Respiration 34: 31-35(1977)
Exercise-Induced Bronchoconstriction in Patients with Bronchial Asthma. Its Prevention with an Antihistaminic Agent J. Zielinski and E. Chodosowska Department of Medicine (Director: Prof. M. Titlezyriski), Institute of Tuberculosis, Warsaw
Key Words. Asthma • Exercise-induced bronchoconstriction ■ Pharmacological protec tion • Thiazinamium • Antihistaminic • Atropine Abstract. 14 asthmatic patients developing regularly exercise-induced bronchocon striction were subjected to a submaximal exercise on a bicycle ergometer. On the first day the exercise was not preceded by any medication; on the second, 50 mg thiazinamium was given, and on the third day 2 mg atropine was given before the exercise. The changes in the calibre of the bronchi were assessed with a Wright peak flow meter. With thiazinamium a complete protection against the bronchoconstriction was observed in 12 patients, in one the protection was partial and in an other no beneficial effect of the drug was found. It seems that protection given by thiazinamium was due to its antihistam inic property and not to the anticholinergic one, as among 10 patients protected by thiazinamium, only 2 were also protected by the atropine. One of the points still unclear is the mechanism of EIB. The good protection against EIB obtained with disodium cromoglycate suggest that it could be mediated by a histamine released from the mast cells [6,
111Former investigations on the protecting effects of antihistaminic agents are scanty and showed them to be ineffective. McNeil et al. [10] have tried to prevent the EIB with mepyramine. Sly et al. [14] did not say what antihistaminic they were using in their trial. It is well known that antihistaminics have little effect on the calibre of the bron-
Downloaded by: Lund University Libraries 130.235.66.10 - 1/1/2019 5:52:24 PM
Since the pioneering paper on exerciseinduced bronchoconstriction (EIB) written by Herxheimer [8] in 1946 a growing inter est has been focused on this problem by clinicians and physiopathologists. The re sults of almost 30 years of investigation and the present position of the subject were deary exposed in a recent excellent revue by Anderson et al. [1]. In conclusion the authors remark: ‘A vast amount of infor mation has accumulated over the last 30 years on the subject of exercise-induced asthma. Thus far, such studies have raised more questions about mechanisms of asthma than they have answered.’
32
Zielitiski/Chodosowska
Table I. The change in PEF in 14 asthmatic patients submitted to the submaximal exercise; the protecting effect of thiazinamium or atropine Case No.
Initials
Sex
Age years
Initial PEF l/min
Lowest PEF after the exercise l/min
Fall in PEF of initial value. %
Fall in PEF after protection initial value, % thiazinamium atropine 2 mg i.v. 50 mg i.m.
1 2 3 4 5 6 7 8 9 10 11 12 13 14
T.W. A.M. J.P. K.J. W.G. M.D. H.S. K.Z. S .t. H.W. J.D. E.K. B.P. A.Z.
F F M F F F M F F M M M F M
42 38 20 45 20 39 22 43 50 48 51 49 32 31
265 240 215 300 320 365 250 315 280 200 435 330 280 270
125 75 115 175 60 160 150 200 205 140 115 165 165 120
52.8 68.8 46.5 41.7 81.3 56.2 40.0 36.8 26.8 30.0 73.6 50.0 41.1 55.6
6.1 3.8 0 18.2 4.9 13.9 19.0 5.6 2.9 18.5 61.3 10.5 16.4 36.5
Materials and Methods 14 asthmatic patients regularly developing bronchospasm when exercised were studied. The group consisted of six males and eight females aged from 20 to 51 years. They all suffered from a severe form of the disease. A change in the bronchial obstruction was recorded by measuring the peak expiratory flow (PEF) using a Wright peak flow meter [15]. At each mea surement the best of three readings was taken into consideration.
—
The patients were exercised on a bicycle ergometer in a sitting position. A submaximal exercise of 10 min duration was performed, the work load having been adjusted in advance according to the heart rate, sex and age [4], The peak flow rate was measured once or twice before the exercise, depending on the day of the investigation, and at the 1st. 5th. 10th, 15th. 30th and 45th min after the exercise. The study was performed on three consecutive mornings. On the first day the exercise was not pre ceded by any medication, on the second day 50 mg thiazinamium was given intramuscularly 30 min before the exercise started. On the third day an intravenous injection of 2 mg atropine was given 5 min before the exercise. All antiasthmatic drugs were discontinued for at least 8 h before the trial.
