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Caffeine: how early is too early?

Pediatric Research (2024)Cite this article

In contrast to older children and adults, premature neonates have decreased sensitivity to carbon dioxide and often experience hypoxic ventilatory depression. This can result in deleterious and prolonged periods of hypoventilation and apnea in response to hypoxemia. Caffeine is a trimethylxanthine which stimulates the respiratory control centers in the medulla through competitive inhibition of adenosine. This increases the ventilatory responsiveness to carbon dioxide and attenuates central hypoxic ventilatory depression. For this reason, caffeine is a commonly prescribed medication administered to many premature neonates in the neonatal intensive care unit (NICU).1 Other pharmacological effects of caffeine include enhanced diaphragmatic contractility, mild diuresis, and increased minute ventilation. Through these physiologic effects and others, caffeine has substantially reduced common morbidities among premature neonates including apnea of prematurity, bronchopulmonary dysplasia (BPD), and patent ductus arteriosus (PDA).2 Most importantly, neonates who receive caffeine have better neurodevelopmental outcomes (e.g., less cerebral palsy and cognitive delays) and a decreased incidence of severe retinopathy of prematurity (ROP).2,3 When considering all the medications administered in the NICU, caffeine has played a very prominent role in improving important neonatal outcomes.

Caffeine has a wider therapeutic index and fewer side effects compared to other methylxanthines such as theophylline and aminophylline.4,5 Despite the profound impact that caffeine has had on the care of premature neonates, the dosing and timing of caffeine administration has changed little since the initial trials of this groundbreaking medication several decades ago.6 In addition, despite the widespread use of caffeine, BPD, neurodevelopmental impairment, ROP, and other morbidities continue to occur frequently in premature neonates.7 Although the efficacy, effectiveness, and safety of caffeine are well established, questions remain about of how clinicians can devise strategies to maximize the benefits. A post hoc analyses of the Caffeine of Prematurity (CAP) Trial in 2010 demonstrated that the duration of positive pressure ventilation was significantly less with earlier treatment (started at <3 postnatal days) compared to later treatment starting at >3 days, suggesting that earlier initiation of caffeine therapy may further improve neonatal outcomes.8 Subsequent large cohort studies, small randomized controlled trials, and metanalyses have favored earlier caffeine administration. However, how early is too early?

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Author contribution

R.K., J.M.D., and J.V.A. drafted the commentary and reviewed it critically for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Authors and Affiliations

  1. Department of Pediatrics, Tufts Medical Center, Boston, MA, USA

    Ryan Kilpatrick & Jonathan M. Davis

  2. Tufts Clinical and Translational Research Institute, Tufts University School of Medicine, Boston, MA, USA

    Jonathan M. Davis

  3. Division of Neonatology and the Neonatal Clinical and Translational Pharmacology Research Laboratory, State University of New York Downstate Health Sciences University, Brooklyn, NY, USA

    Jacob V. Aranda

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  1. Ryan Kilpatrick
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Correspondence to Jonathan M. Davis.

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Kilpatrick, R., Davis, J.M. & Aranda, J.V. Caffeine: how early is too early?. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03199-z

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