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Response to frequent low doses of nebulized salbutamol in acute asthma
672
Clinical and laboratory observations
of cystic fibrosis: Ticarcillin-tobramycin, azlocillin-tobramycin and azlocillin-placebo. J Infect Dis 147:559, 1983. 5. pennington J, Wolff S, Puziss M: Summary of a workshop on infections in patients with cystic fibrosis. J Infect Dis 140:252, 1979. 6. Is!es A, MaClusky J, Corey M, Gold R, Prober C, Fleming P, Levison H: Pseudomonas cepacia infections in cystic fibrosis: Aia emerging problem. J PEDIATR104:206, 1984. 7. Mastella G, Agostini M, Barlocco G, et al: Alternative
The Journal of Pediatrics April 1985
antibiotics for the treatment of Pseudomonas infections in cystic fibrosis. J Antimicrob Chcmother 12(Suppl A):297, 1983. 8. Shwachman H, Kulczycki LL: Long-term study of one hundred five patients with cystic fibrosis. Am J Dis Child 96:6, 1958. 9. Brasfield D, Hicks G, Soong S, Tiller R: The chest roentgenogram in cystic fibrosis: A new Scoring system. Pediatrics 63:24, 1979.
Response to frequent low doses o f nebulized salbutamol in acute asthma Colin F. R0bertson, M.B., Freda Smith, Raphael Beck, M.D., and Henry Levison, M.D. T o r o n t o , Ontario, C a n a d a
M A N y STUDIES have shown inhaled specific beta-2 agonists to be the preferred treatment for acute asthma, being superior to parenteral administration of epinephrine and aminophylline. 1-3 but little has been done to determine the optimum use of nebulized beta-2 agents. The duration of bronchodilation is dependent on the dose administered 4 and the initial physiologic state. In patients with markedly increased smooth muscle tone. intensity and duration of bronchodilation will be decreased, s~ and therefore more frequent administration may be required. In children, common prescribing information7 suggests a dosage interval of 4 hours, although in our hospital it is common practice to reduce the dosage interval to 1 or 2 hours when necessary. However. even with this short dosage interval, it was noted that in some patients severe asthma improves initially, but then becomes worse before the next dose is due. Our study was designed to determine the benefit of frequent administration of low doses of inhaled salbutamol in the initial management of acute asthma in children. METHODS Children aged 6 years or older brought to the Emergency Department with an acute attack of asthma from From the Department of Pediatrics. The Hospital Jbr Sick Children. Submitted for publication May 24. 1984: accepted Sept 28. 1984. Reprint requests: H. Levison. M.D.. The Hospital (or Sick Children. 555 University Ave.. Toronto. Ontario. Canada M5G I)(8.
December 1983 to February 1984 were initially asked to perform simple tests of lung function, including peak expiratory flow rate, forced expiratory volume in one secon d , and forced vital capacity. These were performed on a small, hand-held battery-operated turbine spirometer (P. K. Morgan, Kent, England). The best of three attempts was recorded, and results expressed as percent of predicted value for height, s Those children who could comply with the above tests and had an initial FEV~ <50% of that predicted were entered into the study. Approval by the hospital's H u m a n Ethics Committee and patient or parental consent were obtained. Patients were entered into one of two treatment groups. Grou p 1 consisted of patients brought to the Emergency DePartment on even days of the month, and group 2 on uneven days. Patients in group 1 were given salbutamol 0.15 m g / k g (0.03 ml/kg of the 5% respiratory solution), up to a maximum of 5 mg, at 1-hour intervals for a total of three doses. 7 Group 2 patients were given salbutmol 0.15 mg/kg initially, then 0.05 mg/kg (up to a maximum of 1.7 rag) at 20-minute intervals for a total of six doses (Figure). The salbutamol was added to 2 ml 0.9% saline solution and administered through a nebulizer (Up-Draft II NebU-Mist; H u d s o n Oxygen Therapy Sales Co., Temecula, Calif.) with a continuous flow oxygen output of 5 to 6 L / m i n (mass median diameter 3.18 #m (85%), geometric standard deviation 1.69). Assessment of pulse, blood pressure, respiratory rate, wheezing score, and lung function was made at 20-minute intervals. Wheezing score was as follows: 0, no wheezing; 1,
Volume 106 Number 4
Clinical a n d taborato~'y observations
673
35 3O .-_o
jof
13 13-
25
!/
=* 20 d:l
E 15 o
g =
I
10
O
:; iii ii
*
p<0.05
5
A 9
9 zx
zx
~
,
0
2;
40
9 ~
z~
zx
,
~
so 80 ,oo Time in minutes
,2~
II
Figure. FEV1 (% predicted + SEM) before and at 20-minute intervals after salbutamol 0.15 mg/kg ( A ) and 0.05 mg/kg (A) in group l (e) and group 2 (O). Wheezing (O) score significantly lower (P <0.01) than in group l.
