新生儿疾病的一氧化氮吸入治疗(一)

新生儿低氧血症的病因很多 ,而新生儿肺动脉高压是其中的重要原因之一。长期以来 ,临床上一直缺乏能特异性扩张肺血管、降低肺动脉压而又对体循环血压无影响的药物。直到 2 0世纪 80年代初期 ,一氧化氮 (ｎｉｔｒｉｃｏｘｉｄｅ ,ＮＯ)的发现才令人们重新看到了希望。大量的动物实验表明[1] ,吸入ＮＯ能有效地降低因低氧血症与酸中毒所引起的肺循环高阻力 ,当低浓度吸入时 ,可使已收缩的肺血管扩张 ,肺动脉高压得到缓解。临床试验也表明[2 ] ,ＮＯ对调节围生期新生儿的肺血管张力有着重要的作用。由于ＮＯ通过肺泡和血管壁后 ,进入肺毛细血…     

Inhaled nitric oxide in the term newborn

Inhaled nitric oxide is a selective pulmonary vasodilator that serves integral diagnostic and therapeutic roles in the clinical management of near-term and term newborns with hypoxemic respiratory failure and pulmonary hypertension. Its proper use and potential limitations in current clinical practice are reviewed.     

Recommendations for inhaled nitric oxide treatment in the newborn

The recommendations in this document describe the current indications for inhaled nitric oxide (iNO) treatment in the newborn and clearly distinguish between those supported by scientific evidence and those for which evidence is still lacking, such as its use in preterm infants. The methodology for iNO administration, its dosage and the main secondary effects are discussed, and the reasons for lack of response to this treatment are analyzed.     

Recent developments in inhaled nitric oxide therapy of the newborn

Inhaled nitric oxide therapy improves oxygenation and reduces the need for extracorporeal life support in near-term and term newborns with hypoxemic respiratory failure and persistent pulmonary hypertension of the newborn. Previous studies demonstrated that the efficacy of inhaled nitric oxide therapy is related to the underlying disease associated with persistent pulmonary hypertension and that lung recruitment strategies augment the response to this inhalational vasodilator. This review of recent studies evaluates new insight into important questions regarding the optimal dose of inhaled nitric oxide, potential adverse effects associated with inhaled nitric oxide therapy, and the potential role of inhaled nitric oxide in the premature newborn with hypoxemic respiratory failure.     

一氧化氮吸入治疗新生儿持续肺动脉高压

】　目的　探讨吸入一氧化氮（NO）对新生儿持续肺动脉高压（PPHN）的治疗效果。方法　对6例窒息后PPHN进行NO吸入治疗,入院后经呼吸机支持,应用NO前呼吸机吸入氧浓度平均为0.93±0.10,平均气道压力为(12.7±2.7)cmH     

Role of nitric oxide in hypoxia-induced changes in newborn rats

In order to investigate the role of nitric oxide (NO) in hypoxic tissue damage in newborns, we studied the effects of systemic administration of an inhibitor of NO synthase, N(G)-nitro-L-arginine (L-NNA), and the precursor for the synthesis of NO, L-arginine (L-ARG), on the biochemical and histological changes in brain, heart, lung, liver, kidney, intestine, and skeletal muscle tissues. Four groups of 1-day-old Wistar rat pups were used: control, hypoxic, L-ARG, and L-NNA groups. L-ARG 100 mg/kg or L-NNA 2 mg/kg was administered as a bolus intraperitoneally 1.5 h before hypoxia. Hypoxia increased lipid peroxidation in all tissues except muscle; this increase was prevented by L-NNA and L-ARG in brain, heart, lung, kidney, and liver tissues. L-NNA in intestine and L-ARG in muscle tissue increased lipid peroxidation. The tissue-associated myeloperoxidase activity was decreased in the liver by L-NNA and L-ARG. Histopathological changes in intestines were villous epithelial separation and hyperemia in hypoxic and L-NNA groups which were not observed in control and L-ARG groups. In lungs, pulmonary hemorrhage was observed only in the hypoxic group. These data suggest that NO acts both as a destructive and a protective agent in the pathogenesis of hypoxia-reoxygenation injuries.     

