Aminophylline

Asthma is a major cause of emergency hospitalizations in the United States, accounting for over 450,000 admissions annually in recent years with an average hospital stay of 4.8 days in 1987. [1] Despite little evidence of efficacy, intravenous aminophylline is routinely added to beta agonist and glucocorticoid therapy in the management of hospitalized asthmatic patients, and texts continue to recommend its use. [2,3] Although hundreds of papers have been published regarding theophylline pharmacokinetics and proper monitoring of serum concentrations, cases of life-threatening toxicity and death continue to be reported. [4-7] Therapy with this agent is also costly, especially monitoring serum theophylline concentrations.

Aminophylline therapy has not been shown to add benefit to intensive inhaled beta agonist in the emergency room management of adult asthma, and its use in this setting is now discouraged. [8,9] Systemic glucocorticoid therapy has been demonstrated to be of value in acute asthma exacerbations in adults, and is routinely used in emergency room and hospitalized patients. [10,11] To our knowledge, there are no comparative studies which demonstrate the effectiveness of aminophylline therapy when it is added to inhaled beta gaonists and systemic glucocorticoids in hospitalized adult asthmatics. Therefore, we conducted a randomized, double-blind, placebo controlled study to determine if aminophylline adds any benefit to inhaled albuterol and oral prednisone therapy in hospitalized adult asthmatics. Assessment of any benefits were based primarily on serial spirometry, subjective patient rating, and duration of hospitalization.

METHODS

Patients

We enrolled 44 adult patients aged 18 to 49 with acute asthma who were seen in the emergency department (ED) in a 450-bed city-county teaching hospital over a 13-month period. All patients enrolled in the study were able to give informed consent and were suffering from an acute exacerbation of asthma without other underlying serious conditions. Diagnosis of asthma was defined by the criteria of the American Thoracic Society. [12] Further inclusion criteria were as follow: (a) failed to respond adequately to four hours of standardized treatment in the ED (albuterol, 2.5 mg nebulized every hour for four doses; methylprednisolone, 125 mg intravenously on admission to ED, and oxygen), and (b) deemed in need of hospitalization by the ED physician guided by the criteria of the American Thoracic Society. [12] Patients with chronic bronchitis or emphysema, pregnancy, respiratory failure (defined as P[CO.sub.2]>45, pH<7.35 with signs of respiratory muscle fatigue), and other complicating cardiopulmonary diseases (eg, pneumonia, decompensated heart failure) were excluded. The study was approved by the University Institutional Review Board.

Protocol

Upon admission to our institution's Clinical Research Center, bedside spirometry was performed before any treatments were given. Spirometry was performed by the investigators or by trained respiratory therapists. Spirometric values obtained included forced vital capacity, forced expiratory volume in the first second, and forced midexpiratory flow rate. Each spirometric test result was expressed as a percentage of predicted using accepted standards. [13,14] Several FVC maneuvers were done until three acceptable efforts were obtained. The best values for FVC, [FEV.sub.1] were chosen; FEF 25-75 values were selected from the best FVC maneuver. Hard copy of the flow-volume loop and volume-time curve were obtained from each maneuver; criteria for acceptance or rejection were based on the ATS Statement on Standardization of Spirometry. [15] The spirometer was calibrated daily using a 3.0 L test syringe to calibrate both volume and flow as described in the operator's manual. Spirometry was done each day of hospitalization every eight hours (8 AM, 4 PM, 12 noon) before and 15 minutes after nebulized albuterol treatments. Other laboratory values done on admission to the study included arterial blood gases, blood chemistries, chest x-ray, ECG, and serum theophylline concentration (determined by the enzyme immunoassay techniques).

Following this initial assessment, patients were randomized to receive either intravenous aminophylline (in 1 L D5 1/2 NS to run every eight hours) or intravenous placebo (same intravenous solution at same rate). In this double blind study, the hospital pharmacy kept the randomization code. To further ensure double blinding, the hospital pharmacists were instructed to give placebo loading doses and subsequent placebo partial loading doses during the course of hospitalization. For patients who received aminophylline, loading and maintenance doses were given to achieve a target concentration of 10 to 20 [microgram]/ml. Admission and daily serum theophylline concentrations were done. The randomization code was not known to the investigators until the last patient had completed the study.

