Lung (1992) 170:75-84 ©
Sprin~g~ NewYorkInc.1992
Influence of Exercise-Induced Bronchoconstriction on Refractoriness Dennis Nowak, Rudolf JOrres, and Helgo Magnussen Krankenhaus GroBhansdorf, Zentrum for Pneumologie und Thoraxchirurgie, W6hrendamm 80, D-2070 GrofShansdorf, Germany
Abstract. This study determined if the degree of exercise-induced refractoriness is determined by the degree of exercise-induced bronchoconstriction. In 12 patients with exercise-induced asthma (mean [SEM] age 27 [3] years) we performed 2 pairs of exercise challenges 45 min apart at different work loads on 2 days. Mean (SEM) total respiratory heat loss during low and high work loads was 3.4 (0.2) and 5.1 (0.4) kcal, respectively. After the first and second exercise challenge at low work loads, mean (SEM) SRaw increased by 107 (15) and 73 (16)% (n.s.), as compared to 361 (40) and 98 (25)% at high work loads (p < 0.005). We found a correlation between the initial airways response and refractoriness (r = 0.58, p < 0.005) and conclude that the degree of refractoriness after exercise-induced bronchoconstriction is in part dependent on the severity of exercise-induced bronchoconstriction. Key words: fractoriness.
Asthma,
exercise-induced--Bronchoconstriction--Re-
Introduction In many patients with bronchial asthma, exercise results in bronchoconstriction, the degree of which depends upon the temperature and humidity of the inspired air and the rate of ventilation [7]. One characteristic feature of exercise-induced bronchoconstriction (EIB) is a refractory period during which the repetitive exercise induces less airway obstruction [2, 33]. Refractoriness has been shown to be influenced by a variety of factors such as type of exercise [35], time between serial tests [10], cooling and drying of airways [34], release of mediators [23], and, more recently, the responsivity of bronchial microcirculation [13]. Offprint requests to." H. Magnussen
76
D. Nowak et al.
In addition, Edmunds et al. [10] and Wilson et al. [35] observed that with increasing severity of the initial EIB, a reduced obstructive response after the second test occurred. In the present study, we reevaluated the influence of the initial degree of airway narrowing on exercise-induced refractoriness. In contrast to previous reports we performed, in the same patients, 2 pairs of exercise tests that only differed in terms of exercise ventilation. Thus 1 pair of challenges was done with high ventilation and 1 with low ventilation.
Patients and Methods We studied 12 patients with bronchial asthma, 6 men and 6 women with a mean (SEM) age of 28 (3) years (range, 20-49) whose characteristics are given in Table 1. All of them had a history of exercise-induced asthma. In all patients airway hyperresponsiveness to inhaled histamine could be demonstrated, with a mean provocation concentration necessary to increase specific airway resistance by 100% of 0.12 */1.38 mg/ml. Ten patients were nonsmokers, two were exsmokers. Allergy skin testing with common allergens revealed positive results in all patients but 1. All patients required occasional or regular medication listed in Table 1. Inhaled beta2-agonists and ipratropiumbromide were withheld at least 6 hr before each study period, whereas inhaled and oral steroids and theophylline were taken as usual. The patients were instructed about the aim of the study and gave their informed consent.
Lung Function Measurement Baseline spirometry was performed using a pneumotachograph whose differential pressure signal was electronically integrated to give volume. Airway resistance (Raw) during quiet breathing and thoracic gas volume at functional residual capacity [9] were determined by a constant volume body plethysmograph (Bodytest, E. Jaeger, Wuerzburg, Germany). Raw was multiplied with thoracic gas volume to give specific airway resistance (SRaw). The values were computed as the average of 3 breathing cycles.
Exercise Tests Exercise was performed on a bicycle ergometer in a sitting position. During exercise, patients breathed cold (mean [SEM]-15 [1.0]°C) and dry room air produced by a heat exchanger (RHE-Test, E. Jaeger, Germany). Inspiratory and expiratory temperatures were measured by a thermocouple within the 2 ports of the 2-way breathing valve. Expired air was conducted through a heated pneumotachograph (E. Jaeger, Germany) and airflow was integrated electronically to give minute ventilation. Experimental conditions were carefully matched in terms of constant inspiratory temperature, water content, and duration of exercise during each pair of tests, respectively. Respiratory heat exchange was calculated according to the formula of Deal et al. [7].
Experimental Protocol Each pair of exercise tests was performed between 1.00 p.m. and 5.00 p.m. on 2 different days within 1 week. Before the first paired challenge, lung function was measured to ensure a normal baseline airway tone. On an individual basis, 2 work loads were chosen. The lower work load was selected to produce an increase in SRaw of at least 100%, the higher was chosen as the highest tolerable work load not producing an unacceptably high degree of airway obstruction.
Exercise-Induced Bronchoconstriction and Refractoriness
77
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Lung function was measured before (baseline values) and 3, 10, 15, 30, and 45 min after the end of the first exercise challenge. The SRaw value measured 45 min after the first challenge was taken as baseline value of the second test. Lung function measurements were repeated 3, 10, 15, and 30 min after the end of the second provocation challenge.
Analysis of Data Airway response to exercise was expressed as maximum percentage increase in SRaw with respect to baseline (delta%SRaw) [14]. A refractory index was calculated according to the following equation given by Schoeffel and co-workers [33] (indices (1) and (2) referring to the first and the second test, respectively): Refractory index (%) = 100 x
A %SRaw(1) - A %SRaw(2) A %SRaw(1)
A refractory index of 100% means no airway response in the second test, whereas an index of 0% means equal responses in the 2 tests.
Statistical Evaluations We used nonparametric statistical methods to avoid assumptions on data distributions. Baseline values and airway responses were compared by the Wilcoxon matched-pairs as signed-rank test. Correlation was quantified by the Spearman rank correlation coefficient [31]. Statistical significance was defined as p < 0.05.
