Copyright ©ERS Journals Ltd 2006 Estimation of the bronchodilatory effect of deep inhalation after a free run in children1 Service dExplorations Fonctionnelles Pédiatriques, Hôpital dEnfants, Centre Hospitalier Universitaire de Nancy, and 2 Laboratoire de Physiologie, Faculté de Médecine, Vandoeuvre les Nancy, France. CORRESPONDENCE: F. Marchal, Laboratoire de Physiologie, Faculté de Médecine, Avenue de la Forêt de Haye, F- 54505 Vandoeuvre les Nancy, France, Fax: 33 383683739. E-mail: f.marchal{at}chu-nancy.fr Keywords: Childhood asthma, exercise-induced bronchial obstruction, lung function measurements, respiratory impedance
Received: October 3, 2005
The bronchomotor effects of a deep inhalation (DI) may provide relevant information about the mechanisms of exercise-induced airway obstruction in children and may be assessed by respiratory conductance (Grs) measured using the forced oscillation technique. The aims of the present study were to assess the effect of DI on Grs after exercise in relationship to the lung function response to exercise. Grs at 12 Hz using a head generator and spirometric data were measured in 62 children suspected of asthma before and 5 min after a 6-min free run. After exercise, Grs was significantly increased by DI in 38 subjects, who also showed larger Grs and forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) responses to exercise than the 24 nonresponders. Stepwise regression indicated significant correlation between the response of Grs to DI and both Grs and FEV1/FVC responses to exercise. The data are consistent with exercise-induced bronchoconstriction being reversed by deep inhalation. Exercise is a major cause of acute airway obstruction in asthmatic children 1, and exercise-induced airway obstruction (EIAO) a specific indicator of active asthma disease 2. The forced oscillation technique (FOT) is increasingly being used in children as it is noninvasive and requires little active cooperation 3. Respiratory resistance (Rrs) or its reciprocal, respiratory conductance (Grs), derived from the measured respiratory impedance (Zrs), has the potential to describe the bronchial response to exercise. However, few data are available regarding the Grs response to exercise in children in the routine laboratory. Grs measured at frequencies above a few Hertz is thought to express airway conductance to flow 46, and, in describing this response to exercise, it is important to ensure that the observed decrease in Grs after exercise truly reflects a decrease in airway calibre at the bronchial level. Since the 1980s, the effects of deep breaths on airway mechanics have been the object of intensive research 7, 8, and have potentially important applications in the lung function laboratory 9. The current consensus is that pharmacologically induced bronchoconstriction can be reversed by a deep inhalation (DI) as a result of the stretching of those airways subjected to parenchymal tethering. As a corollary, a significant increase in Grs after a DI could be taken as evidence for the relief of EIAO at this level. There are only few studies on the bronchomotor effects of DI in EIAO 10, 11, and their correspondence with the Grs response to exercise has not been established. When using a single excitation frequency, the FOT offers a fairly simple way of tracking Grs during breathing, thereby providing an estimate of the effect of DI on airway calibre 5, 11, provided the breath-by-breath variability of Grs is taken into account. The aims of the present study were to assess the Grs response to exercise in relation to the effects of DI on airway calibre after exercise in children suspected of asthma. The effects of exercise were also monitored spirometrically. The hypothesis is that positive responses to exercise are associated with a significant increase in Grs after the DI.
Subjects Children aged 716 yrs (n = 62; 39 male) were referred to the Laboratoire dExplorations Fonctionnelles Pédiatriques (Hôpital dEnfants, Vandoeuvre les Nancy, France) for lung function testing and evaluation of their airway response to exercise. Their baseline forced expiratory volume in one second (FEV1) was 75% of the predicted value 12. The population was selected on the basis of the childs ability to complete the free running test and participate in the measurements of lung function, including a successful DI manoeuvre as described below. Forty-five children had doctor-diagnosed asthma, six recurrent cough and 11 dyspnoea on exertion. In 44 children, respiratory complaints were triggered or increased by exercise. Bronchodilator therapy was discontinued >12 h prior to the study, including in nine children on long-acting ß2-agonists. Twenty-three children were on inhaled steroids: budesonide 400 µg or fluticasone 200 µg daily in those aged <12 yrs, and budesonide 800 µg or fluticasone 500 µg daily in those aged >12 yrs. Five children were on montelukast 5 mg daily. The characteristics of the subjects and their baseline lung function data are reported in table 1
Measurements Respiratory conductance Zrs was measured using the head generator technique 13 in order to minimise upper airway wall motion. The measuring system (Pulmosfor; SEFAM, Vandoeuvre les Nancy, France) is in conformity with the recommendations issued by a European Respiratory Society task force 3. The children wore a nose-clip and breathed through a mouthpiece connected to a Fleisch No. 1 pneumotachograph (Metabo, Epalinges, Switzerland). Sinusoidal pressure variation was applied at 12 Hz in the head generator. Pressure and flow signals were low-pass filtered at 32 Hz using analogue filters and digitised at a sampling rate of 96 Hz. The breathing component in the signals was eliminated using a fourth order Butterworth high-pass filter with a corner frequency of 6 Hz. The Fourier coefficients (real and imaginary parts) of pressure (ReP, ImP) and flow (ReV, ImV) were computed and Rrs calculated oscillation cycle by oscillation cycle according to NAVAJAS et al. 14: Rrs = (ReP·ReV+ImP·ImV)/(ReV2+ImV2)(1) Twelve Rrs measurements were thus provided every second. A filtering procedure was included in order to detect spurious data associated with rapid flow transients, a low signal-to-noise ratio or glottis closure 15. Airflow, tidal volume (VT) and Rrs were displayed immediately after each acquisition in order to allow visual inspection and selection of the data that were stored on disk. Grs was computed from the reciprocal of Rrs during inspiration and averaged breath by breath. Therefore, in what follows, Grs refers to inspiration.
