Combined Bronchodilator Therapy Research Articles

Arrhythmogenicity from Combined Bronchodilator Therapy in Patients with Obstructive Lung Disease and Concomitant Ischemic Heart Disease

Twenty-four patients (five women) aged 53-72 yr with both ischemic heart disease and asthma or chronic bronchitis receiving oral beta 2-agonists also received additional bronchodilating therapy with theophylline (600 mg daily), enprofylline (600 mg daily) or placebo. The study was double-blind, randomized, triple-crossover with each regimen given for two weeks. Holter monitoring was used during 48 consecutive hours in each period. Compared with placebo, addition of theophylline and enprofylline were associated with an increased mean hourly heart rate of 6 bpm (p less than 0.001). A small, but statistically significant (p less than 0.05) increase in mean hourly frequency of premature ventricular beats (PVBs) occurred with enprofylline as compared with placebo. However, in only two patients with enprofylline (and one patient with theophylline) the increase in PVBs was such that a clinically relevant proarrhythmic effect seems possible. Furthermore, ventricular tachycardia was not more frequently observed with any xanthine than with placebo. Thus, combined oral bronchodilator therapy is not contraindicated in patients with obstructive lung disease and concomitant ischemic heart disease. Holter monitoring is recommended to assess the individual patient's response to such therapy.

Supraventricular Tachycardia in Patients with Cystic Fibrosis

Reports on arrhythmias in cystic fibrosis (CF) patients are limited. Four CF patients treated at our center had recurrent supraventricular tachycardia (SVT). Three had cor pulmonale, as evidenced by echocardiogram, and all had baseline tachycardia. Twenty-four hour Holter monitoring in three patients showed ectopic atrial pacing and premature atrial and ventricular contractions in one patient, rare PVCs in another, and SVT in all three. All patients had significant bronchospasm requiring the use of theophylline, prednisone, and frequent daily doses of beta-2 adrenergic agonists; two also used nebulized atropine. Average theophylline level for the group was 13.4 micrograms/ml during SVT. There was no correlation between pulmonary obstruction and the frequency of SVT. Factors such as cor pulmonale, ectopy, hypoxia, infection, intensive combination bronchodilator therapy, and corticosteroids probably interacted to precipitate SVT. Altered autonomic responses and a myocardial infiltrative process noted in some patients with CF may also play a role in causing arrhythmias.

1757 NO CARDIAC ARRHYTHMIAS WITH COMBINED BRONCHODILATOR THERAPY IN CHILDREN WITH ASTHMA

Theophylline (T) and beta adrenergic agonists are commonly used in combination therapy for the control of asthma. Previous animal studies have suggested that this may result in the induction of significant cardiac arrhythmias (CA). This study examined the effects of combined bronchodilator therapy in 7 children with chronic asthma (ages 9–14 years) and used 24 hour Holter monitoring (HM) to document the drug effects on cardiac rhythm. Three drug regimens were administered in random order for 24 hour periods:sustained release (SR) T alone; inhaled albuterol (A) alone; and combined SR T plus A. HM was carried out during each 24 hour drug period. During T alone and T plus A, mean trough T levels were 12.8±3.1 and 13.4±3.3 ug/ml (M±SD). For A alone, T had been withheld for 24 hours, with trough T level of 1.6±.1.7. Sequential pulmonary function testing performed for 8 hours for each drug regimen showed comparable improvement of FEV1, PEFR and FEF25–75 above baseline levels. Peak heart rate during a dosing interval was increased to a comparable degree by all treatment regimens: T=18.9±17.5 beats/min; A=12±7.6; T plus A=18.3±11.5. Only 1/7 patients had ventricular ectopy, uniform single ventricular premature depolarizations (VPD), with the mean hourly frequency identical for all treatment regimens (2.4±2.6 VPD/hour). We conclude that the combination of SR T plus A does not significantly increase heart rate more than T or A alone and does not induce significant CA.

In vitro action of combined salbutamol and theophylline on anaphylactic contractions, mediator release and cyclic 3′,5′-adenosine monophosphate in lung parenchyma

The mechanisms involved in the anti-asthmatic action of combined bronchodilator therapy was studied by determining the effects of combined salbutamol and theophylline on anaphylactic contractions, histamine release, prostaglandin (PG)F 2α release, cyclic 3′,5′-adenosine monophosphate (c-AMP) and smooth muscle tone in guinea-pig peripheral airways in vitro. Combined, salbutamol (3 × 10 −8 M) and theophylline (3 × 10 −4 M) markedly inhibited anaphylactic contractions (85.8%) in lung strips. The inhibition of anaphylactic contractions was significantly greater than inhibition of histamine and PGF 2α-induced contractions. Histamine release was reduced by 66.1% but PGF 2α was not significantly altered. Increased c-AMP was observed with combined salbutamol (3 × 10 −8 M) and theophylline (3 × 10 −4 M) in the absence of antigen. The combined effect of salbutamol and theophylline was always always greater than the sum of their individual effects. The results demonstrate that in peripheral airways theophylline potentiates the action of salbutamol both directly via smooth muscle relaxation and indirectly via inhibition in mediator release.