**2.1. Spirometry**

Spirometry is the most common PFT; it is a measurement of maximal airflow after deep inspiration to fill up the lungs. It can provide information about the size of the breathing tubes (mainly large airways) and about the presence of blockages to airflow (63). The measurements usually obtained from spirometry are (64):


The National Asthma Education and Prevention Program (NAEPP) Guidelines previously considered FEV1 as the "gold standard" to assess asthma severity and control, but several studies have suggested that most children have normal or near normal FEV1 even when they are symptomatic. Now the NAEPP has added FEV1/ FVC ratio as an impairment criterion to classify asthma severity and control. The most important pulmonary function abnormalities seen in asthmatic children are decreases in the FEV1/ FVC and the FEF25%-75%, while FEV<sup>1</sup> remain in the normal range in spite of asthma severity (65).

#### **2.2. Forced Oscillation Technique (FOT)**

The fundamental principle of FOT is that respiratory mechanics can be measured from superimposition of external pressure oscillations on the respiratory system during resting breathing (66). Therefore, FOT superimposes small external pressure signals on the natural breathing to determine a subject's breathing mechanics. FOT measures respiratory impedance to this applied forced pressure oscillations produced by a loud speaker (67). FOT is indicated as a reliable diagnostic tool to obtain tidal breathing analysis. One of the great advantages of FOT over other pulmonary function tests is that the results measured are independent of the subject respiratory pattern, therefore it is effort independent; it requires only passive cooperation from the subject breathing normally through a mouth piece, keeping lips airtight closed around it, while wearing a nose clips occluding the nares (68). FOT has been used in humans for more than 50 years; it has been used in children with three major clinical aims (69):


FOT applied at oscillation frequencies between 3 and 35 Hz can provide helpful information to help distinguish between large and small airways. The use of multiple oscillation frequencies in FOT allows a separation of large airways from small airways. Frequencies below 15 Hz, low oscillation frequencies, have been shown to be transmitted more distally (peripherally) in the lungs, whilst frequencies higher than 20 Hz, high oscillation frequencies, can reach only the intermediate size airways. As a result low oscillation frequencies reflect small and large airways, while high oscillation frequencies merely reflect large airways. Therefore, changes in large airway resistance cause uniform changes in resistance at all oscillation frequencies (3-35 Hz), whereas changes in small airway resistance result in noticeable changes in low frequency (3-15 Hz) resistance with small or no change in high frequency resistance. Peripheral airways include all airways with a diameter less than 2mm, and large airways are those with diameters greater than 4 mm (66).

One of the most remarkable features of FOT in relation to spirometry is that it has a relatively greater sensitivity to peripheral airways disease; due to the fact that spirometry does not provide a clear indication of peripheral airway obstruction regardless of the information contained in the flow-volume curve and the values of mid-flow rates (FEF25%-75%) (68).

#### **2.3. Impulse Oscillometry System (IOS)**

106 Practical Applications in Biomedical Engineering

**2.1. Spirometry** 

forced expiration

second of maximal expiration

75% of the FVC has been exhaled

**FEV6:** Forced expiratory volume in six seconds

Parameters with sensitive IOS measures of lung function.

**2. Pulmonary function tests and previous studies** 

discriminate between impaired and non-impaired conditions.

measurements usually obtained from spirometry are (64):

**FEV1/ FVC:** Percentage of the FVC expired in one second

remain in the normal range in spite of asthma severity (65).

**2.2. Forced Oscillation Technique (FOT)** 

quantifying lung function in this population and analyze the correlation of these Model

Pulmonary function refers to how the lungs perform gas exchange. Pulmonary function testing is a practical application of Respiratory Physiology and is necessary for understanding abnormalities in lung function and the effects of treatments. Pulmonary function tests help to determine the severity of functional impairments or defects and the extent to which treatments restore normal function (62). In this section we first review two important pulmonary function tests: Spirometry and Impulse Oscillometry. We then perform a literature review of several studies that have been carried out in previous years to compare several Pulmonary Function Tests (PFTs) to assess the ability of FOT and IOS to measure pulmonary function and to

Spirometry is the most common PFT; it is a measurement of maximal airflow after deep inspiration to fill up the lungs. It can provide information about the size of the breathing tubes (mainly large airways) and about the presence of blockages to airflow (63). The

**FVC (**Forced vital capacity**):** Total volume of air that can be exhaled during a maximal

**FEV1:** Forced expiratory volume in seconds. It is the volume of air expired in the first

 **FEF25%-75%:** Average expired flow over the middle half of FVC. It represents the average flow from the point at which 25% of the FVC has been exhaled to the point at which

The National Asthma Education and Prevention Program (NAEPP) Guidelines previously considered FEV1 as the "gold standard" to assess asthma severity and control, but several studies have suggested that most children have normal or near normal FEV1 even when they are symptomatic. Now the NAEPP has added FEV1/ FVC ratio as an impairment criterion to classify asthma severity and control. The most important pulmonary function abnormalities seen in asthmatic children are decreases in the FEV1/ FVC and the FEF25%-75%, while FEV<sup>1</sup>

The fundamental principle of FOT is that respiratory mechanics can be measured from superimposition of external pressure oscillations on the respiratory system during resting

**PE :** Peak expiratory flow represents the maximal expiratory flow rate achieved

In 1956 Dubois presented the first study on FOT; in this study FOT was applied using sinusoidal oscillations with multiple single frequencies between 2 and 18 Hz. After this study several modifications of FOT were developed, until 1993 when the pulse technique was improved and commercially produced by the German company Jaeger. It was named Impulse Oscillometry System (IOS), as an easier to use method to measure respiratory resistance (R) and reactance (X). The advantages of IOS include good time resolution. It measures 5 pulses per second, with continuous resolution in the frequency domain using a Fourier Integral (65-66) to calculate respiratory impedance. The IOS, as FOT, superimposes small air pressure perturbations on the natural breathing of a subject to measure the impedance of the respiratory system, offering an easy to use method as it does not require any effort from the subject being tested. An additional advantage is the simplicity of the hardware needed to generate the forced oscillations, allowing smaller, more efficient electronic and mechanical structures with minimal power loss (68).

