Clinical Investigations

Area under the Maximum Expiratory Flow-Volume Curve - A Sensitive Parameter in the Evaluation of Airway Patency
Alois Zapletal^{a, c}, Marie Hladíková^b, Jana Chalupová^c, Tamara Svobodová^a, Véra Vávrová<sup>a

a</sup>Department of Pediatrics,
^bDivision of Biostatistics, University Hospital Motol, and
^cPoliclinic Lung Function Laboratory Stodlky, Prague, Czech Republic

Address of Corresponding Author

Respiration 2008;75:40-47 (DOI: 10.1159/000099615)

 Outline

• Key Words
• Abstract
• Introduction
• Patients and Methods
• Bronchoconstriction
• Bronchodilation
• Statistical Analysis
• Results
• Lung Function Parameters after Induced Bronchoconstriction
• Lung Function Parameters after Induced Bronchodilation
• Discussion
• References

• Author Contacts
• Article Information
• Publication Details
• Drug Dosage / Copyright

  Key Words

• Airway patency
• Bronchoconstriction
• Bronchodilation
• Children
• Expiratory flow-volume curve
• FEV₁

  Abstract

Background: The most frequently used parameters for assessing bronchoconstriction and bronchodilation are forced expiratory volume in 1 s (FEV₁) and peak expiratory flow (PEF). Objectives: To assess the sensitivity of other parameters after induced bronchoconstriction and bronchodilation. Methods: From maximum expiratory flow-volume (MEFV) curves, forced vital capacity, FEV₁, PEF, maximum expiratory flows (MEF) at 25, 50 and 75% of vital capacity and the area under the MEFV curve (A_ex) were measured in two groups of asthmatic children after induced bronchoconstriction and bronchodilation, and in children with cystic fibrosis (CF) after bronchodilation. Results: In 142 asthmatics without airway obstruction, bronchoconstriction was induced by inhalation of 1% histamine aerosol. The 20% fall in A_ex compared to baseline was found in all asthmatics, while the 20 and 15% falls in FEV₁ were noted in 36 and 65% of the patients, respectively. Other parameters were less sensitive or interpretation was problematic. Another110 asthmatics with mild-moderate airway obstruction were treated with various bronchodilators. The 20% increase in A_ex was observed in all asthmatics, while the 20% increase in FEV₁ was found in only 33% of the patients and the 15% increase in FEV₁ in 51%. In 9CF children, the pattern of changes in A_ex and FEV₁ after bronchodilation was similar to that in asthmatics. Conclusions: A_ex was a sensitive and less problematic parameter in the evaluation of airway patency in comparison with FEV₁ and other parameters measured from the MEFV curve in our study patients.

Copyright © 2007 S. Karger AG, Basel

 Introduction

Changes in airway patency after inhalation of nonspecific bronchoconstrictors and bronchodilators provide significant information on the airway reactivity in both pediatric as well as adult patients with respiratory diseases. The evaluation of bronchial hyperresponsiveness (BHR) and the reversibility of airway obstruction can be assessed on the basis of selected functional parameters. Currently, forced expiratory volume in 1 s (FEV₁) and peak expiratory flow (PEF) represent the most frequently measured parameters to assess airway response after inhalation of bronchoconstrictors as well as bronchodilators. A large number of reports published in the literature evaluated FEV₁ and PEF in the assessment of BHR and bronchodilation in asthmatics [1,2,3,4,5,6,7,8]. FEV₁ is also the most frequently used parameter in the evaluation of airway function in chronic obstructive pulmonary disease (COPD) [9].

The 20% fall in the absolute value of FEV₁ after inhalation of bronchoconstrictors compared to baseline is generally accepted to evidence BHR in both adults and children, and it is the most frequently used parameter in this respect [1,2,3,4, 8]. The dose of a bronchoconstrictor inducing a 20% fall in FEV₁ compared to baseline is called a provocation dose (PD20_FEV1) and the concentration of a constrictor causing the latter change is a provocation concentration (PC20_FEV1). FEV₁ and PEF are also frequently used in the evaluation of bronchodilation. We observed FEV₁ and PEF to be less sensitive indices of bronchoconstriction and bronchodilation in asthmatics than some other parameters [10,11,12].