Results
Experimental Conditions E x p e r i m e n t a l c o n d i t i o n s are p r e s e n t e d in T a b l e 2. D u r i n g tests at l o w a n d high w o r k l o a d s v e n t i l a t i o n ( p < 0.005) a n d R H E (p < 0.005) differed significantly. T h e r e w a s n o significant d i f f e r e n c e b e t w e e n e x e r c i s e v e n t i l a t i o n a n d R H E b e t w e e n the first a n d s e c o n d test w i t h i n the pairs o f c h a l l e n g e s .
Baseline Lung Function M e a n ( S E M ) b a s e l i n e S R a w v a l u e s are g i v e n in T a b l e 3. B a s e l i n e a i r w a y c a l i b e r in the first a n d s e c o n d e x e r c i s e test at low w o r k load a n d the first test at high w o r k load w a s n o t s i g n i f i c a n t l y different. H o w e v e r , b a s e l i n e S R a w b e f o r e the s e c o n d test p e r f o r m e d with high w o r k load w a s higher t h a n b e f o r e the first test (p < O.OO5).
Exercise Tests I n d i v i d u a l d a t a are g i v e n in T a b l e 3, a n d m e a n ( S E M ) p e r c e n t a g e i n c r e a s e s in S R a w after e x e r c i s e c h a l l e n g e s at low a n d high w o r k l o a d s are p r e s e n t e d in F i g u r e 1.
Exercise-Induced Bronchoconstriction and Refractoriness
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Table 2. Experimental conditions during the tests W
Low Work Load First Test
Mean SEM
140 70 150 60 100 100 80 100 150 100 100 120 105 9
W
High Work Load
Second Test
V
RHE
V
RHE
50.0 30.5 37.7 30.8 31.3 32.3 29.2 31.5 43.0 27.1 33.2 41.5 34.8 2.0
4.96 2.75 3.61 3.08 3.05 3.23 2.34 3.01 4.06 2.58 3.32 4.70 3.39 0.23
54.0 30.2 36.4 29.8 33.0 33.8 23.8 29.6 36.6 26.2 28.7 43.8 33.8 2.4
5.21 2.85 3.48 2.98 3.20 3.37 2.60 2.83 3.50 2.58 2.94 4.96 3.38 0.25
First Test
170 100 180 90 130 200 140 150 250 200 200 240 171 15
Second Test
V
RHE
V
RHE
79.4 39.8 49.8 39.0 46.4 62.4 44.5 50.2 67.8 55.1 41.0 69.6 53.8 3.8
7.93 3.33 4.76 3.73 4A3 5°89 4.25 5.22 5.94 5.91 3.50 7.57 5.2l 0.43
94.1 42.7 47.0 38.7 51.9 51.6 39.8 44.5 56.6 52.4 40.0 63.5 51.9 4.4
8.94 3.57 4.83 3.70 4.96 5.08 3.75 4.62 5.18 5.37 3.41 6.90 5.03 0.45
w, work load (watt); V, ventilation (L/rain); RHE, total respiratory heat exchange during the challenge (kcal).
A t l o w w o r k l o a d , m e a n ( S E M ) m a x i m u m p e r c e n t a g e i n c r e a s e in S R a w w a s 107 (15)% d u r i n g t h e first a n d 73 (16)% d u r i n g the s e c o n d e x e r c i s e t e s t , t h e d i f f e r e n c e b e i n g n o t significant. A t high w o r k l o a d , m e a n ( S E M ) m a x i m u m p e r c e n t a g e i n c r e a s e in S R a w w a s 361 (40)% d u r i n g t h e first a n d 98 (25)% d u r i n g t h e s e c o n d e x e r c i s e t e s t (p < 0.005). M e a n p e r c e n t a g e i n c r e a s e a f t e r t h e first t e s t at l o w w o r k l o a d w a s s i g n i f i c a n t l y l o w e r t h a n at high w o r k l o a d (p < 0.0025), w h e r e a s m e a n p e r c e n t a g e i n c r e a s e a f t e r t h e s e c o n d t e s t s d i d n o t differ b e t w e e n l o w a n d high w o r k l o a d s .
Comparison of Refractoriness at Different Work Loads M e a n ( S E M ) r e f r a c t o r y i n d e x f o r e x e r c i s e at l o w w o r k l o a d w a s 16 (18)%, a n d m e a n ( S E M ) r e f r a c t o r y i n d e x f o r e x e r c i s e at high w o r k l o a d w a s 71 (9)% (p < 0.05). A i r w a y r e s p o n s e a n d r e f r a c t o r i n e s s c o r r e l a t e d significantly (r = 0.58, p < 0.005). R e f r a c t o r y i n d i c e s c a l c u l a t e d f o r t h e p a i r o f e x e r c i s e c h a l l e n g e s p e r f o r m e d at l o w w o r k l o a d s h o w e d c o n s i d e r a b l y m o r e v a r i a b i l i t y t h a n t h e r e s p e c t i v e d a t a at high w o r k l o a d ( T a b l e 3).
Discussion W e o b s e r v e d in s u b j e c t s w i t h m i l d a s t h m a t h a t e x e r c i s e - i n d u c e d r e f r a c t o r i n e s s increases with the severeity of the obstructive airway response following the first o f r e p e t i t i v e c h a l l e n g e s .
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D. N o w a k e t al.