Results The initial values of PEF, its fall after the exercise and protecting effect of thiazi namium and atropine are shown in table I. Downloaded by: Lund University Libraries 130.235.66.10 - 1/1/2019 5:52:24 PM
chi. The only antihistaminic having such property seems to be thiazinamium [3]. The aim of the present study was to assess the protecting effect of thiazinamium in asth matic patients developing EIB. As thiazi namium owes its broncholytic effect not only to the antihistaminic but also to the parasympatholytic property, the results ob tained with thiazinamium were compared with those of an atropine.
30.8 62.9 31.0 46.6 10.4 47.8 38.8 42.2 1.5 23.5 -
Exercise-Induced Bronchoconslriction. Prevention with an Antihistamine
450 -
E 400 -
350 -
300 -
250 -
200
-
150 -
— H h — i-----------1— i— i— i------------------ 1--------------------1----------
-40-15 -10
0
5
10 15
30
45 min
Fig. 1. The effect of exercise on the mean PEF in studied patients. Thin broken line = without protec tion: thick broken line = after the atropine (A), and solid line - after the thiazinaniium (M).
Exercise Without Pharmacological Prot ection The mean initial PEF averaged 290 I/ min. The measurements taken at the 1st min after the exercise have shown values similar or slighty higher than the initial ones. The fall in PEF started immediately after this, the lowest values having been ob served between the 5th and 15th min. The mean PEF fall averaged 50.9% of the ini tial value. From the 5th or 15th min on wards the PEF rose gradually but had not reached the initial level at the 45th min of recovery. In two patients the lowest values of PEF were observed at the 30th and 45th min respectively after the exercise. Exercise Preceded hy Thiazinaniium The mean initial PEF averaged 264 1/ min and increased at the 30th min after the
thiazinamium to 356 l/min. At the first measurement after the exercise was compl eted the PEF was slightly higher than at the beginning. In 12 patients the PEF remained on that level to the end of the observation or decreased by less than 20%. The thiazi namium protected those patients compl etely. In two patients the bronchospasm developed in spite of thiazinamium. In one (J.D.) the fall in PEF was almost identical to that observed without the drug. 61.3 and 73.6%, respectively, below the initial level. The second patient (A.Z.) benefited par tially from thiazinamium. In the group as a whole the average fall in PEF was 14%. The measurements taken at the 45th min after the exercise showed the return of PEF to the pre-exercise level. Exercise Preceded hy Atropine The study was done in 10 patients who benefited completely from thiazinamium. The mean initial PEF averaged 236 l/min and increased at the 5th min after the atropine to 289 l/min. The atropine did not protect eight patients, the fall in PEF being from a few percent more to 21% less than that observed without protection. Two pa tients benefited from the atropine to the same extent as from thiazinamium the fall in PEF being 1.5 and 10%, respectively. The effects of exercise alone on PEF and the protecting effect of thiazinamium or atropine are presented in figure 1.
