PROXIMATE DELIVERY OF A LARGE EXPERIMENTAL DOSE FROM SALBUTAMOL MDI INDUCES EPITHELIAL AIRWAY LESIONS IN INTUBATED RABBITS

The delivery of aerosolized drugs by metered dose inhaler (MDI) to int ubated patients can be substantially improved by actuating the MDI thr ough a narrow catheter placed inside the tracheal tube. However, the d eposition of increased quantities of drug, surfactant, in particular o leic acid, and chlorofluorocarbon propellants on the lung surface coul d result in adverse effects not observed after oral MDI administration . To investigate this hypothesis, 42 adult intubated rabbits (six grou ps, n = 6 to 9/group) received Ventolin(R) MDI, Ventolin placebo, a pl acebo MDI containing lecithin as surfactant, instilled salbutamol sulf ate, instilled oleic acid solution, or no treatment (control). Heart r ate, invasive blood pressure, and hemoglobin oxygen saturation, record ed continuously for the 3-h experiment, were unchanged from baseline ( awake) values. Sections of trachea and lungs were reviewed blindly and graded using a four-point, nine-variable Ophoven scale. Blood was obt ained after either 1 puff or 20 puffs MDI salbutamol to determine the pharmacokinetic profile of salbutamol. Multiple doses of both Ventolin and Ventolin placebo aerosols produced significant lesions to the epi thelium of the trachea and main bronchi (p < 0.05). The histologic inj ury after lecithin placebo or salbutamol solution did not differ signi ficantly from control, and all were significantly less than that obser ved after Ventolin MDI administration. Instilled oleic acid caused gro ss airway lesions. Maximum serum concentrations of salbutamol were 4.4 +/- 1.8 ng/ml after 1 puff and 419 +/- 168 ng/ml after 20 puffs. Afte r 20 puffs, the total body clearance of salbutamol was 108 +/- 27 ml/m in/kg, volume of distribution was 3.6 +/- 1.8 L/kg, and the eliminatio n half-life was 22 +/- 7 min. These results suggest that topical admin istration of high doses of Ventolin MDI and Ventolin placebo can induc e epithelial damage. These effects are most likely due to the oleic ac id contained in the MDI formulation.