Abstract
The measurement of bronchial reactivity is an important aid in the diagnosis of asthma, but the technique using spirometry is not feasible in young children. The aim of the present study was to determine the efficacy and safety of a modification of the chest auscultation method in the assessment of bronchial reactivity to inhaled methacholine in young asthmatic children. One hundred forty-six young children with asthma (mean age, 4.3 yr) underwent bronchial challenges with nebulized methacholine using the auscultation method (PCW). The end point was defined as the appearance of wheezing, oxygen desaturation, or tachypnea. For comparison, 30 children and young adults with asthma underwent bronchial provocation with methacholine using spirometry (PC20). A positive response using the auscultation method was observed in 95.9% of the younger children, and wheezes alone or in combination with other signs appeared in 80.8% of them. The mean desaturation at the end point was 4.6% (PCW) and 5.0% (PC20), with a similar pattern in the two groups. Cough was not helpful in determining the end point. We conclude that the modified auscultation method is effective and safe, with wheeze appearing at the end point in the large majority of the children.
The assessment of bronchial reactivity to nebulized methacholine and adenosine 5′-monophosphate has become an important tool for the differential diagnosis of asthma from other causes of chronic airway diseases and the assessment of the severity of bronchial reactivity in these patients (1-3). In adults and cooperative children older than 6 yr of age the response to these agents is usually assessed by repeated spirometric measurement of lung function, and the end point is defined as the concentration of the test agent that causes a 20% fall in FEV1 from baseline (PC20). In younger children unable to perform spirometry, the bronchoconstrictive response to methacholine can be evaluated by the detection of an audible wheeze over the trachea or the chest (auscultation method) (1) and the end point is defined as the concentration at which an audible wheeze is detected (PCW). We have previously shown that in children old enough to perform spirometry, there was a good correlation between PC20 and PCW (1, 4).
However, there is a controversy as to the sensitivity of the auscultation method to detect wheezing after methacholine nebulization in young children. Wilson and colleagues (5) performed methacholine challenges in 30 children 5 yr of age with a history of wheeze and found that only 16% of the children wheezed at the end-point concentration of methacholine. Sprikkelman and colleagues (6) reported that wheeze was detected in only 33% of 15 asthmatic children 8 to 15 yr of age who were challenged by methacholine. These findings are in contrast to those of Yong and colleagues (7) who studied the response to methacholine of 39 children 8 to 46 mo of age with a history of recurrent wheeze, and found that wheeze occurred in 90% of the tests.
In our original study (1), we performed methacholine challenges in two groups of children. The first group consisted of 15 asthmatic children 6 to 15 yr of age who had simultaneous assessment of the response to methacholine by spirometry and chest auscultation. The end point of the test was defined as a fall in FEV1 of 20%, and 12 of the children (80%) wheezed at the end point of the test. The second group included 65 children 1 to 8 yr of age with asthma assessed by auscultation, and the end point was defined as the appearance of wheeze. All of the children responded with wheezing at methacholine concentration of 8 mg/ml or less, but oxygen saturation (SaO2 ) was not measured, and it is possible that in some children SaO2 could have fallen markedly. During the years since our original study we have included also oxygen saturation monitoring during methacholine challenges, mainly for safety reasons, and have observed that some children respond to methacholine inhalations by a fall in oxygen saturation and an increase in respiratory rate. The aim of the present study was to determine the efficacy and safety of a modified auscultation method by adding the fall in oxygen saturation and increase in respiratory rate to wheeze detection as criteria for a response to methacholine.
One hundred forty-six asthmatic children (89 boys) 2 to 8 yr of age (mean age ± SD, 4.2 ± 1.2 yr), with a typical clinical picture of recurrent episodes of wheezing responsive to antiasthma medications and with symptom-free intervals, undertook bronchial challenges using the modified auscultation method. Ninety-two children had mild intermittent asthma (treated by inhaled β2-agonists) and 54 had mild persistent asthma (treated by inhaled steroids, 200 to 400 μg/d) (Table 1). Methacholine challenges were performed as part of the diagnostic evaluation. The challenges were approved by the local ethics committee, and informed consent was obtained from the parents of each child.
