Interrupter resistance and oxygen saturation for methacholine challenge in young children.

Inspiratory Rint better detects BHR than expiratory Rint and might better match PD20PtcO2 changes http://ow.ly/TrMvB.

To the Editor:

In young children unable to perform reliable and reproducible spirometry, non-cooperative lung function techniques are necessary to measure bronchial hyperreactivity (BHR) during bronchial challenge [1]. Measuring the decrease in transcutaneous partial pressure of oxygen (PtcO) is a robust technique that detects increased ventilation–perfusion mismatch during bronchial challenge [2] in preschool and school-aged children [3-5], and a 20% decrease in PtcO correlates to a 20% forced expiratory volume in 1 s (FEV1) decrease in children aged 6–14 years [3] and in adults (with correlation to arterial oxygen tension) [6]. When neither spirometry nor PtcO is available, other BHR outcomes can be measured such as wheezing that appears for mean±sd decreases of −44.7±14.5% in FEV1 and −6.3±2.7% in transcutaneous saturation of oxygen (SpO) [7]. Respiratory resistances are easy to measure [8-10] but the relevant threshold for BHR is not yet defined and an at least 35% increase variably correlates with PtcO changes [8, 11]. First, we aimed to better study two alternative outcomes (i.e. interrupter resistance (Rint) and SpO) and challenge the current recommendations [1] of measuring resistance during inspiration (as opposed to measuring during expiration for reversibility testing [12]), because the physiological expiratory glottis closure can be enhanced during bronchial challenge-induced bronchoconstriction and specific extrathoracic airway reactivity to bronchoconstrictor agents can occur. Second, we wished to evaluate the proposed thresholds for Rint and SpO (+35% and −5% baseline, respectively), as only a 3% decrease is considered to be significant in sleep studies and a mean±sd SpO decrease of −5.2±3.1% corresponds to a much larger than 20% decrease in FEV1 in 5–8-year-old asthmatic children (−33.3±7.4% decrease in FEV1) [13].

Between June 2013 and September 2014, we prospectively and consecutively included 28 children unable to correctly perform a spirometry who were referred to our lung function laboratory for a methacholine challenge. Children had to be free of treatment and acute respiratory symptoms for 3 weeks. Chest auscultation had to be normal.

At each step of the bronchial challenge, inspiratory and expiratory series of at least five correct interruptions (Rint and Rint, respectively) were performed in random order (but always in the same order with each specific child) using a MicroRint device (Micro Medical, Rochester, UK). PtcO and SpO were recorded throughout the test as previously described [8] using a Tina CombiM (Radiometer, Bronshoj, Denmark). Lung function was checked to be within the range of normal at baseline and assessed after inhalation of saline (diluent) to obtain the reference for changes during the challenge. Doubling doses of methacholine were inhaled, using the dosimeter method, every 5 min [8], from 50 µg up to a cumulative dose of 800 µg. The test ended when PtcO had fallen by 20% or more (PD20PtcO), the child had respiratory symptoms or the maximal dose of methacholine was reached. The study was approved by the Institutional Review Board of the French learned society for respiratory medicine (Société de Pneumologie de Langue Française) (CEPRO 2013-015) and the children's parents gave informed consent to the study.

Repeated measurements in children were compared using paired the Wilcoxon signed-rank test. Comparisons of lung function indices between groups of children (responsive and nonresponsive) were performed using the Fisher exact test.

27 (13 girls and 14 boys, median (range) age 5.5 (4.2–8.1) years) children completed all measurements during the bronchial challenge. One child pulled off the PtcO electrode before the end of the test and was, therefore, excluded. 25 children were referred for chronic cough (started at a median age of 2.7 (0.3–8) years), one for suspicion of wheezing and one for dyspnoea upon exertion.

At baseline, Rint was higher than Rint (mean 0.81 versus 0.60 kPa·s·L−1, with a mean difference of −0.21 kPa·s·L−1 (95% CI −0.26– −0.16 kPa·s·L−1); p<0.0001), but within the range of normal for all children [14]. At the time of interruption, expiratory airflow was lower than inspiratory airflow throughout the test (e.g. at baseline: 0.30 and 0.39 L·s−1, respectively; p<0.002). 20 children reached the PD20PtcO at a median cumulative dose of methacholine of 100 µg (50–400 µg) (responsive children) without any respiratory symptoms. 14 responsive children had an at least 35% Rint increase (PD35Rint) during the methacholine challenge whereas six responsive children and all the nonresponsive children did not reach PD35Rint (p<0.002). Using Rint, there was no association between PD35Rint at any time during the test and the presence of BHR (p=1). Therefore, sensitivity and specificity were 70% (95% CI 48–85%) and 100% (95% CI 65–100%), respectively, for Rint, and 50% (95% CI 30–70%) and 57% (95% CI 25–84%), respectively, for Rint to detect BHR at or before PD20PtcO. Taking into account all cases of discordance between Rint and PtcO changes (significance of the changes at each test step), the number of discordant Rint values (n=19) was higher than that of Rint values (n=11) (table 1). For both Rint measurements, the discordances with PtcO changes were equally due to PD35Rint reached before PD20PtcO or to a less than 35% Rint increase at PD20PtcO. In the majority of cases, Rint steadily increased during the bronchial challenge, whereas Rint had a more irregular pattern of changes and the final change in Rint was smaller than that of Rint in all the study children (table 1). All the children (n=11) whose Rint increased by 35% or more without a concomitant 20% PtcO decrease were eventually responsive, whereas three of the nine children with early PD35Rint remained nonresponsive throughout the test (three Rint false positives). Finally, at PD20PtcO, Rint and Rint would not have diagnosed BHR in six cases and 10 cases, respectively (false negative), representing 12 children, among whom only two had a 5% decrease in SpO at the same time.

