Inhaled nitric oxide in very preterm infants with severe respiratory distress syndrome

AIM: To test the hypothesis that inhaled nitric oxide therapy can decrease the incidence of bronchopulmonary dysplasia and death in preterm infants with severe respiratory distress syndrome; to evaluate the possible predictive factors for the response to inhaled nitric oxide therapy. METHODS: Preterm infants (less than 30 weeks' gestation) were randomized to receive during the first week of life inhaled nitric oxide, or nothing, if they presented severe respiratory distress syndrome. Then, the treated infants were classified as non responders and responders. RESULTS: Twenty infants were enrolled in the inhaled nitric oxide therapy group and 20 in the control group. Bronchopulmonary dysplasia and death were less frequent in the inhaled nitric oxide group than in the control group (50 vs. 90%, p=0.016). Moreover, nitric oxide treatment was found to decrease as independent factor the combined incidence of death and BPD (OR=0.111; 95% C.I. 0.02-0.610). A birth weight lower than 750 grams had a significant predictive value for the failure of responding to inhaled nitric oxide therapy (OR 12; 95% C.I. 1.3-13.3). CONCLUSION: Inhaled nitric oxide decreases the incidence of bronchopulmonary dysplasia and death in preterm infants with severe respiratory distress syndrome. Birth weight may influence the effectiveness of inhaled nitric oxide therapy in promoting oxygenation improvement in preterm infants.     

Nitric oxide-still no consensus

When NO became available for clinical use, it seemed to hold enormous promise for newborn infants with lung disease. With regard to the term and near-term infant, the role of NO seems satisfactorily defined: Near-term and term infants with hypoxic respiratory failure unresponsive to current therapy, excluding infants with diaphragmatic hernia, should have a trial of inhaled nitric oxide. In the preterm infant, the situation is less clear with, as yet, no specific indication identified.     

Inhaled nitric oxide to prevent bronchopulmonary dysplasia in preterm neonates

Bronchopulmonary dysplasia is a chronic lung disease that affects premature infants and contributes to their morbidity and mortality. With the advent of prenatal steroids and postnatal exogenous surfactant and less aggressive respiratory support, premature infants can develop chronic oxygen dependency without even acute respiratory distress. This 'new bronchopulmonary dysplasia' could be the result of impaired postnatal growth. Several experimental studies have suggested a possible role of the vascular endothelial growth factor/nitric oxide (VEGF/NO) pathway in restoring pulmonary angiogenesis and enhancing distal lung growth. The results of the clinical studies are, however, inconclusive, and it is currently unclear which subsets of premature infants might benefit from inhaled nitric oxide. Besides, severe intracranial haemorrhage and/or cystic periventricular leucomalacia may affect the most immature babies, many of whom are spared from severe initial respiratory disease. Recently, inhaled nitric oxide was shown to significantly decrease the incidence of these neurological events, and to improve the long-term outcome in a few clinical trials. At times neuroprotective, at times neurotoxic, nitric oxide is capable of divergent effects depending upon the extent of cerebral damage, the redox state of the cell, and the experimental model used. Recently, our group found that inhaled nitric oxide had remote effects including angiogenesis and maturation on the developing brain in rodent pups. Thus, we await the results of the recently completed randomised clinical trial of inhaled nitric oxide to prevent bronchopulmonary dysplasia (the European Nitric Oxide or 'EUNO' trial) where, besides the primary endpoint of chronic oxygen dependency reduction at 36 weeks' postconceptional age, long-term lung and brain will be followed-up until 7 years of age.     

Neonatal acute respiratory failure

Acute respiratory failure is the most common problem seen in the preterm and term infants admitted to neonatal intensive care units. In preterm infants, the most common cause of acute respiratory failure is respiratory distress syndrome caused by surfactant deficiency. Acute respiratory failure in term and near term infants is usually a result of meconium aspiration syndrome, sepsis, pulmonary hypoplasia, and primary pulmonary hypertension of the newborn. The response to various methods of treatment may vary, depending on the severity of respiratory failure and the cause of the acute respiratory failure. We reviewed the evidence for efficacy and current utilization of newer treatment modalities, including exogenous surfactant administration, high frequency ventilation, inhaled nitric oxide therapy, antenatal steroids for the prevention of respiratory distress syndrome, and use of postnatal steroids for the prevention of chronic lung disease.     

