Bronchial responsiveness (BR) denotes a bronchoconstrictor response to different stimuli such as cold air, exercise, or pharmacologic challenge. Exaggerated BR (bronchial hyperresponsiveness (BHR)) occurs in most patients with asthma and the persistence of BHR is related to atopy (29). Exercise-induced bronchoconstriction (EIB) is a commonly recognized respiratory disorder. It is defined as narrowing of intrathoracic airways shortly after exercise. Climatic conditions during exercise seem to influence the magnitude of the airway response. It has been observed that exercising in cold air enhances bronchoconstriction as compared with exercising in warm air (4,19,21,30). Although the mechanism for EIB seems to differ from that of hyperventilation with cold air, there is a similarity in their ability to induce bronchoconstriction in children with asthma (5,31).
There are several factors that have been reported to contribute to increased airway resistance and BHR, as related to exercise and to hyperventilation with cold air. These include evaporative heat and water loss as well as cold air inhalation (4,17,30). It is suggested that increased osmolarity of the epithelial fluid induced by the vaporization of water stimulates the production and release of bronchoactive substances from mast cells and epithelial cells, and that vagal afferent pathways are activated by changes in osmolarity and by the released mediators. Cold air seems to enhance the response to water loss. Exposure to cold air induces an increased number of inflammatory cells in the lower airways in healthy subjects (18), whereas EIB itself does not seem to cause eosinophilic airway inflammation in asthmatic subjects (14).
The role of the parasympathetic system in the mechanism of BR is controversial. Bronchoconstriction appears to be a component of the “diving response” mediated, like bradycardia, by vagal afferents. This occurs with facial cooling (3,24), stimulation of upper airway receptors (27), deep inspiration (15), and nasal irritation (11). Several studies have shown augmentation of vagal cardiac activity (prolongation of sinus cycle length) caused by facial cooling (1,7,12); this was more pronounced in children than in adults (8) and after than before exercise (22). These responses may provide another explanation why exercising in cold air enhances bronchoconstriction as compared with exercising in warm air. The protective effect of face masks described for asthma induced by cold air (26) may be due to modulation of inspired air conditions, but also due to facial skin warming.
Until now, investigators have not determined the respective contribution to BR of direct (inhalation) and indirect (facial cooling) influences when children exercise in cold air. The purpose of this study was to compare the effects on BR of cold air inhalation and of facial exposure to cold air, as well as the combined effect of both. The results might offer more diagnostic and therapeutic possibilities and contribute to a better understanding of the mechanisms determining exercise- and cold-induced BR in children.
Fourteen patients (six boys and eight girls) with asthma took part in the study. They met the criteria of having EIB, defined as a ≥10% decline in forced expiratory volume in the first second (FEV1) or a ≥20% decline in maximal mid-expiratory flow (MMEF), in at least one of the four visits. The study was approved by the Institutional Research Ethics Board. Subjects gave their assent to participate in the study. This was followed by a written parental consent.
Subjects’ physical characteristics are summarized in Table 1. All had a history of EIB. They suffered from asthma since age 4.4 ± 3.4 yr. Ten had a positive history of atopy. Four participated in competitive sports. Seven were treated with short-acting inhaled β-agonists and 6 with long-acting inhaled β-agonists, 1 with inhaled anticholinergics, 1 with oral antihistamines, 14 with inhaled steroids, and 5 with oral antileukotrienes. Inhaled medication was discontinued for at least 24 h, antihistamines for 3 d, and antileukotrienes for 5 d before testing. No sports activity was performed for at least 8 h before testing. There was no evidence of upper respiratory tract infection, nor any other acute infection at the time of the study.
Subjects served as their own controls. Each child underwent four visits in a climatic chamber. All sessions, for any given child, were conducted at the same time of day to reduce the effect of circadian variation. There were at least 24 h but not more than 2 wk between consecutive visits. The sessions varied in the temperature of the inspired and in ambient air temperature. Vapor pressure of the inspired air was constantly low in all sessions (4–5 mm Hg).