Consequently, we searched for more sensitive lung function parameters after inhalation of a selected bronchoconstrictor to reveal BHR as well as to assess bronchodilation after inhalation of selected bronchodilators. Therefore, we measured functional parameters from maximum expiratory flow-volume (MEFV) curves in asthmatic children after inhalation of a bronchoconstrictor or some bronchodilators, and in patients with cystic fibrosis (CF) after inhalation of a bronchodilator. The present study is the only one dealing with this topic in children.

 Patients and Methods

 Bronchoconstriction

Bronchoconstriction was induced by inhalation of aerosol of 1% histamine solution during tidal breathing in 142 asthmatics attending our clinic (75 males and 67 females) aged 4-19 years (mean: 9.7 years) with body height ranging from 83 to 187 cm (mean: 138.0 cm). The patients were clinically in a stable period of asthma which was classified as persistent mild or moderate at the time of the study. They had characteristic clinical symptoms with periods of deterioration and improvement in airway obstruction, typical immunological findings and positive allergic skin tests. They were treated with various antiasthmatics, but treatment was not further specified since the purpose of our study was to evaluate the changes in airway patency with respect to some functional parameters. Our primary aim was to determine the decline in some functional parameters after the same bronchoconstricting stimulus. Patients with a 20% decline in the area under the MEFV curve (A_ex) after induced bronchoconstriction were included in the study. The study was approved by the local ethics committee.

In each patient, a series of 3-5 MEFV curves was obtained with a spirometer (ZAN 100; ZAN) before and after aerosol inhalation of 1% histamine solution. The best curve was automatically selected by a spirometry program according to the American Thoracic Society (the largest sum of forced vital capacity, FVC, and FEV₁) [13] and our own criteria, with details being described elsewhere [14, 15], and analyzed. The reproducibility of the MEFV curve was primarily based on the reproducible descendent portion of the curve and FVC. At the start of each measurement, the personnel explained how to perform a forced expiratory maneuver to each child. During the measurement, children were in the standing position while wearing a nose clip. From the best curve, the values of FVC, FEV₁, PEF, MEF at 25, 50 and 75% of vital capacity (MEF₂₅, MEF₅₀ and MEF₇₅) and A_ex were calculated. In our previous studies in healthy children, the variability (1 SD from the mean) in FVC was 8%, FEV₁ 9%, PEF 14%, MEF₇₅ 14%, MEF₅₀ 15%, MEF₂₅ 16% and in A_ex 13% [14, 15].

Histamine inhalation was carried out with an inhalator (Pariboy; Pari) during quiet tidal breathing. A cumulative dosage was used to induce a 20% fall in A_ex compared to baseline to evidence a positive test (i.e. BHR) but not that of FEV₁. The initial dose of histamine was 0.3 mg in the majority of patients, and in some patients it was 0.15 mg. After a negative response, the next cumulative dose was 0.3 or 0.7 mg of histamine. The next doses were 1.2 and 2.2 mg, until the final cumulative dose of 3 mg of histamine was achieved. Assumably, some losses in histamine occurred during the expiratory phase of tidal breathing, which was not assessed. Therefore, a dose-response curve was obtained and PD₂₀ was calculated for the functional parameters measured. After completion of the test, each patient inhaled 2 puffs of a bronchodilator (Berodual, ipratropium bromide/fenoterol; Boehringer) to abolish the induced bronchoconstriction. The dose of histamine varied from 0.15 to 3 mg of histamine (mean dose: 1.56 mg, median: 1.5 mg) in the patients. No side effects were observed.The major task of the test was to induce a 20% decrease in A_ex.

 Bronchodilation

Bronchodilation was studied after inhalation of different bronchodilators in asthmatics and CF patients.