TABLE 1

Changes and discordances during methacholine challenge between interrupter resistance (Rint) and transcutaneous partial pressure of oxygen (PtcO)

	Responsive children	Nonresponsive children
Subjects n	20	7
Changes in PtcO2 %	−25.4±4.8	−13.4±8.4
Changes Rintinsp %	+49.1±29.6	+13.2±11.4
Change Rintexp %	+34.3±27.9	+8.8±17.4
Discordance between Rintinsp and PtcO2 n (%, 95% CI)	11 (55, 34–74)	0 (0, 0–35)
Rint increase <35% at PD20PtcO2 n	6
Rint increase ≥35% before PD20PtcO2 n	5
Discordance between PD35Rintinsp+SpO2,3% and PtcO2 n	6	0
Discordance between Rintexp and PtcO2 n (%, 95% CI)	16 (80, 58–92)	3 (42, 16–75)
Rint increase <35% at PD20PtcO2 n	10	0
Rint increase ≥35% before PD20PtcO2 n	6	3
Discordance between PD35Rintexp+ SpO2,3% and PtcO2 n	9	3

Data are presented as mean±sd percentage of post-diluent values unless otherwise stated. Changes are at the provocative dose of methacholine causing a 20% decrease in PtcO (PD20PtcO) in responsive children and at the last dose of methacholine in nonresponsive children. Discordances between Rint and PtcO changes were assessed at every steps of the test. Rint changes are more or less than 35% increase from the post-diluent value (PD35Rint). Rint: inspiratory interrupter resistance; Rint: expiratory interrupter resistance; PD35Rint: provocative dose of methacholine causing a 35% decrease in Rint; SpO: at least 3% decrease in transcutaneous saturation of oxygen from the post-diluent value; PD35Rint: provocative dose of methacholine causing a 35% decrease in Rint.

Using Rint changes expressed as percentage of predicted rather than percentage of baseline would have changed the significance of a Rint increase in two out of 81 Rint measurements performed after methacholine inhalation in all study children. These two measurements occurred after the first dose of methacholine in two discordant children (PD35Rint reached before PD20PtcO) in whom, after the second methacholine inhalation, both changes (% predicted and % baseline) corresponded but remained discordant with that of PD20PtcO. Therefore, the analysis of the concordance between Rint and PD20PtcO changes would not change using percentage predicted or percentage baseline.

If the threshold for Rint were increased by up to 40%, discordance between PtcO and Rint would remain the same, whereas discordance with Rint would decrease from 19 to 15 cases (still with two false positives). If a 3% decrease in SpO were the threshold, 15 out of the 20 responsive children would have reached this threshold at PD20PtcO (none before PD20PtcO), while none of the nonresponsive children would have reached it at any step of the test (p<0.001). Moreover, using PD35Rint or a 3% decrease in SpO as a composite criterion for bronchial responsiveness, only one responsive child would not have been diagnosed as responsive at PD20PtcO (sensitivity 95%, 95% CI 76–99%) versus six false negatives with PD35Rint or −5% SpO criterion.

Our results do not support a universal physiological mechanism to explain discrepancies between Rint and PtcO measurements during bronchial challenge in young children. The lack of Rint increase in responsive children could reflect an early ventilation–perfusion mismatch with no central airway obstruction but the better concordance between PtcO and Rint over Rint remains unexplained. The early reactivity in Rint (before PD20PtcO) might be due to glottis changes but we failed to demonstrate any specific recurring patterns of changes of airflow at interruption or of difference between Rint and Rint explaining the discrepancies recorded.

To challenge the proposed threshold for Rint [1], we switched from a 35% to a 40% increase and the total number of discordances decreased only for Rint although they remained higher than that of Rint. However, as a Rint device may measure only Rint, the threshold of 40% may be useful to implement. In children with no Rint increase at PD20PtcO, a 3% decrease in SpO better detected BHR than a 5% decrease. The better accuracy of a −3% SpO threshold, over a −5% threshold, increases the safety of associating Rint and SpO measurements when PtcO is not available.

In conclusion, Rint better detects BHR than Rint and might better match PD20PtcO changes. Until larger studies confirm these first results, it is reasonable to stick to the proposal of favouring measurement of Rint rather than Rint during methacholine challenge. Our findings strengthen the recommendation to associate bronchial reactivity outcomes when PtcO measurement is not available. Finally, the combination of a 35% Rint increase or a 3% SpO decrease might be a useful criterion for detecting BHR with respect to PtcO changes.