High versus standard dose caffeine for apnoea: a systematic review

Arch Dis Child Fetal Neonatal Ed. 2018 Nov;103(6):F523-F529. doi: 10.1136/archdischild-2017-313556. Epub 2018 Feb 7.


Background: Placebo-controlled trials have shown that caffeine is highly effective in treating apnoea of prematurity and reduces the risk of bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI).

Objective: To identify, appraise and summarise studies investigating the modulating effect of different caffeine dosages.

Methods: A systematic review identified all randomised controlled trials (RCTs) comparing a high versus a standard caffeine treatment regimen in infants with a gestational age <32 weeks, by searching the main electronic databases and abstracts of the Pediatric Academic Societies. Studies comparing caffeine to placebo or theophylline only were excluded. Primary outcomes were BPD and mortality at 36 weeks postmenstrual age. Secondary key-outcome was neurodevelopmental outcome at 12 and 24 months corrected age. Meta-analysis was performed using RevMan 5.3.

Results: Six RCTs including 620 infants were identified. Meta-analysis showed a significant decrease in BPD, the combined outcome BPD or mortality, and failure to extubate in infants allocated to a higher caffeine dose. No differences were found in mortality alone and NDI. The quality of the outcome measures were deemed low to very low according to the Grading of Recommendations Assessment, Development and Evaluation guidelines.

Conclusions: Although this review suggests that administering a higher dose of caffeine might enhance its beneficial effect on death or BPD, firm recommendations on the optimal caffeine dose cannot be given due to the low level of evidence. A large RCT is urgently needed to confirm or refute these findings and determine the optimal dose of caffeine.

Keywords: apnea of prematurity; bronchopulmonary dysplasia; caffeine; dosage regimens.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Apnea / complications
  • Apnea / drug therapy*
  • Apnea / mortality
  • Bronchopulmonary Dysplasia / epidemiology
  • Bronchopulmonary Dysplasia / etiology
  • Caffeine / administration & dosage*
  • Caffeine / adverse effects
  • Central Nervous System Stimulants / administration & dosage*
  • Central Nervous System Stimulants / adverse effects
  • Dose-Response Relationship, Drug
  • Humans
  • Infant
  • Infant Mortality
  • Infant, Newborn
  • Infant, Premature
  • Infant, Premature, Diseases / drug therapy
  • Treatment Outcome


  • Central Nervous System Stimulants
  • Caffeine