Effect Of Early Prophylactic Caffeine Citrate On Apnea And White Matter Imaging In Very Preterm Infants

Preterm births have increased globally,and the survival rate of very preterm infants has increased with the progress of postnatal intensive care.Premature infants are often accompanied by respiratory or neurological developmental disorders,such as frequent apnea,respiratory distress,bronchopulmonary dysplasia(BPD),white matter damage(WMD),intracranial hemorrhage,which can lead to neonatal death or legacy neurological sequelae,including cerebral palsy(CP),intellectual disability,and hearing or visual impairments.Caffeine,an adenosine receptor antagonist,is often used in the treatment of apnea in preterm infants in abroad.It has been found that neonates treated with caffeine can significantly improve neurological outcome without adverse effects.Magnetic resonance imaging(MRI)plays a crucial role in identification of brain injury.Structural brain damage can be identified by signal abnormalities on conventional MRI.Diffusion tensor imaging(DTI)technology is developed from diffusion weighted imaging(DWI),which can detect the changes in the fine structure of white matter and the diffusion of water molecules at the molecular level.Fractional anisotropy(FA)and apparent diffusion coefficient(ADC)are the two important parameters of DTI examination,which can objectively reflect the degree of brain white matter myelination.FA value increases gradually and ADC value decreases with white matter development Therefore,DTI can quantitatively evaluate the maturity and damage of nerve fibers.There are few studies to evaluate the effects of caffeine on the white matter imaging of premature infants.The purpose of this study was to explore the effectiveness of early caffeine application on apnea as well as white matter development by using cerebral MRI.Objective1.To investigate the effectiveness of early application caffeine citrate in the prevention apnea of prematurity.2.To evaluate the effect of early prophylactic caffeine treatment on white matter development in very preterm infants.MethodsInfants with gestational age ≤32 weeks and birth weight<1500 g transferred within 24 hours after birth to the neonatal care unit of the Third Affiliated Hospital of Zhengzhou University from August 2016 to April 2019 were included.Those with genetic,metabolic,or malformation diseases and those with severe intracranial hemorrhage or multiple organ failure were excluded from the study prior to randomization.189 preterm infants were included and randomly assigned to the caffeine(n=96)or placebo(n=93)treatment group.In the caffeine treatment group,infants received the first dose caffeine intravenously at 20 mg/kg within 72 hours after birth,and this was maintained at a dose of 10 mg/kg once a day until 34 weeks corrected gestational age.In the placebo group,caffeine was replaced by the same volume of saline,and when AOP occurred aminophylline was given.Cerebral MRI including DTI examinations were performed at 34-36 weeks of corrected gestational age,and FA and ADC values was measured.In total,160 infants were completed MRI and DTI examinations,including 80 cases in the placebo group and 80 cases in the caffeine group.Data on AOP,assisted ventilation time,basic information,maternal and pregnancy conditions,complications,adverse effects and MRI were collected in the two groups.Results1.There were fewer cases of apnea of prematurity and shorter assisted ventilation time for infants in the caffeine group compared to that in the placebo group(p<0.05),while there were no significant differences between the two groups regarding baseline characteristics or other preterm birth-related complications.2.At 34-36 weeks of corrected gestational age,infants in the caffeine group had significantly higher FA values in white matter,including the posterior limb of the internal capsule,the corpus callosum,the frontal,occipital,and parietal white matter,the cerebellum,and the cerebral peduncle,compared to infants in the placebo group.ADC values in the above white matter area were significantly reduced in the caffeine group.While there were no significant differences regarding the FA and ADC values in the gray matter,including the thalamus,lenticular nucleus,and caudate nucleus between the two groups.Conclusions1.Early application of caffeine citrate can reduce the occurrence of AOP and shorten the time of assisted ventilation;2.Early application of caffeine citrate can improve white matter development in preterm infants.