The feasibility of nitric oxide delivery with high frequency jet ventilation

A 27-year-old female with acute monocytic leukaemia (M5) developed acute respiratory distress syndrome (ARDS). Because of refractory hypoxaemia and severe barotrauma during conventional mechanical ventilation, the patient was switched to high frequency jet ventilation (HFJV) as a salvage therapy. Her refractory hypoxaemia improved temporarily but worsened again. Approval of the Institutional Review Board and the Food and Drug Administration was obtained to use nitric oxide (NO) with HFJV on a compassionate basis considering the grave situation. The NO delivery system was connected to the secondary flow circuit of the HFJV immediately after the humidifier. We measured the concentration of NO at least every hour by inserting a 7-Fr catheter connected to a McNeill analyzer into the endotracheal tube. Despite improvement of oxygenation, the patient's respiratory status deteriorated further and she died. In this case we were able to achieve reliable and constant levels of NO. The purpose of this report is to discuss the technical aspects and pitfalls of this method.     

Influence of ventilatory settings on exhaled nitric oxide during high frequency oscillatory ventilation

Nitric oxide (NO), which is produced in the lower airways, diffuses from cells into the air space and can be measured in exhaled air. The influence of high frequency oscillatory ventilation on the production of exhaled NO (eNO) has not been thoroughly studied. The objectives of this study are to establish an animal model for evaluation of lower airway NO and to evaluate settings in terms of frequency, mean airway pressure (MAP), amplitude pressure (amplitude), and inspiratory time ratio (t_I/t_E) during high frequency oscillatory ventilation on the production of eNO. An observational animal study was performed on 12 female New Zealand White rabbits, which were anesthetized, tracheotomized and ventilated using a SensorMedics 3100A HFOV ventilator (SM3100A). The concentration of NO in exhaled gas was measured by chemiluminescence continuously from the nose and the side hole of the adaptor of endotracheal tube. The individual effects of the respiratory settings were evaluated. The results were analyzed by paired t‐test or by the generalized estimating equation method. We found that the lower airway was the main source of the eNO, that amplitude, MAP, and t_I/t_E were positively correlated with the level of eNO and that frequency was negatively correlated with the level of eNO. These findings fit the stretch theory for the production of endogenous NO. Monitoring of eNO during HFOV may provide insights into lung mechanics and ventilation efficiency and be used in the future as a guide during clinical practice. Pediatr Pulmonol. 2009; 44:800–805. © 2009 Wiley‐Liss, Inc.     

Summary: systemic effects of inhaled nitric oxide

Many effects of inhaled nitric oxide (NO) are not explained by the convention that NO activates pulmonary guanylate cyclase or is inactivated by ferrous deoxy- or oxyheme. Inhaled NO can affect blood flow to a variety of systemic vascular beds, particularly under conditions of ischemia/reperfusion. It affects leukocyte adhesion and rolling in the systemic periphery. Inhaled NO therapy can overcome the systemic effects of NO synthase inhibition. In many cases, these systemic-NO synthase-mimetic effects of inhaled NO seem to involve reactions of NO with circulating proteins followed by transport of NO equivalents from the lung to the systemic periphery. The NO transfer biology associated with inhaled NO therapy is rich with therapeutic possibilities. In this article, many of the whole-animal studies regarding the systemic effects of inhaled NO are reviewed in the context of this emerging understanding of the complexities of NO biochemistry.     

Partial liquid ventilation with and without inhaled nitric oxide in a newborn piglet model of meconium aspiration