Impulse Oscillometric Features and Respiratory System Models Track Small Airway Function in Children 109

IOS also includes hallmarks such as *Resonant Frequency* (Fres) and *Reactance Area* (AX) also known as the *"Goldman Triangle".* IOS yields these indices over a selected frequency range of

The real part of the Impedance (Z) corresponds to the Resistance (R), which includes the resistance of the proximal (central) and distal (peripheral) airways as well as lung tissue and chest wall while these latter resistances are usually negligible. In healthy adult subjects, R is nearly independent of oscillation frequency. When an airway obstruction occurs, either central or peripheral, R5 (Resistance at 5 Hz) is increased above normal values. Central airway obstruction elevates R evenly independent of oscillation frequency. Peripheral airways obstruction is highest at low oscillation frequencies and falls with increasing frequency; this is called the negative frequency-dependence of Resistance (fdR). As peripheral resistance increases, R becomes more frequency dependent. Small children normally present frequency-dependence of resistance, and this may be greater than in adults in the presence of peripheral airflow obstruction.

The imaginary part of Z, the respiratory Reactance (X), includes the mass-inertive forces of the moving air column expressed in terms of Inertance (I) and the Elastic properties (compliance) of lung periphery expressed as capacitance (C) in electrical terms (68).

> 

(3)

*Xf I C* . – 1 / . 

2 0 *f f fmax*

**B. Other IOS parameters: Resonant Frequency (Fres), Reactance Area (AX) and** 

The Resonant Frequency (Fres) is the point at which C and I are equal, therefore

C represents the ability of the respiratory system to store energy, primarily located in the lung periphery. The component of X associated with C is defined to be negative in sign. It means C is dominant at low oscillation frequencies, meanwhile the component of X related to I is positive in sign, meaning that I's property is more prominent at high oscillation frequencies (see figure 1). Reactance is measured in cmH2O/L/s or KPa/L/s (68).

**A. Impedance Parameters: Respiratory Resistance (R) and Respiratory** 

Resistance is measured in cmH2O/L/s or KPa/L/s (68).

**Frequency dependence of resistance (R5-R25)** 

reactance is zero and is measured in Hertz (1/s) (68).

 

3 to 35 Hz (68).

**Reactance (X)** 

**a. Respiratory Resistance (R)** 

**b. Respiratory Reactance (X)** 

where

**a. Resonant Frequency** 

Some disadvantages of the IOS have to be recognized. The fact that IOS measures spontaneous breathing from a subject allows biological variability, and to counteract this fact multiple tests are required to be performed in a subject in order to establish reliable mean values of IOS parameters. A special aspect of applying pulses of pressure is that they are applied within a very short time causing a higher impact on the respiratory system compared with other lung function tests, and this may be perceived as an unpleasant sensation during the measurements (68).

A Jaeger MasterScreen IOS (Viasys Healthcare, Inc. Yorba Linda, CA, USA) was used in this study. The system was calibrated every day using a 3-L syringe for volume calibrations and a reference resistance (0.2 KPa/L/s) for pressure calibrations. Children were asked to wear a nose clip, while breathing normally through a mouthpiece and were instructed to tightly close their lips around it to avoid air leakage. Three to five IOS test replicates were performed on each subject to ensure reproducible tests without artifacts caused by air leaks, swallowing, breath holding or vocalization (9). In each IOS test impulses were applied for a period of 30 to 45 seconds. IOS data were carefully reviewed off line and quality-assured by our expert clinician to reject segments affected by airflow leak or swallowing artifacts. Coherence was also used as a 'quality assurance index'; it is an index of causality between the input and the output of a linear system, therefore if the system is nonlinear or if it is contaminated by extraneous noise then the coherence is lower than expected. Therefore, measurements with low coherence were excluded in this research to avoid problems with artifacts. Coherence is considered by researchers as a useful guide to quality assurance (67).

#### *2.3.1. IOS parameters*

IOS is a multifrequency oscillation method; it provides measures of respiratory mechanics in terms of *respiratory impedance* as a function of frequency Z (*f*).

Respiratory Impedance is the transfer function of pressure (P) and flow (Q), derived from the superimposed forced oscillation, after being separated from the respiratory pressure and flow.

$$Z\begin{pmatrix}f\end{pmatrix} = P\begin{pmatrix}f\end{pmatrix} / \mathbb{Q}(f) \tag{1}$$

The respiratory *Impedance* (Z) measured by IOS is a complex quantity and consists of a real part called respiratory *Resistance* (R) and an imaginary part called respiratory *Reactance* (X).

$$Z\begin{pmatrix}f\end{pmatrix} = \mathbb{R}\begin{pmatrix}f\end{pmatrix} + jX\begin{pmatrix}f\end{pmatrix} \tag{2}$$

IOS also includes hallmarks such as *Resonant Frequency* (Fres) and *Reactance Area* (AX) also known as the *"Goldman Triangle".* IOS yields these indices over a selected frequency range of 3 to 35 Hz (68).

