The Effect of Repetitive Exercise on Airway Temperatures1- 3

ILEEN A. GILBERT, JANIE M. FOUKE, and E. R. MCFADDEN, JR. With the technical assistance of K. A. Lenner and A. J. Coreno, Jr.

Introduction

It has been recognized for a considerable period that a major pathologic feature of asthma consists of hyperplasia and hypertrophy of the capillary bed in the airway wall (1). It is only recently, however, that the pathophysiologic significance of this observation is beginning to be understood. In the last severalyears, data have accumulated that suggest that the narrowing of the tracheobronchial tree that follows at least some of the precipitants of asthma, such as exercise and hyperventilation, may be secondary to alterations in the tone of the bronchial microcirculation with resultant hyperemia and edema of the airway wall (2-4). Using intrathoracic heat flux as an index of bronchial perfusion, we have gathered data that suggest that asthmatics have a greater blood supply to their airways after periods of hyperpnea than do normal persons (2), and that this factor correlates with the development of airway narrowing (3). The present study was undertaken to determine if and how the above relationship between heat flux and airflow limitation in asthmatics changes during repetitive stimulation. Given that the obstructive consequences of exercise are known to diminish when serial challenges are performed over short periods (5-7), we wondered if this phenomenon was associated with concomitant alterations in the thermal profiles within the lungs. Our observations form the basis of this report. Methods After giving informed consent, seven atopic asthmatics (five women and two men with a mean age of 25 ± 2 [SEM] yr) served as our subjects. None of them had experienced an upper respiratory tract infection or used cromolyn or glucocorticoids in the 6 wk preceding the study. None routinely used sustained-release bronchodilator preparations. All participants refrained from any medication for 12 h before any study. The investigation was performed in two parts. On Day 1,each subject underwent two bronchoprovocations, consisting of 4 min of pedaling a cycle ergometer at a work load 826

SUMMARY Todetermine if a relationship exists between intra-airway thermal events and the reduction in pulmonary mechanics that occur in asthmatics when they perform repetitive exercise, we recorded intrathoracic airstream temperatures in seven subjects during and after two identical bouts of cycle ergometry performed 30 min apart. From these data, global and regional thermal energy exchanges were calculated. Inspired air conditions, work loads, and minute ventilations were held constant for both trials. Pulmonary mechanics were measured prior to and serially after each challenge. As expected, the second provocation produced a smaller response than did the first. In association with these mechanical changes, the second challenge also produced less airway cooling and slower rewarming in the central airways. Hence, repetitive exercise trials performed over short Intervals attenuate the essential thermal gradients necessary to produce obstruction. Tothe extent that these differences In Intra-airway temperature reflect changes in perfusion, our data raise the possibility that the responslvlty of the bronchial microcirculation of asthmatics may be altered by AM REV RESPIR DIS 1990; 142:826-831 repetitive exercise.

equivalent to 60070 of his or her maximal oxygen consumption (8). The challenges were separated by 30 min. During each trial, the participants inhaled frigid air through a heat exchanger (2, 3, 9). The water content of the inspirate was < 1 mg H 2 0 / L , which for the purpose of this study was considered to be zero. Recovery took place while breathing room air. The temperature and humidity of the air in the laboratory was measured by standard techniques. During the exercise and recovery periods, minute ventilation (VE) was recorded continuously by passing the expirate into a calibrated dry gas meter. The temperature of the expired gas was measured by a thermocouple protruding into the oral cavity through the mouthpiece of the heat exchanger (2, 3, 9). On this day, using a waterless spirometer, the subjects performed maximal forced exhalations in triplicate before each challenge, at its completion, and seriallyfor 20 min thereafter. Their best effort, as defined by the curve with the largest FEV1, waschosen for analysis. On Day 2 of the study, to obtain data on intra-airway temperatures, the subjects underwent bronchoscopy with insertion of a thermal probe. The nose and throat of each participant wereanesthetized with 4070 lidocaine, and a fiberoptic bronchoscope was inserted through the nasopharynx into a subsegmental bronchus of the anterior basilar segment of the right lower lobe. No premedication was employed, and minimal amounts of 2070 lidocaine were instilled within the airways to ensure subject comfort. As in our previous studies (2-4, 10), the distances from the tip of the nose to the major anatomic landmarks were recorded and a thermal probe containing multiple small thermistors was inserted into the tracheobronchial tree. The technical features of the probe

