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A place for ipratropium bromide in the treatment of severe acute asthma
Br. J. Dis.
Chest
(1985)
79, 374
A PLACE FOR IPRATROPIUM BROMIDE IN THE TREATMENT OF SEVERE ACUTE ASTHMA M. J. WARD*, Department
J. T. MACFARLANE
of Thoracic
Medicine,
Cio NG5
Hospital, 1PB
AND
D. DAVIES
Hucknall
Road,
Nottingham
Summary Twenty-four consecutive patients admitted to hospital with severe acute asthma were studied. Eleven were given 10 mg salbutamol by nebulizer followed 2 hours later by 500 pg of nebulized ipratropium bromide. These patients had a greater response in PEFR than 13 patients given two doses of 10 mg salbutamol 2 hours apart.
Introduction In mild asthma ipratropium bromide inhaled from a pressurized canister is nearly as effective as salbutamol or isoprenaline (Petrie & Palmer 1975; Ruffin et al. 1977). We have shown that in severe acute asthma nebulized ipratropium bromide and salbutamol produce similar increases in mean peak expiratory flow rate of about 50%. When the two drugs were given in sequence 2 hours apart there was more bronchodilatation and the mean expiratory flow rate doubled within 4 hours of admission. The response was not influenced by the order in which the drugs were given (Ward et al. 1981). In that study we used ipratropium bromide and salbutamol in doses which were expected to produce maximal bronchodilatation. It seemed probably that the extra benefit seen after using ipratropium bromide as well as salbutamol was the result of using drugs which acted in different ways. However, it was not certain that equally good results could not be obtained by giving two maximal doses of one drug 2 hours apart. We therefore carried out further studies to see whether this is so. Patients and A4ethods The study lasted 6 months and 25 patients with a mean age of40 years random to double-blind treatment with one oftwo regimens. Numbered by the pharmacy and the patients were given either 10 mg of salbutamol later by 10 mg of salbutamol, or 10 mg salbutamol on admission and
*Present Medicine,
address: Llandough
Department Hospital,
of Tuberculosis Penarth, South
& Chest Glamorgan
(range 14- 75) were allocated at treatment packs were made up on admission followed 2 hours 500 pg of ipratropium bromide 2
Diseases, University CF6 1Xx.
of Wales
College
of
Ward, kfacfarlane,
Davies: Ipratropium
Bromide in Severe Acute Asthma
375
Table I. Patient data for each study group Study treatment
Patients
No in group No. male Age (years&so) Atopic No. using maintenance inhaled corticosteroid Oral prednisolone before admission Mean Pao, on admission breathing air kPa Pulse rate on admission
(beats/min)
(SEM)
Salbutamol
Salbutamolf ipratropium bromide
n=13 3 42t21 9 2 3 7.9 (0.25) 114
n=ll 4 38k39 6 3 3 7.4 (0.23) 118
hours later. One patient in the group allocated to salbutamol and ipratropium bromide was w-ithdrawn soon after receiving salbutamol because of worsening symptoms. All had an arterial oxygen pressure under 9.3 kPa (68 mmHg) and a peak expiratory flow rate (PEFR) b e 1ow 25% of the predicted value. The PEFR was measured with a Wright peak flow meter, the best of three efforts being recorded. The PEFR and pulse rate were measured before treatment and hourly for 4 hours. Salbutamol and ipratropium bromide were given using a Hudson nebulizer fitted with a mouthpiece and driven by an air cylinder at 8 litres/min. Both solutions were made up to 4 ml with 0.9% saline and nebulized until all the solution was used. The doses of salbutamol (10 mg) and ipratropium bromide (500 pg) were chosen to produce maximal effect (Walters et al. 1981; Ward et al. 1981). No other bronchodilators were given. All patients received hydrocortisone (6 mg/kg) by intravenous injection on admission.