Each patient received albuterol, 2.5 mg in 3 ml of saline solution nebulized via a mouthpiece from a hand held jet nebulizer, driven by 100 percent oxygen at a flow of 6 L/min every two hours for four doses and then every four hours for the duration of hospitalization. If the patient response dictated more intensive therapy, every one or two hours nebulized albuterol doses (2.5 mg) were given. Each patient received oral prednisone, 0.5 mg/kg every six hours for the duration of the study, and each patient received oxygen therapy by nasal prongs to assure at least 90 percent saturation of the hemoglobin. If additional therapy was required, subcutaneous epinephrine or terbutaline was given and/or nebulized glycopyrrolate.

Although the primary evaluation of patient response was bedside spirometry, subjective patient assessment of the treatment was also done on a scale of 1 to 5, which corresponded with much worse (1), worse (2), same (3), better (4), much better (5). [16] In addition, aminophylline and placebo groups were compared for duration of hospital stay.

Statistical Analysis

The mean and standard error of the mean were used to express the central tendency of the data. Admission and discharge data for both patient groups were compared using a two-sample Student's t-test for unpaired data. Pulmonary function tests performed at each time point were analyzed using a two-way analysis of variance (ANOVA) with one between-subject factor (placebo-aminophylline), and one within-subject factor (time, baseline [0 h] to 32 h). Subjective patient assessment was evaluated using a repeated measures ANOVA for all patients having two or more scores. Bonferroni comparisons at the 0.05 significance level were made between placebo and aminophylline at each time point. [17] Minimum detectable differences for the Bonferroni comparisons were computed for alpha = 0.05 and beta = 0.2 using the appropriate mean square error, degrees of freedom, and sample size. [18]

RESULTS

Of the 44 patients who entered the study, 39 were followed to the completion of the investigation. Two patients with prior history of intensive care unit admissions for asthma and intubation became severely ill and were transferred to the ICU where they recovered after several days. Both patients had been randomized to the aminophylline group. Three patients were discharged against medical advice. Data analysis was performed for the 39 patients who completed the study. Three of the 39 patients who finished the study were entered twice and crossed over to the opposite treatment on readmission (ie, 36 patients were analyzed for 39 admissions). The mean length of time between admission for these three patients was

Table 2--Comparison of Spirometric Values at Admission

and at Discharge *

* No statistical differences were observed between the admission and discharge value for each spirometric test (two-sample Student's t-test; p>0.1).

5.6 months (range four to eight months).

There were no significant differences in baseline admission characteristics between the placebo and aminophylline groups (Table 1). Percent predicted spirometric values before and after albuterol treatments are shown in Figures 1 to 3 for both groups. We limited our repeated measures ANOVA to the 19 patients with complete data sets through 32 hours (Fig 1 to 3). Given subject variability, our sample size was sufficient to detect a minimum difference of 16 percent between the groups of each time period with beta = .20 and alpha = .05 for the Bonferroni multiple comparisons. Although a repeated measures ANOVA could have been performed with missing data, the analysis would not be as powerful and could possibly have led to invalid conclusions. [19] Of the three patients who were readmitted to the study, one admission for each patient was used in the repeated measures ANOVA because the other three admissions had missing data points during the hospital course (eg, too ill to perform pre- and post-bronchodilator spirometry at every time point early in the course). All six admission of these three patients were included in the admission and discharge analyses. The problem of missed spirometric measurements has been previously encountered by other investigators studying severely ill asthmatics, that is, several of our patients were unable to exert the effort necessary to perform all scheduled spirometric tests.

Both groups improved markedly over the course of hospitalization with no significant differences detected either in spirometry, duration of hospital stay, or subjective patient response. Summarized in Table 2 are the spirometric values for all 39 patients in both groups at admission and discharge. Table 3 shows the

[TABULAR DATA OMITTED]