havebeen reported previously (4, 10).In brief, it consists of a flexible polyvinyltube (0.9 mm OD) containing multiple thermistors 250 urn in diameter in its distal 35 em, such that airstream temperatures can be recorded from the posterior pharynx to airwayslessthan 1.0mm in diameter. Once the tip of the probe was in its intended position, the bronchoscope was removed and the probe was withdrawn in small increments until the distal thermistor showed fluctuations in temperature with a deep breath, confirming its presence in an unobstructed bronchus. By knowing the length of the probe, the distance the tip was inserted, and the location of each anatomic landmark relative to the tip of the nose, the position of each thermistor within the tracheobronchial tree could

(Receivedin originalform September 18, 1989 and in revised form March 28, 1990) 1 From the Airway Disease Center and the Departments of Medicine of the University Hospitals and Case Western Reserve University School of Medicine, and the Department of Biomedical Engineering, Case Western. Reserve University, Cleveland, Ohio. 2 Supported in part by Grant No. Hl.r33791 and Hl.r36156 from the National Heart, Lung, and Blood Institute, by Specialized Center of Research Grant No. Hl.r37117, General Clinical Research Center Grant No. MOI-RR-00080-25, and Program Project Grant No. Hl.r25830 from the National Institutes of Health, and by a Grant-in-Aid from the Northeast Ohio affiliate of the American Heart Association. 3 Correspondence and requests for reprints should be addressed to E. R. McFadden, Jr., M.D., Airway Disease Center, University Hospitals of Cleveland, 2074 Abington Road, Cleveland, OH

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REPETITIVE EXERCISE AND AIRWAY TEMPERATURES

be determined. Once in place, the probe was well tolerated, and the stability of the position of the thermistors wascontinuously verified by monitoring the temperature tracings as detailed in earlier investigations (4, 10). Mouthward movement produces an abrupt decrease in temperature, whereas distal movement creates an increase. After the probe was secured, each subject performed the identical two exercisetrials as on Day 1. The timing of the challenges, the work loads, and the inspired air conditions during exerciseand recoveryexactly matched those used on Day 1. Ventilation was measured as before. The temperatures within the airways were recorded digitally at 8 Hz and displayed on a breath-by-breath basis (Digital Equipment, Maynard, MA) prior to each challenge and then throughout the exercise and recovery periods (2-4, 10). From these data, global and regional respiratory heat exchange was calculated (3), assuming the air to be fully saturated at each measurement point. The data were analyzed using paired t tests and one- and two-factor analyses ofvariance (11).

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Fig. 1. Minute ventilation (VE) during exercise and recovery for exercise Trials 1 and 2 (Ex1 and Ex2) on each study day. The data points are mean values and the brackets represent 1 standard error of the mean. Closed circles = Exerc ise 1; open circles = Exercise 2. o

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Fig. 2. Inspired air temperature and water content (WCi) during exercise and recovery for each exercise trial on both study days. The heights of the bars are mean values, and the brackets represent 1 standard error of the mean . Open bars = Trial 1; hatched bars = Trial 2.

