Aminophylline for acute exacerbations of chronic obstructive pulmonary disease. A controlled trial

Study Objective: To determine the efficacy of intravenous aminophylline in the treatment of patients hospitalized for exacerbation of chronic obstructive pulmonary disease. Design: Randomized, double-blind, placebo-controlled trial during the first 72 hours of hospitalization. Patients: Thirty patients admitted from the emergency room or walk-in clinic with the primary diagnosis of an exacerbation of chronic obstructive pulmonary disease. Twenty-eight patients completed the study; 2 patients, 1 receiving placebo and 1 receiving aminophylline, were removed from the study because of respiratory failure requiring mechanical ventilation. Interventions: Patients received either intravenous aminophylline or placebo, in addition to nebulized, inhaled metaproterenol, 0.3 mL of a 5% solution every 6 hours; methylprednisolone, 0.5 mg/kg body weight every 6 hours intravenously; ampicillin, 500 mg orally every 6 hours (tetracycline or trimethoprim-sulfamethoxazole were substituted in penicillin-allergic patients); and supplemental oxygen as needed. Aminophylline infusion rates were adjusted by an unblinded investigator to achieve theophylline levels of 72 to 83 μmol/L. Changes were also made in placebo infusion rates to maintain the double-blind design. Measurements and Main Results: The forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) before and after metaproterenol inhalation were measured twice daily by a blinded investigator, who also administered a verbal dyspnea index with a scale of 1 to 10 and questioned patients regarding possible side effects of treatment (tremor, palpitations, nausea, or vomiting). Arterial blood gas measurements at 72 hours were compared with those obtained on admission. Significant improvements in FEV₁ and FVC measured before and after metaproterenol treatment and in dyspnea occurred over time in both treatment groups (p < 0.05 for all measurements). However, there were no significant differences between the placebo and aminophylline groups in any of the spirometric measurements or the dyspnea indices (p > 0.5 in all five analyses). The mean increases (± SE) in P(O₂) of 1.9 (± 0.5) kPa with placebo and 1.7 (± 0.7) kPa with aminophylline and the mean decreases in P(CO₂) of 0.5 (± 0.4) kPa with placebo and 1.2 (± 0.4) kPa with aminophylline were not significantly different (p > 0.6 for P(O₂), p > 0.2 for P(CO₂)). Although the difference in the overall incidence of side effects between the two treatment groups, 1 of 13 subjects in the placebo group and 7 of 15 in the aminophylline group was not statistically significant (0.05 < p < 0.10), there was a statistically significant difference in the incidence of gastrointestinal complaints; 6 of 15 and 0 of 13 patients in the aminophylline and placebo groups, respectively (p < 0.05). Conclusions: We were unable to show that the administration of parenteral aminophylline provides significant additional benefits when added to an otherwise standard treatment regimen in patients with chronic obstructive pulmonary disease exacerbations. Although further benefits from aminophylline in this setting might be shown by studies of much larger numbers of patients, these should be weighed against the demonstrated adverse effects.