【作者】 王一飞；

【导师】 孙波；

【作者基本信息】 复旦大学 ， 儿科学， 2009， 博士

【摘要】 背景低氧性呼吸衰竭(Hypoxic Respiratory Failure, HRF)是新生儿最常见的临床表现,也是导致新生儿,特别是早产儿,机械通气的主要原因。其临床病理生理学特征表现为肺泡腔变小、肺内炎症反应、肺表面活性物质(Pulmonary Surfactant, PS)失活、肺间质增生以及肺血管收缩。目前用于HRF的治疗主要包括氧疗、机械通气、PS、血管扩张剂以及体外膜肺。对于重度HRF患儿,在较高的氧浓度、压力及PS使用的情况下,低氧血症仍然不能缓解,可以使用体外膜肺支持治疗。但由于其有创性、操作复杂性及严重的并发症,临床使用受到限制。因而,重度HRF仍是新生儿医生面临的重要难题。一氧化氮(Nitric Oxide, NO)是人体许多细胞合成的化合物,具有扩张血管、介导神经传递、抗炎反应以及抑制增生的作用。自上个世纪80年代发现以来,已经被作为强大的选择性肺动脉扩张剂应用于临床。大量的多中心临床研究证实,严重HRF的足月儿和近足月儿接受吸入NO (iNO)治疗能够迅速改善氧合、降低体外膜肺的使用率,而没有严重的不良反应和后遗症。美国食品和药品管理局和欧洲药品管理局分别于1999年和2001年批准iNO作为胎龄大于34周足月儿和近足月儿HRF的常规治疗。NO除了能选择性舒张肺血管改善氧合外,还具有下调促炎因子表达、抑制肺内白细胞集聚和炎症介质释放的抗炎作用以及促进肺发育作用。正常新生儿需要依靠小剂量内源性NO的作用来维持正常的肺发育和气体交换。由于早产儿发育的不成熟以及iNO治疗潜在的副作用,对早产儿的治疗主要集中在改善氧合、降低BPD以及并发症的发生率方面。目前的研究显示,早期、长时间、预防性使用iNO治疗能够降低支气管肺发育不良(Bronchopulmonary Dysplasia, BPD)以及重度脑室内出血/脑室周围白质软化的发生率。对经过常规治疗后有BPD风险的患儿,在生后7-14天内接受长时间iNO治疗仍然能够降低BPD的发生,但重度脑室内出血的发生率无明显下降。对于中重度HRF患儿,接受长时间iNO治疗不能降低BPD/死亡以及神经系统并发症的发生率。国内关于iNO治疗的研究多为单中心研究,仅有少数研究人员在研究时设立了对照。到目前为止,还没有关于iNO治疗新生儿HRF的多中心研究。本研究在全国新生儿呼吸危重病协作网基础上,组建iNO治疗新生儿HRF协作组。在符合研究条件的单位中开展前瞻性、多中心、群组对照研究。籍此了解iNO在新生儿中的治疗效果,同时也为将来开展多中心随机对照研究奠定基础。目的研究iNO治疗对足月儿和近足月儿HRF的有效性,对改善氧合、降低病死率和并发症的影响；研究iNO治疗对早产儿HRF的安全性,对改善氧合、降低病死率/BPD的发生率的影响。方法本研究采用前瞻性、多中心、群组对照研究。在新生儿呼吸危重病协作网基础上选择28家具备研究条件的单位组建iNO治疗新生儿HRF协作组,对2007年3月至2008年8月连续18个月符合研究标准的HRF患儿进行研究。本研究分为GA>34周的足月儿和近足月儿组和GA≤34周的早产儿组。在足月儿和近足月儿组中,研究单位给予符合条件患儿10 ppm的iNO治疗,然后根据治疗效果,参考研究方案给予相应治疗,或者不使用NO,直接给予常规治疗。在早产儿组中,研究单位给予符合条件患儿连续7天5 ppm的iNO治疗。同时,按照研究方案记录患儿的一般情况、纳入前及纳入后1、12、24、48、72 h等时间点的生命体征、血气结果和呼吸机参数以及患儿的预后和疾病负担。指定复旦大学附属儿科医院为研究协调中心,负责管理调查工作和数据质量的监控。所有资料应用统计软件SPSS 11.5进行统计分析。结果1.在连续18个月的研究期间内,28家NICU共收治患儿273例,足月儿和近足月儿组192例(NO组103例,对照组89例),早产儿组81例(NO组18例,对照组63例)。2.在足月儿和近足月儿组中,a)在NO组患儿病情偏重的情况下,iNO治疗没有降低患儿的病死率；b)iNO治疗明显改善患儿氧合情况；c)NO组患儿PS、高频振荡机械通气和镇静剂的使用比例明显低于对照组；d)iNO治疗没有增加患儿气漏、颅内出血等并发症的发生；e)iNO治疗没有明显改变患儿的氧疗时间和机械通气时间；f)iNO治疗虽然增加了NICU的住院时间及费用,但总的住院时间及费用与对照组无统计学差异；3.足月儿和近足月儿组分层分析后发现,a)iNO联合PS治疗后,患儿达到有效反应所需要的NO浓度偏低；未使用PS的患儿所需NO浓度偏高；b)RDS患儿和MAS患儿对iNO治疗的反应较好,但当对10ppm治疗效果不好时,改用20ppm的效果仍不好；iNO治疗原发性PPHN患儿和肺炎/败血症患儿无效。c)无窒息患儿对iNO治疗有反应,有窒息的患儿对iNO治疗的反应较差；d)生后24h内接受iNO治疗有效,出生24h后再接受iNO治疗效果差；e)15<OI≤20的患儿对iNO的治疗反应好于其他病情较重的患儿；4.在早产儿组中,a)iNO治疗没有降低患儿的病死率以及BPD的发生率；b)iNO治疗没有改善患儿的氧合情况；c)iNO治疗也没有增加患儿并发症的发生。d)患儿接受5ppm×7d的iNO治疗没有降低住院时间及费用,相反,NO组患儿的氧疗、机械通气时间、NICU时间及费用、总的时间及费用均偏高。结论iNO治疗1.没有降低足月儿和近足月儿的病死率,也没有降低早产儿的病死率或BPD的发生率；2.没有增加HRF患儿的疾病负担,也没有增加并发症的发生；3.能够短期改善足月儿和近足月儿的氧合,但没有改善早产儿氧合情况；4.早期治疗能够改善RDS、MAS、无窒息以及病情较轻患儿的氧合。更多还原

【Abstract】 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.更多还原