Clinical And Experimental Studies Of Neonatal Acute Respiratory Failure

IntroductionEfforts to improve outcome of newborn infants with severe respiratory diseases have been exerted in neonatal-perinatal medicine in the past half century. Multicenter, ramdomized, controlled trials (RCTs) and population-based clinical studies have dramatically improved quality of clinical service, and the results of these studies are accepted widely by clinician because of the scientific methods and the high strength of evidence. In 1990's, collaborative clinical investigation was extended through network styles as internet technology developed as well as the maturity of collaboration through experience of multicenter randomized clinical studies. This has a great impact in the evidence-based quality improvement on neonatal medicine. Until now in China, few studies are conducted based on RCT concept in clinical neonatology. Neonatal clinical practice is still dependent on clinician's experiences, or to the best, very small sample size, one-center based, controlled study. However, experience gaining through RCT studies is dependent on very expensive financial background as those of the industrial countries in order to improve clinical study quality, but is not realistic for physicians in developing country to master. In view of the situation, it is considered that through low-cost, high efficient, internet-based technology, it may revolutionize quality assurance as well as clinical investigation of the neonatal medicine and neonatal intensive care service. To this mission, we have made our endeavour and focused on a survey of neonatal acute respiratory failure (ARF), the most commen disorders in NICU. To the same problem, we also conducted a multicenter clinical trial evaluating new indication of exogeneous surfactant replacement in neonatal severe meconiums aspiration syndrome (MAS). We hope to disseminate the collaborative philosophy by two multicenter clinical studies and initiate the establishment of neonatal network in China based on the concept of modern neonatal network. In order to further understant whether adequate ventilatorsettings may help to protect the lungs from injury in immature newborns, we established a new hypoxic respiratory failure model in premature piglets subjected to short term mechanical ventilation, and compared whether positive end-expiratory pressure (PEEP) levels may affect therapeutic efficacy of inhaled nitris oxide (NO), or in combination with surfactant.Part I Prospective, Multicenter Clinical Survey of Neonatal Acute Respiratory Failure in 23 Neonatal Intensive Care Units in ChinaBackground Neonatal acute respiratory failure is a serious clinical problem associated with high mortality, morbidity, and cost. Epidemiological studies may profile the occurrence, clinical course and risk factors of underlying diseases leading to neonatal respiratory failure. This information is essential for planning research, allocating resources, promoting quality improvement of medical care for newborn infants, and designing health and public policy. In the 90's an Italian epidemiologic survey prospectively showed that the incidence of ARF was 2.2% in all live infant born in the 65 hospitals and the mortality was 14.6%. An retrospective study of neonatal ARF based on census and natality data reported that the rate of mechanical ventilation was 18 per 1,000 live births and mean hospital costs was $51,700 in the United States, in which there was a hospital mortality of 11.1%. A population-based national prospective study of 17 tertiary level NICUs across Canada reported 43% of all NICU infants received assisted respiratory support including mechanical ventilation and continuous positive airway pressure (CPAP). The epidemiological data showed that the incidence of ARF was 14 per 1,000 live births in Tobago, 33% of them died. Unfortunately, there is a paucity of information in the clinical epidemiology of ARF in NICU of China, as there is strong demand and move towards NICU service in newly established hospitals for woman and child health care nationwide. Therefore, it is necessary for us to conduct prospectively a clinical epidemiologic survey to determine the incidence, risk factors, clinical management and outcome of neonatal ARF.Objective To determine the incidence, mortality, risk factors and primary diseases of ARF in all infants admitted to NICU for comparison of neonatal-perinatal care with those reported from the inductrial countries.Methods ARF collaborative study group was eatablished based on 23 hospitals withNICU located in 18 cities. Information on ARF infants admitted to all participating hospitals during Mar 1 to Oct 31, 2004 was prospectively collected by trained staffs using a standard case report form. ARP was defined as requiring assisted ventilation including mechnical ventilation or nCPAP >24 hours, or give-up treatment after parents' decision in 24 hours of receiving assisted ventilation. NICU admission was determined according to the same inclusion and exclusion criteria in all hospitals. Patient information include demographic characteristics, ante- and perinatal history, health condition of mother, status of infants and problems at delivery, disease diagnosis, selected NICU practices and procedures, outcome of the patients tracked until death or discharge, and disease burden. Children's Hospital of Fudan University was served as a coordinating center in charge of managing the operation of survey and monitoring data quality. We eastablished a standard central database and the web site for the collaborative study group. With a network assisted by internet techniques, data were electronically submitted to the center in a timely and convenient way. Data management was conducted using software SPSS version 11.0.Results A total of 8,646 of NICU admission, 1,234 of them developed ARF, corresponding to 14.3% of NICU admission. Mean (SD) gestational age (GA) of ARF infants was 35.1 ±4.1 weeks and 66.6% were preterm (GA <38 weeks). Mean birth weight (BW) was 2334 + 835 grams and 57.8% of them had BW <2500 grams. Male/female ratio of ARF infants was 2.8:1 and 15.8% were SGA, 10.6% with congenital anomalies. 