Inhaled Nitric Oxide Treatment Research Articles

NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice.

The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. Whole-exome sequencing was performed on a cohort of 341 probands with congenital hypogonadotropic hypogonadism to identify ultrarare variants in NOS1. The activity of the identified NOS1 mutant proteins was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1-deficient mouse model. We identified five heterozygous NOS1 loss-of-function mutations in six probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss, and intellectual disability. NOS1 was found to be transiently expressed by GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects in sexual maturation as well as in olfaction, hearing, and cognition. The pharmacological inhibition of NO production in postnatal mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1-deficient mice. In summary, lack of NOS1 activity led to GnRH deficiency associated with sensory and intellectual comorbidities in humans and mice. NO treatment during minipuberty reversed deficits in sexual maturation, olfaction, and cognition in Nos1 mutant mice, suggesting a potential therapy for humans with NO deficiency.

Inhaled nitric oxide use in neonates with congenital diaphragmatic hernia.

To describe the use of inhaled nitric oxide (INO) in newborns with congenital diaphragmatic hernia (CDH). Pediatric Health Information System data were queried for newborns with CDH admitted at <8 days of age at tertiary care US pediatric hospitals between 2003 and 2011. INO treatment status and timing in relation to CDH repair were determined for each infant. Hospital-specific rates of INO use, extracorporeal membrane oxygenation (ECMO) use, and mortality were determined. Data were analyzed for 1713 neonates with CDH admitted to 33 hospitals. More than half (57%) received INO during their inpatient stay, and utilization varied dramatically between hospitals (34% to 92%). Neonates treated with INO accumulated >$81 million in pharmacy charges. The proportion of infants receiving INO as well as their duration of therapy increased significantly during the study period. The rate of ECMO utilization and mortality did not change significantly during the study period. Hospital-specific mortality rates did not correlate with INO therapy, ECMO utilization, or case volume. INO use in neonates with CDH is widespread, and has increased at many US tertiary pediatric hospitals without contemporaneous change in ECMO utilization or mortality. The improvement of evidence-based guidelines for the use of INO in newborns with CDH could lead to a reduction in health care costs for these patients.

Cost-effectiveness of early compared to late inhaled nitric oxide therapy in near-term infants

Objective:The purpose of this study was to determine the cost-effectiveness of early versus late inhaled nitric oxide (INO) therapy in neonates with hypoxic respiratory failure initially managed on conventional mechanical ventilation.Research design:A decision analytic model was created to compare the use of early INO compared to delayed INO for neonates receiving mechanical ventilation due to hypoxic respiratory failure. The perspective of the model was that of a hospital. Patients who did not respond to either early or delayed INO were assumed to have been treated with extracorporeal membrane oxygenation (ECMO). The effectiveness measure was defined as a neonate discharged alive without requiring ECMO therapy. A Monte Carlo simulation of 10,000 cases was conducted using first and second order probabilistic analysis. Direct medical costs that differed between early versus delayed INO treatment were estimated until time to hospital discharge. The proportion of successfully treated patients and costs were determined from the probabilistic sensitivity analysis.Results:The mean (±SD) effectiveness rate for early INO was 0.75 (±0.08) and 0.61 (±0.09) for delayed INO. The mean hospital cost for early INO was $21,462 (±$2695) and $27,226 (±$3532) for delayed INO. In 87% of scenarios, early INO dominated delayed INO by being both more effective and less costly. The acceptability curve between products demonstrated that early INO had over a 90% probability of being the most cost-effective treatment across a wide range of willingness to pay values.Conclusions:This analysis indicated that early INO therapy was cost-effective in neonates with hypoxic respiratory failure requiring mechanical ventilation compared to delayed INO by reducing the probability of developing severe hypoxic respiratory failure. There was a 90% or higher probability that early INO was more cost-effective than delayed INO across a wide range of willingness to pay values in this analysis.

