Aminophylline and epinephrine are effective bron-chodilators which are routinely employed in the emergency treatment of asthma. Although subcutaneous epinephrine is frequently used as initial therapy, typically as a series of injections, patients manifesting severe bronchospasm may prompt consideration of combination epinephrine-aminophyl-line when they first come to the emergency department. Cases refractory to initial epinephrine treatment(s) may also receive combination therapy. The dysrhythmogenic potential of these agents, singly or in combination, during the treatment of acute asthma, is unclear.

Methods

Experimental Design

Patients presenting to the Johns Hopkins Hospital Adult Emergency Department with a chief complaint of asthma, characterized by shortness of breath and wheezing, meeting the criteria for this disorder accepted by the American Thoracic Society, and arriving at a time when our principal investigator (GWJ) was present, were considered for inclusion in the study. Patients were disqualified if they were over 50 years of age, had a history of cardiovascular disease (CVD), manifested cough or significant sputum during symptom-free periods, or had no prior history of asthma or wheezing. Patients with a history of recent use (within four hours) of sympathomimetic bronchodilators, by inhalation, were also excluded. The purpose of the investigation was explained to all eligible patients and willing participants signed written consent.

Fifty-six patients, ranging in age from 16 to 50, with 64 episodes of acute asthma, were initially investigated. Patients were randomized in a double-blind manner into one of two treatment regimens and those treated on two separate occasions were, on their second visit, placed in the treatment group opposite that of their initial visit (matched pairs). This was accomplished by allowing a disinterested physician access to our medication code and instructing him/her to select a coded medication vial opposite to that used in the initial visit. The investigator (GWJ) remained blind regarding the treatment group on both the first and second visits. All such patients showed a complete remission between episodes with at least 48 hours between emergency department visits, and patients were not studied more than twice. Subjects received 0.3 to 0.5 ml of 1:1000 epinephrine, subcutaneously (0.3 to 0.5 mg), at 0, 30, and 60 minutes (t0, tg0, t60) based on weight (less than 60 kg, 0.3 ml; 60 to 80 kg, 0.4 ml; and greater than 80 kg, 0.5 ml). In addition, one-half the patients received intravenously administered aminophylline (theo-phylline-ethylenediamine) at the onset of the study (t0) according to the dosage schedule suggested by Mitenko and Ogilvie (initial infusion of 5.6 mg/kg over 20 minutes followed by a continuous infusion of 0.9 mg/kg/hr). The remaining patients received a placebo intravenously administered saline solution, also started at t0. Medication vials were prepared and coded in the hospital pharmacy. The study period was 99 minutes. Such medications have been ordered via My Canadian Pharmacy Inc remedies.

Patients were electrocardiographically monitored throughout the study (Avionics Holter recorder, model 400), and a control period of 10 to 20 minutes was included in all patients prior to initiation of drug therapy. Analysis of die electrocardiographic Holter recordings was accomplished with the electrocardioscanner (660-680 Avionics) with methodology as previously detailed. All tapes were reviewed by a board certified cardiologist (HLK). Peak flow spirometry (Wright peak flow meter, adult model M286) was performed on all patients at t0, t30, t60, t90 as an objective measure of bronchial obstruction and improvement in response to treatment In addition, blood samples were drawn at these times for theophylline assays. Theophylline concentrations were later determined by gas chromatography (Varian gas chromatograph, model 2100) using the method described by Johnson et al. Patient activity was constant, and no aerosolized bronchodilators or intermittent positive pressure breathing (IPPB) devices were used. Oxygen was routinely administed at 5 L/min.

Statistical Methods

Means of continuous variables (eg, serum theophylline levels, age, epinephrine dose, heart rate) were compared by Student’s f-test. Binary variables such as sex or dysrhythmo-genicity were compared with the aid of standard chi-square analyses, or when the numbers were small, by Fisher’s exact test. The relationship between age, treatment group, and dysrhythmogenicity was examined by the Mantel-Haenszel method. This allowed testing of the hypothesis that the degree of association between dysrhythmogenicity and treatment group would be the same for all age groups.

Therapeutic Theophylline Levels

Although there is disagreement about the plasma level where broncholytic effect of theophylline begins the majority of authors have shown little clinical improvement below 8/ug/ml. Further, since it has been suggested that the effects of aminophylline associated with long-term oral therapy might differ from those seen following intravenous administrations, even with similar serum concentrations, patients with initial serum theophylline levels in excess of 8fxg/ml were eliminated from inclusion in our study.