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Comparison of two dosage regimens of albuterol in acute asthma
Comparison of Two Dosage Regimens of Albuterol in Acute Asthma E. R. McFadden, Jr., MD, Louise Strauss, RN, BSN, Rana Hejal, MD, Gale Galan, MD, Lisa Dixon, RN BACKGROUND: The standard therapy for acute episodes of asthma in the United States consists of three 2.5-mg doses of aerosolized albuterol given every 20 minutes. Whether this approach represents optimum therapy has never been tested. METHODS: This study employed a prospective, sequential design in which the effects of two doses of 5.0 mg of aerosolized albuterol administered during 40 minutes (high dose) were contrasted with the standard dose (three 2.5-mg doses). Improvements in pulmonary function, clinical resolution of the asthma attacks, and admission rates were used as primary endpoints. Both regimens were part of an overall care plan that involved objective, pretested decision algorithms. RESULTS: In an emergency department, 160 patients who presented with acute exacerbations of asthma received either standard (n 5 80) or high-dose (n 5 80) albuterol treatment. There were no significant baseline differences in gender, racial com-
position, clinical signs and symptoms, medication use, or peak expiratory flow (PEF) between the groups. Both treatment schedules were effective, but the high-dose regimen increased lung function more rapidly and to a greater extent than standard-dose therapy. It also resulted in lower charges to third party payers. More subjects attained the discharge criteria quicker and left the emergency department with peak expiratory flows closer to normal. Fewer patients in the high-dose group were admitted, but this trend did not quite reach statistical significance. CONCLUSIONS: Two 5.0-mg treatments of aerosolized albuterol at a 40-minute interval provide effective therapy for acute exacerbations of asthma. This combination of dose and frequency promotes maximum bronchodilatation, increases efficiency, and reduces the risks of undertreatment. Am J Med. 1998;105:12–17. q1998 by Excerpta Medica, Inc.
T
METHODS
he current recommendations for the first-line management of acute episodes of asthma call for the administration of an aerosolized b2 agonist every 20 minutes for 1 hour (1– 4). In the United States, this generally means giving three 2.5-mg doses of albuterol (5– 8). Although this strategy relieves symptoms in a large percentage of patients and produces a dose-response increase in pulmonary function (5,6), it has been empirically derived. The assumption that it represents optimal therapy has never been rigorously tested. Since the goal of treatment is to terminate an attack as rapidly as feasible while maximizing lung function (1– 4), it might be more efficacious to administer greater quantities of medication at shorter increments of time. We compared the effects of two treatments of 5.0 mg of aerosolized albuterol given during 40 minutes with those seen with the usual approach in patients with acute exacerbations of asthma. From the Division of Pulmonary and Critical Care Medicine and the Department of Emergency Medicine, University Hospitals, and the Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio. Supported in part by Specialized Center of Research Grant HL-37117 from the National Heart, Lung, and Blood Institute, and General Clinical Research Center Grant MO 1 RR00080 from the National Center for Research Resources. Requests for reprints should be addressed to E. R. McFadden, Jr., MD, Division of Pulmonary and Critical Care Medicine, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio 441065067. Manuscript submitted July 26, 1997 and accepted in revised form March 24, 1998. 12
q1998 by Excerpta Medica, Inc. All rights reserved.
Asthmatic patients 18 years of age or older who came to the emergency department of the University Hospitals of Cleveland with an acute exacerbation of their illness were eligible for participation. Upon presentation, each subject entered a care path in which they underwent clinical and physiologic evaluations and received medications according to a standard format (5,6,9). Symptoms, medical history, and medication usage were recorded on a printed form, as were blood pressure, pulse, respiration, and the presence or absence of cyanosis, diaphoresis, accessory muscle use, dyspnea, and wheezing. The best of three measurements of peak expiratory flow (PEF) were recorded as the subject’s initial state of airway obstruction. These observations were reported in absolute terms as well as a percentage of predicted normal (10). Pulse oximetry was performed with the patient breathing room air, and oxygen was given as required. The first group of subjects received 2.5 mg of aerosolized albuterol in 3 cc of saline every 20 minutes for three doses (standard dosage). Following each aerosol, peak flow measurements were repeated. Admission and discharge decisions were made according to predetermined criteria (5). After the third treatment, the participants were considered ready to be sent home if they were asymptomatic, free of accessory muscle use, had absent or diminished wheezing, and achieved a peak expiratory flow $60% of predicted. Those not meeting these indications were given methylxanthines and glucocorticoids 0002-9343/98/$19.00 PII S0002-9343(98)00132-6
Two Albuterol Regimens in Acute Asthma/McFadden et al
and reassessed periodically. If they subsequently met the discharge requirements, they were released; if not, they were admitted. The second group of subjects received two doses of 5.0 mg of albuterol aerosolized in 3 cc of saline 20 minutes apart (high dosage). Peak flow was examined after each treatment. Following the second aerosol, the presence or absence of the discharge criteria were assessed. All other aspects of the care path remained constant. The length of stay in the emergency department was obtained by subtracting the time at presentation from the time that the final evaluation was made. The adequacy of the therapeutic regimens was evaluated by determining the number of patients who returned to the emergency department for additional care within 24 hours or who were admitted to hospital for 1 day or less (5). Financial data were derived by summing the charges for medication and testing and adding them to an hourly utilization and physician fee that had been multiplied by the average time spent there by each group (5). (These calculations are not intended to convey precise financial data, but rather to provide a monetary overview for comparative purposes.) The study was approved by the Institutional Review Board for Human Investigation. Since b2-selective sympathomimetic agents such as albuterol are standard firstline treatments for acute asthma, and since the dose schedules that we employed were within recommended ranges (4), the committee believed that it was not necessary to obtain a second consent form in addition to the usual one permitting emergency treatment. The emergency department staff was told that we were seeking to ascertain the most effective means of treating acute asthma. The briefings were presented in a neutral fashion, and care was taken to avoid communicating any expectation of results. Information sheets were copied and collected weekly. Data compilation and analysis were performed by investigators who did not have any role in the delivery of health care to the patients. Statistical evaluations were accomplished with paired and unpaired t tests, and chi-square analysis. Continuous data are reported as mean 6 standard dose. A two-tailed P value of #0.05 was considered significant.
