INTRODUCTION

Top Abstract Introduction Materials & Methods Results Discussion References

HISTAMINE OR METHACHOLINE bronchial challenge is a well-known method for assessing bronchial responsiveness that has been proven to be useful in the diagnosis and evaluation of asthma in adults and children. However, spirometric tests that require active cooperation for forced expiratory maneuvers cannot be used in infants and young children because of their inability to perform these tests reliably (5).

Transcutaneous respiratory electromyographic (EMG) measurements have been used for several years in respiratory studies in both adults and infants. However, this technique has not been used to assess bronchial responsiveness in children. Studies in animals show that histamine- or methacholine-induced bronchoconstriction causes increased electrical activity of the diaphragm and intercostal muscles (4, 14-16). This was also found in asthmatic adults during histamine-induced hyperinflation (7). In these studies, invasive techniques were used to measure the electrical activity of the diaphragm. A transcutaneous method for monitoring respiratory EMG activity has been developed at our center as a tool in the field of developmental neurology (8, 12). We have used this technique for diagnosing disordered respiratory behavior of neonates and infants (9, 10). We thus investigated whether this method could be used for measuring bronchoconstriction responses in asthmatic children by examining whether an increase in transcutaneous diaphragmatic and intercostal EMG activity occurs at the same dose step of histamine as that inducing a 20% fall in forced expiratory volume in 1 s (FEV₁) after histamine challenge.

	MATERIALS AND METHODS

Top Abstract Introduction Materials & Methods Results Discussion References

Subjects. Eleven children (4 boys) with mild to moderate asthma (7a), without concomitant diseases, aged 9-15 yr (mean 11.9 yr), were recruited from the outpatient clinic of Beatrix Children's Hospital in Groningen, The Netherlands. All children had a concentration of histamine that induces a 20% drop in FEV₁ (PC₂₀) 8 mg/ml in the year before this pilot study was performed. All children used daily inhaled corticosteroids, with a dosage ranging from 200 to 400 µg twice daily and used bronchodilator therapy on demand. None of the children used oral corticosteroids. The mean baseline Tiffeneau index (FEV₁/vital capacity) before the histamine inhalation challenge test was 85% of predicted (range 76-97%). Four children performed one histamine challenge test. Seven children performed two histamine challenge tests on 2 days, at the same time of day, and separated by 24 h to 1 wk. The repeated challenge tests were part of a more extended study that aimed to investigate the reproducibility of the appearance of lung sounds during the histamine challenges (results will be published elsewhere). All consecutive subjects who performed repeated histamine-challenge tests in the extended study were included in the present study. The first challenge with histamine was requested as part of the children's routine evaluation. No child had a history of a respiratory tract infection for at least 1 mo before the challenge tests or between the 2 test days.

View larger version (21K): [in this window] [in a new window]   Fig. 1.   EMG signal processor. Diaphragm EMG, composite raw signal containing low-amplitude diaphragm EMG and high-amplitude ECG components. QRS, normalized pulse derived after detection of QRS complex. Gated EMG, amplified diaphragm EMG after gating out QRS complex. Avg Dia, average diaphragm EMG signal. Average output signal showing good interpolation during gating and almost no residual heartbeat components. Thermistor, a reference respiration signal measured by a nasal thermistor.

	RESULTS

Top Abstract Introduction Materials & Methods Results Discussion References

The results of the study are presented in Table 1.

Seven children performed two histamine challenge tests on 2 days, and four children performed one challenge test. Six children had a positive histamine challenge test (PC₂₀ 16.0 mg/ml) on 1 test day, one child on 2 test days. Three children had a negative histamine challenge test on both test days, one child on 1 test day. In Fig. 2, an example of the diaphragm and intercostal EMG recordings during a histamine challenge test is shown (patient 3). In eight challenges, an increase in diaphragmatic and intercostal EMGAR was detected at the dose step that induced a fall in FEV₁ of at least 20%. No increase in EMGAR was observed in the dose step before the PC₂₀-histamine was reached. In one challenge, an increase in diaphragmatic and intercostal EMGAR was observed at a fall in FEV₁ of 18% (patient 4). In another challenge, an increase in intercostal EMGAR at a fall in FEV₁ of 17% was observed (patient 5). In six challenges, no fall in FEV₁ was induced, and no increase in EMGAR of the diaphragm and/or intercostal muscles could be detected. In the other two challenges, no fall in FEV₁ was induced, but an increase in both diaphragmatic and intercostal EMGAR (patient 1) and only intercostal EMGAR (patient 9) was observed, respectively.