The object of this study was to determine the effects of partial liquid ventilation (PLV) with and without inhaled nitric oxide (NO) over a 4-h period on lung mechanics, gas exchange, and hemodynamics in an animal model of meconium aspiration syndrome (MAS). Twenty-four fentanyl-anesthetized piglets were instrumented and administered a slurry of human meconium to create a model with hypoxia, hypercarbia, acidosis, and pulmonary hypertension. They were then randomly assigned to conventional ventilation, conventional ventilation plus inhaled NO at 40 ppm, PLV using perfluorodecalin, or PLV plus inhaled NO. The perfluorocarbon was added until a meniscus was visible in the endotracheal tube during expiration. Hemodynamics, lung mechanics, and gas exchange were monitored for 4 h, and then the animals were killed. The conventionally ventilated animals continued to deteriorate, and three of the six died prior to 4 h. All the animals in the remaining groups survived. Oxygenation improved significantly immediately with the start of inhaled NO (from 43.8 SD 10.3 to 62.6 SD 11.7 mm Hg after 30 min) and stayed elevated compared with the control group for the remainder of the study (62.4 SD 21.8 mm Hg at 4 h compared with 44.9 SD 1.6 mm Hg for the control group, p < 0.05). Oxygenation improved more slowly in the PLV alone group, being slightly less than control at 30 min (p = NS) but increasing to 104 SD 34.9 after 4 h (p < 0.01 compared with the control group), at which time it was also greater than inhaled NO alone (p < 0.05). The combined group had an acute increase in oxygenation indistinguishable from the NO alone group and maintained this until the end of the study. Lung compliance was unaffected in the inhaled NO group. In both the liquid ventilation groups the lung compliance improved with the instillation of perfluorodecalin (from 0.46 SD 0.18 to 0.62 SD 0.09 ml/cm H(2)O/kg in the PLV alone group at 1 h, p < 0.05 compared with the control group) and remained stable for the remainder of the study. Cardiac output and pulmonary vascular resistance were not significantly affected by any of the treatments. It was concluded that in this animal model of MAS, inhaled NO led to an acute improvement in gas exchange and prolonged survival compared with conventional therapy. PLV improved lung mechanics, which was maintained over the course of the study. The combination of PLV and inhaled NO produced both effects, acutely improving both gas exchange and lung mechanics. Combined therapy with PLV and inhaled NO may have benefits in the MAS.     

吸入一氧化氮治疗肺血栓栓塞症的临床研究进展

吸入一氧化氮可以降低肺血栓栓塞症患者的肺血管阻力,降低肺动脉高压,解除右心室后负荷;治疗肺血栓栓塞症患者血栓手术后或肺动脉内肺血栓动脉内膜切除术后所形成的肺水肿、再灌注肺损伤和持续肺动脉高压等并发症;改善患者肺通气／血流失调,解除支气管痉挛,改善氧分压;抑制患者血小板活性和聚集,延长出血时间;对心肌损害和心功能的保护作用。吸入一氧化氮对患者有一定的毒副作用,一氧化氮吸入装置的不完善也对一氧化氮吸入在临床上的应用有一定的影响。对这些知识的全面认识,将对临床吸入一氧化氮治疗肺血栓栓塞起到积极的作用。     

一氧化氮吸入联合高频振荡通气治疗新生儿重度呼吸衰竭

目的探讨一氧化氮吸入联合高频通气治疗新生儿重度呼吸衰竭的临床效果。方法 2011年2月至2013年12月我科用一氧化氮吸入联合高频振荡通气治疗新生儿重度呼吸衰竭38例,男27例,女11例,观察治疗前和治疗后1、6、24 h的血气分析、氧合指数(OI),动脉肺泡氧分压比值(a/A),监测治疗效果及副作用。结果所有病例PH、PaCO2、PaO2、OI、a/A在治疗后1、6、24 h均较治疗前改善(P均0.01),治愈28例(73.7%),因病情危重放弃治疗及死亡10例(26.3%),未发现高铁血红蛋白血症。结论一氧化氮吸入联合高频振荡通气治疗重度呼吸衰竭是安全和有效的,值得临床推广。     

Evidence for the extrapulmonary localization of inhaled nitric oxide

Inhaled nitric oxide (NO) has emerged as a promising pulmonary vasodilator to treat pulmonary hypertension associated with heart disease and ventilation/perfusion mismatching. However, the pharmacokinetics of inhaled NO still remains obscure and its cardiopulmonary selectivity appears to be increasingly under debate. In the present study measured NO content and levels of cyclic guanosine 3',5'monophosphate (cGMP), a mediator of NO-induced vasodilation, in a variety of organs from rats subjected to NO inhalation. Electron spin resonance spectroscopy associated to a spin trapping technique using N-methyl D-glucamine dithiocarbamate (FeMGD) was used to directly quantify NO levels in the lung, kidney, liver, aorta, and heart from anesthetized Wistar rats subjected to various doses (0, 20, 50, 100, or 200 ppm) and various times (0, 30, 45, or 75 minutes) of inhaled NO. Inhaled NO at a dose of 100 and 200 ppm significantly increased the NO-FeMGD complex in all organs studied. An increase of cGMP was detected in the lung and the aorta after inhaled NO for 45 minutes at the dose of 50 ppm. No changes in NO levels and its metabolites were shown between 30 and 75 minutes of inhaled NO. The results show that inhaled NO at a dose of 100 ppm or more increases NO levels in other organs beside the lung, strongly suggesting that inhaled NO would be more than a pulmonary vasodilator and its selectivity remains to be reconsidered when used for therapeutic purposes.     

