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Effect of administration technique on bronchodilator response to fenoterol in a metered-dose inhaler
470
Clinical and laboratory observations
The Journal of Pediatrics March 1983
Clinical and laboratory observations Effect o f administration technique on bronchodilator response to fenoterol in a metered-dose inhaler J. Rivlin, M.D., C. Mindorff, R.N., H. Levison, M.D., F. Kazim, M.Sc., P. Reilly, Ph.D., and G. Worsley, M.B., Ch.B. Toronto, Ont., Canada
IN T H E T R E A T M E N T O F A S T H M A , inhalation offers advantages over other routes of drug administration, because the drug is delivered directly to receptor sites within the bronchial tree. This permits lower doses to be used J; the onset of action is more rapid; 2 and the incidence of adverse effects is reduced/ Pressurized metered-dose inhalers are practical because they are compact, portable, and apparently easy to use. However, there is still disagreement about the optimal technique for achieving maximum drug delivery to the lower respiratory tract, 3and many patients may not receive adequate instruction in the use of the inhalers.4.5 Newman et al. 3 demonstrated maximal bronchodilation with the inhaler in the mouth and the dose delivered during the course of a relatively slow deep inhalation (25 L/rain) followed by a 10-second breath hold. However, Dolovich et al., 6 using a radiolabeled metered-dose aerosol, have shown that the maximum dose to the thoracic airways was achieved by activating the inhaler 4 cm from the wide-open mouth. Both these techniques require that the patient coordinate inhalation with actuation of the aerosol canister. Epstein et al. 4 and many other authors have described difficulties faced by asthmatic patients in coordinating actuation of a pressurized aerosol with inhalation. Paterson and Crompton 5 reported that, despite careful instruction by both physicians and outpatient nurses, 14% of 321 patients still used their inhalers inefficiently. The "space" devices currently being studied have been proposed to
From the Division of Chest Medicine, Research Institute, Hospital for Sick Children. Dr. Rivtin is a Canadian Cystic Fibrosis Foundation Fellow. Reprint requests: Henry Levison, M.D., Pulmonary Tunction Laboratory, Hospital for Sick Children, 555 University Ave., Toronto, Ont., Canada, M5G IX8.
overcome this problem of coordination; they allow children to inhale after actuation of the inhaler.7 However, the impact of specific coordination maneuvers on pulmonary response in asthmatic children has not been evaluated in the absence of these additional devices. Our study was designed to measure the bronchodilator effect of a sympathomimetic aerosol under three different conditions of coordination: optimal, sequential, and exhalation. METHODS
Patient selection. We studied 12 asthmatic children aged 6 to 17 years (mean 11.3 years) who fulfilled the American Thoracic Society criteria for reversible obstructive airway disease? Informed consent was obtained, and the protocol was approved by the hospital internal review board. The children were free of acute wheezing at the time of the study, and the mean forced expiratory volume in one second (FEV~) was 1.68 L (78% predicted) (Table). All patients were receiving bronchodilators and other antiasthmatic medications each day, but these medications were withheld for 12 hours before each study day. Study design. The trial was a three-day, randomized, double-blind crossover study designed to assess the bronchodilation resulting from three different techniques of administration of one puff of a beta-2 agonist aerosol (fenoterol hydrobromide, 200 ~g) from a pressurized canister. Each of the three techniques was performed on each of the three consecutive test days. However, only one of the canisters contained active drug on each day; the other two canisters were identical but contained placebo. The order of treatment was randomized. The three techniques were (1) coordinated." slow inhalation from functional residual capacity (FRC) coordinated with simultaneous activation of the inhaler, followed by breath holding for 10 seconds; (2) sequential: actuation of the inhaler, followed immediately (less than one second)
Volume 102 Number 3
47 1
Clinical and laboratory observations
- - - - COORDINATED .6-
--
SEQUENTIAL
---
UNCOORDINATED
,oo|
---COORDINATED--SEQUENTIAL---UNCOORDiNATED
.5-
80-
.4-
!