Table 4--Duration of Hospitalization

comparison of subjective patient rating, and Table 4 the duration of hospitalization. Among the more severely ill patients whose [FEV.sub.1] was [less than or equal to]35 percent predicted on admission to the hospital, analysis revealed no difference in any response parameter between the placebo group (n = 7) and aminophylline group (n = 11). Th mean serum theophylline concentration was 13.6 [+ or -] 4.1 [mu]g/ml during the course of hospitalization for the aminophylline group. Analysis of patients whose serum theophylline concentration was [less than or equal to] 15 [mu]g/ml (n = 9) vs <15 [mu]g/ml (n = 12) revealed no significant difference in any response parameter. Among patients who completed the study, two patients in the placebo group and two patients in the aminophylline group were given nebulized glycopyrrolate during the course of hospitalization. Five patients in the placebo group and three patients in the aminophylline group were given extra doses of nebulized albuterol during the hospital stay. Based on daily queries for specific side effects of nausea, vomiting, palpitations, tremor, or nervousness, eight patients in the aminophylline group had side effects (slight nervousness and tremor, five; palpitations, three; tremor only, two) and seven patients in the placebo group had side effects (slight nervousness, two; tremor, one; palpitations, two; neausea, two). These side effects were usually reported only on the first hospital day. There were no complications in the 39 patients who completed the study.

DISCUSSION

The lack of benefit of aminophylline therapy observed in this study is consistent with previous emergency room investigations. [8,9] In both the placebo and aminophylline groups, there were highly significant improvements over time, including spirometry and subjective patient ratings. It is noteworthy that both groups had a duration of hospital stay less than half the national average of 4.8 days. [1] This finding cannot be attributed to a lack of severity of illness at baseline, but rather to the specific albuterol and prednisone regimen used in this study. If our mean hospital stay of roughly two days less than the US national average is applied to potential cost savings (assume $200 per day bed charge for about 450,000 admissions), $180 million could be saved annually.

Based on current theories of acute bronchospasm and inflammation in asthma, our findings are not surprising. Intensive inhaled beta agonists provide bronchodilation that is not enhanced by aminophylline in the ER. [8,9] Glucocorticoids in relatively large doses effectively treat the inflammatory component of acute asthma. [19,11] A study similar to ours in chronic obstructive pulmonary disease other than asthma found no significant benefit of aminophylline when added to otherwise standard therapies. [20]

Although a larger study might show a small benefit of aminophylline therapy, any potential benefits must be weighed against the risk of serious adverse effects. Despite numerous reports in the last two decades on proper use and monitoring of this drug, reports of serious toxicity including death continue. [4-7] Even without serious toxicity, minor central nervous system and gastrointestinal side effects are bothersome, and serum theophylline concentration monitoring is absolutely necessary but expensive. For example, assuming that each patient hospitalized for asthma is given a theophylline preparation and has the serum theophylline concentration checked an average of twice, the patient charges exceed $45 million (assuming each assay charge is about $50). Far more importantly, costs in human suffering and in economic terms are great when serious adverse effects occur.

Further investigation is needed to establish with certainty that aminophylline does not add significant benefit to other optimal therapies for subgroups of patients. A meta-analysis of this literature was recently reported. [21] However, since our results are consistent with emergency room studies and because of new knowledge of the value of intensive beta agonist aerosols, glucocorticoids, and anticholinergic therapy [22,23] in acute asthma, we believe substantive questions have been raised about the automatic, initial use of aminophylline in hospitalized adult asthmatics. Considering the questionable efficacy, adverse effects, and costs associated with aminophylline, we feel the routine use of this drug in hospitalized adult asthmatics is not justified.

REFERENCES

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[17] Kirk RE. Experimental design, 2nd ed. Belmont, CA: Brooks/Cole Publishing Company, 1982:106-109;489-510

[18] Zar JH. Biostatistical analysis, 2nd ed. Englewood Cliffs, NJ: Prentice-Hall, Inc, 1984:135-37

[19] Fleiss JL. The design and analysis of clinical experiments. New York: John Wiley & Sons, 1986:139

[20] Rice KL, Leatherman JW, Duane PG, Snyder LS, Harmon KR, Abel J, et al. Aminophylline for acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987; 107:305-09

[21] Littenberg B. Aminophylline treatment in severe, acute asthma. JAMA 1988; 259:1678-84

[22] Rebuck AS, Chapman KR, Abboud R, Pare PD, Kreisman H, Wolkove H, et al. Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive pulmonary disease in the emergency room. Am J Med 1987; 82:59-64

[23] O'Driscoll BR, Taylor RJ, Horsley MG, Chambers DK, Bernstein A. Nebulized albuterol with and without ipratropium bromide in acute airflow obstruction. Lancet 1989; 1:1418-20

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