Small airway bronchodilator response to different doses of salbutamol in 7-year-old children

The Global Initiative for Asthma (GINA) guidelines do not specify a bronchodilator range for bronchodilator response (BDR) testing and simply recommend a salbutamol dose of 200 to 400 μg. We determined the oscillometric BDR results of children given low-dose (2 puffs, 200 μg) and standard-dose (4 puffs, 400 μg) salbutamol to compare the small airway responses of healthy controls (defined using criteria based on the guidelines developed at the American Thoracic Society) and exclusion subjects (defined as any child that did not meet the inclusion criteria for healthy controls). The oscillometric reactance of small airways is significantly associated with the dose of salbutamol used for BDR testing in exclusion children. We suggest use of the standard-dose of salbutamol for oscillometric BDR testing.

In this study, we determined the oscillometric BDR results of children given low-dose (2 puffs, 200 μg) and standard-dose (4 puffs, 400 μg) salbutamol to compare the small airway responses of healthy controls (defined using criteria based on the guidelines developed at the American Thoracic Society) and exclusion subjects (defined as any child that did not meet the inclusion criteria for healthy controls) [14].

Methods
We prospectively recruited 248 Korean children who were 7 years-old (167 boys, 81 girls) who participated in the atopy prevention project in the Seongnam Atopy Prevention program (SAP 2016) between January 2016 and December 2016. The present study was designed as a cross-sectional and general population-based study including 11 randomly selected elementary schools from Seongnam city, Gyeonggi province, Republic of Korea for the prevalence of allergic diseases in children. All parents or caregivers signed written informed consent documents, and the study protocol was approved by the appropriate Institutional Review Board of CHA University.
We performed the oscillometric [16] and spirometry [15] BDR tests according to current guidelines. The pulmonary function tool was the impulse oscillometry (IOS) system from Jaeger Company (Würzburg, Germany). Each subject was given salbutamol (2 or 4 puffs), using a randomized and physician-blinded method, prior to IOS BDR testing. We performed computerized randomization by generated random number series assigned to the low-dose and standarddose salbutamol groups. The absolute changes and relative changes with respect to baseline respiratory function in reactance at 5 Hz (Xrs5) and 10 Hz (Xrs10), resistance at 5 Hz (Rrs5) and 10 Hz (Rrs10), reactance area (AX), and difference of Rrs5 and Rrs20 (Rrs20-5) were determined.
We reviewed the questionnaires to identify factors related to pulmonary function. A healthy child (n = 168) was one who had [14]: 1) no history of acute or past chronic disease, major respiratory disease, or thoracic surgery (excluded: n = 20); 2) no systemic disease which could influence the respiratory tract (excluded: n = 0); 3) no exposure to second-hand smoke (excluded: n = 22); 4) normal body mass index (2 < BMI z-score < −2) (excluded: n = 23); 5) no upper respiratory tract infection in the previous 1 month (excluded: n = 5); 6) gestational age of at least 37 weeks, birth weight of at least 2.5 kg, and no history of transient respiratory problems during the neonatal period (excluded: n = 43); 7) predicted forced expiratory volume in 1 s (FEV 1 ) greater than 80% (excluded: n = 9). Data was analyzed using SPSS version 23.0 (IBM Co, Armonk, NY, USA). A P value of <0.05 was considered statistically significant.
Comparison of the oscillometric BDR data of healthy subjects in the low-dose and standard-dose groups indicated no significant absolute or relative differences in Xrs5, Xrs10, Rrs5, Rrs10, AX, and Rrs20-5 (Table 1). However, the exclusion subjects in Table 1 Impulse oscillation measurements of bronchodilator response following low-dose (2 puffs, 200 μg) and standard-dose Δabs absolute change from the initial value, Δrelative relative change from the initial value, % change in FEV 1 percentage change in FEV 1 over baseline, Xrs5 reactance at 5 Hz, Xrs10 reactance at 10 Hz, Rrs5 resistance at 5 Hz, Rrs10 resistance at 10 Hz, AX reactance area, Rrs20-5 difference of Rrs5 and Rrs20 Numbers in bold indicate a significant difference between the low-dose and standard-dose salbutamol groups (P < 0.05) the low-dose and standard-dose groups had significant differences in relative Xrs5

Discussion
Our results show that the oscillometric BDR data of healthy controls were similar for children given standard and low doses of salbutamol. In fact, epidemiological studies accept standard BDR reference values based on oscillometric BDR data from low-dose salbutamol in healthy volunteers [9][10][11][12][13]. However, previous researchers have used different criteria to define "healthy control" such as the following: no history of asthma, cystic fibrosis, neonatal chronic lung disease, or respiratory infection in the 2 weeks prior to study onset (Thamrin et al. criteria) [10,11]; and the Thamrin et al. criteria in addition to no preterm and low birth weight infants (>36 weeks gestational age and >2.5 kg of birth weight) who had not received oxygen at birth [12,13]; in addition to no exposure to second-hand smoke and normal body mass index such as criteria of the American Thoracic Society [14]. We used a more stringent set of criteria for healthy children than the criteria of the American Thoracic Society because we added an additional criteria of FEV 1 [14]. Although the healthy group had similar low-dose and standard-dose BDR data, the exclusion group had significantly different BDR data following low-dose and standard-dose salbutamol. Thus, the use of oscillometric BDR data should be carefully considered in epidemiologic studies of children.
Our results show that the measured reactance of small airways in exclusion children depended on the dose of salbutamol used for BDR testing. Interestingly, all previous pediatric oscillometric patient-control studies only used low-dose salbutamol for BDR testing [4][5][6][7][8]. As far as we know, this study is the first to analyze oscillometric small airway hyper-responsiveness in children using low and standard doses of a bronchodilator. The BDR results following low-dose salbutamol may not accurately reflect the reactance of small airway dysfunction. Many researchers have shown that resistance is a more sensitive measure of airway caliber than reactance in children with asthma [6,[8][9][10]. Our study suggests that use of low-dose bronchodilator may make it difficult to predict the reversibility of reactance in oscillometric BDR testing.
There is limited clinical IOS results in the exclusion group. In particular, the exclusion group presents various characteristics with children representing different phenotype. It was difficult to further divide the exclusion group for homogenous phenotype due to insufficient sample size. We expect further research as a homogeneous phenotype group such as exclusively asthmatic patients compared to healthy group.

Conclusions
Use of low-dose and standard-dose salbutamol for oscillometric BDR testing yielded similar results in healthy children, although our criteria for "healthy" were more stringent than those of other studies. The oscillometric reactance of small airways is significantly associated with the dose of salbutamol used for BDR testing in exclusion children. For further examination of reactance, we suggest use of the standard dose of salbutamol for oscillometric BDR testing. Since there is no accurate BDR guideline for other pulmonary function tests, many researchers extended the GINA guideline for 200-400μg of salbutamol for BDR to the IOS [4][5][6][7][8][9][10][11][12][13]. It is also necessary for the GINA guidelines to specify the amount of salbutamol inhaler to be used for BDR testing to the IOS.