吸入一氧化氮治疗早产儿低氧性呼吸衰竭的应用

动物实验表明,吸入一氧化氮（inhaled NO,iNO）可减少早产动物肺部炎症发生率,提高表面活性物质功能,促进肺生长。自20世纪90年代初iNO首次被用于治疗持续性肺动脉高压以来,已逐渐在新生儿重症监护病房得到应用。虽然多项研究结果均证实iNO治疗早产儿低氧性呼吸衰竭（hypoxic respiratory failure,HRF）的有效性,但至今尚无确切证据表明对早产儿可常规使用iNO治疗。本文结合国内外近年文献,就目前iNO治疗早产儿的作用机制、治疗的临床方案、iNO的有效性及安全性做一综述,以期为临床提供参考。     

Surfactant and continuous positive airway pressure for the prevention of chronic lung disease: History,reality, and new challenges

The discovery of surfactant was one of the most significant research events to occur in the history of neonatology. Certainly, surfactant saved lives for premature infants who were otherwise considered non-viable. However, the prevention of chronic lung disease did not progress and it became clear that a significant portion of the help surfactant provides to the premature lung is counteracted by mechanical ventilation. A dilemma exists over the priorities in premature management to intubate and administer surfactant or not to intubate and support these infants non-invasively with the use of continuous positive airway pressure. A new hydrophilic surfactant preparation has been developed with the hope to enable the introduction of surfactant therapy without the need for tracheal intubation. Clinical trials on this product are currently in progress. This article provides the history and prospect of respiratory distress management in premature infants and evaluates the current evidence for non-invasive practices.     

The use of inhaled nitric oxide in the premature infant with respiratory distress syndrome

The identification of the biologic properties of nitric oxide (NO) is one of the key scientific discoveries of the century, but its potential for treating human disease is yet to be fully realized. NO has a basic role in regulating vascular tone of the pulmonary circulation, and recent animal models have suggested a more wide reaching influence on perinatal lung development. In animal models, NO has effects on lung growth, angiogenesis, airway smooth muscle proliferation, vascular remodeling, surfactant function, inflammation, and pulmonary mechanics. However, despite extensive basic science investigation and completion of several large clinical trials, the role of NO in the treatment of the premature infant with respiratory distress syndrome remains unclear. One must conclude that the interaction of lung immaturity, ventilator and oxygen-induced lung injury, and NO biology in the premature newborn is incompletely understood. Clinical trial results of inhaled NO therapy in the premature infant are accumulating, but the results do not suggest a clear-cut advantage for the population at greatest risk for death and disability. Whether trial design, dose, duration of therapy, or other factors are responsible has not been determined. Further research is needed to answer these questions and more clearly define the population of premature infants who may derive benefit from this new therapy.     

The lungs in immature infants: How important is surfactant therapy in preventing chronic lung problems?

Seventy-five premature infants weighing between 600 and 3200 g were studied over a period of 1 year. All of the infants received surfactant therapy for hyaline membrane disease immediately after birth and, thereafter, up to four doses every 6 h. The roentgenographic findings in all patients were documented at birth and at 2 days, 7–10 days, and 21–28 days of life. Larger babies responded to surfactant therapy better than did smaller infants. The smaller infants, even after initial clearing, were prone to develop pulmonary edema and the bubbly lungs of bronchopulmonary dysplasia. These data suggest that small infants, while initially responding to surfactant therapy with clearing of their lungs, are still at considerable risk of developing chronic lung disease in the form of pulmonary edema and bronchopulmonary dysplasia. An explanation is offered for why this occurs; at the same time it is suggested that, in view of our findings and those in the literature, the problems of pulmonary edema and bubbly lungs be more clearly separated.     

What’s new in surfactant?

