High‐versus low‐dose caffeine in preterm infants: a systematic review and meta‐analysis

Aim: Though caffeine is a consolidated treatment in preterm infants, the efficacy and safety of a higher dose have not been systematically appraised. Methods: A systematic review was conducted to compare high (loading dose >20 mg/kg and maintenance >10 mg/kg/day) versus low dose of caffeine. MEDLINE, EMBASE, Central and conference proceedings for randomised controlled trials (RCTs) and quasi-RCTs were searched. Two authors independently screened the records, extracted the data and assessed the risk of bias. Results: As only six RCTs enrolling a total of 816 preterm infants were included, the required information size was not reached. The loading and maintenance doses varied between 20 and 80 mg/kg/day and 3 and 20 mg/kg/day, respectively. The use of high dose had no impact on mortality (RR: 0.85; 95% CI: 0.53–1.38; RCTs = 4) or bronchopulmonary dysplasia (RR: 0.93; 95% CI: 0.72–1.20; studies = 4); however, it resulted in fewer cases of extubation failure and apnoeas and shorter duration of mechanical ventilation. The quality of the evidence was low due to imprecision of the estimates. Conclusion: Due to imprecision, it is not possible to determine whether high-dose caffeine is more effective and safe than a low dose. High dose might improve short-term respiratory function without reducing bronchopulmonary dysplasia.