One-year continuous inhaled nitric oxide for primary pulmonary hypertension

We describe a case of long-term administration of nitric oxide (NO) in a 32-year-old man who was admitted with exertional dyspnea and anasarca. A diagnosis of primary pulmonary hypertension was made. An acute vasodilator trial with inhaled NO showed a 5% reduction of the mean pulmonary artery pressure. Long-term NO inhalation therapy was initiated. Twenty days later, the dyspnea improved, the anasarca resolved, and the PaO(2) level increased. After 12 months of NO therapy, the patient remained stable and no signs of toxicity or tachyphylaxis were observed. To our knowledge, this is the first report of 1 year of continuously inhaled NO in an adult patient with primary pulmonary hypertension. These findings suggest that prolonged NO therapy might be an effective alternative, at a lower cost, to the continuous IV infusion of epoprostenol.     

The biological chemistry of nitric oxide as it pertains to the extrapulmonary effects of inhaled nitric oxide

The chemical properties of nitric oxide (NO) have been studied for over 200 years. However, it is only within the last 20 years that the biological implications of this chemistry have been considered. The classical model of NO action within the vasculature centers on production in the endothelium, diffusion to the smooth muscle, and subsequent activation of guanylate cyclase via binding to its heme iron. In the context of this model, it is difficult to conceptualize extrapulmonary effects of inhaled NO. However, NO possesses complex redox chemistry and is capable of forming a range of nitrogen oxide species and is therefore capable of interacting with a variety of biomolecules. Of particular interest is its reaction with reduced cysteine to form an S-nitrosothiol (SNO). SNOs are formed throughout NO biology and are a post-translational modification that has been shown to regulate many proteins under physiologic conditions. Hemoglobin, which was considered to be solely a consumer of NO, can form SNO in a conformationally dependent manner, which allows for the transport of inhaled NO beyond the realm of the lung. Higher oxides of nitrogen are capable of modifying proteins via nitration of tyrosines, which has been shown to occur under pathologic conditions. By virtue of its redox reactivity, one can appreciate that inhaled NO has a variety of routes by which it can act and that these routes may lead to extrapulmonary effects.     

Long-term inhaled nitric oxide plus dipyridamole for pulmonary arterial hypertension

Inhaled nitric oxide (iNO) has been shown to be a potent and selective vasodilator in pulmonary arterial hypertension (PAH). However, the clinical experience in prolonged treatment is limited. We assess the safety and effectiveness of long-term administration of iNO in severe PAH. Two female patients were admitted to our hospital because of severe dyspnea (World Health Organization functional class IV) and hypoxemia. They were diagnosed with PAH (primary and secondary to congenital heart disease) and treated with iNO for 2 years. The delivery system consisted of an NO tank of 800 ppm, a modified gas-pulsing device, and nasal cannulas. On iNO treatment the patients showed remarkable improvement of symptoms, oxygenation and 6-min walk distance. After 16 months the patients began to experience a progressive rebound of symptoms. A phosphodiesterase type 5 inhibitor (dipyridamole) was added to iNO. This intervention proved useful in improving clinical deterioration and hemodynamics. This is the first study reporting 2-year iNO therapy in 2 patients with primary and secondary pulmonary hypertension. The combination of dipyridamole with iNO augments the pulmonary vasodilatation and may be useful in managing PAH.     