Surfactant therapy has significantly changed clinical practice in neonatology over the last 25 years. Recent trials in infants with respiratory distress syndrome (RDS) have not shown superiority of any natural surfactant over another. Advancements in the development of synthetic surfactants are promising, yet to date none has been shown to be superior to natural preparations. Ideally, surfactant would be administered without requiring mechanical ventilation. An increasing number of studies investigate the roles of alternative modes of administration and the use of nasal continuous positive airway pressure to minimise the need for mechanical ventilation. Whether children with other lung diseases benefit from surfactant therapy is less clear. Evidence suggests that infants with meconium aspiration syndrome and children with acute lung injury/acute respiratory distress syndrome may benefit, while no positive effect of surfactant is seen in infants with congenital diaphragmatic hernia. However, more research is needed to establish potential beneficial effects of surfactant administration in children with lung diseases other than RDS. Furthermore, genetic disorders of surfactant metabolism have recently been linked to respiratory diseases of formerly unknown origin. It is important to consider these disorders in the differential diagnosis of unexplained respiratory distress although no established treatment is yet available besides lung transplantation for the most severe cases. Conclusion: Research around surfactant is evolving and recent developments include further evolution of synthetic surfactants, evaluation of surfactant as a therapeutic option in lung diseases other than RDS and the discovery of genetic disorders of surfactant metabolism. Ongoing research is essential to continue to improve therapeutic prospects for children with serious respiratory disease involving disturbances in surfactant. Funding: Jasper Been is supported by a Profileringsfonds grant from the Maastricht University Hospital.     

Pulmonary Hypertension in the Preterm Infant with Chronic Lung Disease can be Caused by Pulmonary Vein Stenosis: A Must-Know Entity

Pulmonary hypertension (PHT) in the preterm infant is frequently due to chronic lung disease. Rarely, PHT can be caused by pulmonary vein (PV) stenosis that has been described to be associated with prematurity. This study is a retrospective analysis of all premature infants <37 weeks of gestation with PV stenosis and PHT in two French pediatric congenital cardiac centers from 1998 till 2015. Diagnosis, hemodynamics and outcome are described. Sixteen patients met the inclusion criteria. Median gestational age was 28 weeks (25 + 6–35) with a median birth weight of 842 g (585–1500). The majority of infants (87.5 %) had chronic lung disease and associated cardiac defects. Median age at diagnosis was 6.6 months (1.5–71). Fifty-six percentage (n = 9) had initially unilateral PV stenosis affecting in 89 % the left PV. Median initial invasive mean pulmonary artery pressure was 42 mmHg (25–70). Treatment options included surgical intervention (n = 6), interventional cardiac catheter (n = 3) and/or targeted therapy for pulmonary arterial hypertension (n = 5). In six patients, decision of nonintervention was taken. Global mortality was 44 %. All deaths occurred within 7 months after diagnosis regardless of chosen treatment option. Mean follow-up was 6 years (4.9 months–12 years). At last visit, all eight survivors were in stable clinical condition with five of them receiving targeted therapy for pulmonary arterial hypertension. PV stenosis is an unusual cause of PHT in the premature infant with chronic lung disease. Diagnosis is challenging since initial echocardiography can be normal and the disease is progressive. Treatment options are numerous, but prognosis remains guarded.     

Pathology of the Lung in Surfactant-Treated Neonates

Respiratory distress syndrome (RDS) is associated with prematurity-related deficiency of surfactant. Surfactant replacement therapy has been used in premature infants to prevent RDS or reduce its severity. In this study we describe the pathology of the lungs after surfactant replacement therapy. All the neonatal autopsies during the years 1989 and 1990 (n = 235) were examined. Infants ≥ 31 weeks gestation, with congenital anomalies or who lived more than 2 weeks were excluded from the study. Infants who had received intratracheal Survanta, a modified surfactant extracted from cow lung (n = 14), were compared with infants who did not receive exogenous surfactant (n = 20). The two groups were statistically comparable in terms of weight, gestational and postnatal age, gender, and clinical management. H&E-stained lung sections were examined independently by two pathologists without knowledge of surfactant treatment status; any discrepancies in histological evaluation were resolved by joint review. Nine histological features were evaluated including hyaline membranes, necrosis of the epithelium, hemorrhage, edema, inflammation, metaplasia, arteriolar muscular hyperplasia, interstitial fibrosis, and pulmonary interstitial emphysema (PIE). Histological changes were graded from 0 to 3+. When it was present, cerebral periventricular-intraventricular hemorrhage (PVH-IVH) was graded 1-4. The presence or absence of sepsis and necrotizing enterocolitis (NEC) were also determined. Comparisons between patient groups were performed using the Mann-Whitney U, Student's t and χ² tests. The severity of hyaline membrane disease, PIE, and epithelial necrosis was less severe in the surfactant-treated group than in the untreated group. There were no differences between the two groups in the degree of pulmonary hemorrhage or in the incidence of PVH-IVH, sepsis, or NEC.     