T a b l e 3. C h a n g e in s p e c i f i c a i r w a y r e s i s t a n c e ( S R a w ) f r o m b a s e l i n e t o m a x i m a l v a l u e s a f t e r p a i r s o f e x e r c i s e t e s t s a t l o w a n d h i g h w o r k l o a d s , a n d r e f r a c t o r y i n d i c e s (RI) L o w Work L o a d First Test
Mean SEM
RI
High Work Load
Second Test
Base
Max
%SRaw
Base
Max
%SRaw
5.8 6.6 13.2 6.6 8.0 13.8 7.7 14.5 12.3 19.5 15.7 10.9 11.2 1.2
14.4 13.5 21.8 17.4 24.8 22.1 14.8 37.2 21.1 35.7 24.4 18.8 22.2 2.2
148 105 65 164 210 60 92 156 71 83 55 72 107 15
5.3 6.8 8.2 7.5 9.2 9.4 12.4 33.6 9.8 15.5 13.5 20.5 12.6 2.3
9.8 18.4 11.5 6.7 19.5 18.8 27.3 30.7 18.8 30.1 22.4 24.8 19.9 2.2
85 171 40 -11 112 100 120 9 92 94 66 21 73 16
First Test
43 -63 38 107 47 -66 -30 105 28 -13 - 19 71 16 18
RI
Second Test
Base
Max
%SRaw
Base Max % S R a w
7.8 8.9 12.1 9.1 8.9 11.4 17.7 11.7 8.2 10.2 13.6 9.7 10.8 0.8
48.3 32.7 72.3 68.2 30.7 59.8 52.8 46.2 40.9 45.0 46.2 34.7 48.2 3.8
519 267 498 649 245 425 198 295 399 341 240 258 361 40
9.9 8.0 16.9 9.7 9.4 30.4 19.5 33.7 19.4 16.9 30.2 16.7 18.4 2.6
34.7 251 19.3 141 43.8 159 14.6 51 33.2 253 52.2 72 29.6 52 36.0 7 33.2 71 30.8 82 29.3 - 3 22.6 35 31.6 98 2.9 25
52 47 68 92 -3 83 74 98 82 76 101 86 71 9
Attenuation of airway obstruction with multiple exercise challenges has been carefully described in the literature, and large interindividual variability has been reported [5, 10, 12, 13, 18, 21, 23, 26, 28, 32, 33]. Many factors are known that may contribute to the variability of exercise-induced refractoriness between subjects with bronchial asthma. The degree of refractoriness depends on the time between the challenges, and with intervals of more than 2 hr refractoriness will disappear [10, 34]. Based on these observations, in most reports the time interval between repeated exercise trials was restricted to 30-45 min. As a consequence, not all subjects will totally recover from airway obstruction, resulting in significant differences in prechallenge baseline values [10, 13]. The influence of baseline airway tone on the airway response to bronchoconstrictor stimuli has been a matter of debate for a long time. There is now increasing evidence that in asthma baseline pulmonary function is not an important factor determining responsiveness of the airways to a given stimulus. Recently, this has convincingly been shown by an absent or only weak correlation between circadian variation of airway tone and airway responsiveness in asthmatic subjects [1, 6, 24]. Although differences in the prechallenge airway caliber are unlikely to affect interpretation of our data, they will, of course, influence presentation of the results. Calculation of refractoriness is usually performed on the basis of percentage changes rather than absolute lung function values [33]. In the present study we preferred to express refractoriness in the conventional manner, although we are aware that in the presence of different baseline SRaw the degree of refractoriness will decrease using absolute values rather than relative changes of SRaw. To test the influence of baseline airway
Exercise-Induced Bronchoconstriction and Refractoriness A%
SRaw
HIGH WORK
LOW WORK LOAD
400 t
400 --
300
300 --
200
200 --
100
100 -1st test
2nd test
81 LOAD
1st test 2nd test
Fig. 1, Mean (SEM) percentage increases in airway resistance after first and second exercise challenges at low and high work loads.
tone on the results, we also evaluated the airway response and refractoriness in terms of absolute increases in SRaw from baseline (r s = 0.55, p < 0.005) and in terms of absolute maximum SRaw values (rs = 0.42, p < 0.025). Therefore, the main finding of a significant correlation between the degree of airway response and refractoriness was not caused by changes in baseline lung function. Four patients were taking theophylline and 7 were taking inhaled corticosteroids, which may inhibit exercise-induced bronchoconstriction [17, 22]. Identical dosages were allowed before the challenges to achieve normal baseline lung function levels, and experiments were performed at the same time of the day. A comparison of patients taking and not taking theophylline or inhaled corticosteroids revealed no difference in response to high and low work loads. We therefore believe that medication did not considerably influence our findings. McFadden et al. have demonstrated that the intraairway thermodynamic events occuring during exercise and the recovery period are major determinants of the obstructive airway response [25]. Although temperature and water content in the inspired air at a given level of ventilation determine exercise-induced bronchoconstriction [12], they cannot predict individual airway response [2, 20, 27]. In the present study exercise-induced bronchoconstriction significantly increased with exercise work load. Intrasubject variability of repeated exercise tests, as reflected by the refractory indices, varied between - 63 and 107 at low work load and between - 3 and 101 at high work load. The large variability of the airway response following a weak stimulus is an inherent problem of any study using a similar experimental approach. However, the low work load will presumably occur more often with activities of than daily life the higher one. Inspection of Table 3 reveales that in most of our subjects refractoriness increased with the severity of EIB. Our results resemble in many aspects the data of Edmunds and co-workers [I0], who found that in repeated exercise tests, the first being performed at varying metabolic loads and the second at constant load, EIB increased in
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proportion to the load of the first test and that the severity of the obstructive airway response of the second test was inversely related to EIB after the first test. Our data and those previously published therefore demonstrate that refractoriness depends on individual airway responsiveness, temperature and water content of the inspired air, strength of the initial work load, and the time interval between repeated tests. The complex relationship between these factors probably explains why some asthmatic subjects use a "warm up" exercise to reduce symptoms during ongoing activity, or prefer prolonged submaximal warm up to protect against EIB [30]. There have been many attempts to elucidate the pathogenesis of exerciseinduced refractoriness. Our study was not designed to contribute to current hypotheses on mediator depletion [3, 19], increased release of catecholamines [4, 8, 33], release of inhibitory prostaglandins [11, 23, 29], reduced responsiveness of bronchial smooth muscles [ 15, 16], or an alteration of the responsivity of the bronchial microcirculation [13] to explain exercise-induced refractoriness. However, one might speculate that with exercise performed at low work loads the capacity of the bronchial microcirculation is not sufficient to contribute to the intra-airway termal events shown to occur with higher levels of exercise ventilation [12], resulting in refractoriness. In summary, consistent exercise-induced refractoriness or the ability of a first exercise test to protect against the obstructive airway response of a second test can only be observed with a relatively high metabolic work load.
