Contribution of pulmonary surfactant with inhaled nitric oxide for treatment of pulmonary hypertension

BACKGROUND: Combined therapy of inhaled nitric oxide (iNO) with pulmonary surfactant replacement was reported to improve oxygenation in patients or animal models of persistent pulmonary hypertension of the newborn with pulmonary surfactant deficiency lung. To evaluate the potential of iNO for the treatment of persistent pulmonary hypertension of the newborn, pulmonary arterial pressure (PAP) was measured during iNO before and after pulmonary surfactant replacement in an animal model of pulmonary hypertension with surfactant deficiency. METHODS: Seven newborn piglets were injected with L-nitro-arginine-methylester to produce an animal model of pulmonary hypertension. After PAP increased, iNO (30 p.p.m.) was introduced. Then iNO was stopped, and animals were subjected to lung lavage with saline. After recording the effect of iNO, all animals then received exogenous pulmonary surfactant installation. After surfactant treatment, iNO was again introduced. RESULTS: Pulmonary arterial pressure and systemic arterial pressure were increased significantly by >30% after infusion of L-nitro-arginine-methylester. During iNO only PAP was reduced significantly. Respiratory system compliance decreased significantly after lung lavage, and increased significantly after pulmonary surfactant replacement with concomitant increase of PaO2. In contrast, significant reduction of PAP with iNO before and after pulmonary surfactant replacement were also observed. The reduction ratios of PAP under each condition were 75.2 +/- 7.4%, 81.3 +/- 3.1%, and 79.1 +/- 5.3%, respectively (not significant among conditions). CONCLUSION: These results suggest that iNO is still a potent pulmonary arterial vasodilator even under pulmonary surfactant deficiency in an animal model of pulmonary hypertension.     

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.     

Variable oxygenation response to inhaled nitric oxide in severe persistent pulmonary hypertension of the newborn

The causes of variable responsiveness to inhaled nitric oxide (NO) in Persistent Pulmonary Hypertension of the Newborn (PPHN) are unknown. The changes in the severity of respiratory failure after the onset of inhaled NO (maximal dose 20ppm) were studied in 13 consecutive neonates with severe PPHN. Response was defined as a sustained decrease of alveolar-arterial oxygen gradient (AaD0₂) by > 20%, or a decrease in oxygenation index (OI) by > 40%. Six neonates had a rapid response within 30min, three had an intermediate response within 8h, and three had a delayed response within 12 h after the onset of NO. Three infants with birth asphyxia responded rapidly to inhaled NO. One infant with sepsis did not respond, and two with suspected sepsis had a delayed response. The infants with Meconium Aspiration Syndrome and idiopathic PPHN had a variable response time. Twelve neonates required 4 to 14 days of mechanical ventilation and survived. Infants with PPHN may benefit from a trial of inhaled NO therapy that exceeds 30min. The variability of the response time to inhaled NO is likely to be multifactorial and dependent on the disease process associated with PPHN.     

Developmental outcomes in persistent pulmonary hypertension treated with nitric oxide therapy

Background:  The aim of the present study was to assess 3 year auditory and neurodevelopmental outcomes of persistent pulmonary hypertension of the newborn (PPHN) before and after introducing inhaled nitric oxide (i-NO) therapy, and to detect the clinical factors affecting poor outcome.
Methods:  A retrospective historical cohort study of 26 survivors with PPHN with oxygenation index (OI) ≥25 (13 infants without i-NO therapy, control group; 13 with i-NO therapy, i-NO group) was performed. Auditory brainstem response (ABR) at 6 and 12 months and neurodevelopmental outcomes at 3 years of age were evaluated.
Results:  ABR abnormalities at 6 months were observed in one infant in the i-NO group and six in the control group ( P  = 0.04). At 1 year, one infant in the i-NO group and two of six infants in the control group still had ABR abnormality. In the i-NO group, two children had abnormal neurodevelopmental outcomes, as compared with five children in the control group at 3 year follow up. Two children in the control group and no children in the i-NO group had hearing loss at 3 years of age. Hypocapnea ( P  = 0.04) and elevated creatine phosphokinase ( P  = 0.04) were found to be most predictive for neurodevelopmental abnormality.
Conclusion:  Avoidance of excessive hypocapnea via introduction of i-NO therapy might reduce both ABR and neurodevelopmental abnormalities.     