28.4% of infants <34 weeks' GA received antenatal steroids. 28.8% had intrauterine stress signs before delivery. The overall cesarean section rate was 43.3%, and multiple birth rate was 13.2%. 21.0% of infants had Apgar scores <7 at 5 minutes. Mean age of mothers with ARF infants was 27.8+4.7 years and 15.9% of them received no prenatal care before delivery. Gestational hypertension, placenta praevia and premature rupture of placentae were the most common diseases in the pregnant women who had infants subsequently developed ARF. Primary causes of assisted ventilation were respiratory distress syndrome (RDS, 34.8%), pulmonary infection developed before or during delivery (14.7%), amniotic fluid aspiration syndrome (10.3%), MAS (9.9%) and transient tachypnea (7.1%). 16.5% of infants received surfactant treatment in delivery rooms or NICUs, and 39.4% of RDS received rescure surfactant. 3.2% received inhaled nitric oxide treatment. nCPAP, CMV and HFV were applied to 49.0%, 61.9% and 3.3% of ARF infatns. Mean ventilation time was 80 + 103 hours and median (range) was 57(1, 1446) hours. Themean highest FiO2 and PEEP were applied to ARF infants in 55±20% and 4.3±1.2 cmH2O, respectively. The mortality of ARF was 31.7% including hospital death (9.0%) and give-up treatment (22.7%) after parents' decision. Mean admission day SNAPPE-II for evalution of illness severity was 8, 20, 34, 52 and 62 in the 25th, 50th, 75th, 90th, 95th percentile, respectively. The mortality rate increased with increasing SNAPPE-II (r = 0.9959). Mean length of stay and costs in NICU were 8.6+9.0 days and 8609 ± 9902 Yuan, respectively. Mean length of stay in hospital and costs were 13.9+14.1 days and 10433 + 11176 Yuan, respectively.Conclusion The results provided a preliminary profile of neonatal ARF in the emerging areas of China, with high incidence, mortality and cost, and calls for attention in improvement of service quality, resource and staff competence as well as welfare policies for perinatal and neonatal care. It also serves as a basis for further multicenter, prospective clinical studies of neonatal severe illness and development of our own neonatal network.Part II Treatment of severe meconium aspiration syndrome with porcine surfactant: A multicenter, randomized, controlled trialBackground Meconium aspiration syndrome (MAS) is the common disorder causing neonatal acute respiratory failure. There is no specific therapy for MAS and conventional therapy includes oxygen supplementation, positive pressure mechanical ventilation and general supportive intensive care. Some cases of severe MAS have to be treated with extracorporeal membrane oxygenation (ECMO), which is costly and currently not available in areas of limited resource. The pathophysiologic mechanism involved in the development of MAS is surfactant inactivation by meconium. Several reports demonstrated that surfactant replacement therapy could attenuate or reverse the clinical sequelae of meconium aspiration, but most of them were retrospective and uncontrolled studies. Multicenter, randomized, controlled trials have been required to dertermine the efficacy of this treatment. If meconium-induced lung injury and impaired gas exchange could be improved by exogenous surfactant, it would be great benefits for neonates with severe MAS in circumstances where the use of ECMO is limited.Objective A randomized, controlled clinical trial was performed to evaluate the safety and efficacy of exogenous surfactant replacement therapy for severe meconium aspiration syndrome (MAS) in term and near-term neonates.Methods MAS study group was eatablished based on 19 hospitals located in Beijing, Shanghai, Jiangsu and Zhejiang. Each randomization center was set up in Shanghai and Beijing. Sixty-one term infants with severe MAS were randomly assigned to either a surfactant or a control group within 36 h after birth. The infants in the surfactant group (n=31) received an initial dose of porcine lung-derived surfactant (Curosurf?) at 200 mg/kg, and repeated doses of 200, 100 and 100 mg/kg were given at 6-12 h intervals to a maximum of four doses if oxygenation index (OI) deteriorated by >2 from baseline. Blood gas and ventilator settings were monitored at 0, 1, 6, 12, 24 hours, and 3, 7, 14, 28 days of treatment. Adverse events were recored and reported to the center. The primary outcomes were a reduction of OI to less than 10 and an increase of the pre-treatment a/A PO2 ratio of 100% over baseline 24 h after surfactant treatment. The secondary outcomes were duration of mechanical ventilation, occurrence of complications and survival to discharge from hospital.Results The general demographic characteristics of the study subjects between the 2 groups were similar. There was a trend for surfactant-treated infants to have an improvement in arterial oxygenation compared to the control group. In comparison with the control group at 24 h, the surfactant group had a lower mean OI (8.1 vs. 10.9), more infants with a 100% increase of a/A PO2 (83% vs. 48%, P <0.01) over baseline, and a larger area under the curve for PaO2/FiO2 over baseline (3762±1877 vs. 2715±1644 mmHg.h, PO.05). Repeated measures of these parameters were also