I
~. 7 0 -
./"
"........
u-, ~3-
40-
.2-
I
"~ 3 0 -
.1-
I .... I ........
.................
I
0.0 0
310 8I0 910 1~0 TIME AFTER ADMINISTRATION IN MINUTES
20-
I
150
0
0
I
310 6~0 910 120 TiME AFTER ADMINISTRATION IN MINUTES
1~0
Figure. A, Change from baseline in FEV1 (_+SE) for the three techniques of administration. B, Change from baseline for PEFR (_+SE) for the three techniques of administration. by slow inhalation from FRC and breath holding for 10 seconds; (3) uncoordinated." actuation of the inhaler, followed by exhalation from FRC. This technique should prevent drug entering the lungs. Pulmonary function was measured before administration of the drug and 15, 30, 60, and 120 minutes afterward, using a 9 L water-sealed Collins Spirometer (Warren E. Collins, Braintree, Mass.). The functions measured were forced expiratory volume in one second (FEVI), flow rate at 25% of vital capacity (V25), flow rate at 50% of vital capacity (Vs0), and peak expiratory flow rate (PEFR). Bronchodilation was determined by the relative and absolute changes from the baseline (pretreatment) value for each of the measurements. Blood pressure, heart rate, and a visual estimation of tremor were also recorded. Data analysis. The data were subjected to statistical analysis employing analysis of variance and eovariance techniques appropriate to a two-factor repeated-measures model with repeated measures on both factors. This is essentially a parametric method to perform overall matched comparisons of subject responses using the three modes of administration. The Wilcoxon signed-rank test was used to assess differences between coordinated and uncoordinated, sequential and uncoordinated, and coordinated and sequential techniques. RESULTS All 12 patients completed the three days of testing. There were no significant differences in baseline measurements during the trial. Hence we computed change from baseline as an assessment of pulmonary response. Both the coordinated and sequential techniques of inhalation resulted in a significant increase in pulmonary function (Figure). This improvement was observed by 15 minutes
Table. Baseline pulmonary function Measurement
Absolute value
FEV~ (L) V25 (L/sec) Vso (L/sec) PEFR (L/rain)
1.68 _+ 0.16 0.84 _+ 0.14 1.65 _+ 0.21 249 _+ 21.6
% Predicted
78.0 54.1 56.4 75.3
_+ 6.9 _+ 9.2 _+ 8.4 + 6.6
All v a l u e s expressed as m e a n • s t a n d a r d error, n = 12.
after delivery, and was maximal 60 minutes after inhalation. For the uncoordinated technique a much smaller bronchodilator response was observed at 15 minutes, and this slight increase was maintained throughout the observation period. When the pulmonary responses were calculated as percentage change, essentially the same relationships were obtained. These differences among techniques were confirmed when the data were analyzed using analysis of variance. Overall, there was a significant difference among the three methods of administration (P < 0.05) when FEV~, Vs0, and PEFR were compared, whereas V25 yielded a P value of 0.057. The mean increase of 0.13 L in FEVt following the uncoordinated method was significantly different from baseline. To investigate the differences among the three techniques of administration, the absolute changes from baseline at 60 minutes (peak effect) for the four ventilatory function measurements were compared using the Wileoxon test. On the basis of FEV~ and PEFR, both the coordinated and sequential techniques were better than the uncoordinated technique (P < 0.05 for all comparisons). The differences in FEV~ and PEFR between the coordinated and sequential methods were not statistically significant (P > 0.5). Changes in heart rate and blood pressure were small and
472
Clinical and laboratory observations
inconsistent. N o differences related to mode of administration were detected. Tremor effects were slight and not frequent enough to analyze by conventional statistical methods. DISCUSSION In this double-blind randomized study, the bronchodilator response to fenoterol administered by a metered-dose inhaler was similar for both the coordinated and sequential modes of aerosol delivery. In a previous study, Newman et al. 3 measured similar bronchodilator responses after doses given during inhalation at 20%, 50%, or 80% of vital capacity, implying that lung volume at inspiration is not an important variable when considering optimum inhalation technique. However, the bronchodilator effect diminished when the aerosol was given three seconds before inhalation at residual volume (RV). The three-second delay probably resulted in a larger fraction of the dose being deposited in the mouth, leaving less to be inhaled in the airways. An evaluation of aerosol technique by Lawford and McKenzie 9 also showed that inhalation from F R C is as effective as inhaling from RV. Our trial of three degrees of coordinated technique has shown that a short delay between activation and inhalation does not affect bronchodilator response to an aerosol sympathomimetic agent in asthmatic children. N o t unexpectedly, exhalation during aerosol drug delivery virtually eliminates the therapeutic effect of the drug. Most physicians currently advocate a coordinated aerosol technique with open or closed mouth, which occasionally results in patients actually exhaling while attempting this maneuver.~~ We suggest that some leeway be allowed in the execution of these steps of aerosol activation and inhalation. Minimal dyscoordination does not compromise response.