Results Thirteen patients received salbutamol on admission followed by more salbutamol2 hours later. The mean PEFR rose from 90 to 127 litres/min after the first treatment and to 135 litres/min after the second, a total response of 50% (Fig. 1). After the second treatment the PEFR improved by more than 15% in only four of the 13 patients. Eleven patients had salbutamol on admission and ipratropium bromide 2 hours later. The mean PEFR in this group rose from 93 to 145 litres/min after salbutamol and to 18 1 litres/min after ipratropium bromide, a total response of 95% (Fig. 1). Eight of 11 patients improved by more than 15% after the second nebulization. The response to ipratropium bromide after salbutamol was significant (P < 0.01 paired t-test), whilst that to the second dose of salbutamol was not. In the patients treated with sequential salbutamol the mean pulse rate rose from 114 beats/ min on admission to 120. Five complained of tremor or palpitation. In the group given salbutamol followed by ipratropium bromide the mean pulse rate fell from 118 beats/min on admission to 102. No side effects were noted. There was no difference between the two groups with respect to age or atopic status (Table I). Discussion Salbutamol followed 2 hours later by ipratropium bronchodilatation than sequential treatments with
bromide produced greater salbutamol. In those given
376
Br. J. Dis. Chest: Vol. 79 No. 4
191t-
18ClI I
!I---_
I
,
17cl-
I ,
-r
160I-
I I
I I’ I
I
I I’
150I-
140 ': f = Ei 2
130
120
110
100
90
80
1
I
I
I
I
I
0
1
2
3
4
Time (hour) Fig. 1. Changes in peak expiratory flow rate (mean i SEM) after administration ofnebulized salbutamol and ipratropium bromide. Response to the two nebulizations are indicated by __ for salbutamol and ---for ipratropium bromide
salbutamol alone the second nebulization produced only a marginal increase PEFR which was not statistically significant. It also led to tremor or palpitations five of 13 patients and a rise in the mean pulse rate.
in in
Ward, Macfarlane,
Davies: Ipratropium
Bromide in Severe Acute Asthma
377
In contrast ipratropium bromide given 2 hours after salbutamol produced a further significant improvement, the mean PEFR increasing by 95% within 4 hours of admission, results almost identical with our earlier study (Ward et al. 1981). There were no side effects and pulse rate fell. It therefore appears that in acute severe asthma it is beneficial to use two drugs which act in different ways: salbutamol stimulating beta-adrenoceptors and ipratropium bromide blocking parasympathetic receptors. In mild asthma there is little advantage from adding ipratropium bromide to salbutamol (Petrie & Palmer is may be because in that situation salbutamol produces 1975; R&in et al. 1977). Th almost complete bronchodilatation, leaving little room for ipratropium bromide to act. However, patients with acute severe asthma may benefit from both drugs because there may be reduced beta-adrenoceptor function (Parker & Smith 1973; Brooks et al. 1979) and increased parasympathetic reflex airway activity (Boushey et al. 1980). The results could also be explained by assuming that the salbutamol only group had more severe asthma which was therefore less responsive to treatment. The mean initial PEFR (90 litres/min) was marginally below the salbutamol/ipratropium bromide group (93 litres/min). After the first nebulization the PEFR rose by 41% in one hour and by 33% in 2 hours in the salbutamol group. The corresponding rises in the salbutamol/ipratropium group were 55.9% and 55.9% respectively (Fig. 1) and these differences were not significant. There was nothing else to indicate greater severity of asthma in those given salbutamol only; the mean pulse rate and Pao, on admission were very similar in each group (Table I). Also the elderly, non-atopic, and those using maintenance corticosteroid therapy have been shown to have a slow recovery from severe asthma Uenkins et al. 1981) but these factors occurred with similar frequency in each treatment group (Table I). At the time of discharge from hospital the mean PEFR (% predicted) had risen in the salbutamol only group to 305 litres/min (63%) and in the salbutamollipratropium group to 295 litres/min (60%). Most of the improvement in these asthmatics may be attributed to the bronchodilators, because hydrocortisone in severe acute asthma produces little increase in PEFR in 4 hours (Collins et al. 1975; McFadden et al. 1976). For the best results in severe acute asthma it may be necessary to use two drugs which act in different ways but with an interval between the first and second nebulizations. Further studies are desirable to determine whether salbutamol and ipratropium bromide should be mixed prior to nebulization.
