Study objective: Patients with acute asthma often have difficulty using a conventional metereddose inhaler. The Maxair Autohaler (3M Pharmaceuticals; St. Paul, MN) is a hand-held breath-actuated device developed to help patients coordinate drug administration. The study objective is to compare the efficacy of the Autohaler with inhaled [Beta]-agonist administered by wet nebulizer in treating acute asthma exacerbations.
Design: Parallel, randomized, placebo-controlled clinical trial.
Setting: Emergency department (ED) of a university-affiliated hospital.
Participants: Patients aged 18 to 55 years presenting to the ED with acute asthma and an [FEV.sub.1] 40 to 70% on hospital arrival.
Interventions and measurements: Patients were given either six puffs of the Maxair Autohaler (1,200 [micro]g pirbuterol) plus saline solution by nebulizer (active Autohaler group) or six puffs placebo by Autohaler plus 2,500 [micro]g albuterol via nebulizer (active nebulizer group). Treatment was repeated at 30 and 60 min, with clinical evaluation performed before each treatment and again at 120 min. At 120 min, the protocol was completed.
Results: Twenty-four patients were enrolled, with 5 excluded because of protocol violations. Baseline [FEV.sub.1] percent predicted values for the active Autohaler group were 53% vs 51% for the active nebulizer group (p=not significant [NS]). At time 120 min, values were 66% for Autohaler and 64% for nebulizer (p-NS). The average time to administer Autohaler was 2.9 min, vs 9.1 min for nebulizer. No patient was excluded because of the inability to use the Autohaler device adequately.
Conclusion: In patients with moderate asthma exacerbations, similar improvements in pulmonary function are obtained when [Beta]-agonists are given by either the Maxair Autohaler or a wet nebulizer device.(CHEST 1998; 114: 766-770)
Key words: acute disease; adrenergic [Beta]-agonists; asthma; drug delivery systems
Abbreviations: ED=emergency department; MDI=metered-dose inhaler
Inhaled [Beta]-agonists are the mainstays of therapy for patients with acute bronchospasm. Among methods of administering aerosolized bronchodilators are the wet nebulizer and the metered-dose inhaler (MDI). The advantage of the MDI device over the nebulizer is its small size, the ability to administer the desired dose more quickly, greater lung deposition of particles, lower costs, need for fewer resources, and the minimal risks of contamination.[2,3] The MDI, however, requires a significant amount of hand-breathing coordination to use effectively.[2,4-9] Various spacers or holding devices help to avoid difficulties in timing inspirations with discharge of medications and have been used with the MDI to overcome this problem. Many reports have shown that the use of an MDI with a holding chamber or spacer-type device is therapeutically equivalent to the wet nebulizer, [10-21]
The Autohaler (3M Pharmaceuticals; St. Paul, MN) is a breath-actuated device that allows the patient to coordinate inhalation of medication with release of the inhalant.[7,22-26] Similar in size to a standard MDI, the patient presses a lever on top of the device and starts to breathe through a mouth piece. A fixed dose of aerosolized medication is automatically released during the early part of inspiration, avoiding the need to time breathing with pressing of the MDI. Relatively low-flow states are not a contraindication to the Autohaler use, as patients with severe obstruction ([FEV.sub.1] [is less than] 1 L) can fire the actuator after a brief instruction period.
Given the therapeutic equivalence to nebulizers noted with MDI/spacer combinations, the question arises as to whether the Autohaler device can be substituted for nebulizers in acute asthma episodes. The goals of this study are to determine if patients presenting to the emergency department (ED) with moderate exacerbations of asthma can be quickly trained to use the Autohaler device, and to determine if aerosolized bronchodilators administered by the Autohaler device are equivalent in efficacy to standard wet nebulizer treatment.
MATERIALS AND METHODS
This was a randomized, double-blinded, parallel study done in the ED of' Long Island Jewish Medical Center. Patients aged 18 to 55 years with the previous diagnosis of asthma who presented with an acute exacerbation were screened on arrival. Protocol inclusion criteria were an asthma exacerbation starting within the past 72 h and an [FEV.sub.1] on arrival between 40% and 70% predicted. Patients were excluded if they had significant medical problems, including diabetes, angina, cardiomyopathy, hypertension requiring medication, renal insufficiency, chronic liver problems, or any chronic lung disease other than asthma. Also excluded were patients with a temperature of [is greater than or equal to]38.8[degrees]C, pregnant, and those who received systemic steroids in the preceding 24 h, theophylline in the preceding 12 h, or [Beta]-agonists within 1 h of study entry. Informed consent was obtained on patients and the study was approved by the hospital human subject review committee.
A computer-generated 1:1 randomization table was used by the study pharmacist to prepare the identically appearing interventions. Patients were assigned the next study number and the intervention was labeled only with the study number and instructions on use.