in favor of surfactant group during 24 h to 3 and 7 days compared to the baseline (PO.05). No significant differences were found in mean duration of mechanical ventilation (105±81 vs. 80±40), occurrence of major complications and survival rate (96.8% vs. 90.0%) between the surfactant and the control groups.Conclusion Surfactant replacement therapy improved oxygenation but did not increase complications in the study subjects, suggesting that surfactant may be effective and safe for treatment of severe MAS in term and near-term infants.Part III Effects of Ventilation with Different Positive End-expiratory Pressure on Ventilation Efficiency and Inflammatory Lung Injury in Premature PigletsBackground Mechanical ventilation is an important rescue treatment for neonates with acute respiratory failure. The preterm lung is uniquely susceptible to injury to develop ventilator associated lung injury (VALI), when depending on high pressure or high tidal volume ventilation to maintain normal oxygenation in severe hypoxaemia. Previous studies have shown that the application of PEEP during the mechanical ventilation of premature infants with respiratory distress syndrome improved blood oxygenation and alleviated VALI. This is because PEEP increases functional redual capacity, conserves surfactant and reduces alveolar collapse, hyaline membrane formation, and the expression of proinflammatory mediators. Considering the depressant effects of PEEP on systemic circulation and immature lung being susceptible to injury with the initiation of ventilation, clinicians are careful for premature lung in selecting PEEP level and the applied PEEP level is low in most situations. Recently, it has been demonstrated in clinical trials that lung protective ventilation strategy combined low tidal volume and optimal PEEP could improve prognosis of acute respiratory distress syndrome (ARDS). For preterm infants with hypoxic respiratory failure, could current PEEP level prevent alveolar atelectasis? Especially for infants who failed to respond to mechanical ventilation and other respiratory therapies, was the applied PEEP level not enough to maintain suitable FRC? Could an increase in PEEP level improve blood oxygenation, alleviate lung injury and improve the response to PS or iNO treatment in infants who had previously failed to respond? The answers to these questions are not obvious, as far as we known, no consistent data has addressed these questions in medical literature. Probyn ME found that oxygenation was significantly improved by applying 8 and 12 cmHiO of PEEP in extremely premature lamb, without adverse effects in PaCC>2 and blood pressure. But further studies are required to determine which level of PEEP is optimal for oxygenation improvement and safety in premature lungs. In addition, application of PS and iNO have been extended to most disorders causing hypoxic respiratory failure, so that further studies are required to explore combined effects of the PEEP, iNO and surfactant and confirm the best combination which could improve oxygenation and alleviate lung injury.Objective: To compare effects of high and low PEEP on ventilation efficiency andinflammatory injury in ventilated premature lungs treated with surfactant and/or iNO, and explore the combined effects of the PEEP, iNO and surfactant and confirm the optimal combination which could improve oxygenation and alleviate lung injury.Methods: Preterm piglets (97-100 days, 85% gestation) were delivered by cesarean section. The piglets were dried and resuscitated by airway suctioning and oxygen supply, then were transported to the laboratory. The umbilical artery and vein were catheterized for blood sampling, and fluid and drug administration, respectively. A tracheotomy was performed with placement of an endotracheal tube which then connected to the ventilator circuit. The piglets were randomly subjected to mechanical ventilation with either 5-6 or 10-12 cmH20 PEEP (PEEP5 or PEEP 10). After stabilizing for 15 min of mechanical ventilation, serial ventilation parameters and blood gas values were recorded as zero value, and the piglets with PaO2/FiO2 <250 mmHg were selected for treatment with porcine surfactant (100 mg/kg, PS), iNO (10 ppm, NO), both surfactant and iNO (SNO). In total, animals were divided into 8 groups as following: PEEP5 (C5), PEEP5 +iNO (NO5), PEEP5+PS (PS5), PEEP5 +iNO+PS (SNO5); PEEPIO(CIO), PEEP10+iNO(NO10), PEEP10 +PS (PS 10), PEEP10 +iNO+PS (SNO10). Heart rate, blood gas (pH, PaO2, PaCO2, BE), and respiratory mechnics parameters [including peak inspiratory pressure (PIP), mean airway pressure (MAP), respiratory rate (RR), fraction of inspired oxygen (FiO2), respiratory dynamic compliance (Cdyn) and resistance of respiratory system (Raw)] were recorded during 6 h treatment. Oxygenation index (OI = MAP><0.01).4. NO toxicity measurement: No differences were seen in the contents of MetHb and NOVNO~3 between groups receiving iNO treatment and their control groups.5. Inflammatory injury: The comparison of W/D showed no differences among high or low PEEP subgroups. There was a decreased trend in W/D in low PEEP subgroups compared to the according high PEEP subgroups and significant difference was seen in the comparison between NO5 and NO 10 (6.23±0.73 vs. 7.16±0.46, P<0.05)o Within low PEEP subgroups, MPO in NO5 and SNO5 significantly decreased in contrast to C5 (1.98±0.52,1.69±0.60 vs. 3.31±0.42 U/g tissue, P<0.0\), but no difference among high PEEP subgroups. There was an increased trend in MPO in high PEEP subgroups compared to the according low PEEP subgroups and significant difference was seen in the comparison between NO5 and NO 10 (3.08±0.70, P<0.05). The comparison of...