Visit 1 was intended for orientation and habituation. It included consent, physical examination, and an interview regarding medication, atopy and the child’s habitual physical activity. In addition, an exercise challenge test was performed to establish the work rate (1 ± 0.1 kJ·kg−1 BW for girls and 1.2 ± 0.2 kJ·kg−1 BW for boys) that caused the heart rate (HR) to increase to 165–175 beats·min−1 and to determine the bronchial response while inhaling “warm” air and exposing the face to “warm” air (WW, 21°C, 25% relative humidity). The warm environment was considered the safest condition and was therefore chosen for the first visit for all subjects. The sequence of visits 2–4 was counterbalanced. Exercise challenges in visits 1–4 were identical, but they differed in air temperature in the climatic chamber and the temperature of the inhaled air. In visits 2–4, after a brief history and physical examination, the bronchial response to exercise was measured under one of the following conditions: 1) inhaling warm air (21°C, 25% relative humidity) while the face was exposed to cold air (WC, 0°C, 80% relative humidity); 2) inhaling cold air while the face was exposed to warm air (CW); and 3) inhaling cold air while the face was exposed to cold air (CC). This study was not designed to separately determine the effects of cold air on the resting child. We therefore did not perform spirometry before the child entered the chamber. Preexercise spirometry in all sessions was performed 5 min after the child had entered the chamber and inhaled air at the prescribed temperature and humidity.
Upon entering the chamber, the child sat down for 5 min, while inhaling cold or warm air, as prescribed for the respective visit. This was followed by baseline resting spirometry, and then the child performed the 8-min exercise test. Spirometry was repeated at 0, 5, 10, 15, and 20 min postexercise. The child then left the chamber. Exercise was performed on a Fleisch cycle ergometer (METABO SA, Switzerland). Pedal length and seat location were determined for each subject and remained constant in all visits. Before each chamber session, the subject was fitted with identical clothes (sweater, T-shirt, pants, gloves, and balaclava covering neck, ears, and head) to standardize the conditions. A heart rate monitor was attached to the chest (Polar Vantage NV, Kempele, Finland) and a skin thermistor placed on the forehead (400 Yellow Springs, Yellow Springs, OH). Upon entering the chamber, the child breathed through a valve system, inhaling either cold or warm air for 5 min, while sitting on the cycle ergometer. Resting spirometry was then taken (Vitalograph, Kansas). To provoke bronchoconstriction, the child then cycled for 8 min at a predetermined intensity, while breathing the same conditioned air. At the end of exercise, the child performed forced expiratory maneuvers, at 0, 5, 10, 15, and 20 min postexercise while sitting on a chair. In between spirometries the child was sitting on the cycle ergometer and breathing through the valve system during the 20-min recovery. We measured FEV1 and MMEF. Testing was done in triplicate and we took the highest value of the three trials for further analysis.
The same valve and tubing system was used throughout the study. To achieve warm conditions while the child was exposed to cold ambient air or cold conditions during exposure to warm ambient air, the inhaled air was passed through a 137- to 203-cm length of tubing (30-mm internal diameter). The tube was fixed to a porthole in the climatic chamber wall and wrapped with thermal insulation material along its entire length. This helped maintain the required air temperature, which was monitored every 5 min 5 cm distal to the breathing valve (400 Yellow Springs thermistor). To monitor the effect of different air conditions on the face, skin temperature of the forehead was measured every 5 min.
A two-way repeated measures ANOVA was completed to identify differences in bronchial response after exposure at rest and exercise in the four facial and inhaled air combinations. A one-way ANOVA was performed to detect differences in maximal fall of FEV1 and MMEF as compared with predicted values, as well as to identify differences in resting FEV1 and MMEF values as percent of predicted (% pred). A Tukey post hoc test was used when indicated. P < 0.05 was taken as the level of significance.
