Treatment of diaphragmatic fatigue with inhaled aminophylline therapy in an experimental canine model: an open-label, dose-ranging, pharmacologic study.

BACKGROUND

Diaphragmatic fatigue may contribute to the development of respiratory failure. Although aminophylline administered IV has been widely used to treat diaphragmatic fatigue, to date it has not been used in aerosol formulation for this purpose.

OBJECTIVE

The aim of this study was to assess the efficacy of inhaled aminophylline on contractility of fatigued diaphragm in an experimental canine model.

METHODS

This open-label, dose-ranging, pharmacologic study was conducted at the Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba (Ibaraki, Japan). Diaphragmatic fatigue was induced in healthy, male, mongrel dogs by intermittent supramaximal bilateral electrophrenic stimulation at a low frequency (20 Hz) applied for 30 minutes. Immediately after the end of the fatigue-producing period, group 1 received inhaled vehicle only, group 2 received inhaled aminophylline 12.5 mg/mL, group 3 received inhaled aminophylline 25 mg/mL, and group 4 was infused with verapamil 0.1 mg/kg·min during inhalation of aminophylline 25 mg/mL. Diaphragmatic contractility was assessed using transdiaphragmatic pressure (Pdi).

RESULTS

Twenty-eight dogs were used in the study (7 dogs were assigned to each treatment group). When fatigue was established, Pdi at low-frequency stimulation decreased significantly from baseline in all groups (all P<0.05), and no significant change in Pdi was found at high-frequency stimulation. In groups 2 and 3, during aminophylline inhalation, Pdi at 20-Hz stimulation increased significantly from fatigued values (both P<0.05). Pdi increased significantly more in group 3 than in group 2 (P<0.05). In group 4, infusion of verapamil offset the increase in Pdi seen with aerosolized aminophylline in fatigued diaphragm. The integrated electrical activity of the diaphragm did not change significantly in any group.

CONCLUSIONS

Inhaled aminophylline significantly improved contractility of fatigued diaphragm in a dose-related manner in this experimental canine model (P<0.05). Its potent effect may be caused by transmembrane calcium movement.