#### **A. Impedance Parameters: Respiratory Resistance (R) and Respiratory Reactance (X)**

#### **a. Respiratory Resistance (R)**

108 Practical Applications in Biomedical Engineering

sensation during the measurements (68).

*2.3.1. IOS parameters* 

flow.

Fourier Integral (65-66) to calculate respiratory impedance. The IOS, as FOT, superimposes small air pressure perturbations on the natural breathing of a subject to measure the impedance of the respiratory system, offering an easy to use method as it does not require any effort from the subject being tested. An additional advantage is the simplicity of the hardware needed to generate the forced oscillations, allowing smaller, more efficient

Some disadvantages of the IOS have to be recognized. The fact that IOS measures spontaneous breathing from a subject allows biological variability, and to counteract this fact multiple tests are required to be performed in a subject in order to establish reliable mean values of IOS parameters. A special aspect of applying pulses of pressure is that they are applied within a very short time causing a higher impact on the respiratory system compared with other lung function tests, and this may be perceived as an unpleasant

A Jaeger MasterScreen IOS (Viasys Healthcare, Inc. Yorba Linda, CA, USA) was used in this study. The system was calibrated every day using a 3-L syringe for volume calibrations and a reference resistance (0.2 KPa/L/s) for pressure calibrations. Children were asked to wear a nose clip, while breathing normally through a mouthpiece and were instructed to tightly close their lips around it to avoid air leakage. Three to five IOS test replicates were performed on each subject to ensure reproducible tests without artifacts caused by air leaks, swallowing, breath holding or vocalization (9). In each IOS test impulses were applied for a period of 30 to 45 seconds. IOS data were carefully reviewed off line and quality-assured by our expert clinician to reject segments affected by airflow leak or swallowing artifacts. Coherence was also used as a 'quality assurance index'; it is an index of causality between the input and the output of a linear system, therefore if the system is nonlinear or if it is contaminated by extraneous noise then the coherence is lower than expected. Therefore, measurements with low coherence were excluded in this research to avoid problems with artifacts. Coherence is considered by researchers as a useful guide to quality assurance (67).

IOS is a multifrequency oscillation method; it provides measures of respiratory mechanics in

Respiratory Impedance is the transfer function of pressure (P) and flow (Q), derived from the superimposed forced oscillation, after being separated from the respiratory pressure and

The respiratory *Impedance* (Z) measured by IOS is a complex quantity and consists of a real part called respiratory *Resistance* (R) and an imaginary part called respiratory *Reactance* (X).

*Z f P f Qf* / () (1)

*Z f R f jX f* (2)

terms of *respiratory impedance* as a function of frequency Z (*f*).

electronic and mechanical structures with minimal power loss (68).

The real part of the Impedance (Z) corresponds to the Resistance (R), which includes the resistance of the proximal (central) and distal (peripheral) airways as well as lung tissue and chest wall while these latter resistances are usually negligible. In healthy adult subjects, R is nearly independent of oscillation frequency. When an airway obstruction occurs, either central or peripheral, R5 (Resistance at 5 Hz) is increased above normal values. Central airway obstruction elevates R evenly independent of oscillation frequency. Peripheral airways obstruction is highest at low oscillation frequencies and falls with increasing frequency; this is called the negative frequency-dependence of Resistance (fdR). As peripheral resistance increases, R becomes more frequency dependent. Small children normally present frequency-dependence of resistance, and this may be greater than in adults in the presence of peripheral airflow obstruction. Resistance is measured in cmH2O/L/s or KPa/L/s (68).

#### **b. Respiratory Reactance (X)**

The imaginary part of Z, the respiratory Reactance (X), includes the mass-inertive forces of the moving air column expressed in terms of Inertance (I) and the Elastic properties (compliance) of lung periphery expressed as capacitance (C) in electrical terms (68).

$$X\begin{pmatrix}f\end{pmatrix} = \begin{pmatrix}a.I\ \vdots\end{pmatrix} \begin{pmatrix}1\end{pmatrix} \begin{pmatrix}a.\mathbb{C}\end{pmatrix} \tag{3}$$

where

$$\rho = 2\pi f \left\{ 0 < f \le f \text{max} \right\}$$

C represents the ability of the respiratory system to store energy, primarily located in the lung periphery. The component of X associated with C is defined to be negative in sign. It means C is dominant at low oscillation frequencies, meanwhile the component of X related to I is positive in sign, meaning that I's property is more prominent at high oscillation frequencies (see figure 1). Reactance is measured in cmH2O/L/s or KPa/L/s (68).

#### **B. Other IOS parameters: Resonant Frequency (Fres), Reactance Area (AX) and Frequency dependence of resistance (R5-R25)**

#### **a. Resonant Frequency**

The Resonant Frequency (Fres) is the point at which C and I are equal, therefore reactance is zero and is measured in Hertz (1/s) (68).