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.     

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     

Inhaled nitric oxide and extracorporeal membrane oxygenation in persistent pulmonary hypertension of the newborn

Persistent pulmonary hypertension of the newborn (PPHN) may occasionally require an invasive treatment with extracorporeal membrane oxygenation (ECMO). Inhaled nitric oxide (NO) has recently been introduced as a selective pulmonary vasodilator for treatment of PPHN. We describe a case of PPHN in which neither inhaled NO nor ECMO was effective in reversing pulmonary hypertension. The clinical course of the patient suggested a potential role of NO inhalation in predicting the outcome of ECMO treatment for PPHN.     

一氧化氮治疗新生儿持续肺动脉高压42例疗效观察

目的　探讨一氧化氮 (NO)吸入疗法治疗新生儿持续肺动脉高压 (PPHN)的疗效。方法　对 4 2例新生儿PPHN和呼吸衰竭患儿按解剖性血管梗阻和肺血管痉挛分为Ⅰ组和Ⅱ组 ,分别在呼吸机机械通气情况下 ,将NO气源加入呼吸机环路中 ,NO质量浓度从 2 0× 10 -6mg/L(2 0 ppm)开始 ,每经 15～ 30min无效者增加 (5～10 )× 10 -6mg/L(5～ 10 ppm) ,达到 4 0× 10 -6mg/L仍无效者停用。有效者经予吸入较高浓度NO 6h后 ,每 30min降低NO质量浓度 (5～ 10 )× 10 -6mg/L ,如患儿的PaO2 下降不超过 15 % ,可降至 6× 10 -6mg/L后维持 36～ 72h ,治疗时观察全身氧合情况的变化 ,监测心率、血压、吸入前后血高铁血红蛋白 (MHb)定量及凝血功能。结果　Ⅱ组 33例患儿中 2 7例 (81 82 % )治疗后氧合情况显著改善 ;Ⅰ组治疗后氧合情况无改善。两组心率、血压、凝血功能无明显改变 ,MHb定量的改变无临床意义。结论　低浓度短期NO吸入疗法治疗肺血管痉挛所致持续肺动脉高压有显著疗效 ,且未见明显副作用 ,但对解剖性血管梗阻所致持续肺动脉高压疗效欠佳。     

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.     

Early risk factors for death in neonates with persistent pulmonary hypertension of the newborn treated with inhaled nitric oxide北大核心CSCD

Objective To evaluate the early risk factors for death in neonates with persistent pulmonary hypertension of the newborn (PPHN) treated with inhaled nitric oxide (iNO). Methods A retrospective analysis was performed on 105 infants with PPHN (gestational age ≥34 weeks and age <7 days on admission) who received iNO treatment in the Department of Neonatology, Children's Hospital of Nanjing Medical University, from July 2017 to March 2021. Related general information and clinical data were collected. According to the clinical outcome at discharge, the infants were divided into a survival group with 79 infants and a death group with 26 infants. Univariate and multivariate Cox regression analyses were used to evaluate the risk factors for death in infants with PPHN treated with iNO. The receiver operating characteristic (ROC) curve was used to calculate the cut-off values of the factors in predicting the death risk. Results A total of 105 infants with PPHN treated with iNO were included, among whom 26 died (26/105, 24.8%). The multivariate Cox regression analysis showed that no early response to iNO (HR=8.500, 95%CI: 3.024-23.887, P<0.001), 1-minute Apgar score ≤3 points (HR=10.094, 95%CI: 2.577-39.534, P=0.001), a low value of minimum PaO2/FiO2 within 12 hours after admission (HR=0.067, 95%CI: 0.009-0.481, P=0.007), and a low value of minimum pH within 12 hours after admission (HR=0.049, 95%CI: 0.004-0.545, P=0.014) were independent risk factors for death. The ROC curve analysis showed that the lowest PaO2/FiO2 value within 12 hours after admission had an area under the ROC curve of 0.783 in predicting death risk, with a sensitivity of 84.6% and a specificity of 73.4% at the cut-off value of 50, and the lowest pH value within 12 hours after admission had an area under the ROC curve of 0.746, with a sensitivity of 76.9% and a specificity of 65.8% at the cut-off value of 7.2. Conclusions Infants with PPHN requiring iNO treatment tend to have a high mortality rate. No early response to iNO, 1-minute Apgar score ≤3 points, the lowest PaO2/FiO2 value <50 within 12 hours after admission, and the lowest pH value <7.2 within 12 hours after admission are the early risk factors for death in such infants. Monitoring and evaluation of the above indicators will help to identify high-risk infants in the early stage. © 2022 Xiangya Hospital of CSU. All rights reserved.     