Discussion One of the proposed mechanisms for EIB is a humoral one. According to it, an as yet unidentified bronchoconstricting fac tor is released during the exercise. There is
Downloaded by: Lund University Libraries 130.235.66.10 - 1/1/2019 5:52:24 PM
PEFJ l/mm
33
34
Although the presented results are con sistent with the histaminic theory of EIB. the lack of benefit from thiazinamium ob served in one patient as well as protection obtained by means of the atropine in two patients and the conflicting results of the previous studies on the mechanism of the EIB, raise the question of the uniformity of the symptoms labelled as the exercise-in duced bronchoconstriction. References 1 Anderson, S. D.: Silverman, M.; König. P.. and Godfrey. S.: Exercise-induced asthma. Br. J. Dis. Chest 69: 1-39 (1975). 2 Booij-Noord. H.: Orie. N. G. M.; Berg. W. C.. and De Vries, K.: Results of provocation of human bronchial airways with allergic and non-allergic sti muli and of drug protection tests; in Bronchitis. III. pp. 316-330 (Royal Vangorcum Publisher, Assen 1970). 3 Booij-Noord, M.: Orie. N. G. M.:Ten Cate. H. J.; Sloots. S.. and Bolt, D.: The influence of various drugs on the vital capacity of asthmatics. Int. Archs Allergy appl. Immun. 10: 321-341 (1957). 4 Borg, G. and Lindercoln, H.: Preceivcd exertion and pulse rate during graded exercise in various age groups. Acta med. scand., suppl. 472. pp. 194— 206(1967). 5 Cox, J. S. G.: Review of chemistry, pharmacology, toxicity, metabolism, side effects, anti-allergic properties in vitro and in vivo of disodium cromo glycate; in Disodium cromoglycate in allergic air ways disease, pp. 13-25 (Butterworths. London 1970). 6 Davies, S. E.: Effect of disodium cromoglycate on exercise-induced asthma. Br. med. J. Hi: 593-594 (1968). 7 Granerus, G.; Simonsson, B. G.; Skoogh. B. E.. and Wetterquist. H.: Exercise-induced broncho constriction and histamine release. Scand. J. Resp. Dis. 52: 131-136(1971). 8 Herxheimer, H.: Hyperventilation asthma. Lancet /V83-87 (1964). 9 Jones, R. S.; Wharton. M. J.. and Buston. M. H.: The place of physical exercise and bronchodilator Downloaded by: Lund University Libraries 130.235.66.10 - 1/1/2019 5:52:24 PM
some indirect evidence provided by the good protecting results obtained with diso dium cromoglycate that a histamine could play a role of that mediating factor as it is supposed that disodium cromoglycate pre vents the releasing of histamine from the mast cells [5]. The results of this study sup port that view. The complete protection ob tained with thiazinamium in 12 from 14 pa tients and a partial protection in one shows that effects of that drug were even better than those obtained with disodium cromo glycate [12, 13]. The protecting effect of thiazinamium seems to be due to its antihistaminic prop erty and not to the parasympatholytic one. Of 10 patients who benefited completely from thiazinamium eight reacted with bronchospasm when exercise was preceded by atropine given in a high dose. The results of other studies also showed that atropine had rather poor protecting effects [9, 14], The results of this study suggest that the EIB may be mediated by histamine. Al though Granerus el at. [7] did not find pa tients developing EIB in either an increase of the histamine level in the blood or the increase of its metabolites in urine their re sults did not exclude the possibility that lo cally in the lung tissue the histamine level could have been increased. The results ob tained by Booij-Noord et al. [2] point also to the histamine as a mediator of EIB. They have found that thiazinaminum pro tects against bronchospasm induced by inhalation of an allergen. The EIB and the allergen-induced bronchoconstriction closely resemble each other clinically. It is assumed that allergen-induced broncho spasm is a result of an immunologic reac tion type I with a histamine as a mediating agent.
Zieliriski/Chodosowska
Exercise-Induced Bronchoconstriction. Prevention with an Antihistamine
11
12
13
14
Strick, L.: Exercise-induced bronchospasm: effect of adrenergic or cholinergic blockage. J. Allergy 40: 93-99 (1967). 15 Wright. B. M. and McKcrrow, C. B.: Maximum forced expiratory flow rate as a measure of ventila tory capacity. With a description of a new portable instrument for measuring it. Br. med. J. ii: 10411047 (1959). Received: June 3. 1975 Accepted: August 3, 1975
J. Zielitiski, Department of Medicine. Institute of Tuberculosis, Plocka 26. 01-138 Warszawa (Po land)
Downloaded by: Lund University Libraries 130.235.66.10 - 1/1/2019 5:52:24 PM
10