The children were first familiarised with the equipment and instructed to breathe calmly and regularly and to take a deep breath on demand. Once this was learnt, the children breathed quietly for 1 min through the pneumotachograph, avoiding taking a DI while VT was continuously displayed on the computer screen. Grs was then measured for 2 min as follows. 1) During the first minute, Grs was obtained during tidal breathing and used to assess variability and response to exercise. 2) During the second minute, after four to six tidal breaths, the children performed a DI and then resumed normal breathing. The initial end-point set for validating the DI was an inspired volume of
Spirometry
Protocol
Data analysis The response to exercise was expressed in terms of number of SDws (nSDw): the difference between exercise and baseline divided by SDw, where baseline is the mean of A and B. Responses to exercise were analysed by FEV1 and Grs and considered positive when the relevant nSDw was <-2. The responses to exercise were also expressed as percentage change from baseline.
Grs breath-by-breath variability
Grs response to deep inhalation
Statistics
Repeatability of lung function and response to exercise data The repeatability of measurements of Grs, FEV1, FVC and FEV1/FVC were characterised by SDws of 0.019 L·s-1·hPa-1, 0.06 L, 0.07 L and 2.8%, respectively. The corresponding mean coefficients of variation were 9, 3, 3 and 3%, respectively. Exercise was associated with a significant decrease in Grs, FEV1 and FEV1/FVC (p<0.0001) and FVC (p<0.009; table 2
Grs variability and response to deep inhalation Grs spontaneous within-breath variability after exercise was expressed as a Grs,95 of 1.131.52 (Grs,95,mean = 1.26). The DI after exercise was at least 40% pred FVC in all but six children, in whom it ranged 3040% pred FVC. The data in these children were nonetheless kept for analysis since they showed full cooperation at baseline, where DI amplitude, expressed as a percentage of either measured or predicted vital capacity, was 40%. Indeed, in the whole group, a significant decrease in DI amplitude was observed after exercise (1.44±0.44 L) compared to baseline (1.62±0.48 L, p<0.0001). An example of response to DI after exercise is shown in figure 1
tDI in the 38 DI responders ranged 392 s (21±19 s) and was found to be independent of any parameter of the response to exercise by stepwise regression.
To the best of the present authors knowledge, this is the first study identifying bronchodilation by DI after exercise in children based on Grs breath-by-breath variability and demonstrating the association of this effect with the Grs response to exercise.
