Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity

Background Very preterm infants often require respiratory support and are therefore exposed to an increased risk of bronchopulmonary dysplasia (chronic lung disease) and later neurodevelopmental disability. Caffeine is widely used to prevent and treat apnea (temporal cessation of breathing) associated with prematurity and facilitate extubation. Though widely recognized dosage regimes have been used for decades, higher doses have been suggested to further improve neonatal outcomes. However, observational studies suggest that higher doses may be associated with harm. Objectives To determine the effects of higher versus standard doses of caffeine on mortality and major neurodevelopmental disability in preterm infants with (or at risk of) apnea, or peri‐extubation. Search methods We searched CENTRAL, MEDLINE, Embase, CINAHL, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and clinicaltrials.gov in May 2022. The reference lists of relevant articles were also checked to identify additional studies. Selection criteria We included randomized (RCTs), quasi‐RCTs and cluster‐RCTs, comparing high‐dose to standard‐dose strategies in preterm infants. High‐dose strategies were defined as a high‐loading dose (more than 20 mg of caffeine citrate/kg) or a high‐maintenance dose (more than 10 mg of caffeine citrate/kg/day). Standard‐dose strategies were defined as a standard‐loading dose (20 mg or less of caffeine citrate/kg) or a standard‐maintenance dose (10 mg or less of caffeine citrate/kg/day). We specified three additional comparisons according to the indication for commencing caffeine: 1) prevention trials, i.e. preterm infants born at less than 34 weeks' gestation, who are at risk for apnea; 2) treatment trials, i.e. preterm infants born at less than 37 weeks' gestation, with signs of apnea; 3) extubation trials: preterm infants born at less than 34 weeks' gestation, prior to planned extubation. Data collection and analysis We used standard methodological procedures expected by Cochrane. We evaluated treatment effects using a fixed‐effect model with risk ratio (RR) for categorical data and mean, standard deviation (SD), and mean difference (MD) for continuous data. Main results We included seven trials enrolling 894 very preterm infants (reported in Comparison 1, i.e. any indication). Two studies included infants for apnea prevention (Comparison 2), four studies for apnea treatment (Comparison 3) and two for extubation man