Exhaled Nitric Oxide

International guidelines recommend that a diagnosis of asthma be based on a combination of clinical history, the presence of variable airflow obstruction, and response to a bronchodilator or to a trial of corticosteroids. Smith and coworkers examined 47 consecutive patients with symptoms suggestive of asthma to assess the utility of exhaled NO (FE_NO) as a test for asthma. Sensitivities for peak flow, spirometry, and changes in these parameters after a trial of steroids were lower (0–47%) than for FE_NO (88%) and for sputum eosinophils (86%). The diagnostic accuracy when using FE_NO and sputum eosinophils was significantly greater. The authors concluded that single measurements of FE_NO or induced sputum in patients with undiagnosed chronic respiratory symptoms are strongly predictive of a diagnosis of asthma, and that FE_NO, because it is quick and easy to perform, may be readily incorporated into routine pulmonary function tests used to make the diagnosis of asthma.

With the increasing use of FE_NO as an indirect measure of airway inflammation, there is need for information about factors that can potentially alter FE_NO levels and therefore confound the measurement. In a randomized, double-blind, crossover study, Taylor and colleagues administered either caffeinated or noncaffeinated coffee to 20 subjects with asthma (10 steroid-naive and 10 steroid-treated), and performed FE_NO measurements before and 30, 60, 120, and 180 minutes after ingestion. No significant changes in FE_NO occurred after caffeine, despite significant increases in serum caffeine levels. The authors concluded that caffeinated foods and beverages are unlikely to influence FE_NO measurements in subjects with asthma.

Current methods for measuring FE_NO generally do not distinguish between NO that originates from the airway versus alveolar compartments. Gelb and coworkers measured FE_NO at three different expiratory flow rates (100, 150, and 200 ml/second) in 53 subjects with stable asthma taking inhaled corticosteroids, 13 subjects with stable asthma who were inhaled corticosteroid–naive, and 34 normal control subjects. Both bronchial NO and alveolar NO were increased in subjects with asthma compared with normal control subjects. There was no significant correlation between FEV₁ % predicted or lung elastic recoil and bronchial or alveolar NO. However, there was a significant correlation between NO bronchial flux and alveolar concentration. In 10 subjects with asthma who were taking inhaled corticosteroids, the addition of prednisone significantly decreased alveolar NO, but did not change total FE_NO or NO bronchial flux. The authors concluded that inflammation in asthma may behave differently in different parts of the lung, and suggested that even in patients with stable asthma taking inhaled corticosteroids there may be ongoing, prednisone-suppressible inflammation in the alveolar compartment.

In 105 healthy subjects, Grasemann and coworkers examined the relationship between exhaled nitric oxide and gene variants for the two constitutive forms of nitric oxide synthase. Exhaled nitric oxide was higher in men than in women among both the 33 smokers (19.8 versus 11.4 ppb) and the 72 nonsmokers (35.5 versus 18.6 ppb). Among nonsmokers, exhaled nitric oxide was lower in women with a greater number of repeats (both alleles with 12 or more repeats) in neuronal nitric oxide synthase than in women with fewer repeats: 13.6 versus 19.4 ppb. Exhaled nitric oxide was not associated with neuronal nitric oxide synthase genotype in men. Exhaled nitric oxide was not related to the gene variant for endothelial nitric oxide. The authors conclude that gene variants in neuronal nitric oxide synthase contribute to the variability in exhaled nitric oxide in healthy women.

To measure fractions of exhaled nitric oxide in intubated, mechanically ventilated patients, Tornberg and coworkers developed a method for obtaining multiple single-breath measurements at preset expiratory flows. A suction ejection system connected to a restriction valve was used to obtain multiple single-breath exhalations. Intubation produced a 50% decrease in the fraction of exhaled nitric oxide and a 36% decrease in the airway wall transfer rate of nitric oxide. Neither the fraction of nitric oxide originating in alveoli or in airway wall epithelium was affected by intubation. The peak concentration of nitric oxide after 20 seconds of apnea was similar to the value of nitric oxide calculated as originating in the airway wall epithelium. The authors conclude that the vacuum aspiration method for multiple single-breath measurements in mechanically ventilated patients enables the calculation of alveolar and bronchial fractions of nitric oxide.