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     

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.     

钙敏感受体对持续性肺动脉高压新生小鼠内皮型一氧化氮合酶及一氧化氮的影响

目的 探讨钙敏感受体（CaSR）在持续性肺动脉高压（PPH）新生小鼠模型中对内皮型一氧化氮合酶（eNOS）表达及一氧化氮（NO）浓度的影响。方法 将80只新生C57BL/6小鼠随机分为对照组、PPH组、激动剂组和抑制剂组。对照组小鼠暴露于空气中,PPH组、激动剂组和抑制剂组小鼠暴露于12%的氧浓度中。激动剂组和抑制剂组分别腹腔注射CaSR激动剂（GdCl₃）16 mg/kg、CaSR抑制剂（NPS2390）1 mg/kg,PPH组和对照组以生理盐水替代,共14 d。采用苏木精-伊红染色检测各组小鼠肺泡和肺血管变化;采用Westernblot、qRT-PCR和免疫组化检测各组小鼠肺组织中eNOS蛋白、mRNA的表达;采用ELISA法分别检测肺组织匀浆中脑利钠肽（BNP）及NO的含量。结果 与对照组相比,PPH组和激动剂组肺泡平均内衬间隔、肺小动脉血管壁厚度、右心室与左心室壁厚度比（RV/LV）及BNP浓度均明显增大,径向肺泡计数明显减少（P < 0.05）;除RV/LV外,上述指标在抑制剂组均较PPH组和激动剂组有所改善（P < 0.05）。与对照组相比,eNOS蛋白、mRNA表达量及NO浓度在PPH组明显增高,在激动剂组中表达水平进一步增加,而在抑制剂组中表达减少（P < 0.05）。结论 CaSR可能通过影响eNOS的表达和NO浓度在新生小鼠PPH发病中发挥重要作用。     

常频通气联合一氧化氮吸入治疗新生儿持续肺动脉高压

Objective To evaluate the effects of inhaled nitric oxide (iNO) therapy combined with conventional ventilation in the infants with persistent pulmonary hypertension of the newborn (PPHN).Methods NO inspiration was added for 22 infants with PPI-IN ventilated with FiO2≥0. 9,PIP≥30 cm H2O,PEEP≥3 cm H2O,RR≥50 bpm for 4～6 hours,with SpO2 still < 90% and PaO2 <55 mm Hg. The iNO concentration started at (10～20)×10-6 for 20 infants,and (20～40)×10-6 for 2 infants. The iNO would be stopped when the concentration reached 40×10 -6 without any sign of improvement. The SpO2 ,blood gas analyses,blood pressure, heart rate and NO: concentration were moraitored during therapy and the resulting data compared to readings before administration of int. Results Clinical situation were significantly improved in 20 (91%) of the infants with SpO2 gradually going up after 10 minutes of int. Before iNO,mean Fit2 was 0. 9±0. 1 ,SpO2 was(76. 3±13.3)% ,and Pat2 was (46. 4±10. 1 ) man Hg. From 1 to 6 hours after iNO,SpO2 increased to(95. 1±3.8)% ,Pat2 increased to(92. 8±24.7) mm Hg,FiO2 decreased to 0.6 s0. 1.The differences were significant (P < 0. 01 ). Eighteen of 22 (82%) infants surviving. Conclusion iNO is effective in alleviating PPHN in infants. There are no remarkable side effects. It is more beneficial to start the iNO concentration at (10～20)×10-6 while some infants may need NO concentration at up to (20～40)×10-6.     

