Theophylline for Recurrent Apnea in Preterm Infants
Yes, theophylline is an effective and established treatment for recurrent apnea of prematurity, though caffeine is now generally preferred due to its superior safety profile and therapeutic advantages. 1, 2
Evidence Supporting Use
Theophylline is a safe and effective respiratory stimulant for apnea of prematurity, working by stimulating the central nervous system and respiratory center, which decreases apnea frequency and increases ventilation. 3, 4 The drug has been studied extensively in preterm neonates and demonstrates consistent efficacy in reducing apneic episodes. 3
Dosing Recommendations
Loading Dose
- Administer 5-6 mg/kg of theophylline (or 6.2 mg/kg aminophylline) intravenously as a loading dose. 3, 5
Maintenance Dosing
For premature neonates:
- < 24 days postnatal age: 1 mg/kg every 12 hours 6
- ≥ 24 days postnatal age: 1.5 mg/kg every 12 hours 6
Alternative maintenance approach:
- 2 mg/kg every 12 hours (total 4 mg/kg/day) after the loading dose, which will maintain therapeutic levels in most infants without toxicity. 3
- Some sources recommend 4.4 mg/kg per day to achieve serum levels of 6-12 mg/L. 5
Target Therapeutic Range
- Maintain serum theophylline levels between 5-15 mg/L (some sources specify 6-12 mg/L for neonates). 1, 7, 6, 5
- Monitor serum levels closely as the therapeutic window is narrow and neonates show inter-infant variability in metabolism. 1, 3
Important Pharmacokinetic Considerations
Neonates have unique theophylline pharmacokinetics compared to older children:
- Prolonged half-life and low clearance rates 3
- Larger apparent volume of distribution (0.71 ± 0.18 L/kg) 5
- Decreased protein binding 3
- Unique metabolism involving methylation to caffeine 3
Monitoring Requirements
Strict attention must be paid to dosing and serum level monitoring:
- Check serum theophylline levels regularly to individualize dosing based on concentration measurements and clinical response. 1, 3
- Monitor for signs of toxicity: tachycardia (occurs at plasma concentrations ≥13 mg/L), gastroesophageal reflux, altered sleep patterns, irritability, and behavioral changes. 1, 4
- Evidence of toxicity in neonates may be subtle and requires vigilant clinical observation. 3
Caffeine as Preferred Alternative
While theophylline is effective, caffeine is now the preferred methylxanthine for apnea of prematurity due to several therapeutic advantages:
- Similar efficacy in reducing apnea/bradycardia episodes (no difference in treatment failure rates at 1-3 days or 5-7 days). 2, 8
- Significantly lower toxicity: adverse effects requiring dose changes occur less frequently with caffeine (RR 0.17,95% CI 0.04-0.72). 2, 8
- Higher therapeutic ratio 8
- More reliable enteral absorption 8
- Longer half-life allowing less frequent dosing 8
- Target caffeine levels: 5-20 mg/L 1
Clinical Pitfalls to Avoid
- Do not use oral choline theophyllinate as it is erratically absorbed in preterm infants. 5
- Avoid excessive dosing as neonates appear more sensitive to cardiovascular effects, with tachycardia occurring at relatively low concentrations. 4
- Do not abruptly discontinue chronic methylxanthine therapy; taper judiciously. 7
- Be aware of altered glucose homeostasis and increased oxygen consumption even at therapeutic doses. 4
- Recognize that theophylline is commonly used in the NICU for apnea of prematurity but inhaled bronchodilators are preferred after NICU discharge once apnea risk has passed. 1