Inhaled nitric oxide therapy in the near-term or term neonate with hypoxic respiratory failure

Inhaled nitric oxide (iNO) has altered the management strategy for treating near-term and term infants with hypoxic respiratory failure (HRF). There is a strong relationship between HRF and persistent pulmonary hypertension of the newborn (PPHN). PPHN is characterized by elevated pulmonary resistance, pulmonary vasoconstriction, and altered vascular reactivity. The resulting high pulmonary pressure may lead to HRF, which is defined as a relative deficiency of oxygen in arterial blood and insufficient minute ventilation. iNO improves oxygenation and decreases the need for extracorporeal membrane oxygenation. Although iNO therapy is effective, its efficacy can depend on the fine points of its use and on other care the infant is receiving. Even in NICUs that do not have iNO available, those who care for term infants with HRF must be familiar with its use and know when and how to transfer these infants and how to help families through this difficult period. Because iNO therapy will probably be used more frequently in nurseries over the next few years, more information on the safety and efficacy of its use in the broader neonatal population needs to be available.     

Disease-related response to inhaled nitric oxide in newborns with severe hypoxaemic respiratory failure

Inhaled nitric oxide (iNO) has been shown to improve oxygenation in severe persistent pulmonary hypertension of the newborn (PPHN). However, PPHN is often associated with various lung diseases. Thus, response to iNO may depend upon the aetiology of neonatal acute respiratory failure. A total of 150 (29 preterm and 121 term) newborns with PPHN were prospectively enrolled on the basis of oxygenation index (OI) higher than 30 and 40, respectively. NO dosage was stepwise increased (10–80 ppm) during conventional mechanical or high-frequency oscillatory ventilation while monitoring the oxygenation. Effective dosages ranged from 5 to 20 ppm in the responders, whereas iNO levels were unsuccessfully increased up to 80 ppm in the nonresponders. Within 30 min of iNO therapy, OI was significantly reduced in either preterm neonates (51 ± 21 vs 23 ± 17, P < .0001) or term infants with idiopathic or acute respiratory distress syndrome (45 ± 20 vs 20 ± 17, P < .0001), `idiopathic' PPHN (39 ± 14 vs 14 ± 9, P < .0001), and sepsis (55 ± 25 vs 26 ± 20, P < .0001) provided there was no associated refractory shock. Improvement in oxygenation was less significant and sustained (OI = 41 ± 16 vs 28 ± 18, P < .001) in term neonates with meconium aspiration syndrome and much less (OI = 58 ± 25 vs 46 ± 32, P < .01) in those with congenital diaphragmatic hernia. Only 21 of the 129 term newborns (16%) required extracorporeal membrane oxygenation (57% survival). Survival was significantly associated with the magnitude in the reduction in OI at 30 min of iNO therapy, a gestational age ≥34 weeks, and associated diagnosis other than congenital diaphragmatic hernia. Conclusion, iNO improves the oxygenation in most newborns with severe hypoxaemic respiratory failure including preterm neonates. However, response to iNO is disease-specific. Furthermore, iNO when combined with adequate alveolar recruitment and limited barotrauma using exogenous surfactant and HFOV may obviate the need for extracorporeal membrane oxygenation in many term infants. Received: 24 April 1997 / Accepted in revised form 3 January 1998     

Treatment of persistent pulmonary hypertension of the newborn

OBJECTIVE: To review the medical literature, emphasizing the new scientific advances in the treatment of persistent pulmonary hypertension of the newborn. SOURCES: Literature review using Medline and Cochrane library. SUMMARY OF THE FINDINGS: Persistent pulmonary hypertension of the newborn (PPHN) is characterized by an increase in pulmonary vascular resistance associated with right to left shunt through the foramen ovale or ductus arteriosus, leading to marked hypoxemia and respiratory failure. The balance between the vasoconstrictor (endothelin) and vasodilator (nitric oxide and prostaglandin I2) mediators plays an important role in the regulation of the transition from fetal circulation with high pulmonary vascular resistance to postnatal circulation with low pulmonary vascular resistance. In addition to general management, cardiovascular support, the treatment of the cause of the PPHN, and the use of selective pulmonary vasodilator such as inhaled nitric oxide (iNO) are indicated. Furthermore, the combined therapy with iNO and high-frequency oscillatory ventilation significantly improved the oxygenation of patients who were refractory to iNO therapy and conventional ventilation. The practice of hyperventilation and the administration of nonspecific pulmonary vasodilators (tolazoline) should be avoided. On the other hand, the administration of surfactant to patients with PPHN due to meconium aspiration should be considered. However, if all these therapies fail, extracorporeal membrane oxygenation (ECMO) should be considered as rescue therapy. CONCLUSIONS: The mortality due to PPHN has significantly decreased with the use of new therapies, and the major concern today is the quality of life of these patients, especially in terms of neuropsychomotor development.     