RESULTS One hundred and sixty acutely ill asthmatic patients were enrolled. Eighty received the standard dose of albuterol and 80 were given the high dose. The populations were similar in age, race, gender, signs, symptoms, and pulmonary function (Table 1). Our subjects consisted predominantly of black women in their mid to late thirties. Tachypnea and tachycardia were common. Diaphoresis and cyanosis were infrequent. The mean baseline peak
Table 1. Demographic, Clinical, and Physiologic Characteristics of Study Subjects at Presentation*
Age, years Black, % Female, % Respirations per minute Heart rate per minute Wheezing, % Accessory muscle use, % Diaphoresis, % Cyanosis, % Oxygen saturation, %† Peak expiratory flow, L/min Peak expiratory flow as % of predicted
StandardDose Albuterol (n 5 80)
HighDose Albuterol (n 5 80)
P
38 6 2 81 79 26 6 1 102 6 2 92 49 9 0 96 6 0.5 162 6 8
36 6 2 91 70 25 6 1 97 6 2 96 36 9 0 96 6 0.5 188 6 7
0.56 0.50 0.15 0.10 0.06 0.18 0.13 0.28 .0.99 .0.99 0.02
35 6 2
39 6 1
0.11
* Plus-minus values are mean 6 SE. † Measured by pulse oximetry.
expiratory flow was less than 40% of normal. The mean absolute value for this variable was slightly less in the standard dose group (D 5 26 L/min; P 5 0.02), but there were no differences in percentages of predicted flows. The majority were using one or more bronchodilators on a regular basis, particularly inhaled b2 agonists (Table Table 2. Percentages of Patients in Each Group Who Were Using Various Medications for Asthma at Baseline
Medication Bronchodilator medications Inhaled b2 agonists only† Methylxanthines only† Ipratropium only† Anti-inflammatory medications Inhaled steroids only† Nedocromil/Cromolyn only† Oral steroids only† Combinations* No medication
StandardDose Albuterol (n 5 80)
HighDose Albuterol (n 5 80)
P
76 63 20 40 10 10 0 34
90 80 34 35 2 9 0 38
0.02 0.01 0.05 0.30 0.06 0.80 .0.99 0.60
29 3 3 0 8 1 30 6
26 1 4 0 18 0 36 6
0.86 0.34 0.75 .0.99 0.07 0.30 0.71 .0.99
* Indicates bronchodilator and anti-inflammatory medications. † Only medication used. July 1998
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Figure 1. Cumulative dose-response effects on peak expiratory flow (PEF) as percentage of predicted for the standard (SD) and high-dose (HD) regimens of albuterol. Data are shown as mean 6 SE.
2). The overall consumption of these drugs and the use of bronchodilators, in particular adrenergic agonists, was greater in the subjects in the high-dose group. Typically, medications were employed in combination. A little over a third of the patients took anti-inflammatory agents, mainly inhaled glucocorticoids. More patients in the high-dose group were taking oral steroids, but the difference did not quite reach statistical significance (P 5 0.07). Both dosage regimens improved lung function (Figure 1). Peak expiratory flows improved in a stimulus-response fashion as the cumulative quantity of medication increased. Each point on the curve was significantly greater than baseline (P #0.001 for all comparisons), and the effects of the two regimens were similar, whether the data were expressed in absolute terms, percentages of baseline, or as a percentage of predicted normal. A single treatment of 5 mg of albuterol produced the same mean effect on peak expiratory flow (55% 6 2% of predicted) as 2.5 mg given twice (51% 6 2%; P 5 0.21), and 10 mg led to greater bronchodilatation (peak flow 63% 6 2% predicted) than did 7.5 mg (56% 6 2%; P ,0.02). In terms of efficacy, the high-dose (5 mg) treatment produced larger improvements at each treatment point (Figure 2). After the first standard dose (2.5 mg) treatment (at 20 minutes) mean peak flow was 47% 6 2% of predicted, while in the high-dose group it was 55% 6 2% (P ,0.001). Following the second treatment the resulting levels were 51% 6 2% in the standard dose group and 63% 6 2% of normal in the high-dose group (P ,0.001). 14
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Analyzing the data as percentage changes from baseline values showed the same pattern. In the high-dose group, 33 of the subjects could have been released from the emergency department with a single 5.0 mg dose of albuterol (ie, they achieved a peak expiratory flow $60% of predicted), whereas 32 patients in the standard dose group needed two treatments to reach the same endpoint. Fewer patients in the high-dose group (25 of 80, 31%) required admission than in the standard dose group (37 of 80, 46%), but this difference did not quite reach statistical significance (P 5 0.06). The rates of recurrence were similar in the two groups. Three of the subjects originally sent home following the standard-dose treatment and 4 who received the highdose treatment suffered relapses and returned to the emergency department within 24 hours for additional therapy (P 5 0.90). Five standard-dose and 3 high-dose subjects who had been hospitalized were discharged within 24 hours and were considered to be inappropriate admissions (P 5 0.83). The average inpatient stays for the remainder of the subjects were 4.0 6 0.5 in the standarddose group and 3.6 6 0.5 days in the high-dose group (P 5 0.72). The mean length of stay in the emergency department was 89 6 6 minutes in the standard-dose group, and 75 6 3 minutes in the high-dose group (P 5 0.06). Total emergency department charges to third party payers were 24% lower in the high-dose group ($561) than in the standarddose group ($734, P ,0.01). Stratifying the groups by final disposition altered these results slightly (Figure 3). There were major differences between the subjects sent home and those who were hos-
Figure 2. Changes in peak expiratory flow (PEF) as percentage of predicted with each treatment period with standard (SD) and high-dose (HD) albuterol. Data points are shown as mean 6 SE. Treatment refers to the number of nebulizations given.