Asthmatics. The group comprised 110 asthmatics (68 males and 42 females) aged 4-19 years (mean: 11.0 years) with body height ranging from 103 to 190 cm (mean: 147.0 cm). Bronchodilation was evaluated 30 min after inhalation of the following bronchodilators, i.e. 2 puffs of Berodual, 4 puffs of Ventolin (salbutamol; GlaxoSmithKline), 4 puffs of Ecosal (salbutamol; Ivax) and 2 puffs of the Symbicort-Turbuhaler (formoterol/budesonide; AstraSeneca) according to the manufacturers' instructions. Each patient inhaled only one bronchodilator. The patients had characteristic clinical features of asthma and various degrees of airway obstruction. They were treated with different antiasthmatic drugs. Patients with a 20% increase in A_ex were included into the study. Our major aim was to determine the largest increase in the functional parameters after bronchodilator administration.

CF Patients. The CF group comprised 9 children with CF (4 males and 5 females) aged 3-18 years (mean: 10.3 years) with body height ranging from 94 to 175 cm (mean: 140.0 cm). Bronchodilation was also evaluated 30 min after 2 puffs of Berodual. We aimed to determine whether or not the changes in functional parameters in CF patients are similar to those in asthmatics, and thus specific or nonspecific for asthmatics. The CF patients had chronic airway obstruction with viscous mucus secretion and a positive sweat test with increased chloride levels. CF patients were treated with mucolytics, antibiotics and physical therapy, and in some of the patients the efficacy of bronchodilators on airway obstruction has been proven [16, 17].

A series of MEFV curves was carried out before and after inhalation of bronchodilators. Similar to the group of asthmatics after bronchoconstriction, the best curves before and after bronchodilation were selected according to the criteria of the American Thoracic Society and our own criteria, and analyzed [13,14,15]. The functional parameters required for the assessment of bronchodilation were derived from the curves (see bronchoconstriction test).

 Statistical Analysis

All parameters before and after induced bronchoconstriction and bronchodilation in the patients were compared with the reference values for children and adolescents matched for body height, age and sex [14, 15]. The absolute values of the data in the tables are given as means ± SD and as percentages of predicted values. The changes in values before versus after inhalation of histamine and bronchodilators were tested by paired t test; p < 0.05 were considered significant. Percent decreases, increases and z-scores (number of SD from the predicted value) of parameters after inhalation versus before inhalation of bronchomotoric agents were also calculated. We focused our analysis primarily on the parameters A_ex and FEV₁. The incidence rates of asthmatics with 15 and 20% declines in FEV₁, and 20 and 30% declines in A_ex after inhalation of histamine were then calculated as well as the incidence rates of asthmatics and CF patients with 20% increases in A_ex and FEV₁, and a 15% increase in FEV₁ after inhalation of bronchodilators. A further McNemar test (² test for the same subject) was performed in order to compare the proportions of patients with positive responses in A_ex and FEV₁.

 Results

 Lung Function Parameters after Induced Bronchoconstriction

In all studied asthmatics, all parameters measured before induced bronchoconstriction were within normal limits (table 1). After bronchoconstriction, all functional parameters significantly (p < 0.03-0.00001) decreased in all of them. However, the mean percent decline was different for each parameter (table 1). The fall in MEF₂₅ was about 37% on average, A_ex dropped by 34% and MEF₅₀ also decreased by about 34% on average. The fall in FEV₁ was 18.5% and that of PEF only 15.8% on average after induced bronchoconstriction. The value of the z-score for A_ex showed the largest decline after bronchoconstriction (table 1).

Table 1. Mean absolute and predicted [14, 15] values of lung function parameters before and after induced bronchoconstriction in 142 asthmatics (age: 4-19 years, mean: 9.7 years, body height: 83-187 cm, mean: 138 cm)

Further, the incidence of positive bronchoconstriction tests, i.e. BHR, was assessed individually according to decreases 20% in FEV₁ and A_ex from baseline (table 2). Based on a 20% decrease in A_ex, BHR was detected in all (100%) patients. The 30% decrease in A_ex, another criterion of BHR, showed BHR in 66% of the patients. Based on the 20% fall in FEV₁, BHR was found in 36% of the patients, which implies BHR remained undetected in almost two thirds of our asthmatics. Based on the 15% decline in FEV₁, BHR was disclosed in 65% of the asthmatics. McNemar test showed the significantly higher proportions of subjects with a positive response in A_ex than FEV₁ (table 2). We did not evaluate the individual incidence of BHR based on the fall in MEF values because these parameters were not measured at the same lung volume levels before and after histamine inhalation due to decreases in FVC.