wheezing heard only with a stethoscope; 2, audible wheezing during quiet breathing; 3, obvious wheezing with dyspnea; 4, respiratory distress with obvious use of accessory muscles. Results were analyzed using nonpaired t tests and analysis of variance. RESULTS Thirty-three children, ages 6 to 17 years, were entered into the study (16 in group 1, 17 in group 2). The two groups were similar for age, duration Of asthma, and initial FEV~ (Table). Both groups had a similar response to the initial dose of salbutamol, with an improvement in FEV~ to 44.5% _+ 3.9% and 46.7% _+ 5.0% predicted for groups 1 and 2, respectively, at 20 minutes (Figure). Thereafter, all the patients in group 2 continued to improve during the first hour, whereas 30% in group 1, after an initial improvement at 20 minutes, showed deterioration of at least 15% in FEVt prior to the next dose. At 60 minutes, FEV~ in group 2 had improved by 84%, whereas in group 1 it had only improved by 38% (P < 0.05) (Figure). After 60 minutes, despite further frequent doses of salbutamol, patients in group 2 improved only a further 9%, to achieve a mean FEV~ of 60% predicted. Gi'oup 1 achieved an improvement of 19%, to reach a mean FEV, of 50% predicted. Wheezing scores improved in both groups, with group 2 showing significantly more improvement than
Table. Clinical characteristics
Age (yr) Duration of asthma (yr) Regular medication Theophylline Beta-2 agents Cromoglycate Steroids None This attack Duration <24 hours Beta-2 agent within 6 hours Initial FEVI
Group I (n = 16)
Group 2 (n ~- 17)
9.8 +_ 3.4 6.0 • 3.05
9.7 -+ 3.9 6.4 +- 3.8
10 6 3 2 5
7 4 1 1 8
10 11 31 _+ 2.7
14 8 30 ___2.4
group 1 at 120 minutes (Figure). The overall outcome for both groups, as demonstrated by final FEV~ (using oneway analysis of variance) and admission rates (by chi square analysis), was not significantly different. Of the 17 patients taking theophylline, only six had therapeutic levels (10 to 20 rag/L). As a group, they did not show a different pattern of response than did those not given theophylli~e, Side effects of therapy were mild in both groups. Mild tremor was the commonest side effect, seen in eight patients in group 1 and nine"~n group 2. Two chi!dren in group 2 vomited at the end of the study, but had otherwise demonstrated an excellent clinical response and
674
Clinical and laboratory observations
were discharged. The one child who became mildly hyperactive had a history of similar reactions to salbutamol in the past. There were no significant changes in blood pressure and pulse. DISCUSSION We evaluated two regimens of delivering nebulized salbutamol in acute asthma in which the total dose remained the same. The more frequent administration in group 2 resulted in a smooth rise in FEV~, to achieve an earlier peak response, which was maintained throughout the study, compared with the fluctuating course seen in group 1. The earlier peak response seen in patients in group 2 could result from more effective deposition of the drug throughout the airways. The bronchodilation that follows the initial dose allows more distal deposition of particles during further dosing, resulting in dilation of smaller airways, and the short dosage interval prevents any deterioration of clinical status. Reilly et al? have shown that suboptimal doses of beta-2 agents produce adequate bronchodilation but that the duration is much reduced. The small dose that is delivered to the peripheral airways, because of the severity of airway obstruction in acute asthma, c o u l d account for the short duration of effect seen in the 