Effect Of Early Application Of Caffeine Citrate On Brain Development And Outcome In Premature Infants

With the continuous improvement of Obstetric and Neonatal care,the survival rate of premature infants has also been greatly improved.But the complications of premature infants,such as bronchopulmonary dysplasia(BPD),retinopathy of prematurity,necrotizing enterocolitis,nervous system damage still haunt us.Especially for the brain injury of preterm infants,the incidence is high,the onset is insidious,the etiology is complex,and no specific clinical symptoms are present,which brings huge obstacles to diagnosis and treatment.The high mortality and disability rate also bring heavy economic and mental burden to families and society.Therefore,exploring new methods of diagnosis and treatment has always been the focus of the work of newborns.Coffeine is presently one of the most frequently prescribed medications in neonatal intensive care.It has been used for more than 40 years to prevent premature infants from apnea.It has been widely recognized for its safety and effectiveness.In the process of application,researchers found that caffeine can not only cure the apnea,also had an influence on the short-term and long-term outcomes of premature infants.in the protection of brain injury in preterm infants also have certain contribution,it can reduce the incidence of cerebral palsy,improve motor and cognitive function,so as to improve the premature infant neurodevelopmental outcomes.Diffusion tensor imaging(DTI)is a magnetic resonance imaging technology,it quantitatively analyzes the degree and direction of water diffusion within individual units of volume within the magnetic resonance image and combines the diffusion tractography(DTT)to show cerebral white matter fiber shape,orientation,packing density etc.The fractional anisotropy(FA)increases with the increase of myelination of white matter,which can be used to assess brain development of prematures quantitatively.Up to date,DTI is the best imaging method to evaluate the development of white matter.However,this technology used to evaluate premature brain development in our country is just at the initial stage.The objective of this study is to evaluate the effect of early preventive caffeine citrate on brain development and prognosis in premature infants by using DTI technology,and to explore its safety.ObjectiveThe objective is to determine the effects and adverse reactions of early administration caffeine on the brain development and outcome of premature infants.Methods100 preterm infants <1500 g birth weight who were hospitalized in the Neonatal Intensive Care Unit of The Third Affiliated Hospital of ZhengZhou University from August 2016 to February 2017 were recruited.The subjects were randomly allocated to either caffeine group(n=50)or placebo group(n=50).The infants of the caffeine group within the first 3 days were allocated to caffeine citrate which was used to the corrected gestational age of 34 weeks.The control group were administrated with an equal dose of Sterile Water for Injection,and aminophylline was given if there was an apnea.The primary outcome of this study was the comparison of Head MRI and DTI which were performed before discharged(at average corrected gestational age of 35.80 weeks±0.65 weeks).Fractional anisotropy(FA)was measured for the same regions of interest(ROI)in the two groups.At the corrected gestational age 8-9 months,the mental development index(MDI)and psychomotor development index(PDI)were assessed by the Chinese children’s Development Center(CDCC)’s developmental scale.Secondary outcomes were the comparison of the incidence of apnea of preterm(AOP),bronchopulmonary dysplasia(BPD),necrotizing enterocolitis(NEC),retinopathy of prematurity(ROP),feeding intolerance,intracranial hemorrhage(ICH),spesis,duration of assisted ventilation and length of hospitalization between the two groups.ResultsThere were no significant differences between the two groups in the extent of MR-defined cerebral injury or macrostructural cerebral development(P>0.05).In contrast,caffeine exposure was associated with increase in the fractional anisotropy of 10 ROI in the white matter of frontal lobe and parietal white matter,occipital lobe,corpus callosum,posterior limb of internal capsule,cerebellum,cerebral pedunclein the superior brain regions(P<0.05).Fiber tracts of 16 cases were sparsity showed by fiber tractography,4 caffeine groups,and 12 controls(8%vs24%,P<0.05).The incidence of mental retardation(MDI<80 score)and dysplasia(PDI<80 score)in caffeine group was lower than that of the control group at 8-9 months of gestational age correction(P<0.05).The incidence of AOP and the duration of ventilation in the caffeine group were lower than those in the control group(P<0.05).There was no significant difference in the incidence of feeding intolerance,intracranial hemorrhage,NEC,BPD,and ROP between the two groups(P>0.05).ConclusionEarly administration of caffeine can promote myelin development,fiber tracts formation,reduce the incidence of mental retardation and dysplasia at 8-9 months of gestational age,and have no obvious adverse reactions in premature infants.