drugs in the assessment of the asthmatic child. Archs Dis. Childh. 38: 539-545 (1963). McNeil. R. S.: Nairn. J. R.; Millar, J. S.. and In gram, C. G.: Exercise-induced asthma. O. J. Med. 35: 55-67 (1966). McCarthy. O. R.: The prevention of exercise-in duced asthma. Br. J. Dis. Chest 66: 133-140 (1972). Muittari. A. and Kreus. K. E.: Disodium cromoglycate in exercise-induced asthma. Br. med. J. iv: 170(1969). Poppius, H.: Muittari. A.; Kreus. K. E.: Korhonen. O., and Viljanen. A.: Exercise asthma and disodium cromoglycate. Br. med. J. iv: 337-339 (1970). Sly. R. M.; Heimlich. E. M.: Busscr, R. J.. and
35
Exercise-Induced Bronchoconstriction in Patients with Bronchial Asthma. Its Prevention with an Antihistaminic Agent J. Zielinski and E. Chodosowska Department of Medicine (Director: Prof. M. Titlezyriski), Institute of Tuberculosis, Warsaw
Key Words. Asthma • Exercise-induced bronchoconstriction ■ Pharmacological protec tion • Thiazinamium • Antihistaminic • Atropine Abstract. 14 asthmatic patients developing regularly exercise-induced bronchocon striction were subjected to a submaximal exercise on a bicycle ergometer. On the first day the exercise was not preceded by any medication; on the second, 50 mg thiazinamium was given, and on the third day 2 mg atropine was given before the exercise. The changes in the calibre of the bronchi were assessed with a Wright peak flow meter. With thiazinamium a complete protection against the bronchoconstriction was observed in 12 patients, in one the protection was partial and in an other no beneficial effect of the drug was found. It seems that protection given by thiazinamium was due to its antihistam inic property and not to the anticholinergic one, as among 10 patients protected by thiazinamium, only 2 were also protected by the atropine. One of the points still unclear is the mechanism of EIB. The good protection against EIB obtained with disodium cromoglycate suggest that it could be mediated by a histamine released from the mast cells [6,
111Former investigations on the protecting effects of antihistaminic agents are scanty and showed them to be ineffective. McNeil et al. [10] have tried to prevent the EIB with mepyramine. Sly et al. [14] did not say what antihistaminic they were using in their trial. It is well known that antihistaminics have little effect on the calibre of the bron-
Downloaded by: Lund University Libraries 130.235.66.10 - 1/1/2019 5:52:24 PM
Since the pioneering paper on exerciseinduced bronchoconstriction (EIB) written by Herxheimer [8] in 1946 a growing inter est has been focused on this problem by clinicians and physiopathologists. The re sults of almost 30 years of investigation and the present position of the subject were deary exposed in a recent excellent revue by Anderson et al. [1]. In conclusion the authors remark: ‘A vast amount of infor mation has accumulated over the last 30 years on the subject of exercise-induced asthma. Thus far, such studies have raised more questions about mechanisms of asthma than they have answered.’
32
Zielitiski/Chodosowska
Table I. The change in PEF in 14 asthmatic patients submitted to the submaximal exercise; the protecting effect of thiazinamium or atropine Case No.
Initials
Sex
Age years
Initial PEF l/min
Lowest PEF after the exercise l/min
Fall in PEF of initial value. %
Fall in PEF after protection initial value, % thiazinamium atropine 2 mg i.v. 50 mg i.m.
1 2 3 4 5 6 7 8 9 10 11 12 13 14
T.W. A.M. J.P. K.J. W.G. M.D. H.S. K.Z. S .t. H.W. J.D. E.K. B.P. A.Z.
F F M F F F M F F M M M F M
42 38 20 45 20 39 22 43 50 48 51 49 32 31
265 240 215 300 320 365 250 315 280 200 435 330 280 270
125 75 115 175 60 160 150 200 205 140 115 165 165 120
52.8 68.8 46.5 41.7 81.3 56.2 40.0 36.8 26.8 30.0 73.6 50.0 41.1 55.6
6.1 3.8 0 18.2 4.9 13.9 19.0 5.6 2.9 18.5 61.3 10.5 16.4 36.5
Materials and Methods 14 asthmatic patients regularly developing bronchospasm when exercised were studied. The group consisted of six males and eight females aged from 20 to 51 years. They all suffered from a severe form of the disease. A change in the bronchial obstruction was recorded by measuring the peak expiratory flow (PEF) using a Wright peak flow meter [15]. At each mea surement the best of three readings was taken into consideration.
—
The patients were exercised on a bicycle ergometer in a sitting position. A submaximal exercise of 10 min duration was performed, the work load having been adjusted in advance according to the heart rate, sex and age [4], The peak flow rate was measured once or twice before the exercise, depending on the day of the investigation, and at the 1st. 5th. 10th, 15th. 30th and 45th min after the exercise. The study was performed on three consecutive mornings. On the first day the exercise was not pre ceded by any medication, on the second day 50 mg thiazinamium was given intramuscularly 30 min before the exercise started. On the third day an intravenous injection of 2 mg atropine was given 5 min before the exercise. All antiasthmatic drugs were discontinued for at least 8 h before the trial.
