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(Chest. 1999;115:92-96.)
© 1999 American College of Chest Physicians

Comparison of 2.5 vs 7.5 mg of Inhaled Albuterol in the Treatment of Acute Asthma*

Charles L. Emerman, MD; Rita K. Cydulka, MD and E. Regis McFadden, MD

* From the Departments of Surgery (Drs. Cydulka and Emerman) and Medicine (Dr. McFadden), Case Western Reserve University, Department of Emergency Medicine, MetroHealth Medical Center (Drs. Cydulka and Emerman), and the Department of Medicine (Dr. McFadden), University Hospitals, Cleveland, OH.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Purpose: 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.

Subjects: We studied 160 patients presenting to the emergency department with acute asthma.

Methods: 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.

Results: 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).

Conclusion: 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.

Key Words: albuterol • asthma exacerbation • ß-agonists • dose response


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Nebulized ß-agonist aerosols are the mainstay of treatment for acute asthma. The National Asthma Education Prevention Program (NAEPP), in its latest revision, recommends initiation of therapy with aerosolized ß-agonists, including albuterol in a dose of 2.5 to 5 mg, every 20 min for the first hour. There does not appear to be substantial experimental data to support these dosing recommendations. While albuterol is generally very safe, with a wide therapeutic index, annoying side effects can occur, including nausea, vomiting, headache, tremor, and hypokalemia.1 Up to 28% of patients may experience side effects, most of which are mild.1 Previous studies have found sequential increases in pulmonary function in patients given repeated doses of albuterol, 2.5 mg every 20 min. In one such study2 56% of patients responded to <= 5 mg of aerosolized albuterol. Similarly, another recent study3 found that 53% of patients achieved discharge criteria with a cumulative dose of 1.2 mg of albuterol given by metered dose inhaler.

While the optimal dose of albuterol to use in acute asthma has not been well studied in adults, studies in children have suggested increased efficacy with higher doses.4 The substitution of continuous for intermittent administration and the use of higher cumulative doses lead to greater improvement in pediatric patients.4 ,5 These pediatric studies have used doses ranging from 0.05 mg/kg to 0.15 mg/kg every 20 min for six doses.4 ,5 One study6 in adults that compared hourly vs more frequent administration of metaproterenol suggested that a higher cumulative dose may lead to greater improvement in pulmonary function. Another study in adults,7 however, did not demonstrate that more frequent administration of metaproterenol aerosols with a higher cumulative dose led to a greater improvement in pulmonary function.

In European countries, higher doses of albuterol are commonly used for the treatment of acute asthma. Doses of 5 to 10 mg, or even higher, have been recommended for acute asthma management in various guidelines, including those of the British Thoracic Society.8 There does not appear to be adequate evidence on which to base albuterol dosing in acute asthma. One previous study1 suggested a greater improvement in the FEV1 with 7.5 mg of nebulized albuterol, although the differences did not reach statistical significance. The purpose of this study was to evaluate the efficacy of a 7.5-mg dose of albuterol compared with a 2.5-mg dose in adult patients presenting with acute asthma.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
This study was conducted in the emergency department of MetroHealth Medical Center, a large urban county-owned institution. Adult patients between the ages of 18 and 50 years presenting to the emergency department with acute asthma, as manifested by cough, dyspnea, and/or wheezing were enrolled by one of the department's research nurses. Patients were excluded from this study if they had a previous diagnosis of COPD, a history consistent with chronic bronchitis, previous lung surgery, or a diagnosis of lung carcinoma. Patients were also excluded from the study if they had clinical evidence of pneumonia, pneumothorax, or decompensated congestive heart failure. Patients were only enrolled in the study if they were able to perform spirometry.

After initial informed consent had been obtained, blood was drawn for a CBC count, and theophylline and serum potassium levels were measured. Pulse oximetry was obtained and, if necessary, the patient was placed on oxygen by nasal cannula, to maintain an oxygen saturation of > 91%. Spirometry was performed with the patient seated and wearing nose clips, using a computerized, Fleisch, pneumotachygraph type spirometer (Spiroscan 4000; Brentwood Instruments; Portland, OR). At least three expiratory maneuvers were performed with the highest FEV1 used for analysis.

Patients received, in a randomized, double-blind fashion, albuterol by air-driven nebulizer in a dose of either 2.5 or 7.5 mg every 20 min for a total of three doses. The albuterol was mixed to a total of 4 mL with normal saline and administered with an airflow of 6 L/min in order to maximize drug delivery. All nebulized treatments were given with a nebulizer (Model 646 Acorn nebulizer; DeVilbis Health Care; Somerset, PA) in order to minimize drug loss. All patients were given prednisone, 60 mg, orally.

Spirometry was repeated immediately after each of the first two treatments and again 40 min after the completion of therapy. A second potassium level was drawn at the end of the last aerosol administration. Patients were either discharged or admitted from the hospital following the performance of the last spirometry, at the discretion of the treating physician. At all times, the research nurses, patients, and treating physicians were blinded to the identity of the treatment dose.