30% of patients in group 1 who showed FEV~ deterioration of at least 15% at 1 hour, after their initial, improvement. In group 2 patients, a plateau was achieved at 60 minutes, when FEV~ had improved to between 55% and 60% of predicted normal values. The inability to improve FEV~ further with repeated doses of salbutamol suggests that the residual air flow limitation may be related to factors unresponsive to beta-2 bronchodilat0rs , such as mucosal oedema, increased secretions, and ch01inergic bronchomotor tone. The use of the hand-held portable spirometer, which gives a digital readout of peak expiratory flow rate, F E V , and forced vital capacity, is very convenient for emergency room and bedside use. Its accuracy had been checked in our laboratory and elsewherefl and shows excellent correlation with more complex instruments. T h e r e has been much controversy regarding the dangers of frequent use of inhaled beta-2 agents, which has resulted in an ill-founded fear of these agents by medical practitioners, thereby denying patients adequate therapy. ~~ The safety of frequent use of inhaled beta-2 agents has been
The Journal of Pediatrics April !985
demonstrated in our study, and is confirmed by the high doses of salbutamol used intravenously elsewhere, lz The danger occurs when a patient with severe asthma fails to respond to inhaled medication despite frequent use and the severity of the asthma goes unrecognized by either the patient or the attending physician. The frequent use of nebulized salbutamol is safe, results in an earlier maximal response, and prevents deterioration between doses. Although it is not necessarY for the routine treatment of acute asthma, in those patients with severe acute airways obstruction, aggressive treatment with frequent doses of salbutamol every 20 minutes for the first hour is a superior method of achieving early, maximal bronchodilation. We thank Dr. J. Fallis, Director of Emergency Services, and his staff for their cooperation in this study. REFERENCES 1. Ben-Zvi Z, Lain C, Hoffman J, Teets-Grimm K, Kattan M: An evaluation of the initial treatment of acute asthma. Pediatrics 70:348, 1982. 2. Becker AB, Nelson NA, Simons FER: Inhaled salbutamol vs injected epinephrine in the treatment of acute asthma in children. J PEDIATR 102:465, 1983. 3. Tinkleman DG, Vanderpool GE, Carroll MS, et al: Comparison of nebulized terbutaline and subcutaneous epinephrine in the treatment of acute asthaa. Ann Allergy 50:398, 1983. 4. Reilly PA, Yahav J, Mindorff C, Kazim F, Levison H: Dose response characteristics of nebulized fenoterol in asthmatic children. J PEDIATR 103:i21, 1983. 5. Stenfield GM, Hodson MEI Clark SW, et al: Patterns of response to isoprenaline in asthma patients. Br J Dis Chest 69:273, 1975. 6. Rebuck AS, Read J: Assessment and management of severe asthma. Am J Med 51:788, 1971. 7. Phelan PD, Landau M, Olinsky A: Respiratory illness in children, ed 2. Boston, 1982, Blackwell Scientific Publications, p 188. 8. Weng TR, Levison H: Standards of pulmonary function in children. Am Rev Respir Dis 99:879, 1969. 9. Chowienczyk P J, Lawson CP: Pocket-sized device for measur!ng forced expiratory flow volume in one second and forced vital capacity. Br Med J 285:15, 1982. 10. Crompton GK: Illogical warning on Ventolin inhalers. Br Med J 288:1231, 1984. 11. Simon DNK, Russel G: Illogical warning on Ventolin inhalers. Br Med J 288:1614, 1984. 12. Bohn D, Holtby H, Mullins, Edmonds J, Barker G: The management of status asthmaticus with intravenous salbuta-mol in children. Am Rev Respir Dis 129(4, part 2): A206, 1984.