New methods advance treatment for respiratory distress syndrome

The past 20 years of hard labor in neonatal respiratory distress have resulted in several important advances arising from our understanding of lung chemistry and physiology. Our knowledge of surfactant chemistry has enabled us to identify infants at high risk for developing neonatal distress due to surfactant deficiency, reducing this risk with antenatal corticosteroid treatment, and improving the neonatal outcome by means of administration of effective surfactant replacement. Recognition of the roles of oxygen toxicity and barotrauma in promoting lung injury has premitted the development of more effective means of assisted ventilation less likely to injure the lungs of severely ill infants with pulmonary failure. Nitric oxide has proven to be an effective pulmonary vasodilator and permits the successful treatment of patients with pulmonary hypertension who might previously have required an invasive surgical treatment to achieve a desirable clinical outcome.     

Mechanisms of ventilator-induced lung injury in premature infants

Mechanical ventilation in premature infants may injure the lungs or exacerbate the pre-existing condition that led to the need for mechanical ventilation. Ventilator-induced lung injury (VILI) may be associated with alveolar structural damage, pulmonary oedema, inflammation, and fibrosis. This injury is not uniform and is associated with surfactant dysfunction. Recovery from VILI includes clearance of pulmonary oedema and alveolar structural repair. Mechanisms of VILI include high airway pressure (barotrauma), large gas volumes (volutrauma), alveolar collapse and re-expansion (atelectotrauma), and increased inflammation (biotrauma). Injury to the lung may lead to other organ dysfunction. The premature lung is more susceptible to VILI, and lung injury may exacerbate the disturbance of lung development that occurs after birth. Therapies targeting specific processes in lung injury, and which complement the protective ventilator management strategies to avoid atelectotrauma and lung overdistension are an area of active research.     

Congenital diaphragmatic hernia

Congenital diaphragmatic hernia occurs in approximately 1 in every 2500 live births and is associated with a reported mortality of almost 35% in live-born patients and a higher mortality when in utero deaths are counted. Ventilator-induced lung injury, pulmonary hypoplasia, and other associated anomalies account for the high death rate. Numerous adjunctive measures have been used to treat these patients. Inhaled vasodilators (nitric oxide), intravenous vasodilators, and fetal therapy have no proven benefit. While animal models of congenital diaphragmatic hernia are surfactant deficient, controversy remains over the use of surfactant in infants. There has been no clinical trial showing any clear benefit with the use of exogenous surfactant in these patients. Similarly, prenatal corticosteroids show some improvements in animal models, but again, there is a complete absence of supportive data to show benefit in humans. Mechanical ventilator strategies that limit ventilator-induced lung injury by avoiding hyperventilation and lung over inflation are the strategies currently in use that have been associated with improved survival. Long-term follow-up of these patients is quite important since gastroesophageal reflux, developmental delay, chronic lung disease, and chest wall deformity are all seen with increased frequency in these children.     

Respiratory distress syndrome

RDS, due to surfactant deficiency or abnormality, remains a major cause of neonatal mortality and morbidity. It is now a condition primarily affecting very immature infants. Extensive research has been directed at optimising respiratory support of premature infants with RDS. Effective prophylaxis is now available both maternally administered and as surfactant replacement therapy.     

History of surfactant up to 1980

Remarkable insight into disturbed lung mechanics of preterm infants was gained in the 18th and 19th century by the founders of obstetrics and neonatology who not only observed respiratory failure but also designed devices to treat it. Surfactant research followed a splendid and largely logical growth curve. Pathological changes in the immature lung were characterized in Germany by Virchow in 1854 and by Hochheim in 1903. The Swiss physiologist von Neergard fully understood surfactant function in 1929, but his paper was ignored for 25 years. The physical properties of surfactant were recognized in the early 1950s from research on warfare chemicals by Pattle in Britain and by Radford and Clements in the United States. The causal relationship of respiratory distress syndrome (RDS) and surfactant deficiency was established in the USA by Avery and Mead in 1959. The Australian obstetrician Liggins induced lung maturity with glucocorticoids in 1972, but his discovery was not fully believed for another 20 years. A century of basic research was rewarded when Fujiwara introduced surfactant substitution in Japan in 1980 for treatment and prevention of RDS.     