To determine whether endogenous endothelium-dependent vasoactive substances cause release of nitric oxide that can be detected in exhaled air, Malmstrom and coworkers administered intravenously various pharmacologic compounds in anesthetized pigs and humans. Administration of acetylcholine, bradykinin, substance P, endothelin-1, and nitroglycerine produced dose-dependent increases of exhaled nitric oxide in pigs. Each compound caused a highly individual and reproducible release pattern. Angiotensin converting enzyme inhibition enhanced the release of nitric oxide induced by bradykinin. Endothelin receptor antagonism reduced the response of exhaled nitric oxide to endothelin-1. Atropine abolished the response to acetylcholine. Inhibition of nitric oxide synthase abolished the basal levels of exhaled nitric oxide and also decreased the exhaled nitric oxide response to all compounds except nitroglycerine. In six human subjects, acetylcholine evoked a dose-dependent increased in exhaled nitric oxide. The authors conclude that release of nitric oxide in response to endogenous vasoactive compounds can be measured online in exhaled air.

Citations 1-6 of 6 total displayed.

Alveolar and Airway Sites of Nitric Oxide Inflammation in Treated Asthma

Arthur F. Gelb, Colleen Flynn Taylor, Eliezer Nussbaum, Carlos Gutierrez, Aaron Schein, Chris M. Shinar, Mark J. Schein, Joel D. Epstein, and Noe Zamel
Am. J. Respir. Crit. Care Med. 170: 737 -741. First published online as doi:10.1164/rccm.200403-408OC [Abstract] [Full text]

Effect of Caffeine Ingestion on Exhaled Nitric Oxide Measurements in Patients with Asthma

Elizabeth S. Taylor, Andrew D. Smith, Jan O. Cowan, G. Peter Herbison, and D. Robin Taylor
Am. J. Respir. Crit. Care Med. 169: 1019 -1021. First published online as doi:10.1164/rccm.200310-1473OC [Abstract] [Full text]

Diagnosing Asthma: Comparisons between Exhaled Nitric Oxide Measurements and Conventional Tests

Andrew D. Smith, Jan O. Cowan, Sue Filsell, Chris McLachlan, Gabrielle Monti-Sheehan, Pamela Jackson, and D. Robin Taylor
Am. J. Respir. Crit. Care Med. 169: 473 -478. First published online as doi:10.1164/rccm.200310-1376OC [Abstract] [Full text]

Multiple Single-breath Measurements of Nitric Oxide in the Intubated Patient

Daniel C. Törnberg, Håkan Björne, Jon O. Lundberg, and Eddie Weitzberg
Am. J. Respir. Crit. Care Med. 168: 1210 -1215. First published online as doi:10.1164/rccm.200306-784OC [Abstract] [Full text]

Endogenous Nitric Oxide Release by Vasoactive Drugs Monitored in Exhaled Air

Rickard E. Malmström, Daniel C. Törnberg, Göran Settergren, Jan Liska, Monika Angdin, Jon O. Lundberg, and Eddie Weitzberg
Am. J. Respir. Crit. Care Med. 168: 114 -120. First published online as doi:10.1164/rccm.200302-159OC [Abstract] [Full text]

Effects of Sex and of Gene Variants in Constitutive Nitric Oxide Synthases on Exhaled Nitric Oxide

Hartmut Grasemann, Karin Storm van's Gravesande, Rainer Büscher, Jeffrey M. Drazen, and Felix Ratjen
Am. J. Respir. Crit. Care Med. 167: 1113 -1116. First published online as doi:10.1164/rccm.200211-1342OC [Abstract] [Full text]

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