Concomitant administration of nitric oxide and glucocorticoids improves protection against bronchoconstriction in a murine model of asthma

Glucocorticoids (GC) remain the first choice of treatment in asthma, but GC therapy is not always effective and is associated with side effects. In a porcine study in our laboratory, simultaneous administration of GC and nitric oxide (NO) attenuated the endotoxin-induced inflammatory response and made GC treatment more effective than inhaled NO or steroids alone. In the present study, we aimed to further investigate the interactions between NO and GC treatment in two murine models of asthma. Inflammation was induced by endotoxin, ovalbumin, or a combination of both. With an animal ventilator and a forced oscillation method (FlexiVent), lung mechanics and airway reactivity to methacholine in response to various treatments were assessed. We also describe histology and glucocorticoid receptor (GR) protein expression in response to inhaled NO treatment [40 ppm NO gas or NO donors sodium nitroprusside (SNP) or diethylamine NONOate (DEA/NO)]. SNP and GC provided protection against bronchoconstriction to a similar degree in the model of severe asthma. When GC-treated mice were given SNP, maximum airway reactivity was further reduced. Similar effects were seen after DEA/NO delivery to GC-treated animals. Using 1-H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), a soluble guanylate cyclase inhibitor, we found this effect of NO donors to be mediated through a cGMP-independent mechanism. In the severe model, prolonged NO treatment restored or even increased the nuclear levels of GR. In conclusion, in our murine model of severe asthma GC treatment provided protection to only a limited degree against bronchoconstriction, while concomitant treatment with a NO donor was markedly more potent than the use of either NO or GC alone.

The Initial Response to Inhaled Nitric Oxide Treatment for Intensive Care Unit Patients with Acute Respiratory Distress Syndrome

Background: Inhaled nitric oxide (INO) can improve hypoxemia and reduce pulmonary hypertension, but there is a wide range of response to INO. Objectives: The aim of this study was to evaluate the effect of different INO concentrations in acute respiratory distress syndrome (ARDS) patients. Methods: Thirty-two adult ARDS patients who were supported by mechanical ventilator were included. INO was given at a concentration of 1, 5, 10, 20 and 40 ppm, sequentially. Arterial blood gas and mean pulmonary artery pressure (MPAP) were measured 30 min after INO concentrations changed. Results: There was a significant increase in PaO₂/FiO₂ (p < 0.0001) and a decrease in pulmonary vascular resistance index and MPAP (p < 0.0001) after INO use. INO concentrations required for improving oxygenation were in the range of 1–20 ppm, whereas concentrations required for decreasing MPAP were in the range of 1–40 ppm. PaO₂/FiO₂ worsened when the INO dose was adjusted above 20 ppm. Sixty-nine percent of ARDS patients were responders; 31% of them were nonresponders. Among responders, 64% of patients responded at 1 ppm, 36% at 5 ppm. Conclusions: The optimal doses for improving oxygenation and reducing PAP differ. The maximum PaO₂/FiO₂ was observed at a lower INO concentration than that required for the minimal MPAP. There was no further improvement in PaO₂/FiO₂ when the INO dose was adjusted above 20 ppm. Higher doses of INO treatment worsened oxygenation.

Effects of Inhaled Nitric Oxide on Inflammation and Apoptosis After Cardiopulmonary Bypass

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. 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). 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. 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.

Inhaled Nitric Oxide Enhances Distal Lung Growth after Exposure to Hyperoxia in Neonatal Rats