Maturational changes in ovine pulmonary vascular responses to inhaled nitric oxide

Developmental changes in modulation of pulmonary vasomotor tone by endothelium-derived nitric oxide (EDNO) may reflect maturational differences in endothelial synthesis of and/or vascular smooth muscle response to nitric oxide. This study sought to determine whether pulmonary vascular sensitivity and responsiveness to nitric oxide change during newborn development, and whether this is related to changes in guanylate cyclase activity. Pulmonary artery dose-responses to inhaled nitric oxide (iNO, 0.25-100 parts per million) were measured in hypoxic, indomethacin-treated, isolated lungs from 1-day (1-d)- and 1-month (1-m)-old lambs. The lungs of 1-m-old lambs were ventilated with 4% (oxygen) O2, and lungs of 1-d-old lambs were ventilated with either 4% or 7% O2 in order to achieve similar stimuli or vasomotor tone. Cyclic guanosine monophosphate (cGMP) concentrations in the perfusate were measured at iNO concentrations of 0, 5, and 100 parts per million (ppm). Basal and stimulated pulmonary guanylate cyclase activity was also measured in lung extracts in vitro. The effects of iNO were similar in both 1-d groups, even though baseline hypoxic tone was significantly higher in 1-d lungs ventilated with 4% O2 than with 7% O2. Furthermore, both the 1-d 7% O2 and 1-d 4% O2 lungs exhibited greater responsiveness and sensitivity to iNO than 1-m lungs. Perfusate cGMP concentrations and soluble guanylate cyclase activity were higher under stimulated than basal conditions, but neither differed statistically between 1 d and 1 m. These data suggest that pulmonary vascular responsiveness and sensitivity to nitric oxide decrease with age, but the mechanisms underlying these maturational changes require further investigation.     

Response of premature infants with severe respiratory failure to inhaled nitric oxide

Elevated pulmonary vascular resistance is seen in premature infants with severe respiratory distress syndrome (RDS). Inhaled nitric oxide (NO) has been shown to decrease pulmonary vascular resistance and to improve oxygenation in some patients with respiratory failure. The purpose of this study was to determine whether premature infants with severe RDS would respond to inhaled NO with an improvement in oxygenation. Eleven premature infants (mean gestational age 29.8 weeks) with severe respiratory failure caused by RDS were treated with NO in four concentrations [1, 5, 10, 20 parts per million (ppm) NO] and with placebo (0 ppm NO). Arterial blood gas measurements were drawn immediately before and at the end of each of the 15-minute treatments and were used to determine the arterial/alveolar oxygen ratio (Pao₂/PAo₂). Ten of the 11 infants had a greater than 25% increase in Pao₂/PAo₂. Five of the 11 had a greater than 50% increase in Pao₂/PAo₂. Despite normal cranial ultrasound imaging prior to NO, 3 infants had intracranial hemorrhage (ICH) noted on their first ultrasound scan after this brief period of NO treatment, and 4 additional infants developed ICH later during their hospitalization. No infant had significant elevations of methemoglobin concentrations after the total 60-minute exposure to NO. NO may be an effective method of improving oxygenation in infants with severe RDS. The disturbing incidence of ICH in this small group of infants needs to be carefully evaluated before considering routine use of NO for preterm infants. Pediatr. Pulmonol. 1997; 24:319–323. © 1997 Wiley-Liss, Inc.     

Effects of inhaled nitric oxide on inflammation and apoptosis after cardiopulmonary bypass

BACKGROUND: Cardiopulmonary bypass (CPB), a procedure often used during cardiac surgery, is associated with an inflammatory process that leads to lung injury. We hypothesized that inhaled nitric oxide (INO), which has anti-inflammatory properties, possesses the ability to modulate lung cell apoptosis and prevent CPB-induced inflammation. METHODS: Twenty male pigs were randomly classified into four groups: sham, sham plus INO, CPB, and CPB plus INO. INO (20 ppm) was administered for 24 h after anesthesia. CPB was performed 90 min into INO treatment. BAL fluid and blood were collected at time 0 (before CPB), at 4 h after beginning CPB, and 24 h after beginning CPB (T24). RESULTS: At T(24), BAL interleukin (IL)-8 levels and neutrophil percentages were elevated significantly in the CPB group. At T(24), INO reduced IL-8 concentrations and attenuated the increase of neutrophil percentage in the CPB-plus-INO group. Nitrite-plus-nitrate (NOx) concentrations were decreased significantly in groups without INO. Moreover, animals treated with INO showed higher rates of pulmonary apoptosis compared to their respective control groups except for the sham-plus-INO group, in which they were diminished. CONCLUSION: These results demonstrate that NOx production is reduced after CPB, and that INO acts as an anti-inflammatory agent by decreasing neutrophil numbers and their major chemoattractant, IL-8. INO also increases cell apoptosis in the lungs during inflammatory conditions, which may explain, in part, how it resolves pulmonary inflammation.