Efficacy And Safety Of Caffeine Prevents Apnea Of Premature:A Meta-analysis

Objective:There were 2 parts in this study.Part one: To evaluate the efficacy and safety of different doses of caffeine in the treatment of apnea of premature.Part two: To evaluate the efficacy and safety of different times of caffeine in the treatment of apnea of premature.Methods:Part one: Chinese national knowledge internet(CNKI),Wanfang data,Chongqing Weipu Chinese scientific journal full-text database(VIP),China biomedical literature disc(CBMdisc),PubMed Databases,EMbase and Cochrane Library were retrieved for randomized controlled trials about different doses of caffeine in the treatment of AOP.The publication date of trials was ranged from the earliest dates of each database to May 31,2018.Patient were infants with apnea.Grouping and Intervention: the experimental group was called a high-dose caffeine group(load dose: 20~80 mg/kg,maintenance dose: 10~30 mg/kg),the control group was called a low-dose caffeine group(load dose: 20~30 mg/kg,maintenance dose: 2.5~15 mg/kg).Outcome Indicators: mortality before hospital discharge,the rate of extubation failure,incidence of bronchopulmonary dysplasia(BPD).Literature was screened and extracted by two evaluators according to inclusion and exclusion criteria,and the quality of RCTs was evaluated using the “biased risk assessment” tool recommended by the Cochrane Collaboration.Meta-analysis of the included literature was analyzed using Review Manager 5.3 software.Part two: The computer search database,search strategy and retrieval time limit are the same as the first part.Search all RCTs,quasi-randomized controlled trials(QRCT),cohort study of caffeine-treated AOP at different stage.Patient were infants with apnea.Grouping and Intervention: the experimental group was called the early caffeine group(caffeine was used within 3 days after birth),the control group was the late caffeine group(more than 3 days after birth).Outcome Indicators: mortality and BPD incidence.The literature was strictly screened and extracted by two reviewers according to the inclusion and exclusion criteria,and The cohort study(4-5 divided into medium,?6 divided into high quality)was evaluated using the "The Newcastle-Ottawa Scale(NOS)" scale.Documents of medium or higher quality were Selected.Meta-analysis of the included literature was analyzed using Review Manager 5.3 software and Comprehensive Meta-Analysis software version 2.0 software.Results:Part one: 10 RCTs were included in the Meta-analysis,including 904 infants,445 in the high-dose group,and 459 in the low-dose group.Meta-analysis showed that the high-dose group did not reduce the risk of death before hospital discharge(RR=0.81,95%CI 0.52~1.25,P=0.34)compared with the low-dose group,but it reduced the rate of extubation failure(RR=0.53,95%CI 0.41~0.69,P<0.00001)and the risk of BPD(RR=0.76,95%CI 0.62~0.95,P=0.01),reduced the frequency of apneas(MD=-5.90,95%CI-7.01~-4.79,P<0.00001)and the days of apnea(MD=-1.60,95%CI-2.95~-0.24,P=0.02);shortened respiratory support time,especially CPAP-assisted ventilation(MD=-1.68,95%CI-2.34~-1.01,P<0.00001)and oxygen therapy time(MD=-5.82,95%CI-7.46~-4.17,P<0.00001),it increased the risk of tachycardia(heart rate >180 beats/min)(RR=2.74,95%CI 1.63~4.60,P=0.0001)and feeding intolerance(RR=1.32,95%CI 1.02~1.70,P=0.03).Part two: Eight articles(2 RCTs,6 cohort studies)were included,including 64422 infants,37355 infants was in the early group(0-3 d),and 27067 infants was in the late group(>3 d).Meta-analysis showed that the early caffeine group compared to the late caffeine group,can not reduce the risk of death(OR=0.929,95%CI 0.858~1.005,P=0.065),but the early group use caffeine can reduced the risk of BPD(36 weeks)(OR=0.58,95%CI 0.37~0.91,P=0.017)and other diseases,such as Intraventricular hemorrhage(IVH)(OR=0.54,95%CI 0.36~0.80,P=0.002),Patent ductus arteriosus(PDA)(OR=0.52,95%CI 0.34~0.79,P=0.002),Periventricular leukomalacia(PVL)(OR=0.56,95%CI 0.49~0.64,P<0.00),the early group use caffeine can also shorten respiratory support time,such as: mechanical ventilation(MD=-6.56,95%CI-11.28~-1.84,P=0.006),oxygen therapy time(MD=-1.48,95%CI-2.42~-0.53,P=0.002).Conclusion:Part one: High dose(load: 20~80 mg/kg,maintenance: 10~30 mg/kg)caffeine has better clinical efficacy in treating apnea of premature,but it has the risk of increasing adverse reactions.Part two: Early(?3 d)use of caffeine in the treatment of apnea of premature has good efficacy and safety.