Interaction between surfactant and ventilatory support in newborns with primary surfactant deficiency

The interaction between exogenous surfactant and various modes of ventilatory support in terms of timing, quality and quantity can influence both short- and long-term outcomes of immature infants. Alterations to the pulmonary surfactant system can occur with all forms of mechanical ventilation. Experimental data suggest possible interaction between ventilatory support and exogenous surfactant even during the first breaths in the delivery room. The adverse effect on surfactant function at this time can increase the need for and duration of ventilatory support. The logical approach to ventilatory support is to be minimally aggressive with optimal recruitment of the lungs to avoid ventilator-induced lung injury. Nasal continuous positive airway pressure (CPAP) in combination with early prophylactic surfactant administration may be an effective and less damaging method capable of reducing the need of artificial ventilation, but its benefit has not been proven in extremely preterm infants less than 28 weeks' gestation. Because of unproven efficacy of nasal CPAP in extremely premature infants, the population most at risk for adverse pulmonary and neurologic outcome, this paper focuses on the comparison of conventional and high-frequency oscillatory ventilation (HFOV) with respect to alteration of surfactant function, and short- and long-term outcomes, in both human and experimental trials. Though the two most recent large clinical trials provide reassurance with respect to the safety of first-intention high-frequency ventilation, the reduction in the risk of chronic lung disease appears to be only modest or absent. Recent laboratory investigations suggest that the key element of HFOV, namely optimization of volume, can, under some circumstances, be replicated with low tidal volume conventional ventilation and high positive end-expiratory pressure. Recent introduction of patient-triggered volume-targeted conventional ventilation into clinical practice offers the promise of a practical means of providing gentle conventional ventilation capable of minimizing ventilator-induced lung injury. Ultimately, well-designed comparative clinical trials with long-term outcomes are essential to accurately quantify risks and benefits of any new approach to mechanical ventilation. Without such data, these experimental results should not be extrapolated into clinical practice, because of the multifactorial pathophysiology of the development of chronic pulmonary disease in extremely premature infants and the risk of unanticipated adverse effects.     

Biophysical properties of protein-free,totally synthetic pulmonary surfactants,ALEC and Exosurf,in comparison with surfactant TA

An artificial pulmonary surfactant prepared from chloroform-methanol extract of bovine pulmonary surfactant (surfactant TA) has been shown to be effective in both the prevention and the treatment of respiratory distress syndrome in premature babies. Recently, two types of protein-free totally synthetic surfactants, artificial lung expanding compound (ALEC) and Exosurf, have been evaluated in clinical trials of surfactant therapy. Artificial lung expanding compound was used initially as a dry powder, but is now prepared as a crystalline suspension in saline at 4°C. In this study we compared the biophysical properties of three different forms of ALEC (dry powder, crystalline suspension at 4°C and 37°C), Exosurf and surfactant TA (Surfacten) using a modified Wilhelmy surface balance and a pulsating bubble surfactometer. Surface activity of a crystalline suspension of ALEC in cold saline was no better than the dry powder of ALEC. Surfactant activity of ALEC was improved by addition of hydrophobic surfactant protein B and C (SP-B, SP-C) which are important constituents of surfactant TA. Surface properties of ALEC in any form and Exosurf were not superior to those of surfactant TA. These results suggest that a surfactant which contains SP-B and SP-C does not necessarily have to be dry or crystalline for an effective exogenous surfactant.     

The potential of recombinant surfactant protein D therapy to reduce inflammation in neonatal chronic lung disease, cystic fibrosis, and emphysema

By lowering surface tension at the air-water interface in the surfactant deficient premature lung, exogenous surfactant replacement therapy for neonatal respiratory distress syndrome has been highly successful in decreasing mortality after preterm birth. It has emerged in recent years that surfactant components not present in current surfactant formulations--particularly surfactant associated proteins A and D (SP-A and SP-D)-have additional roles in host defence distinct from the surface tension lowering effects of surfactant. SP-A and SP-D are calcium dependent carbohydrate binding proteins of the innate immune system important in the first line defence of the lung against microorganisms and in the control of lung inflammation. This review addresses the possibility that recently developed recombinant forms of SP-D could be useful therapeutically in attenuating inflammatory processes in neonatal chronic lung disease, cystic fibrosis, and emphysema.     