**Figure 1.** IOS parameters [76]

$$a\_0.I = \begin{pmatrix} 1/\ a\_0.\mathbb{C} \end{pmatrix} \tag{4}$$

Impulse Oscillometric Features and Respiratory System Models Track Small Airway Function in Children 111

**Figure 2.** Reactance measurements in a Normal and a SAI child as a function of oscillation frequency.

It is simply the subtraction of the measured resistance at 20 Hz from the resistance at 5 Hz or 3 Hz. Frequency-dependence of resistance is a characteristic of peripheral airway

Changes in AX with treatment interventions parallel changes in frequency-dependence of R. It has been suggested by Goldman et al. (66) that the magnitudes of frequency dependence of R and AX appear to reflect a similarly predominant influence of

Frequency-dependence of resistance occurs in healthy children, and to a better extent in children with respiratory system distresses (67). There is now plenty of evidence that peripheral airway inflammation is present in asthma patients, and frequency-

The bronchodilation response as a physiological response to short-acting beta agonist medicines has been recommended to demonstrate reversibility of airflow obstruction

Bronchoconstriction is defined as increased tone of airway smooth muscles due to inflammation; and bronchodilation is defined as decrease in smooth muscle tone, and as a result a decrease in inflammation. When an increase of airways smooth muscle tone occurs, R increases due to a corresponding decrease in airway lumen. R also increases due to inflammation or edema. In asthmatics, high and low frequency R decreases after bronchodilation, showing a larger decrease in low-frequency R and a resultant decrease in frequency-dependence of resistance. In addition FOT has been reported to demonstrate larger sensitivity to inhaled corticosteroid or to β-agonist inhalation than spirometry (68).

*RR R R* 5 – 20 5 – 20 (5)

**a) Frequency-dependence of resistance (fdR or R5-R20)** 

dependence of resistance occurs significantly in asthma (68).

peripheral airway mechanical function.

**2.4. Bronchodilation phenotype** 

consistent with the definition of asthma (65).

dysfunction (66).

This parameter should not be interpreted as a particular respiratory system mechanical property; instead it can be used as a suitable marker to separate low frequency from high frequency impedance. Respiratory system abnormalities cause Fres value to be increased [74].

#### **b. Reactance Area (AX)**

The Reactance Area (AX), – the "Goldman Triangle" - was introduced by Michael Goldman in his study on "Clinical applications of forced oscillations" (67); AX is the integrated low frequency respiratory reactance magnitude between 5 Hz and Fres, and is measured in cmH2O/L or KPa/L. AX is a practical FO index related to respiratory compliance. AX is a single quantity that reflects changes in the degree of peripheral airway obstruction and closely correlates with fdR(68). *AX is a useful and sensitive index of peripheral airway function* (66).

Figure 2 shows data collected from a Normal (N) child and a child with Small Airway Impairment (SAI) for this research as an example. In this figure it can be observed that the **AX (the Goldman's Triangle)** area is bigger for the child with SAI than for the normal child. It is interesting to notice that the values of Fres are very close for both children.

**Figure 2.** Reactance measurements in a Normal and a SAI child as a function of oscillation frequency.

#### **a) Frequency-dependence of resistance (fdR or R5-R20)**

It is simply the subtraction of the measured resistance at 20 Hz from the resistance at 5 Hz or 3 Hz. Frequency-dependence of resistance is a characteristic of peripheral airway dysfunction (66).

$$R5 - R20 = R5 - R20 \tag{5}$$

Changes in AX with treatment interventions parallel changes in frequency-dependence of R. It has been suggested by Goldman et al. (66) that the magnitudes of frequency dependence of R and AX appear to reflect a similarly predominant influence of peripheral airway mechanical function.

Frequency-dependence of resistance occurs in healthy children, and to a better extent in children with respiratory system distresses (67). There is now plenty of evidence that peripheral airway inflammation is present in asthma patients, and frequencydependence of resistance occurs significantly in asthma (68).

#### **2.4. Bronchodilation phenotype**

110 Practical Applications in Biomedical Engineering

**Figure 1.** IOS parameters [76]

increased [74].

children.

**b. Reactance Area (AX)** 

*of peripheral airway function* (66).

0 0

 

This parameter should not be interpreted as a particular respiratory system mechanical property; instead it can be used as a suitable marker to separate low frequency from high frequency impedance. Respiratory system abnormalities cause Fres value to be

The Reactance Area (AX), – the "Goldman Triangle" - was introduced by Michael Goldman in his study on "Clinical applications of forced oscillations" (67); AX is the integrated low frequency respiratory reactance magnitude between 5 Hz and Fres, and is measured in cmH2O/L or KPa/L. AX is a practical FO index related to respiratory compliance. AX is a single quantity that reflects changes in the degree of peripheral airway obstruction and closely correlates with fdR(68). *AX is a useful and sensitive index* 

Figure 2 shows data collected from a Normal (N) child and a child with Small Airway Impairment (SAI) for this research as an example. In this figure it can be observed that the **AX (the Goldman's Triangle)** area is bigger for the child with SAI than for the normal child. It is interesting to notice that the values of Fres are very close for both

. 1/ . *I C* (4)

The bronchodilation response as a physiological response to short-acting beta agonist medicines has been recommended to demonstrate reversibility of airflow obstruction consistent with the definition of asthma (65).

Bronchoconstriction is defined as increased tone of airway smooth muscles due to inflammation; and bronchodilation is defined as decrease in smooth muscle tone, and as a result a decrease in inflammation. When an increase of airways smooth muscle tone occurs, R increases due to a corresponding decrease in airway lumen. R also increases due to inflammation or edema. In asthmatics, high and low frequency R decreases after bronchodilation, showing a larger decrease in low-frequency R and a resultant decrease in frequency-dependence of resistance. In addition FOT has been reported to demonstrate larger sensitivity to inhaled corticosteroid or to β-agonist inhalation than spirometry (68).

