Clinical Research Of Nasal Intermittent Positive Pressure Ventilation(NIPPV)for The Facilitation Of Extubation In Preterm Infants

BackgroundNeonatal respiratory distress syndrome (RDS) is one of the most common diseases of preterm infants, and in some degree its treatment is still dependent on mechanical ventilation. Although the wide range of applications of antenatal corticosteroids and postpartum pulmonary surfactant(PS) improved the survival rate and disability morbidity of preterm infants in past decades, the bronchopulmonary dysplasia (BPD) is still one of the main reasons for the death and disability of very low birth weight infant (VLBWI) and extremely low birth weight infant (ELBWI).Based on the current technology and literatures, RDS is still dependent largely on mechanical ventilation. But prolonged length of mechanical ventilation can cause ventilator-induced lung injury by the main mechanism including barotrauma injury, capacity injury, scissors injury, and ventilator associated pneumonia, etc, which may lead to BPD. Therefore, one of the main treatment of RDS is to extubate and avoid prolonged mechanical ventilation, which may avoid ventilator-induced lung injury. So how to maximize the use of non-invasive respiratory support, whether it is in the newborn or the entire treatment period, is worth discussion and research. Nasal continuous positive airway pressure(NCPAP) is the earliest and most common methods in the NICU, which can make the airway stable and in expansion state throughout the whole respiratory cycle, and increase transpulmonary pressure to reduce pulmonary surfactant consumption and prevent alveolar collapsed and improve compliance of the lung. Since1971it has made a good effect for clinical use. Studies have shown that NCPAP obviously improved the outcomes of the preterm infants of gestation age28-32weeks with RDS and improved that early application of NCPAP can prevent the pathogenesis of RDS and lower incidence of the application of exogenous PS. At the same time, it was also able to reduce preterm infants of GA25to28weeks the ratios of reintubation, the length of hospitalization time and time of ventilation, although it did not reduce the mortality. However, clinical studies have shown that despite the premature infants with more severe RDS selected the early use of NCPAP, they still required intubation and mechanical ventilation in the end, which means NCPAP still have high failure rate. The researchers also found that excessive PEEP may lead to pneumothorax and other complications. All of these fasts prompted clinicians to turn to other non-invasive ventilation mode, such as nasal intermittent positive pressure ventilation(NIPPV). In decade, there are numbers of clinical trials about NIPPV conducted in the foreign and our country and achieved good results.Due to lack of unified name, NIPPV have variety of clinical names currently. Conceptually, it can be referred to as NIPPV only if the non-invasive ventilation in intermittent positive pressure mode is given by the way of nasal prong, nasal mask or casal cannulae. The common names reported in the literature include NIPPV, SNIPPV (Synchronized nasalintermittent positive pressure ventilation), NPSIMV (Nasopharyngeal-synchronized intermittent mandatory ventilation), nsNIMV (non-synchronized Nasopharyngeal Intermittent Mandatory Ventilation), NSIMV (nasal synchronized intermittent mandatory ventilation), NFSIPPV (Nasal flow-synchronized intermittent positive pressure ventilation), nBiPAP (nasal biphasic positive airway pressure), BP-NCPAP (biphasic nasal continuous positive airway pressure), NI-PSV (non-invasive pressure support ventilation) and so on. As an important non-invasive respiratory mode, the main application of NIPPV in neonatal respiratory distress syndrome is for the following three purposes:the initial mode of treatment, secondary mode after weaning, and the prevention and treatment of apnea. In2001, Cochrane Library had published the Meta-analysis about NIPPV comparing with NCPAP as a transitional mode after extubation in preterm children. However, the center did not do any updates in the past10years, and there were a large number of trials about NIPPV with diverse application mode listed above and more comprehensive outcome measurements carried out during these time. In view of this, the Chinese scholars, respectively, published two meta-analysis about NIPPV vs. NCPAP for treatment of RDS in2009and2011. But both of them had too comprehensive topic including initial mode and secondary mode and take in too little literature and, most important of all, miss some kind of NIPPV mode, such as nBiPAP.The nBiPAP is considered to be a form of NIPPV with some special characteristics: it can provide two different levels of pressure, and airflow switching between