All children avoided bronchodilator and cromolyn sodium therapy for at least 12 h before the challenges, but inhaled steroids were not stopped. In order to undertake bronchial provocations in small children, we adapted the original tidal breathing method of Cockcroft and colleagues (8, 9). Bronchial provocation was performed using fresh solutions of methacholine (0.03 to 8.00 mg/ml) dissolved in phosphate buffer. Solutions were nebulized using a Hudson nebulizer (Hudson RCI, Temecula, CA), driven by compressed air with a flow of 5 L/min giving a mean output of 0.4 ml/min. Inhalations were performed using a face mask and continued for 2 min of tidal breathing, starting with the buffer solution and then followed by doubling concentrations of methacholine every 5 min until the maximal concentration or the end point was reached (2).
The end point of a challenge was defined as the concentration of methacholine resulting in one or more of the following: (1) wheezing heard over the chest or the trachea; (2) a fall in oxygen saturation of at least 5% from baseline (desaturation); (3) an increase in respiratory rate of at least 50% from baseline (tachypnea).
Chest and tracheal auscultations were performed using a regular pediatric stethoscope. The trachea and two zones of both lungs (upper front and lower back) were each auscultated repeatedly in sequence during quiet breathing for about 20 s beginning immediately after the end of the nebulization and continuing for a total of 3 min. Arterial oxygen saturation and heart rate were monitored continuously by pulse oximetry (Biox 3700e; Ohmeda, Louisville, KY). Whenever oxygen saturation fell below 5% of baseline, methacholine nebulization was stopped immediately and albuterol was nebulized using compressed oxygen. The appearance of cough was noted, and the concentration of methacholine at which it was present was recorded.
In order to compare the changes in oxygen saturation in response to methacholine nebulization in young children with those of older children and young adults, we also performed methacholine bronchial challenges in 30 asthmatic subjects (mean age, 11.9 ± 6.3 yr; range, 6 to 25), using spirometry and continuous measurement of SaO2 by pulse oximetry. Seventeen patients had mild intermittent asthma and were receiving β2-agonists as needed, and 13 had mild persistent asthma, four treated by cromolyn sodium and nine by inhaled steroids 200 to 400 μg/d (Table 1).
The protocol of the challenges in this group of subjects was similar to that for the younger children, except that the nebulized solutions were inhaled via a mouthpiece, and the end point of the test was defined as the concentration of methacholine causing a 20% fall in baseline FEV1 (7, 8). The subjects inhaled the nebulized solutions during tidal breathing for 2 min, and lung function was then measured using a pneumotachograph-based system (Compact; Vitalograph, Buckingham, UK) after 1 and 3 min. Doubling concentrations of methacholine were then administered until the end point or a maximum concentration of 8 mg/ml was reached.
Statistical comparisons were performed using Student's t tests and chi-square analysis when appropriate. PCW values were compared after logarithmic transformations. Differences were considered significant when p was less than 0.05.
One hundred forty children (95.9%) responded to methacholine by one or more of the criteria of the auscultation method at a concentration of 8 mg/ml or less, and the logarithmic mean PCW of methacholine was 0.4 mg/ml (95% confidence interval [CI], 0.33 to 0.49). Mean PCW of the children with mild persistent asthma was 0.2 mg/ml; 95% CI, 0.14 to 0.27, which was significantly lower than the PCW of the children with mild intermittent asthma (0.63 mg/ml; 95% CI, 0.52 to 0.76; p < 0.0001).
