How accurately should we estimate the anatomical source of exhaled nitric oxide?

Abstract

FOR MORE THAN A DECADE it has been recognized that nitric oxide (NO) appears in the exhaled breath and the level is altered in numerous pulmonary diseases in which inflammation plays an integral role (e.g., asthma) (1,8). Thus the exhaled NO signal has the potential to uniquely delineate the contribution of inflammatory processes to lung disease in a noninvasive manner complementing more traditional measurements of lung function, namely, lung volumes and expiratory airflow that focus solely on structural properties of the respiratory system. This potential, combined with the relative ease with which it can be detected and the serious and ongoing epidemic of asthma and other chronic lung diseases, has imbued the measurement of exhaled NO with the promise of becoming a useful clinical tool. However, this promise has not yet been fulfilled. Skepticism regarding the measurement of exhaled NO persists due to both its variability among clinically similar subjects and the inconsistent correlations with other indexes of lung function and symptoms. This skepticism is appropriate and stems both from the relatively crude techniques currently employed to characterize exhaled NO and from our still incomplete understanding of the fundamental biological mechanisms that determine the appearance of NO in the exhaled breath.Since the initial observation that NO appears in the exhaled breath, several research groups have made seminal contributions toward our understanding of the unique features of NO exchange in the lungs. In particular, exhaled NO has sources from both the airway and alveolar regions, which has been determined from a combined approach implementing experimental observations (5,7,15,19) and "two-compartment" mathematical models (9,14,20,21). The present clinical approach for exhaled NO measures the concentration during a vital capacity maneuver while holding expiratory flow and pressure constant (2). The recommended exhalation flow is low enough (50 ml/s) to cause the concentration to be predominantly of airway origin and is thus ineffective at describing the lower alveolar concentration of NO, ignoring this potentially important signal.Although asthma is traditionally thought to be an inflammatory disease of the airways, several groups have employed the two-compartment model of NO exchange and reported an elevated alveolar concentration of NO during periods of enhanced symptoms (11, 13), or in patients who are refractory to inhaled corticosteroids and bronchodilators (3,6,12). The observations of increased alveolar NO are particularly relevant as these patients have proven to be difficult to manage, are hospitalized more frequently, and could well benefit from early detection of disease exacerbation and alternate therapeutic regimens.Since the alveolar concentration cannot be directly measured, estimating the alveolar concentration requires a model of NO exchange in the lungs that, when combined with experimental measurements, can partition the exhaled NO signal into proximal and peripheral contributions. This fea...

Estimation of Parameters in the Two-Compartment Model for Exhaled Nitric Oxide

“…Guidelines have been developed for the standardized measurement of FeNO at a single 50 ml/s exhalation flow rate [6]. At the relatively low flow rate of 50 ml/s, FeNO is primarily from proximal airway sources [7]. Higher flow FeNO provides more information about distal/alveolar sources, but is an imperfect proxy for alveolar NO concentration [8].…”

Impact of different fixed flow sampling protocols on flow‐independent exhaled nitric oxide parameter estimates using the Bayesian dynamic two‐compartment model

“…This is because for any given subject the concentration of NO exhaled depends strongly on the exhalation rate (Hogman et al, ; Silkoff et al, ). A significant drawback to this approach is that a flow rate of 50 ml/s primarily provides information on NO arising from proximal airway wall sources (George, ). Measuring FeNO at multiple flow rates enables estimation of NO sources from distinct anatomical subregions (Eckel et al, ; Hogman, Drca, Ehrstedt, & Merilainen, ; Pietropaoli et al, ; Silkoff, Sylvester, Zamel, & Permutt, ; Tsoukias & George, ), which may provide added clinical information for the monitoring of rhinitis and asthma (Hogman, ; Högman, Malinovschi, Norbäck, & Janson, ; Hogman & Merilainen, ; Thornadtsson et al, ).…”

Bayesian estimation of physiological parameters governing a dynamic two-compartment model of exhaled nitric oxide

“…To control for this effect, guidelines for assessment (ATS 1999;ATS/ERS 2005) and interpretation (Dweik et al 2011) of the fractional concentration of exhaled NO (FE NO ) have been developed around a standardized exhalation rate of 50 mL/sec (FE NO,50 ). A significant drawback to this approach is that this flow rate provides information on NO arising primarily from proximal airway wall sources (George 2008).…”