References Boushey, H. A., Holtzman, M. J., Sheller, J. R. et al. (1980) State ofthe art: Am. Rev. resp. Dis. 121, 389-413. Brooks, S. M., McGowan, K., Bernstein, L. et al. (1979) Relationship adrenergic receptors in lymphocytes and disease severity in asthma. 40 l-406. Collins, J. V., Clark, T. J. H., Brown, D. et al. (1975) The use ofcorticosteroids asthma. Q. J. Med. 44, 259-273. Jenkins, P. F., Banfield, 0. F. A. & Smith, A. P. (1981) Predicting recovery Thorax 36, 835-84 1.
bronchial
hyperreactivity.
between number of beta J. Allergy clin. Immunol. 63, in the treatment ofacute from acute severe asthma.
378
Br. J. Dis. Chest:Vol. 79 No. 4
McFadden, E. R., Kiser, R., deGroot, W. J. et al. (1976) A controlled study ofthe effects ofa single dose of hydrocortisone on the resolution of acute attacks of asthma. Am.]. Med. 60, 52-59. Parker, C. W. & Smith, J. W. (1973) Alterations in cyclic adenosine monophosphate metabolism in human bronchial asthma. I Leukocyte responsiveness to p-adrenergic agents. J. clin. Invest. 52, 48-59. Petrie, G. R. & Palmer, K. N. V. (1975) Comparison ofaerosol ipratropium bromide and salbutamol in chronic bronchitis and asthma. Br. med. J. 1, 430-432. Rufhn, R. E., Fitzgerald, J. D. & Roebuck, A. S. (1977) A comparison of the bronchodilator activity of Sch 1000 and salbutamol. J. Allergy clin. Immunol. 59, 136-141. Walters, E. H., Cockroft, A., Grilliths, T., Rocchioccioli, K. & Davies, B. H. (1981) Optimum dose of salbutamol respiratory solution: comparison of three doses with plasma levels. Thorax 77; 625628. Ward, M. J., Fentem, P. H., Roderick Smith, W. H. et al. (1981) Ipratropium bromide in acute asthma. Br. med. J. 282, 598-600.
Chest
(1985)
79, 374
A PLACE FOR IPRATROPIUM BROMIDE IN THE TREATMENT OF SEVERE ACUTE ASTHMA M. J. WARD*, Department
J. T. MACFARLANE
of Thoracic
Medicine,
Cio NG5
Hospital, 1PB
AND
D. DAVIES
Hucknall
Road,
Nottingham
Summary Twenty-four consecutive patients admitted to hospital with severe acute asthma were studied. Eleven were given 10 mg salbutamol by nebulizer followed 2 hours later by 500 pg of nebulized ipratropium bromide. These patients had a greater response in PEFR than 13 patients given two doses of 10 mg salbutamol 2 hours apart.
Introduction In mild asthma ipratropium bromide inhaled from a pressurized canister is nearly as effective as salbutamol or isoprenaline (Petrie & Palmer 1975; Ruffin et al. 1977). We have shown that in severe acute asthma nebulized ipratropium bromide and salbutamol produce similar increases in mean peak expiratory flow rate of about 50%. When the two drugs were given in sequence 2 hours apart there was more bronchodilatation and the mean expiratory flow rate doubled within 4 hours of admission. The response was not influenced by the order in which the drugs were given (Ward et al. 1981). In that study we used ipratropium bromide and salbutamol in doses which were expected to produce maximal bronchodilatation. It seemed probably that the extra benefit seen after using ipratropium bromide as well as salbutamol was the result of using drugs which acted in different ways. However, it was not certain that equally good results could not be obtained by giving two maximal doses of one drug 2 hours apart. We therefore carried out further studies to see whether this is so. Patients and A4ethods The study lasted 6 months and 25 patients with a mean age of40 years random to double-blind treatment with one oftwo regimens. Numbered by the pharmacy and the patients were given either 10 mg of salbutamol later by 10 mg of salbutamol, or 10 mg salbutamol on admission and
*Present Medicine,
address: Llandough
Department Hospital,
of Tuberculosis Penarth, South
& Chest Glamorgan
(range 14- 75) were allocated at treatment packs were made up on admission followed 2 hours 500 pg of ipratropium bromide 2
Diseases, University CF6 1Xx.