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Results

The mean work load performed during the first challenge on Day 1 was 779 ± 128 (SEM) kpm. The work load for each subject was held constant for each trial. The ventilatory patterns during exercise and recovery for each of the experiments on both days are depicted in figure 1. For Exercise 1 (Exl) on Day I, VE rose progressively from a resting value of 9.9 ± 1.5 (SEM) L/min to a maximal level of 53.6 ± 7.9 L/min, thereafter falling exponentially once the work load ceased to 15.5 ± 1.3 L/min by the end of the observation period. The data from Trial 2 on Day 1, and Trials 1 and 2 on Day 2, were similar, and there were no significant differences in VE at any time point among exercise trials or between study days . Inspired air conditions during exercise and recovery are shown in figure 2. On Day 1, the mean inspired air temperature during exercise was - 9 ± 4 0 C for Trial 1, and -10 ± 4 0 C for Trial 2 (p = NS). In the recovery periods, inspired air temperature (Ti) was 22 ± 10 C with a water content (WC i) of 9.8 ± 1.3 mg/L. On Day 2, Ti averaged -12 ± 2 and -11 ± 3 0 C for the two challenges, respectively. During the recovery period on this day, T, averaged 23 ± 2 0 C, and WCi was 8.3 ± 1.2 mg/L. There were no significant differences for any variable from trial to trial or day to day. Comparison of the changes in pulmonary mechanics after Exl and Ex2 on Day 1 are displayed in figure 3. The mean val-

ue for the baseline FEV 1 prior to the onset of the first trial was 3.10 ± 0.35 L (90 ± 4070 of predicted). Fifteen minutes after initiating this challenge, FEV 1 fell 24 ± 5% (L\FEV 1 = 0.68 ± 0.126) (p < 0.001). Over the ensuing 15 min, the FEV 1 improved and at the onset of Ex2 , it had reached a value within 15 % of the original baseline. The second exercise stint resulted in a significantly smaller effect than the first one. Here, the maximal fall in FEV 1 was only 5 ± 4% (L\FEV 1 = 0.12 ± 0.11 L) (p = NS).

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T1ME(MIN) Fig. 3. The mechanical effects of repet itive exercise as a function of time. The data points are mean values and the brackets represent 1 standard error of the mean . The closed and open circles represent exercise Trials 1 and 2, respect ively. The application of each stimulus is shown by the rectangles labeled Ex .

The inspiratory and expiratory thermal profiles during rest and during the fourth minute of exercise for both trials are presented in figures 4 and 5. Airstream temperatures are displayed for the glottis, the midtrachea, the main carina, and the orifices of the right lower lobe and arterior segmental bronchus (AS). At rest, in Exl, the temperatures (T) during inspiration at the glottis averaged 31.0 ± 0.5 0 C, and as the air moved towards the periphery, T rose progressively to 34.9 ± 0.40 C at the AS (figure 4). During the fourth minute of the first exercise period, the temperature during inspiration fell significantly at each anatomic location, reaching values of 26.4 ± 0.6 and 30.7 ± 0.5 0 C at the glottis and the AS, respectively (figure 4). During the second exercise trial, airstream temperatures at the glottis equaled those in the first challenge; however, less cooling developed in the trachea, and temperatures here were 1.0 ± 0.3 0 C warmer than previously (p < 0.01). Similar effects were seen to the right lower lobe, but the changes did not reach statistical significance. These temperature differences gradually disappeared as the air moved into the periphery of the lung. During expiration, the temperatures of the expired gas , for both trials, fell as the air moved from the AS to the glottis (figure 5). During the last minute of hyperpnea, T at each anatomic location was ap-

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Fig. 4. Intra-airway temperature during inspiration (T) as a function of anatomic location during exercise Trials 1 and 2 on study Day 2. The data points are mean values, and the brackets represent 1 standard error of the mean (ALL = right lower lobe; AS = anterior segmental bronchus of right lower lobe). The upper set of lines are the data obtained at resting ventilation, and the lower lines are data obtained during the fourth minute of exercise. Closed circles = Exercise 1;open circles = Exercise 2.