The test was terminated because of wheeze in 118 of the children (80.8%). In these children wheeze was associated with tachypnea in 19, with desaturation in 20, and with both signs in 69. The test was terminated without the presence of wheeze in 22 children (15.1%). In 12 of these children there was both desaturation and tachypnea at the end point. In eight there was desaturation alone, and in two there was tachypnea alone (Table 2). The distribution of the severity of asthma was similar between the wheezers and the nonwheezers (p = 0.63, chi-square analysis). In the wheezers group, 74 children had mild intermittent asthma and 44 had mild persistent asthma, whereas in the nonwheezers group 12 had intermittent asthma and 10 had mild persistent asthma. At the end point of the challenge there were no significant differences between the wheezers and the nonwheezers in terms of methacholine concentration (PCW), frequency of appearance of tachypnea, or desaturation (Table 3).
| Signs at End Point | No. of Children (%) | |
|---|---|---|
| With wheeze at end point | 118 (80.8) | |
| Wheeze alone | 10 (6.8) | |
| Wheeze + tachypnea | 19 (13.0) | |
| Wheeze + desaturation | 20 (13.6) | |
| Wheeze + tachypnea + desaturation | 69 (47.3) | |
| Without wheeze at end point | 22 (15.1) | |
| Tachypnea alone | 2 (1.4) | |
| Desaturation alone | 8 (5.5) | |
| Tachypnea + desaturation | 12 (8.2) | |
| Any signs at end point | 140 (95.9) | |
| Nonresponders | 6 (4.1) |
| PCW (mg/ml ) | Subjects with ΔSaO2 > 7% (%) | Patients with ΔRR ⩾ 50% (%) | ||||
|---|---|---|---|---|---|---|
| ASTHMA | ||||||
| Wheezers, n = 118 | 0.40 | 12.7 | 52.5 | |||
| Nonwheezers, n = 22 | 0.42 | 13.6 | 68.2 | |||
| p Value | 0.15 | 1.0 | 0.24 | |||
| Statistics | t test | chi-square | chi-square |
The pattern of the distribution of desaturation at the end point of the challenge is shown in Figure 1. SaO2 fell by less than 5% in 50.7% of the children, by 5 to 7% in 40.7%, by 8 to 10% in 8.6%, and by 11% in 0.7% of the children. Methacholine nebulization was stopped immediately whenever saturation fell by more than 5% and albuterol was nebulized with oxygen, resulting in an immediate increase in oxygen saturation. No correlation was found between the magnitude of desaturation and the concentration of methacholine (PCW) at the end point of the challenge (linear regression, r = 0.13, p = 0.12). Cough was recorded in most of the patients (81%) at the end-point concentration of methacholine. However, in some children cough developed as early as five concentrations before the end point of the test (Table 4).
Fig. 1. The distribution of the magnitude of the fall in arterial oxygen saturation at the end-point concentration of nebulized methacholine in the younger children with asthma using the auscultation (PCW) method and in the older asthmatics using spirometry (PC20).
[More] [Minimize]| Methacholine Concentration | Asthma (% of patients) | |
|---|---|---|
| n* | 81 | |
| n-1 | 31 | |
| n-2 | 13 | |
| n-3 | 8 | |
| n-4 | 5 | |
| n-5 | 5 | |
| n-6 | 0 |
The distribution of the severity of asthma in the 30 older asthmatics was not significantly different from that of the younger asthmatics (p = 0.66, chi-square analysis). Mean baseline FEV1 was 91 ± 10%, and mean PC20-methacholine was 0.53 mg/ml (95% CI, 0.30 to 0.93), which was not significantly different from the mean PCW of the younger asthmatics (p = 0.25). The mean fall in FEV1 at the end-point concentration of methacholine was 29.9 ± 9.5% (95% CI, 26.3 to 33.4%), and the mean fall in SaO2 was 5.0 ± 2.6%. No correlation was found between the magnitude of desaturation at the end point of the challenge and the PC20-methacholine (r = −0.07, p = 0.72) or the percent fall in FEV1 (r = 0.013, p = 0.94). The pattern of changes in saturation was very similar in this group as compared with the younger children. SaO2 fell by less than 5% in 53.3% of the patients, by 5 to 7% in 33.3%, by 8 to 10% in 10.0%, and by 11% in 3.3% of the patients (Figure 1).
We have shown in this study that the auscultation method can detect bronchial hyperresponsiveness to inhaled methacholine in most of the young asthmatic children tested (95.9%) and that the majority of the challenges (80.8%) ended with wheezing.