Mean resting FEV1 was 98% pred, ranging from 77 to 114% pred (16) (Table 1). Changes in FEV1 and MMEF as % pred over time are summarized in Figures 1 and 2, respectively. There was a significant condition × time interaction for FEV1 (P < 0.001) and for MMEF (P < 0.001). Preexercise values were lowest in the two sessions where the face was exposed to cold air (WC and CC). For FEV1 (Fig. 1) WC had significantly (P < 0.001) lower values than did the other three exposures, and CC was significantly (P < 0.001) lower than CW. For MMEF (Fig. 2), WC was significantly lower than CW (P < 0.001) and WW (P < 0.02). There were no differences in the preexercise pulmonary functions between sessions CW and WW, in which the face was exposed to warm air. Postexercise FEV1 at CC was significantly lower than CW (P < 0.001 or 0.01) at all time points and than WW at all time points (P < 0.05 or 0.001) apart from 15 min. Likewise, WC was lower (P < 0.001) than CW at all postexercise time points and than WW (P < 0.001 or 0.01) at all time points apart from 15 min. FEV1 at WW was significantly (P < 0.001 or 0.01) lower than CW at 10, 15, and 20 min postexercise. The net exercise-induced decline in FEV1 during CC and CW was significant at 5 min postexercise (P < 0.001) and during WW at 10 min postexercise (P < 0.001), compared with the preexercise value. There was no significant exercise-induced decline in FEV1 during WC. MMEF in CC was significantly (P < 0.001) lower than in CW at all postexercise time points and than WW at 5, 10, and 20 min postexercise. MMEF was lower (P < 0.001) in WC than in CW at 0 and 20 min postexercise. The net exercise-induced decline in MMEF during CC, CW, and WW was significant at 5 min postexercise (P < 0.001), compared with the preexercise value. There was no significant exercise-induced decline in MMEF during WC. The greatest decline in lung functions did not occur at the same postexercise time in all patients. Figures 3 and 4 are therefore plotted to document the greatest decline in the four visits, irrespective of the time in which it occurred. For FEV1 (Fig. 3), the two visits with cold facial air (WC and CC) had the greatest decline, but the difference was only significant versus CW. For MMEF (Fig. 4), the lowest value was at the CC visit. Heart rate, measured during the last 4 min of exercise, was 181 ± 3 beats·min−1 for WW, 176 ± 3 beats·min−1 for WC, 181 ± 3 beats·min−1 for CC, and 185 ± 3 beats·min−1 for CW. These differences were not significant. Forehead skin temperature, measured immediately before exercise, was 34 ± 1°C for WW, 28.6 ± 2.1°C for WC, 29.3 ± 1.4°C for CC, and 34.6 ± 0.4°C for CW. The skin temperatures at the two facial cooling sessions (WC and CC) were significantly lower than the two other sessions (P < 0.001).
This study indicates that, under the preceding experimental conditions, the two challenges when the face is exposed to cold air cause greater EIB in children with mild asthma, as compared with the two challenges when the face is exposed to warm air. The provocation provided by facial cooling (approximately 5°C decline in skin temperature) may be due to increased vagal activity in the CC and WC sessions. Facial immersion testing in cold water has been shown to cause a greater vagal response after exercise than before exercise in healthy children (22). Fujii et al. (13) showed that cardiac vagal tone during recovery from exercise, in asthmatic children, is higher than that in control children. They also found a significant correlation between high frequency band amplitude, an index of cardiac vagal tone, and the magnitude of the decrease in FEV1. However, skin cooling of the head and thorax does not change the response to methacholine in asthmatic subjects (28). Therefore, our findings support the suggestion that cold air challenge induces a different type of bronchial responsiveness than does a pharmacological challenge (23), although cold air and methacholine challenges seem to be equally sensitive in detecting airway hyperreactivity in asthmatic children (9,25).
The little difference in postexercise pulmonary functions between WW and the cold challenges, as seen in Figures 3 and 4, may be explained by the dryness of the air (vapor pressure 4–5 mm Hg) during all sessions (4). Although the relative importance of convective and evaporative heat loss is still unclear, it has been suggested that osmotic effects and evaporative heat loss are the more important factors that induce EIB than does convective heat loss (17).
Our results show a significant exercise-induced decline in FEV1 and MMEF during all experimental sessions, except for WC. However, the overall effect of resting and exercise during WC on pulmonary functions is not different from CC, and they both cause the greatest bronchoconstriction. This is particularly so for FEV1, as seen in Figures 1 and 3. Facial cooling, as an isolated challenge, seems to have the greater bronchoconstrictive effect at rest, whereas the added provocation provided by cold air inhalation seems to play a major role in EIB. This again may be due to increased vagal activity; however, it is unclear why the combined challenge of facial cooling and cold air inhalation causes less bronchoconstriction at rest. Maximal fall in both FEV1 and MMEF is greater for CC than for WC. This suggests that a decrease in pulmonary functions after exercise in cold air is, in part, due to cooling of intrathoracic airways. Deal et al. (10) showed an increase in the contribution of small airways of asthmatics to flow limitation after exercising in cold air. However, we cannot exclude the possibility that exercising in cold air under the conditions of this study does not affect the small airways. This hypothesis is supported by previous work from Malo et al. (19).