Analysis of categorical variables was performed using the {chi}2 test. Analysis of continuous variables was performed using the Student's t test. The effect of the two different doses of albuterol over the course of three treatments was assessed using an analysis of variance method for repeated measures. The study was originally sized for 100 patients based on an absolute difference of 15% in the percent improvement in FEV1 with a standard deviation of 25%. The study was resized to 160 patients based on an interim analysis that demonstrated a higher variance than originally expected. A p value of < 0.05 was considered to indicate statistical significance. All data are expressed as the mean ± SD. This study was approved by our Hospital's Institutional Review Board.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
One hundred and sixty patients were enrolled in the study, including 123 women and 37 men with a mean age of 36.5 ± 11.2 years (Table 1 ). On arrival in the emergency department, 84% of the patients had a history of using ß-agonists, 27% of the patients were using theophylline products, 37% of the patients were using inhaled steroids, and 10% of the patients were using oral steroids. This did not differ between the patients in the high- or low-dose groups. Thirty percent of the patients had a current history of cigarette use with an average of 12.8 ± 14.8 pack-years of cigarette use. This again, did not differ between the two groups.


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  		Table 1. Patient Demographics

 
The mean pretreatment FEV1 was 36.9 ± 16.6% of predicted normal in the high-dose group as compared with 41.5 ± 15.4% of predicted normal in the high-dose group (p = 0.07). The mean final post-treatment FEV1 was 50.6 ± 19.6% of predicted normal in the low-dose group and 56.3 ± 18.2% of predicted normal in the high-dose group (p = 0.06). Repeated-measures analysis of variance failed to show an interaction between the treatment allocation and time (F = 0.64, p = 0.59). Overall, there was a 50.2 ± 62.6% improvement in pre- to post-treatment FEV1 in the low-dose group and a 44.6 ± 48.1% improvement in the high-dose group (p = 0.52).

Of the patients in the low-dose group, 43% were admitted compared with 39% of patients in the high-dose group (p = 0.65). Within 7 days, 17.1% of patients in the low-dose group relapsed as compared with 16.7% of patients in the high-dose group (p = 0.70). Overall, 49.4% of patients in the low-dose group complained of side effects, which could be attributed to albuterol (tremor, chest pain, headache, palpitations, nausea, and vomiting) as compared with 44.2% of patients in the high-dose group (p = 0.51). There was a decrease of 0.5 ± 0.7 mEq/L in serum potassium in the low-dose group as compared with a decrease of 0.5 ± 0.4 mEq/L in the high-dose group (p = 0.18).

Thirty-five of the patients (19%) had a pretreatment FEV1 level of < 25% of predicted normal. In this subset of patients, the mean pretreatment FEV1 in the low-dose group was 18.8 ± 3.5% of predicted normal in the low-dose group and 18.7% ± 4.8% of predicted normal in the high-dose group. The patients in the low-dose group had an average of 88.8 ± 96.3% improvement in FEV1 pre- to post-treatment, whereas those in the high-dose group had an average of 117.9 ± 84.6% improvement in pulmonary function (p = 0.43, ß = 0.8) (Fig 1 ).



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  		Figure 1. Change in pulmonary function with treatment. Closed circles = high dose; open circles = low dose.

 
There was no difference in percent improvement in FEV1 between the two groups when separated by final disposition. Overall, patients who ultimately required admission had a smaller improvement in FEV1 at 40 and 100 min than those who were discharged home (Fig 2 ). Analysis by a general linear model failed to demonstrate an interaction between group assignment and final disposition compared with percent improvement in FEV1 at 40 min.



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  		Figure 2. Difference in response between patients admitted or discharged. Closed circles and open boxes = 7.5-mg group; open circles and open triangles = 2.5-mg group.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
This study has failed to demonstrate a difference between two doses of albuterol in the treatment of acute asthma. This study had an 80% power to determine an absolute difference of 17% in the percent of improvement in FEV1 pre- to post-treatment. We also failed to find a difference in admission rate between the two groups.

A previous study9 in patients with stable asthma found a log-linear dose response to increasing doses of albuterol. Nelson studied 44 asthmatic patients who received increasing doses of albuterol up to 15 mg delivered by intermittent positive pressure breathing. The response to 15 mg exceeded the response to any of the lower doses. Haahtela et al,10 on the other hand, did not find a difference between 25-, 50-, and 100-µg doses of albuterol administered via metered dose inhaler to patients with stable asthma. Lipworth et al11 also found a log-linear increase in FEV1 in stable asthmatics given up to 4000 µg of albuterol by metered dose inhaler. Bardin and Joubert12 studied 23 asthmatic patients over the course of 8 weeks receiving either 200 or 1000 µg of albuterol by metered dose inhaler. They did not find a difference in morning peak expiratory flow rate, although the patients in the higher group appeared to be more sensitive to histamine than the patients in the lower dose group. Vathenen et al13 studied patients with severe chronic air flow limitation, using doses of albuterol administered by dry powder inhaler, up to 4 mg. With the increasing doses of albuterol, there was a linear increase in FEV1 with a longer duration of effect at the higher doses.