proximately 1.3 ± 0.2 and 1.2 ± 0.2 0 C warmer than during inspiration for Exl and Ex2, respectively. There were no differences in absolute temperatures between the challenges at rest; however, during the last minute of the work load in Ex2, airstream temperatures in the trachea were 0.5 ± 0.2 0 C higher (p < 0.05) than those observed in the first challenge. As with inspiration, the changes in the carina and right lower lobe did not reach statistical significance. Global and regional heat exchange and the thermal energy losses that occurred during the fourth minute of each exercise period are shown in figure 6. These data depict the heat lost during the warming and humidification of the air during inspiration and the heat recovered as the air cooled and water vapor condensed onto the respiratory mucosa in expiration. In Trial 1, 1.263kcal/min were expended to fully condition the inspired air in the fourth minute of exercise. The corresponding value for Trial 2 was 1.282 kcal/min. In Challenges 1 and 2, respectively, 57 and 58070 of the thermal energy was expended by the upper airways, 13 and 14070 by the central bronchi, and 30 and 28070 by the peripheral respiratory units. Of the total energy mobilized during inspiration, 56070 was recovered during expiration for Trial 1 and 59070 for Trial 2. Although global respiratory heat exchange was identical for both exercisetrials, the second challenge was associated

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Fig. 5. Intra-airway temperature (T)during expiration as a function of anatomic location during exercise Trials 1 and 2 on study Day 2. The format and abbreviations are identical to those in figure 4. Closed circles = Exercise 1; open circles = Exercise 2.

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with a smaller net heat flux in the trachea (figures 6 and 7). The average net heat exchange between inspiration and expiration (figure 7) for challenges 1 and 2 were 0.07 ± 0.01 and 0.05 ± 0.01 kcal/min (p < 0.02). The time courses of the absolute and the relative changes in inspiratory airstream temperature that occurred in the trachea during exercise and recovery for each trial are shown in figure 8. Temperature progressively fell with time in both challenges. However, for each minute of work, significantly lesscooling developed during the second challenge (p ~ 0.05 for each time point). During recovery, airstream temperatures rapidly rose after the first trial. The second challenge, however, was associated with a significantly slower rate of rewarming. As can be seen after Ex2, temperature rose only 2.5 ± 0.4 0 C in the first 15 s, as opposed to 3.7 ± 0.3 0 C in the first trial over this same time period (p < 0.02). By the end of the fourth minute of recovery,the temperature in Trial 1 had risen 6.5 ± 0.6 0 C compared with 5.5 ± 0.4 0 C in Trial 2 (p < 0.05). Discussion

The results of the current investigation present, for the first time, an evaluation of the thermal events that transpire in the airways of asthmatics when they perform consecutive bouts of physical exertion over short intervals. The data in figures 4 through 8 demonstrate that when a person repeats the same exercise task within 30 min, the second challenge is associated with less cooling of the central air-

Fig. 6. Comparison of the global and regional quantities of thermal energy that were expended during the fourth minute of each exercise trial on study Day 2. The upper set of lines indicate the heat lost to the air during inspiration, and the lower set represents the heat lost in inspiration plus the heat recovered from the air during expiration. The region between the upper and lower lines indicate the net heat exchange. The data points are mean values, and the brackets represent 1 standard error of the mean (AHE = respiratory heat exchange). The anatomic landmarks of the respiratory tract are shown at the bottom of the graph (ALL = right lower lobe; AS = anterior segmental bronchus of right lower lobe). Closed circles = Exercise 1; open circles = Exercise 2.

ways, smaller hyperpnea-recovery gradients, and slower rates of rewarming when hyperpnea ceases. As these temperature changes develop, the obstructive response diminishes in concert (figure 3). Because the degree of airway cooling and the rate and magnitude of rewarming are suspected to be major determinants of the severity of the bronchial narrowing in exercise-induced asthma (EIA) (2, 3, 9), our data suggest a causal relationship between the alterations in temperature profiles that occur with multiple episodes of exercise and the obstructive response. Further, in humans, since the bronchial circulation appears to be the prime source of heat to the airways during periods of hyperpnea (3, 4), our observations suggest that the temporary decrease in response to exercise may be a vascular phenomenon in which repetitive work results in a temporary decrease in microvascular reactivity. The absolute magnitude of the decrease in cooling and rewarming that we

