Aminophylline

We conducted a randomized, double-blind, placebocontrolled study to determine if intravenous aminophylline adds any benefit to high doses of inhaled salbutamol in patients who presented for treatment of acute asthma. We studied 94 patients (mean age, 35.6 [+ or -] 11.2 years) with moderate to severe acute asthma. All patients received therapy with salbutamol delivered with metered-dose inhaler (MDI) into a spacer device (Volumatic) in four puffs (400 [micro]g) at 10-min interval, and intravenous hydrocortisone (500 mg). Patients were randomy assigned to receive either a loading dose of intravenous aminophylline followed by a routine infusion (n=45) or an equal volume of placebo as a loading dose and infusion (n=49). The two groups showed no differences in measurements of peak expiratory flow, [FEV.sub.1], and FVC at baseline and at the end of treatment. However, the patients treated with aminophylline had significantly more adverse effects (p<0.05). There were no differences in the final mean dose of salbutamol (6.3 [+ or -] 44.5 mg for the placebo group and 5.8 [+ or -] 4.2 mg for the aminophylline group), hospital admission rate (10.2 percent for the placebo group and 9.0 percent for the aminophylline group), and mean duration of Emergency Department treatment (2.5 [+ or -] 1.83 h for the placebo group and 2.37 [+ or -] 1.75 h for the aminophylline group). The results were similar when the patients were divided in accord with the degree of respiratory obstruction (baseline [FEV.sub.1] <30 percent of predicted) and theophylline level at 30 min of treatment (placebo group patients with theophylline level<10 mg/L vs aminophylline group patients with theophylline level [greater than or equal to] 10 mg/L). We conclude that intravenous aminophylline adds to the toxicity but not the efficacy of inhaled salbutamol in the treatment of acute exacerbations of asthma.

(Chest 1994; 106:1071-76) ED=emergency department; FVC=forced vital capacity; MDI=metered-dose inhaler; PEF=peak expiratory flow;

Key words: inhaled salbutamol, intravenous aminophylline, treatment of acute asthma

Intravenously administered aminophylline is widely used together with inhaled [beta]-agonists in the treatment of patients with acute exacerbation of asthma. Early studies have established the superiority of adequate doses of [beta]-agonists over aminophylline, and subsequently studies were conducted to examine the question of the usefulness of adding aminophylline to optimal [beta]-agonist therapy in the setting of acute asthma.(1)(2)(3)(4)(5)(6)(7) Additionally, the declining use of aminophylline can be attributed to the lack of well-designed trials that prove aminophylline's efficacy(8) and to the narrow therapeutic range, side effects, and toxicity.(9)(10)(11)(12)

The preponderance of evidence suggested that the addition of aminophylline played no useful role, and this thinking is reflected in the recommendations released by the National Heart, Lung, and Blood Institute, National Asthma Educational Program Expert Panel Report on the diagnosis and management of asthma.(13) They have excluded theophylline from the treatment recommendations for the Emergency Department (ED) management of acute asthma exacerbations in children and adults.

However, the question has been reopened by three new studies that suggest that using aminophylline may lead to improved airflow and reduced duration of treatment among patients with severe asthma.(14)(15)(16)

Therefore, we conducted a reandomized, double-blind, placebo-controlled study to determine if intravenous aminophylline adds any benefit to high doses of inhaled salbutamol and intravenous hydrocortisone therapy in patients who presented for treatment of acute asthma to our ED.

METHODS

Patients

We studied 94 patients who presented to the ED of Military Hospital from Montevideo, Uruguay, for treatment of an acute exacerbation of asthma. All patients met the criteria of the American Thoracic Society (ATS).(17) The inclusion criteria for patients were as follows: (1) age between 18 and 50 years; (2) peak expiratory flow (PEF) and [FEV.sub.1] below 50 percent of predicted value; (3) excluded were patients with history of chronic cough, cardiac, hepatic, renal, or other medical disease, or pregnancy; and (4) an expressed willingness to participate in the study, with written informed consent obtained. The study was approved by the Hospital Ethics Committee.