According to a study on PFT in preschool children in 2007, FOT has been successfully performed in different settings, and a number of studies have demonstrated that FOT was capable of identifying airway obstruction and reactions to bronchodilators and bronchoconstrictors (71). Several studies have been developed to assess bronchodilator responses using FOT. Marotta et al. (7) performed a study in 4-year old children concluding that IOS bronchodilator responses are remarkably abnormal in this population (children presented a significant bronchodilator response), and that IOS is a useful diagnostic tool in detection of early asthma development. Oostveen et al. (72) performed a comprehensive review on methodology, recommendations and future developments of FOT in clinical practice stating that FOT is a reliable method to assess bronchial hyperresponsiveness in adults and children. Ortiz et al. (8) performed an IOS study in children 2 to 5 years old in El Paso, Texas, finding that IOS is an acceptable method of assessing airway responses to bronchoactive drugs in this age group. In a more recent study related to the use of FOT to detect bronchodilation in children, Bar-Yishay et al. (73) concluded that FOT could reliably measure response to bronchodilator therapy. Recently Song et al (13) researched the utility of impulse oscillometry in young children with asthma finding that asthmatic children differed from control subjects in IOS-assessed bronchodilator response and that there were some significant correlations between bronchodilator responses of spirometric and IOS parameters. Galant et al. (65) stated that bronchodilator response (BDR) would appear to give important additional information about airway inflammation and found that IOS is a promising test to identify asthmatic preschoolers.

Impulse Oscillometric Features and Respiratory System Models Track Small Airway Function in Children 113

**Parameters Conclusions** 

asthmatic R5, X5, Fres IOS bronchodilator responses are remarkably

AX were seen.

**adolescents.** 

spirometry

inhaled

**spirometry**

therapy in

Resistance values measured at 5Hz showed to be

**indirect** 

Spirometry did not present statistically significant

between

IOS parameters.

**measure.** 

FEV1 and PEFR showed significant correlation with

in both groups,

asthmatic patients whose FEV1 fails to improve

**Evaluated** 

2003 4 years abnormal in this population.

**IOS is a useful tool for asthma assessment** 

[9] asthmatics R5, R5-R15, AX Significant differences between R5, R5-R15 and

2002 10-17 years Spirometric indices showed no change. **IOS parameters are sensitive measures of bronchomotor tone changes in these** 

Saadeh et al. [11] asthma symptoms R5, R5-R15, AX Some asthmatic patients manifest normal

Gaylor et al. [6] asthmatics R5, R5-R15, AX IOS shows systematic improvements after

Hz

R5, R10, R20, R35

R and X at 5-35 Hz

2008 3-6 years differences between groups.

2003 5-17 years superior to PEF measurements,

**IOS parameters can be easily used as an** 

There were some significant correlations

bronchodilator responses of spirometry and

 **IOS is a useful diagnostic tool and might be a helpful objective outcome** 

2008 7-15 years R5-R20 impedance and resistance at 5,10,20 and 35 Hz

**measure of airflow obstruction.** 

2003 5-80 years levalbuterol, **FO is more sensitive than** 

and IOS should be considered before changing

2003 4-62 years despite continuing symptoms, **these patients may be more sensitively managed using IOS** 

**Researchers Evaluated** 

Marota et al. [7] asthmatic and non-

Goldman et al.

**Population** 

Vink et al. [12] asthmatics R and X at 5-35

controls

controls

Song et al. [13] asthmatics and

Song et al. [14] asthmatics and

All this evidence confirms that lung function in children and adolescents is sensitively and accurately assessed by IOS, before and after bronchodilation. Nevertheless few longitudinal Forced Oscillation (FO) data exist in healthy subjects or in those with airflow obstruction. Oostveen et al. (72) noted the need for a practical FO index to define airway obstruction.

#### **2.5. IOS studies**

#### *2.5.1. IOS vs. Spirometry*

Table 1 provides a summary of several IOS vs Spirometry studies, with their descriptions, different IOS parameters analyzed and conclusions.

Table 1 summarizes the utility of different IOS indexes of lung function in relation to spirometric parameters in different subpopulations studied between 2002 and 2009. The conclusions emphasize the necessity to analyze these parameters to determine their efficacy to differentiate between Healthy and Impaired respiratory systems. In our study we focused on the most significant IOS indexes of lung function and pushed the boundary by further analyzing the respiratory impedance Model Parameters to differentiate between Healthy and Impaired respiratory conditions in children.

Impulse Oscillometric Features and Respiratory System Models Track Small Airway Function in Children 113

112 Practical Applications in Biomedical Engineering

preschoolers.

obstruction.

**2.5. IOS studies** 

*2.5.1. IOS vs. Spirometry* 

different IOS parameters analyzed and conclusions.

and Impaired respiratory conditions in children.

According to a study on PFT in preschool children in 2007, FOT has been successfully performed in different settings, and a number of studies have demonstrated that FOT was capable of identifying airway obstruction and reactions to bronchodilators and bronchoconstrictors (71). Several studies have been developed to assess bronchodilator responses using FOT. Marotta et al. (7) performed a study in 4-year old children concluding that IOS bronchodilator responses are remarkably abnormal in this population (children presented a significant bronchodilator response), and that IOS is a useful diagnostic tool in detection of early asthma development. Oostveen et al. (72) performed a comprehensive review on methodology, recommendations and future developments of FOT in clinical practice stating that FOT is a reliable method to assess bronchial hyperresponsiveness in adults and children. Ortiz et al. (8) performed an IOS study in children 2 to 5 years old in El Paso, Texas, finding that IOS is an acceptable method of assessing airway responses to bronchoactive drugs in this age group. In a more recent study related to the use of FOT to detect bronchodilation in children, Bar-Yishay et al. (73) concluded that FOT could reliably measure response to bronchodilator therapy. Recently Song et al (13) researched the utility of impulse oscillometry in young children with asthma finding that asthmatic children differed from control subjects in IOS-assessed bronchodilator response and that there were some significant correlations between bronchodilator responses of spirometric and IOS parameters. Galant et al. (65) stated that bronchodilator response (BDR) would appear to give important additional information about airway inflammation and found that IOS is a promising test to identify asthmatic