Acknowledgment. This study was supported by a grant from LVA Freie und Hansestadt Hamburg, Germany.
References 1. Aalderen WM van, Postma DS, Koeter GH, Knol K (1989) Circadian change in bronchial responsiveness and airflow obstruction in asthmatic children. Thorax 44:803-807 2. Anderson SD (1985) Issues in exercise-induced asthma. J Allergy Clin Immunol 76:763-772 3. Barnes PJ, Brown MJ (1981) Venous plasma histamine in exercise and hyperventilation-induced asthma in man. Clin Sci 61:159-162 4. Barnes P, Brown M, Silverman M, DoUery C (1981) Circulating catecholamines in exerciseand hyperventilation-induced asthma. Thorax 30:435-440 5. Ben-Dov I, Bar-Yishay E, Godfrey S (1982) Refractory period after exercise-induced asthma unexplained by respiratory heat loss. Am Rev Respir Dis 125:530-534 6. Bonnet R, J0rres R, Heitmann U, Magnussen H (1991) Circadian rhythm in airway responsiveness and airway tone in patients with mild asthma. J Appl Physiol, 71:1598-1605 7. Deal EC Jr, McFadden ER Jr, Ingram RH Jr, Strauss RH, Jaeger JJ (1979) Role of respiratory heat exchange in production of exercise-induced asthma. J Appl Physiol 46:467-475
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8. Dosani R, van Loon GR, Burki NK (1987) The relationship between exercise-induced asthma and plasma catecholamines. Am Rev Respir Dis 136:973-978 9. DuBois AB, Botelho SY, Comroe JH Jr (1956) A new method for measuring airway resistance in man using a body plethysmograph: values in normal subjects and patients with respiratory diseases. J Clin Invest 35:327-335 10. Edmunds A, Tooley M, Godfrey S (1978) The refractory period after exercise-induced asthma: the duration and relation to the severity of exercise. Am Rev Respir Dis 117:247-254 11. Gelb AF, Tashkin DP, Epstein JD, Gong H Jr, Zamel N (1985) Exercise-induced bronchodilation in asthma. Chest 87:196-201 12. Gilbert IA, Fouke JM, McFadden ER (1987) Heat and water flux in the intrathoracic airways and exercise-induced asthma. J Appl Physiol 63:1681-1691 13. Gilbert IA, Fouke JM, McFadden ER (1990) The effect of repetitive exercise on airway temperatures. Am Rev Respir Dis 142:826-831 14. Godfrey S, Silverman M, Anderson SD (1973) Problems of interpreting exercise-induced asthma. J Allergy Clin Immunol 52:199-202 15. Hahn AG, Nogrady SG, McTumilty D, Lawrence SR, Morton AR (1984) Histamine reactivity during the refractory period after exercise induced asthma. Thorax 39:919-923 16. Hamielec CM, Manning PJ, O'Byrne PM (1988) Exercise refractoriness after histamine inhalation in asthmatic subjects. Am Rev Respir Dis 138:794-798 17. Henriksen JM, Dahl R (1983) Effects of inhaled budesonide alone in combination with lowdose terbutaline in children with exercise-induced asthma. Am Rev Respir Dis 128:993-997 18. James L, Faciane J, Sly RM (1976) Effect of treadmill exercise on asthmatic children. J Allergy Clin Immunol 57:408-416 19. Lee T, Nagakura T, Cromwell O, Brown M, Causon R, Kay A (1984) Neutrophil chemotactic activity and histamine in atopic and nonatopic subjects after exercise-induced asthma. Am Rev Respir Dis 129:409-412 20. Magnussen H, Scheidt-Mackes M, Kesseler KH (1983) K6rperliche Belastung und Hyperventilation als ausl6sende Faktoren der Atemwegsobstruktion beim Asthma bronchiale. Prax Kiln Pneumol 37:685-686 21. Magnussen H, Reuss G, J6rres R (1986) Airway response to methacholine during exercise induced refractoriness in asthma. Thorax 41:667-670 22. Magnussen H, Reuss G, J6rres R (1988) Methylxanthines inhibit exercise-induced bronchoconstriction at low serum theophylline concentration and in a dose-dependent fashion. J Allergy Clin Immunol 81:531-537 23. Margolskee DJ, Bigby BG, Boushey HA (1988) Indomethacin blocks airway tolerance to repetitive exercise but not to eucapnic hyperpnea in asthmatic subjects. Am Rev Respir Dis 137:842-846 24. Martin RJ, Cicutto LC, Ballard RD (1990) Factors related to the nocturnal worsening ofasthma. Am Rev Respir Dis 141:33-38 25. McFadden ER Jr, Lenner KAM, Strohl KP (1986) Postexertional airway rewarming and thermally induced asthma. J Clin Invest 78:18-25 26. McNeill RS, Nairn JR, Millar JS, Ingram CG (1965) Exercise-induced asthma. Q J Med 35:55-67 27. Novisky N, Bar-Yishay E, Gur I, Godfrey S (1988) Respiratory heat/water loss alone does not determine the severity of exercise-induced asthma. Eur Respir J 1:253-256 28. Nowak D, Kuziek G, J6rres R, Magnussen H (1991) Comparison of refractoriness after exercise- and hyperventilation-induced asthma. Lung 169:57-67 29. O'Byrne PM, Jones GL (1986) The effect of indomethacin on exercise-induced bronchoconstriction and refractoriness after exercise. Am Rev Respir Dis 134:69-72 30. Reiff DB, Choudry NB, Pride NB, Ind PW (1989) The effect of prolonged submaximal warmup exercise on exercise-induced asthma. Am Rev Respir Dis 139:479-484 31. Sachs L (1984) Angewandte Statistik.Berlin: Springer, 6th ed. 32. Schnall RP, Landau LI (1980) Protective effect of repeated short sprints in exercise-induced asthma. Thorax 35:828-832
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33. Schoeffel RE, Anderson SD, Gillam I, Lindsay DA (1980) Multiple exercise and histamine challenges in asthmatic patients. Thorax 35:164-170 34. Stearns DR, McFadden ER, Breslin FJ, Ingrain RH (1981) Reanalysis of the refractory period in exertional asthma. J Appl Physiol 50:503-508 35. Wilson BA, Bar-Or O, Seed L (1990) Effects of humid air breathing during arm or treadmill exercise on exercise-induced bronchoconstriction and refractoriness. Am Rev Respir Dis 142:349-352 Accepted for publication: 5 September 1991
Sprin~g~ NewYorkInc.1992
Influence of Exercise-Induced Bronchoconstriction on Refractoriness Dennis Nowak, Rudolf JOrres, and Helgo Magnussen Krankenhaus GroBhansdorf, Zentrum for Pneumologie und Thoraxchirurgie, W6hrendamm 80, D-2070 GrofShansdorf, Germany
