J. Zimmerman, M.D., D. Jardine, M.D.
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.