The Study On Prevention And Treatment Of Some Serious Complications In Preterm Infants

IntroductionThere were around0.012to0.013billion preterm infants born in the world.Survival rates for preterm infants have dramatically improved following advances inperinatal and neonatal care. However, respiratory distress syndrome, retinopathy ofprematurity and brain injury in this population remains common, and threat to thequality of life in survivors’. Prevention and treatment of serious complications inpreterm infants becomes the focus of neonatal medicine.Erythropoietin (EPO) is a30.4kDa natural glycoprotein, and initially recognizeddue to the role of erythropoiesis. EPO has been reported to induce cell responses inwide range to directly protect and repair tissue damage in the brain. Inhibition ofapoptosis is the basic mechanism for EPO neuroprotection, includinganti-inflammatory, antioxidant, angiogenesis, anti-epilepsy, and neurotrophic effects.Now, EPO is one of the most promising neuroprotective agents, but the protectiveeffect of EPO on brain injury in preterm infants and related mechanisms are stillrarely reported.Therefore, this study investigates optimal methods for prevention and treatmentof serious complications in preterm infants from four parts.1. To evaluate the effectof gestational age on respiratory distress syndrome, to analyze the optimal management of RDS for preterm infants with different gestational age, decrease theincidence of complications, reduce brain injury, and improve the prognosis of preterminfants.2. To investigate the effect of different mechanical ventilation on theprognosis of preterm infants with severe respiratory distress syndrome.3. To evaluatethe screening algorithm WINROP for the prediction of retinopathy of prematurity in aChinese population.4. To investagte the role of EPO on prevetion of brain inury inpreterm infants in prospective randomized controlled trial, and exploreneuroprotective mechanisms of EPO in preterm infants from clinical, cellular andmolecular level.Part I: The impact of gestational age on neonatal respiratorydistress syndromeObjectiveNeonatal respiratory distress syndrome is common in neonates. Thecharacteristic of respiratory distress syndrome was different in infants with differentgestational age. The management was difficult for some sick bigger newborn infants.The purpose of this study was to evaluate the effect of gestational age on respiratorydistress syndrome; and to analyze the optimal management of RDS for newborninfants with different gestational age, decrease the incidence of complications, reducebrain injury, and improve the prognosis of preterm infants.MethodsA retrospective study was conducted on neonates admitted to the NICU betweenJanuary2006and December2010. The enrolled infants with RDS were categorizedas very preterm (<320/7weeks gestation), moderately preterm (320/7-336/7weeks), latepreterm (340/7-366/7weeks), and term (370/7-420/7weeks). The rates of RDS, potentialrisk factors, clinical characteristics, managements, and complications of RDS werecomparatively analyzed between these four groups. The t test, χ2test and ANOVAtest were used for statistical analysis; the level of statistical significance was set at P<0.05. ResultsThe incidence of RDS significantly increased in2010compared to2006(5.4%in2006, and9.4%,12.4%,17.9%,21.1%in2007,2008,2009,2010respectivly) asthe NICU admissions (4437infants in2006, and4288,5693,5581,6635infants in2007,2008,2009,2010respectivly). The morbidity of RDS was significantly higherin male infants than females. Maternal diabetes, choriomnionitis, reduced fetalmovements were the significant risk factors for RDS in preterm infants’ subgroup.(P<0.001).The Cesarean section without labor was significantly associated with RDSin term and late preterm infants (P<0.001). When age on NICU admission wasconsidered, term infants and late preterm infants were significantly older than verypreterm infants (P <0.001). Ventilator need was similar in very preterm infants andterm infants, and it was least with late preterm infants. This difference wasstatistically significant (P<0.001). Requirement of pulmonary surfactant (PS) wassimilar in very preterm and term infants while it was significantly lower in latepreterm infants (P<0.001). OI value did not reduce dramatically in late preterm andterm infants compared to very preterm infants, which accompanied with slowimprovement in the PaO2/FiO2ratio (P<0.05). The occurrence of pneumothorax washighest in term infants group and lowest in very preterm group (P<0.001).SummaryThe high rsik was different with different