新生儿支气管肺发育不良诊治进展

支气管肺发育不良（bronchopulmonarydy splasia,BPD）是一种慢性肺部疾病,常见于长期氧疗和机械通气的早产儿。BPD由Northway于1967年首次报道,近年来其发生率有逐年增加的趋势,并成为NICU最为棘手的问题之一以及婴儿期慢性肺疾病（CLD）的主要病因。产前糖皮质激素和出生后外源性表面活性物质的应用,以及保护性通气策略实施,使BPD表现形式发生了很大变化,更为常见的是一种轻型BPD（又称为“neWBPD”）,这种“newBPD”与40年前的“oldBPD”从病因、病理改变及临床表现等方面均有很大区别。文章对BPD最新定义、诊断标准及治疗进展作一介绍。     

Epidemiology of preterm birth and neonatal outcome

In industrialized countries, 5–11% of infants are born preterm (<37 weeks' gestation), and the rate has been increasing since the early 1980s. Preterm births account for 70% of neonatal deaths and up to 75% of neonatal morbidity, and contribute to long-term neurocognitive deficits, pulmonary dysfunction and ophthalmologic disorders. In the past several decades, major progress has been made in improving the survival of extremely premature newborns, mostly attributable to timely access to effective interventions that ameliorate prematurity-associated mortality and morbidity such as antenatal administration of corticosteroids and exogenous surfactant therapy, rather than preventing preterm births. However, the societal and healthcare costs to care for survivors with severe morbidity and neurological handicaps remain substantial. Future research should concentrate on the ways to reduce long-term health sequelae and developmental handicaps among survivors of infants born preterm, as well as elucidating the mechanisms and aetiology of preterm births.     

INACTIVATION OF PULMONARY SURFACTANT AND THE TREATMENT OF ACUTE LUNG INJURIES

Inactivation of pulmonary surfactant may be important in acute lung injury and acute respiratory distress syndrome. Treatment of surfactant dysfunction by instilling exogenous surfactants may improve gas exchange and pulmonary mechanics. Surfactants used for treatment vary in their attributes and effects, so when various surfactants are considered for therapy, resistance to inactivation is an important consideration. Animal models of acute lung injury exist in which the relative merits of surfactants can be compared. We hypothesize that the surfactants most resistant to inactivation in vitro will be the ones that are most effective in treatment of animal models of acute lung injury. Surfactants with higher concentrations of surfactant proteins (specifically A, B, and C) are more resistant to inactivation. Nonionic polymers mimic surfactant proteins in preventing surfactant inactivation under some conditions. Adding nonionic polymers to surfactant containing minimal amounts of SP-B and SP-C markedly improves lung function of animals with lung injury. Making surfactants more "inactivation-proof" may improve surfactant therapy of acute lung injuries.     

Surfactant replacement therapy at birth: final analysis of a clinical trial and comparisons with similar trials

A randomized trial of surfactant replacement therapy at birth was conducted at the University of Rochester between June 1983 and November 1985. Thirty-four premature infants, 25 to 29 weeks' gestational age, received a preventilatory dose of a calf lung surfactant extract in saline prepared at the University of Rochester. A control group of 31 infants received a preventilatory dose of saline alone. The major finding of this trial is that a single preventilatory dose of calf lung surfactant extract reduces the severity of the respiratory distress syndrome during the first 24 hours of life. The beneficial effects, however, are not sustained in many infants and diminish after 24 hours of life. The survival rate was 71% in both the control and surfactant-treated groups. There was a lower incidence of pneumothorax in the surfactant-treated group. There were no differences in the incidence of bronchopulmonary dysplasia, patent ductus arteriosus, and intraventricular hemorrhage. No adverse effects of surfactant replacement therapy were identified. Results of this study suggest that multiple postventilatory doses of surfactant will be required for optimal therapy.