Table 2. Incidence of positive induced bronchoconstriction (BHR) in 142 asthmatics (age: 4-19 years, mean: 9.7 years, body height: 83-187 cm, mean: 138 cm)

 Lung Function Parameters after Induced Bronchodilation

In all studied asthmatics, before inhalation of bronchodilators airway obstruction was established by significantly reduced MEF₇₅, MEF₅₀ and MEF₂₅values (table 3). Airway obstruction was classified into mild, moderate and severe. FEV₁ <80% of the predicted value showed airway obstruction in only 25% of our asthmatics [14, 15].

Table 3. Mean absolute and predicted [14, 15] values of lung function parameters before and after induced bronchodilation in 110 asthmatics (age: 4-19 years, mean: 11 years, body height: 103-190 cm, mean: 147 cm)

In the whole group of patients, all parameters significantly (p < 0.05-0.00001) increased after inhalation of bronchodilators (table 3), particularly in MEF₂₅, MEF₅₀ and A_ex. FEV₁ increased by about 17% and PEF by 14%. The z-score showed a pattern similar to the latter parameters (table 3).

According to the individual increases in the parameters after induced bronchodilation, the increase in A_ex was 20% compared to baseline in all our asthmatics. However, the positive bronchodilation based on an increase in FEV₁ 20% was revealed in only 33% of our asthmatics and based on a 15% increase in FEV₁ it was found in 51% of them (table 4). Using McNemar test, the proportion of patients with a positive response in A_ex was higher compared to FEV₁ (table 4).

Table 4. Incidence of a positive bronchodilation test 30 min after inhalation of Berodual in 9 CF patients (age: 3-18 years, mean: 10.3 years, body height: 94-175 cm, mean: 140 cm) and after inhalation of bronchodilators in 110 asthmatics (age: 4-19 years, mean: 11 years, body height: 103-190 cm, mean: 147 cm)

Before inhalation of Berodual, all lung function parameters in all CF patients were significantly reduced suggesting moderate/severe airway obstruction (table 5). Following Berodual inhalation, these parameters significantly increased (p < 0.05-0.0001) and normalized except for MEF₂₅. Major increases were noted in A_ex, MEF₂₅ and MEF₅₀. FEV₁ increased by 14% and PEF by 18% on average. The largest z-score was observed for A_ex (table 5).

Table 5. Mean absolute and predicted [14, 15] values of lung function parameters before and after induced bronchodilation in 9 CF patients (age: 3-18 years, mean: 10.3 years, body height: 94-175 cm, mean: 140 cm)

A positive bronchodilation test defined as an increase in A_ex 20% was observed in all patients. The 15% increase in FEV₁ was revealed in 56% of the patients and the 20% increase in FEV₁ was found in none of them (table 4). McNemar test also showed higher numbers of patients with a positive response in A_ex compared with FEV₁ (table 4).

We assessed induced bronchodilation in patients based primarily on the increase in absolute values of A_ex and FEV₁ compared to baseline and not on the increase in MEF values. Nevertheless, MEF values also increased substantially after bronchodilation, which may be explained by the different lung volume levels for MEF before and after bronchodilation due to FVC increases after bronchodilation (tables 3, 5).

 Discussion

In our asthmatic children and patients with CF, the lung function parameters derived from MEFV curves after induced bronchoconstriction and bronchodilation showed rather different results concerning the positivity of bronchoconstriction and bronchodilation (1, 2, 3, 4, 5). The largest decline in the z-score of the mean A_ex value suggested A_ex to be the most sensitive parameter in the detection of BHR in our asthmatics (table 1).