The use of F-arginine and phosphodiesterase inhibitor (dipyridamole) to wean from inhaled nitric oxide

A full-term, female neonate developed acute hypoxemic respiratory failure complicated by persistent pulmonary hypertension of the newborn (PPHN), and responded to high-frequency oscillatory ventilation (HFOV) and inhaled nitric oxide (iNO). Discontinuation of iNO was attempted three times and was followed by severe desaturation due to right-to-left shunt through the patent ductus arteriosus and patent foramen ovale. As a result of iNO dependency state and rebound pulmonary hypertension, the neonate was maintained on iNO therapy for dipyridamole alone was unsuccessful. However, successful discontinuation of iNO therapy was achieved by combination of L-Arginine and dipyridamole. Exogeous NO may lead to down regulation of endogenous NO production, and further lead to rapid hydrolization of cyclic guanosine 3′, 5′ monophosphate (cGMP), the smooth muscle relaxant, by the enzyme phosphodiesterase. Moreover L-Arginine, the precursor for the formation of endogenous NO, has been found to be deficient in neonates with PPHN,^1,2 so we speculated that by inhibiting phosphodiesterase and administrating L-Arginine smooth muscle relaxation occurred, and consequent weaning from iNO was achieved.     

Inhaled NO in the experimental setting

Nitric oxide, a gas molecule, is a unique pharmaceutical agent that can be inhaled and thus delivered directly to the lung. More than a decade of intensive laboratory and clinical investigation has culminated in the current role for inhaled NO as the only selective pulmonary vasodilator for the treatment of persistent pulmonary hypertension of the newborn (PPHN). Not surprisingly, this potent and successful therapy continues to be studied intensively to better define its mechanism of action and role in PPHN treatment. In addition, there remains intense interest in possible new applications for newborns, as well as strategies that may enhance its efficacy. This review describes several areas of current research on amplification of NO signaling in the neonatal pulmonary vasculature, and reviews our current knowledge about the role of iNO in other conditions such as congenital diaphragmatic hernia and congenital heart disease. In addition, laboratory and clinical studies addressing a potential role for iNO as a therapeutic modality for the preterm infant are reviewed.     

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。     

Early functional echocardiogram and inhaled nitric oxide: usefulness in managing neonates born following extreme preterm premature rupture of membranes (PPROM)

Aim: Poor neonatal outcome of preterm premature rupture of membranes (PPROM) <24 weeks' gestational age (GA) is probably a result of abnormalities in both airway and vascular developments, ventilation perfusion mismatch, and possibly persistent pulmonary hypertension of the newborn (PPHN). Perinatal mortality of 50–90% has been reported in the past, with recent literature reporting significant improvement in neonatal survival. We report our 8‐year experience in this group of infants using early diagnostic functional echocardiography (fECHO), high‐frequency ventilation (HFV) and inhaled nitric oxide (iNO). Methods: The obstetric and neonatal databases were searched to identify babies with PPROM (<20 weeks' gestation) or rupture earlier than 25 weeks for more than 14 days. Results: Twenty‐six infants were identified, of whom 20 were admitted to the neonatal intensive care unit (NICU; mean GA 27.8 weeks, mean birth weight (BW) 1207 g). Early echocardiographic data were available in 12/15 infants requiring mechanical ventilation of whom 10 had evidence of PPHN. All infants who received iNO therapy survived to discharge and only two infants died. Survival to discharge was 69% for the whole cohort of infants and 90% for infants admitted to the NICU. In contrast, for the cohort from pre‐iNO and ‐HFV era, the overall survival to discharge was 62% and 66% for the infants admitted to the NICU. Conclusion: Premature infants with PPROM and presumed severe hypoxemic respiratory failure because of hypoplastic lungs often have significant PPHN and may show improvement in oxygenation after treatment with HFV and iNO. Early fECHO results in earlier identification and treatment of infants with PPHN in this high‐risk group.     

