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High versus standard dose caffeine for apnoea: a systematic review
  1. Roos Vliegenthart,
  2. Martijn Miedema,
  3. Gerard J Hutten,
  4. Anton H van Kaam,
  5. Wes Onland
  1. Department of Neonatology, Emma Children’s Hospital, Academic Medical Center, Amsterdam, Noord-Holland, The Netherlands
  1. Correspondence to Roos Vliegenthart, Department of Neonatology, Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands; %E2%80%83%E2%80%83%E2%80%83%E2%80%83%E2%80%83%E2%80%83%E2%80%83%E2%80%83r.j.vliegenthart{at}


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.

  • caffeine
  • apnea of prematurity
  • bronchopulmonary dysplasia
  • dosage regimens

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  • Contributors Conception and study design: RV, MM, GJH, AHvK and WO. Collection, analysis and interpretation of data: RV, MM, GJH, AHvK and WO. Drafting the manuscript for important intellectual content: RV, MM, GJH, AHvK and WO. Decision to submit the paper for publication: RV, MM, GJH, AHvK and WO. RV wrote the first draft of the manuscript. All authors approved the final version to be published. RV will act as corresponding author for this paper.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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