Abstract. This study determined if the degree of exercise-induced refractoriness is determined by the degree of exercise-induced bronchoconstriction. In 12 patients with exercise-induced asthma (mean [SEM] age 27 [3] years) we performed 2 pairs of exercise challenges 45 min apart at different work loads on 2 days. Mean (SEM) total respiratory heat loss during low and high work loads was 3.4 (0.2) and 5.1 (0.4) kcal, respectively. After the first and second exercise challenge at low work loads, mean (SEM) SRaw increased by 107 (15) and 73 (16)% (n.s.), as compared to 361 (40) and 98 (25)% at high work loads (p < 0.005). We found a correlation between the initial airways response and refractoriness (r = 0.58, p < 0.005) and conclude that the degree of refractoriness after exercise-induced bronchoconstriction is in part dependent on the severity of exercise-induced bronchoconstriction. Key words: fractoriness.
Asthma,
exercise-induced--Bronchoconstriction--Re-
Introduction In many patients with bronchial asthma, exercise results in bronchoconstriction, the degree of which depends upon the temperature and humidity of the inspired air and the rate of ventilation [7]. One characteristic feature of exercise-induced bronchoconstriction (EIB) is a refractory period during which the repetitive exercise induces less airway obstruction [2, 33]. Refractoriness has been shown to be influenced by a variety of factors such as type of exercise [35], time between serial tests [10], cooling and drying of airways [34], release of mediators [23], and, more recently, the responsivity of bronchial microcirculation [13]. Offprint requests to." H. Magnussen
76
D. Nowak et al.
In addition, Edmunds et al. [10] and Wilson et al. [35] observed that with increasing severity of the initial EIB, a reduced obstructive response after the second test occurred. In the present study, we reevaluated the influence of the initial degree of airway narrowing on exercise-induced refractoriness. In contrast to previous reports we performed, in the same patients, 2 pairs of exercise tests that only differed in terms of exercise ventilation. Thus 1 pair of challenges was done with high ventilation and 1 with low ventilation.
Patients and Methods We studied 12 patients with bronchial asthma, 6 men and 6 women with a mean (SEM) age of 28 (3) years (range, 20-49) whose characteristics are given in Table 1. All of them had a history of exercise-induced asthma. In all patients airway hyperresponsiveness to inhaled histamine could be demonstrated, with a mean provocation concentration necessary to increase specific airway resistance by 100% of 0.12 */1.38 mg/ml. Ten patients were nonsmokers, two were exsmokers. Allergy skin testing with common allergens revealed positive results in all patients but 1. All patients required occasional or regular medication listed in Table 1. Inhaled beta2-agonists and ipratropiumbromide were withheld at least 6 hr before each study period, whereas inhaled and oral steroids and theophylline were taken as usual. The patients were instructed about the aim of the study and gave their informed consent.
Lung Function Measurement Baseline spirometry was performed using a pneumotachograph whose differential pressure signal was electronically integrated to give volume. Airway resistance (Raw) during quiet breathing and thoracic gas volume at functional residual capacity [9] were determined by a constant volume body plethysmograph (Bodytest, E. Jaeger, Wuerzburg, Germany). Raw was multiplied with thoracic gas volume to give specific airway resistance (SRaw). The values were computed as the average of 3 breathing cycles.
Exercise Tests Exercise was performed on a bicycle ergometer in a sitting position. During exercise, patients breathed cold (mean [SEM]-15 [1.0]°C) and dry room air produced by a heat exchanger (RHE-Test, E. Jaeger, Germany). Inspiratory and expiratory temperatures were measured by a thermocouple within the 2 ports of the 2-way breathing valve. Expired air was conducted through a heated pneumotachograph (E. Jaeger, Germany) and airflow was integrated electronically to give minute ventilation. Experimental conditions were carefully matched in terms of constant inspiratory temperature, water content, and duration of exercise during each pair of tests, respectively. Respiratory heat exchange was calculated according to the formula of Deal et al. [7].
Experimental Protocol Each pair of exercise tests was performed between 1.00 p.m. and 5.00 p.m. on 2 different days within 1 week. Before the first paired challenge, lung function was measured to ensure a normal baseline airway tone. On an individual basis, 2 work loads were chosen. The lower work load was selected to produce an increase in SRaw of at least 100%, the higher was chosen as the highest tolerable work load not producing an unacceptably high degree of airway obstruction.
Exercise-Induced Bronchoconstriction and Refractoriness
77
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Lung function was measured before (baseline values) and 3, 10, 15, 30, and 45 min after the end of the first exercise challenge. The SRaw value measured 45 min after the first challenge was taken as baseline value of the second test. Lung function measurements were repeated 3, 10, 15, and 30 min after the end of the second provocation challenge.
Analysis of Data Airway response to exercise was expressed as maximum percentage increase in SRaw with respect to baseline (delta%SRaw) [14]. A refractory index was calculated according to the following equation given by Schoeffel and co-workers [33] (indices (1) and (2) referring to the first and the second test, respectively): Refractory index (%) = 100 x
A %SRaw(1) - A %SRaw(2) A %SRaw(1)
A refractory index of 100% means no airway response in the second test, whereas an index of 0% means equal responses in the 2 tests.
