Combination Of Nitric Oxide Research Articles

Studying the Role of Alveolar Exhaled Nitric Oxide in Combination with Bronchial Nitric Oxide to Predict Asthma Control in Children with Asthma: A Real-Life Prospective Study

Background: Fractional exhaled nitric oxide (FENO) is currently used as a biomarker of airway inflammation in patients with asthma. However, the role of alveolar nitric oxide (CANO) in asthmatic children has not been clearly demonstrated Methods: It was a prospective and descriptive study. The measurement of FENO and CANO, spirometry, blood eosinophil counts (BEC), and total IgE levels were performed for each study subject. Results: This study included 109 uncontrolled asthmatic children without inhaled corticosteroid (ICS) treatment. The exhaled NO level in asthmatic patients was significantly higher than in control subjects: FENO: 22.5 vs. 8.4 ppb; CANO: 5.9 vs. 2.8 ppb; J’awNO (maximum airway nitric oxide flux): 56.9 vs. 18.7 ppb; respectively. The sensitivities and specificities for asthma diagnosis with the cut-off of CANO at 3.5 ppb and 5.0 ppb were 74.3% and 73.3%, and 46.0% and 83.3%, respectively. There were the moderate and the weak correlations between CANO with FENO and CANO with IgE in asthmatic patients (r = 0.465, 95%CI (0.133-0.659), P=0.001; r=0.133, 95%CI (0.068- 0.497), P=0.184; respectively). The percentage of controlled asthma in patients with CANO ≥5 ppb at inclusion was higher than that in CANO <5 ppb group. Conclusion: Exhaled NO is a relevant biomarker of allergic asthma. The level of FENO and CANO might be used to predict asthma control in children.

Exogenous Nitric Oxide Improves Antibiotic Susceptibility in Resistant Bacteria.

Antibiotic resistance in bacteria is a major global threat and a leading cause for healthcare-related morbidity and mortality. Resistant biofilm infections are particularly difficult to treat owing to the protective biofilm matrix, which decreases both antibiotic efficacy and clearance by the host. Novel antimicrobial agents that are capable of eradicating resistant infections are greatly needed to combat the rise of antibiotic-resistant bacteria, particularly in patients with cystic fibrosis who are frequently colonized by multidrug-resistant species. Our research group has developed nitric oxide-releasing biopolymers as alternatives to conventional antibiotics. Here, we show that nitric oxide acts as a broad-spectrum antibacterial agent while also improving the efficacy of conventional antibiotics when delivered sequentially. Alone, nitric oxide kills a broad range of bacteria in planktonic and biofilm form without engendering resistance. In combination with conventional antibiotics, nitric oxide increases bacterial susceptibility to multiple classes of antibiotics and slows the development of antibiotic resistance. We anticipate that the use of nitric oxide in combination with antibiotics may improve the outcome of patients with refractory infections, particularly those that are multidrug-resistant.

Study of the beneficial role of exhaled nitric oxide in combination with GINA guidelines for titration of inhaled corticosteroids in children with asthma

Background. The use of FENO in association with current guidelines in the treatment of asthma has not been studied thoroughly. This study aimed to evaluate the beneficial role of FENO in combination with GINA (Global Initiative for Asthma) guidelines for titration of inhaled corticosteroids (ICS) in asthmatic children. Methods. It was a prospective and descriptive study. Uncontrolled asthmatic children were randomized to two groups: group 1 (followed GINA guidelines) or group 2 (followed GINA guidelines + FENO modification for ICS titration). The two groups were followed-up for 12 months. Results. The mean age of the patients in the study was 10 ± 4 years for group 1 (n = 116) and 11 ± 5 years for group 2 (n = 108). There were 87.9% patients in group 1 and 82.4% in group 2 that had a familial allergic history. There were 58.6% of moderate asthma and 41.4% of severe asthma in group 1, versus 56.4% and 43.6% in group 2, respectively. The percentage of moderate and severe asthma was also significantly modified after 6th and 12th month versus at inclusion (43.1% and 35.3% versus 58.6%, P < 0.01 and P < 0.005; 23.2% and 12.9% versus 41.4%, P < 0.005 and P < 0.001, respectively). The total daily dose of ICS in group 2 at 12th months was significantly lower than that in group 1 (3515 ± 1175 versus 4785 ± 1235 mcg; P < 0.005). The daily cost of ICS treatment in group 2 was also lower than that of group 1 (18 ± 4 versus 27 ± 3 USD; P < 0.05). Conclusion. The use of FENO in combination with GINA guidelines for ICS titration is useful in reducing the daily ICS dose and treatment cost.