Two Albuterol Regimens in Acute Asthma/McFadden et al
Figure 3. Cumulative dose-response effects on peak expiratory flow (PEF) as percentage of predicted for the standard (SD) and high-dose (HD) treatment programs in subjects who were discharged and those who were admitted. Data are shown as mean 6 SE.
pitalized. In subjects discharged to home, the exacerbations terminated rapidly and both the single and cumulative 5.0 mg doses of albuterol increased the peak expiratory flows by about 50% from baseline. The next treatment in each arm then improved peak flows close to the lower limit of normal (72% 6 2% in the standarddose group; 73% 6 2% in the high-dose group). In these patients, there were no statistical differences between the effects of 7.5 and 10.0 mg. The patients who did not improve presented with more severe obstruction (P ,0.001), and those in the high-dose group had better initial peak flows (P 5 0.005). Both treatments improved peak flows significantly (P ,0.05 for all comparisons), but the overall cumulative effect was small, and the peak flows remained less than 45% of predicted. At each point, however, the high-dose group improved more (P ,0.05).
DISCUSSION We sought to provide information on the optimal dose of albuterol for use in resolving acute exacerbations of asthma. Our results demonstrate that three doses of 2.5 mg of this agent every 20 minutes and 2 doses of 5.0 mg every 20 minutes are both effective forms of treatment.
Each protocol achieved prompt resolution of the attacks with few return visits or inappropriate admissions. The larger doses, however, provided some distinct advantages. Overall, the high-dose (5 mg) regimen increased lung function more rapidly and to a greater extent than the standard (2.5 mg) approach. Patients attained the discharge criteria more quickly and left the emergency department with peak expiratory flows that were closer to normal (Figures 1 and 2). In fact, 60% of those ultimately discharged in the high-dose group could have been sent home within 20 minutes. It took twice as much treatment, and thus twice the time, to achieve this endpoint with the standard dose. There were fewer admissions with the high-dose regimen, although this difference did not reach statistical significance (P 5 0.06). Similarly, the high-dose protocol, was associated with a decreased (P 5 0.06) length of stay in the emergency department. Given the limitations of studies such as these in which clinicians have multiple responsibilities and are not in constant attendance to the subject during all phases of treatment, this finding was not entirely unexpected. Although differences in length of stay were not statistically significant, the charges to third party payers were approximately 24% lower in the high-dose group. In our institution this would amount to savings of more than $100,000 per year. Since each participant in this study had to complete all parts of the protocol before final disposition, these estimates may represent only part of what may be achieved. Since the majority of the costs incurred by patients with asthma involve the treatment of acute decompensations (11), widespread adoption of the high-dose regimen might have a substantial effect. We believe that the high-dose regimen was well tolerated, but since data on side effects were not routinely gathered, we cannot objectively confirm this impression. This is an important limitation as attempts to speed resolution must always be balanced against the development of untoward reactions. On the other hand, the quantities of albuterol that we used are commonly recommended (4) and provide the pharmacological equivalent to 0.5 mg of drug given intravenously, with plasma levels of approximately 8 –10 mg/mL (12). Typically, such amounts have not been associated with untoward cardiac or musculoskeletal problems even when continuously administered (13,14). They can, however, occasionally cause unwanted toxicity, so careful monitoring is essential. The lack of controlled studies that have evaluated the relative utility of various doses of sympathomimetic agents makes confirmation of our conclusions difficult. Nonetheless, available data are consistent with our findings. Douglas and associates (15) did not find any differences among the effects of 1.25, 2.5, or 5.0 mg of albuterol, but this investigation had a small sample size and only used single doses of medication. In contrast, Schur and colleagues (16) in children and Nelson et al (17) in July 1998
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adults demonstrated that larger quantities of albuterol and metaproterenol, respectively, led to better results than did smaller ones. Unfortunately, neither of these trials were designed to determine the quantity of b agonist that led to the optimal effect. Most recently, Colacone and coworkers (8) administered 2.5 mg of albuterol every 30 minutes to symptomatic asthmatic patients until pulmonary function stabilized. Although the aim of their study was to evaluate the relative merits of different delivery techniques, and not to determine the optimum amount of medication to use in emergency situations, they found that 5.0 to 10.0 mg of albuterol produced the most consistent results. An obvious question is whether even greater amounts of adrenergic agonist would have been more efficacious. Our data, combined with those in the literature (7,8,18), suggest that the answer will be no. One problem that plagues attempts at dose ranging is the temporal heterogeneity of the bronchodilator response. Some patients respond quite quickly while others require days to reach a given level of functional relief (5,6,9,19,20). The net effect in a study at any time is the mean of these responses. Sensitive individuals move the therapeutic effects to the left, while insensitive ones skew the curve to the right (Figure 3). In responsive