Changes in the Lung Clearance Index in Pediatric Patients With Asthma
Changes in the Lung Clearance Index in Pediatric Patients With Asthma
The multiple breath washout (MBW) is one of pulmonary function test that displays flow and
 gas concentration plotted against time, and shows an exponential decay in end-tidal gas
 concentration (washout curve). A number of of indices to describe the washout curve have been
 proposed, the most commonly reported is the Lung Clearance Index (LCI). This is a simple
 measure of ventilation heterogeneity derived from MBW, that can be used after challenge with
 a short action bronchodilator and in response to inhaled steroids, both in the conductive
 airways as acinar. Patients with moderate and severe asthma are characterized by an
 abnormality in both, conductive and the acinar airway. Therefore the following research
 question could be: what are the abnormalities in the heterogeneity of ventilation in children
 with mild and moderate asthma, with respect to the healthy population measured by MBW, and
 whether these alterations persist after challenge with inhaled steroids and B2 agonists
 short-acting.
The method most used to measure lung function, have been the spirometric tests, which
 generally reflect the function of the airway of highest caliber and elastic retraction of the
 lung. However, its use in clinical practice is limited by physiological variability and
 inconsistency in the measurements, therefore its value as a predictor of peripheral
 obstruction has been questioned. The Lung Clearance Index (LCI) is a simple measure of
 ventilation heterogeneity derived from multiple breath-washout (MBW) curve, that can be used
 after challenge with a short action bronchodilator and inhaled steroids, both in the
 conductive and acinar airways. Patients with moderate and severe asthma are characterized by
 an abnormality in both, conductive and the acinar airway. The LCI is one index derived from
 the concentration curves obtained during MBW to quantify the inefficiency in gas mixing of
 the lungs. A phase III slope analysis of the MBW curve can distinguish maldistribution of
 ventilation due to structural changes (acinar vs conductive lung zone). The conductive MBW
 index of ventilation heterogeneity is related to proximal lung structure, where convection
 dominates gas transport. The acinar MBW index of ventilation heterogeneity is related to
 peripheral lung, where convection-diffusion interaction occurs. Therefore the following
 research question could be: what are the abnormalities in the heterogeneity of ventilation in
 pediatric patients with a diagnosis of asthma, both mild and moderate, with respect to the
 healthy population, measured by MBW and whether these alterations persist using conventional
 treatment with inhaled steroids and B2 agonists short-acting.

 The general objetive will be to identify changes in the LCI (heterogeneity of ventilation)
 retrieved from the MBW curve in children with diagnosis of mild and moderate asthma, before
 and after challenge with short-acting B2 agonists and after one month of treatment with
 knowledge dose of inhaled steroid.

 Specific objectives;

 1. . Difference in the baseline results of spirometry and LCI (derived form the MBW curve),
 between the control health group, and children with mild and moderate asthma.

 2. . Changes in LCI (acinar or conductive ventilation heterogeneity) obtained from the MBW
 curve, from the baseline values and after challenge with short-acting B2 agonist and
 with inhaled steroids between groups of patients with mild or moderate asthma.

 3. . Determine whether the alterations in the LCI of patients with mild and moderate asthma
 are originated from acinar or from the conductive airway.

 Methodology. The LCI is calculated with the cumulative volume exhaled (CVE) during MBW test,
 divided between the functional residual capacity (FRC). This index is the number of turnovers
 of lung volume that the patient must breathe to clean the lungs of tracer gas (1/40th of the
 initial concentration). The expiratory N2 concentration will be plotted against volume
 changes between Total Lung Capacity (TLC) and Residual Volume (RV), and the slope (dN2) of
 the N2 alveolar plateau will be calculated by computer analysis of the best-fit line through
 phase III of the expiratory volume-concentration curve. The measurements will be accepted
 only if the vital capacity (VC) during the MBW is within 10% of the VC. During the MBW test,
 patients most perform a slow, full inspiratory and expiratory VC maneuver at inspiratory and
 expiratory flow rates of approximately 0.5 l/s.The VC will be obtained from the spirometry
 test.

 Design; Clinical, controlled, parallel, longitudinal, comparative trial.

 Sample universe; Patients of both sexes between 7-17 years of age that attending to Pediatric
 Pulmonology Service of the Hospital Infantil de Mexico, with a diagnosis of controlled mild
 or moderate asthma. It will included a control group (health children), as a criterion for
 normality and to compare the results of the spirometry and the LCI derived from the MBW curve
 obtained in this group, with the results of the same studies in a group of patients with mild
 and moderate asthma.

 Inclusion criteria;

 -  For patients with asthma: Informed written consent signed by a parent or guardian of the
 patient and assent if signed by the patient.

 -  For control group: Informed written consent signed by parent or guardian consent and
 subject control where appropriate, signed by the subject.

 -  Patients from 7 to 17 years of age with a diagnosis of mild or moderate asthma according
 to the criteria of the Global Initiative for Asthma 2014 (Global Strategy for Asthma
 Management and Prevention. National Institutes of Health 2014), treated with inhaled
 steroids and who come to the outpatient clinic of Pediatric Pulmonology Service of
 Hospital Infantil de Mexico.