View larger version (50K): [in this window] [in a new window]   Fig. 2.   Diaphragm and intercostal EMG recordings during a histamine-challenge test. Averaged diaphragm and intercostal EMGs are shown at baseline and at dose steps of 2, 4, and 8 mg/ml histamine.

In Fig. 3, the correlation between the maximum fall in FEV₁ and the logarithm of the EMGAR is shown. The correlation coefficient for the diaphragmatic EMGAR was 0.65 (P = 0.05) and for the intercostal EMGAR was 0.72 (P = 0.01).

View larger version (19K): [in this window] [in a new window]   Fig. 3.   Correlation between fall in forced expiratory volume in 1 s (FEV1) and EMG activity ratio (EMGAR) (at a logarithmic scale) of diaphragm and intercostal muscles.

	DISCUSSION

Top Abstract Introduction Materials & Methods Results Discussion References

We found that an increase of the transcutaneous diaphragmatic and intercostal EMGAR corresponds closely to a histamine-induced 20% fall in FEV₁ in asthmatic children. In all children reaching a 20% fall in FEV₁ after histamine challenge, an increase in the EMG activity of the diaphragm and intercostal muscles was observed. In these children, no increase in diaphragmatic and/or intercostal EMGAR was found at the dose step before the PC₂₀-histamine was reached. Our observation that EMG activity in asthmatic children increases after histamine-induced bronchoconstriction is in accordance with Haxhiu et al. (4) and Van Lunteren et al. (15, 16), who found an increase in diaphragmatic and intercostal EMG activity after histamine- and methacholine-induced bronchoconstriction in dogs, and with Trippenbach and Kelly (14), who made the same observation in rabbits.

Although our observations are in accordance with observations in animal studies, before this study was performed we were not sure whether the observations in animal studies could be extrapolated to humans. The investigated animals breathe in a supine position and, therefore, might have a different physiological diaphragm mechanism. It should be mentioned that, in contrast to our study, invasive electrodes inserted in the diaphragm and intercostal muscles were used in these animal studies.

To our knowledge, no data have been published on the use of diaphragmatic and intercostal EMG after histamine- or methacholine-induced bronchoconstriction in the assessment of bronchial responsiveness in humans. Muller et al. (7) found an increase in tonic activity of the diaphragm and intercostal muscles after histamine-induced hyperinflation in adult asthmatic patients. Tonic activity was defined as electrical activity in the EMG present at the end of expiration. In this study, intercostal EMG was recorded with surface electrodes and diaphragmatic EMG with esophageal electrodes. Using esophageal electrodes, Gandevia and McKenzie (2) observed changes in the diaphragmatic EMG activity when posture or lung volume was changed.

The application of surface electrodes is sometimes criticized for possible contamination by the activity of other muscles and for possible effects of variation in posture. However, it has been shown in earlier studies that the electrical activity of the diaphragm detected by surface electrodes is comparable to the activity detected by esophageal electrodes (3, 13). To avoid these contaminations, the children in our study were placed in a sitting position with their hands resting on their legs and they were asked not to move or talk during the recordings. Besides these precautionary measures, we found in two patients (patients 1 and 9) an increase in the EMG activity of the diaphragm and intercostal muscles without a fall in FEV₁ after histamine challenge. Possible causes of these false positives could be changes in posture not observed by us, movement of electrodes over the skin, or changes in lung volume (hyperinflation) not noticed by the investigator. It is likely that children use various breathing strategies during histamine-induced bronchoconstriction, and because of this changes in posture or lung volume may occur, causing an increase in EMGAR. Different breathing strategies such as chest breathing, abdominal breathing, or a combination of both are possible and were observed in all patients. An example is shown in Fig. 2. These various breathing strategies result in changes in diaphragmatic and intercostal EMGAR. At baseline, there is mainly intercostal activity, whereas after inhalation of 2 mg/ml histamine, the breathing strategy changes toward more diaphragmatic activity, suggesting a shift from chest to abdominal breathing. After inhalation of 4 mg/ml histamine, the abdominal breathing shifts back to chest breathing again, but after inhalation of 8 mg/ml a strong combination of abdominal and chest breathing is present at first, and both diaphragmatic and intercostal EMGAR are clearly increased.

In conclusion, increase in the EMGAR as a parameter for increased electrical activity of the diaphragm and intercostal muscles in asthmatic children is easy to detect and corresponds closely to a histamine-induced 20% fall in FEV₁. In the present study, we initiated the development of an alternative method to recognize the fall in FEV₁ of 20% or more, at a certain dose of inhaled histamine, in the assessment of bronchial responsiveness in asthmatic children. The assessment of bronchial responsiveness by measuring the transcutaneous diaphragmatic and intercostal muscle activity during the inhalation challenge could be a method used in younger children who are not able to perform spirometry reliably.