The bronchodilator response to inhalation of increasing doses of aerosolized albuterol

doi:10.1016/0091-6749(83)90502-X

Journal of Allergy and Clinical Immunology

Volume 72, Issue 4, October 1983, Pages 371-375

https://doi.org/10.1016/0091-6749(83)90502-X Get rights and content

Abstract

Forty-four asthmatic patients were treated on separate days with increasing doses of albuterol in four double-blind studies that included placebo controls. Twenty-six subjects received one, two, four, six, and eight inhalations from a metered dose inhaler; 18 subjects received 1.25, 2.5, 5, 10, and 15 mg delivered by IPPB. There was a significant linear relationship in both groups between the maximum increase in FEV₁ and the log dose of albuterol. The response to four, six, and eight inhalations from the metered dose inhaler was significantly greater than the response to one inhalation, and the response to 15 mg by IPPB was significantly greater than the response to any other dose by IPPB. The results suggest that in many patients maximum possible bronchodilation is not achieved by customarily recommended doses.

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Cited by (44)

Review of Asthma: Pathophysiology and Current Treatment Options
2007, Clinical Pediatric Emergency Medicine
Citation Excerpt :
Children will respond better to aggressive high-dose therapy than adults. For example, there is a significant relationship between albuterol dosing and improvement in pulmonary function [15]. Higher and more frequent administration also leads to greater bronchodilatation [16].
Asthma remains one of the leading chronic diseases in children and one of the leading reasons for emergency department visits. As our understanding of the underlying pathophysiology continues to improve, so does our armamentarium for the management of acute exacerbations. Combination therapy with multiple agents is showing promise especially for the child with a severe attack. In addition, there seems to be significant benefit in the implementation of inhaled corticosteroids at the time of emergency department discharge.
A methacholine challenge dose-response study for development of a pharmacodynamic bioequivalence methodology for albuterol metered-dose inhalers
2002, Journal of Allergy and Clinical Immunology
Background: With the expiration of the patent on albuterol metered-dose inhalers (MDIs) in 1989, methods to assess in vivo bioequivalence of generic formulations required investigation. Objective: In an effort to develop a sensitive method to document bioequivalence, bronchoprovocation with methacholine chloride was used to assess the dose-response relationship of albuterol as delivered by MDI. Sensitivity was assessed in terms of magnitudes of ED₅₀, the estimated albuterol dose required to achieve 50 % of the fitted maximal value of the pharmacodynamic effect above baseline, and change in response as a function of dose, with emphasis on 1 and 2 actuations. Methods: On separate study days, 15 nonsmokers with mild asthma received randomized nominal albuterol doses of 0 to 576 μg by using specially manufactured MDI canisters. FEV₁ was measured 15 minutes after MDI dosing. Serially increasing doses of methacholine were administered, and FEV₁ was measured after each methacholine dose until a 20 % decrease in FEV₁ (PD₂₀) was achieved. Results: Mean PD₂₀ values after use of each of the albuterol-containing MDIs were significantly greater than either mean screening or mean placebo PD₂₀ values (P <.05). Mean responses and most individual subject responses to 1 and 2 actuations (90 and 180 μg) of albuterol MDI were within the sensitive region of the dose-response curve. The mean estimated ED₅₀ value on the basis of nonlinear mixed effect modeling was 119.2 μg (range, 33.3-337.1 μg), with an intersubject percentage coefficient of variation of 69.0 %. Conclusions: The methacholine bronchoprovocation model is safe and useful in the study of albuterol MDI dose-response in asthmatic subjects. Bronchoprovocation studies may be used for determination of bioequivalence of multisource albuterol MDI products. (J Allergy Clin Immunol 2002;110:713-20.)
Characterization of aerosol output from various nebulizer/compressor combinations
2001, Annals of Allergy, Asthma and Immunology
Different commercially available nebulizers and compressors are available. However, the optimal combination for drug delivery is unknown.
Flow rates of five different compressors (n = 3/compressor) tested alone and in combination with five different commercial nebulizers (n = 9 of each brand of nebulizer) were evaluated. Thereafter, the performances of the different nebulizers were evaluated using 2.5 mg albuterol solution (0.5 mL) added to 2.5 mL saline at flow rates of 2, 3, 4, and 5 L/minute using a laser particle analyzer. Volume median diameter and percentage of particles in the respirable range (1-5 μm) were calculated from this data. Time for nebulization (in seconds) and residual volume (in milliliters) were also recorded.
The mean flow rates for the compressors evaluated without a nebulizer attached ranged from 6.6 L/minute (LifeCare Freedom-neb; LifeCare International, Lafayette, CO) to 12.2 L/minute (DeVilbiss Pulmo-Aide; DeVilbiss Health Care, Somerset, PA). Flow rates for the nebulizer/compressor combinations ranged from 2.08 L/minute (Pari LC Jet Proneb; Pari Respiratory Equipment, Richmond, VA) to 5.42 L/minute (Puritan Bennett Raindrop; Puritan Bennett, Lenexa, KS/Omron Compare; Omron, Health Care, Vernon Hills, IL). Using the repeated measure ANOVA model, the interaction between flow rate and device was significant (P < 0.001) for both percentage of particles in the respirable range and log volume median diameter. It was observed that the percentage of particles in the respirable range for the Pari LC Jet did not increase across flow rates in contrast to the other 4 nebulizers. All comparisons to the Pari LC Jet at 2 L/minute were significant.
Marked variability exists in the flow rates among different commercially available compressors used for home nebulization of inhaled pulmonary medications. Different nebulizer/compressor combinations have markedly different performance characteristics which could result in different efficacy and safety profiles of the medications being administered via these devices. We recommend that this type of information be used as a starting point for selecting different nebulizer/compressor combinations. Further clinical evaluation is warranted.