high-and low-pressure can improve the functional residual capacity, lower respiratory workload to enable the expansion of unstable alveoli and avoid alveolar collapse, and increase end-expiratory lung volume for better oxygenation and ventilation, and thereby reducing the incidence of respiratory failure. In the past, this mode is mainly used for adults and children with heart or lung diseases. Due to the high extubation failure rate of nCPAP, the scholars abroad try to apply it in newborns as the initial mode of treatment of RDS and the transition mode after extubation. But there is no literature about the application for the newborns have been reported in our country.Therefore, the purpose of this article is to:1)compare nBiPAP vs. NCPAP and assesse the efficacy of nBiPAP.as the transitional mode after extubation in preterm infants≤32weeks with RDS;and2) retrieve RCT literatures published before the December2012about NIPPV vs. NCPAP as a transitional mode after extubation, make the systematic review and meta-analysis to assess the efficacy of NIPPV used for the treatment after extubation.Part1the prospected randomized controlled trial of nBiPAP for the facilitation for the extubation of extubation in preterm infants<32weeks with RDS. Patients and methodsPetientsThe patients were preterm infants with GA≤32weeks admitted in our NICU from January2011to December2012and were diagnosed of the RDS. Infants satisfying the following inclusion criteria will be eligible to participate:(1)meet the diagnostic criteria of RDS based on Practical Neonatology(and);(2)gestational age≤32 weeks(and);(3) less than28days old (and);(4) need for endotracheal intubation and mechanical ventilation after birth, and meet weaning standards before grouping. Infants with the following exclusion criteria will be not be eligible to participate: patients with severe congenital disease, neuromuscular disease, upper respiratory diseases or abnormalities, Presence of intraventricular hemorrhage with parenchymal extension, proposed to surgery recently, no need for noninvasive assisted ventilation after extubation. The patients meeting the inclusion criteria were randomly divided into two groups after extubation:NCPAP group and nBiPAP group.MethodsDevices:the noninvasive the ventilator were Infant flow SiPAP (Viasys corporation, U.S.). Due to synchronous probes are not sensitive, we did not use the synchronous device during the study period. Ventilator tube and nasal prongs and masks are the company’s standard configuration including Infant flow generator and Infant flow neonatal ventilator.Timing of extubation:Extubation was carried out when Ventilator parameters achieve the following levels:(1)the mode of HFOV meet the following criteria:Paw10≤cmH2O, FiO2<35%, amplitude<2.0)(or);(2) the mode of SIMV meet the following criteria:PIP<16cmH20, FiO2<35%, PEEP<4cmH2O, f≤30times/min)(and);(3)infants had spontaneous breathing(and);(4) infants had stable condition of circulation.Parameters regulation of noninvasive ventilator:Infant flow SiPAP ventilator has two kinds of ventilation modes:nCPAP and nBiPAP. When the nCPAP mode was adopted, only to adjusted PEEP and FiO2:the range of PEEP was3to7cmH2O. In the beginning we adjusted PEEP to6cmH20and regulate it based on the SpO2. FiO2was begun with0.4and may be regulated in the range of0.21-1.0just based on the SpO2. the best value of SpO2was88%to92%. There were four parameters when using nBiPAP mode. The initial parameters of nBiPAP mode were:f30～40times/min, PEEP4～6cmH20, PIP(PEEPhigh)7～9cmH20, inspiratory time (Ti)0.5～Is, FiO20.3～0.4. when the infants were stable and then reduced f at first;when f dropped to15beats/min, then gradually lowered PEEP until reduced to6cmH2O.Timing of weaning from noninvasive ventilator:(1)nCPAP mode:PEEP≤4cmH2O, FiO2<0.3(or);(2)nBiPAP mode:Pmean≤4cmH20, FiO2≤0.3(and);(3) infants had stable condition of circulation.Definition of failure of extubation:Dyspnea, and one of the following conditions were met:(1)pH<7.2and PaCO2≥60mmHg;(2) PaO2<50mmHg;(3) SaO2<85%when FiO2>50%;(4) the repeated apnea with decline of heart rate and SpO2and need resuscitation by self-inflating bag.Primary outcome measure:extubation failure rate within7d after the initial extubation; the first(within2hours) and12hours of blood gas analysis after the initial extubation.Secondary outcome measures:the length of non-invasive ventilation, oxygen and hospitalization; mortality; rate of complications. Complications include:nasal septum injury, intraventricular hemorrhage (IVH)/periventricular leukomalacia (PVL), BPD (still need oxygen in36weeks’postmenstrual age), abdominal distension, necrotizing enterocolitis (NEC), feeding intolerance, pneumothorax, retinopathy of premature (ROP), patent ductus arteriosus(PDA), the sepsis after extubation.Statistical