Patients arriving in the ED had spirometry done by a study investigator (ii. S. or S.G.) using a spirometer (Spiromate AS-600; Riko Medical Instruments; Tokyo, Japan). Since patients with acute asthma may not be able to perform spirometry according to accepted standards, we developed criteria to capture the best possible [FEV.sub.1]. The best of at least three efforts were taken and the maneuver was considered acceptable if the two best [FEV.sub.1] values were within 10% of each other, expiratory effort was at least 3 s duration, the calculated back extrapolation was [is less than] 5%, and a sharp peak was noticed on the flow/volume loop. After spirometry was performed, enrolled patients were instructed on how to use the Autohaler device. Six puffs of either pirbuterol (200 [micro]g per puff) or a like-appearing device containing placebo was self-administered by the patient under investigator supervision. The subjects were encouraged to hold their breath for up to 10 s after each inhalation. Feedback regarding technique was given if needed after each actuation. Patients were then given the wet nebulizer treatment by a device (Micro Mist; Hudson RCI; Temecula, CA) containing either albuterol (2,500 [micro]g) or placebo in 3 mL of saline solution and administered with 5 to 7 L/min of oxygen. Nebulization was continued until a mist was no longer present. Each patient therefore received placebo in one device, and active medication in the other.
Study treatments were again given at time 30 and 60 min. An evaluation consisting of spirometry, measurement of vital signs, pulmonary examination, pulse oximetry, dyspnea scores, and tremor assessment was recorded before each treatment, and again at 90 and 120 min. Dyspnea was measured using a modified Borg index scaled 0 through 10, with 0 representing no symptoms and 10 the most severe response. Hand tremors were visually assessed by the investigator, and rated as absent, mild, moderate, or severe (0 to 3). At 2 h, the protocol ended, and the clinician could administer any additional therapy or discharge the patient from the ED. Blood for measurement of electrolytes was drawn before the first treatment and at completion of the protocol.
After each actuation with the Autohaler, the investigators (R.S. or S.G.) rated the individual on ability to coordinate device triggering with deep inspiration, with technique rated as poor, fair, good, very good, or excellent. The number of seconds the patients could hold their breath after the medication was delivered was also noted. The frequency of additional instructions needed was recorded, as was the time it took to administer the Autohaler and nebulizer. In addition, patients were asked to evaluate the ease of use and satisfaction with the Autohaler and nebulizer device.
Patients were withdrawn from the study if their [FEV.sub.1] doubled or improved to [is greater than]90% predicted after the first treatment. They were also withdrawn if there was no improvement in [FEV.sub.1] by 60 rain or if in the judgment of the investigator, the patient's condition was worsening at anytime.
Baseline characteristics were compared by univariate analysis, including the Students's t test and [chi square] test. To reduce between-patient variability, the differences between each patient's baseline and final measures were compared between groups using independent Student's t tests. All tests were two tailed, and a p[is less than]0.05 was considered statistically significant.
A total of 24 patients were randomized, with 12 receiving active medication by Autohaler and 19, receiving active medication by nebulizer. A total of five patients (two randomized to active Autohaler and three to active nebulizer) were withdrawn before completion of the 2-h trial in accordance with protocol guidelines. Of the two patients receiving active Autohaler, one patient was withdrawn because the [FEV.sub.1] doubled after a single treatment, and one was withdrawn at 45 rain due to an investigator error in medication administration. Of the three patients withdrawn from the active nebulizer group, two had no improvement in pulmonary function after two treatments, and one was found to be pregnant after randomization. This left 19 patients whose data are presented herein.
Except for pulse and systolic pressure, there were no significant differences in historical and baseline clinical variables between the two treatment groups. Results are shown in Tables 1 and 2.
(*) Values represent mean + SD. NS = not significant.
(*) Values represent mean [+ or -] SD. Numbers in parentheses represent range of values. PEFR=peak expiratory flow rate.
The responses to treatments are shown in Figure 1 and Table 3. The change in [FEV.sub.1] from time 0 to 120 min was similar in both groups. There was no significant difference in [FEV.sub.1] between the two groups at baseline or at any of the post-treatment times. There were no significant differences in other clinical variables either before or after treatments in both groups. In addition, serum magnesium, potassium, and phosphate levels were similar in both groups, both before and after treatment.
(*) Values are expressed as mean [+ or -] SD. See Table 1 and 2 footnotes for explanation of abbreviations.
[Figure 1 ILLUSTRATION OMITTED]
Patients were evaluated for their ability to use the Autohaler device correctly. This included the ability to actuate the device and effectively coordinate inspiration with Autohaler actuation. Overall, patients were able to learn to use the device quickly. For time 0, six patients used poor or fair technique in only one of the six puffs and this always occurred on the first attempt. Good to excellent ratings for technique were noted for all of the other attempts at time 0. For time 30 and 60 min, technique was rated as good or better for all puffs. The average time that patients held their breath after Autohaler actuation for time 0, 30, and 60 min was 9.9., 9.7, and 9.7 s. After the final evaluation, the patient was asked to assess use of the Autohaler. All 19 patients found it easy or very easy to train using and administering the device. All patients could self-administer the device with minimal or no assistance, with 15 of 19 able to by completion of time 0, and the remaining 4 patients by time 60 min. All patients stated they believed they could effectively use the Autohaler at home during an asthma attack. When asked as to their preference for ED treatment, 10 of 19 preferred the Autohaler and 9 of 19 preferred the nebulizer treatment. The patients' preferences were found to be independent of the treatment received.