gestional age. There were more latepreterm infants and term infants with RDS in whom RDS was associated withcesarean section without labor and lung infection. They had slower improvement ofoxygenation after surfactant administration and mechanical ventilation, and morecomplication of pneumothorax. Part II: High-frequency oscillatory ventilation in preterm infantswith severe respiratory distress syndromeObjectiveThe purpose of this study was to compare the efficacy and safety of high-frequency oscillatory ventilation (HFOV) and conventional mechanical ventilation(CV) in preterm infants with severe RDS; to analyze the changes of inflammatorycytokines on different modes of mechanical ventilation; to investigate the mechanismabout high frequency oscillatory ventilation on the lung by the cellular and molecularlevel; and to evaluate the prognosis of preterm infants with severe RDS on HFOV.MethodsA prospective randomized controlled trial was conducted on preterm infantsadmitted to the NICU with gestational ages≤32weeks, birth weight≤1500g, andless than24hours old after birth who developed RDS requiring mechanicalventilation; presented a partial pressure of oxygen (PaO2): fraction of inspired oxygen(FIO2) ratio<200; and radiograph criteria of severe RDS. The eligible preterm infantswere randomly assigned to treatment with HFOV or CV. Surfactant was applied ifPaO2/FIO2<200after two hours of ventilation. Luminex xMAP technology was usedfor testing the changes of serum inflammatory cytokines (IFN-γ, IL-6, TNF-a MCP-1IL-8) on different ventilation mode. Primary outcomes were mortality or incidence ofBPD. Secondary outcomes were duration of ventilation and hospitalization, surfactantrequirements, pneumothorax, retinopathy of prematurity (≥stage2), andneurodevelopment at18months of corrected age. The t test, χ2test, ANOVA test, andMantel-Haenszel test were used for statistical analysis; the level of statisticalsignificance was set at P<0.05.ResultsAfter4hours of ventilation, the change about the mean airway pressure (MAP),arterial oxygen tension/fraction of inspired oxygen (PaO2/FiO2) ratio, arterial partialpressure of carbon dioxide (PaCO2), oxygenation index (OI)arterial/alveolar oxygenpartial pressure (a/APO2) ratio was observed between CV group and HFOV group.The PaCO2decreased significantly faster in HFOV group compared to CV group, andthe improvement of PaO2/FIO2ratio, OI, a/APO2is better in HFOV group than theCV group. On d15, the serum IL-6and IL-8was significantly lower in HFOV group compared to CV group (P<0.05). Incidence of death or BPD was significantly higherin the CV group (P=0.001). According to gender, gestational age, birth weight,prenatal hormones, surfactant applications, intubation time, multiple births stratifiedsubgroup comparison, the application of pulmonary surfactant was significantly lowerin HFOV group than the CV group (P=0.002). There was no interaction betweensubgroup and HFOVor CV group. The overall effect of the subgroups favours HFOVtherapy. The duration of mechanical ventilation and hospitalization was shorter andthe incidence of surfactant requirement and ROP was lower in the HFOV group(P<0.05). Moderate or severe neurological disability was less frequent in the HFOVgroup than in the CV group at18months (P<0.05). The combination of HFOV andsurfactant dramatically reduced negative outcomes in preterm infants with severeRDS.SummaryHFOV significantly reduced the mortality and the incidence of BPD for preterminfants with severe RDS. Early application of HFOV may improve survival of theseinfants with severe RDS.Part III: The screening algorithm WINROP for the prediction ofsevere retinopathy of prematurity in a Chinese populationObjectiveThe puruse of this study was to evaluate the WINROP（The weight, insulin-likegrowth factor, neonatal ROP） algorithm as a method of predicting severe ROP in aChinese population.MethodsAccording to the guideline of ROP screening issued in China in2004. The highrisk of preterm infants for ROP was screened. According to gestational age, thepreterm infants were divided into gestational age (GA)>32weeks preterm infantsgroup and≤32weeks preterm infants group. The two groups of preterm infants were then divided into no ROP, mild ROP and severe ROP groups according to ROPdisease staging. The weight gain was monitored per week until to42weeks ofcorrected gestational age. The selected infants were entered into an on-linesurveillance system (www.winrop.com) that included ROP evaluations and weeklyweight measurements from birth to a postnatal age of42weeks. If the rate of weightgain decreased to a certain