patients, 10 mg of albuterol did not improve lung function significantly more than 7.5 mg did, strongly suggesting that these patients had reached the top of the stimulus-response relationship. If this supposition is correct, then administering more medication beyond this point would only increase side effects. Further study is necessary to establish this hypothesis, but plateaus in lung function, similar in magnitude to those we observed, can be found in other studies in which the cumulative dose of albuterol equalled 10 mg per hour or more (7,8,12,13,18). We believe that it is unlikely that our findings were affected by the type of patients recruited or the experimental protocol employed. Our observations were obtained in a large number of unselected individuals in a typical urban emergency department using a simple clinical protocol that incorporated predetermined, experimentally verified, endpoints (5). While the subjects in the two arms were enrolled at different times of the year (winter and spring), before initiating these studies we prospectively tracked the demographic data, medication usage, admission patterns, and therapeutic responses of all asthmatic patients who presented to our emergency department on a monthly basis for 3 years (5,6,9). The current study population did not differ in any appreciable way from our usual patients with asthma. We designed this study—in which one treatment was followed up for a period of time and then supplanted by the second—so that we could collect data in a non-research– oriented environment without interfering with its primary mission. In our institution, urgent care is provided by rotating 16
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contract physicians whose chief responsibility is the delivery of clinical services. This lack of continuity, combined with the service orientation of the department, markedly limits the successful conduct of clinical trials unless the research goals blend into medical management. Such an environment does, however, provide a practical testing ground in which the advantages and disadvantages of a given treatment can be evaluated by experienced clinicians. Our study was designed to be sensitive to these issues and to allow the caregivers to follow well-defined routines without being distracted from their fundamental duties. Similar protocols have been used successfully in the past to investigate other treatment modalities (9). Our results suggest that the majority of asthmatic patients can leave an urgent care center within 20 to 40 minutes of arrival if given two aerosol treatments of 5.0 mg of albuterol. If there are concerns about side effects, the second dose could be reduced to 2.5 mg without any loss of effectiveness. Conversely, failure to respond to 5.0 mg of albuterol with an increase in peak expiratory flow to at least 40% to 45% of predicted is a clear indication for hospitalization. Subjects who did not achieve this endpoint in the emergency department required 3.6 6 0.5 days of inpatient care before their attacks terminated. Hence, there seems to be little point in prolonging the emergency department stay in these patients to see how they will do with more medication. Our data suggest that such patients can now be identified within 20 minutes.
REFERENCES 1. National Asthma Education Program. Expert Panel Report. Executive summary: guidelines for the diagnosis and management of asthma. Bethesda, Md: US Department of Health and Human Services, 1991; NHLBI NAEP Publication No. 92-3091. 2. International Consensus Report of Diagnosis and Treatment of Asthma. 1992; National Heart, Lung and Blood Institute, NIH Publication No. 92-3091. 3. Global Initiative for Asthma. National Heart, Lung, and Blood Institute and World Health Organization. 1995; NIH Publication No. 95-3659. 4. National Asthma Education and Prevention Program. Highlights of the Expert Panel Report 11: guidelines for the diagnosis and management of asthma. Bethesda, Md: US Department of Health and Human Services, 1997. 5. McFadden ER Jr, Elsanadi N, Dixon L, et al. Protocol therapy for acute asthma: therapeutic benefits and cost savings. Am J Med. 1995;99:651– 661. 6. Strauss L, Hejal R, Galan G, et al. Observations on the effects of aerosolized albuterol in acute asthma. Am J Respir Crit Care Med. 1997;155:454 – 458. 7. Rudnitsky GS, Everlein RS, Schoffstall JM, et al. Comparison of intermittent and continuously nebulized albuterol for treatment of asthma in an urban emergency department. Ann Emerg Med. 1993; 22:1842–1846. 8. Colacone A, Afilalo M, Wokove N, Kreisman H. A comparison of albuterol administered by metered dose inhaler (and holding chamber) or wet nebulizer in acute asthma. Chest. 1993;104:835– 841.
Two Albuterol Regimens in Acute Asthma/McFadden et al 9. McFadden ER Jr, Elsanadi N, Strauss L, et al. The influence of parasympatholytics on the resolution of acute attacks of asthma. Am J Med. 1997;102:7–13. 10. Leiner GC, Abramowitz S, Mall M, et al. Expiratory peak flow rate. Standard values for normal subjects. Use as a clinical test of ventilatory function. Am Rev Respir Dis. 1963;88:644 – 651. 11. Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation of asthma in the United States. NEJM. 1992;326:862– 866. 12. Salmeron S, Brochard L, Mal H, et al. Nebulized versus intravenous albuterol in hypercapnic acute asthma. Am J Respir Crit Care Med. 1994;149:1466 –1470. 13. Resiner C, Kotch A, Dworkin G. Continuous versus frequent intermittent nebulization of albuterol in acute asthma: a randomized, prospective study. Ann Allergy Asthma Immunol. 1995;75:41– 47. 14. Levitt MA, Gambrioli EF, Fink JB. Comparative trial of continuous nebulization versus metered-dose inhaler in the treatment of acute bronchospasm. Ann Emerg Med. 1995;26:273–277. 15. Douglas JG, Rafferty P, Fergusson RJ, et al. Nebulized salbutamol
16.
17.
18.
19.
