High versus low-dose caffeine for apnea of prematurity: a randomized controlled trial

Eur J Pediatr. 2015 Jul;174(7):949-56. doi: 10.1007/s00431-015-2494-8. Epub 2015 Feb 3.


The optimum caffeine dose in preterm infants has not been well investigated. We aimed to compare the efficacy and safety of high versus low-dose caffeine citrate on apnea of prematurity (AOP) and successful extubation of preterm infants from mechanical ventilation. We compared high-dose (loading 40 mg/kg/day and maintenance of 20 mg/kg/day) versus low-dose (loading 20 mg/kg/day and maintenance of 10 mg/kg/day) caffeine citrate in preterm infants <32 weeks gestation, presented with AOP within the first 10 days of life. A total of 120 neonates (60 in each group) were enrolled. High-dose caffeine was associated with a significant reduction in extubation failure in mechanically ventilated preterm infants (p<0.05), the frequency of apnea (p<0.001), and days of documented apnea (p<0.001). High-dose caffeine was associated with significant increase in episodes of tachycardia (p<0.05) without a significant impact on physician decision to withhold caffeine.

Conclusion: The use of higher, than current standard, dose of caffeine may decrease the chance of extubation failure in mechanically ventilated preterm infants and frequency of AOP without significant side effects.

What is known: • Caffeine therapy for treatment of apnea of prematurity has been well established over the past few years. The optimal loading and maintenance dose of caffeine in preterm infants is not well-studied. What is New: • This double blind randomized controlled trial demonstrated that using a higher, than current standard, loading and maintenance doses of caffeine for treatment of apnea in preterm infants is well tolerated and significantly decrease the frequency of apnea.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Airway Extubation / adverse effects
  • Apnea / drug therapy*
  • Caffeine / administration & dosage*
  • Caffeine / adverse effects
  • Central Nervous System Stimulants / administration & dosage*
  • Central Nervous System Stimulants / adverse effects
  • Citrates / administration & dosage*
  • Citrates / adverse effects
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Egypt / epidemiology
  • Female
  • Hospital Mortality
  • Humans
  • Infant, Newborn
  • Infant, Premature
  • Infant, Premature, Diseases / drug therapy*
  • Male
  • Pilot Projects
  • Prospective Studies
  • Respiration, Artificial
  • Tachycardia / chemically induced
  • Tachycardia / epidemiology


  • Central Nervous System Stimulants
  • Citrates
  • Caffeine
  • caffeine citrate