All this evidence confirms that lung function in children and adolescents is sensitively and accurately assessed by IOS, before and after bronchodilation. Nevertheless few longitudinal Forced Oscillation (FO) data exist in healthy subjects or in those with airflow obstruction. Oostveen et al. (72) noted the need for a practical FO index to define airway

Table 1 provides a summary of several IOS vs Spirometry studies, with their descriptions,

Table 1 summarizes the utility of different IOS indexes of lung function in relation to spirometric parameters in different subpopulations studied between 2002 and 2009. The conclusions emphasize the necessity to analyze these parameters to determine their efficacy to differentiate between Healthy and Impaired respiratory systems. In our study we focused on the most significant IOS indexes of lung function and pushed the boundary by further analyzing the respiratory impedance Model Parameters to differentiate between Healthy



Impulse Oscillometric Features and Respiratory System Models Track Small Airway Function in Children 115

**Parameters Conclusions** 

4-20 years spirometry. A mean drop of R5 by -24 was

**Parameters General Conclusions** 

measured by

by

found to be significant

**and** 

**function,** 

values.

plethysmographic Raw and the strongest correlation was observed for R5.

**IOS may be useful in diagnosing children with obstructive respiratory diseases.**

**Evaluated** 

al. [29] 46 inner-city children R5 and R20 There is increased airway resistance as

Other researchers have compared IOS with spirometry and other techniques. Table 2 presents a summary of several such studies, with their descriptions, different IOS

**IOS, Spirometry and Whole body Plethysmography** 

et al. [18] asthmatics R5, R20, X5 **IOS was well accepted for young asthmatic children** 

2005 3-6 year old **produced reproducible and sensitive indices of lung** 

R5 correlated with spirometry and plethysmographic

diseases R5, R20, R35 All three resistances correlated significantly with

**IOS and Whole body Plethysmography** 

**Evaluated** 

2009 with asthma IOS when there is airway obstruction measured

**Researchers Evaluated** 

**Table 1.** IOS vs Spirometry Studies

*2.5.2. IOS vs Other techniques* 

**Researchers Evaluated** 

Olaguibel

Tomalak et al. [19]

parameters analyzed and conclusions.

**Population** 

chronic respiratory

diseases, cystic

fibrosis, bronchiectasis and lung

5-18 years

<sup>2006</sup>(asthma, allergic

fibrosis)

Graw-Panzer et

**Population** 

Impulse Oscillometric Features and Respiratory System Models Track Small Airway Function in Children 115


#### **Table 1.** IOS vs Spirometry Studies

114 Practical Applications in Biomedical Engineering

**Population** 

mild and moderate

[16] asthmatics R5, X5, Fres

Nieto et al. [24] mild asthma Z5, R5,

[28] healthy and asthmatic R and X at 5-35

Larsen et al. [26] mild to moderate

asthmatics Z, R5, X5, Fres

**Evaluated** 

FVC correlated with Z and R at 10, 20 and 35

**IOS is an appropriate measure of lung** 

**when spirometry and PEF can not be** 

2006 6 years IOS presented significant increase in total

**IOS may be more sensitive than spirometry** 

**inflammatory process and degree of asthma** 

2002 6-15 years best correlation: R5 and FEV1, and R5 and

al. [17] asthmatics R5 Spirometry and IOS should be used together in

2006 no changes were found in the control group. **IOS is more sensitive than conventional** 

<sup>2008</sup>detecting decreased lung function and showed

2009 6-14 years in contrast to spirometric values, **AX might** 

1998 kindergarten children A change in R5 of 40% is to be considered as the

2.7 - 6.6 years old for a "positive" bronchodilator response.

**spirometry.** 

Hz, Fres

asthma AX AX was unique in reflecting ongoing

Hur et al. [25] children X5 and R5 **IOS parameters were more discriminative** 

2005 5-18 years evaluation.

R20,X5,Fres

**Parameters Conclusions** 

Hz in both groups.

**function** 

**performed.** 

No significant differences for spirometry were found,

impedance (Z), R5 and Fres, and significant decrease in X5.

**for assessment of** 

**severity.**

**There were good correlation between spirometry and IOS,** 

FEF25.

asthma

Z5, R5, R20, X5, and Fres showed improvements,

**spirometry.**

**than FEV1** for

a good correlation with FEV1.

improvement

**detect**

No significant differences between groups for IOS parameters

cut-off

alterations in airway mechanics not reflected by

**Researchers Evaluated** 

Antonova et al. [15]

Linares et al.

Lewis-Brown et

Hellinckx et al.

#### *2.5.2. IOS vs Other techniques*

Other researchers have compared IOS with spirometry and other techniques. Table 2 presents a summary of several such studies, with their descriptions, different IOS parameters analyzed and conclusions.



Impulse Oscillometric Features and Respiratory System Models Track Small Airway Function in Children 117

**Parameters General Conclusions** 

**response** 

**mechanical** 

children.

in pre-school children with asthma

subpopulations studied between 1995 and 2009. The conclusions emphasize the necessity to analyze these IOS parameters to determine their efficacy to differentiate between Healthy

Table 3 presents a summary of several IOS studies, with their descriptions, different IOS

Ortiz et al. [8] asthmatics X5 **IOS is an acceptable method to assess airway** 

2002 2-5 years to bronchoactive drugs in this age group.