We considered the possibility that the three different criteria for determining the end point of the challenge (wheeze, desaturation, and tachypnea) may not necessarily reflect the same degree of response. However, when comparing the children who wheezed with those who did not wheeze, we could not find any significant clinical differences between the groups, nor could we find any significant difference in the PCW, frequency of the appearance of tachypnea, or of oxygen desaturation below 90% between the groups (Table 3).
For some time we have been aware that many children cough during this type of challenge but the appearance of cough seemed to vary between individuals and was unrelated to the end point of the challenge (Table 4). It is possible that the effect of methacholine on cough may be related to a dose- response relationship, resulting in stimulation of irritant receptors in the lung, rather than an effect on bronchoconstriction measured by wheeze, tachypnea, or desaturation.
Wilson and colleagues (5) compared the sensitivity of three methods to detect a response to bronchial provocation with methacholine in a group of young children with a history of wheeze. The methods used were an increase in respiratory resistance measured by the forced oscillation technique, a fall in transcutaneous oxygen tension (PtcO2 ), and the appearance of wheeze detected by auscultation. The inhalations of methacholine were stopped when the PtcO2 had fallen by at least 20%, the child was heard to wheeze or was dyspneic, or until the maximum concentration of methacholine was reached. In their study they found that only 16% of the children wheezed at the end point concentration of methacholine, and in some, oxygen tension fell by as much as 33% in the absence of wheeze. They concluded that the most reliable method was a fall in PtcO2 of 15%, whereas the forced oscillation technique was unreliable and the auscultation method was not valid. We estimated the change in oxygen saturation from the PtcO2 data presented by Wilson and colleagues (5) and found that the mean drop in SaO2 was 5.6%, which was very similar to our own results. However, the different responses in wheezing of the children in Wilson's study as compared with ours are probably secondary to the different degree of bronchial reactivity to methacholine and the severity of asthma. In Wilson's study, the mean concentration of methacholine at the end point was 17.8 mg/ml (compared with the mean PCW of 0.4 mg/ml in our study) and 83% of the children responded to methacholine concentrations of 16 to 32 mg/ml.
Sprikkelman and colleagues (6) performed methacholine challenges in a group of 15 asthmatic children 8 to 15 yr of age. Twelve of the children responded to methacholine by a fall in FEV1 of 20% or more at a dose of 39.3 mg/ml or less, but wheeze was detected in only four children. In a recent study the same investigators performed histamine challenges on two different days in 15 children 9 to 15 yr of age with mild to moderate asthma (10). Twenty-six of the 30 tests ended with a positive response, with a PD20 of 16 mg/ml or less. In 20 of these 26 tests (77%), wheeze was also detected by tracheal auscultation. Also, Yong and colleagues (7) recently reported that methacholine challenges performed on 39 young children with a history of recurrent wheezing were terminated because of wheezing in 90% of tests at methacholine concentrations of 8 mg/ml or less. In our present study, we obtained similar results to those of Sprikkelman and colleagues (10) and Yong and colleagues (7) in that 81% of our children wheezed at the end-point concentration of methacholine. When adding the two other criteria used for the end-point determination (tachypnea and desaturation), the efficacy of the auscultation method increased to above 95%. With regard to the safety of the auscultation method, 91.1% of the younger children who responded to methacholine nebulization had a fall in SaO2 of 7% or less, and only 8.9% had a fall of 8 to 11%. Methacholine nebulization was stopped immediately whenever saturation fell by more than 5% and albuterol was nebulized with oxygen, resulting in an immediate increase in oxygen saturation. Bronchial provocation in older children and adults is usually performed using spirometry and a fall in FEV1 for the detection of a response, whereas arterial oxygen saturation, if measured, is usually undertaken for safety reasons. In the present study, we found a similar pattern of oxygen desaturation in our older subjects compared with the group of younger children (Figure 1). We therefore suggest that bronchial challenges in older children and adults should be performed with continuous measurement of oxygen saturation.
We have shown that the auscultation method for the assessment of bronchial reactivity to methacholine in young children is an effective method and is as safe as the conventional method performed in older children and adults using spirometry.
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