 -  An evolution of the asthma > 6 months.

 -  Control subjects (healthy) from 7 to 17, which will be contacted by telephone in
 accordance with a list that is counted in the Laboratory of Pulmonary Physiology who
 have participated in other studies or bioassays for calibration of equipment.

 -  Able to perform spirometry test and multiple-breath washout.

 -  No exacerbation of asthma in the past 4 weeks.

 -  Accept a washout period (without treatment) for 1 week before the realization of studies
 of pulmonary function (visit 2).

 -  Accept the use of short-acting B2 as necesary reason.

 -  Do not suffer from any other chronic disease, other than asthma.

 Exclusion criteria;

 -  Patient with acute or chronic pulmonary disease other than asthma.

 -  Patient with a history of asthma exacerbation in the 4 weeks prior to inclusion in the
 study.

 -  Patients with a diagnosis of severe asthma according to criteria of the Global
 Initiative for Asthma 2014 (Global Strategy for Asthma Management and Prevention.
 National Institutes of Health 2014),

 -  Other co-morbidities.

 Criteria of elimination;

 -  Patients who do not meet criteria of acceptability and repeatability at the spirometry,
 or MBW interpretation according with American Thoracic Society.

 -  Asthma exacerbation during the week of the washout period.

 -  Removal of informed consent.

 Sample size; Taking into account the magnitude of the effect on the LCI during the MBW in
 pediatric subjects with asthma, pre and postbronchodilation on the basis of clinical studies
 carried out previously (Singer F, Abbas Ch, Yammine S, Casaulta C, Frey U, Latzin P. Abnormal
 small airway function in children with mild asthma.) Chest 2014; 145 (3): 492-499). Where the
 rate of LCI prebronchodilator was 2.96 ± 1.6 and the 20 minutes postbroncodilatador the
 clearance rate was 1.83 ± 1.24. Considering that the magnitude of the effect on the rate of
 LCI is 1.13, with standard deviation of 1.6. With a α = 0.05 (bilateral), β = 0.20, 80%
 statistical power. The sample size will be of 30 patients per group, taking into account a
 greater loss of 20%, the sample size will be increased to 35 subjects per group.

 Selection of patients for the sample and its distribution; 3 groups of patients will be
 included: Group 1) Healthy group (controls). Group 2) Patients with mild asthma in treatment
 with low dose of inhaled steroids.

 Group 3) Patients with moderate asthma in treatment with intermediatte dose of inhaled
 steroids.

 Visit 1. Explanation of the study. Review of criteria for inclusion. Signature in the case of
 written informed consent. For Group 1; Only baseline spirometry and MBW test will be
 performed. No other intervention.

 For groups 2 and 3. Be asked to suspend his current medication for 7 days (washout period),
 indicating only albuterol inhaled if necessary.

 Visit 2 (1 week after Visit 1). Groups 2 and 3; baseline spirometry and MBW test. At the end
 of both studies, patients from to groups will receive one dose of 400 mcg of inhaled
 albuterol with spacer device. Twenty minutes after the dose of albuterol, they repeat
 spirometry and MBW test.

 After patient have completed both studies, they will be asked to restart her medication with
 inhaled steroid; 100 mcg/day of fluticasone for the group of patients with mild asthma (Group
 2) and 200 mcg/day of fluticasone for moderate asthma patients group (Group 3).

 Visit 3 (4 weeks after Visit 2). Groups 2 and 3; basal spirometry and MBW test.

 Statistical analysis. Descriptive statistics will by used to obtain measures of central
 tendency and dispersion in quantitative variables (average, standard deviation and 95%
 confidence interval). It will be compared and evaluate the effect of inhaled steroids and β2
 agonists for short action on the rate of LCI and distribution of ventilation (acinar and
 conductive airways) through analysis of Student's t for related samples. The level of
 significance will be established with a p = ≤ 0.05.

 Ethical Issues There will be any procedure until to obtain the approval of the Ethics
 Committee of the Hospital Infantil de México.
Inclusion Criteria:

 -  Informed written consent signed by a parent or guardian of the patient and by the
 patient (asthma and healthy controls).

 -  Diagnosis of mild asthma and moderate asthma according to the criteria of the Global
 Initiative for Asthma 2014 (Global Strategy for Asthma Management and Prevention.
 National Institutes of Health 2014), treated with inhaled steroids and who come to the
 outpatient Clinic of Pediatric Pulmonology at Hospital Infantil de Mexico.

 -  An evolution of the asthma > 6 months.

 -  Able to perform spirometry test and multiple-breath washout test.

 -  No exacerbation of asthma in the past 4 weeks.

 -  Accept a washout period (without treatment) for 1 week before the realization of
 studies of pulmonary function.

 -  Accept the use of necessary short-acting B2 bronchodilator during the washout period.

 -  Do not suffer from any other chronic disease other than asthma.

 Exclusion Criteria:

 -  Patient with acute or chronic pulmonary disease other than asthma.

 -  Patient with asthma exacerbation in the last 4 weeks prior to inclusion in the study.

 -  Patients with a diagnosis of severe asthma.

 -  Other co-morbidities.