The delivery of aerosolized drugs by metered dose inhaler (MDI) to intubated patients can be substantially improved by actuating the MDI through a narrow catheter placed inside the tracheal tube. However, the deposition of increased quantities of drug, surfactant, in particular oleic acid, and chlorofluorocarbon propellants on the lung surface could result in adverse effects not observed after oral MDI administration. To investigate this hypothesis, 42 adult intubated rabbits (six groups, n = 6 to 9/group) received Ventolin MDI, Ventolin placebo, a placebo MDI containing lecithin as surfactant, instilled salbutamol sulfate, instilled oleic acid solution, or no treatment (control). Heart rate, invasive blood pressure, and hemoglobin oxygen saturation, recorded 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 obtained 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 epithelium of the trachea and main bronchi (p < 0.05). The histologic injury after lecithin placebo or salbutamol solution did not differ significantly from control, and all were significantly less than that observed after Ventolin MDI administration. Instilled oleic acid caused gross 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. After 20 puffs, the total body clearance of salbutamol was 108 +/- 27 ml/min/kg, volume of distribution was 3.6 +/- 1.8 L/kg, and the elimination half-life was 22 +/- 7 min.(ABSTRACT TRUNCATED AT 250 WORDS)