Exposure of newborn rats to hyperoxia impairs alveolarization and vessel growth, causing abnormal lung structure that persists during infancy. Recent studies have shown that impaired angiogenesis due to inhibition of vascular endothelial growth factor (VEGF) signaling decreases alveolar and vessel growth in the developing lung, and that nitric oxide (NO) mediates VEGF-dependent angiogenesis. The purpose of this study was to determine whether hyperoxia causes sustained reduction of lung VEGF, VEGF receptor, or endothelial NO synthase (eNOS) expression during recovery, and whether inhaled NO improves lung structure in infant rats after neonatal exposure to hyperoxia. Newborn rat pups were randomized to hyperoxia [fraction of inspired oxygen (Fio(2)), 1.00] or room air exposure for 6 d, and then placed in room air with or without inhaled NO (10 ppm) for 2 wk. Rats were then killed for studies, which included measurements of body weight, lung weight, right ventricular hypertrophy (RVH), morphometric analysis of alveolarization (by mean linear intercept (MLI), radial alveolar counts (RAC), and vascular volume (Vv), and immunostaining and Western blot analysis. In comparison with controls, neonatal hyperoxia reduced body weight, increased MLI, and reduced RAC in infant rats. Lung VEGF, VEGFR-2, and eNOS protein expression were reduced after hyperoxia. Inhaled NO treatment after hyperoxia increased body weight and improved distal lung growth, as demonstrated by increased RAC and Vv and decreased MLI. We conclude that neonatal hyperoxia reduced lung VEGF expression, which persisted during recovery in room air, and that inhaled NO restored distal lung growth in infant rats after neonatal hyperoxia.

Patterning of rhythmical feeding behaviour by brainstem neurons and sensory afferents.

Objective: To study the clinical efficacy as well as the cost‐effectiveness of inhaled nitric oxide (NO) compared with extra‐corporeal membrane oxygenation (ECMO) in neonates with pulmonary hypertension and hypoxic respiratory failure accepted for ECMO treatment. Design: Retrospective study of the first 10 consecutive neonatal patients treated with inhaled NO during 1992–94. Inhaled NO was administered after failure of conventional treatment as a last resort before initiating ECMO. For cost‐effectiveness calculations the above‐described patient population was compared with ECMO patients having a very favourable ECMO course. Setting: Twelve‐bed neonatal and paediatric intensive care unit with ECMO capabilities at a tertiary university referral hospital. Results: Inhaled NO was found to significantly decrease the oxygenation index (OI pre‐NO: median 80.5; OI post‐NO: median 22.5; P=0.003) and five of the patients could successfully be handled without the use of ECMO. ECMO was found to be more than four times as expensive as inhaled NO treatment on a per hour basis ($244 vs. $53 per hour) and the net savings from being able to avoid ECMO in five patients was calculated to be $156 200. Conclusion: Initiation of inhaled NO caused a significant improvement in oxygenation index and reduced the need for ECMO by 50% in critically ill neonatal patients with hypoxic respiratory failure. Inhaled NO was also found to compare very favourably with ECMO regarding cost‐effectiveness ($53 vs. $244 per treatment hour).

A retrospective analysis of nitric oxide inhalation in patients with severe acute lung injury in Sweden and Norway 1991-1994.

Patients with severe acute lung injury (ALI) have been treated compassionately on doctors' initiative with inhaled nitric oxide (INO) in Sweden and Norway since 1991. In 1994 the previously used technical grade nitric oxide was replaced by medical grade nitric oxide. We have carried out a retrospective data collection on all identified adult patients treated with INO for >4 h during the period 1991-1994 focusing on safety aspects and patient outcome. We used the following exclusion criteria (1) Age <18 years, (2) Simultaneous treatment with extracorporeal removal of CO2 (3) NO inhalation period <4 h, (4) Incomplete or missing patient charts, (5) Use of INO in order to treat pulmonary hypertension following cardiac surgery, with little or no acute lung injury. Inclusion criteria were met by 56 out of 73 identified patients. Mean age was 48+/-19 years and the median duration of INO treatment was 102 h. PaO2/FIO2 ratio at start of treatment was 85 +/- 33 mm Hg with a lung injury score (LIS) of 3.2+/-0.8. The aetiology of the lung injury was pneumonia (n= 27), sepsis (n=12) and trauma (n=8). Survival to hospital discharge was 41% and survival after 180 d was 38%. Three serious adverse events were identified, two from technical failures of the INO delivery device and one withdrawal reaction necessitating slow weaning from INO. No methaemoglobin values >5% were reported during treatment. The overall mortality did not differ dramatically from historical controls with high mortality. Only a randomised study may determine whether INO as an adjunct to treatment alters the outcome in severe ALI. One cannot at present advocate the routine use of INO in patients with ALI outside such studies.