The time needed to administer six puffs of Autohaler preparation was 2.9 min, compared with 9.12 min to complete the nebulizer treatment. This does not take into account the time for setting either device up or instructions given before the first puff of the Autohaler, which were not recorded.
Patients with moderate exacerbations of asthma who received [Beta]-agonists by the Autohaler device had similar improvement in pulmonary function and the sensation of dyspnea to patients who received [Beta]-agonists by wet nebulizer. Our results agree with other studies that found [Beta]-agonists administered by devices designed to improve drug delivery, such as spacers or holding chambers, to be equivalent to nebulizer treatment,[10-21] Advantages of the Autohaler device over the nebulizer include compact size, portability, ease of use, and shorter treatment time.
Participants in this study were able to use the Autohaler effectively during an acute asthma exacerbation. Only two study patients had been prescribed the Autohaler in the past and therefore had some experience in its use. Most patients required coaching for two to three puffs to improve coordination of device actuation and encourage the steady deep breathing needed for optimal aerosol delivery. By the second round of therapy (time 30 min), all patients were using the Autohaler adequately for all actuations and by the 60-min treatment, all patients were able to use the device adequately and independently.
Patients presenting to the ED with acute asthma are often treated with [Beta]-agonists via wet nebulizer. This occurs even though many studies indicate [Beta]-agonists administered by spacer will offer similar improvements in pulmonary function in children and adults. In the present study, all patients found the Autohaler device "easy to use" and yet half of the patients still preferred the nebulizer device. Perhaps patients or even clinicians have the perception that a nebulizer, traditionally associated with institutional care, is a more effective form of therapy. Treating the patient in the ED or a clinician's office provides an opportunity to educate the patient and promote the use of spacer or actuator devices for moderate asthma episodes. Those patients who cannot use either device could be identified and recommended to use a nebulizer for treatment of asthma both at home and in the clinical setting.
Although spacer and Autohaler devices are commonly available, many patients treat their asthma by using a standard MDI alone. In a recent survey of patients presenting to the ED in four New York City hospitals, only 18% claim to use a spacer or actuation device regularly when using an MDI. Studies have shown that patients using an MDI to administer medications often have ineffective inhalation technique.[4,7] It is likely that many patients using only an MDI are not receiving their expected dose of asthma medication.
There were no significant side effects seen with Autohaler administration of pirbuterol. The change in levels of magnesium, phosphate, and potassium were similar in the active Autohaler and active nebulizer groups. The incidence of tremors and change in heart rate and systolic BP were also similar in both groups.
Previous study found that in patients with stable asthma 600 to 800 [micro]g of pirbuterol was needed to achieve maximum bronchodilatation at 2 to 4 h. To our knowledge, there are no studies that compare pirbuterol with albuterol in acute asthma, nor are there previous studies that compare pirbuterol with nebulizer treatment. Each puff of a standard MDI contains 90 [micro]g of albuterol, while each puff from the Autohaler contains 200 [micro]g of pirbuterol. Other studies comparing spacer devices with wet nebulizers have given 4 to 10 puffs of albuterol via inhaler at each treatment time.[13,14,16] In a histamine bronchoprovocation study, 10 puffs of albuterol administered by MDI/holding device were found to be equivalent to 2,500 [micro]g of the nebulizer solution. Based on these data, it appears that the dose of pirbuterol used approximated the dose of albuterol. As we did not perform a dose-response study, the optimal dose of pirbuterol for our population cannot be determined from this protocol.
Limitations of our study include the small sample size, and the exclusion of more severely ill asthmatics. Based on our sample size, we could detect with a power of 0.80 for a two-tailed alpha of 0.05 an absolute difference of 12.8 percentage points predicted between the two groups. Study of a larger number of patients with a wider range of airway obstruction is needed to document the efficacy of the Autohaler in the acutely ill population.
In summary, patients with moderate asthma exacerbations obtained similar benefit from [Beta]-agonists via the Autohaler as they did from a wet nebulizer. The patients were able to learn to quickly and effectively use the device in an acute care setting. The Autohaler may be an effective delivery device for patients with acute exacerbations of asthma.
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(*) From the Department of Emergency Medicine (Dr. Silverman and Ms. Greene), Long Island Jewish Medical Center, New York, NY, the Long Island Campus for the Albert Einstein College of Medicine (Ms. Flaster), Long Island, NY, and 3M Pharmaceuticals (Ms. Sellers and Dr. Colice), St. Paul, MN.
This work was supported by a grant from 3M Pharmaceuticals, maker of the Maxair Autohaler.
Manuscript received September 23, 1997; revision accepted January 30, 1998.
Correspondence to: Robert Silverman, MD, Dept of Emergency Medicine, Long Island Jewish Hospital, New Hyde Park, NY 11040
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