Theophylline for Bronchopulmonary Dysplasia
Theophylline has limited evidence supporting its use in bronchopulmonary dysplasia (BPD) and is not routinely recommended, though it may provide modest bronchodilator effects in select symptomatic infants with established chronic lung disease. 1
Evidence for Theophylline in BPD
Mechanism and Physiologic Effects
Theophylline acts as a methylxanthine bronchodilator that can relieve bronchospasm, decrease airway resistance, and increase lung compliance in infants with chronic lung disease of infancy (CLDI). 1
The drug also improves diaphragmatic contractility, which may benefit ventilator-dependent infants. 1
Theophylline requires fairly high serum levels (5-15 mg/L) to achieve bronchodilator effects, which increases the risk of side effects. 1, 2
Clinical Evidence
Studies demonstrate that theophylline can produce short-term improvements in pulmonary function measurements in infants with established BPD, including increased compliance and decreased airway resistance. 1
However, trials have not demonstrated that regular theophylline therapy improves long-term outcomes in ventilated infants with BPD. 1
The evidence suggests restricting theophylline use to symptomatic patients with obvious bronchospasm interfering with effective ventilation, such as those displaying prolonged expiratory phase or use of accessory muscles. 1
Practical Limitations and Safety Concerns
Side Effect Profile
Theophylline causes significant side effects including tachycardia, gastroesophageal reflux, and altered sleep and behavior patterns. 1, 3
The narrow therapeutic window (5-15 mg/L for theophylline, 5-20 mg/L for caffeine) requires strict dose monitoring and frequent serum level checks. 1, 4
Gastrointestinal side effects occur three times more frequently with theophylline compared to other bronchodilators, leading to high discontinuation rates. 3
Monitoring Requirements
Serum levels must be monitored regularly to maintain therapeutic range and avoid toxicity. 1, 2
The drug is metabolized by hepatic cytochrome P450 enzymes, creating numerous clinically significant drug interactions that can alter serum levels unpredictably. 3, 2
Preferred Alternatives
Inhaled Bronchodilators
Inhaled beta-agonists are generally preferred over oral methylxanthines for BPD management after NICU discharge, once the risk of apnea of prematurity has passed. 1
Aerosolized sympathomimetics (albuterol, salbutamol) improve pulmonary function with fewer systemic side effects than theophylline. 1
Caffeine for Apnea Management
Caffeine is the preferred methylxanthine for apnea of prematurity and has been shown to improve important clinical outcomes including reduced BPD rates. 5
When comparing caffeine to other methylxanthines (including theophylline), there may be little to no difference in mortality or BPD outcomes, but caffeine has a more favorable side effect profile. 5
Clinical Recommendation Algorithm
For infants with established BPD:
First-line: Use inhaled beta-agonists for symptomatic bronchospasm after NICU discharge. 1
Consider theophylline only if: The infant has obvious bronchospasm interfering with ventilation that is not adequately controlled by inhaled bronchodilators. 1
If using theophylline: Start with low doses, monitor serum levels strictly (target 5-15 mg/L), and assess for clinical response versus side effects. 1, 2
Discontinue if: No clear clinical benefit is observed or if side effects (tachycardia, feeding intolerance, reflux) develop. 1, 3
Key Caveats
Bronchodilator responsiveness in BPD is not universal, and some infants show no benefit from theophylline therapy. 1
The lack of long-term outcome data means theophylline should not be used as a preventive strategy for BPD. 1
Current pharmacologic approaches to BPD prevention focus on caffeine, vitamin A, and selective corticosteroid use rather than theophylline. 6, 7