Results The initial values of PEF, its fall after the exercise and protecting effect of thiazi namium and atropine are shown in table I. Downloaded by: Lund University Libraries 130.235.66.10 - 1/1/2019 5:52:24 PM
chi. The only antihistaminic having such property seems to be thiazinamium [3]. The aim of the present study was to assess the protecting effect of thiazinamium in asth matic patients developing EIB. As thiazi namium owes its broncholytic effect not only to the antihistaminic but also to the parasympatholytic property, the results ob tained with thiazinamium were compared with those of an atropine.
30.8 62.9 31.0 46.6 10.4 47.8 38.8 42.2 1.5 23.5 -
Exercise-Induced Bronchoconslriction. Prevention with an Antihistamine
450 -
E 400 -
350 -
300 -
250 -
200
-
150 -
— H h — i-----------1— i— i— i------------------ 1--------------------1----------
-40-15 -10
0
5
10 15
30
45 min
Fig. 1. The effect of exercise on the mean PEF in studied patients. Thin broken line = without protec tion: thick broken line = after the atropine (A), and solid line - after the thiazinaniium (M).
Exercise Without Pharmacological Prot ection The mean initial PEF averaged 290 I/ min. The measurements taken at the 1st min after the exercise have shown values similar or slighty higher than the initial ones. The fall in PEF started immediately after this, the lowest values having been ob served between the 5th and 15th min. The mean PEF fall averaged 50.9% of the ini tial value. From the 5th or 15th min on wards the PEF rose gradually but had not reached the initial level at the 45th min of recovery. In two patients the lowest values of PEF were observed at the 30th and 45th min respectively after the exercise. Exercise Preceded hy Thiazinaniium The mean initial PEF averaged 264 1/ min and increased at the 30th min after the
thiazinamium to 356 l/min. At the first measurement after the exercise was compl eted the PEF was slightly higher than at the beginning. In 12 patients the PEF remained on that level to the end of the observation or decreased by less than 20%. The thiazi namium protected those patients compl etely. In two patients the bronchospasm developed in spite of thiazinamium. In one (J.D.) the fall in PEF was almost identical to that observed without the drug. 61.3 and 73.6%, respectively, below the initial level. The second patient (A.Z.) benefited par tially from thiazinamium. In the group as a whole the average fall in PEF was 14%. The measurements taken at the 45th min after the exercise showed the return of PEF to the pre-exercise level. Exercise Preceded hy Atropine The study was done in 10 patients who benefited completely from thiazinamium. The mean initial PEF averaged 236 l/min and increased at the 5th min after the atropine to 289 l/min. The atropine did not protect eight patients, the fall in PEF being from a few percent more to 21% less than that observed without protection. Two pa tients benefited from the atropine to the same extent as from thiazinamium the fall in PEF being 1.5 and 10%, respectively. The effects of exercise alone on PEF and the protecting effect of thiazinamium or atropine are presented in figure 1.