The Journal of Pediatrics March 1983
Furthermore, if a particular individual is unable to perform two maneuvers simultaneously, the sequential techo nique is a reasonable alternative. Because technique need not be perfect, a larger number of children may be able to derive benefit from this route of administration than was previously believed. Painstaking training, extra spacer devices, or orally administered medications should be considered only if there is severe dyscoordination. We thank the staff and patients of the Ontario Crippled Children Center for their cooperation. REFERENCES 1. Sterling GM: Diseases of the respiratory system: Asthma. Br Med J !:1259, 1978. 2. Plit M, Goldman HI, Cassel ML, Zwi S: The bronchodilator action of fenoterol (berotec) in asthma. Med Proc 18:41, 1972. 3. Newman SP, Pavia D, Clarke SW: Simple instructions for using pressurised aerosol bronchodilators. J R Soc Med 73:776, 1980. 4. Epstein SW, Manning CPR, Ashley M J, Corey PN: Survey of the clinical use of pressurized aerosol inhalers. Can Med Assoc J 120:813, I979. 5. Paterson IC, Crompton GK: Use of pressurized aerosols by asthmatic patients. Br Med J 1:76, 1976. 6. Dolovich M, Ruffin RE, Roberts R, Newhouse M: Optimal delivery of aerosols from metered dose inhalers. Chest 80(suppl):911, I981. 7. Ellul-Micallef R, Moren F, Wetterlin K, Hidinger KC: Use of a special inhaler attachment in asthmatic children. Thorax 35:320, 1980. 8. American Thoracic Society: Chronic bronchitis, asthma and pulmonary emphysema: A statement by the Committee on Diagnostic Standards for Nontuberculous Respiratory Disease. Am Rev Respir Dis 85:762, 1962. 9. Lawford P, McKenzie D: Pressurized aerosol technique. Lancet 1:1003, 1981. 10. Shim C, William MH Jr: The adequacy of inhalation of aerosol from canister nebulizers. Am J Med 69:891, 1980.
Reduced theophylline half-life induced by carbamazepine therapy Kathleen R. Rosenberry, Pharm.D., Carmine J. Defusco, M.D., Herbert C. Mansmann, Jr., M.D., Stephen J. McGeady, M.D. Philadelphia, Pa.
From the Division of Allergy and Clinical Immunology, Jefferson Medical College of the Thomas Jefferson University; and the Department of Pharmacy, Children's Hospital of Philadelphia. Reprint requests: Dr. Kathleen R. Rosenberry, Department of Pharmacy, Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104.