Clinical and laboratory observations
of cystic fibrosis: Ticarcillin-tobramycin, azlocillin-tobramycin and azlocillin-placebo. J Infect Dis 147:559, 1983. 5. pennington J, Wolff S, Puziss M: Summary of a workshop on infections in patients with cystic fibrosis. J Infect Dis 140:252, 1979. 6. Is!es A, MaClusky J, Corey M, Gold R, Prober C, Fleming P, Levison H: Pseudomonas cepacia infections in cystic fibrosis: Aia emerging problem. J PEDIATR104:206, 1984. 7. Mastella G, Agostini M, Barlocco G, et al: Alternative
The Journal of Pediatrics April 1985
antibiotics for the treatment of Pseudomonas infections in cystic fibrosis. J Antimicrob Chcmother 12(Suppl A):297, 1983. 8. Shwachman H, Kulczycki LL: Long-term study of one hundred five patients with cystic fibrosis. Am J Dis Child 96:6, 1958. 9. Brasfield D, Hicks G, Soong S, Tiller R: The chest roentgenogram in cystic fibrosis: A new Scoring system. Pediatrics 63:24, 1979.
Response to frequent low doses o f nebulized salbutamol in acute asthma Colin F. R0bertson, M.B., Freda Smith, Raphael Beck, M.D., and Henry Levison, M.D. T o r o n t o , Ontario, C a n a d a
M A N y STUDIES have shown inhaled specific beta-2 agonists to be the preferred treatment for acute asthma, being superior to parenteral administration of epinephrine and aminophylline. 1-3 but little has been done to determine the optimum use of nebulized beta-2 agents. The duration of bronchodilation is dependent on the dose administered 4 and the initial physiologic state. In patients with markedly increased smooth muscle tone. intensity and duration of bronchodilation will be decreased, s~ and therefore more frequent administration may be required. In children, common prescribing information7 suggests a dosage interval of 4 hours, although in our hospital it is common practice to reduce the dosage interval to 1 or 2 hours when necessary. However. even with this short dosage interval, it was noted that in some patients severe asthma improves initially, but then becomes worse before the next dose is due. Our study was designed to determine the benefit of frequent administration of low doses of inhaled salbutamol in the initial management of acute asthma in children. METHODS Children aged 6 years or older brought to the Emergency Department with an acute attack of asthma from From the Department of Pediatrics. The Hospital Jbr Sick Children. Submitted for publication May 24. 1984: accepted Sept 28. 1984. Reprint requests: H. Levison. M.D.. The Hospital (or Sick Children. 555 University Ave.. Toronto. Ontario. Canada M5G I)(8.
December 1983 to February 1984 were initially asked to perform simple tests of lung function, including peak expiratory flow rate, forced expiratory volume in one secon d , and forced vital capacity. These were performed on a small, hand-held battery-operated turbine spirometer (P. K. Morgan, Kent, England). The best of three attempts was recorded, and results expressed as percent of predicted value for height, s Those children who could comply with the above tests and had an initial FEV~ <50% of that predicted were entered into the study. Approval by the hospital's H u m a n Ethics Committee and patient or parental consent were obtained. Patients were entered into one of two treatment groups. Grou p 1 consisted of patients brought to the Emergency DePartment on even days of the month, and group 2 on uneven days. Patients in group 1 were given salbutamol 0.15 m g / k g (0.03 ml/kg of the 5% respiratory solution), up to a maximum of 5 mg, at 1-hour intervals for a total of three doses. 7 Group 2 patients were given salbutmol 0.15 mg/kg initially, then 0.05 mg/kg (up to a maximum of 1.7 rag) at 20-minute intervals for a total of six doses (Figure). The salbutamol was added to 2 ml 0.9% saline solution and administered through a nebulizer (Up-Draft II NebU-Mist; H u d s o n Oxygen Therapy Sales Co., Temecula, Calif.) with a continuous flow oxygen output of 5 to 6 L / m i n (mass median diameter 3.18 #m (85%), geometric standard deviation 1.69). Assessment of pulse, blood pressure, respiratory rate, wheezing score, and lung function was made at 20-minute intervals. Wheezing score was as follows: 0, no wheezing; 1,
Volume 106 Number 4
Clinical a n d taborato~'y observations
673
35 3O .-_o
jof
13 13-
25
!/
=* 20 d:l
E 15 o
g =
I
10
O
:; iii ii
*
p<0.05
5
A 9
9 zx
zx
~
,
0
2;
40
9 ~
z~
zx
,
~
so 80 ,oo Time in minutes
,2~
II
Figure. FEV1 (% predicted + SEM) before and at 20-minute intervals after salbutamol 0.15 mg/kg ( A ) and 0.05 mg/kg (A) in group l (e) and group 2 (O). Wheezing (O) score significantly lower (P <0.01) than in group l.