Response to pulmonary vasodilators in infants with congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is associated with lung hypoplasia, cardiac dysfunction and pulmonary hypertension. Inhaled nitric oxide (iNO) and milrinone are commonly used pulmonary vasodilators in CDH. We studied the hemodynamic effects of iNO and milrinone in infants with CDH. A retrospective chart review was performed of all CDH infants admitted to two regional perinatal centers and infants classified into three groups: No-iNO group; iNO-responders and iNO-nonresponders. Oxygenation and hemodynamic effects of iNO and milrinone were assessed by blood gases and echocardiography. Fifty-four percent (39/72) of infants with CDH received iNO and 31% of these infants (12/39) had complete oxygenation response to iNO. Oxygenation response to iNO was not associated with a decrease in right ventricular pressures (RVP) or ECMO use. Four infants (33%) in the iNO-responder group and eight infants (30%) in the iNO-nonresponder group received milrinone. Milrinone lowered RVP and improved ejection fraction (EF). Response to iNO was associated with improved oxygenation to milrinone and increased survival following ECMO (67 vs. 20% among nonresponders). Response to inhaled nitric oxide in combination with milrinone may be associated with improved oxygenation and better survival after ECMO in infants with CDH.

Nitric oxide protects against chloroquine resistant Plasmodium yoelii nigeriensis parasites in vitro

Malaria is a life-threatening disease of global concern. The role of nitric oxide in the clearance of malarial parasites is still under debate. Several reports suggest a possible role for nitric oxide in the protection during initial stages of malarial infection. In the present study, we demonstrate that the nitric oxide in combination with low concentrations of chloroquine controls the parasitaemia in vitro. Activated peritoneal macrophages co-cultured with lipopolysaccharide + interferon-γ or extracts from Tenospora cordifolia as an immunomodulator promoted nitric oxide production by macrophages. The high concentration of nitric oxide in combination with sub-optimal chloroquine suppressed the parasitaemia in the chloroquine resistant malarial infection. Further, the nitric oxide synthase inhibitor, N G-mono-methyl- l-arginine, downregulated nitric oxide production by peritoneal macrophages and the resulting levels of parasitaemia were higher, similar to those of untreated controls. These findings support the proposition that nitric oxide has a crucial role in the control of parasitaemia at the initial periods of blood stage malarial infection.

Lung physiology and histopathology during cumulated exposure to nitric oxide in combination with assisted ventilation in healthy piglets

Inhaled nitric oxide (iNO) is routinely used for hypoxic respiratory failure and persistent pulmonary hypertension of the newborn, and investigation of its new indications requiring various levels of iNO is underway. Cumulated exposure of high level of iNO may exert adverse effects on lung function and morphology, which may be confounded with ventilator-associated lung injury. Sixteen healthy piglets (5.5–11 kg) were anaesthetised, intubated and mechanically ventilated at low FiO 2 on continuous positive airway pressure and pressure support mode. The animals were randomly allocated to receive 40 ppm iNO (NO group, n=8) or no iNO (Control group, n=8). In both groups at 24 and 48 h, mild to moderate lung injury was observed, with mean values of PaO 2/FiO 2<300 mmHg. Compared to the Control, iNO at 40 ppm for 24–48 h did not adversely affect dynamic compliance or resistance of respiratory system, oxygenation, pulmonary and systemic hemodynamics. Neither did it affect composition and surface activity of surfactant phospholipids and white cell counts in bronchoalveolar lavage fluid. Inhaled NO resulted in elevated total serum nitrite/nitrate to 352±90 μmol/l and methemoglobin (MetHb) to 5.0±3.4%, in contrast to 88±38 μmol/l and 0.88±0.52% in the Control; 50% of the iNO animals having MetHb>3%. The lung injury scores as well as alveolar expansion were similar between the two groups at 24 h. At 48 h, low wet/dry lung weight ratio and lung injury score were found in the NO group. We conclude that no significant adverse effects on lung physiology and structure were found in the piglets receiving 40 ppm iNO for 24 or 48 h, on the contrary lung injury was moderately alleviated. The significantly impaired gas exchange over time associated with discrete morphological changes suggests adverse effects of prolonged positive pressure breathing and not necessarily exposure to oxides of nitrogen.