MANAGEMENT OF SEIZURE DISORDERS in asthmatic children treated with theophylline poses a therapeutic challenge, because several anticonvulsant drugs are reported to alter theophylline metabolism. ~,2 Carbamazepine (Tegretol) is known to hasten the metabolism of various
Clinical and laboratory observations
The Journal of Pediatrics March 1983
Clinical and laboratory observations Effect o f administration technique on bronchodilator response to fenoterol in a metered-dose inhaler J. Rivlin, M.D., C. Mindorff, R.N., H. Levison, M.D., F. Kazim, M.Sc., P. Reilly, Ph.D., and G. Worsley, M.B., Ch.B. Toronto, Ont., Canada
IN T H E T R E A T M E N T O F A S T H M A , inhalation offers advantages over other routes of drug administration, because the drug is delivered directly to receptor sites within the bronchial tree. This permits lower doses to be used J; the onset of action is more rapid; 2 and the incidence of adverse effects is reduced/ Pressurized metered-dose inhalers are practical because they are compact, portable, and apparently easy to use. However, there is still disagreement about the optimal technique for achieving maximum drug delivery to the lower respiratory tract, 3and many patients may not receive adequate instruction in the use of the inhalers.4.5 Newman et al. 3 demonstrated maximal bronchodilation with the inhaler in the mouth and the dose delivered during the course of a relatively slow deep inhalation (25 L/rain) followed by a 10-second breath hold. However, Dolovich et al., 6 using a radiolabeled metered-dose aerosol, have shown that the maximum dose to the thoracic airways was achieved by activating the inhaler 4 cm from the wide-open mouth. Both these techniques require that the patient coordinate inhalation with actuation of the aerosol canister. Epstein et al. 4 and many other authors have described difficulties faced by asthmatic patients in coordinating actuation of a pressurized aerosol with inhalation. Paterson and Crompton 5 reported that, despite careful instruction by both physicians and outpatient nurses, 14% of 321 patients still used their inhalers inefficiently. The "space" devices currently being studied have been proposed to
From the Division of Chest Medicine, Research Institute, Hospital for Sick Children. Dr. Rivtin is a Canadian Cystic Fibrosis Foundation Fellow. Reprint requests: Henry Levison, M.D., Pulmonary Tunction Laboratory, Hospital for Sick Children, 555 University Ave., Toronto, Ont., Canada, M5G IX8.
overcome this problem of coordination; they allow children to inhale after actuation of the inhaler.7 However, the impact of specific coordination maneuvers on pulmonary response in asthmatic children has not been evaluated in the absence of these additional devices. Our study was designed to measure the bronchodilator effect of a sympathomimetic aerosol under three different conditions of coordination: optimal, sequential, and exhalation. METHODS
Patient selection. We studied 12 asthmatic children aged 6 to 17 years (mean 11.3 years) who fulfilled the American Thoracic Society criteria for reversible obstructive airway disease? Informed consent was obtained, and the protocol was approved by the hospital internal review board. The children were free of acute wheezing at the time of the study, and the mean forced expiratory volume in one second (FEV~) was 1.68 L (78% predicted) (Table). All patients were receiving bronchodilators and other antiasthmatic medications each day, but these medications were withheld for 12 hours before each study day. Study design. The trial was a three-day, randomized, double-blind crossover study designed to assess the bronchodilation resulting from three different techniques of administration of one puff of a beta-2 agonist aerosol (fenoterol hydrobromide, 200 ~g) from a pressurized canister. Each of the three techniques was performed on each of the three consecutive test days. However, only one of the canisters contained active drug on each day; the other two canisters were identical but contained placebo. The order of treatment was randomized. The three techniques were (1) coordinated." slow inhalation from functional residual capacity (FRC) coordinated with simultaneous activation of the inhaler, followed by breath holding for 10 seconds; (2) sequential: actuation of the inhaler, followed immediately (less than one second)
Volume 102 Number 3
47 1
Clinical and laboratory observations
- - - - COORDINATED .6-
--
SEQUENTIAL
---
UNCOORDINATED
,oo|
---COORDINATED--SEQUENTIAL---UNCOORDiNATED
.5-
80-
.4-
!