Discussion One of the proposed mechanisms for EIB is a humoral one. According to it, an as yet unidentified bronchoconstricting fac tor is released during the exercise. There is
Downloaded by: Lund University Libraries 130.235.66.10 - 1/1/2019 5:52:24 PM
PEFJ l/mm
33
34
Although the presented results are con sistent with the histaminic theory of EIB. the lack of benefit from thiazinamium ob served in one patient as well as protection obtained by means of the atropine in two patients and the conflicting results of the previous studies on the mechanism of the EIB, raise the question of the uniformity of the symptoms labelled as the exercise-in duced bronchoconstriction. References 1 Anderson, S. D.: Silverman, M.; König. P.. and Godfrey. S.: Exercise-induced asthma. Br. J. Dis. Chest 69: 1-39 (1975). 2 Booij-Noord. H.: Orie. N. G. M.; Berg. W. C.. and De Vries, K.: Results of provocation of human bronchial airways with allergic and non-allergic sti muli and of drug protection tests; in Bronchitis. III. pp. 316-330 (Royal Vangorcum Publisher, Assen 1970). 3 Booij-Noord, M.: Orie. N. G. M.:Ten Cate. H. J.; Sloots. S.. and Bolt, D.: The influence of various drugs on the vital capacity of asthmatics. Int. Archs Allergy appl. Immun. 10: 321-341 (1957). 4 Borg, G. and Lindercoln, H.: Preceivcd exertion and pulse rate during graded exercise in various age groups. Acta med. scand., suppl. 472. pp. 194— 206(1967). 5 Cox, J. S. G.: Review of chemistry, pharmacology, toxicity, metabolism, side effects, anti-allergic properties in vitro and in vivo of disodium cromo glycate; in Disodium cromoglycate in allergic air ways disease, pp. 13-25 (Butterworths. London 1970). 6 Davies, S. E.: Effect of disodium cromoglycate on exercise-induced asthma. Br. med. J. Hi: 593-594 (1968). 7 Granerus, G.; Simonsson, B. G.; Skoogh. B. E.. and Wetterquist. H.: Exercise-induced broncho constriction and histamine release. Scand. J. Resp. Dis. 52: 131-136(1971). 8 Herxheimer, H.: Hyperventilation asthma. Lancet /V83-87 (1964). 9 Jones, R. S.; Wharton. M. J.. and Buston. M. H.: The place of physical exercise and bronchodilator Downloaded by: Lund University Libraries 130.235.66.10 - 1/1/2019 5:52:24 PM
some indirect evidence provided by the good protecting results obtained with diso dium cromoglycate that a histamine could play a role of that mediating factor as it is supposed that disodium cromoglycate pre vents the releasing of histamine from the mast cells [5]. The results of this study sup port that view. The complete protection ob tained with thiazinamium in 12 from 14 pa tients and a partial protection in one shows that effects of that drug were even better than those obtained with disodium cromo glycate [12, 13]. The protecting effect of thiazinamium seems to be due to its antihistaminic prop erty and not to the parasympatholytic one. Of 10 patients who benefited completely from thiazinamium eight reacted with bronchospasm when exercise was preceded by atropine given in a high dose. The results of other studies also showed that atropine had rather poor protecting effects [9, 14], The results of this study suggest that the EIB may be mediated by histamine. Al though Granerus el at. [7] did not find pa tients developing EIB in either an increase of the histamine level in the blood or the increase of its metabolites in urine their re sults did not exclude the possibility that lo cally in the lung tissue the histamine level could have been increased. The results ob tained by Booij-Noord et al. [2] point also to the histamine as a mediator of EIB. They have found that thiazinaminum pro tects against bronchospasm induced by inhalation of an allergen. The EIB and the allergen-induced bronchoconstriction closely resemble each other clinically. It is assumed that allergen-induced broncho spasm is a result of an immunologic reac tion type I with a histamine as a mediating agent.
Zieliriski/Chodosowska
Exercise-Induced Bronchoconstriction. Prevention with an Antihistamine
11
12
13
14
Strick, L.: Exercise-induced bronchospasm: effect of adrenergic or cholinergic blockage. J. Allergy 40: 93-99 (1967). 15 Wright. B. M. and McKcrrow, C. B.: Maximum forced expiratory flow rate as a measure of ventila tory capacity. With a description of a new portable instrument for measuring it. Br. med. J. ii: 10411047 (1959). Received: June 3. 1975 Accepted: August 3, 1975
J. Zielitiski, Department of Medicine. Institute of Tuberculosis, Plocka 26. 01-138 Warszawa (Po land)
Downloaded by: Lund University Libraries 130.235.66.10 - 1/1/2019 5:52:24 PM
10
drugs in the assessment of the asthmatic child. Archs Dis. Childh. 38: 539-545 (1963). McNeil. R. S.: Nairn. J. R.; Millar, J. S.. and In gram, C. G.: Exercise-induced asthma. O. J. Med. 35: 55-67 (1966). McCarthy. O. R.: The prevention of exercise-in duced asthma. Br. J. Dis. Chest 66: 133-140 (1972). Muittari. A. and Kreus. K. E.: Disodium cromoglycate in exercise-induced asthma. Br. med. J. iv: 170(1969). Poppius, H.: Muittari. A.; Kreus. K. E.: Korhonen. O., and Viljanen. A.: Exercise asthma and disodium cromoglycate. Br. med. J. iv: 337-339 (1970). Sly. R. M.; Heimlich. E. M.: Busscr, R. J.. and
35
