Inhaled Nitric Oxide In Neonatal Infants With Hypoxic Respiratory Failure: A Multicenter, Cohort Trial

BACKGROUNDHypoxic Respiratory Failure (HRF) is the most common clinical feature for newborn and one of the major reasons for them to be ventilated, especially for preterm infants. The pathophysiological features of HRF include reduction of alveolar space, activation of inflammatory response, deactivation of the pulmonary surfactant (PS), abnormal proliferation of the pulmonary mesenchymal cells and pulmonary vasospasm. Oxygen, mechanical ventilation, PS, vasodilator and extracorporeal membrane oxygenation (ECMO) are used in the treatment of HRF. For infants with severe HRF, high concentration of oxygen, high ventilation pressure and the use of PS are not helpful enough to alleviate the hypoxemia. After the failure of conventional treatments, ECMO would be chosen which has not yet been widely used for its invasiveness, complicated operation and pot ential severe complications. Therefore, severe HRF is still a challenge for neonatologists.Nitric oxide (NO) is a compound produced by many cells of the body, having the abilities of vasodilation, mediating the signaling pathway activities of neurons, anti-inflammatory and anti-proliferative effects. NO has been widely used in clinical practice as a powerful selective pulmonary vasodilator since the discovery 80s, last century. Sixteen well-designed clinical trials have shown that the use of inhaled Nitric Oxide (iNO) in newborn of more than 34 weeks of gestation could relieve severe hypoxemia, reduce the use of ECMO without severe complications. Therefore, iNO was approved to be used in the treatment of newborn of more than 34 gestational weeks with progressive HRF by Food and Drug Administration of USA in 1999 and European Medical Evaluation Agency in 2001 respectively.Except for the role of selective vasodilation, NO could downregulate the expression of proinflammatory factors, inhibit the recruitment and activation of neutrophils into lung and the release of inflammatory mediators, maintain the normal development of the lung and gas exchange. Under the consideration of the immaturation of the preterm infants and the potential side effects of the iNO treatment, the main targets of iNO therapy used in preterm infants are to improve oxygenation and to reduce the incidences of bronchopulmonary dysplasia (BPD) and complications.The results of published trials indicate that early, long term, prophylactic treatment of iNO could reduce the incidences of BPD, severe intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) in preterm infants with mild HRF. Meanwhile, the incidences of BPD/death or neurological complications of the infants with severe HRF couldn't be reduced by long term iNO treatment.Most of the clinical studies of iNO therapy of newborn in China were performed as a single center study without control group. Only few trials had control group in their studies. Moreover, no multicenter clinical trial on the treatment of neonatal HRF by iNO therapy has been reported. The aim of our study was to set up an iNO collaborative group for neonatal HRF treatment, which was based on the Chinese collaborative study group for neonatal respiratory disease, to conduct a prospective, multicenter, cohort study to determine the treatment effects of iNO therapy in HRF newborn and to get some experience for further multicenter randomized control trial.OBJECTIVESTo determine the effectiveness of the iNO treatment in term and late preterm infants with HRF and the influences on oxygenation, mortality and complications; to determine the safety of iNO treatment in preterm infants with HRF and the influences on oxygenation, mortality, incidences of BPD and complications.METHODSA prospective, multicenter, cohort study was performed in 28 Chinese neonatal intensive care units (NICU), based on the Chinese Collaborative Study Group for Neonatal Respiratory Diseases, to set up an Inhaled Nitric Oxide Group for Neonatal Hypoxic Respiratory Failure to determine the effects of inhaled nitric oxide on ventilated infants due to HRF since March 1st 2007 to August 31st 2008. These infants were divided into two groups according to the gestational age (GA), with GA more than 34 weeks in the term and late preterm group and at or less than 34 weeks in the preterm group. In the term and late preterm group, infants less than 28 days of age, being ventilated for more than 48 hours and oxygenation index (OI) of more than 15 were eligible for the trial. Those infants were ineligible, even though they met the above criteria, if they had lethal deformation and the diseases intending to influence the results of iNO therapy, such as life-threatening diseases, structural heart diseases other than patent ductus arteriosus (PDA) or patent foramen ovale, congenital diaphragmatic hernia and bleeding tendency. In the preterm group, the same criteria were used except for the OI of more than 10, instead of 15. The treatment of iNO or conventional therapy was decided by the attending in each unit. A concentration of 10 parts per million (ppm) of NO was used in the term and late preterm group and 5 ppm in the preterm group. The data required were collected on specific time points in accordance with the protocol. The Children's Hospital of Fudan University worked as the coordinating center in charge of the supervision of the research progress and the quality of data collected. Data management was conducted using software SPSS version 11.5.RESULTSTwo hundred and seventy three cases were enrolled, among which 192 was in term and late preterm group and 81 in preterm group.In term and late preterm group, iNO treatment didn't reduce the mortality of ventilated infants with HRF, though the infants in NO group are more severe. INO treatment of 10 ppm could shortly improve the oxygenation, after which the usage of PS, high-frequency oscillatory ventilation and sedation is significantly lower in NO group than in control group, without improving the incidence of air leak, IVH and pneumonia/sepsis. The durations of receiving oxygen and ventilation, length of stay in NICU and hospital, costs of stay in NICU and hospital are not different between NO group and control group. After the subgroup analysis, the usage of PS could decrease the effective concentration of NO defined as increasing PaO2 by more than 20 mmHg. Infants without asphyxia, enrolled in less than 24 hours, with OI between 15 and 20, with RDS or MAS could respectively have a better improvement in oxygenation in NO group than in control group.In preterm group, iNO treatment didn't reduce the mortality or the incidence of BPD of ventilated infants with HRF. INO treatment of 5 ppm for 7 days couldn't improve oxygenation. At the same time, iNO treatment didn't improve the incidence of air leak, pneumonia/sepsis, PDA, PVL and severe IVH. The durations of receiving oxygen and ventilation, length of stay in NICU and hospital, costs of stay in NICU and hospital are not statistically different between NO group and control group.CONCLUSIONSINO treatment couldn't reduce the mortality of infants of GA more than 34 gestational weeks with HRF and the combined incidence of death and BPD of infants of GA at or less than 34 gestational weeks. INO treatment could shortly improve the oxygenation of term and late preterm infants with HRF, especially those with RDS, MAS, with mild HRF or without asphyxia and didn't increase the disease burden and the incidences of complications.