degree, the algorithm signaled an alarm that the infant wasat risk for developing sight-threatening ROP. Each infant was categorized into alarmgroup and no alarm group. The t test, χ2test, and Clopper-Pearson method were usedfor statistical analysis; the level of statistical significance was set at P<0.05.ResultsDuring evaluation of the WINROP algorithm, there were695eligible preterminfants, which entered online WINROP system testing,105cases gestational age>32weeks, there were3cases of severe ROP among them, all preterm infants withGA>32weeks did not trigger severe WINROP system ROP warning signal. Therewere590preterm infants with GA≤32weeks,56cases developed severe ROP, and109infants triggered severe WINROP system ROP warning signal. That is109infants were in alarm group, and481infants in no alarm group for preterm infantswith GA≤32weeks. For56infants with severe ROP, there are50cases in alarm group,and6cases in no alarm group. The sensitivity of the WINROP algorithm in detectingsevere ROP in preterm infants with a GA of32weeks or less was89.3%and thespecificity was89.0%. Among50infants who developed severe ROP, twenty infantstriggered the alarm signal in the first week after birth and seven infants triggered thealarm at birth. The median GA at birth for these27infants was31weeks, the birthweight was1057g, this birth weight was below the3rdpercentile for their gestationalage, and they were considered to have suffered intrauterine growth restriction (IUGR).The GA and birth weight (BW) were significantly lower in alarm group than no alarmgroup (P<0.01). Within10weeks for the preterm infants developed severe ROP, theweight gain weekly were significantly lower than prererm infants without ROP orwith mild ROP (P <0.05). Summary1. The screening algorithm WINROP system can be used for the prediction ofsevere retinopathy of prematurity in a Chinese population.2. The GA, BW, and weight gain after birth in preterm infants was closelyrelated to the occurrence of ROP, the optimal weight gain can reduce the incidence ofROP.Part IV: Neuroprotective effect of erythropoietin on brain injury inpreterm infants in randomized controlled trialObjectiveThe brain injury of preterm infants became the focus of the whole society. EPO iscurrently one of the most promising neuroprotective agent, is widely used in clinicalfor treatment of anemia in premature infants. The neuroprotection of EPO is dosedependent and the treatment of EPO was found to be ineffective at low dose or atmultiple high doses.The puruse of this study was to evaluate the safety and efficacyof EPO by using500IU/kg higher than the dose of anemia treatment for preterminfants (250IU/kg), and analyze EPO protection on neurodevelopment in preterminfants. This study was to investigate the neuroprotective mechanisms of EPO inpreterm infants on cellular and molecular level.Methods1. Population: A prospective randomized controlled trial was conducted onpreterm infants admitted to the NICU with gestational age≤32weeks, birth weight≤1500g, and less than72hours old after birth. The infants with congenitalmalformations, genetic metabolic disease were excluded. The preterm infants wererandomly divided into EPO group and control group.2. Treatment: In EPO group, the EPO500IU/kg was given every other dayintravenously for2weeks. Recombinant human erythropoietin was configured by thehospital pharmacy intravenous Center Configuration, melted EPO with saline to1ml/kg solution. For severe patients, they were started to treat with EPO when their vital signs, blood pressure were stable. In control group, normal saline1ml/kg wasused; the process was same as to EPO.3. Evaluation: The preterm infants were given assessment during treatment andfollow-up after discharge, the incidence of mortality, intracranial hemorrhage, PVL,ROP, BPD, NEC were evaluated; the erythrocytes, hemoglobin, platelet count, andthe number of required blood transfusion were calculated during hospitalization. Theserum cytokines (IFN-γ, IL-17A, IL-1b, IL-6, IL-8, TNF-a), and related biologicalprotein MCP-1, CRP, Complement C4, VEGF, IGF-1, NSE, S100B were testedbefore and after treatment. Before and after treatment, the amplitude-integratedelectroencephalography (aEEG) was used for cerebral function monitor in preterminfants. At corrected gestational age42weeks, the preterm infants were givenassessment by the neonatal behavioral neurological assessment (NBNA). Themental development were evaluated by Bayley II at corrected age of3months,6months,12months and18months, at the same time, the hearing and vision were alsoevaluated. Using SPSS17.0statistical