Published ahead of print on November 12, 2004, doi:10.1164/rccm.200404-528OC
© 2005 American Thoracic Society doi: 10.1164/rccm.200404-528OC
Hyperventilation with Cold versus Dry Air in 2- to 5-Year-Old Children with AsthmaPulmonary Service, Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet; Copenhagen Prospective Study on Asthma in Childhood (COPSAC) Clinical Research Unit, Department of Pediatrics, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark Correspondence and requests for reprints should be addressed to Kim G. Nielsen, M.D., Department of Pediatrics, Pulmonary Service, Copenhagen University Hospital, Rigshospitalet DK-2100, Copenhagen, Denmark. E-mail: kgn{at}dadlnet.dk
Cold air challenge (CACh) has been shown to discriminate between children with asthma and healthy young children. Hyperventilation with dry room-temperature air is a simplified alternative. We compared responsiveness in young children with asthma between two standardized, single-step protocols: dry air challenge (DACh) performed as 6 minutes of eucapnic hyperventilation with dry room-temperature air and CACh as 4 minutes of hyperventilation. Response was measured as specific airway resistance by whole-body plethysmography and expressed as change from baseline in numbers of within-subject SDs (SDw). The challenge sequence was randomly assigned. A comparator challenge was performed 1 hour later if the first challenge gave a change of 3 SDw or more. Forty 2- to 5-year-old children with asthma were included. Responsiveness to cold versus dry air showed significant, but weak, correlation (r2 = 0.34, p < 0.0001), but responsiveness to CACh exceeded DACh (7.6 vs. 5.4 SDw, p < 0.02). CACh seemed to induce reduction in response to the following DACh (p < 0.01), whereas no such reduction was seen after DACh. Conclusion: Responsiveness to CACh exceeded responsiveness to DACh, and CACh seemed to induce refractoriness in contrast to DACh, probably because of the additional stimulus from airway cooling. This finding suggests CACh as the preferred method of challenge.
Key Words: preschool • bronchial challenge • asthma • plethysmography Bronchial hyperresponsiveness (BHR) is a key feature of bronchial asthma (1–3), which may conveniently be tested in preschool children by cold dry air hyperventilation (4). The mechanism of airflow limitation from such stimulus is not fully understood but probably involves heat flux and mucosal cooling from the hyperventilation (2) and transient hyperosmolarity with inflammatory and neuronal cells acting on bronchial smooth muscles (1–3, 5–8). The relative importance of water evaporation and airway cooling is debated (1, 3, 5–7, 9–12). We previously reported BHR to cold air challenge (CACh) measured by specific airway resistance (sRaw) in a whole-body plethysmograph to be sensitive and specific in separating children with asthma from healthy subjects among young children aged 2 to 5 years (4). The usefulness of this measure of BHR in young children with asthma was further demonstrated by assessments of the effects of short- (13) and long-acting ß2-agonists (14), inhaled corticosteroids (15), and leukotriene receptor antagonists (16) in young preschool children. However, CACh requires a refrigerator unit and a heat exchanger, whereas hyperventilation with dry room-temperature air only requires pressurized air (which is dry) and is therefore a more inexpensive and easily accessible method (17). This method would allow wider dissemination of measure of BHR in young children with asthma, such as was recently demonstrated in 526 5-year-old children undergoing eucapnic voluntary hyperventilation and sRaw measurements (18). Previous comparisons of dry air challenge (DACh) and CACh have reported DACh to be inferior (5, 19–21) or superior (22) to CACh. Both DACh and CACh have been shown to cause refractoriness to bronchoconstriction in subsequent challenges in schoolchildren and adults (23–26). None of these aspects has previously been studied in young children. This article compared responsiveness to DACh and CACh in young children with asthma aged 2 to 5 years. This article previously has been reported in the form of an abstract (27).
Subjects Children with asthma aged 2 to 5 years with known good compliance to plethysmographic measurements and previous positive challenge tests and who were attending the outpatient asthma clinic were eligible for the study. Diagnosis was based on history of typical symptoms, symptom relief from inhaled ß2-agonists and inhaled corticosteroids, and relapse after pausing the inhaled corticosteroids. Exclusion criteria were as follows: signs of acute asthma symptoms, history of any respiratory tract infections within the last 3 weeks, or change of treatment within the last month. Leukotriene receptor antagonists and short- and long-acting ß2-agonists were not allowed within 5 days, and 8 and 24 hours, respectively. The study was approved by the local ethics committee (KF-02–115/96). Written, informed consent was obtained from parents.