Statistical Evaluations We used nonparametric statistical methods to avoid assumptions on data distributions. Baseline values and airway responses were compared by the Wilcoxon matched-pairs as signed-rank test. Correlation was quantified by the Spearman rank correlation coefficient [31]. Statistical significance was defined as p < 0.05.
Results
Experimental Conditions E x p e r i m e n t a l c o n d i t i o n s are p r e s e n t e d in T a b l e 2. D u r i n g tests at l o w a n d high w o r k l o a d s v e n t i l a t i o n ( p < 0.005) a n d R H E (p < 0.005) differed significantly. T h e r e w a s n o significant d i f f e r e n c e b e t w e e n e x e r c i s e v e n t i l a t i o n a n d R H E b e t w e e n the first a n d s e c o n d test w i t h i n the pairs o f c h a l l e n g e s .
Baseline Lung Function M e a n ( S E M ) b a s e l i n e S R a w v a l u e s are g i v e n in T a b l e 3. B a s e l i n e a i r w a y c a l i b e r in the first a n d s e c o n d e x e r c i s e test at low w o r k load a n d the first test at high w o r k load w a s n o t s i g n i f i c a n t l y different. H o w e v e r , b a s e l i n e S R a w b e f o r e the s e c o n d test p e r f o r m e d with high w o r k load w a s higher t h a n b e f o r e the first test (p < O.OO5).
Exercise Tests I n d i v i d u a l d a t a are g i v e n in T a b l e 3, a n d m e a n ( S E M ) p e r c e n t a g e i n c r e a s e s in S R a w after e x e r c i s e c h a l l e n g e s at low a n d high w o r k l o a d s are p r e s e n t e d in F i g u r e 1.
Exercise-Induced Bronchoconstriction and Refractoriness
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Table 2. Experimental conditions during the tests W
Low Work Load First Test
Mean SEM
140 70 150 60 100 100 80 100 150 100 100 120 105 9
W
High Work Load
Second Test
V
RHE
V
RHE
50.0 30.5 37.7 30.8 31.3 32.3 29.2 31.5 43.0 27.1 33.2 41.5 34.8 2.0
4.96 2.75 3.61 3.08 3.05 3.23 2.34 3.01 4.06 2.58 3.32 4.70 3.39 0.23
54.0 30.2 36.4 29.8 33.0 33.8 23.8 29.6 36.6 26.2 28.7 43.8 33.8 2.4
5.21 2.85 3.48 2.98 3.20 3.37 2.60 2.83 3.50 2.58 2.94 4.96 3.38 0.25
First Test
170 100 180 90 130 200 140 150 250 200 200 240 171 15
Second Test
V
RHE
V
RHE
79.4 39.8 49.8 39.0 46.4 62.4 44.5 50.2 67.8 55.1 41.0 69.6 53.8 3.8
7.93 3.33 4.76 3.73 4A3 5°89 4.25 5.22 5.94 5.91 3.50 7.57 5.2l 0.43
94.1 42.7 47.0 38.7 51.9 51.6 39.8 44.5 56.6 52.4 40.0 63.5 51.9 4.4
8.94 3.57 4.83 3.70 4.96 5.08 3.75 4.62 5.18 5.37 3.41 6.90 5.03 0.45
w, work load (watt); V, ventilation (L/rain); RHE, total respiratory heat exchange during the challenge (kcal).
A t l o w w o r k l o a d , m e a n ( S E M ) m a x i m u m p e r c e n t a g e i n c r e a s e in S R a w w a s 107 (15)% d u r i n g t h e first a n d 73 (16)% d u r i n g the s e c o n d e x e r c i s e t e s t , t h e d i f f e r e n c e b e i n g n o t significant. A t high w o r k l o a d , m e a n ( S E M ) m a x i m u m p e r c e n t a g e i n c r e a s e in S R a w w a s 361 (40)% d u r i n g t h e first a n d 98 (25)% d u r i n g t h e s e c o n d e x e r c i s e t e s t (p < 0.005). M e a n p e r c e n t a g e i n c r e a s e a f t e r t h e first t e s t at l o w w o r k l o a d w a s s i g n i f i c a n t l y l o w e r t h a n at high w o r k l o a d (p < 0.0025), w h e r e a s m e a n p e r c e n t a g e i n c r e a s e a f t e r t h e s e c o n d t e s t s d i d n o t differ b e t w e e n l o w a n d high w o r k l o a d s .
Comparison of Refractoriness at Different Work Loads M e a n ( S E M ) r e f r a c t o r y i n d e x f o r e x e r c i s e at l o w w o r k l o a d w a s 16 (18)%, a n d m e a n ( S E M ) r e f r a c t o r y i n d e x f o r e x e r c i s e at high w o r k l o a d w a s 71 (9)% (p < 0.05). A i r w a y r e s p o n s e a n d r e f r a c t o r i n e s s c o r r e l a t e d significantly (r = 0.58, p < 0.005). R e f r a c t o r y i n d i c e s c a l c u l a t e d f o r t h e p a i r o f e x e r c i s e c h a l l e n g e s p e r f o r m e d at l o w w o r k l o a d s h o w e d c o n s i d e r a b l y m o r e v a r i a b i l i t y t h a n t h e r e s p e c t i v e d a t a at high w o r k l o a d ( T a b l e 3).
Discussion W e o b s e r v e d in s u b j e c t s w i t h m i l d a s t h m a t h a t e x e r c i s e - i n d u c e d r e f r a c t o r i n e s s increases with the severeity of the obstructive airway response following the first o f r e p e t i t i v e c h a l l e n g e s .