software for statistical processing, Statisticalmethods t test, χ2test and Mantel-Haenszel test were used, P<0.05was consideredstatistically significant.Results1. Comparison of mortality and complications between EPO group and controlgroup: The mortality, the incidence of ROP and sepsis were compared between twogroups, there was no significant difference. However, the incidence of intracranialhemorrhage, PVL, NEC, and BPD were significantly lower in EPO group comparedto control group (P<0.05).2. The change of the blood cells: The red blood cells, hemoglobin, hematocritwere similar before EPO treatment, and red blood cells, hemoglobin were significanthigher in EPO group compared to control group after EPO administration. Plateletswere similar between two groups during treatment. For the blood transfusion, it wassignificantly less in EPO group than the control group (P<0.001).3. Cerebral function monitor：Before EPO treatment, the results of aEEG wassimilar, there was no significant difference. After EPO treatment, the amplitude minimum voltage of aEEG background wave was significantly higher in EPO groupthan control group (p <0.05). The score of NBNA at corrected gestational age of42weeks were significant higher in EPO group compared to control group (P=0.001).4. Cytokines and Chemokines: The interferon-γ (IFN-γ), interleukin-6(IL-6),monocyte chemoattractant protein-1(MCP-1) were significantly lower than thecontrol group after EPO treatment (P<0.001).5. NSE, S100B, and other related biomarkers: The serums NSE, S100B, VEGF,and IGF-1were similar between the two groups before treatment. After treatment, theNSE was8.52±4.12ug/L, S100B was1.10±0.19ug/L in EPO group, and NSE,S100B value was12.21±4.77ug/L,1.90±0.23ug/L respectively in control group,they were significantly lower in the EPO group (P<0.001); VEGF and IGF-1weresimilar between two group after treatment, there were no significant difference.6. Bayley II assessment: At the corrected age3months,6months,12months,18months, The MDI, PDI scores were significantly higer and the ratio of MDI<70、PDI<70were significantly lower in EPO group.7. Hearing assessment: In all of ages of follow-up, in the EPO group, the resultsof brainstem auditory evoked potential response (ABR) and multi-frequency auditorysteady-state response (ASSR) were better than the control group.8. Vision assessment: At the corrected age3months,6months,18months, theresults of flash video evoked potentials (FVEP) were better in EPO group than in thecontrol group. At the corrected gestational age12months, there was no significantdifference between the two groups. For the ERG of two groups, at the correctedgestational age3months,6months,18months, ERG incubation period wassignificantly longer in EPO group than control group (P<0.001); For the effect ofERG amplitude between the two groups, the rod response b-wave was significantlylonger in EPO group than in the control group at the corrected age3months (P=0.002), The cone response b-wave was significantly longer in EPO group at thecorrected gestational age of6months (P<0.001).9. The results of subgroup analysis: For the MDI<70in the two groups at thecorrected age of18months, the subgroup Meta analyses were performed on the basisof gender, gestational age, birth weight, postnatal surfactant treatment, pregnancy-induced hypertension, singleton or multiple birth, sepsis, more than grade3IVH, PVL, BPD, and mechanical ventilation more than7days. There were nosignificant interaction terms between EPO and any of these subgroups. There wereoverall effects of EPO for any subgroups.Summary1. The intervention of EPO can promote the neurodevelopment of preterminfants, and decrease incidence of the sequelae of brain injury in preterm infants. Conclusion1. The high rsik was different with different gestional age. There were more latepreterm infants and term infants with RDS in whom RDS was associated withcesarean section without labor and lung infection. They had slower improvement ofoxygenation after surfactant administration and mechanical ventilation, and morecomplication of pneumothorax.2. HFOV significantly reduced the mortality and the incidence of BPD forpreterm infants with severe RDS. Early application of HFOV may improve survivalof these infants with severe RDS.3. The screening algorithm WINROP system can be used for the prediction ofsevere retinopathy of prematurity in a Chinese population, the optimal weight gaincan reduce the incidence of ROP.4. The intervention of EPO can promote the neurodevelopment of preterminfants, and decrease incidence of the sequelae of brain injury in preterm infants.