REPETITIVE EXERCISE AND AIRWAY TEMPERATURES

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describe may appear to be small, and so of little physiologic significance. However, when viewed in the context of the overall ventilation-thermal and ventilation-obstructive relationships that exist in the airways, they are actually quite meaningful. When breathing cold air, the temperature in the trachea falls approximately 0.07° C for each liter of air inspired in both normal subjects and in asthmatics (2, 10). Thus, a 1.0 to 1.5° C increase in temperature corresponds to a 15 to 20 L/min decrease in ventilation and a rightward shift in the stimulus response curve. In effect, a subject acts as though he or she were performing a substantially lower work load and in turn develops less obstruction. These are the sort of shifts in stimulus response curves both in direction and magnitude that one sees after the administration of a betaagonist or cromolyn (12, 13). Why are the central airways affected primarily? The changes in intra-airway temperature that develop with hyperpnea are a distributed function, with the largest effects being seen in the central airways (2-4, 10). As the air moves toward the periphery of the lung, it warms toward body temperature, and the gradient between the airway wall and airstream narrows. Because the bronchial circulation enters the lung at the central

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Fig. 8. Temporal change in intra-airway temperature (T) in the trachea during exercise and recovery for Trials 1 and 2 on Day 2. The top graph shows the absolute data, and the bottom graphs show the relative changes for each trial. In the latter, the left-hand side displays the fall in airstream temperatures from resting values that occurred during each minute of exercise. The right-hand side shows the rise in airstream temperatures from the values recorded at the end of the exercise periods (END Ex) that occurred during recovery. The data points in all graphs are mean values, and the brackets represent 1 standard error of the mean. Closed circles = Exercise 1; open circles = Exercise 2.

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airways, it is expected that any change in perfusion would have a maximum effect there. This is exactly what we found. We observed less cooling and slower rewarming out to the right lower lobe; however, the changes beyond the trachea did not reach statistical significance. Part of the reason for the latter probably relates to the fact that at high frequencies our probe slightly underestimates the true breath-by-breath temperature excursions that occur (4, 10). We view it unlikely that our results derived from technical issues stemming from our protocols or from subject selection. The technical features of our probe have been described previously (2, 4, 10), and since this was a comparative study, any limitations in temperature measurements would have applied equally to both exercise studies on Day 2. Further, we do not believe that the presence of bronchial narrowing prior to the second challenge influenced our findings. While it is theoretically possible that a tube smaller in diameter would conduct heat in a different manner from larger ones, we know from previous studies that the airway obstruction induced by one exercise trial dissipates during a second one (14). Thus, in our study airway diameters were equivalent during both challenges. Finally, our subjects are quite typical of patients with exercise-induced asthma, and their mechanical responses to serial exercise challenges mirror those already in the literature (5, 15-19). The reason why multiple thermal stimuli alter the physiologic response of the microcirculation is unknown, but several theoretical, potentially overlapping, mechanisms exist. For example, the increased heat production associated with the performance of the second challenge in short order following the first (20, 21) may have caused the vascular bed to remain dilated so as to lose heat to the environment. In this fashion, the bronchial and cutaneous circulations would function in parallel to regulate core temperature. It is also possible, that once having responded to a given stimulus, the capacitance vessels may have a long recovery time so that their reactivity and/or permeability only slowly return to baseline, either because of local thermal considerations or because of the neurohumoral adaptations that accompany strenuous work (14, 22-24). Irrespective of mechanism, if the bronchial circulation needed time to regain its original tone and restore its permeability to normal, and/or if any mucosal