吸入一氧化氮治疗早产儿低氧性呼吸衰竭的临床研究

目的探讨吸入一氧化氮（iNO）治疗早产儿低氧性呼吸衰竭的疗效及安全性。方法将2007年3月至2010年3月本院收治的因呼吸窘迫综合征引起低氧性呼吸衰竭,且胎龄〈34周的早产儿随机分为干预组（iNO组）和对照组。两组均采用基础治疗及机械通气等常规治疗。iNO组在常规治疗基础上加用NO吸入治疗,NO吸入浓度从5ppm开始,最高20ppm,持续吸入时间24～72h,同时动态监测主要血气指标,包括pH、PaO2、PaCO2、PaO2/FiO2、SaO2、动脉-肺泡血氧分压差[（A-a）PO2]以及氧合指数（OI）的变化。结果 iNO组（n=16）与对照组（n=19）比较,治疗后12、24、48h及72h血气指标明显改善（P均〈0.05）,其中24h最明显[pH（7.4±0.1）比（7.2±0.1）,PaO2（68.7±10.1）mmHg比（51.6±11.3）mmHg,PaCO2（38.6±8.2）mmHg比（48.4±12.1）mmHg,PaO2/FiO2（206.8±32.5）mmHg比（165.2±22.7）mmHg,SaO2（0.93±0.07）比（0.81±0.09）,（A-a）PO2（227.4±126.8）mmHg比（346.7±160.2）mmHg,OI（5.8±3.5）比（9.2±6.2）]。iNO组气道NO2浓度〈1ppm,出血时间正常,死亡数及并发症的发生未增加。结论 iNO治疗早产儿低氧性呼吸衰竭能够显著改善氧合功能,纠正高碳酸血症和酸中毒,并未增加不良反应的发生。     

Adjunct pharmacotherapy in acute lung disease in children

Mechanical ventilation, while accepted as standard therapy for critically ill infants and children with respiratory failure, has significant morbidity and mortality. While recent emphasis on low tidal volume ventilation and low airway pressures may result in decreased lung stretch and limit lung disease, adjunctive therapies have been tried to reduce the stressors of mechanical ventilation. Therapies included inhaled nitric oxide, heliox and surfactant. There are compelling physiological reasons why these drugs may be of benefit in these patients. However, our understanding of their role is hindered by studies with small numbers of patients and its use in diseases with varied pulmonary pathology. Studies have shown potential for benefit of inhaled nitric oxide in newborns with hypoxemic respiratory failure and pulmonary hypertension, surfactant in respiratory distress syndrome in preterm neonates and heliox in severe upper airway obstruction. However, the use in other respiratory conditions has led to mixed results and hence paucity of firm recommendations.     

Recent research on inhaled nitric oxide in preterm infants with a gestational age of <34 weeks北大核心CSCD

一氧化氮作为血管平滑肌细胞舒张的信使分子,吸入一氧化氮（inhaled nitric oxide, iNO）能够扩张肺部血管,降低肺血管阻力,从而降低肺动脉压力,而对体循环压力没有影响。国内外指南均推荐iNO用于足月儿和晚期早产儿,已证实对足月儿和晚期早产儿持续肺动脉高压和低氧性呼吸衰竭具有明显效果。但是近年来的研究显示,iNO用于胎龄<34周早产儿的超适应证治疗越来越多。该文就iNO治疗胎龄<34周早产儿的有效性、安全性、应用时机、剂量、撤离方式和与血管活性药物联合使用的国内外研究进展作一综述,以期为临床应用提供参考。     