wheezing heard only with a stethoscope; 2, audible wheezing during quiet breathing; 3, obvious wheezing with dyspnea; 4, respiratory distress with obvious use of accessory muscles. Results were analyzed using nonpaired t tests and analysis of variance. RESULTS Thirty-three children, ages 6 to 17 years, were entered into the study (16 in group 1, 17 in group 2). The two groups were similar for age, duration Of asthma, and initial FEV~ (Table). Both groups had a similar response to the initial dose of salbutamol, with an improvement in FEV~ to 44.5% _+ 3.9% and 46.7% _+ 5.0% predicted for groups 1 and 2, respectively, at 20 minutes (Figure). Thereafter, all the patients in group 2 continued to improve during the first hour, whereas 30% in group 1, after an initial improvement at 20 minutes, showed deterioration of at least 15% in FEVt prior to the next dose. At 60 minutes, FEV~ in group 2 had improved by 84%, whereas in group 1 it had only improved by 38% (P < 0.05) (Figure). After 60 minutes, despite further frequent doses of salbutamol, patients in group 2 improved only a further 9%, to achieve a mean FEV~ of 60% predicted. Gi'oup 1 achieved an improvement of 19%, to reach a mean FEV, of 50% predicted. Wheezing scores improved in both groups, with group 2 showing significantly more improvement than
Table. Clinical characteristics
Age (yr) Duration of asthma (yr) Regular medication Theophylline Beta-2 agents Cromoglycate Steroids None This attack Duration <24 hours Beta-2 agent within 6 hours Initial FEVI
Group I (n = 16)
Group 2 (n ~- 17)
9.8 +_ 3.4 6.0 • 3.05
9.7 -+ 3.9 6.4 +- 3.8
10 6 3 2 5
7 4 1 1 8
10 11 31 _+ 2.7
14 8 30 ___2.4
group 1 at 120 minutes (Figure). The overall outcome for both groups, as demonstrated by final FEV~ (using oneway analysis of variance) and admission rates (by chi square analysis), was not significantly different. Of the 17 patients taking theophylline, only six had therapeutic levels (10 to 20 rag/L). As a group, they did not show a different pattern of response than did those not given theophylli~e, Side effects of therapy were mild in both groups. Mild tremor was the commonest side effect, seen in eight patients in group 1 and nine"~n group 2. Two chi!dren in group 2 vomited at the end of the study, but had otherwise demonstrated an excellent clinical response and
674
Clinical and laboratory observations
were discharged. The one child who became mildly hyperactive had a history of similar reactions to salbutamol in the past. There were no significant changes in blood pressure and pulse. DISCUSSION We evaluated two regimens of delivering nebulized salbutamol in acute asthma in which the total dose remained the same. The more frequent administration in group 2 resulted in a smooth rise in FEV~, to achieve an earlier peak response, which was maintained throughout the study, compared with the fluctuating course seen in group 1. The earlier peak response seen in patients in group 2 could result from more effective deposition of the drug throughout the airways. The bronchodilation that follows the initial dose allows more distal deposition of particles during further dosing, resulting in dilation of smaller airways, and the short dosage interval prevents any deterioration of clinical status. Reilly et al? have shown that suboptimal doses of beta-2 agents produce adequate bronchodilation but that the duration is much reduced. The small dose that is delivered to the peripheral airways, because of the severity of airway obstruction in acute asthma, c o u l d account for the short duration of effect seen in the 