Noninvasive Ventilation For Preterm Twin Neonates With Respiratory Distress Syndrome: A Randomized Controlled Trial

backgroundIn preterm infant with respiratory distress syndrome(RDS),endotracheal ventilation and exogenous surfactant replacement therapy are two important cornerstones to reduce neonatal mortality.Although improving the survival,endotracheal ventilation is actually related to increasing risks of infection and ventilation-associated lung injury.Importantly,prolonged duration of endotracheal ventilation induces more death,neurologic impairment,and bronchopulmonary dysplasia(BPD)in the post-neonatal period.These complications and sequelea induce increased medical burden.How to reduce the need for endotracheal ventilation and subsequent complications constitutes a challenge for neonatologists.To this day,early use of noninvasive respiratory support strategies has been suggested to be the most effective pathway to reduce those risks.Nasal continuous positive airway pressure(NCPAP)and nasal intermittent positive pressure ventilation(NIPPV)are two widely used ways of noninvasive ventilation strategies in preterm infant.As compared with invasive ventilation,NCPAP reduces the risks of BPD and abnormal neurodevelopment.However,there is only 60% success rate of avoiding intubation in the preterm neonate supported with NCPAP.Supplying with an intermittent peak pressure on NCPAP,NIPPV is considered as a strengthened version of NCPAP with increased flow delivery in the upper airway,increased minute volume and functional residual capacity and recruitment of collapsed alveoli,improved stability of the chest wall and reduced asynchrony of thoraco-abdominal movement,which have been proven to be crucial to decrease the incidences of invasive ventilation,BPD and death.Several studies have compared NIPPV with NCPAP in non-twin neonates with RDS,which were mainly conducted in very preterm infants(less than 32 weeks' gestational age).There was a rarity of similar study in moderate and late preterm infants(between 32 and 36 weeks' gestational age).Actually,moderate and late infants accounted for more than 80% of preterm births.Studies are needed to determine the impact of respiratory distress coupled with mild-moderate prematurity on short-term and long-term outcomes.The purpose of the present study was to compare NIPPV with NCPAP on the need for endotracheal ventilation and subsequent complications in preterm twins,especially in moderate and late preterm twins.Materials and MethodsStudy Design and ParticipantsThis was a single-center,paired design,randomized controlled trial conducted ina tertiary neonatal intensive care unit(NICU)from Jan 2011 to July 2014 at Daping Hospital,Third Military Medical University,China.The trial was approved by the ethics committee of Daping hospital and research institute of surgery and registered at http://www.clinicaltrials.gov.(ID: NCT01926106)(the registration date: 08/19/2013).It was from a prospective protocol.Informed parental written consents from all s ubjects were obtained.The trial was performed in accordance with the approved gui delines and regulations.All operations in the trial were performed in accordance with relevant guidelines and regulationsIncluded criteria:(1)the gestational age was from 28 to 36 weeks;(2)these infants were twins;(3)they were diagnosed as RDS.The diagnosis of RDS was based on clinical manifestations and chest X-ray findings,which was similar in twin neonates.The clinical signs and symptoms of RDS were respiratory distress,tachypnea,nasal flaring,groan,and cyanosis after birth.The typical X-ray picture of RDS showed a grain shadow,air bronchogram or white lung,and X-rays of twin neonates must be the same grades.X-rays were judged by two radiologists blinded to the patient's condition.Infants were excluded from this study if they were not fit for the use of NIPPV or met any of the following criteria: different clinical manifestations and/or grades of radiological findings in twin neonates,major congenital anomalies,intubation at admission to NICU because of severe conditions such as clinically severe respiratory distress with severe respiratory acidosis(Pa CO2>60mm Hg),neonatal pulmonary hemorrhage,cardiopulmonary arrest without effective resuscitation needing continued ventilation and rescue,and died or left the NICU within 24 hr and/or before randomization.Allocation and BlindingA table of random