I
~. 7 0 -
./"
"........
u-, ~3-
40-
.2-
I
"~ 3 0 -
.1-
I .... I ........
.................
I
0.0 0
310 8I0 910 1~0 TIME AFTER ADMINISTRATION IN MINUTES
20-
I
150
0
0
I
310 6~0 910 120 TiME AFTER ADMINISTRATION IN MINUTES
1~0
Figure. A, Change from baseline in FEV1 (_+SE) for the three techniques of administration. B, Change from baseline for PEFR (_+SE) for the three techniques of administration. by slow inhalation from FRC and breath holding for 10 seconds; (3) uncoordinated." actuation of the inhaler, followed by exhalation from FRC. This technique should prevent drug entering the lungs. Pulmonary function was measured before administration of the drug and 15, 30, 60, and 120 minutes afterward, using a 9 L water-sealed Collins Spirometer (Warren E. Collins, Braintree, Mass.). The functions measured were forced expiratory volume in one second (FEVI), flow rate at 25% of vital capacity (V25), flow rate at 50% of vital capacity (Vs0), and peak expiratory flow rate (PEFR). Bronchodilation was determined by the relative and absolute changes from the baseline (pretreatment) value for each of the measurements. Blood pressure, heart rate, and a visual estimation of tremor were also recorded. Data analysis. The data were subjected to statistical analysis employing analysis of variance and eovariance techniques appropriate to a two-factor repeated-measures model with repeated measures on both factors. This is essentially a parametric method to perform overall matched comparisons of subject responses using the three modes of administration. The Wilcoxon signed-rank test was used to assess differences between coordinated and uncoordinated, sequential and uncoordinated, and coordinated and sequential techniques. RESULTS All 12 patients completed the three days of testing. There were no significant differences in baseline measurements during the trial. Hence we computed change from baseline as an assessment of pulmonary response. Both the coordinated and sequential techniques of inhalation resulted in a significant increase in pulmonary function (Figure). This improvement was observed by 15 minutes
Table. Baseline pulmonary function Measurement
Absolute value
FEV~ (L) V25 (L/sec) Vso (L/sec) PEFR (L/rain)
1.68 _+ 0.16 0.84 _+ 0.14 1.65 _+ 0.21 249 _+ 21.6
% Predicted
78.0 54.1 56.4 75.3
_+ 6.9 _+ 9.2 _+ 8.4 + 6.6
All v a l u e s expressed as m e a n • s t a n d a r d error, n = 12.
after delivery, and was maximal 60 minutes after inhalation. For the uncoordinated technique a much smaller bronchodilator response was observed at 15 minutes, and this slight increase was maintained throughout the observation period. When the pulmonary responses were calculated as percentage change, essentially the same relationships were obtained. These differences among techniques were confirmed when the data were analyzed using analysis of variance. Overall, there was a significant difference among the three methods of administration (P < 0.05) when FEV~, Vs0, and PEFR were compared, whereas V25 yielded a P value of 0.057. The mean increase of 0.13 L in FEVt following the uncoordinated method was significantly different from baseline. To investigate the differences among the three techniques of administration, the absolute changes from baseline at 60 minutes (peak effect) for the four ventilatory function measurements were compared using the Wileoxon test. On the basis of FEV~ and PEFR, both the coordinated and sequential techniques were better than the uncoordinated technique (P < 0.05 for all comparisons). The differences in FEV~ and PEFR between the coordinated and sequential methods were not statistically significant (P > 0.5). Changes in heart rate and blood pressure were small and
472
Clinical and laboratory observations
inconsistent. N o differences related to mode of administration were detected. Tremor effects were slight and not frequent enough to analyze by conventional statistical methods. DISCUSSION In this double-blind randomized study, the bronchodilator response to fenoterol administered by a metered-dose inhaler was similar for both the coordinated and sequential modes of aerosol delivery. In a previous study, Newman et al. 3 measured similar bronchodilator responses after doses given during inhalation at 20%, 50%, or 80% of vital capacity, implying that lung volume at inspiration is not an important variable when considering optimum inhalation technique. However, the bronchodilator effect diminished when the aerosol was given three seconds before inhalation at residual volume (RV). The three-second delay probably resulted in a larger fraction of the dose being deposited in the mouth, leaving less to be inhaled in the airways. An evaluation of aerosol technique by Lawford and McKenzie 9 also showed that inhalation from F R C is as effective as inhaling from RV. Our trial of three degrees of coordinated technique has shown that a short delay between activation and inhalation does not affect bronchodilator response to an aerosol sympathomimetic agent in asthmatic children. N o t unexpectedly, exhalation during aerosol drug delivery virtually eliminates the therapeutic effect of the drug. Most physicians currently advocate a coordinated aerosol technique with open or closed mouth, which occasionally results in patients actually exhaling while attempting this maneuver.~~ We suggest that some leeway be allowed in the execution of these steps of aerosol activation and inhalation. Minimal dyscoordination does not compromise response.