[22] asthmatics R5, R5-R20, AX **IOS indices are sensitive measures of lung** 

2008 2-5 years **responses** to bronchodilators in this group of

[31] asthmatics R5,R5-R20, AX **IOS R5, R5-R20, AX are sensitive measures of**  2008 2-5 years **lung mechanics** responses to SABA and LABA

Jee et al. [32] asthmatics and R, X, Fres and AX **IOS parameters were significantly different** 

The outcomes of most recent studies carried out between 2002 and 2010 presented in table 3 show the utility of different IOS parameters including the AX, "the Godlman's Triangle", as

As mentioned before, a number of previous IOS studies, summarized in tables 1, 2 and 3, demonstrate that IOS is able to sensitively and accurately evaluate lung function in children and adolescents, using Pre- and Post-bronchodilation conditions and bronchial challenge. These studies further show that that different IOS parameters at different frequencies serve as quantitative indicators to evaluate the Pre- and Post-bronchodilation response and bronchial challenge results. It is also remarkable that very few studies, only the most recent ones, reported the analysis of the AX parameter, which could offer critical information about lung function in children and adolescents as stated by Goldman et al. (9, 22), Nieto et al. (24), Larsen et al. (26) and Menendez et al. (31). Therefore, here we aim to statistically evaluate the performance of all IOS measured and calculated parameters (Resistances and Reactances, Fres, AX, frequency-dependence of resistance R3-R20 and R5-R20) over 3-35 Hz

(controls) **between groups** in the methacholine challenge

and Impaired respiratory systems.

parameters analyzed and conclusions.

<sup>2010</sup>chronic couugh

children

sensitive measures to assess lung function.

**Researchers Evaluated Population Evaluated** 

*2.5.3. IOS studies* 

Goldman et al.

Menendez et al.

**Table 3.** IOS studies

**Table 2.** IOS vs other Techniques Studies

Table 2 summarizes the utility of different IOS indexes of lung function in relation to parameters acquired from a variety of other pulmonary function test in different subpopulations studied between 1995 and 2009. The conclusions emphasize the necessity to analyze these IOS parameters to determine their efficacy to differentiate between Healthy and Impaired respiratory systems.

#### *2.5.3. IOS studies*

116 Practical Applications in Biomedical Engineering

al. [20] suspected asthma R and X at 5-35

[10] asthmatics R and X at 5-35

Caucasian, no chronic diseases

asthmatics and

asthmatics and

62 asthmatics, 13 wheezy and

**Table 2.** IOS vs other Techniques Studies

Bisgaard et

Klug et al.

Klug et al. [4]

Nielsen et al. [21]

Nielsen et al. [23]

Todaki et al [30]

**IOS, Interrupter Technique Resistance (Rint), Transcutaneous Measurement of Oxygen Tension (Ptc, O2) and Whole Body Plethysmography** 

1995 4-6 years in parallel with sRaw and FEV1, **these three** 

**provide convenient indices of changes in lung** 

**IOS, Interrupter Technique Resistance (Rint) and Whole Body Plethysmography** 

1998 2-7 years **measurement of lung function in 80% o**f the tested

controls R5, X5 **Whole body plethysmography (sRaw) was superior** 

controls R5, X5 **Whole body plethysmography (sRaw) was superior** 

R20 **A significant decrease occurred in the eNO level** 

IOS total respiratory impedance (Z), Rint, and Ptc,O2 changed

**parameters**

**function.** 

**All the evaluated techniques reliably reflect shortterm** 

**Techniques require minimal cooperation and allowed** 

children.

Hz

Hz

R5,R10,X5,X10, Z5,Fres

1996 2-4 years **changes in lung function.** 

2000 2-5 years **in separating both groups.** 

2001 2-5 years **in separating both groups.** 

**vital capacity R5-R20** 

R20 and R5-

**IOS, Spirometry and exhaled nitric oxide (eNO)** 

2009 17 healthy children **and it correlated with maximal expiratory flow at 50%** 

Table 2 summarizes the utility of different IOS indexes of lung function in relation to parameters acquired from a variety of other pulmonary function test in different Table 3 presents a summary of several IOS studies, with their descriptions, different IOS parameters analyzed and conclusions.


**Table 3.** IOS studies

The outcomes of most recent studies carried out between 2002 and 2010 presented in table 3 show the utility of different IOS parameters including the AX, "the Godlman's Triangle", as sensitive measures to assess lung function.

As mentioned before, a number of previous IOS studies, summarized in tables 1, 2 and 3, demonstrate that IOS is able to sensitively and accurately evaluate lung function in children and adolescents, using Pre- and Post-bronchodilation conditions and bronchial challenge. These studies further show that that different IOS parameters at different frequencies serve as quantitative indicators to evaluate the Pre- and Post-bronchodilation response and bronchial challenge results. It is also remarkable that very few studies, only the most recent ones, reported the analysis of the AX parameter, which could offer critical information about lung function in children and adolescents as stated by Goldman et al. (9, 22), Nieto et al. (24), Larsen et al. (26) and Menendez et al. (31). Therefore, here we aim to statistically evaluate the performance of all IOS measured and calculated parameters (Resistances and Reactances, Fres, AX, frequency-dependence of resistance R3-R20 and R5-R20) over 3-35 Hz

during pre-post- bronchodilation conditions. We place special emphasis on the previously observed most significant IOS and Model Parameters and will determine which one of these parameters is more effective in differentiating between Pre- and Post-bronchodilation conditions.