Challenge Procedures CACh (4) was performed as a single-step 4-minute isocapnic hyperventilation test. A respiratory heat exchange system (E. Jaeger, GmbH, Würzburg, Germany) delivered –15°C cold, dry air mixed with 5% CO2. The hyperventilation rate was aimed at 1 L/minute/kg of bodyweight and measured at the exhalation valve by a pneumotachograph. Hyperventilation was achieved by having the child compete with a computer animation of a balloon, the flying height of which reflected the hyperventilation level. DACh was also performed as a single-step provocation procedure. The child hyperventilated dry room-temperature air from a commercially available tank with a 5% CO2–enriched, calibrated gas mixture (AGA Gas, Stockholm, Sweden). The gas was delivered via a flow meter (rotameter) (17). Hyperventilation guidance and rate were similar to the CACh experiment, but with a duration of 6 minutes (28). (See also online supplement.)
Specific Airway Resistance
Study Design
Data Analysis
Forty-eight patients were challenged with either hyperventilation of cold or dry air as the initial challenge. Five and three patients who were initially tested with dry and cold air, respectively, did not meet the inclusion criteria. The characteristics of the remaining 40 young children with asthma included in this study are summarized in Table 1. The mean duration of asthma treatment was 23 months, ranging between 1 and 60 months. Two children were not currently treated for asthma; six were treated with short-acting ß2-agonists only; 30 (75%) were on regular treatment with inhaled corticosteroids in a mean dose of 333 µg (range 200 – 800 µg) of budesonide inhaled from a pressurized metered dose inhaler via a metals pacer (Nebuchamber, AstraZeneca, Lund, Sweden); one child was treated with inhaled corticosteroids and leukotriene receptor antagonists; and one was treated exclusively with leukotriene receptor antagonists.
The parent accompanied the child inside the box on one occasion (30). The median (95% CI) baseline sRaw as percentage of predicted was 113 (106–127% predicted) and 112 (103–127% predicted) at the first and second test, respectively (i.e., significantly increased compared with reference values) (31). There was no difference between median baseline values before CACh and DACh. Twenty children followed the sequence CACh to DACh and 20 the reverse sequence, with a mean interval of 74.8 minutes (range 60 to 141 minutes) between tests and without difference in time interval from the first to second challenge between challenge sequences. Both tests were positive, defined as increase in sRaw of 3 SDw or more, in all but five patients (second challenge was negative in four patients when DACh was the second test). The response to CACh (7.6 SDw units) was significantly greater than the response to DACh (5.4 SDw units; p < 0.02; Figure 1). The Bland-Altman plot of change in number of SDw units in sRaw after CACh versus DACh indicated no bias (not shown). There was a significant but weak correlation between the two methods (r2 = 0.34, p = 0.0001); that is, only approximately one third of the variability of the response to CACh was explained by the variability in response to DACh. A Bland-Altman plot of difference between CACh and DACh in sRaw response calculated as numbers of SDw units versus the mean change in SDw units after CACh and DACh, respectively, gave limits of agreement of –8 SDw and 12 SDw (not shown).
The subgroup challenged with cold air as the first test showed a tendency toward greater response than those patients starting with DACh (p = 0.066; Figure 2). The response to DACh was significantly reduced when second to CACh (8.2 vs. 7.6 SDw units, p < 0.01), suggesting the occurrence of refractoriness. Sixteen of 20 (80%) children showed reduced response to DACh. In contrast, the response to CACh was not reduced following DACh (p > 0.2; Figure 2).