20.
without oxygen in severe acute asthma: how effective and how safe? Thorax. 1985;40:180 –183. Schuh S, Reider MJ, Canny G, et al. Nebulized albuterol in acute childhood asthma: comparison of two doses. Pediatrics. 1990;86: 509 –513. Nelson MS, Hofstadter A, Parker J, Hargis C. Frequency of inhaled metaproterenol in the treatment of acute asthma exacerbation. Ann Emerg Med. 1990;19:21–25. Lin RY, Sauter D, Newman T, et al. Continuous versus intermittent albuterol nebulization in the treatment of acute asthma. Ann Emerg Med. 1993;22:1847–1853. Rossing TH, Fanta CH, Goldstein DH, et al. Emergency therapy of asthma: comparison of the acute effects of parenteral and inhaled sympathomimetics and infused aminophylline. Am Rev Respir Dis. 1980;122:365–371. Fanta CH, Rossin RH, McFadden ER Jr. Emergency room treatment of asthma: relationships among therapeutic combinations, severity of obstruction and the time course of response. Am J Med. 1982;72:416 – 422.
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position, clinical signs and symptoms, medication use, or peak expiratory flow (PEF) between the groups. Both treatment schedules were effective, but the high-dose regimen increased lung function more rapidly and to a greater extent than standard-dose therapy. It also resulted in lower charges to third party payers. More subjects attained the discharge criteria quicker and left the emergency department with peak expiratory flows closer to normal. Fewer patients in the high-dose group were admitted, but this trend did not quite reach statistical significance. CONCLUSIONS: Two 5.0-mg treatments of aerosolized albuterol at a 40-minute interval provide effective therapy for acute exacerbations of asthma. This combination of dose and frequency promotes maximum bronchodilatation, increases efficiency, and reduces the risks of undertreatment. Am J Med. 1998;105:12–17. q1998 by Excerpta Medica, Inc.
T
METHODS
he current recommendations for the first-line management of acute episodes of asthma call for the administration of an aerosolized b2 agonist every 20 minutes for 1 hour (1– 4). In the United States, this generally means giving three 2.5-mg doses of albuterol (5– 8). Although this strategy relieves symptoms in a large percentage of patients and produces a dose-response increase in pulmonary function (5,6), it has been empirically derived. The assumption that it represents optimal therapy has never been rigorously tested. Since the goal of treatment is to terminate an attack as rapidly as feasible while maximizing lung function (1– 4), it might be more efficacious to administer greater quantities of medication at shorter increments of time. We compared the effects of two treatments of 5.0 mg of aerosolized albuterol given during 40 minutes with those seen with the usual approach in patients with acute exacerbations of asthma. From the Division of Pulmonary and Critical Care Medicine and the Department of Emergency Medicine, University Hospitals, and the Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio. Supported in part by Specialized Center of Research Grant HL-37117 from the National Heart, Lung, and Blood Institute, and General Clinical Research Center Grant MO 1 RR00080 from the National Center for Research Resources. Requests for reprints should be addressed to E. R. McFadden, Jr., MD, Division of Pulmonary and Critical Care Medicine, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio 441065067. Manuscript submitted July 26, 1997 and accepted in revised form March 24, 1998. 12
q1998 by Excerpta Medica, Inc. All rights reserved.
Asthmatic patients 18 years of age or older who came to the emergency department of the University Hospitals of Cleveland with an acute exacerbation of their illness were eligible for participation. Upon presentation, each subject entered a care path in which they underwent clinical and physiologic evaluations and received medications according to a standard format (5,6,9). Symptoms, medical history, and medication usage were recorded on a printed form, as were blood pressure, pulse, respiration, and the presence or absence of cyanosis, diaphoresis, accessory muscle use, dyspnea, and wheezing. The best of three measurements of peak expiratory flow (PEF) were recorded as the subject’s initial state of airway obstruction. These observations were reported in absolute terms as well as a percentage of predicted normal (10). Pulse oximetry was performed with the patient breathing room air, and oxygen was given as required. The first group of subjects received 2.5 mg of aerosolized albuterol in 3 cc of saline every 20 minutes for three doses (standard dosage). Following each aerosol, peak flow measurements were repeated. Admission and discharge decisions were made according to predetermined criteria (5). After the third treatment, the participants were considered ready to be sent home if they were asymptomatic, free of accessory muscle use, had absent or diminished wheezing, and achieved a peak expiratory flow $60% of predicted. Those not meeting these indications were given methylxanthines and glucocorticoids 0002-9343/98/$19.00 PII S0002-9343(98)00132-6
Two Albuterol Regimens in Acute Asthma/McFadden et al
and reassessed periodically. If they subsequently met the discharge requirements, they were released; if not, they were admitted. The second group of subjects received two doses of 5.0 mg of albuterol aerosolized in 3 cc of saline 20 minutes apart (high dosage). Peak flow was examined after each treatment. Following the second aerosol, the presence or absence of the discharge criteria were assessed. All other aspects of the care path remained constant. The length of stay in the emergency department was obtained by subtracting the time at presentation from the time that the final evaluation was made. The adequacy of the therapeutic regimens was evaluated by determining the number of patients who returned to the emergency department for additional care within 24 hours or who were admitted to hospital for 1 day or less (5). Financial data were derived by summing the charges for medication and testing and adding them to an hourly utilization and physician fee that had been multiplied by the average time spent there by each group (5). (These calculations are not intended to convey precise financial data, but rather to provide a monetary overview for comparative purposes.) The study was approved by the Institutional Review Board for Human Investigation. Since b2-selective sympathomimetic agents such as albuterol are standard firstline treatments for acute asthma, and since the dose schedules that we employed were within recommended ranges (4), the committee believed that it was not necessary to obtain a second consent form in addition to the usual one permitting emergency treatment. The emergency department staff was told that we were seeking to ascertain the most effective means of treating acute asthma. The briefings were presented in a neutral fashion, and care was taken to avoid communicating any expectation of results. Information sheets were copied and collected weekly. Data compilation and analysis were performed by investigators who did not have any role in the delivery of health care to the patients. Statistical evaluations were accomplished with paired and unpaired t tests, and chi-square analysis. Continuous data are reported as mean 6 standard dose. A two-tailed P value of #0.05 was considered significant.