Treatment Regimens

Patients who agreed to participate in the study received salbutamol delivered with metered-dose inhaler (MDI) into a spacer device (Volumatic, Allen & Hanburys Ltd, England) in four puffs actuated one at a time, at 10-min intervals (100 [micro]g per actuation). Volumatic is a pear-shaped extension tube of 750 ml and 22 cm length with a one-way inhalation valve. Each puff was followed by two deep inhalations from the spacer. They also received hydrocortisone, 500 mg intravenously. At once, patients were randomly assigned in a double-blind fashion to receive a loading dose of either aminophylline, 5.6 mg/kg of body weight over 20 min (n=45), or an equivalent volume of placebo (0.9 sodium chloride) (n=49), followed by a constant infusion of aminophylline, 0.9 mg/kg/h, or an equivalent volume of placebo. Each patient was given [O.sub.2] by nasal prongs at a rate of 4 L/min.

Measurements

The following variables were measured in each patient immediately before starting treatment and, in 30-min intervals until hospital discharge or hospital admission, within the first 6 h after presentation: heart rate, respiratory rate, systolic and diastolic blood pressure, PEF, [FEV.sub.1], FVC, accessory-muscle use, dyspnea, and wheezing. Heart rate was measured from continuous electrocardiogram. The PEF was measured with a flowmeter (Mini-Wright Peak Flowmeter, Armstrong Industries Inc, Northbrook, Ill). The highest of three values was recorded. The [FEV.sub.1] and FVC were measured using a spirometer (Vitalograph Compact Spirometer, Vitalograph Ltd, Maids Moreton House, Buckingham, UK) that was calibrated daily using a test syringe. Three successive maximal expiratory curves were recorded at each assessment, and the highest value was selected, according to the criteria of the ATS.(18) Accessory-muscle use was defined as visible retraction of the sternocleidomastoid muscles. Dyspnea was defined as the patient's own assessment of breathlessness. Wheezing was defined as musical or whistling breath sounds heard with a stethoscope during expiration. Serum theophylline concentrations were determined from all subjects pretreatment and at 30 min of treatment after the completion of the loading infusion.

Patients were admitted to the hospital according to standard and accepted guidelines for admission: previous ED treatment within 24 h, the self-reported (patient) inability to attain preexacerbation status, if accessory-muscle use was abated, if wheezing was judged minimal to complete resolved, if they were free of dyspnea, and the inability of the patient to walk 20 m without exacerbation of symptoms and signs, despite 6 h of ED treatment. The decision to discharge or admit a patient was made by senior ED staff without knowledge of previous patient group allocation. At the end of the therapy (either to hospital admission or to home), the patient was asked to indicate the presence or absence of each five symptoms (nausea, palpitations, tremor, anxiety, and headache). To compare side effects in each group, we compiled a composite symptom score for each subject by arbitrarily assigning each symptom a value of 1 if present and 0 if absent. Thus, for example, a subject who reported all five symptoms was assigned a score of 5, and a subject reporting no symptoms was assigned a score of 0.

Statistical Analysis

Standard sample-size calculations for a [FEV.sub.1] increase of 18 percent with [alpha]=0.05 and [beta]=0.20 yielded a necessary sample size of approximately 92.(19) The Mann-Whitney U test, the [chi.sup.2] test with Yates' correction, and unpaired Student's t test were used to compare baseline and discharge data for both patient groups. Changes in PEF, FVC, and [FEV.sub.1] were evaluated using a two-way analysis of variance with one between-subject factor (placeboaminophylline), and one within-subject factor (time, baseline, 30 min, 60 min, and end of treatment), with the Newman-Keul's multiple range test. All probabilities reported are two tailed. All data are reported as mean [+ or -] 1 SD. A p value of less than 0.05 was considered statistically significant.

RESULTS

The two groups were comparable with respect for any measured variable (Table 1).

[TABULAR DATA OMITTED]

The number of patients who used corticosteroids within the past 7 days was 18 (36.7 percent) in the placebo group and 15 (33.3 percent) in the aminophylline group (p>0.2). Twenty-six patients (53.0 percent) used methylxanthines 24 h before presenting in the placebo group, and 21 (47.7 percent) in the aminophylline group (p>0.2). Finally, 31 patients (63.2 percent) had received [beta]-agonists pretreatment in the placebo group and 29 (65.9 percent) in the aminophylline group (p>0.2).