numbers concealed in opaque envelops was used to allocate and blind.After documenting parental consent,one of an eligible twin was randomly allocated to NIPPV,while another to NCPAP.Blinding for doctor was not possible due to the nature of the intervention.Study InterventionA time-cycled,pressure-limited and continuous-flow neonatal ventilator(Babylog 8000,Drager,Germany)was used for neonates assigned to the NIPPV group in a non-synchronized mode.The initial settings were: frequency of 10–30 breaths/min,peak inspiratory pressure(PIP)of 15–25 cm H2 O,and positive end expiratory pressure(PEEP)of 4–6 cm H2 O.The fraction of inspired oxygen(Fi O2)was regulated from 0.21 to 0.40 in order to maintain oxygen saturation(Sp O2)from 90% to 95% by a pulse oximeter.Neonates assigned to the NCPAP group were initiated on a pressure of 4–6 cm H2 O by bubble CPAP system(Stephan),with Fi O2 from 0.21 to 0.40 to maintain Sp O2 from 90% to 95%.To avoid stomach/intestine dilatation,a tube was used from mouth to stomach when the interventions were conducted.When the neonate was admitted to the NICU and had fulfilled the entry criteria,NIPPV or NCPAP was started immediately on the basis of the group assignment.Other care was at the discretion of the attending neonatologist.Pulmonary surfactant(Curosurf,Chiesi Pharmaceuticals,Parma,Italy)was administered with a dosage of 100 mg/ kg as a rescue treatment if an infant needed Fi O2>0.40 to maintain the targeted Sp O2.We used the INSURE(intubation-surfactant-extubation)technique of surfactant administration.Clinical DataThe clinical data of all enrolled neonates were recorded,including main clinical characteristics,intubation,surfactant administration and complications within 100 days.100 days were defined for the following causes: 1).The gestational age of the smallest infant included was 200 days,and 100 days after birth ensured the corrected age to 40-44 weeks.2).the observation time of the primary and secondary outcomes were 100 days.And 100 days later,the assessment of the primary and secondary outcomes were discontinued.Evaluation of OutcomesThe primary outcome of this study was to determine the need for endotracheal ventilation in twins randomized to the two groups.Neonates were intubated if they were not improved and needed mechanical ventilation,which was based on the standard indication.The criteria for intubation and mechanical ventilation were as follows: severe respiratory acidosis(Pa CO2>60 mm Hg),severe apnea and bradycardia(defined as recurrent apnea with >3 episodes per hour associated with heart rate <100/min,a single episode of apnea that required bag and mask ventilation,or associated with hypoxemia with Sp O2<85% and Fi O2>0.6),severe respiratory distress,neonatal pulmonary hemorrhage,and cardiopulmonary arrest without effective resuscitation needing continued ventilation and rescue.The secondary outcomes included surfactant administration and the incidences of bronchopulmonary dysplasia(BPD),patent ductus arteriosus(PDA),retinopathy of prematurity(ROP),necrotizing enterocolitis(NEC),intraventricular hemorrhage(IVH)and possible side effects of the noninvasive modes.To further evaluate the effects of surfactant and gestational age on the rate of intubation,the subgroups were defined and compared in these infants administrated with surfactant.The defined subgroups of gestational age were as follows: 1)less than 32 weeks,2)32-33 weeks,3)34-36 weeks.For all neonates,effective NIPPV was defined as avoiding intubation successfully,and ineffective NIPPV was defined as intubation within 100 days after birth.And similarity appeared in NCPAP.Sample Size Estimation.The sample size estimation was calculated by PASS software(2008 v8.0.3).According to previous studies,average 40% of preterm neonates administered with early NCPAP and surfactant treatment for RDS needed endotracheal ventilation.Our previous experience has indicated that the success rate of NIPPV and NCPAP was about 90% and 80%,respectively45.A plausible estimate of the coincidence rate both NIPPV and NCPAP success is 70%.With 80% power,as well as a 2-sided significance level of 0.05,114 neonates would be needed at least in each group.Actually,during the study period from Jan 2011 to July 2014,129 pairs were enrolled and finished the trials.The success rate of NIPPV and NCPAP were about 88.4%(114/129)and 79.8%(103/129),the coincidence rate both NIPPV and NCPAP