RESULTS One hundred and sixty acutely ill asthmatic patients were enrolled. Eighty received the standard dose of albuterol and 80 were given the high dose. The populations were similar in age, race, gender, signs, symptoms, and pulmonary function (Table 1). Our subjects consisted predominantly of black women in their mid to late thirties. Tachypnea and tachycardia were common. Diaphoresis and cyanosis were infrequent. The mean baseline peak
Table 1. Demographic, Clinical, and Physiologic Characteristics of Study Subjects at Presentation*
Age, years Black, % Female, % Respirations per minute Heart rate per minute Wheezing, % Accessory muscle use, % Diaphoresis, % Cyanosis, % Oxygen saturation, %† Peak expiratory flow, L/min Peak expiratory flow as % of predicted
StandardDose Albuterol (n 5 80)
HighDose Albuterol (n 5 80)
P
38 6 2 81 79 26 6 1 102 6 2 92 49 9 0 96 6 0.5 162 6 8
36 6 2 91 70 25 6 1 97 6 2 96 36 9 0 96 6 0.5 188 6 7
0.56 0.50 0.15 0.10 0.06 0.18 0.13 0.28 .0.99 .0.99 0.02
35 6 2
39 6 1
0.11
* Plus-minus values are mean 6 SE. † Measured by pulse oximetry.
expiratory flow was less than 40% of normal. The mean absolute value for this variable was slightly less in the standard dose group (D 5 26 L/min; P 5 0.02), but there were no differences in percentages of predicted flows. The majority were using one or more bronchodilators on a regular basis, particularly inhaled b2 agonists (Table Table 2. Percentages of Patients in Each Group Who Were Using Various Medications for Asthma at Baseline
Medication Bronchodilator medications Inhaled b2 agonists only† Methylxanthines only† Ipratropium only† Anti-inflammatory medications Inhaled steroids only† Nedocromil/Cromolyn only† Oral steroids only† Combinations* No medication
StandardDose Albuterol (n 5 80)
HighDose Albuterol (n 5 80)
P
76 63 20 40 10 10 0 34
90 80 34 35 2 9 0 38
0.02 0.01 0.05 0.30 0.06 0.80 .0.99 0.60
29 3 3 0 8 1 30 6
26 1 4 0 18 0 36 6
0.86 0.34 0.75 .0.99 0.07 0.30 0.71 .0.99
* Indicates bronchodilator and anti-inflammatory medications. † Only medication used. July 1998
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Figure 1. Cumulative dose-response effects on peak expiratory flow (PEF) as percentage of predicted for the standard (SD) and high-dose (HD) regimens of albuterol. Data are shown as mean 6 SE.
2). The overall consumption of these drugs and the use of bronchodilators, in particular adrenergic agonists, was greater in the subjects in the high-dose group. Typically, medications were employed in combination. A little over a third of the patients took anti-inflammatory agents, mainly inhaled glucocorticoids. More patients in the high-dose group were taking oral steroids, but the difference did not quite reach statistical significance (P 5 0.07). Both dosage regimens improved lung function (Figure 1). Peak expiratory flows improved in a stimulus-response fashion as the cumulative quantity of medication increased. Each point on the curve was significantly greater than baseline (P #0.001 for all comparisons), and the effects of the two regimens were similar, whether the data were expressed in absolute terms, percentages of baseline, or as a percentage of predicted normal. A single treatment of 5 mg of albuterol produced the same mean effect on peak expiratory flow (55% 6 2% of predicted) as 2.5 mg given twice (51% 6 2%; P 5 0.21), and 10 mg led to greater bronchodilatation (peak flow 63% 6 2% predicted) than did 7.5 mg (56% 6 2%; P ,0.02). In terms of efficacy, the high-dose (5 mg) treatment produced larger improvements at each treatment point (Figure 2). After the first standard dose (2.5 mg) treatment (at 20 minutes) mean peak flow was 47% 6 2% of predicted, while in the high-dose group it was 55% 6 2% (P ,0.001). Following the second treatment the resulting levels were 51% 6 2% in the standard dose group and 63% 6 2% of normal in the high-dose group (P ,0.001). 14
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Analyzing the data as percentage changes from baseline values showed the same pattern. In the high-dose group, 33 of the subjects could have been released from the emergency department with a single 5.0 mg dose of albuterol (ie, they achieved a peak expiratory flow $60% of predicted), whereas 32 patients in the standard dose group needed two treatments to reach the same endpoint. Fewer patients in the high-dose group (25 of 80, 31%) required admission than in the standard dose group (37 of 80, 46%), but this difference did not quite reach statistical significance (P 5 0.06). The rates of recurrence were similar in the two groups. Three of the subjects originally sent home following the standard-dose treatment and 4 who received the highdose treatment suffered relapses and returned to the emergency department within 24 hours for additional therapy (P 5 0.90). Five standard-dose and 3 high-dose subjects who had been hospitalized were discharged within 24 hours and were considered to be inappropriate admissions (P 5 0.83). The average inpatient stays for the remainder of the subjects were 4.0 6 0.5 in the standarddose group and 3.6 6 0.5 days in the high-dose group (P 5 0.72). The mean length of stay in the emergency department was 89 6 6 minutes in the standard-dose group, and 75 6 3 minutes in the high-dose group (P 5 0.06). Total emergency department charges to third party payers were 24% lower in the high-dose group ($561) than in the standarddose group ($734, P ,0.01). Stratifying the groups by final disposition altered these results slightly (Figure 3). There were major differences between the subjects sent home and those who were hos-
Figure 2. Changes in peak expiratory flow (PEF) as percentage of predicted with each treatment period with standard (SD) and high-dose (HD) albuterol. Data points are shown as mean 6 SE. Treatment refers to the number of nebulizations given.