The positivity of BHR in our asthmatics, based on a 20% decrease in the absolute A_ex value after versus before inhalation of histamine, showed BHR in all of them (table 2). Based on the 20% fall in the absolute FEV₁ value compared to baseline, BHR remained undiscovered in almost two thirds of our asthmatics. The 20% fall in A_ex was chosen as the cutoff value because the lower limit of A_ex was close to 20% in our healthy preschool and school children as well as adolescents studied [14, 15]. Another reason for selecting a 20% fall in A_ex as a criterion indicating a positive BHR was an already generally accepted 20% fall in FEV₁ (PD20_FEV1) compared to baseline in the past [1,2,3,4]. The 30% fall in A_ex as another criterion of BHR still proved BHR in a large number of asthmatics, i.e. in 66% of our patients. We do not consider the 10-15% fall in FEV₁ (PD10 or PC10, PD15 or PC15) to be a correct cutoff of BHR, as quoted previously [18, 19], since the lower confidence limit (i.e. -2SD) from the mean FEV₁ was 18% in our healthy children [14, 15]. The 10-15% change in FEV₁ is still within the physiological range for this parameter. The 15% decline in FEV₁ as a measure of BHR did not show BHR in about one third of our asthmatics (table 2). Therefore, we suggestPD20_Aex as a parameter determining BHR.

The histamine dose in our asthmatics was probably lower due to a certain loss of histamine during the expiratory phase of tidal breathing. Such an error occurred similarly in all patients. We aimed to induce bronchoconstriction by the same manner in all patients and to evaluate the various declines in functional parameters.

In asthmatics, the incidence rates of BHR based primarily on the fall in FEV₁ and A_ex compared to baseline obviously differed depending on the therapeutic regimen employed. In the long-term management of asthmatics, using BHR as an additional guide is considered indispensable because BHR significantly correlates with chronic airway inflammation in asthma [3, 4]. Therefore, to assess BHR, sensitive lung function parameters are mandatory. First of all, we compared the sensitivity of A_ex with the most frequently and routinely used parameter FEV₁, and then with other parameters derived from the MEFV curve.

We considered the parameters MEF₂₅, MEF₅₀ and MEF₇₅ to be less suitable in the evaluation of BHR in our asthmatics, because they were measured at different absolute lung volume levels before and after induced bronchoconstriction due to a decrease in FVC resulting in a change in lung volume levels at which MEF values were measured. MEF values obtained after induced bronchoconstriction were actually falsely higher.

In spite of the problematic lung volume level, MEF values showed a larger increase after inhalation of histamine and bronchodilators than FEV₁ in our asthmatics, which was in agreement with previous studies [7]. Nevertheless, they might be used as a measure of bronchoconstriction and bronchodilation responses assuming that lung volume might be a source of error. If FVC remains constant, the measurement of MEF values is accurate. MEF values reflect primarily the obstruction of peripheral airways which are the predominant site of airway obstruction in patients with obstructive lung disease [20].

In our asthmatics, the bronchodilation test assessed by FEV₁ was less often positive than with A_ex. The 20% increase in the parameter A_ex revealed a positive bronchodilation response in all our asthmatics while the 20% increase in FEV₁ indicated a positive bronchodilation in only one third of them. Based on the 15% increase in FEV₁, about half of the patients had a positive test (table 4). A similar increase in z-scores for MEF₂₅, MEF₅₀ and A_ex suggested a similar degree of bronchodilation (table 3).

In patients with CF, the positive bronchodilation test resembled that found in asthmatics. Based on a 20% increase in A_ex, bronchodilation was revealed in all patients (table 4), based on a 15% increase in FEV₁ in 56%, and on a 20% increase in none of them. The largest z-score for A_ex also proved A_ex to be the most sensitive parameter indicating bronchodilation.

The number of patients with a 12% increase in FEV₁ after bronchodilation was not included, similar to a previous study [18], due to the physiological variability in FEV₁.

Our results suggest that the parameter A_ex can be considered as a sensitive, simple and reliable index in the evaluation of airway patency, and is thus suitable for routine use. A_ex reflects both lung volume and airflow changes during the whole forced expiratory maneuver. It provides thus information on both central and peripheral airway obstruction. A_ex is expressed as l²/s because the area under the MEFV curve is calculated as a product of volume × volume per second ( l²/s).

The greater sensitivity of A_ex in the evaluation of induced bronchoconstriction and bronchodilation can be attributed to both airflow and FVC changes as a result of residual volume increase or decrease during forced expiration. A_ex was not a specific feature of asthmatics because the pattern and magnitude of changes for FEV₁, PEF, MEF values and A_ex after bronchodilation were similar in both asthmatics and CF patients (2, 3, 4, 5).