success is 72.1%(93/129),with 80% power,as well as a 2-sided significance level of 0.05,123 neonates would be needed at least in each group.Therefore,the actual sample size was more than theoretical need.Statistical AnalysisContinuous variables,expressing as mean ± standard deviation,were compared using paired samples t test.Categorical variables were compared using the Mc Nemar's test.Predefined three subgroups were <32 weeks,32-33 weeks and 34-36 weeks,and subgroup analyses were conducted for the primary outcome in the preterm infants administrated with surfactant.Other than,to further justify the effect of surfactant on intubation within subgroup,the test of treatment-by-gestational age subgroup interaction was also conducted using the paired binary logistic regression.For the preterm infant loss to follow-up,the missing values of the primary and secondary outcomes were replaced using multiple imputation.All analyses were carried out using computer software(SPSS 16.0 for windows).P-values less than 0.05 were regarded as statistically significant.ResultsStudy neonates234 pairs were screened,of which 143 pairs underwent randomization and 14 parents of twins did not continue the interventions in the follow-up,and 129 pairs were ultimately enrolled and finished the trials,(129 in NIPPV group with 60 first born and 69 second born;129 in NCPAP group with 69 first born and 60 second born)(Fig.1).All preterm twins undergoing randomization,including those who lose to follow-up,were included in the final analysis.The number of involved twins reached the calculated needed sample size.Analysis according to the intention to treat principle was considered to be the most proper way of analyzing randomized controlled trial results.Data analyses followed the intention to treat principle.Intention to treat principle analysis required all randomized participants to be included and analyzed according to the treatment group to which they were originally assigned.All the neonates arrived at the NICU within six hours.There were also no significant differences in main clinical characteristics of neonates at birth weight,the ratio of the first or second born twin,Apgar score,and gender between the two groups(Table 1).Among them,47(32.9%)pairs come from an egg.Antenatal steroids were given to 135(94.4%)pregnant women.Preterm premature rupture of the membrane,pregnant diabetes,hypertensive disorders and intrahepatic cholestasis of pregnancy appeared in 94(65.7%),40(28.0%),46(32.2%)and 39(27.3%)pregnant mothers,respectively.89(62.2%)women received urgent cesarean delivery,22(17.1%)in vaginal delivery,and the others(20.7%)received selective cesarean delivery.Primary and secondary outcomesExcept for the intervention,the twins received the same clinical treatment including surfactant administration.122 pairs received endotracheal administration of surfactant within six hours after admission,and other parents of 21 pairs rejected surfactant administration.There was no significant difference in rate of intubation(11.9% vs 19.6%,P=0.080)between the two groups.This difference was also not observed in the subgroup of infants who received surfactant therapy(11.1% vs 19.7%,P=0.087).(Table 2).No secondary outcomes differed significantly between the two groups(Table 3).Other than,no gastrointestinal perforation/ dilatation and nasal trauma were observed.Subgroup AnalysesIn subgroup analyses,when surfactant was administrated to rescue infants,those infants whose gestational age between 32-33 weeks were showed statistically significant difference between NIPPV and NCPAP groups(13.7% vs 31.4%,P=0.049)(Table 2).However,the 95% confidence interval covered 1(0.350-9.138).To further assess the effects between treatment and gestational age on the rate of intubation,the test of treatment-by-gestational age subgroup interaction was also conducted,and no interaction was observed(?2=0.234,P=0.628).ConclusionsIn this single-center,paired design,randomized,controlled trial,we aimed to decrease the incidence of endotracheal intubation in preterm twins with RDS,especially in moderate and late twins,through comparing NIPPV with NCPAP.As a result,we found that NIPPV did not reduce significantly the need for endotracheal ventilation as compared with NCPAP(11.9% vs 19.6%,P=0.080).Similarities also appeared in the subgroup of infants who received surfactant therapy(11.1% vs 19.7%,P=0.087)and the secondary outcomes.