Two Albuterol Regimens in Acute Asthma/McFadden et al
Figure 3. Cumulative dose-response effects on peak expiratory flow (PEF) as percentage of predicted for the standard (SD) and high-dose (HD) treatment programs in subjects who were discharged and those who were admitted. Data are shown as mean 6 SE.
pitalized. In subjects discharged to home, the exacerbations terminated rapidly and both the single and cumulative 5.0 mg doses of albuterol increased the peak expiratory flows by about 50% from baseline. The next treatment in each arm then improved peak flows close to the lower limit of normal (72% 6 2% in the standarddose group; 73% 6 2% in the high-dose group). In these patients, there were no statistical differences between the effects of 7.5 and 10.0 mg. The patients who did not improve presented with more severe obstruction (P ,0.001), and those in the high-dose group had better initial peak flows (P 5 0.005). Both treatments improved peak flows significantly (P ,0.05 for all comparisons), but the overall cumulative effect was small, and the peak flows remained less than 45% of predicted. At each point, however, the high-dose group improved more (P ,0.05).
DISCUSSION We sought to provide information on the optimal dose of albuterol for use in resolving acute exacerbations of asthma. Our results demonstrate that three doses of 2.5 mg of this agent every 20 minutes and 2 doses of 5.0 mg every 20 minutes are both effective forms of treatment.
Each protocol achieved prompt resolution of the attacks with few return visits or inappropriate admissions. The larger doses, however, provided some distinct advantages. Overall, the high-dose (5 mg) regimen increased lung function more rapidly and to a greater extent than the standard (2.5 mg) approach. Patients attained the discharge criteria more quickly and left the emergency department with peak expiratory flows that were closer to normal (Figures 1 and 2). In fact, 60% of those ultimately discharged in the high-dose group could have been sent home within 20 minutes. It took twice as much treatment, and thus twice the time, to achieve this endpoint with the standard dose. There were fewer admissions with the high-dose regimen, although this difference did not reach statistical significance (P 5 0.06). Similarly, the high-dose protocol, was associated with a decreased (P 5 0.06) length of stay in the emergency department. Given the limitations of studies such as these in which clinicians have multiple responsibilities and are not in constant attendance to the subject during all phases of treatment, this finding was not entirely unexpected. Although differences in length of stay were not statistically significant, the charges to third party payers were approximately 24% lower in the high-dose group. In our institution this would amount to savings of more than $100,000 per year. Since each participant in this study had to complete all parts of the protocol before final disposition, these estimates may represent only part of what may be achieved. Since the majority of the costs incurred by patients with asthma involve the treatment of acute decompensations (11), widespread adoption of the high-dose regimen might have a substantial effect. We believe that the high-dose regimen was well tolerated, but since data on side effects were not routinely gathered, we cannot objectively confirm this impression. This is an important limitation as attempts to speed resolution must always be balanced against the development of untoward reactions. On the other hand, the quantities of albuterol that we used are commonly recommended (4) and provide the pharmacological equivalent to 0.5 mg of drug given intravenously, with plasma levels of approximately 8 –10 mg/mL (12). Typically, such amounts have not been associated with untoward cardiac or musculoskeletal problems even when continuously administered (13,14). They can, however, occasionally cause unwanted toxicity, so careful monitoring is essential. The lack of controlled studies that have evaluated the relative utility of various doses of sympathomimetic agents makes confirmation of our conclusions difficult. Nonetheless, available data are consistent with our findings. Douglas and associates (15) did not find any differences among the effects of 1.25, 2.5, or 5.0 mg of albuterol, but this investigation had a small sample size and only used single doses of medication. In contrast, Schur and colleagues (16) in children and Nelson et al (17) in July 1998
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adults demonstrated that larger quantities of albuterol and metaproterenol, respectively, led to better results than did smaller ones. Unfortunately, neither of these trials were designed to determine the quantity of b agonist that led to the optimal effect. Most recently, Colacone and coworkers (8) administered 2.5 mg of albuterol every 30 minutes to symptomatic asthmatic patients until pulmonary function stabilized. Although the aim of their study was to evaluate the relative merits of different delivery techniques, and not to determine the optimum amount of medication to use in emergency situations, they found that 5.0 to 10.0 mg of albuterol produced the most consistent results. An obvious question is whether even greater amounts of adrenergic agonist would have been more efficacious. Our data, combined with those in the literature (7,8,18), suggest that the answer will be no. One problem that plagues attempts at dose ranging is the temporal heterogeneity of the bronchodilator response. Some patients respond quite quickly while others require days to reach a given level of functional relief (5,6,9,19,20). The net effect in a study at any time is the mean of these responses. Sensitive individuals move the therapeutic effects to the left, while insensitive ones skew the curve to the right (Figure 3). In responsive patients, 10 mg of albuterol did not improve lung function significantly more than 7.5 mg did, strongly suggesting that these patients had reached the top of the stimulus-response relationship. If this supposition is correct, then administering more medication beyond this point would only increase side effects. Further study is necessary to establish this hypothesis, but plateaus in lung function, similar in magnitude to those we observed, can be found in other studies in which the cumulative dose of albuterol equalled 