GILBERT, FOUKE, AND MCFADDEN

edema and hyperemia that were present needed to clear before the microcirculation could once again fully respond to exercise, one would anticipate that the tachyphylaxis seen with serial exercise would have a temporal dependency that would dissipate as the time between challenges lengthened. This is precisely what has been observed. Attenuation of obstruction with exercise is found only when multiple challenges are performed over relatively short periods (5,6, 15, 19). As the time between challenges is lengthened, the degree of refractoriness decreases, and by 2 h the phenomenon is totally gone (5, 15). We appreciate that our hypotheses regarding the nature of the obstruction in EIA and the etiology of the temporary loss of response to repetitive challenges with exercise are major departures from the conventional view that the airway narrowing in asthma derives from contraction of the bronchial smooth muscle. All authorities agree that edema and increased capillary permeability playa part in the airway limitation characteristic of this illness, but there has been no reason to think of these phenomena as primary causes; however, a reevaluation may be in order. Analysis of the currently available data indicates that thermally induced bronchial narrowing does not appear to have the same pathogenesis as other precipitants, nor does it produce the same short- and long-term sequelae. For example, episodes of asthma incited by antigen are associated with increases in airway reactivity (25-28) and late reactions (26, 27, 29), whereas those after exercise are not (30-32). Thus, different mechanisms appear to be at work with these two stimuli. Moreover, tachyphylaxis only occurs with exercise and is not seen with other types of challenges (17, 18), again emphasizing the unique nature of the obstruction that follows exercise. Finally, when the airways are unresponsive to exercise, they readily respond to other precipitants with divergent mechanisms of action such as antigen and histamine (17, 18). Hence, airway smooth muscle has not lost its ability to constrict in these situations. As a group, these observations suggest that the cause of the bronchial narrowing in EIA may not be the same as that which develops after other stimuli. This view is further strengthened by the findings that nonbronchodilator drugs with potent vasoconstrictive properties such as alpha agonists can reverse or prevent thermally induced obstruction (24).

Hence, our postulate fits quite well with the clinical features of EIA and may help explain many previously perplexing observations. References 1. Dunill MS. The pathology of asthma with special reference to changes in the bronchial mucosa. 1 Clin Pathol 1960; 13:27-33. 2. Gilbert lA, Fouke 1M, McFadden ER 1r. Heat and water flux in the intrathoracic airways and exercise-induced asthma. 1 Appl Physiol 1987; 63:1681-91. 3. Gilbert lA, Fouke 1M, McFadden ER lr. Intraairway thermodynamics during exerciseand hyperventilation in asthmatics. 1 Appl Physiol 1988; 64:2167-74. 4. McFadden ER lr, Pichurko BM. Intra-airway thermal profiles during exerciseand hyperventilation in normal man. 1 Clin Invest 1985;76:1007-10. 5. Edmunds AT,TooleyM, Godfrey S. The refractory period after exercise-induced asthma: its duration and relationship to the severity of exercise. Am Rev Respir Dis 1978; 117:247-54. 6. lames L, Faciane 1, Sly RM. Effect of treadmill exercise on asthmatic children. 1 Allergy Clin Immunol 1976; 57:408-16. 7. Schnall RP, Landau LI. Protective effect of repeated short sprints in exercise-induced asthma. Thorax 1980; 35:828-32. 8. Jones NL, Campbell El. Clinical exercisetesting. 2nd ed. Philadelphia, PA: WB Saunders, 1982; 118. 9. McFadden ER lr, Lenner KA, Strohl KP. Postexertional airway rewarming and thermally induced asthma. 1 Clin Invest 1986; 78:18-25. 10. McFadden ER lr, Pichurko BM, Bowman KF, et al. Thermal mapping in the airways in man. 1 Appl Physiol 1985; 58:564-70. 11. Armitage E. Statistical methods in medical research. 2nd ed. New York: John Wiley and Sons, 1973. 12. RossingTH, WeisslW, BreslinFl, Ingram RH Jr, McFadden ER lr. Effects of inhaled sympathomimetics on obstructive response to respiratory heat loss. 1 Appl Physiol 1982; 52:1119-23. 13. Latimer KM, O'Byrne PM, Morris MM, Roberts R, Hargreave FE. Bronchoconstriction stimulated by airway cooling. Better protection with combined inhalation of terbutaline sulfate and cromolyn sodium than either alone. Am Rev Respir Dis 1983; 128:440-3. 14. Gilbert lA, Lenner KA, McFadden ER lr. Sympathoadrenal response to repetitive exercisein normal and asthmatic subjects.1 Appl Physiol1988; 64:2667-74. 15. Stearns DR, McFadden ER lr, Breslin 1, Ingram RH 1r. Reanalysis of the refractory period in exertionalasthma. 1 Appl Physiol1981;50:503-8. 16. Ben-Dov I, Bar-Yishay E, Godfrey S. Refractory period after exercise-induced asthma unexplained by respiratory heat loss. Am Rev Respir Dis 1982; 125:530-4. 17. Halin AG, Nogrady SG, Burton GR, Morton AR. Absence of refractoriness in asthmatic subjects after exercise with warm, humid inspirate.Thorax 1985; 40:418-21. 18. Weiler-Ravell D, Godfrey S. Do exercise and antigen-induced asthma utilize the same pathways? 1 Allergy Clin Immunol 1981; 67:391-9. 19. Schoeffel RE, Anderson SD, Gillans I, Lindsay DA. Multiple exerciseand histamine challenge in asthmatic patients. Thorax 1980; 35:164-70. 20. Johnson 1M. Nonthermoregulatory control of human skin blood flow. 1 Appl Physiol 1986;