Continuous versus intermittent nebulization of salbutamol in acute severe asthma: A randomized, controlled trial
2000, Annals of Emergency Medicine
Citation Excerpt :
There is a consensus that frequent intermittent nebulizations (3 in the first hour) are appropriate,1,2,6-9 but continuous nebulization is also proposed.1,2 Frequent administration of bronchodilators is thought to dilate the proximal bronchial tree, thereby allowing further distal deposition of subsequent bronchodilator treatments, which produces sustained bronchodilation and prevents bronchospastic rebounds.10-13 All these benefits also might be obtained with continuous nebulization of bronchodilators.13-18
Study Objective: This study was conducted to compare the clinical and spirometric effects of continuous and intermittent nebulization of salbutamol in acute severe asthma. Methods: Forty-two consecutive patients presenting to the emergency department for acute severe asthma (peak expiratory flow [PEF] mean±SD, 24%±12% predicted) were prospectively randomly assigned to receive 27.5 mg of salbutamol by either continuous or intermittent nebulization over a 6-hour period. The continuous nebulization group received 15 mg of salbutamol during the first hour and 12.5 mg over the next 5 hours. The intermittent nebulization group received 5 mg of salbutamol every 20 minutes during the first hour and 2.5 mg hourly over the next 5 hours. All participants received oxygen and intravenous hydrocortisone. Clinical and spirometric assessment was performed at baseline, 40 minutes, 60 minutes, and at 3 and 6 hours after the start of the nebulization. Secondary endpoints were the respective rates of hospitalization and treatment failure. Results: A significant clinical and spirometric improvement was observed in both groups over baseline as soon as the 40th minute and was sustained thereafter (absolute PEF increase at the sixth hour 30%±18% and 32%±22% in the continuous and intermittent nebulization groups, respectively; P <.01 over baseline). PEF and the clinical score evolved similarly in both groups. There was no difference between the groups regarding the failure rate of the initial bronchodilator treatment to terminate the asthma attack (3 [14%] in the continuous nebulization group and 2 [9.5%] in the intermittent nebulization group, absolute difference 4.5% [95% confidence interval –14% to 23%]). Eight (38%) patients and 9 (43%) patients from the continuous and intermittent nebulization groups, respectively, required hospitalization according to predefined criteria (absolute difference 4.8% [95% confidence interval –24% to 34%]). Conclusion: We did not observe an appreciable difference between continuous and intermittent nebulization of salbutamol in acute severe asthma. The decision to use one of these nebulization methods should be based on logistical considerations. [Besbes-Ouanes L, Nouira S, Elatrous S, Knani J, Boussarsar M, Abroug F. Continuous versus intermittent nebulization of salbutamol in acute severe asthma: a randomized, controlled trial. Ann Emerg Med. September 2000;36:198-203.]
Comparison of 2.5 vs 7.5 mg of inhaled albuterol in the treatment of acute asthma
1999, Chest
The optimal dose of albuterol to use in the treatment of acute asthma has yet to be established. The National Asthma Education and Prevention Program (NAEPP) recommends a starting dose of 2.5 to 5 mg of aerosolized albuterol every 20 min, although European authorities recommend higher doses. The purpose of this study was to compare 2.5 vs 7.5 mg of nebulized albuterol for the treatment of acute asthma.
We studied 160 patients presenting to the emergency department with acute asthma.
On enrollment, patients underwent baseline testing, including initial spirometry. All patients received prednisone, 60 mg, orally. Patients then received in a randomized, double-blinded fashion, nebulized albuterol either 2.5 or 7.5 mg every 20 min for a total of three doses. Spirometry was repeated after each of the first two treatments and again 40 min after completion of the three treatments.
The pretreatment FEV₁ was 36.9 ± 16.6% of predicted normal in the low-dose group vs 41.5 ± 15.4% of predicted normal in the high-dose group (not significant [NS]). The patients in the low-dose group had a 50.3 ± 62.6% improvement in FEV₁ pretreatment to post-treatment, whereas those in the high-dose group had a 44.6 ± 48.2% improvement in FEV₁ (NS). There was no difference in the admission rate in the low-dose group (43%) as compared with that of the high-dose group (39%; NS).
We conclude that there is no advantage to the routine administration of doses of albuterol higher than 2.5 mg every 20 min. It is possible that there may be an advantage in the most severely obstructed patients, although this study did not enroll enough patients with very severe asthma to evaluate this. As has been previously demonstrated, patients who subsequently require admission have a diminished response to albuterol. This decreased responsiveness is seen with the first aerosol administration and is unaffected by increasing the dose.
Respiratory pearls, pitfalls, and updates
1997, Emergency Medicine Clinics of North America

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^☆: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

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Original articleThe bronchodilator response to inhalation of increasing doses of aerosolized albuterol☆

Abstract

Am J Med

Chest

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

J Allergy Clin Immunol

Thorax

Comparison of infused and inhaled terbutaline in patients with asthma

Scand J Respir Dis

Comparison of intravenous and aerosol salbutamol

Br Med J

Oral and inhaled salbutamol in the prevention of exercise-induced bronchospasm

Pediatrics

Bronchodilating effect and side effects of beta-2 adrenoceptor stimulants by different modes of administration (tablets, metered aerosol and combinations thereof)

Am Rev Respir Dis

Emergency therapy of asthma: comparison of the acute effects of parenteral and inhaled sympathomimetics and infused aminophylline

Am Rev Respir Dis

Comparison of salbutamol given intravenously and by intermittent positive-pressure breathing in life-threatening asthma

Br Med J

Original article
The bronchodilator response to inhalation of increasing doses of aerosolized albuterol☆