1st Tier Drugs+Theophylline in Pediatric Severe Asthma

描述（由申请人提供）： 哮喘是影响近1500万儿童的最常见的儿童慢性疾病，并且是美国儿童住院的最常见原因，每年近50万。哮喘持续状态的当代标准一级治疗包括持续雾化沙丁胺醇、预定静脉内皮质类固醇和米剂量吸入异丙托溴铵。虽然这种药物组合对大多数哮喘持续状态儿童有益，但有些儿童需要包括机械通气在内的连续治疗。以前，茶碱和各种同系物被用作哮喘的一线治疗，包括慢性哮喘和哮喘持续状态。然而，雾化β 2-受体激动剂的引入在很大程度上取代了其使用。除了已知的支气管扩张作用外，茶碱还表现出不同于类固醇的抗炎活性。最近的研究表明，哮喘持续状态的危重患儿除了常规的第一级哮喘持续状态治疗外，还可以从持续输注氨茶碱中获益，如上所述。这种方法似乎与定量哮喘评分的更快解决、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量测定变量的加速改善相关。来自西雅图儿童医院的先前数据表明，哮喘持续状态患者避免机械通气的安全性和经济效益，并且还需要（重新）探索β 2-激动剂以外的药物类别的潜在效益。 因此，拟定的多机构、随机、双盲、安慰剂对照试验将进一步研究静脉内茶碱加标准一级治疗对入住PICU的重症儿童哮喘持续状态的潜在获益。研究的主要终点将定时，以在停止持续雾化沙丁胺醇后至少4小时内达到稳定的儿童哮喘严重程度评分0-2，在进入儿科重症监护室后每2小时进行一次评估。研究的次要具体目的包括比较安慰剂治疗和氨茶碱治疗的受试者在以下方面的情况：呼吸急促和低氧血症的缓解;与气道阻塞相关的肺活量测定变量的改善;标准治疗失败的发生率;反映气道炎症的生物标志物的改变;不良反应的发生率; PICU住院时间/达到非危重状态;并在PICU出院后24-48小时随访患者满意度调查。密切监测血清茶碱水平将有助于将目标浓度控制在14 <$3 ug/mL范围内，特别是避免 已知与高茶碱水平相关的不良事件。总之，拟定的研究将严格检查与静脉内氨茶碱添加到哮喘持续状态重症儿童的标准1级治疗中相关的潜在不良事件增加相关的潜在治疗获益。

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.