analysisThe software of SPSS17.0was used for data processing. Continuous data were expressed as mean±standard deviation (x±s) and Student’s t test was used for this kind of data. Continuous data with highly skewed distributions were expressed with a median (interquartile range) and were tested by the Wilcoxon rank sum test. Categorical data were using x2test (when the number of cases is small and t<5, then Fisher’s exact test would be adopted). A P value of0.05was considered statistically significant.ResultsConditions of both groups:there were no statistically significantly differences about the conditions between both groups, such as gestational age, birth weight, time of ventilation, mode of ventilation pre-extubation, blood gas analysis, and so no.Primary outcome measure: Extubation failure rate in nBiPAP group was lower than NCPAP group(2/27vs.9/29, p=0.042). The first(within2hours after extubation) and the second (12h after extubation) blood gas analysis showed that the PaO2in the nBiPAP group is higher than NCPAP group, while PaCO2in the former lower than the latter group. All of above differences ware statistically significant.Conditions of both group with reintubation:the failure cases in nBiPAP group failed cases are the result of a variety of factors mixed; while the cases failed to extubation in the the nCPAP group showed that three cases was due to hypoxemia, one with hypercapnia, one with frequent apnea and four because of mixed factors.Secondary outcome measure:there were no statistically significantly differences in both groups related to the secondary outcome measure, such as length of non-invasive ventilation, oxygen and hospitalization, BPD, grade3intraventricular hemorrhage/periventricular leukomalacia, NEC, and so on.ConclusionnBiPAPis safe and feasible for preventing extubation failure in preterm infants≤32weeks with RDS and more effective than nCPAP. However, due to the small sample size of this study and the insufficient efficiency of the inspection of the statistical results, the definite conclusions may need to be confirmed by randomized controlled study with larger sample size.Part2A meta-analysis of nasal intermittent positive pressure ventilation for the facilitation for the extubation of extubation in preterm infants with RDS MethodsData sources and study selectionInclusion criteria:(1).randomized or quasi-randomized trials, without language restriction (and);(2). Preterm infants were the first to wean from ventilation within six weeks after birth and the length of ventilation last no less than28days(and).(3). NIPPV as interventions factors was compared with NCPAP.Exclusion criteria:The outcome measure of research did not included the primary outcome measures in the our study.Primary outcome measure:extubation failure rate with the time set in eligible literatures after the initial extubation since birth.Secondary outcome measures:morbidity of nasal septum injury, brain injury in preterm infants(including IVH and PVL), BPD (can not wean from oxygen in36weeks’ postmenstrual age), pneumothorax, retinopathy of premature (ROP), gastrointestinal diseases (abdominal distension, necrotizing enterocolitis (NEC), feeding intolerance and gastroesophageal reflux)Data resources and search strategy:EMBASE, Springer, PubMed, Ovid, Cochrane CENTRAL, CNKI, Wangfang and Vip database within the time from their building up to December2012were selected. And the terms of extubation OR weaning AND nasal intermittent positive pressure ventilation OR nasopharyngeal synchronized intermittent mandatory ventilation OR nasal biphasic positive airway pressure AND nasal continuous positive airway ventilation were used in the English database. Chinese database may use the following terms, such as extubation, weaning, nasal intermittent positive ventilation, nasal continuous positive airway pressure, non-invasive ventilation, RDS. We may selected the literatures about NIPPV vs. NCPAP for the facilitation for the extubation of preterm infants by reading the text of the title and summary. If unable to get the full text directly, We may depend on manual searches, document delivery, commercial purchase or contacting the author directly. Quality test for methodological quality of selected litetatures was carried out by corrected Jadad scales which meant low-quality literature when scoring1-3while high-quality literature scoring4-7.Statistical analysis The meta-analysis was carried out by the software of RevMan5.1from Cochrane Library. Categorical data were expressed by OR and95%CI and Continuous data were expressed as the weighted mean difference (WMD) and its95%CI. p<0.05indicates a significant difference.Funnel plot was used for testing publication bias of primary outcome measures. Determining the heterogeneity analysis of the eligible studies