Management of respiratory failure in the preterm infant

Respiratory failure is common in the preterm infant. Support of the infant with oxygen, positive pressure, and assisted ventilation are among the commonest interventions required in neonatal care. This article is an overview of many features of respiratory care of the preterm infant, including the goals of therapy, continuous positive airways pressure (CPAP), non-invasive ventilation, various modes of 'conventional' ventilation, high frequency ventilation and inhaled nitric oxide use. The proven benefits and limitations of various interventions are discussed, and areas requiring further investigation are highlighted. Although it is clear that respiratory support is life-saving, there is a lack of good evidence to choose one mode of support over another. Many prospective trials have been performed which, in general, have failed to demonstrate a significant additional benefit of any newer mode of ventilation over conventional time-cycled pressure limited ventilation. Many of the currently available modes of respiratory support have never been subjected to adequate study. Newer modes of respiratory support including such innovations as volume targeted ventilation, pressure support ventilation, and inhaled nitric oxide use in the preterm, require further investigation prior to their adoption for routine clinical use.     

早产儿支气管肺发育不良防治新理念

尽管新生儿医学在呼吸领域已取得显著进展,但支气管肺发育不良（BPD）在早产儿的发病率仍相当高。文章重点探讨近期研究对于无创通气技术作为极早早产儿的一种治疗模式的重要性的评估和对BPD发生率的影响。同时也探讨了与早产儿肺转归相关的其他治疗策略包括允许性高碳酸血症及糖皮质激素、支气管扩张剂、咖啡因、吸入一氧化氮的应用。     

Inhaled nitric oxide therapy in premature newborns

PURPOSE OF REVIEW: Inhaled nitric oxide therapy reduces the need for extracorporeal membrane oxygenation in near-term and term newborns with hypoxemic respiratory failure and persistent pulmonary hypertension, and is now a standard of care for this population. There is also considerable interest, however, in the potential role of inhaled nitric oxide in premature newborns with hypoxemic respiratory failure. The purpose of this review is to summarize the results of clinical trials of inhaled nitric oxide in premature newborns, with particular emphasis on studies published in the last 12 months. RECENT FINDINGS: Several trials of inhaled nitric oxide in premature newborns with respiratory failure have been published in the last year. Interpretation of the findings is complicated by differences in the severity of illness of the study populations, the trial designs, and relevant outcome measures recorded. SUMMARY: Trials of inhaled nitric oxide in premature newborns have yielded conflicting results to date, and the role of inhaled nitric oxide therapy in this population remains controversial. The largest trials of inhaled nitric oxide therapy in premature newborns have completed enrollment but have yet to be published. The results of these ongoing trials will help clarify the potential risks and benefits of inhaled nitric oxide therapy in the premature newborn.     

Use of inhaled nitric oxide in the preterm infant

PURPOSE OF REVIEW: Inhaled nitric oxide is established therapy for term infants with hypoxemic respiratory failure. Laboratory studies demonstrate that inhaled nitric oxide improves lung function and morphology in animal models of bronchopulmonary dysplasia, creating a rationale for clinical studies in premature infants. Four large multicenter randomized trials have now completed enrollment, and one trial has reported neurodevelopmental outcomes at 18-22 months. The purpose of this review is to summarize the results of the most recent preclinical studies and clinical trials. RECENT FINDINGS: In 2006, short-term outcomes from two large multicenter randomized trials were published. These studies differed in their target population and study design. Early use of inhaled nitric oxide was associated with a decrease in brain injury, and decreased chronic lung disease in infants over 1000 g. Inhaled nitric oxide use in older infants (7-21 days) was associated with decreased chronic lung disease, particularly if started early. SUMMARY: Neurodevelopmental outcomes after discharge are still needed from three large multicenter randomized trials. These results will help confirm the long-term implications of the benefits reported in the two most recent trials.     