The Journal of Pediatrics March 1983
Furthermore, if a particular individual is unable to perform two maneuvers simultaneously, the sequential techo nique is a reasonable alternative. Because technique need not be perfect, a larger number of children may be able to derive benefit from this route of administration than was previously believed. Painstaking training, extra spacer devices, or orally administered medications should be considered only if there is severe dyscoordination. We thank the staff and patients of the Ontario Crippled Children Center for their cooperation. REFERENCES 1. Sterling GM: Diseases of the respiratory system: Asthma. Br Med J !:1259, 1978. 2. Plit M, Goldman HI, Cassel ML, Zwi S: The bronchodilator action of fenoterol (berotec) in asthma. Med Proc 18:41, 1972. 3. Newman SP, Pavia D, Clarke SW: Simple instructions for using pressurised aerosol bronchodilators. J R Soc Med 73:776, 1980. 4. Epstein SW, Manning CPR, Ashley M J, Corey PN: Survey of the clinical use of pressurized aerosol inhalers. Can Med Assoc J 120:813, I979. 5. Paterson IC, Crompton GK: Use of pressurized aerosols by asthmatic patients. Br Med J 1:76, 1976. 6. Dolovich M, Ruffin RE, Roberts R, Newhouse M: Optimal delivery of aerosols from metered dose inhalers. Chest 80(suppl):911, I981. 7. Ellul-Micallef R, Moren F, Wetterlin K, Hidinger KC: Use of a special inhaler attachment in asthmatic children. Thorax 35:320, 1980. 8. American Thoracic Society: Chronic bronchitis, asthma and pulmonary emphysema: A statement by the Committee on Diagnostic Standards for Nontuberculous Respiratory Disease. Am Rev Respir Dis 85:762, 1962. 9. Lawford P, McKenzie D: Pressurized aerosol technique. Lancet 1:1003, 1981. 10. Shim C, William MH Jr: The adequacy of inhalation of aerosol from canister nebulizers. Am J Med 69:891, 1980.
Reduced theophylline half-life induced by carbamazepine therapy Kathleen R. Rosenberry, Pharm.D., Carmine J. Defusco, M.D., Herbert C. Mansmann, Jr., M.D., Stephen J. McGeady, M.D. Philadelphia, Pa.
From the Division of Allergy and Clinical Immunology, Jefferson Medical College of the Thomas Jefferson University; and the Department of Pharmacy, Children's Hospital of Philadelphia. Reprint requests: Dr. Kathleen R. Rosenberry, Department of Pharmacy, Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104.
MANAGEMENT OF SEIZURE DISORDERS in asthmatic children treated with theophylline poses a therapeutic challenge, because several anticonvulsant drugs are reported to alter theophylline metabolism. ~,2 Carbamazepine (Tegretol) is known to hasten the metabolism of various