常频通气联合一氧化氮吸入治疗新生儿持续肺动脉高压

Objective To evaluate the effects of inhaled nitric oxide (iNO) therapy combined with conventional ventilation in the infants with persistent pulmonary hypertension of the newborn (PPHN).Methods NO inspiration was added for 22 infants with PPI-IN ventilated with FiO2≥0. 9,PIP≥30 cm H2O,PEEP≥3 cm H2O,RR≥50 bpm for 4～6 hours,with SpO2 still < 90% and PaO2 <55 mm Hg. The iNO concentration started at (10～20)×10-6 for 20 infants,and (20～40)×10-6 for 2 infants. The iNO would be stopped when the concentration reached 40×10 -6 without any sign of improvement. The SpO2 ,blood gas analyses,blood pressure, heart rate and NO: concentration were moraitored during therapy and the resulting data compared to readings before administration of int. Results Clinical situation were significantly improved in 20 (91%) of the infants with SpO2 gradually going up after 10 minutes of int. Before iNO,mean Fit2 was 0. 9±0. 1 ,SpO2 was(76. 3±13.3)% ,and Pat2 was (46. 4±10. 1 ) man Hg. From 1 to 6 hours after iNO,SpO2 increased to(95. 1±3.8)% ,Pat2 increased to(92. 8±24.7) mm Hg,FiO2 decreased to 0.6 s0. 1.The differences were significant (P < 0. 01 ). Eighteen of 22 (82%) infants surviving. Conclusion iNO is effective in alleviating PPHN in infants. There are no remarkable side effects. It is more beneficial to start the iNO concentration at (10～20)×10-6 while some infants may need NO concentration at up to (20～40)×10-6.     

吸入一氧化氮治疗先天性心脏病术后肺动脉高压

目的评价吸入一氧化氮(NO)在左向右分流性先天性心脏病(先心病)术后严重肺动脉高压的治疗效果。方法81例先天性心脏病患儿术后予以吸入NO治疗,治疗指征:肺/体动脉收缩压之比(Pp/Ps)>0.5,氧合指数(PaO2/FiO2)<150mmHg,传统降肺动脉压治疗无效。初始吸入浓度为20×10-6vol/vol,根据血气及血流动力学情况进一步调整,不超过45×10-6vol/vol,同时监测二氧化氮(NO2)浓度及高铁血红蛋白浓度。结果81例吸入NO治疗后肺动脉压力明显下降,从(54.0±15.8)mmHg降至(45.7±12.8)mmHg(P<0.01),而体动脉压力无明显变化,同时PaO2/FiO2明显改善,从100.6±40.1升至135.8±29.7(P<0.01)。监测NO2浓度<1×10-6vol/vol,高铁血红蛋白浓度<2%。未发现明显出血及其他不良反应。结论吸入NO治疗可以安全有效地降低肺动脉压力,提高氧合指数,从而改善先心病合并肺动脉高压的预后。     

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 via nasopharyngeal tube in an infant with end-stage pulmonary hypertension

Abstract The delivery of nitric oxide (NO) via a nasopharyngeal tube is an alternative to endotracheal intubation. A male infant with end-stage pulmonary hypertension (PH) due to a severe hypoplastic lung developed a PH crisis on day 145 and received NO inhalation via a nasopharyngeal tube. Clinical improvement was maintained for 7 days with18–22ppm NO inhalation. The patient remained in close physical contact with his parents without the use of sedation. Blood methemoglobin levels remained below 1%. The environmental NO levels were less than 0.06 ppm and NO₂ less than 0.3 ppm throughout the treatment, well within the safety margin. On day 152, the patient succumbed to hypoxemia and heart failure. The use of a nasopharyngeal NO delivery system without sedation, as an alternative to endotracheal intubation with sedation, was a practical method in treating a patient with PH while maintaining a certain quality of life for the patient and the family.