Validity criteria and comparison of analytical methods of flow-independent exhaled NO parameters

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Abstract

The objective was to assess both validity and comparability of multiple constant (MCF, mainly performed) and dynamically changing (DCF, new method) flow analyses calculating alveolar concentration (CalvNO), maximum conducting airway flux (J′awNO) and airway diffusing capacity (DawNO) of exhaled NO (FENO).

(CalvNO, J′awNO)R where R is the correlation coefficient of the linear regression between NO output and expiratory flow rate (MCF) and (CalvNO, J′awNO, DawNO)Δ100 where Δ100 is the ratio ([observed  predicted FENO]/observed FENO) at 100 ml/s (DCF) were assessed in 18 healthy subjects (10 atopic).

MCF demonstrated a linear relationship (R  0.80) between NO output and expiratory flow in 15/18 subjects. DCF was valid (Δ100  30%) in 12/18 subjects. A good agreement between MCF and DCF was evidenced in the nine subjects with R  0.80 and Δ100  30%. Failure of validity criteria was mainly observed in atopic subjects.

In conclusion, when validity criteria are satisfied, the new DCF method similarly characterizes NO exchange parameters than MCF approach.

Introduction

Nitric oxide (NO) has been investigated as a noninvasive means of assessing lung inflammation. Recent international guidelines have standardized the method of measurement of exhaled nitric oxide fraction (FENO) (Anonymous, 1999). Besides the single constant expiratory flow rate method that allows this measurement, more sophisticated methods have been proposed in order to provide information about the anatomical source of exhaled NO (George et al., 2004). These approaches have been successfully used in healthy and pathologic conditions by specialized centers. Before widespread utilization, methodological studies are warranted to precisely delineate their applicability, inasmuch as some pathological conditions may not accurately be described by a simple model describing the healthy physiological condition.

The dependency of FENO on exhalation flow rate can be explained by a simple two-compartment model of the lung that has been used by several research groups (George et al., 2004). This two-compartment model describes exhaled NO arising from two compartments, the airways and the alveolar region, using three flow-independent exchange parameters: one describing the alveolar region (the steady-state NO alveolar concentration [CalvNO]), and two describing the airway region (airway NO diffusing capacity [DawNO] and either the maximum airway wall NO flux [J′awNO] or the airway wall NO concentration [CawNO]). A potential advantage of the two-compartment model is the ability to partition exhaled NO into an airway and alveolar source and thus improve the specificity of detecting altered NO exchange dynamics that differentially impact these regions of the lungs, such as in asthma (Mahut et al., 2004a, Mahut et al., 2004b).

The general equation governing these parameters is:FENO(V)=CawNO+(CalvNOCawNO)expDawNOVwhere V′ is the expiratory flow rate.

Two general approaches have been described in the literature to estimate flow-independent NO parameters (George et al., 2004): multiple constant flows (MCF), and more recently, dynamically changing flow (DCF) analytical methods. The two approaches have never been compared. The objective was to provide simple validity criteria for both methods and to evaluate their comparability in healthy subjects.

The linear analysis of MCF method takes advantages of a non-limited NO transfer from bronchi to lumen at relatively high expiratory flow rates (>50 ml/s) giving a linear relationship between expiratory flow rate and NO output. In this approach, (CalvNO, J′awNO) are inferred from the slope and the intercept of this linear relationship (Tsoukias et al., 2001). The two-compartment model predicts that NO concentration measured during a single prolonged exhalation at a constant flow rate is related to a stable alveolar NO output plus a constant NO flux from conducting airways, which results in a constant value (the NO plateau). In the MCF approach, the respective contribution of each compartment is estimated by successive analysis of NO output at several expiratory flow rates. We first analyzed whether the multiple constant exhalation flows method satisfied these underlying hypotheses (validity), namely a constant plateau (during each exhalation) and a linearity of the relationship (obtained from successive exhalations).

The DCF method is based upon the measurement of a single breath maneuver (Condorelli et al., 2004, Tsoukias et al., 2001). By using optimization techniques this approach determines the best set of flow-independent NO parameters (CalvNO, J′awNO, DawNO) allowing the best fit between the measured concentration of NO during a single breath maneuver and the concentration predicted for the same breath flow by the two-compartment model. Either data obtained from one single breath after an apnea (DCFSB) (Shin et al., 2001) or several exhalations during tidal breathing (DCFTB) (Condorelli et al., 2004) can be computed, the sole difference being a less accuracy in conducting airway NO parameters estimation in the second approach (George et al., 2004). In this methodological study, the validity of DCF method was tested by comparing the concentration of NO measured at a constant expiratory flow rate and the predicted value of FENO for this flow rate computed with the set of NO parameters determined by the dynamically changing flow rate method.

The subsequent step was to compare both approaches in non-atopic and atopic healthy subjects, since atopy is the underlying condition leading to increased exhaled NO in asthmatic patients (Franklin et al., 2003).

Section snippets

Subjects

Eighteen healthy adults (14 men and 4 women) between 20 and 51 years of age (mean 33 years), were recruited to participate in the study. Subjects were categorized as healthy on the basis of their normal spirometry, the absence of pulmonary disease and smoking history. Ten subjects were categorized as atopic on the basis of history and positive prick test for common allergens. These atopic subjects had no asthma symptoms and were treatment-naïve. The local Institutional Review Board approved the

Statistics

Data were expressed as mean ± standard deviation (S.D.). The significance of differences in continuous variables between non-atopic and atopic subjects was determined using the Mann–Whitney U-test. For method comparisons, continuous variables were compared using the Wilcoxon paired test. The correlation between J′awNO,TB and CalvNO,TB was evaluated using nonparametric test, i.e., Spearman's rank correlation coefficient.

Assessment of the linear approach: the expected value of the correlation

MCF method: validity and results

  • (1)

    The mean value of the normalized slope was negative: −0.020 ± 0.01 s−1 that is significantly different from zero (model hypothesis), in presence of stable expiratory flow rates. A significant relationship between the normalized phase III slope and expiratory flow rate was evidenced (Fig. 1).

  • (2)

    A linear relationship between NO output (QNO) and expiratory flow rates (V′) is expected from Eq. (2), leading to an expected coefficient correlation R higher than 0.81 (see Section 2). The mean R value was

Comparison of the methods in atopic and non-atopic healthy subjects

Flow-independent NO parameters were compared in the nine subjects who satisfied the conditions of validity of MCF and DCF method (two atopic and seven non-atopic subjects). The Bland and Altman representation illustrates the good agreement observed between J′awNO and CalvNO calculated with MCF and DCFSB(10s) analyses (Fig. 3).

Discussion

A growing number of studies describe the flow-independent NO parameters of the two-compartment model in various settings. This is the first methodological study that proposes validity criteria for each analytical method, and that compared the flow-independent NO parameters obtained from the two methods. This study further emphasizes that atopic subjects with increased NO output are less reliably characterized by the model and/or method of measurement. When validity criteria are satisfied,

References (12)

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