Impulse Oscillometric Features and Respiratory System Models Track Small Airway Function in Children 119

7 to 12 years old **seems to be useful to diagnose a variety** 

**before.** 

**Used Evaluated Population Conclusions** 

Table 4 shows that only few studies have been developed in order to determine Reference

In 1991, the American Thoracic Society published guidelines focusing on spirometry as the most widely used lung function test. This document states that it is common practice to interpret the results of lung function tests in relation to Reference Values and in terms of

The European Respiratory Society published a workshop report in 1995 (34) about some commonly measured spirometry parameters such as RV, FRC and TLC. In this document it is stated that reference values play an important role in establishing whether the measured respiratory volumes fall within an expected range for healthy individuals of the same sex, similar stature, age, and other characteristics. In this report reference values (values for healthy subjects) and prediction equations for lung volumes for children and adults are obtained using different techniques like helium dilution and body plethysmography. These values are presented for different heights. However, this report does not include reference

From table 4 we observe that it is crucial to have IOS Reference Values for children. These have been very effective in the detection of lung abnormalities, as demonstrated in table 1, 2, and 3. Therefore, in our research here we attempt to take the first steps towards establishing IOS Reference Values in Healthy North American Anglo and Hispanic children 5 to 19 years old. We also aim to present baseline (pre-) and post-bronchodilation IOS parameter values for this subpopulation of children with Probable Small Airway Impairment (PSAI), Small

The IOS and FOT impedance curves can be represented by equivalent electrical circuit models of the human respiratory system with components analogous to the resistances, compliances and inertances inherent in the characterization of this system. Respiratory system component values could be estimated using well-established parameter estimation methods. These could then be used to assist physicians in the diagnosis and treatment of

whether or not they are considered to be within the "normal" range (33).

 **of respiratory diseases.** Jee et al. [42] IOS Korean children **Healthy young children had better results in IOS**  2010 143 **parameters than main reference values reported** 

3-6 years

values and prediction equations based on the FOT or IOS.

Airway Impairment (SAI) and Asthma (A).

**3. Respiratory system models** 

different respiratory diseases (43).

**Researchers Method** 

**Table 4.** IOS Reference Values

IOS Values for children.

### *2.5.4. IOS reference values - Previous studies*

Table 4 below presents a summary of several studies performed to determine Reference FOT and IOS values in children.



**Table 4.** IOS Reference Values

and IOS values in children.

**Researchers Method** 

Clement et al.

Ducharme et

Dencker et al.

Nowowiejska

*2.5.4. IOS reference values - Previous studies* 

al. [36] FOT North American

(white,black,asian,oth

3 to 17 years

 360 children 90-160 cm

1998 206 healthy children

100 to 150 cm in

children

ers)

conditions.

during pre-post- bronchodilation conditions. We place special emphasis on the previously observed most significant IOS and Model Parameters and will determine which one of these parameters is more effective in differentiating between Pre- and Post-bronchodilation

Table 4 below presents a summary of several studies performed to determine Reference FOT

**Used Evaluated Population Conclusions** 

[35] FOT Belgian R and X vs frequency data depended on 1987 403 healthy children age or height, on sex, and slightly on weight.

**Adult values of R and X can be observed at** 

Frei et al. [37] IOS North American **Standing height was the only significant**  2005 222 white children **predictor for all variables** 

[38] IOS Swedish **All variables were related to body height,**  2006 2 to 10 years and most of them were weakly related to weight.

et al. [39] IOS Polish **Body height was the best predictor** and resistances 2008 626 healthy children were best predicted with exponential

Amra et al. [40] IOS Iranian **These measurements can be used clinically**  2008 509 healthy children **to help diagnose and monitor respiratory disorders, independent of effort.**  Wee et al. [41] IOS Korean IOS is a feasible method to measure the respiratory 2007 92 children resistance in children. **The reference values using IOS**

4 to 20 years With growth R and the frequency-dependence

3 to 10 years old Resistance and Fres decreased by height,

aged 3-18 models while reactances with linear ones.

height but also by age, and reactance increased.

of R decrease while X increases.

**15 years of age in girls and at 18 years in boys.** 

**Height is the best predictor for total respiratory resistance at 8,12 and 16 Hz in children.** 

R decreased with height while X increased.

Table 4 shows that only few studies have been developed in order to determine Reference IOS Values for children.

In 1991, the American Thoracic Society published guidelines focusing on spirometry as the most widely used lung function test. This document states that it is common practice to interpret the results of lung function tests in relation to Reference Values and in terms of whether or not they are considered to be within the "normal" range (33).

The European Respiratory Society published a workshop report in 1995 (34) about some commonly measured spirometry parameters such as RV, FRC and TLC. In this document it is stated that reference values play an important role in establishing whether the measured respiratory volumes fall within an expected range for healthy individuals of the same sex, similar stature, age, and other characteristics. In this report reference values (values for healthy subjects) and prediction equations for lung volumes for children and adults are obtained using different techniques like helium dilution and body plethysmography. These values are presented for different heights. However, this report does not include reference values and prediction equations based on the FOT or IOS.

From table 4 we observe that it is crucial to have IOS Reference Values for children. These have been very effective in the detection of lung abnormalities, as demonstrated in table 1, 2, and 3. Therefore, in our research here we attempt to take the first steps towards establishing IOS Reference Values in Healthy North American Anglo and Hispanic children 5 to 19 years old. We also aim to present baseline (pre-) and post-bronchodilation IOS parameter values for this subpopulation of children with Probable Small Airway Impairment (PSAI), Small Airway Impairment (SAI) and Asthma (A).