was depending on Chi-square test which p≥0.10meant no statistical heterogeneity and then fixed effects model was adopted while random effects model selected when p<0.10. ResultsResults of literature retrieval:Characteristics of eligible literature:six studies were eligible and both of them were in English; one study in Chinese was exclude because of meeting report without detail of the study. NIPPV group was defined as NIPPV adopted in eligible study and the number was206while NCPAP group was200.Quality assessment:score of corrected Jadad scales of eligible studies were both5, and it meant high-quality literature.Analysis of publication bias:funnel plot of extubation failure rate was symmetrical basically and it meant no publication bias statically.Results of meta analysis:Comparison of extubation failure rate:Extubation failure rate was the primary outcome measure of both six studies, so both of these studies were eligible for meta-analysis. Random effects model was adopted due to p=0.01of Chi-square test for heterogeneity analysis. The result of meta-analysis showed that OR was0.19and95%CI were0.07～0.52, and p=0.001meant statistically significance in difference, which indicated NIPPV is better than NCPAP in the prevention of extubation failure rate.Comparison of morbidity of BPD:4studies had mentioned morbidity of BPD(both defined as unable to wean from oxygen in36weeks’postmenstrual age). The result of heterogeneity analysis was p=0.38and fixed effects model was applied. Meta-analysis got the results that OR was0.65and95%CI were0.40～1.06, and p=0.08meant no statistically significance in difference, which indicated NIPPV did not lower the incidence of BPD statistically.Comparison of morbidity of brain injury in preterm infants:brain injury in preterm infants was defined as PVL and IVH.3studies had discussed morbidity of IHV and/or PVL. The result of heterogeneity analysis was p=0.48and fixed effects model was adopted. Meta-analysis of the results showed that OR was0.46and95%CI were0.22～0.97, and p=0.08meant statistically significance in difference, which implied NIPPV may lower the incidence of morbidity of brain injury in preterm infants statistically. Comparison of morbidity of ROP:3studies had mentioned morbidity of ROP. Random effects model was adopted due to p=0.009of Chi-square test for heterogeneity analysis. The result of meta-analysis showed that OR was0.83and95%CI were0.16～4.42, and it meant no statistically significance in difference, which indicated morbidity of ROP is equal in both groups statistically.Comparison of morbidity of nasal injury:4studies had mentioned the morbidity of nasal injury. The result of heterogeneity analysis was p=0.50and fixed effects model was adopted. Meta-analysis of the results showed that OR was0.86and95%CI were0.40～1.83, and p=0.08meant no statistically significance in difference, which implied morbidity of ROP is equal in both groups statistically.Comparison of morbidity of gastrointestinal diseases:the definition of gastrointestinal diseases was abdominal distension, necrotizing enterocolitis (NEC), feeding intolerance and gastroesophageal reflux.5studies had discussed morbidity of gastrointestinal diseases. The result of heterogeneity analysis was p=0.46and fixed effects model was considered. Meta-analysis of the results showed that OR was0.72and95%CI were0.45～1.16, and p=0.18meant no statistically significance in difference, which indicated, comparing to NCPAP, NIPPV did not lower the incidence of morbidity of gastrointestinal diseases statistically.Comparison of daily mean times of apnea:2studies had comparing the morbidity of daily mean times of apnea in both groups. Fixed effects model was adopted due to p=0.18of Chi-square test for heterogeneity analysis. The result of meta-analysis showed that WMD was0.19and95%CI were-0.18-0.56, and p=0.31meant no statistically significance in difference, which manifested daily mean times of apnea in NIPPV group were equal to that in NCPAP group statistically.Comparison of lengths of hospitalization:3studies had discussed the lengths of hospitalization in both groups. Random effects model was applied due to p=0.004of Chi-square test for heterogeneity analysis.The result of meta-analysis showed that WMD was-0.93and95%CI were-7.78～5.91,and p=0.79meant no statistically significance in difference, which manifested lengths of hospitalization in NIPPV group were equal to that in NCPAP group statistically.ConclusionCompared to NCPAP, NIPPV can significantly reduce extubation failure rate in preterm infants and it meant safe and effective. However, due to the small sample size of the study and the insufficient efficiency of the inspection of the statistical results, the definite conclusions may need to be confirmed by randomized controlled study with larger sample size.