Inhaled nitric oxide in combination with volume resuscitation refines a porcine model of endotoxic shock

Existing porcine models of endotoxic shock poorly represent the human situation. To assess whether the cardiovascular profile of a porcine model could be improved by refining the protocol. In 30 pigs, right and left heart pressures and cardiac output were measured. Lipopolysaccharide (LPS) was administered as a bolus (n=12), as a 30 minute infusion (n=6) or as a 30 minute infusion along with inhaled NO and volume resuscitation (n=6) and six sham-treated pigs received normal saline. Haemodynamic values were measured over three hours. LPS increased pulmonary vascular resistance (PVR) (13.3 +/- 1.4 to 37.0 +/- 3.9kPa/l per sec, p<0.05) and reduced cardiac output (6.0 +/- 0.6 to 4.8 +/- 0.41/min). Mortality was 50% within 30 minutes. Inhaled NO and volume resuscitation controlled pulmonary vascular resistance (PVR) and preserved CO. Systemic vascular resistance (SVR) declined in the first hour (118.4 +/- 11.8 to 65.8 +/- 8.2kPa/l per sec, p<0.05) and remained low. Porcine models of endotoxaemia based on LPS administration are a poor model of human septic shock, but can be improved by regulating PVR and supporting CO which may contribute to future studies of septic shock

Effect of inhaled nitric oxide in combination with almitrine on ventilation-perfusion distributions in experimental lung injury.

To investigate a possible additive effect of combined nitric oxide (NO) and almitrine bismesylate (ALM) on pulmonary ventilation-perfusion (V(A)/Q) ratio. Prospective, controlled animal study. Animal research facility of a university hospital. Three conditions were studied in ten female pigs with experimental acute lung injury (ALI) induced by repeated lung lavage: 1) 10 ppm NO, 2) 10 ppm NO with 1 microg/kg per min ALM, 3) 1 microg/ kg per min ALM. For each condition, gas exchange, hemodynamics and V(A)/Q distributions were analyzed using the multiple inert gas elimination technique (MIGET). With NO + ALM, arterial oxygen partial pressure (PaO2) increased from 63 +/- 18 mmHg to 202 +/- 97 mmHg while intrapulmonary shunt decreased from 50 +/- 15 % to 26 +/- 12% and blood flow to regions with a normal V(A)/Q ratio increased from 49 +/- 16 % to 72 +/- 15 %. These changes were significant when compared to untreated ALI (p < 0.05) and NO or ALM alone (p < 0.05), although improvements due to NO or ALM also reached statistical significance compared to ALI values (p < 0.05). We conclude that NO + ALM results in an additive improvement of pulmonary gas exchange in an experimental model of ALI by diverting additional blood flow from non-ventilated lung regions towards those with normal V(A)/Q relationships.

Nitric oxide and almitrine: the definitive answer for hypoxemia

Hypoxia-induced by acute lung injury results from abnormal ventilation/perfusion ratio distribution towards shunt or low ventilation/perfusion zones. Pharmacological modification of pulmonary blood flow distribution improving ventilation/perfusion ratio should correct hypoxia. The development of inhaled nitric oxide therapy had confirmed this concept, but with a relatively high proportion of 'non responders'. Then development of other drugs used alone or in association with nitric oxide may reinforce the benefit of nitric oxide. This has been tested with almitrine bismesylate, a lipophilic drug that reinforce hypoxic pulmonary vasoconstriction. Using inhaled nitric oxide in combination with almitrine, several studies in adult respiratory distress syndrome or acute lung injury patients have shown spectacular results in term of PaO2 and pulmonary shunt reduction. Moreover, the proportion of responders to this combination seems largely great than those observed for each drug alone. In conclusion, pulmonary blood flow manipulation improving ventilation/perfusion mismatching is one of the major strategies to correct severe hypoxia.