CACh caused a significantly greater response than DACh despite shorter duration of hyperventilation and seemed to induce significant refractoriness, whereas DACh did not. We have previously demonstrated that CACh is a useful test for BHR in young children with asthma (4). However, the equipment for CACh is more expensive than the equipment for DACh because dry air is simply obtained from compressed air. Such simplified set-up could ease the dissemination of a simple, indirect challenge test for BHR in young children. In adults with asthma, DACh demonstrated higher sensitivity than CACh in one study (22), whereas other studies found CACh to be slightly superior to DACh (5, 19–21). Comparisons previously have not been performed in young children. Our protocol for DACh used a 6-minute, uninterrupted, eucapnic hyperventilation challenge with dry room-temperature gas with a modified target minute ventilation of 25 x FEV1, corresponding to 1 liter/minute/kg of bodyweight, similar to the ventilation rate we used in CACh and found acceptable in most young children (4). The hyperventilation in the DACh experiment was continued for 6 minutes as suggested by Argyros and colleagues (28), whereas it was continued for only 4 minutes in the CACh, which has been the method of choice in schoolchildren and young children (4). The difference in duration would be expected to put DACh at an advantage because both duration of challenge and total ventilation are major determinants of the response (33). However, CACh caused greater increase in sRaw, both in the total group, disregarding test order, and in the comparison between CACh and DACh at the first test where a tendency in favor of CACh was found. The fact that the response to CACh was superior despite this difference in duration suggests that cooling of the airways also may be an important additional stimulus in young children with asthma, as previously suggested from studies in adults (5, 12, 34). McFadden and colleagues (5) demonstrated that FEV1 decreased significantly more after CACh than after DACh despite greater water loss in the DACh experiment. Still, we cannot exclude the possibility that the increased response to CACh may be an artifact of the timing of the response. Because response to isocapnic hyperventilation testing is short and steep (35) and the time point was identical, although the ventilation 2 minutes longer in the DACh, this latter measurement may be at a time point when the response is declining. However, the importance of duration of challenge is controversial because some authors find increasing response from an extension of the challenge period (33), whereas decreased response seems to be related only to challenge procedures extended beyond 12 minutes (36). The statistically significant but small difference in favor of CACh may be explained by refractoriness induced by CACh but not DACh as suggested by the subanalysis (Figure 2) where CACh seemed to induce refractoriness to the subsequent DACh in 80% of our patients. The ability of CACh to induce refractoriness is in keeping with some previous reports in adults (25, 37) and children (23), implying that CACh is a stronger and different stimulus to both induce and overcome refractoriness to a weaker stimulus. This finding lends further support to the distinct mechanism of the airway cooling. It has been speculated that one such effect from the cold air is an increased number of airway generations becoming dehydrated in the humidifying process (7). Argyros and colleagues (25) did, however, find significant refractoriness from one 6-minute DACh to the next DACh made at least 1 hour apart.There are some limitations to the interpretation of our results regarding refractoriness because of the following factors: first, for simplification, we made no attempts to account for water or heat loss between challenges; second, no strict timetable was followed; and third, no direct intrasubject comparison of refractoriness was performed because each child performed only one pair of challenges. The indirect challenge tests are becoming increasingly recognized for evaluation of BHR (2, 35) and for monitoring treatment with controller treatments (2, 15). The advantage of indirect challenges compared with direct challenge with a single pharmacologic substance is that a significant positive response signifies that inflammatory cells and their mediators are present in the airways in sufficient numbers and concentration to suggest that asthma is active at the time of testing (2, 3). The corollary is that a negative test in children with asthma indicates good control or mild disease. Another advantage is that healthy children rarely have significant airflow limitation to indirect challenge tests and therefore the separation between children with asthma and healthy children is generally good (2–4). Therefore, the use of indirect challenge tests has been encouraged (2–4). Other indirect challenge tests, such as inhalation of adenosine (2, 38) or mannitol (39), may be interesting candidates of even simpler tests for BHR in young children with asthma in future studies. In conclusion, the bronchial response to CACh and DACh measured by whole-body plethysmography (sRaw) are useful tests for asthma in young children. CACh is shorter in duration and exceeds DACh in magnitude of response. Furthermore, it seems to induce refractoriness, probably explained by the additional stimulus of airway cooling. We therefore suggest CACh as the more appropriate test for BHR in young children with asthma.
The authors thank Ivan Seerup for his contribution on the dry air challenge equipment.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Conflict of Interest Statement: K.G.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.B. has within the last 3 years received honoraria for lectures and attendance at pediatric advisory boards for Aerocrine, AstraZeneca (AZ), GlaxoSmithKline (GSK), Hoffman-La-Roche, Merck Sharpe and Dohme (MSD), Novartis, and Yamanouchi and owns world patents in the pharmaceutical industry in the respiratory field and the COPSAC clinical research unit. In addition, in the last 3 years, he has received research grants from the following industry partners in order of increasing support: Aerocrine, MSD, GSK, and AZ. Received in original form April 21, 2004; accepted in final form November 4, 2004
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