Nitric oxide treatment and acute pulmonary inflammatory response in very premature infants with intractable respiratory failure shortly after birth

Aim: Premature infants with respiratory failure and early-onset pneumonia have low inducible nitric oxide synthase (NOS2) and no evidence of nitric oxide (NO) toxicity. However, inhalation of NO may not be indicated in sepsis because excessive NO generation has been reported. This prospective study was designed to test the hypothesis that inhaled NO is effective in a select group of small premature infants and that the responsiveness to NO is associated with low NOS2 enzyme. Methods: 246 very low birthweight infants (birthweight 31500 g, VLBW) were screened for severe, intractable respiratory failure (oxygenation index 340, arterial-alveolar ratio for oxygen tension 30.10) that does not respond to two doses of surfactant within 5 h from birth. Infants with severe cardiac failure or a bleeding disorder were excluded. Five of the nine eligible cases received inhaled NO. They all had prolonged rupture of foetal membranes, early-onset pneumonia and persistent pulmonary hypertension. Results: All five responded strikingly, survived and appeared normal in follow-up. Airway specimens during the first day of life revealed very low NOS2, interleukin-13 and surfactant protein A, compared with VLBW infants who had no acute infection despite histological chorioamnionitis. In early-onset pneumonia, NOS2 and other inflammatory mediators increased first during the recovery 1-2 d after birth. Conclusion: VLBW infants with progressive respiratory failure and infection at birth have deficient pulmonary NOS2 and cytokine response. After surfactant therapy, these infants responded strikingly to inhaled NO. An acute pulmonary inflammatory response may contribute to respiratory adaptation in early-onset pneumonia.     

Ureaplasma urealyticum respiratory infection in newborn infants]

The neonatal respiratory infection by Ureaplasma urealyticum is rare, but it could represent a major risk for the newborn infants. CASE REPORTS: A term newborn infant presented an early respiratory distress with persistent pulmonary hypertension, requiring artificial ventilation and inhaled nitric oxide therapy. Tracheal aspirates were positive for Ureaplasma urealyticum, although his mother was not contamined. A preterm newborn infant (gestational age: 33 weeks) presented a severe respiratory distress, requiring mechanical ventilation. The tracheal aspirates we positive for Ureaplasma urealyticum, as well as his mother's cervico-vaginal swab. Both recovered thanks to antibiotics (intravenous macrolid during ten days). The outcome was favorable for both babies. CONCLUSION: Neonatal infection due to Ureaplasma is serious. The clinical diagnosis is difficult, recalling group B streptococcal infection. Clinical aggravation, despite antibiotics associated with negative bacteriological standard detection, leads one to evoke this diagnosis and perform specific bacteriological cultures.     

Relationship of vitamin A (retinol) status to lung disease in the preterm infant

Plasma concentrations of retinol and retinol-binding protein were measured at birth in 91 preterm infants. In 64% of these babies retinol values were less than 20 micrograms/dl, suggestive of vitamin A deficiency. Forty-seven of these infants were observed with sequential measurements of retinol and retinol binding protein through 21 days of age. In babies with respiratory distress syndrome retinol values were similar to those in babies without respiratory distress syndrome. The retinol binding protein levels were lower on the third day of life in babies with respiratory distress syndrome. Babies who developed bronchopulmonary dysplasia had lower concentrations of retinol at birth (P less than 0.05) and on day 21 (P less than 0.05) than did babies who did not develop bronchopulmonary dysplasia, despite receiving recommended intakes of vitamin A. Many preterm infants are deficient in vitamin A at birth, and failure to correct this deficiency may contribute to the development of chronic lung disease.     

Outcome predictors in nitric oxide treated preterm infants

Our aim was to identify factors predictive of death in preterm infants in whom inhaled nitric oxide was administered in response to poor oxygenation (oxygenation index ≥15). Of the 23 (median gestational age 28 weeks, range 24–36) infants consecutively so treated, 15 died. Non-survival was commoner in infants with air leaks (12 of 12, P < 0.002) and/or a change in their oxygenation index of less than 30% in response to inhaled nitric oxide administration (P < 0.05). Conclusion In preterm infants given inhaled nitric oxide because of poor oxygenation, a diagnosis of airleak and a lack of initial response are predictive of death. Received: 18 June 1998 / Accepted in revised form: 4 November 1998     

早产儿机械通气治疗的研究进展

机械通气在治疗早产儿严重并发症尤其是呼吸系统疾病中起着非常重要的作用.随着产前及新生儿期护理技术和治疗策略的改进,早产儿生存率逐年增加,支气管肺发育不良的发生率也在持续增加,严重影响早产儿的预后.近年新生儿学者在非侵袭性呼吸支持技术对减轻肺损伤、降低早产儿并发症方面进行了许多有益的探索.本文就不同机械通气模式在治疗早产儿呼吸衰竭中的作用及肺保护策略在降低早产儿肺损伤中的应用现状进行综述.     