Rrs or Grs measured using the FOT is increasingly used as an index of airway dimensions during breathing 46, and represents a potentially powerful tool for evaluating the bronchomotor effects of DI. Two significant physiological sources of Grs variability, however, should be minimised in order to specifically address this effect. Respiratory flow is a well-known determinant of Grs and it is important that ventilation should remain stable and regular, a condition that was required in the present study to measure Grs before and after the DI. It was also established, in a preliminary study, that ventilation was close to baseline 5 min after exercise, at the time the measurement was made 11. An alternative is the measurement of end-inspiratory and end-expiratory values to eliminate the flow dependence of Rrs 5, 17. Upper airway calibre changes during breathing and the tendency for the laryngeal folds to close during expiration probably account for larger Rrs variability compared to that found during inspiration in children 18. Since the current primary interest was to estimate the change in intrathoracic airway dimensions after the DI, it was decided to focus on the Grs during inspiration. Grs spontaneous variability was expressed in a way that could easily be compared with the Grs,DI. For instance, a Grs,95,mean of 1.26 indicates that the upper limit of the 95% CI for between-breath spontaneous variability corresponds to a 26% increase in Grs. Therefore, a Grs,DI of
An increase in absolute lung volume, an important determinant of airway resistance, could occur after a DI and thus contribute to increase Grs 22. Although absolute lung volume was not measured during the manoeuvre, the tracking of VT, as illustrated in figure 1 The most likely explanation of the Grs increase after DI relates to the mechanical interaction between lung parenchyma and conducting airway wall subjected to parenchymal tethering 7. In adult subjects challenged with methacholine, the bronchoconstriction can be transiently reversed by DI as long as lung parenchyma hysteresis is not increased. Conversely, subjects showing increased lung hysteresis, such as that resulting from peripheral airway contraction, do not show much bronchodilation after the DI 25, 26. The effect of DI on airway calibre may be accounted for by a decrease in smooth muscle tension and airway wall elastance. This suggestion comes from in vitro experiments on contracted tracheal smooth muscle subjected to short oscillations, where a sudden increase in amplitude of the oscillation was associated with a dramatic decrease in smooth muscle stiffness and increase in hysteresivity that indicated a stretch-induced decrease in the dynamics of the actinmyosin interaction 27. The association of positive Grs responses to exercise and significant Grs,DI is suggestive of the reversal of exercise-induced conducting airway constriction because, above a few Hertz, Grs is a good indicator of the dimensions of these airways 28. The current observations are thus in keeping with the mechanisms initiating EIAO. Cooling and dehydration are induced by the hyperventilation of exercise primarily in those airways most exposed to thermal and evaporative losses 29, 30, and are thought to initiate mediator release, which promotes airway obstruction in the corresponding part of the airway tree 29. Bronchoconstriction in the conducting airways, but not in the peripheral lung, results in differential hysteresis and may therefore be transiently reversed after DI 25, 26.
Discrepancies between Grs and FEV1 responses to exercise are likely to occur because the maximal airway distension required by the forced expiratory manoeuvre may attenuate the degree of bronchial obstruction detected by FEV1 compared to Grs. Nevertheless, the agreement between FEV1 and Grs was surprisingly good since responses to exercise were discordant in 11 children, being negative by FEV1 and positive by Grs in only five. Although the Grs,DI was significantly larger in exercise responders than in nonresponders by both FEV1 and Grs, the most significantly different lung function parameters between DI responders and nonresponders were the Grs and FEV1/FVC responses to exercise. Furthermore, only the latter two were shown to be significantly correlated to the Grs,DI by stepwise regression. A recent interpretation of alterations in spirometric results induced by methacholine challenge has suggested that a decrease in FEV1/FVC is indicative of airway narrowing in the conducting airways 7, 31, 32, whereas a decrease in FEV1 and FVC, and therefore no change in FEV1/FVC, is thought to reflect an increase in residual volume and gas trapping associated with airway closure 31, 33. Gas trapping has been demonstrated during severe EIAO 24, i.e. those responses extending from the conducting into the more peripheral airways 29, increasing peripheral lung as well as conducting airway hysteresis. Relative hysteresis is therefore unchanged, resulting in only a minimal airway response to DI 26. In a previous study of a different group of children in whom definite EIAO had been documented by a decrease in FEV1 of An important issue in studying the airway effects of DI is that the induced bronchodilation is significant and prolonged in control adults but mild and transient or even absent in asthmatics 79, possibly because of the characteristics of the airway smooth muscle contractile apparatus in asthma 8. Such evidence on bronchodilation by DI after methacholine challenge may be difficult to translate to EIAO because the condition is unlikely to occur in healthy subjects. The current evidence indicates that children with EIAO may readily exhibit bronchodilation by DI. Diagnosis of asthma throughout childhood encompasses more heterogeneous conditions than at adult age; from the many early childhood wheezers, a comparatively smaller fraction will be identified as asthmatic at adolescence 34. Moreover, some children in the current study were on steroid or montelukast therapy, which prevented further analysis of the determinants of Grs,DI. Adult asthmatics receiving methacholine were reported to show not only lesser bronchodilation but also a faster rate of renarrowing after DI compared with controls 5. The rate of renarrowing disclosed in the present study was found to be unrelated to the response to exercise, possibly because it was estimated in a rather crude way. A more detailed analysis of the latter parameter during EIAO would deserve further investigation. It is concluded that significant bronchodilation may be demonstrated after deep inhalation by respiratory conductance measurements in children with exercise-induced airway obstruction. The effect is consistent with the mechanisms of airway obstruction and the mechanical interaction between lung and conducting airways. The identification of a positive response of respiratory conductance to deep inhalation after exercise may thus help in improving the detection of exercise-induced bronchoconstriction in children. Whether or not the pattern of airway response to deep inhalation after exercise-induced airway obstruction permits the identification of different forms of asthma in children is an interesting speculation that deserves further investigation.
The authors would like to thank G. Colin, C. Duvivier and S. Méline for technical assistance, and N. Bertin and E. Gerhardt for secretarial help.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||