一氧化氮吸入治疗新生儿持续肺动脉高压

新生儿持续肺动脉高压（persistent pulmonary hypertension of newborn，PPHN）治疗困难，病死率高。近年来由于机械通气技术的改进，尤其应用体外膜肺（extracorporeal membrance oxygenation，ECMO）治疗后。病死率有所下降，但EMCO设备昂贵，在新生儿应用技术要求复杂，普遍推广有困难。1992年起美国开始用一氧化氮（NO）吸入治疗PPHN，获得良好效果。我们对8例确诊为PPHN的患儿在机械通气同时应用NO吸入治疗。并动态监测相关指标变化，现报告如下。     

Inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn

Increasing evidence suggests that the pulmonary vascular endothelium is an important mediator of resting pulmonary vascular tone through the synthesis and release of a variety of vasoactive substances including nitric oxide (NO). In addition, pulmonary endothelial dysfunction (such as impairment of NO synthesis) is present in lung injury and may contribute to the pathophysiology of pulmonary hypertensive disorders. Recently, exogenously administered NO gas has been utilized to treat infants with persistent pulmonary hypertension of the newborn (PPHN). These preliminary studies suggest that inhaled NO is a promising new therapy for the treatment of infants with PPHN. Controlled clinical trials must now be performed to determine if the use of inhaled NO improves the long-term outcome of patients with PPHN. Long-term exposure must be monitored closely for potential toxicity which includes methemoglobinemia and lung injury secondary to peroxynitrite and nitrogen dioxide production.     

Endothelial nitric oxide synthase in hypoxic newborn porcine pulmonary vessels

AIMS—To determine if the failure of neonatal pulmonary arteries to dilate is due to a lack of nitric oxide synthase (NOS).
METHODS—A monoclonal antibody to endothelial NOS was used to demonstrate the distribution and density of NOS in the developing porcine lung after a period in hypobaric hypoxia. Newborn piglets were made hypertensive by exposure to hypobaric hypoxia (50.8 kPa) from < 5 minutes of age to 2.5 days of age, 3-6 days of age or 14-17 days of age. A semiquantitative scoring system was used to assess the distribution of endothelial NOS by light microscopy.
RESULTS—NOS was present in the arteries in all hypoxic animals. However, hypoxia from birth caused a reduction in NOS compared with those lungs normal at birth and those normal at 3 days. Hypoxia from 3-6 days led to a high density of NOS compared with normal lungs at 6 days. Hypoxia from 14-17 days had little effect on the amount of NOS. On recovery in room air after exposure to hypoxia from birth there was a transient increase in endothelial NOS after three days of recovery, mirroring that seen at three days in normal animals.
CONCLUSIONS—Suppression of NOS production in the first few days of life may contribute to pulmonary hypertension in neonates.

     

Abundance of endothelial nitric oxide synthase in newborn intrapulmonary arteries.

A monoclonal antibody to endothelial NOS (eNOS) was used to demonstrate the distribution and density of eNOS in the developing porcine lung. Lung tissue from large white pigs aged from less than 5 minutes to 3 months was immunostained and, using light microscopy, distribution of eNOS was assessed by a semiquantitative scoring system. At all ages eNOS was located on the endothelial cells of pulmonary and bronchial arteries and veins. Immunoreactivity for eNOS was greater in the larger, more proximal pulmonary arteries than at the periphery. In the lung of newborn pigs immunoreactivity for eNOS was present in arteries of all sizes but some showed no positive staining. At 2-3 days of age almost all arteries showed positive immunoreactivity. By 3 months of age the amount of eNOS had decreased and was less than that seen in the newborn. The highest level of eNOS was seen immediately after birth when the pulmonary arteries are dilating. eNOS may therefore play an important part in adaptation to extra-uterine life.     

Endogenous nitric oxide and endothelin-1 in persistent pulmonary hypertension of the newborn

We studied changes in endogenous nitric oxide (NO) synthesis and endothelin-1 (ET-1) production in infants with persistent pulmonary hypertension of the newborn (PPHN). We determined concentrations of serum NO metabolites, i.e., nitrites and nitrates (NOx), and of plasma ET-1 in five infants with PPHN (PPHN group) and in 25 healthy full-term neonates (control group). In both groups, serum NOx concentrations increased over time and plasma ET-1 concentrations decreased with age. The differences in serum NOx concentrations between groups were not significant at <12 h and 24 h of age; however, they were significantly higher in the PPHN group than in the control group at 5 days of age. The differences in plasma ET-1 concentrations between groups were not significant at 5 days of age, but were significantly higher in the PPHN group than in the control group at <12 h and 24 h of age. Conclusion Limited endogenous nitric oxide synthesis and elevated endogenous endothelin-1 production during the first few days of life may contribute to pulmonary hypertension in infants with persistent pulmonary hypertension of the newborn. Received: 2 September 2000 / Accepted: 15 June 2000     