80
D. N o w a k e t al.
T a b l e 3. C h a n g e in s p e c i f i c a i r w a y r e s i s t a n c e ( S R a w ) f r o m b a s e l i n e t o m a x i m a l v a l u e s a f t e r p a i r s o f e x e r c i s e t e s t s a t l o w a n d h i g h w o r k l o a d s , a n d r e f r a c t o r y i n d i c e s (RI) L o w Work L o a d First Test
Mean SEM
RI
High Work Load
Second Test
Base
Max
%SRaw
Base
Max
%SRaw
5.8 6.6 13.2 6.6 8.0 13.8 7.7 14.5 12.3 19.5 15.7 10.9 11.2 1.2
14.4 13.5 21.8 17.4 24.8 22.1 14.8 37.2 21.1 35.7 24.4 18.8 22.2 2.2
148 105 65 164 210 60 92 156 71 83 55 72 107 15
5.3 6.8 8.2 7.5 9.2 9.4 12.4 33.6 9.8 15.5 13.5 20.5 12.6 2.3
9.8 18.4 11.5 6.7 19.5 18.8 27.3 30.7 18.8 30.1 22.4 24.8 19.9 2.2
85 171 40 -11 112 100 120 9 92 94 66 21 73 16
First Test
43 -63 38 107 47 -66 -30 105 28 -13 - 19 71 16 18
RI
Second Test
Base
Max
%SRaw
Base Max % S R a w
7.8 8.9 12.1 9.1 8.9 11.4 17.7 11.7 8.2 10.2 13.6 9.7 10.8 0.8
48.3 32.7 72.3 68.2 30.7 59.8 52.8 46.2 40.9 45.0 46.2 34.7 48.2 3.8
519 267 498 649 245 425 198 295 399 341 240 258 361 40
9.9 8.0 16.9 9.7 9.4 30.4 19.5 33.7 19.4 16.9 30.2 16.7 18.4 2.6
34.7 251 19.3 141 43.8 159 14.6 51 33.2 253 52.2 72 29.6 52 36.0 7 33.2 71 30.8 82 29.3 - 3 22.6 35 31.6 98 2.9 25
52 47 68 92 -3 83 74 98 82 76 101 86 71 9
Attenuation of airway obstruction with multiple exercise challenges has been carefully described in the literature, and large interindividual variability has been reported [5, 10, 12, 13, 18, 21, 23, 26, 28, 32, 33]. Many factors are known that may contribute to the variability of exercise-induced refractoriness between subjects with bronchial asthma. The degree of refractoriness depends on the time between the challenges, and with intervals of more than 2 hr refractoriness will disappear [10, 34]. Based on these observations, in most reports the time interval between repeated exercise trials was restricted to 30-45 min. As a consequence, not all subjects will totally recover from airway obstruction, resulting in significant differences in prechallenge baseline values [10, 13]. The influence of baseline airway tone on the airway response to bronchoconstrictor stimuli has been a matter of debate for a long time. There is now increasing evidence that in asthma baseline pulmonary function is not an important factor determining responsiveness of the airways to a given stimulus. Recently, this has convincingly been shown by an absent or only weak correlation between circadian variation of airway tone and airway responsiveness in asthmatic subjects [1, 6, 24]. Although differences in the prechallenge airway caliber are unlikely to affect interpretation of our data, they will, of course, influence presentation of the results. Calculation of refractoriness is usually performed on the basis of percentage changes rather than absolute lung function values [33]. In the present study we preferred to express refractoriness in the conventional manner, although we are aware that in the presence of different baseline SRaw the degree of refractoriness will decrease using absolute values rather than relative changes of SRaw. To test the influence of baseline airway
Exercise-Induced Bronchoconstriction and Refractoriness A%
SRaw
HIGH WORK
LOW WORK LOAD
400 t
400 --
300
300 --
200
200 --
100
100 -1st test
2nd test
81 LOAD
1st test 2nd test
Fig. 1, Mean (SEM) percentage increases in airway resistance after first and second exercise challenges at low and high work loads.
tone on the results, we also evaluated the airway response and refractoriness in terms of absolute increases in SRaw from baseline (r s = 0.55, p < 0.005) and in terms of absolute maximum SRaw values (rs = 0.42, p < 0.025). Therefore, the main finding of a significant correlation between the degree of airway response and refractoriness was not caused by changes in baseline lung function. Four patients were taking theophylline and 7 were taking inhaled corticosteroids, which may inhibit exercise-induced bronchoconstriction [17, 22]. Identical dosages were allowed before the challenges to achieve normal baseline lung function levels, and experiments were performed at the same time of the day. A comparison of patients taking and not taking theophylline or inhaled corticosteroids revealed no difference in response to high and low work loads. We therefore believe that medication did not considerably influence our findings. McFadden et al. have demonstrated that the intraairway thermodynamic events occuring during exercise and the recovery period are major determinants of the obstructive airway response [25]. Although temperature and water content in the inspired air at a given level of ventilation determine exercise-induced bronchoconstriction [12], they cannot predict individual airway response [2, 20, 27]. In the present study exercise-induced bronchoconstriction significantly increased with exercise work load. Intrasubject variability of repeated exercise tests, as reflected by the refractory indices, varied between - 63 and 107 at low work load and between - 3 and 101 at high work load. The large variability of the airway response following a weak stimulus is an inherent problem of any study using a similar experimental approach. However, the low work load will presumably occur more often with activities of than daily life the higher one. Inspection of Table 3 reveales that in most of our subjects refractoriness increased with the severity of EIB. Our results resemble in many aspects the data of Edmunds and co-workers [I0], who found that in repeated exercise tests, the first being performed at varying metabolic loads and the second at constant load, EIB increased in
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D. Nowak et al.
proportion to the load of the first test and that the severity of the obstructive airway response of the second test was inversely related to EIB after the first test. Our data and those previously published therefore demonstrate that refractoriness depends on individual airway responsiveness, temperature and water content of the inspired air, strength of the initial work load, and the time interval between repeated tests. The complex relationship between these factors probably explains why some asthmatic subjects use a "warm up" exercise to reduce symptoms during ongoing activity, or prefer prolonged submaximal warm up to protect against EIB [30]. There have been many attempts to elucidate the pathogenesis of exerciseinduced refractoriness. Our study was not designed to contribute to current hypotheses on mediator depletion [3, 19], increased release of catecholamines [4, 8, 33], release of inhibitory prostaglandins [11, 23, 29], reduced responsiveness of bronchial smooth muscles [ 15, 16], or an alteration of the responsivity of the bronchial microcirculation [13] to explain exercise-induced refractoriness. However, one might speculate that with exercise performed at low work loads the capacity of the bronchial microcirculation is not sufficient to contribute to the intra-airway termal events shown to occur with higher levels of exercise ventilation [12], resulting in refractoriness. In summary, consistent exercise-induced refractoriness or the ability of a first exercise test to protect against the obstructive airway response of a second test can only be observed with a relatively high metabolic work load.