The spirometric values at 30, 60, and 120 min are shown in Figure 1. Mean PEF improved significantly over baseline values for the placebo and aminophylline groups (p<0.001 by analysis of variance). The magnitude of placebo and aminophylline PEF improvements were significant at 30 min (75.7 [+ or -] 46.0 L/min and 73.1 [+ or -] 49.2 L/min, p<0.01), and at the end of treatment (112.4 [+ or -] 52.4 L/min and 113.3 [+ or -] 62.8 L/min, p<0.01). Mean FVC improved significantly over pretreatment values for both groups (p<0.001). The placebo and aminophylline improvements were significant at 30 min (0.68 [+ or -] 0.44 L and 0.62 [+ or -] 0.47 L, respectively, p<0.01) and at the end of treatment (0.94 [+ or -] 0.58 L and 0.87 [+ or -] 0.54 L, p<0.01). Finally, the same pattern held for changes in [FEV.sub.1]: at 30 min, [FEV.sub.1] increased 0.51 [+ or -] 0.30 L in the placebo group and 0.48 [+ or -] 0.38 L in the aminophylline group (p<0.01), and at the end of treatment, [FEV.sub.1] rose 0.75 [+ or -] 0.41 L in the placebo group and 0.68 [+ or -] 0.45 L in the aminophylline group. However, there was no significant difference between both groups for any variable at any time point studied.

[CHART OMITTED]

At final disposition, both groups did not present significant differences. The mean duration of ED treatment was 2.50 [+ or -] 1.83 h in the placebo group and 2.37 [+ or -] 1.75 h in the aminophylline group (p>0.2). The hospital admission rate did not differ between both groups; of nine admitted patients, five (10.2 percent) were from the placebo group and four (9 percent) were from the aminophylline group (p>0.2 by [[chi].sup.2] test). Similar results were obtained when patients admitted to the hospital were examined separately (Table 2).

[TABULAR DATA OMITTED]

The final mean dose of salbutamol was 63 puffs, equivalent to 6.3 mg (range between 12 puffs or 1.2 mg and 148 puffs or 14.8 mg) for the placebo group and 58 puffs, equivalent to 5.8 mg (range between 12 puffs or 1.2 mg and 148 puffs or 14.8 mg) for the aminophylline group (p>0.2).

At discharge from the ED, the mean theophylline level in the patients receiving aminophylline was 14.7 [+ or -] 7.4 mg/L (median, 12.0 mg/L with an interquartile range of 10 to 17.5 mg/L), whereas the mean level in the placebo group was 3.3 [+ or -] 4.53 mg/L (median, 2.6 mg/L with an interquartile range of 0 to 4.5 mg/L) (p<0.001). Further, among subjects receiving aminophylline, at 30 min of treatment, 62 percent of discharged patients had theophylline levels of more than 10 mg/L, and all the admitted patients had theophylline levels of more than 10 mg/L. Linear regression analysis did not reveal any significant correlation between initial and final plasma theophylline concentrations over the course of the study and improvement in [FEV.sub.1] in either placebo group or aminophylline group.

The patients were divided in accord with the theophylline level at 30 min of treatment (placebo group patients with serum theophylline level <10 mg/L, n=40, vs aminophylline group patients with serum theophylline level [greater than or equal to] 10 mg/L, n=38). There were no differences in ED treatment duration (2.43 [+ or -] 1.88 h and 2.36 [+ or -] 1.79 h respectively, p>0.2), baseline PEF as mean percent of predicted (34.0 [+ or -] 10.9 percent and 29.7 [+ or -] 12.8 percent, respectively, p=0.13), final PEF as mean percent of predicted (56.7 [+ or -] 19.4 percent and 51.0 [+ or -] 17.6 percent, respectively, p=0.17), baseline [FEV.sub.1] as mean percent of predicted (28.2 [+ or -] 9.55 percent and 27.9 [+ or -] 14.4 percent, respectively, p>0.2), and final [FEV.sub.1] as mean percent of predicted (53.6 [+ or -] 17.0 percent and 51.9 [+ or -] 20.9 percent, respectively, p>0.2).

