Caffeine and preterm infants: multiorgan effects and therapeutic creep: scope to optimise dose and timing

Caffeine is a methylxanthine used for nearly 50 years in the treatment of apnoea of prematurity (AOP). Caffeine citrate is effective in the treatment of AOP using standard dosing (loading dose 20 mg/kg, maintenance 5-10 mg/kg/day) and is associated with long-term neurological benefits and other improved organ outcomes as well as immunomodulatory effects. Therapeutic creep has been noted in the use of caffeine in preterm infants differing from the criteria in randomised controlled trials. A Cochrane review showed insufficient evidence to support prophylactic use of caffeine citrate in preterm neonates to prevent AOP, although it is still recommended in many national and local guidelines. Concerns about adverse reactions exist with high-dose caffeine regimens with one high-dose trial reporting statistically significant increases in abnormal neurological outcomes compared with standard doses (80 mg/kg compared to 20 mg/kg). International clinical guidelines vary from clinical trials regarding timing, dose, and duration of caffeine therapy. Further clinical research could help to understand optimal doses for different indications, such as peri-extubation, early postnatal use while ventilated, multiorgan and psychoactive effects, and long-term neurodevelopmental outcomes. This review describes the mechanism and multiorgan effects of caffeine highlighting areas of therapeutic creep and uncertainty requiring further research, such as comparative effectiveness trials. IMPACT: Caffeine citrate is indicated for the management of apnoea of prematurity. Therapeutic creep is evident in international guidelines for the use of caffeine citrate in preterm infants. Caffeine has multiorgan effects involving renal, respiratory, and inflammatory responses, which, by optimising dosing and timing, may improve outcomes. Optimising indications, dose, and timing of caffeine citrate in preterm infants in further large-scale trials is warranted and may have other multiorgan benefits.