Our study was not designed to compare preexercise pulmonary functions. We therefore did not take baseline measurements before the child entered the climatic chamber. It is noteworthy, though, that there were differences in preexercise pulmonary functions among the sessions. FEV1 and MMEF values were lower after facial cooling, especially while breathing warm air. There were no differences in the preexercise pulmonary functions between the two sessions when the face was exposed to warm air. Previous studies showed that skin cooling causes bronchial narrowing at rest independent of any ventilatory effect (6,20). This may be related to increased vagal activity. Araùjo et al. (2) concluded that sudden facial exposure to low air temperature increases vagal activity in healthy people, whereas breathing cold air at low ventilatory volumes does not. Hyperventilation seems to be the more potent stimulus than skin cooling for the development of airway obstruction in asthmatic subjects, while breathing cold air at low tidal volumes has no effect on pulmonary function (6).
Another limitation of our study is the lack of ventilation data during the challenges. The complexity of our experimental setting did not allow us to take these additional measurements. However, because the heart rate values did not differ among the four sessions, we can assume that exercise intensity and, thus, minute ventilation were similar among the challenges.
In summary, our data support the following general conclusions for children with mild asthma: facial cooling combined with either cold or warm air inhalation is accompanied by the greatest EIB, as compared with an isolated challenge with cold air inhalation; pulmonary functions at rest are lowest after facial cooling. These conclusions suggest that vagal mechanisms play a major role in exercise- and cold-induced bronchoconstriction, and that vagal activity may be the primary trigger for cold-induced bronchoconstriction at rest.
We thank Dr. José Peralta for his technical assistance, Dr. Alan Bostrom and Dr. Anthony Luke for their statistical advice, and give special thanks to all the subjects who were willing to perform this demanding task.
Dr. Mona Zeitoun was supported by the Swiss Centre for Allergy, Skin and Asthma, the Swiss Society of Sports Medicine and the Zurich Lung Association.
1. Allen, M. T., K. S. Shelley, and A. J. Boquet, Jr. A comparison of cardiovascular and autonomic adjustments to three types of cold
stimulation tasks. Int. J. Psychophysiol.
2. Araùjo, C. G. S., B. Wilk, F. Meyer, and O. Bar-Or. Exercise-induced vagal inhibition is affected by sudden facial cooling but not by inspiration of cold
air. Med. Sci. Sports Exerc.
3. Avital, A., S. Godfrey, and C. Springer. Exercise, methacholine, and adenosine 5′-monophosphate challenges in children with asthma: relation to severity of the disease. Pediatr. Pulmonol.
4. Bar-Or, O., I. Neumann, and R. Dotan. Effects of dry and humid climates on exercise-induced asthma in children and preadolescents. J. Allergy Clin. Immunol.
5. Ben Dov, I., E. Bar-Yishay, and S. Godfrey. Refractory period after exercise-induced asthma unexplained by respiratory heat loss. Am. Rev. Respir. Dis.
6. Berk, J. L., K. A. Lenner, and E. R. McFadden, Jr. Cold
-induced bronchoconstriction: role of cutaneous reflexes vs. direct airway effects. J. Appl. Physiol.
7. Berk, W. A., M. J. Shea, and B. J. Crevey. Bradycardic responses to vagally mediated bedside maneuvers in healthy volunteers. Am. J. Med.
8. Collins, K. J., T. A. Abdel-Rahman, J. C. Easton, P. Sacco, J. Ison, and C. J. Dore. Effects of facial cooling on elderly and young subjects: interactions with breath-holding and lower body negative pressure. Clin. Sci. (Lond.)
9. de Benedictis, F. M., G. J. Canny, I. B. MacLusky, and H. Levison. Comparison of airway reactivity induced by cold
air and metacholine challenges in asthmatic children. Pediatr. Pulmonol.
10. Deal, E. C., Jr., E. R. McFadden, Jr., R. H. Ingram, Jr., and J. J. Jaeger. Effects of atropine on potentiation of exercise-induced bronchospasm by cold
air. J. Appl. Physiol.
11. Fontanari, P., H. Burnet, M. C. Zattara-Hartmann, and Y. Jammes. Changes in airway resistance induced by nasal inhalation of cold
dry, dry, or moist air in normal individuals. J. Appl. Physiol.
