most common cause of hospitalization among children in the United States, nearly 500,000 annually. Contemporary standard 1st tier treatment of status asthmaticus includes continuously nebulized albuterol; scheduled intravenous corticosteroids, and meter-dosed inhaled ipratropium. Although this combination of drugs is beneficial to most children with status asthmaticus, some require adjunctive therapy including mechanical ventilation. Previously, theophylline and various congeners were utilized as front-line therapy for asthma, both chronically and for status asthmaticus. However, introduction of nebulized (32-agonists have largely supplanted its use. In addition to its known bronchodilator effects, theophylline also exhibits anti-inflammatory activity distinct from steroids. Recently it has been demonstrated that critically ill children with status asthmaticus may benefit from a continuous infusion of aminophylline in addition to usual 1st tier status asthmaticus therapy, noted above. This approach appears to be associated with faster resolution of quantitative asthma scores, more rapid normalization of pulse oximetry saturation, and respiratory rate, and accelerated improvement in spirometry variables associated with small airway obstruction. Previous data from Seattle Children's Hospital indicates the safety and economic benefit of avoiding mechanical ventilation in patients with status asthmaticus, and also that (re)exploration of the potential benefit of drug classes other than (32-agonists is warranted. Accordingly, the proposed multi-institutional, randomized double-blinded, placebo-controlled trial would further investigate the potential benefit of intravenous theophylline in addition to standard 1st tier therapy for status asthmaticus in critically ill children admitted to the PICU. Primary endpoint for the investigation will be timed to achieve a stable Pediatric Asthma Severity Score of 0-2 for at least 4 hours following discontinuation of continuously nebulized albuterol, as assessed every two hours after admission to the Pediatric Intensive Care Unit. Secondary specific aims for the investigation include comparison of placebo-treated and aminophylline-treated subjects with respect to: resolution of tachypnea and hypoxemia; improvement in spirometry variables related to airway obstruction; incidence of standard treatment failure; alterations in biologic markers reflecting airway inflammation; incidence of adverse affects; PICU length of stay/ attainment of non-critical status; and follow-up patient satisfaction survey 24-48 hours following PICU discharge. Close monitoring of serum theophylline levels will help target concentration to the range 14 ¿ 3 ug/mL, specifically to avoid adverse events known to be associated with high theophylline levels. In summary the proposed investigation will rigorously examine the potential therapeutic benefits in relation to the potential for increased adverse events associated with intravenous aminophylline added to standard 1st tier therapy for critically ill children with status asthmaticus.