30% of patients in group 1 who showed FEV~ deterioration of at least 15% at 1 hour, after their initial, improvement. In group 2 patients, a plateau was achieved at 60 minutes, when FEV~ had improved to between 55% and 60% of predicted normal values. The inability to improve FEV~ further with repeated doses of salbutamol suggests that the residual air flow limitation may be related to factors unresponsive to beta-2 bronchodilat0rs , such as mucosal oedema, increased secretions, and ch01inergic bronchomotor tone. The use of the hand-held portable spirometer, which gives a digital readout of peak expiratory flow rate, F E V , and forced vital capacity, is very convenient for emergency room and bedside use. Its accuracy had been checked in our laboratory and elsewherefl and shows excellent correlation with more complex instruments. T h e r e has been much controversy regarding the dangers of frequent use of inhaled beta-2 agents, which has resulted in an ill-founded fear of these agents by medical practitioners, thereby denying patients adequate therapy. ~~ The safety of frequent use of inhaled beta-2 agents has been
The Journal of Pediatrics April !985
demonstrated in our study, and is confirmed by the high doses of salbutamol used intravenously elsewhere, lz The danger occurs when a patient with severe asthma fails to respond to inhaled medication despite frequent use and the severity of the asthma goes unrecognized by either the patient or the attending physician. The frequent use of nebulized salbutamol is safe, results in an earlier maximal response, and prevents deterioration between doses. Although it is not necessarY for the routine treatment of acute asthma, in those patients with severe acute airways obstruction, aggressive treatment with frequent doses of salbutamol every 20 minutes for the first hour is a superior method of achieving early, maximal bronchodilation. We thank Dr. J. Fallis, Director of Emergency Services, and his staff for their cooperation in this study. REFERENCES 1. Ben-Zvi Z, Lain C, Hoffman J, Teets-Grimm K, Kattan M: An evaluation of the initial treatment of acute asthma. Pediatrics 70:348, 1982. 2. Becker AB, Nelson NA, Simons FER: Inhaled salbutamol vs injected epinephrine in the treatment of acute asthma in children. J PEDIATR 102:465, 1983. 3. Tinkleman DG, Vanderpool GE, Carroll MS, et al: Comparison of nebulized terbutaline and subcutaneous epinephrine in the treatment of acute asthaa. Ann Allergy 50:398, 1983. 4. Reilly PA, Yahav J, Mindorff C, Kazim F, Levison H: Dose response characteristics of nebulized fenoterol in asthmatic children. J PEDIATR 103:i21, 1983. 5. Stenfield GM, Hodson MEI Clark SW, et al: Patterns of response to isoprenaline in asthma patients. Br J Dis Chest 69:273, 1975. 6. Rebuck AS, Read J: Assessment and management of severe asthma. Am J Med 51:788, 1971. 7. Phelan PD, Landau M, Olinsky A: Respiratory illness in children, ed 2. Boston, 1982, Blackwell Scientific Publications, p 188. 8. Weng TR, Levison H: Standards of pulmonary function in children. Am Rev Respir Dis 99:879, 1969. 9. Chowienczyk P J, Lawson CP: Pocket-sized device for measur!ng forced expiratory flow volume in one second and forced vital capacity. Br Med J 285:15, 1982. 10. Crompton GK: Illogical warning on Ventolin inhalers. Br Med J 288:1231, 1984. 11. Simon DNK, Russel G: Illogical warning on Ventolin inhalers. Br Med J 288:1614, 1984. 12. Bohn D, Holtby H, Mullins, Edmonds J, Barker G: The management of status asthmaticus with intravenous salbuta-mol in children. Am Rev Respir Dis 129(4, part 2): A206, 1984.