of Wales
College
of
Ward, kfacfarlane,
Davies: Ipratropium
Bromide in Severe Acute Asthma
375
Table I. Patient data for each study group Study treatment
Patients
No in group No. male Age (years&so) Atopic No. using maintenance inhaled corticosteroid Oral prednisolone before admission Mean Pao, on admission breathing air kPa Pulse rate on admission
(beats/min)
(SEM)
Salbutamol
Salbutamolf ipratropium bromide
n=13 3 42t21 9 2 3 7.9 (0.25) 114
n=ll 4 38k39 6 3 3 7.4 (0.23) 118
hours later. One patient in the group allocated to salbutamol and ipratropium bromide was w-ithdrawn soon after receiving salbutamol because of worsening symptoms. All had an arterial oxygen pressure under 9.3 kPa (68 mmHg) and a peak expiratory flow rate (PEFR) b e 1ow 25% of the predicted value. The PEFR was measured with a Wright peak flow meter, the best of three efforts being recorded. The PEFR and pulse rate were measured before treatment and hourly for 4 hours. Salbutamol and ipratropium bromide were given using a Hudson nebulizer fitted with a mouthpiece and driven by an air cylinder at 8 litres/min. Both solutions were made up to 4 ml with 0.9% saline and nebulized until all the solution was used. The doses of salbutamol (10 mg) and ipratropium bromide (500 pg) were chosen to produce maximal effect (Walters et al. 1981; Ward et al. 1981). No other bronchodilators were given. All patients received hydrocortisone (6 mg/kg) by intravenous injection on admission.
Results Thirteen patients received salbutamol on admission followed by more salbutamol2 hours later. The mean PEFR rose from 90 to 127 litres/min after the first treatment and to 135 litres/min after the second, a total response of 50% (Fig. 1). After the second treatment the PEFR improved by more than 15% in only four of the 13 patients. Eleven patients had salbutamol on admission and ipratropium bromide 2 hours later. The mean PEFR in this group rose from 93 to 145 litres/min after salbutamol and to 18 1 litres/min after ipratropium bromide, a total response of 95% (Fig. 1). Eight of 11 patients improved by more than 15% after the second nebulization. The response to ipratropium bromide after salbutamol was significant (P < 0.01 paired t-test), whilst that to the second dose of salbutamol was not. In the patients treated with sequential salbutamol the mean pulse rate rose from 114 beats/ min on admission to 120. Five complained of tremor or palpitation. In the group given salbutamol followed by ipratropium bromide the mean pulse rate fell from 118 beats/min on admission to 102. No side effects were noted. There was no difference between the two groups with respect to age or atopic status (Table I). Discussion Salbutamol followed 2 hours later by ipratropium bronchodilatation than sequential treatments with
bromide produced greater salbutamol. In those given
376
Br. J. Dis. Chest: Vol. 79 No. 4
191t-
18ClI I
!I---_
I
,
17cl-
I ,
-r
160I-
I I
I I’ I
I
I I’
150I-
140 ': f = Ei 2
130
120
110
100
90
80
1
I
I
I
I
I
0
1
2
3
4
Time (hour) Fig. 1. Changes in peak expiratory flow rate (mean i SEM) after administration ofnebulized salbutamol and ipratropium bromide. Response to the two nebulizations are indicated by __ for salbutamol and ---for ipratropium bromide
salbutamol alone the second nebulization produced only a marginal increase PEFR which was not statistically significant. It also led to tremor or palpitations five of 13 patients and a rise in the mean pulse rate.
