Caffeine Citrate Dosing for Apnea of Prematurity
For neonates with apnea of prematurity, administer caffeine citrate with a loading dose of 20 mg/kg (10 mg/kg caffeine base) followed by a maintenance dose of 5 mg/kg/day (2.5 mg/kg/day caffeine base), given either intravenously or orally. 1, 2
Loading Dose Protocol
- Administer 20 mg/kg caffeine citrate (equivalent to 10 mg/kg caffeine base) as a single intravenous loading dose 1, 2
- The loading dose can be given to preterm infants with gestational age 28 to <33 weeks who have at least 6 apnea episodes lasting >20 seconds in a 24-hour period 1, 2
- Peak plasma levels (Cmax) of 6-10 mg/L are achieved within 30 minutes to 2 hours after oral administration 1, 2
Maintenance Dose Protocol
- Start maintenance dosing 24 hours after the loading dose at 5 mg/kg/day caffeine citrate (2.5 mg/kg/day caffeine base) 1, 2
- Administer once daily, either intravenously or orally (typically via feeding tube) 1, 2
- Formula feeding does not affect absorption timing 1, 2
Dose Escalation Considerations
While standard dosing is FDA-approved and effective, evidence suggests higher maintenance doses may provide additional benefit in select cases:
- If apnea persists on standard dosing, consider increasing maintenance to 10 mg/kg/day caffeine citrate 3
- Higher maintenance doses (10-20 mg/kg/day) show greater treatment efficacy (RR: 1.37) and improved ventilator removal success (RR: 1.74), though with increased tachycardia risk (RR: 2.02) 4
- A loading dose of 25 mg/kg with 6 mg/kg daily maintenance produces faster response within 8 hours compared to standard dosing 5
Common pitfall: Using the lower 12.5 mg/kg loading dose previously recommended—this produces slower response times and may be inadequate for very preterm infants 5
Therapeutic Monitoring
- Target serum caffeine levels of 5-20 mg/L 6, 7
- Monitor levels in infants with inadequate clinical response, suspected toxicity, or those requiring dose adjustments 6
- Check levels particularly in neonates with hepatic or renal impairment, as caffeine half-life is 3-4 days in neonates (versus 5 hours in adults) 1, 2
Monitoring for Adverse Effects
Watch for signs of caffeine toxicity:
- Tachycardia (most common dose-related effect) 4
- Irritability and altered sleep patterns 6
- Continuous heart rate monitoring is essential, as bradycardia often accompanies apneic episodes 7
Special Populations
- Use with extreme caution in neonates with hepatic or renal impairment—immature enzyme systems dramatically slow caffeine elimination 1, 2
- Caffeine metabolism is limited due to immature hepatic CYP1A2 systems in preterm neonates 1, 2
- Volume of distribution (0.8-0.9 L/kg) and clearance increase with weight, supporting weight-based dosing 8
Expected Clinical Response
- Significant reduction in apnea episodes occurs within 24-48 hours (26.7% of treated infants had zero apnea events on day 2 versus 8.1% with placebo, p=0.03) 1, 2
- Mean reduction of 3.9 apnea events after loading dose 3
- Treatment typically continues for 10-12 days, though duration should be individualized based on clinical response 1, 2