内源性一氧化氮合酶/一氧化氮体系对反复高热惊厥脑损伤的影响

目的 研究神经元型一氧化氮合酶(nNOS)在反复高热惊厥(FS)中的变化规律，探讨NOS／一氧化氮(NO)体系对反复FS脑损伤的影响．方法 采用热水浴诱导大鼠FS。实验分两步进行。时第1批大鼠，采用定量RT-PCR方法检测海马nNOS cDNA含量，Western blot检测nNOS蛋白表达；对第2批大鼠，记录惊厥强度。潜伏期、持续时间及惊厥时肛温，HE染色观察海马神经元形态学改变。结果 反复FS后海马nNOS cDNA含量明显高于正常对照组和高热对照组，同时nNOS蛋白表达也出现一致性增高；随惊厥次数的增加。FS组大鼠惊厥潜伏期呈波动状，惊厥持续时间呈延长趋势，NOS抑制剂的干预使惊厥潜伏期呈延长趋势，惊厥持续时间的延长趋势较FS组降低。惊厥强度和惊厥时肛温在两组间无统计学意义；反复FS后，光镜下可观察到海马神经元出现组织学改变，抑制剂减轻了神经元损伤。结论 反复FS诱导nNOS的基因表达，NOS／NO体系的上调可能参与反复FS脑损伤发展。     

Methaemoglobinaemia risk factors with inhaled nitric oxide therapy in newborn infants

Background: Inhaled nitric oxide (iNO), commonly used for hypoxic neonates, may react with haemoglobin to form methaemoglobin (MetHb). MetHb monitoring during iNO therapy has been questioned since low doses of iNO are used. Aim: To evaluate the incidence of and identify risk factors associated with elevated MetHb in neonates treated with iNO. Methods: Neonates who were treated with iNO and had at least one MetHb measurement were included. Demographic characteristics and methods of iNO administration (dosage, duration) at the time of each MetHb measurement were analysed. Results: Four hundred and fifty‐two MetHb measurements from 81 premature and 82 term and near‐term infants were analysed. MetHb was above 5% in one‐term infant, and between 2.5–5% in 16 infants. A higher maximum dose of iNO (22.7 vs 17.7 p.p.m.), but not gestational age, was a significant risk factor for elevated MetHb. Significantly higher oxygen levels (75.5% vs 51.7%) were associated with higher MetHb in term infants. Preterm infants had no risk for high MetHb when iNO was kept below 8 p.p.m. These data suggest the possibility of limiting blood withdrawal when low doses iNO are used. Conclusion: High MetHb is exceptional in neonates treated with low dose iNO. Associated risk factors are related to high iNO dose and the simultaneous use of high concentrations of oxygen.     

吸入一氧化氮对胎粪吸入综合征新生猪脑的保护作用

目的探讨机械通气下吸入一氧化氮(NO)对胎粪吸入综合征(MAS)新生猪脑不同部位胆碱能神经元的保护作用及对星形胶质细胞增殖的影响。方法 建立新生猪胎粪吸入模型,并予间歇正压通气,随机分为胎粪吸入组(n=10)和NO治疗组(n=4),另设正常对照组(n=4)。HE染色计数大脑皮质、海马及基底节神经元细胞,免疫组化法检测皮层、海马及基底节胆碱乙酰基转移酶(ChAT)和胶质纤维酸性蛋白(GFAP)免疫阳性细胞数。结果 胎粪吸入组脑不同部位的神经元细胞和ChAT阳性细胞数均较正常对照组减少[神经元细胞:皮质(29.6±2.3)比(58.2±3.8),海马(27.0±12.7)比(56.0±3.7),基底节(25.0±4.6)比(56.0±4.6);ChAT阳性细胞:皮质(16.7±3.9)比(38.3±9.0),海马(17.5±2.7)比(34.3±11.6),基底节(17.0±1.2)比(35.3±7.1),P均<0.01],GFAP阳性细胞数增多[皮质(54.8±11.0)比(22.0±5.5),海马(54.9±14.7)比(21.0±1.7),基底节(53.8±7.1)比(19.0±4.6),P均<0.001)]。NO治疗组神经元细胞数和ChAT阳性细胞数均多于胎粪吸入组,GFAP阳性细胞数少于胎粪吸入组,P均<0.05。结论 新生猪MAS后吸入NO可减少脑不同部位胆碱能神经元的丢失及星形胶质细胞的增殖,提示吸入NO可能对MAS引起的脑损伤具有保护作用。