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.     

Nitric oxide levels in preterm and term infants and in premature infants with bacteremia

OBJECTIVE: To determine the serum nitric oxide levels in healthy neonates and in infants with bacteremia. METHODS: We performed a prospective study in a tertiary neonatal intensive care unit. The serum nitric oxide levels were measured in all infants at birth (basal) and in the infected neonates also on the first 2 days of bacteremia. RESULTS: Thirty-three neonates (10 term, 23 preterm) were included. Eleven preterm infants (mean gestational age 27 weeks) had bacteremia. The main blood culture isolates included coagulase-negative staphylococci (n=4), Klebsiella pneumoniae (n=3), and Escherichia coli (n=3). The serum nitric oxide levels increased during infection in 10 infants (p <0.008). The mean nitric oxide level before infection was 44 microM and during infection 96 microM (p=0.008). In the healthy babies, the mean nitric oxide level was 26 microM in those with a gestational age <27 weeks, 44 microM in those born between 28 and 36 weeks of gestation, and 63 microM in term infants. CONCLUSIONS: Bacteremic preterm infants produce significantly higher amounts of nitric oxide. The basal nitric oxide levels at birth may be correlated with gestational age.     

Combination therapy for life-threatening pulmonary hypertension in a premature infant: first report on bosentan use

Premature infants with preterm premature rupture of membranes (PPROM) are at high risk of severe respiratory failure because of lung hypodysplasia associated with persistent pulmonary hypertension of the newborn (PPHN). We describe the clinical course of a 28-week gestation infant with PPROM from the 20th week and prolonged oligohydramnios before delivery, who developed refractory hypoxia treated with oral bosentan as adjunct therapy to inhaled nitric oxide (iNO) and oral sildenafil. Conclusion Our experience suggests that bosentan can be used in the premature infant with PPHN after PPROM. To the best of our knowledge, this is the first report of bosentan treatment in a premature infant.     

A critical appraisal of a systematic review: Sokol J, Jacob SE, Bohn D: Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults. Cochrane Database Syst Rev 2003 (1): CD002787.

OBJECTIVE: To review the findings and discuss the implications of the use of inhaled nitric oxide for acute hypoxemic respiratory failure in patients beyond the neonatal period. DESIGN: A critical appraisal of a systematic review. Findings: The authors conducted a systematic review with meta-analysis to determine the effect of inhaled nitric oxide on clinical outcomes of patients with acute hypoxemic respiratory failure. The outcomes included mortality, changes in oxygenation, ventilator-free days, duration of intensive care and hospital stays, and adverse effects. It was a high-quality systematic review provided with strict entry criteria, an extensive literature search, and thorough critical appraisals. Only five trials (n = 623) met entry criteria. Inhaled nitric oxide had no effect on mortality in studies without crossover of treatment failures to open-label inhaled nitric oxide (relative risk, 0.98; 95% confidence interval, 0.66-1.44). A statistically significant improvement in oxygenation was observed in one study. The effect, however, was observed only in the first 4 days of treatment and was not clinically significant. The heterogeneity in study findings precluded meta-analyses of other clinical outcomes and adverse effects in the selected studies. CONCLUSIONS: There is insufficient evidence to determine whether inhaled nitric oxide is beneficial or harmful for acute hypoxemic respiratory failure in children and adults. While awaiting further studies to prove its benefit, inhaled nitric oxide should not either be recommended as a standard management or excluded for the treatment of acute hypoxemic respiratory failure.