A practical approach to the theoretical models to calculate NO parameters of the respiratory system

Abstract

Expired nitric oxide (NO) is used as a biomarker in different respiratory diseases. The recommended flow rate of 50 mL s⁻¹ (F(E)NO₀.₀₅) does not reveal from where in the lung NO production originated. Theoretical models of NO transfer from the respiratory system, linear or nonlinear approaches, have therefore been developed and applied. These models can estimate NO from distal lung (alveolar NO) and airways (bronchial flux). The aim of this study was to show the limitation in exhaled flow rate for the theoretical models of NO production in the respiratory system, linear and nonlinear models. Subjects (n = 32) exhaled at eight different flow rates between 10-350 mL s⁻¹ for the theoretical protocols. Additional subjects (n = 32) exhaled at tree flow rates (20, 100 and 350 mL s⁻¹) for the clinical protocol. When alveolar NO is calculated using high flow rates with the linear model, correction for axial back diffusion becomes negligible, -0.04 ppb and bronchial flux enhanced by 1.27. With Högman and Meriläinen algorithm (nonlinear model) the corrections factors can be understood to be embedded, and the flow rates to be used are ≤20, 100 and ≥350 mL s⁻¹. Applying these flow rates in a clinical setting any F(E)NO can be calculated necessitating fewer exhalations. Hence, measured F(E)NO₀.₀₅ 12.9 (7.2-18.7) ppb and calculated 12.9 (6.8-18.7) ppb. In conclusion, the only possibility to avoid inconsistencies between research groups is to use the measured NO values as such in modelling, and apply tight quality control to accuracies in both NO concentration and exhaled flow measurements.

A European Respiratory Society technical standard: exhaled biomarkers in lung disease

“…1) on a plot of NO output versus flow rate allows the derivation of CANO, DawNO and CawNO [271]. The Högman & Merilänen Algorithm (HMA) is such a model [239,274,275]. A special added feature of the approach by the HMA is to use an algorithm to test if the measured set of data points is mathematically consistent with the model.…”

“…Mathematically, at least two NO values at different flow rates (⩾100 mL•s −1 ) must be used to compute CANO and JawNO, reflecting NO dynamics in the peripheral compartment and central compartment, respectively [270,277]. To divide JawNO into its components CawNO and DawNO, a third low (<20 mL•s −1 ) flow must be included [275]. In addition, a number of different mathematical solutions to calculate these NO parameters have been presented [271] and standardisation of both flows and mathematics is therefore needed to allow for comparison between studies.…”

“…It is extremely important to understand that these corrections were established, and are therefore only applicable, in healthy subjects or in patients free of obstruction. In case of peripheral reduction of airway calibre, back diffusion may be less important and blind application of these formulae in disease states may lead to overcorrection [275,279]. Calculations of NO parameters are also flow dependent and the use of correction factors will over-adjust the CANO, sometimes into negative values [275].…”

“…In case of peripheral reduction of airway calibre, back diffusion may be less important and blind application of these formulae in disease states may lead to overcorrection [275,279]. Calculations of NO parameters are also flow dependent and the use of correction factors will over-adjust the CANO, sometimes into negative values [275]. Therefore, the use of correction factors for axial back diffusion is not recommended (supplement 7).…”

Online Measurement of Exhaled NO Concentration and Its Production Sites by Fast Non-equilibrium Dilution Ion Mobility Spectrometry

“…The two-compartment model (2CM) based on Fick’s first law of diffusion is most commonly used while many algorithms have been developed to calculate it 10 11 . Among them, linear and nonlinear algorithms were frequently described in the literatures 12 . For example, Tsoukias and George proposed a linear technique (T&G) to calculate the 2CM 13 , while Högman and Meriläinen found a nonlinear algorithm (HMA), by which all of the flow-independent NO exchange parameters can be determined 14 .…”