When we considered the severity of respiratory obstruction and the theophylline level at 30 min of treatment, there were no differences between groups (placebo group patients with [FEV.sub.1] <30 percent predicted on admission to the ED, and serum theophylline level <10 mg/L vs aminophylline group patients with [FEV.sub.1] <30 percent predicted on admission to the ED, and serum theophylline level [greater than or equal to] 10 mg/L) (Table 3).

[TABULAR DATA OMITTED]

The overall symptom score in patients treated with aminophylline (1.2 [+ or -] 1.25, mean [+ or -] SD) was significantly greater than the score in the placebo group (0.65 [+ or -] 0.86, p<0.05, Mann-Whitney U test), and there was a higher incidence in four (nausea, palpitation, anxiety, and headache) of five symptoms monitored (Fig 2). Tremor was the most common side effect in the placebo group (30 percent) and nausea was more frequent in the aminophylline group (37.5 percent).

[CHART OMITTED]

Finally, the two groups produced a nonsignificant decrease in the heart rate. At the end of treatment, the placebo group showed a decrease of -1.24 [+ or -] 11.9 percent (median, 0 percent with an interquartile range of -8.00 to 7.00 percent) and the aminophylline group showed a decrease of -3.45 [+ or -] 16.0 (median, -7.00 percent with an interquartile range of -13 to 5.0 percent) (p>0.2).

DISCUSSION

As in previous studies,(2)(3)(4)(5) we found that the addition of intravenous aminophylline in standard doses to a regimen of intensive inhaled salbutamol, for moderate to severe acute exacerbations of asthma, does not improve short-term outcome. At final disposition, placebo and aminophylline groups did not differ in airflow, hospital admission rate, and time in the ED. Moreover, combined therapy with aminophylline and salbutamol did cause a higher incidence of side effects and a significantly higher overall adverse symptom score than did therapy with salbutamol alone.

With respect to the possibility of drug interaction between previous therapy and the study treatments as an explanation of these results, we can reject this possibility. Thus, there were no significant differences when we considered the severity of respiratory obstruction and the theophylline level at 30 min of treatment. Additionally, we did not find any positive correlation between the initial and final plasma theophylline concentrations over the course of the study and the changes in [FEV.sub.1]. In the same way, previous treatments with corticosteriods and [beta]-agonists did not differ between groups.

Recently, in a randomized, double-blind, placebocontrolled study, Wrenn et al(16) reported that the administration of aminophylline to acutely symptomatic patients with asthma or chronic obstructive pulmonary disease markedly decreased hospital admissions. Surprising, the authors also found that adding aminophylline to [beta]-agonists had no effect on pulmonary function, physician assessment of the response of treatment, or time in the ED. It is difficult to understand how aminophylline could influence hospital admission rates differentially without producing identifiable clinical or physiologic differences (or both) between groups. One possibility suggested by the protocol is that factors other than, or in addition to, objective measures of severity were used in deciding whom to admit. Although the authors did not participate in the disposition of the patients, one must wonder about the uniformity of the application of the hospital admission criteria by those who did.(20)

Finally, we did not confirm results from Lalla et al,(14) who found significant differences between placebo and aminophylline groups in [FEV.sub.1] at 1 h and 4 h of treatment. Nevertheless, this article presents important methodologic problems, the most significant being an inadequate sample size (n=18). Similarly, the mean theophylline concentration of the aminophylline group obtained after 4 h of treatment was 8.31 [+ or -] 2.71, suggesting that many patients of this group were undertreated.

In summary, our study suggests that intravenous aminophylline adds little or nothing to the short-term bronchodilator effect of an inhaled [beta]-adrenergic agonist in patients with acute exacerbated asthma. On the basis of this, we conclude that aminophylline is weak and potentially toxic bronchodilator with a narrow therapeutic window and numerous drug interactions that make its use complicated. It suggests that repeated inhalation of high doses of a [beta]-adrenergic alone delivery by MDI with a spacer device (Volumatic) may be the optimal bronchodilator therapy for ED treatment of acute exacerbations of asthma. When the combination of systemically administered corticosteroid and inhaled salbutamol is used in the treatment of patients with moderate to severe acute asthma, addition of aminophylline may not be justified.

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