The parameter A_ex was advantageous in the evaluation of airway patency in both asthmatics and patients with CF because A_ex includes both lung volume and flow changes over the whole range of FVC. It thus reflects airway obstruction during the complete forced expiratory maneuver. In contrast, FEV₁ reflects changes in airway patency at about 80-90% of FVC in the majority of healthy children [14, 15]. In patients with obstructive diseases, FEV₁ reflects airway obstruction even in patients with a smaller lung volume range than 80% of FVC and primarily a central airway obstruction.

The PEF parameter showed low sensitivity in the evaluation of airway patency in all of our patients (1, 2, 3, 4, 5). It represents the highest expiratory flow derived from the MEFV curve and reflects primarily central airway obstruction. Both FEV₁ and PEF thus provide limited information mainly on the caliber of smaller airways. Nevertheless, both parameters (FEV₁ and PEF) are recommended in the guidelines of the Global Initiative for Asthma for the evaluation of airway obstruction in asthmatics [3]. It might result in unrecognized airway obstruction or BHR and consequently in inappropriate treatment in patients with mild/moderate asthma, for example.

Similarly, in patients with COPD the most commonly used spirometry parameter FEV₁ also showed only a weak correlation with the characteristic symptoms of COPD, such as dyspnea, reduced activity and poor health status, and did not reflect the severity of the disease [9, 21, 22] or frequency of exacerbations in COPD patients [23].

In the literature, there are few relevant studies on using the parameter A_ex in the evaluation of bronchoconstriction and bronchodilation. No study on this topic exists in children. Vermaak et al. [24] first introduced the parameter A_ex as a very sensitive indicator of lung function impairment and developed the equation for calculating A_ex. He assumed A_ex is a triangle with FVC as a base, PEF as a perpendicular and straight descendent portion of the MEFV curve as a hypotenuse. However, the MEFV curve is not a triangle in patients with obstructive disease. Sovijarvi [25] tested the sensitivity and reliability of A_ex after methacholine challenges in patients with BHR. A_ex showed the greatest decrease compared to baseline among the parameters derived from the MEFV curve. Struthers and Addis [26] measured A_ex before and after aminophylline in patients with COPD. A_ex was the most sensitive index assessing bronchodilation in the patients studied. Seppala [27] used A_ex to express the reproducibility of methacholine-induced bronchoconstriction in healthy subjects and established a higher sensitivity for A_ex than for FEV₁ and MEFs. Currently, studies using A_ex in the evaluation of airway patency in asthmatics or patients with other obstructive diseases are rare. Further studies are required to determine the significance of the parameter A_ex in the evaluation of BHR and bronchodilation as well as airway function in all patients with abnormalities of airway patency.

In conclusion, among the functional parameters derived from the MEFV curve following inhalation of a bronchoconstrictor and several bronchodilators in two groups of asthmatic children and one group of CF patients, the parameter A_ex was more suitable in the evaluation of BHR and bronchodilation than FEV₁ or PEF, and other parameters measured. The introduction of A_ex in the evaluation of airway function in patients with initial forms of asthma and CF patients as well as the routine use of A_ex to follow-up asthmatics and CF patients (probably also patients with COPD) might provide better information on their health status than the currently used parameter FEV₁.

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  Author Contacts

Alois Zapletal, MD
Policlinic Lung Function Laboratory
Hostinského 1533
CZ-155 00 Prague 5 (Czech Republic)
Tel. +420 235 519 620, Fax +420 284 826 627, E-Mail a.zapletal@c-mail.cz

  Article Information

Received: January 25, 2005
Accepted after revision: December 12, 2006
Published online: February 13, 2007
Number of Print Pages : 8
Number of Figures : 0, Number of Tables : 5, Number of References : 27

  Publication Details

Respiration (International Journal of Thoracic Medicine)

Vol. 75, No. 1, Year 2008 (Cover Date: January 2008)

Journal Editor: Bolliger, C.T. (Cape Town)
ISSN: 0025-7931 (print), 1423-0356 (Online)

For additional information: http://www.karger.com/RES

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