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.     

Neonatal persistent pulmonary hypertension treated with milrinone: four case reports

Current standard therapy for persistent pulmonary hypertension of the newborn (PPHN) consists of optimal lung inflation, hemodynamic support and selective vasodilation with inhaled nitric oxide (iNO). However, not all infants will respond. Milrinone, a phosphodiesterase (PDE) III inhibitor, is routinely used in pediatric cardiac intensive care units to improve inotropy and reduce afterload. Although its use in post-operative cardiac failure has been proven in a randomized trial, it has not been reported to be beneficial in PPHN. We report four cases with severe PPHN treated with a combination of iNO and Milrinone. All four cases were unresponsive to therapy including iNO, with a mean oxygenation index (OI) of 40 (standard deviation (SD) 12)) before Milrinone. Substantial improvement in OI (mean of 28; SD 16) was followed by extubation and survival. However, of 4 patients, 2 developed serious intraventricular hemorrhages (IVHs), and 1 had a small IVH. To clarify the risk benefit ratio, of death versus survival with impairment, a randomized controlled trial is needed.     

Inhaled nitric oxide therapy in children

Inhaled nitric oxide therapy improves oxygenation and reduces the need for treatment with extracorporeal membrane oxygenation in term newborns with hypoxaemic respiratory failure and persistent pulmonary hypertension. In this review, we summarise the current status of iNO therapy in the newborn and the potential role of iNO in other paediatric populations.     

Nitric oxide in neonatal transposition of the great arteries

Three newborn infants with transposition of the great arteries (TGA) and intact ventricular septum (IVS) developed postnatal persistent pulmonary hypertension of the newborn (PPHN) and were successfully treated with inhaled nitric oxide (iNO). Intervention with balloon atrial septostomy (BAS) was performed in two of the infants before the iNO treatment, but they continued to be severely hypoxic with metabolic acidosis. However, the iNO immediately improved oxygenation and the clinical condition. The third neonate had a moderately large atrial communication and echocardiographic signs of PPHN. He received iNO before BAS with dramatic clinical improvement, which therefore postponed BAS.

Conclusion: Early diagnosis of PPHN and treatment with iNO may improve final outcome in neonates with TGA and IVS. In the presence of moderately large atrial communication and PPHN, treatment with iNO might be considered before BAS.     

Bedeutung von inhalativem Stickstoffmonoxid (iNO) für die Behandlung der pulmonalen Hypertonie Neugeborener

Nearly 25 years ago it could be shown that nitric oxide is an important modulator of vascular tone. The inhalation of nitric oxide (NO) resulted in a reduction of pulmonary hypertension without affecting the systemic vascular resistance. Up to now, twelve prospective trials randomized about 1300 newborns in the therapy and control groups. It is demonstrated, that infants born at or near term (>34 weeks gestational age) with severe respiratory failure or persistent pulmonary hypertension could benefit from inhaled NO (iNO) by improved oxygenation. In addition the combined incidence of death and need of extracorporeal membrane oxygenation was decreased. However, mortality was not reduced in neonates treated with iNO when compared with controls. Up to date, iNO has not been shown to be a risk-factor for neurodevelopmental sequelae. The survival-rate of premature newborns with a gestational age of <34 weeks was not improved by iNO in three of controlled randomized trials. The rates of bronchopulmonary dysplasia or intraventricular hemorrhage was not affected by iNO. There were 205 premature infants in the therapy and control groups. Newborns at or near to term (>34 weeks) can be treated with iNO in defined cases of severe respiratory illness. In all other cases iNO is still a non-registered therapy which should be applicated in clinical trials or as rescue treatment for infants with severe pulmonary hypertension. The legal implications have to be strictly considered by the responsible physician.     