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61:1613-22. 21. Johnson JM, Brengelmann GL, Hales JRS, Vanhoutte PM, Werger CB. Regulation of the cutaneous circulation. Fed Proc 1986; 45:2841-50. 22. Clutter WE, Bier DM, Shah SD, Cryer PEe Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man. J Clin Invest 1980; 66:94-101. 23. Cryer PEe Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med 1980; 303:436-44. 24. Pichurko BM, Sullivan B, Porcelli RJ, McFadden ER Jr. Endogenous adrenergic modification of exercise-induced asthma. J Allergy Clin Immunol 1986; 77:796-801.

831 25. Mussaffi H, Springer C, Godfrey S. Increased bronchial responsiveness to exercise and histamine after allergen challenge in children with asthma. J Allergy Clin Immunol 1986; 77:48-52. 26. Boulet LP, Cartier A, Thomson NC, Roberts RS, Dolovich J, Hargreave FE. Asthma and increases in nonallergic bronchial responsiveness from seasonal pollen exposure. J Allergy Clin Immunol 1983; 71:399-406. 27. Cartier A, Thomson NC, Frith PA, Roberts R, Hargreave FE. Allergen-induced increase in bronchial responsiveness to histamine: relationship to the late asthmatic response and change in airway caliber. J Allergy Clin Immunol 1982; 70:170-7. 28. Thorpe JE, Steinberg D, Bernstein IL, Murlas CG. Bronchial reactivity increases soon after

the immediate response in dual-responding asthmatic subjects. Chest 1987; 91:21-5. 29. Dahl R, Henriksen JM. Development of late asthmatic reactions after allergen or exercise challenge tests. Eur J Respir Dis 1980; 61:320-4. 30. Rubinstein I, Levinson H, Slutsky AS, et ale Immediate and delayed bronchoconstriction after exercisein patients with asthma. N Engl J Med 1987; 317:482-5. 31. Zawadski DK, Lenner KA, McFadden ER Jr. Effect of exercise on nonspecific airway reactivity in asthmatics. J Appl Physiol 1988; 64:812-6. 32. Zawadski DK, Lenner KA, McFadden ER Jr. Re-examination of the late asthmatic response to exercise. Am Rev Respir Dis 1988; 137:837-41.

The effect of repetitive exercise on airway temperatures.

To determine if a relationship exists between intra-airway thermal events and the reduction in pulmonary mechanics that occur in asthmatics when they ...
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