Nitrogen dioxide production in a nitric oxide inhalation system using the Servo Ventilator 900C

During nitric oxide (NO) inhalation therapy, toxicity may be produced by the reactive metabolite nitrogen dioxide (NO₂). The purpose of the present study was to determine the NO₂ concentration in a NO inhalation system used for respiratory failure in children at relatively low concentrations of NO (< 20 ppm). The production of NO₂ in the NO inhalation system using the Servo Ventilator 900C connected to the test lung under each of 30 combinations of NO concentrations (0, 4, 8, 12, 16, and 19 ppm) and inspired oxygen (O₂) concentrations (21, 40, 60, 80, and 100%). Pressure controlled ventilation was used with a respiratory rate of 20 breaths/min. NO and NO₂ measurements were obtained on the inspiratory side of the Y-piece connected to the test lung. At a given NO level, increases in the concentration of inspired O₂ resulted in increases in the concentration of NO₂ produced, as did increases in the amount of NO at a given concentration of O₂. The mean NO₂ concentration at the inspiratory site of the Y-piece did not exceed 0.05 ppm (the limit of NO₂ as an outdoor air pollutant in the United States) when the NO concentration did not exceed 8 ppm, regardless of the O₂ concentration. NO inhalation therapy for children with severe respiratory failure using the Servo Ventilator 900C can be performed safely when the concentration of NO does not exceed 8 ppm.     

The safety of a nitric oxide inhalation system with high frequency oscillatory ventilation

Nitric oxide (NO) inhalation and high frequency oscillatory ventilation (HFOV) has been indicated in infants with severe respiratory failure. The purpose of the present study was to evaluate the safety of an NO inhalation system with HFOV in terms of nitrogen dioxide (NO₂) production. The NO inhalation system consisted of a high frequency oscillatory ventilator, a neonatal circuit and a test lung. The NO concentration was changed from 0 to 19 p.p.m. At each level of NO, the oxygen (O₂) concentration was changed from 21 to 100%. The NO and NO₂ concentrations were measured with a chemiluminescence analyzer using a molybdenum converter. The NO₂ concentration was increased when either the O₂ or the NO concentration was increased. The interposition of the endotracheal tubes increased NO₂ concentrations at 4 p.p.m. NO. The high stroke volume and high mean airway pressure produced a significant increase in NO₂ production at 4 p.p.m. NO. The increase in NO₂ production was prevented by placing a one-way valve at the joint of the NO gas line to the inspired limb. It was concluded that the NO inhalation system with HFOV can be safely used when a one-way valve is placed at the joint of the NO gas line to the inspired limb and when inhaled NO is at a relatively low concentration.     

Nitric oxide inhalation and nitric oxide synthase inhibitor supplement for endotoxin-induced hypotension

BACKGROUND: This study was performed to determine whether a combined therapy of nitric oxide (NO) inhalation and nitric oxide synthase (NOS) inhibitor is effective in experimental animals with endotoxin-induced refractive hypotension accompanied by pulmonary hypertension. METHODS: Escherichia coli lipopolysaccharide (1 mg/kg) was administered to 10 newborn piglets to induce endotoxemia. The experiment then began 60 min later, when the systemic arterial pressure dropped. The inhalation of 20 p.p.m. NO at 60 and 120 min of endotoxemia created a control group. Another group was also administered N w-nitro-L-arginine (L-NNA; 5 mg) after the first NO inhalation at 60 min of endotoxemia (the L-NNA group). Pulmonary arterial pressure, systemic arterial pressure and cardiac output were measured and compared among the groups. RESULTS: Three of the 5 piglets in the control group died of hypotensive shock, while in the L-NNA group the systemic arterial pressure recovered to pre-endotoxin administration levels. The L-NNA group produced a further increase in pulmonary arterial pressure against which NO inhalation was effective. CONCLUSION: Nitric oxide inhalation alone carries a potential risk of further lowering systemic arterial pressure in a piglet with hypotension induced by endotoxin, whereas the combined therapy resulted in the recovery of the blood pressure to pre-endotoxin levels. The combined therapy was simultaneously effective against pulmonary hypertension.     

Inhaled nitric oxide during emergency neonatal transportation

ABSTRACT Inhaled nitric oxide is currently being investigated as a selective pulmonary vasodilator for neonates with persistent pulmonary hypertension. The use of continuous inhaled nitric oxide during emergency transportation of three critically ill neonates with meconium aspiration and pulmonary hypertension is described. The successful application of this technique may allow safer transportation of neonates who require high level intensive care including ongoing nitric oxide, high frequency ventilation and/or extracorporeal life support. Regionally based nitric oxide-equipped retrieval teams may relieve the pressure on smaller neonatal intensive care units to provide inhaled nitric oxide therapy and allow centralization of nitric oxide resources, thus facilitating development of expertise and the completion of meaningful research programs with substantial recruitment.     