Acknowledgment. This study was supported by a grant from LVA Freie und Hansestadt Hamburg, Germany.
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8. Dosani R, van Loon GR, Burki NK (1987) The relationship between exercise-induced asthma and plasma catecholamines. Am Rev Respir Dis 136:973-978 9. DuBois AB, Botelho SY, Comroe JH Jr (1956) A new method for measuring airway resistance in man using a body plethysmograph: values in normal subjects and patients with respiratory diseases. J Clin Invest 35:327-335 10. Edmunds A, Tooley M, Godfrey S (1978) The refractory period after exercise-induced asthma: the duration and relation to the severity of exercise. Am Rev Respir Dis 117:247-254 11. Gelb AF, Tashkin DP, Epstein JD, Gong H Jr, Zamel N (1985) Exercise-induced bronchodilation in asthma. Chest 87:196-201 12. Gilbert IA, Fouke JM, McFadden ER (1987) Heat and water flux in the intrathoracic airways and exercise-induced asthma. J Appl Physiol 63:1681-1691 13. Gilbert IA, Fouke JM, McFadden ER (1990) The effect of repetitive exercise on airway temperatures. Am Rev Respir Dis 142:826-831 14. Godfrey S, Silverman M, Anderson SD (1973) Problems of interpreting exercise-induced asthma. J Allergy Clin Immunol 52:199-202 15. Hahn AG, Nogrady SG, McTumilty D, Lawrence SR, Morton AR (1984) Histamine reactivity during the refractory period after exercise induced asthma. Thorax 39:919-923 16. Hamielec CM, Manning PJ, O'Byrne PM (1988) Exercise refractoriness after histamine inhalation in asthmatic subjects. Am Rev Respir Dis 138:794-798 17. Henriksen JM, Dahl R (1983) Effects of inhaled budesonide alone in combination with lowdose terbutaline in children with exercise-induced asthma. Am Rev Respir Dis 128:993-997 18. James L, Faciane J, Sly RM (1976) Effect of treadmill exercise on asthmatic children. J Allergy Clin Immunol 57:408-416 19. Lee T, Nagakura T, Cromwell O, Brown M, Causon R, Kay A (1984) Neutrophil chemotactic activity and histamine in atopic and nonatopic subjects after exercise-induced asthma. Am Rev Respir Dis 129:409-412 20. Magnussen H, Scheidt-Mackes M, Kesseler KH (1983) K6rperliche Belastung und Hyperventilation als ausl6sende Faktoren der Atemwegsobstruktion beim Asthma bronchiale. Prax Kiln Pneumol 37:685-686 21. Magnussen H, Reuss G, J6rres R (1986) Airway response to methacholine during exercise induced refractoriness in asthma. Thorax 41:667-670 22. Magnussen H, Reuss G, J6rres R (1988) Methylxanthines inhibit exercise-induced bronchoconstriction at low serum theophylline concentration and in a dose-dependent fashion. J Allergy Clin Immunol 81:531-537 23. Margolskee DJ, Bigby BG, Boushey HA (1988) Indomethacin blocks airway tolerance to repetitive exercise but not to eucapnic hyperpnea in asthmatic subjects. Am Rev Respir Dis 137:842-846 24. Martin RJ, Cicutto LC, Ballard RD (1990) Factors related to the nocturnal worsening ofasthma. Am Rev Respir Dis 141:33-38 25. McFadden ER Jr, Lenner KAM, Strohl KP (1986) Postexertional airway rewarming and thermally induced asthma. J Clin Invest 78:18-25 26. McNeill RS, Nairn JR, Millar JS, Ingram CG (1965) Exercise-induced asthma. Q J Med 35:55-67 27. Novisky N, Bar-Yishay E, Gur I, Godfrey S (1988) Respiratory heat/water loss alone does not determine the severity of exercise-induced asthma. Eur Respir J 1:253-256 28. Nowak D, Kuziek G, J6rres R, Magnussen H (1991) Comparison of refractoriness after exercise- and hyperventilation-induced asthma. Lung 169:57-67 29. O'Byrne PM, Jones GL (1986) The effect of indomethacin on exercise-induced bronchoconstriction and refractoriness after exercise. Am Rev Respir Dis 134:69-72 30. Reiff DB, Choudry NB, Pride NB, Ind PW (1989) The effect of prolonged submaximal warmup exercise on exercise-induced asthma. Am Rev Respir Dis 139:479-484 31. Sachs L (1984) Angewandte Statistik.Berlin: Springer, 6th ed. 32. Schnall RP, Landau LI (1980) Protective effect of repeated short sprints in exercise-induced asthma. Thorax 35:828-832
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33. Schoeffel RE, Anderson SD, Gillam I, Lindsay DA (1980) Multiple exercise and histamine challenges in asthmatic patients. Thorax 35:164-170 34. Stearns DR, McFadden ER, Breslin FJ, Ingrain RH (1981) Reanalysis of the refractory period in exertional asthma. J Appl Physiol 50:503-508 35. Wilson BA, Bar-Or O, Seed L (1990) Effects of humid air breathing during arm or treadmill exercise on exercise-induced bronchoconstriction and refractoriness. Am Rev Respir Dis 142:349-352 Accepted for publication: 5 September 1991