in in
Ward, Macfarlane,
Davies: Ipratropium
Bromide in Severe Acute Asthma
377
In contrast ipratropium bromide given 2 hours after salbutamol produced a further significant improvement, the mean PEFR increasing by 95% within 4 hours of admission, results almost identical with our earlier study (Ward et al. 1981). There were no side effects and pulse rate fell. It therefore appears that in acute severe asthma it is beneficial to use two drugs which act in different ways: salbutamol stimulating beta-adrenoceptors and ipratropium bromide blocking parasympathetic receptors. In mild asthma there is little advantage from adding ipratropium bromide to salbutamol (Petrie & Palmer is may be because in that situation salbutamol produces 1975; R&in et al. 1977). Th almost complete bronchodilatation, leaving little room for ipratropium bromide to act. However, patients with acute severe asthma may benefit from both drugs because there may be reduced beta-adrenoceptor function (Parker & Smith 1973; Brooks et al. 1979) and increased parasympathetic reflex airway activity (Boushey et al. 1980). The results could also be explained by assuming that the salbutamol only group had more severe asthma which was therefore less responsive to treatment. The mean initial PEFR (90 litres/min) was marginally below the salbutamol/ipratropium bromide group (93 litres/min). After the first nebulization the PEFR rose by 41% in one hour and by 33% in 2 hours in the salbutamol group. The corresponding rises in the salbutamol/ipratropium group were 55.9% and 55.9% respectively (Fig. 1) and these differences were not significant. There was nothing else to indicate greater severity of asthma in those given salbutamol only; the mean pulse rate and Pao, on admission were very similar in each group (Table I). Also the elderly, non-atopic, and those using maintenance corticosteroid therapy have been shown to have a slow recovery from severe asthma Uenkins et al. 1981) but these factors occurred with similar frequency in each treatment group (Table I). At the time of discharge from hospital the mean PEFR (% predicted) had risen in the salbutamol only group to 305 litres/min (63%) and in the salbutamollipratropium group to 295 litres/min (60%). Most of the improvement in these asthmatics may be attributed to the bronchodilators, because hydrocortisone in severe acute asthma produces little increase in PEFR in 4 hours (Collins et al. 1975; McFadden et al. 1976). For the best results in severe acute asthma it may be necessary to use two drugs which act in different ways but with an interval between the first and second nebulizations. Further studies are desirable to determine whether salbutamol and ipratropium bromide should be mixed prior to nebulization.
References Boushey, H. A., Holtzman, M. J., Sheller, J. R. et al. (1980) State ofthe art: Am. Rev. resp. Dis. 121, 389-413. Brooks, S. M., McGowan, K., Bernstein, L. et al. (1979) Relationship adrenergic receptors in lymphocytes and disease severity in asthma. 40 l-406. Collins, J. V., Clark, T. J. H., Brown, D. et al. (1975) The use ofcorticosteroids asthma. Q. J. Med. 44, 259-273. Jenkins, P. F., Banfield, 0. F. A. & Smith, A. P. (1981) Predicting recovery Thorax 36, 835-84 1.
bronchial
hyperreactivity.
between number of beta J. Allergy clin. Immunol. 63, in the treatment ofacute from acute severe asthma.
378
Br. J. Dis. Chest:Vol. 79 No. 4
McFadden, E. R., Kiser, R., deGroot, W. J. et al. (1976) A controlled study ofthe effects ofa single dose of hydrocortisone on the resolution of acute attacks of asthma. Am.]. Med. 60, 52-59. Parker, C. W. & Smith, J. W. (1973) Alterations in cyclic adenosine monophosphate metabolism in human bronchial asthma. I Leukocyte responsiveness to p-adrenergic agents. J. clin. Invest. 52, 48-59. Petrie, G. R. & Palmer, K. N. V. (1975) Comparison ofaerosol ipratropium bromide and salbutamol in chronic bronchitis and asthma. Br. med. J. 1, 430-432. Rufhn, R. E., Fitzgerald, J. D. & Roebuck, A. S. (1977) A comparison of the bronchodilator activity of Sch 1000 and salbutamol. J. Allergy clin. Immunol. 59, 136-141. Walters, E. H., Cockroft, A., Grilliths, T., Rocchioccioli, K. & Davies, B. H. (1981) Optimum dose of salbutamol respiratory solution: comparison of three doses with plasma levels. Thorax 77; 625628. Ward, M. J., Fentem, P. H., Roderick Smith, W. H. et al. (1981) Ipratropium bromide in acute asthma. Br. med. J. 282, 598-600.