Inhalation therapy with nitric oxide in pulmonary hypertension: Comparison of preterm infants versus newborn infants

BACKGROUND: Inhaled nitric oxide (iNO) is used as a vasodilator in pulmonary hypertension (PH) of the newborn infant. PATIENTS AND METHODS: Retrospective analysis of patients, who were treated at our department with iNO in the period from 1994-2001. Response was defined as an increase of the paO (2)/FiO (2) Ratio > or = 20 % and/or a decrease of the oxygenation index (OI) >/= 20 % after 2 h (early response), and consecutively after 24 h (late response). The patients were divided into a) primary persistent pulmonary hypertension of the newbom (PPHN), or b) pulmonary hypertension secondary to meconium aspiration syndrome (MAS), sepsis or congenital diaphragmatic hernia (CDH). RESULTS: Between 1994 and 2001 we treated 47 patients with iNO at our neonatal intensive care unit. We included 16 (35 %) preterm infants (GA 34,5 [25 - 37] weeks, GG 2061 [680 - 3410] g) (Median/Range) and 31 (65 %) newbom (GA 40 [38 - 42] weeks, GG 3510 [2550 - 4560] g). 18 (38 %) patients suffered from primary PPHN, 29 (62 %) from secondary PPHN (14 MAS [30 %], 8 sepsis [17 %], 4 CDH [8 %]). 8 (50 %) preterm and 20 (64 %) term infants showed a positive iNO response after 2 h, again 8 (50 %) preterm and 20 (64%) term infants showed a positive iNO response after 24 h. There was neither a significant difference between term and preterm infants at 2 h, nor at 24 h. Between 2 h and 24 h 10 patients changed in their response to iNO. 5 (18 %) patients with early response showed a significant degradation after 24 h, whereas 5 (26 %) of the patients without early response showed a significant improvement of the oxygenation alter 24 h. Alltogether 13 (72 %) patients with PPHN, 8 (57 %) with MAS, 2 (50 %) with CDH, 4 (50 %) with sepsis showed a positive iNO response after 24 h. In regard to the oxygenation parameters at start of iNO-therapy, the patients with early response did not differ from the patient without response (median OI: 20,0 versus 21,8, median paO (2)/FiO (2) Ratio: 59,3 versus 55,0 mmHg at the start of the iNO therapy). CONCLUSION: In regard to iNO response, there was no significant difference between term and preterm infants. Due to the changing response, a positive iNO-response after 2 h had no predictive value for the further prognosis of the oxygenation situation under iNO therapy.     

Low-dose inhaled nitric oxide for neonates with pulmonary hypertension

Objective : Inhaled nitric oxide (iNO) has been shown to cause selective pulmonary vasodilatation and improve ventilation-perfusion matching and may be an important therapeutic option for the treatment of persistent pulmonary hypertension of the newborn (PPHN). We report our experience on the use of iNO in neonates with severe PPHN.
Methodology : Inhaled NO was administered to 10 infants with PPHN and persistent hypoxaemia (meconium aspiration syndrome, n = 9; pneumonia, n = 1) after failure of conventional therapy to improve oxygenation. With the exception of one infant, iNO was commenced at 10 ppm.
Results : After 30 min exposure to iNO, the arterial oxygen tension (PaO₂) rose from a median of 49 mmHg (6.5 kPa) [range 12-82 mmHg (1.6-10.9 kPa)] to 75 mmHg (10 kPa) [range 17-450 mmHg (2.3-60 kPa)] ( P = 0.005), while the median oxygenation index fell (pre-iNO of 37 vs post-iNO 20) ( P = 0.005) and median systemic arterial pressure rose (pre-iNO 46.5 mmHg (6.2 kPa) [range 32-63 mmHg (4.3 to 8.4 kPa vs post-iNO 54.5 mmHg (7.3 kPa) [range 36-74 kPa]) P = 0.005). All infants subsequently continued to receive iNO with the duration of exposure to iNO ranging from 12 to 168 h (median duration 100 h). Three infants died despite showing an initial beneficial response to iNO. The mean duration of intubation for survivors was 11.9 ± 2.6 days. Methaemoglobinaemia and toxic levels of nitrogen dioxide were not seen during iNO administration. Of the seven survivors, 12 month follow up in two infants and 4 month follow up in four infants showed age-appropriate neurodevelopmental skills, with one infant having very mild hearing loss.
Conclusions : Inhaled NO reduces the oxygenation index by improving the PaO₂ and decreasing ventilation pressures, and appears to be clinically useful in severely hypoxaemic infants with PPHN refractory to conventional treatment.     