10 mg per hour or more (7,8,12,13,18). We believe that it is unlikely that our findings were affected by the type of patients recruited or the experimental protocol employed. Our observations were obtained in a large number of unselected individuals in a typical urban emergency department using a simple clinical protocol that incorporated predetermined, experimentally verified, endpoints (5). While the subjects in the two arms were enrolled at different times of the year (winter and spring), before initiating these studies we prospectively tracked the demographic data, medication usage, admission patterns, and therapeutic responses of all asthmatic patients who presented to our emergency department on a monthly basis for 3 years (5,6,9). The current study population did not differ in any appreciable way from our usual patients with asthma. We designed this study—in which one treatment was followed up for a period of time and then supplanted by the second—so that we could collect data in a non-research– oriented environment without interfering with its primary mission. In our institution, urgent care is provided by rotating 16
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contract physicians whose chief responsibility is the delivery of clinical services. This lack of continuity, combined with the service orientation of the department, markedly limits the successful conduct of clinical trials unless the research goals blend into medical management. Such an environment does, however, provide a practical testing ground in which the advantages and disadvantages of a given treatment can be evaluated by experienced clinicians. Our study was designed to be sensitive to these issues and to allow the caregivers to follow well-defined routines without being distracted from their fundamental duties. Similar protocols have been used successfully in the past to investigate other treatment modalities (9). Our results suggest that the majority of asthmatic patients can leave an urgent care center within 20 to 40 minutes of arrival if given two aerosol treatments of 5.0 mg of albuterol. If there are concerns about side effects, the second dose could be reduced to 2.5 mg without any loss of effectiveness. Conversely, failure to respond to 5.0 mg of albuterol with an increase in peak expiratory flow to at least 40% to 45% of predicted is a clear indication for hospitalization. Subjects who did not achieve this endpoint in the emergency department required 3.6 6 0.5 days of inpatient care before their attacks terminated. Hence, there seems to be little point in prolonging the emergency department stay in these patients to see how they will do with more medication. Our data suggest that such patients can now be identified within 20 minutes.
REFERENCES 1. National Asthma Education Program. Expert Panel Report. Executive summary: guidelines for the diagnosis and management of asthma. Bethesda, Md: US Department of Health and Human Services, 1991; NHLBI NAEP Publication No. 92-3091. 2. International Consensus Report of Diagnosis and Treatment of Asthma. 1992; National Heart, Lung and Blood Institute, NIH Publication No. 92-3091. 3. Global Initiative for Asthma. National Heart, Lung, and Blood Institute and World Health Organization. 1995; NIH Publication No. 95-3659. 4. National Asthma Education and Prevention Program. Highlights of the Expert Panel Report 11: guidelines for the diagnosis and management of asthma. Bethesda, Md: US Department of Health and Human Services, 1997. 5. McFadden ER Jr, Elsanadi N, Dixon L, et al. Protocol therapy for acute asthma: therapeutic benefits and cost savings. Am J Med. 1995;99:651– 661. 6. Strauss L, Hejal R, Galan G, et al. Observations on the effects of aerosolized albuterol in acute asthma. Am J Respir Crit Care Med. 1997;155:454 – 458. 7. Rudnitsky GS, Everlein RS, Schoffstall JM, et al. Comparison of intermittent and continuously nebulized albuterol for treatment of asthma in an urban emergency department. Ann Emerg Med. 1993; 22:1842–1846. 8. Colacone A, Afilalo M, Wokove N, Kreisman H. A comparison of albuterol administered by metered dose inhaler (and holding chamber) or wet nebulizer in acute asthma. Chest. 1993;104:835– 841.
Two Albuterol Regimens in Acute Asthma/McFadden et al 9. McFadden ER Jr, Elsanadi N, Strauss L, et al. The influence of parasympatholytics on the resolution of acute attacks of asthma. Am J Med. 1997;102:7–13. 10. Leiner GC, Abramowitz S, Mall M, et al. Expiratory peak flow rate. Standard values for normal subjects. Use as a clinical test of ventilatory function. Am Rev Respir Dis. 1963;88:644 – 651. 11. Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation of asthma in the United States. NEJM. 1992;326:862– 866. 12. Salmeron S, Brochard L, Mal H, et al. Nebulized versus intravenous albuterol in hypercapnic acute asthma. Am J Respir Crit Care Med. 1994;149:1466 –1470. 13. Resiner C, Kotch A, Dworkin G. Continuous versus frequent intermittent nebulization of albuterol in acute asthma: a randomized, prospective study. Ann Allergy Asthma Immunol. 1995;75:41– 47. 14. Levitt MA, Gambrioli EF, Fink JB. Comparative trial of continuous nebulization versus metered-dose inhaler in the treatment of acute bronchospasm. Ann Emerg Med. 1995;26:273–277. 15. Douglas JG, Rafferty P, Fergusson RJ, et al. Nebulized salbutamol
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without oxygen in severe acute asthma: how effective and how safe? Thorax. 1985;40:180 –183. Schuh S, Reider MJ, Canny G, et al. Nebulized albuterol in acute childhood asthma: comparison of two doses. Pediatrics. 1990;86: 509 –513. Nelson MS, Hofstadter A, Parker J, Hargis C. Frequency of inhaled metaproterenol in the treatment of acute asthma exacerbation. Ann Emerg Med. 1990;19:21–25. Lin RY, Sauter D, Newman T, et al. Continuous versus intermittent albuterol nebulization in the treatment of acute asthma. Ann Emerg Med. 1993;22:1847–1853. Rossing TH, Fanta CH, Goldstein DH, et al. Emergency therapy of asthma: comparison of the acute effects of parenteral and inhaled sympathomimetics and infused aminophylline. Am Rev Respir Dis. 1980;122:365–371. Fanta CH, Rossin RH, McFadden ER Jr. Emergency room treatment of asthma: relationships among therapeutic combinations, severity of obstruction and the time course of response. Am J Med. 1982;72:416 – 422.
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