Efficacy and Safety of Different Maintenance Doses of Caffeine Citrate for Treatment of Apnea in Premature Infants: A Systematic Review and Meta-Analysis

Background. Caffeine is widely used for the treatment of neonatal apnea, but there is no agreement on the optimum maintenance dose for preterm infants. Objective. The aims of this meta-analysis were to compare the efficacy and safety of high versus low maintenance doses of caffeine citrate for the treatment of apnea in premature infants. Methods. Literature searches were conducted using PubMed, Cochrane Library, OVID, Embase, Web of Science, Chinese Biomedical Literature, Weipu Journal, Wanfang, and CNKI databases up to September 2018. Only randomized controlled trials (RCTs) of caffeine citrate for apnea treatment in premature infants were included. Trials were divided into those testing high maintenance doses (10-20 mg/kg daily) and low maintenance doses (5-10 mg/kg daily) for comparison. Data collection and extraction, quality assessment, and data analyses were performed according to the Cochrane standards. Results. Among the 345 studies initially identified, thirteen RCTs involving 1515 patients were included. Compared to the low-dose group, the high-dose group exhibited greater effective treatment rate (RR: 1.37, 95%CI: 1.18 to 1.60, P<0.0001) and success rate for ventilator removal (RR: 1.74, 95%CI: 1.04 to 2.90, P=0.03), but higher incidence of tachycardia (RR: 2.02, 5%CI: 1.30 to 3.12, P=0.002). The high-dose group also demonstrated lower extubation failure rate (RR: 0.5, 95%CI: 0.35 to 0.71, P=0.0001), frequency of apnea (WMD: -1.55, 95%CI: -2.72 to -0.39, P=0.009), apnea duration (WMD: -4.85, 95%CI: -8.29 to -1.40, P=0.006), and incidence of bronchopulmonary dysplasia (RR: 0.79, 95%CI: 0.68 to 0.91, P=0.002). There were no significant group differences in other adverse events including in-hospital death (P>0.05). Conclusions. Higher maintenance doses of caffeine citrate appear more effective and safer than low maintenance doses for treatment of premature apnea, despite a higher incidence of tachycardia.