12. Frey, M. A., E. A. Selm, and J. W. Walther, Jr. Reflex cardiovascular responses to cold
exposure of the face
or foot. Jpn. Heart J.
13. Fujii, H., O. Fukutomi, R. Inoue, et al. Autonomic regulation after exercise evidenced by spectral analysis of heart rate variability in asthmatic children. Ann. Allergy Asthma Immunol.
14. Gauvreau, G. M., G. M. Ronnen, R. M. Watson, and P. M. O’Byrne. Exercise-induced bronchoconstriction does not cause eosinophilic airway inflammation or airway hyperresponsiveness in subjects with asthma. Am. J. Respir. Crit. Care Med.
15. Gayrard, P., J. Orehek, C. Grimaud, and J. Charpin. Broncho-constrictor effects of a deep inspiration in patients with asthma. Am. Rev. Respir. Dis.
16. Godfrey, S., P. L. Kamburoff, and J. R. Nairn. Spirometry, lung volumes and airway resistance in normal children aged 5 to 18 years. Br. J. Dis. Chest
17. Hahn, A., S. D. Anderson, A. R. Morton, J. L. Black, and K. D. Fitch. A reinterpretation of the effect of temperature and water content of the inspired air in exercise-induced asthma. Am. Rev. Respir. Dis.
18. Larsson, K., G. Tornling, D. Gavhed, C. Muller-Suur, and L. Palmberg. Inhalation of cold
air increases the number of inflammatory cells in the lungs in healthy subjects. Eur. Respir. J.
19. Malo, J. L., S. Filiatrault, and R. R. Martin. Combined effects of exercise and exposure to outside cold
air on lung functions of asthmatics. Bull. Eur. Physiopathol. Respir.
20. McDonald, J. S., J. Nelson, K. A. Lenner, M. L. McLane, and E. R. McFadden, Jr. Effects of the combination of skin cooling and hyperpnea of frigid air in asthmatic and normal subjects. J. Appl. Physiol.
21. McFadden, E. R., Jr., J. A. Nelson, M. E. Skowronski, and K. A. Lenner. Thermally induced asthma and airway drying. Am. J. Respir. Crit. Care Med.
22. Miyazoe, H., Y. Harada, S. Yamasaki, and Y. Tsuji. Clinical study on accentuated antagonism in the regulation of heart rate in children. Jpn. Heart J.
23. Modl, M., E. Eber, B. Steinbrugger, E. Weinhandl, and M. S. Zach. Comparing methods for assessing bronchial responsiveness in children: single step cold
air challenge, multiple step cold
air challenge, and histamine provocation. Eur. Respir. J.
24. Mukhtar, M. R., and J. M. Patrick. Bronchoconstriction: a component of the “diving response” in man. Eur. J. Appl. Physiol. Occup. Physiol.
25. O’Byrne, P. M., G. Ryan, M. Morris, et al. Asthma induced by cold
air and its relation to nonspecific bronchial responsiveness to methacholine. Am. Rev. Respir. Dis.
26. Schachter, E. N., E. Lach, and M. Lee. The protective effect of a cold
weather mask on exercised-induced asthma. Ann. Allergy
27. Simonsson, B. G., F. M. Jacobs, and J. A. Nadel. Role of autonomic nervous system and the cough reflex in the increased responsiveness of airways in patients with obstructive airway disease. J. Clin. Invest.
28. Skowronski, M. E., R. Ciufo, J. A. Nelson, and E. R. McFadden, Jr. Effects of skin cooling on airway reactivity in asthma. Clin. Sci. (Colch.)
29. Spahn, J. D., and S. J. Szefler. The etiology and control of bronchial hyperresponsiveness in children. Curr. Opin. Pediatr.
30. Strauss, R. H., E. R. McFadden, Jr., R. H. Ingram, Jr., and J. J. Jaeger. Enhancement of exercise-induced asthma by cold
air. N. Engl. J. Med.
31. Tal, A., H. Pasterkamp, C. Serrette, F. Leahy, and V. Chernick. Response to cold
air hyperventilation in normal and in asthmatic children. J. Pediatr.
Keywords:©2004The American College of Sports Medicine
COLD; VAGAL ACTIVITY; BRONCHIAL RESPONSE; FACE