Caffeine versus theophylline for apnea of prematurity: a randomised controlled trial

J Paediatr Child Health. 2009 Oct;45(10):587-92. doi: 10.1111/j.1440-1754.2009.01570.x. Epub 2009 Sep 14.


Aim: To compare standard doses of theophylline and caffeine for apnea of prematurity in terms of apnea frequency and assess the need for therapeutic drug monitoring.

Methods: Seventy neonates less than 33 weeks gestation, breathing spontaneously, were randomly assigned (open-label) to receive either theophylline or caffeine for treatment or prevention of apnea. The primary outcome measure was the difference in apnea frequency between theophylline and caffeine patient groups. Methylxanthine serum levels were measured on the 1st, 3rd and 7th days of therapy and every 7 days thereafter.

Results: Thirty-seven neonates received theophylline (T) and 33 caffeine (C) for treatment (8 T/10 C) or prevention of apnea (29 T/23 C). Treatment with either methylxanthine significantly decreased apnea events (T, P= 0.012; C, P= 0.005) while only C prophylaxis appeared to control apnea in infants at risk. Analysis of combined (treatment plus prophylaxis) data showed a significant decrease in apnea frequency only in those infants receiving caffeine (P= 0.001). However, there was no sustained benefit of C over T beyond the first week of therapy. T and C concentrations (2.2-13.9 mg/L; 5.5-23.7 mg/L, respectively) in the majority of cases fell within the recommended therapeutic ranges and were not significantly associated with apnea events.

Conclusions: This study shows an advantage of C over T for premature infants <33 weeks gestation during the first week of therapy. Standard regimens of both methylxanthines do not seem to require routine concentration monitoring in the first 3 weeks of treatment unless indicated by clinical effect.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apnea / drug therapy*
  • Apnea / prevention & control
  • Bronchodilator Agents / administration & dosage
  • Bronchodilator Agents / therapeutic use
  • Caffeine / administration & dosage
  • Caffeine / blood
  • Caffeine / therapeutic use*
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / therapeutic use
  • Drug Therapy, Combination
  • Greece
  • Humans
  • Infant, Newborn
  • Infant, Premature
  • Infant, Premature, Diseases / drug therapy*
  • Infant, Premature, Diseases / prevention & control
  • Secondary Prevention
  • Theophylline / administration & dosage
  • Theophylline / blood
  • Theophylline / therapeutic use*


  • Bronchodilator Agents
  • Central Nervous System Stimulants
  • Caffeine
  • Theophylline