Innovative neonatal ventilation and meconium aspiration syndrome

Respiratory failure remains a major cause of morbidity and mortality in the neonatal population. Infants with hypoxemic respiratory failure because of meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the newborn (PPHN), and pneumonia/sepsis have a potential for increased survival with extracorporeal membrane oxygenation (ECMO). Other treatment options previously limited to inotropic support, conventional ventilatory management, respiratory alkalosis, paralysis and intravenous vasodilators have been replaced by high-frequency oscillatory ventilation (HFOV), surfactant, and inhaled nitric oxide (iNO). HFOV has been advocated for use to improve lung inflation while potentially decreasing lung injury through volutrauma. Other reports describe enhanced efficacy of HFOV when combined with iNO. Subsequent to studies reporting surfactant deficiency or inactivation may contribute to neonatal respiratory failure exogenous surfactant therapy has been implemented with apparent success. Recent studies have shown that iNO therapy in the neonate with hypoxemic respiratory failure can result in improved oxygenation and decreased need for ECMO. In this article, the authors place in context of a system-based strategy the prenatal, natal and postnatal management of babies delivered through meconium stained amniotic fluid (MSAF) so that adverse outcomes are minimized, and the least number of babies require innovative ventilatory support. At Pennsylvania Hospital, over a six-year period (1995 to 2000), 14.5% (3370/23,175 of live births babies were delivered with MSAF. These data show that 4.6% (155/3370) of babies with MSAF sustained MAS. Overall, 26% (40/155) of babies with MAS needed ventilatory support or 0.17% of all live-births); of these only 20% (8/40 or 0.035% of live births) needed innovative ventilatory support. None died or needed ECMO. These data describe the impact of a system-based approach to prevent and manage adverse outcomes related to MSAF at regional Level III perinatal center.     

Three-year follow up of term and near-term infants treated with inhaled nitric oxide

BACKGROUND: The present study describes the outcome at 3 years in term and near-term infants treated with inhaled nitric oxide (iNO) for persistent pulmonary hypertension of the newborn (PPHN). METHODS: The study population consisted of 18 infants delivered at 34 weeks by best obstetric estimate who were admitted to the neonatal intensive care units with a diagnosis of PPHN. RESULTS: Eighteen infants (mean gestational age 38.5 +/- 2.6 weeks, mean birthweight 3015 +/- 587 g) were treated with iNO. The mean oxygenation index before iNO was 27.2 +/- 15.2. Responses to iNO were classified into three groups: (i) early response in eight infants; (ii) late response in two; and (iii) poor response in eight infants. Three infants died within seven postnatal days. Fifteen surviving infants were followed up to 3 years. The mean developmental scale was 98.4 +/- 9.0. One infant was diagnosed with severe neurodevelopmental disability due to cerebral palsy. Another infant was diagnosed with mild neurodevelopmental disability because of a low developmental scale. No infant showed significant hearing loss. Five infants had reactive airway disease (RAD) at 18 months, these infants required a significantly longer duration of mechanical ventilation in their neonatal period than non-RAD infants (P = 0.02). The frequency of survival with normal neurodevelopmental outcome was significantly higher in the early response group than the late or poor response groups (P = 0.03). CONCLUSION: In iNO-treated PPHN, mortality and neurodevelopmental outcome were associated with response to iNO, and pulmonary outcome was associated with duration of mechanical ventilation.     