Few studies have been performed evaluating differing doses of inhaled ß-agonist agents in acute asthma. McDermott7 compared the administration of metaproterenol either every hour or every 20 min and failed to find a difference in pulmonary function between the two groups. Colacone et al14 compared the effects of bolus vs continuous nebulization of albuterol in adult acute asthmatics and did not find a difference between the two groups, although they each received the same cumulative dose rate. In an older study, Nelson et al6 compared hourly vs every-20-min administration of metaproterenol to adult acute asthmatics. They found a greater improvement in pulmonary function in the patients receiving metaproterenol every 20 min, although this did not reach statistical significance. Another study15 did not find a difference between 5-, 10-, or 15-mg doses of continuously aerosolized albuterol. Rodrigo and Rodrigo16 compared patients receiving 1,400 or 1,500 µg of albuterol by metered dose inhaler every 10 min for 3 h. The patients in the higher dose group had a greater, although not statistically significant, improvement in pulmonary function. Shrestha et al1 compared patients receiving 2.5 or 7.5 mg of albuterol by either continuous or intermittent nebulization for 2 h. They found a greater improvement in FEV1 for the continuous groups than for the group with 2.5-mg intermittent nebulization. The difference in percentage improvement between the 2.5- and 7.5-mg intermittent groups had an absolute value of 14%. Their study differed from ours in that they only enrolled patients with a pretreatment FEV1 of < 40%.

These results differ from those in children. Studies in children have compared bolus vs continuous nebulization as well as hourly vs more frequent administration of albuterol.4 ,5 ,17 These studies have found a greater improvement in pulmonary function in patients given a higher cumulative dose, in a more frequent administration rate. It does not appear that the experience in children is similar to that in adults.

Studies in European centers have used greater doses of albuterol than are commonly administered in the United States. Previous studies comparing IV vs inhaled albuterol used doses of 0.15 mg/kg administered by nebulizer every 30 min.18 They did not find a difference between inhaled vs infused albuterol. One study used a dose of 0.4 mg/kg/h of continuously aerosolized albuterol over the course of 4 h and found that this dose was associated with high serum albuterol levels.19 There was a significant drop in serum potassium levels over the course of the 4-h treatment.

In this study, we have failed to find a clinically significant advantage to higher dose albuterol for adult asthmatic patients. It is possible that a small advantage exists that would be below the power of this study to detect. This study had relatively few asthmatics with very severe asthma. Both our study, and that of Shrestha et al,1 found improvements with higher doses in very obstructed patients, although this did not achieve statistical significance. It is also possible that a larger study involving more patients with very severe asthma would determine that there is an advantage to higher dose albuterol. We have not examined the effects of even higher doses of albuterol. We limited our study to a total accumulative dose of 24 mg of albuterol out of concern for possible toxicity at higher levels. This study evaluated two different doses of albuterol given on a repetitive basis. There has been some suggestion of greater efficacy for continuous administration of albuterol, although our study was not designed to evaluate this.20 ,21 Other studies,2 ,3 which have evaluated the dose response to albuterol, have suggested that the response to albuterol is predicted with the first several administrations of the drug. Although our study was not designed to evaluate this, recent data suggest that a single administration of a threshold dose of albuterol may be sufficient to make disposition decisions.2 ,3 As has been previously demonstrated, patients who require admission fail to respond in an adequate manner to albuterol, regardless of dose. This is evident early in the patient's course and may be a factor that can be used to quickly determine patient disposition. If these findings are verified in larger studies, it might suggest that patients who fail to respond adequately to an initial short series of aerosol treatments should be admitted promptly.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
We conclude that there is no advantage to the administration of doses of albuterol greater than 2.5 mg every 20 min for adult asthmatic patients. Some subpopulations may benefit from higher dose albuterol that were not detected by this study design.


   Footnotes
 
Correspondence to: Charles L. Emerman, MetroHealth Medical Center, Department of Emergency Medicine, 2500 MetroHealth Drive S1-203, Cleveland, OH 44109-1998; e-mail: cemerman@metrohealth.org

Received for publication May 26, 1998. Accepted for publication July 16, 1998.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. Shrestha, M, Bidadi, K, Gourlay, S, et al (1996) Continuous vs intermittent albuterol, at high and low doses, in the treatment of severe acute asthma in adults. Chest 110,42-47[Abstract/Free Full Text]
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  8. . British Thoracic Society Research. (1990) Unit of the Royal College of Physicians of London. Guidelines for management of asthma in adults: II. Br Med J 301,797-800
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