Weaning strategy with inhaled nitric oxide treatment in persistent pulmonary hypertension of the newborn

AIM—To determine if infants who had become dependent on inhaled nitric oxide treatment could be successfully weaned off it if FIO₂ was increased briefly during withdrawal.
METHODS—Sixteen infants admitted for conditions associated with increased pulmonary vascular resistance responded well to inhaled nitric oxide treatment with a significant increase in PaO₂ (maximum inhaled nitric oxide given 25 ppm). Weaning from inhaled nitric oxide in 5 ppm decrements was initiated once the FIO₂ requirement was less than 0.5. When patients were stable on 5 ppm of inhaled nitric oxide, the gas was then discontinued. If a patient showed inhaled nitric oxide dependence—that is, oxygen saturation fell by more than 10% or below 85%—inhaled nitric oxide was reinstated at 5 ppm and the patient allowed to stabilise for 30 minutes. At this time, FIO₂ was increased by 0.40 and weaning from inhaled nitric oxide was attempted again.
RESULTS—Nine infants were successfully weaned on the first attempt. The seven infants who failed the initial trial were all successfully weaned following the increase in FIO₂. After successful weaning, FIO₂ was returned to the pre-weaning level in mean 148(SD 51) minutes and inhaled nitric oxide was never reinstated.
CONCLUSION—Infants showing inhaled nitric oxide dependency can be successfully weaned by increasing FIO₂ transiently.

     

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.     

Comparability of a hand-held nitric oxide analyser with online and offline chemiluminescence-based nitric oxide measurement

Practicability is crucial for successful implementation of fractional exhaled nitric oxide (FeNO) measurement into asthma management. The study aimed at comparing a conventional chemiluminescence NO analyser (EcoMedics^®) with a hand-held device (NIOX MINO^®) and offline FeNO measurement using a commercially available system in an unselected cohort of children aged 6–16 yr. A secondary objective was to confirm FeNO stability over time in 15 samples from adult volunteers obtained using the offline system. Sixty-six children (mean ± s.d. age 11.8 ± 3.0 yr) underwent single breath FeNO measurement in triplets with each device. Offline collected FeNO was measured after offline breath collection into a Mylar balloon and subsequent analysis using the chemiluminescence NO analyser. Variability and between-method agreement were assessed, and stability over time within the Mylar balloons was tested by repeated hourly measurements. FeNO levels ranged from 2 to 113 p.p.b. Intra-class correlation was excellent (r = 0.98, p <   0.001 for each pair). Bland–Altman plots and back-transformation of logarithmic mean differences revealed fair agreement between methods. Stability over time was confirmed over 10 h both at room temperature and when stored under cooling conditions. FeNO values obtained using the chemiluminescence NO analyser, the portable NIOX MINO^® system and the offline collection technique show between-method agreement within clinically acceptable range.     

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.     

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.     

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目的评价呼出气一氧化氮(FeNO)监测在哮喘控制治疗中的评估指导作用。方法收集深圳市儿童医院哮喘专科门诊的41例患儿,根据抽签分组,20例进入FeNO组,21例进入对照组。控制治疗中,对照组根据儿童哮喘控制水平分级进行调整;FeNO组在此基础上结合FeNO检测结果进行调整。在10个月治疗后,观察两组之间哮喘症状、短效β受体激动剂使用情况、肺功能结果,吸入激素使用量,从而判断FeNO检测在哮喘控制治疗中的作用。结果 FeNO组使用短效β受体激动剂平均天数为(4.3±3)d,对照组为(3.7±2.8)d;FeNO组总发作次数9次,对照组为11次;第1秒用力呼气容积(FEV1)占预计值%在FeNO组为100.96±7.69,对照组为90.37±12.95;达50%用力肺活量时最大呼气流速(MEF50)占预计值%在FeNO组为95.77±9.32,对照组为87.01±13.84。以上指标比较均为P>0.05,差异无统计学意义。FeNO组平均吸入糖皮质激素量为(290±75)μg,对照组为(225±50)μg(P<0.01)。结论在哮喘控制治疗评估中,加入FeNO浓度检测,对吸入糖皮质激素(ICS)有指导作用,但未能显...     

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.     

Regulation of bacterial translocation by nitric oxide

Nitric oxide (NO) appears to play a paradoxical role in intestinal physiology. Although NO has potent bactericidal effects, a growing body of evidence suggests that it mediates intestinal injury and breakdown of gut barrier function. Data from our lab and others show an increased incidence of bacterial translocation following endotoxin challenge, and upregulation of inducible NO synthase (iNOS) mRNA and protein in the intestine. These phenomena co-localize with enterocyte apoptosis at the tips of the intestinal villi and immunoreactivity to nitrotyrosine. Electron microscopy reveals swollen mitochondria, implicating these organelles as putative targets for NO or its reactive nitrogen intermediates. We review some of the literature and discuss our current work in trying to define this mechanism. Accepted: 13 December 1999