Inhaled nitric oxide therapy in preterm infants

According to a number of recently published, randomized controlled trials, treatment of persistent pulmonary hypertension of the newborn (PPHN) by the use of inhaled nitric oxide (iNO) has emerged as an established procedure in neonatology. The situation in premature infants appears to be more complicated than in the term infant. Due to the fact that nitric oxide interferes with platelet aggregation, the risk of intraventricular hemorrhage or its aggravation during iNO therapy is being discussed in a controversial manner. Since most studies are aimed at endpoints like oxygenation parameters, the presently available studies report extremely variable incidences of intraventricular hemorrhages (IVH). Meanwhile two large studies could demonstrate that clinical application of iNO in preterm infants is not associated with an increased incidence of IVH. Further randomized controlled trials of iNO in preterm neonates are highly desirable in order to establish the future role of this therapy and its indications.     

常频通气联合一氧化氮吸入治疗新生儿持续肺动脉高压

目的 探讨常频通气联合一氧化氮吸入(iNO)治疗新生儿持续肺动脉高压(PPHN)的疗效.方法 对22例确诊为PPHN且入院时采取常频通气疗效不满意的患儿给予iNO.NO初始吸入浓度上,20例为(10～20)×10-6,2例为(20～40)×10-6.当SpO2≥93%并已经稳定20min以上,开始下调呼吸机参数,并逐渐下调NO吸入浓度.当NO吸入浓度降至(5～10)×10-6时,再持续2～3h后,若PaO2>55mm Hg(1 mm Hg=0.133 kPa)、SpO2>93%时停止吸入.在NO吸入前和吸入后1～6 h分别进行血气分析,连续记录生命体征、SpO2和监测NO2值等.结果 20例在吸人NO后5～20 min左右SpO2逐渐升高,临床缺氧状态逐步改善.有效率达91%.吸入NO 1～6 h,SpO2、PaO2分别由吸入前的(76.3±13.3)%、(46.4±10.1)mm Hg升到(94.4±2.9)%和(92.8±24.7)mm Hg,FiO2由(0.9±0.1)降至(0.6±0.1),差异均有非常显著性(P<0.001).患儿生命体征平稳,未发现急性合并症.全组治愈18例,治愈率达82%,自动放弃4例.结论 iNO能有效地缓解PPHN患儿的乏氧状态.提高氧分压和治愈率.NO吸入不良反应小、易操作.iNO初始吸人浓度以(10～20)×10-6开始为宜,极个别病例可以(20～40)×10-6开始.     

高频振荡通气、肺表面活性物质联合一氧化氮吸入治疗新生儿低氧性呼吸衰竭的临床研究

目的 探讨用高频振荡通气（HFOV）、肺表面活性物质（PS）联合一氧化氮吸入（iNO）治疗新生儿低氧性呼吸衰竭（HRF）的疗效。方法 116例HRF患儿随机分为三联组和二联组,各58例。三联组采用HFOV、PS联合iNO治疗;二联组采用HFOV 联合iNO治疗。观察两组患儿治疗前及治疗后24 h、48 h的血气分析、PaO2/FiO2（P/F）、OI值和肺动脉压力（PA）的变化,比较不同P/F值、OI值和是否合并PPHN患儿的治疗结局。结果 三联组的上机时间和iNO治疗时间均短于二联组（P<0.01）,且治疗后24 h、48 h的血气指标PaO2 、PaCO2均优于二联组（P<0.01）。三联组合并PPHN的患儿治疗后24 h、48 h的PA值均较二联组下降明显（P<0.01）。在P/F值≤50的病例中,三联组的治愈率优于二联组（P<0.05）;两组死亡者的P/F值均低于存活者（P<0.01）。在OI值≥40的病例中,三联组的治愈率优于二联组（P<0.05）;两组死亡者的OI值均高于存活者（P<0.01）。三联组合并PPHN患儿治愈率优于二联组（P<0.05）。三联组住院时间较二联组缩短（P<0.01）。三联组总治愈率高于二联组（P<0.05）。两组患儿并发症发生率比较差异无统计学意义（P >0.05）。治疗中两组均未监测到严重不良反应。结论 HFOV、PS和iNO三联治疗较HFOV和iNO二联治疗新生儿HRF更为有效,可显著改善氧合,提高患儿的存活率,尤其是为患严重肺部疾病合并PPHN,且P/F值≤50或OI值≥40的病情极危重患儿提供了一个新的治疗手段。