To establish the effect of an aerosolized synthetic surfactant (Exosurf) on pulmonary 99mTc-diethylenetriamine pentaacetic acid (DTPA) aerosol deposition and clearance, radioaerosol studies were performed at varying times and under varying conditions after surfactant inhalation in canine lungs. METHODS Twenty-three dogs had a baseline 99mTc-DTPA study; 2 days later the study was repeated after inhalation of a 1.5-ml/kg dose of Exosurf aerosolized by an ultrasonic nebulizer. The clearance half-time (T1/2) of 99mTc-DTPA from each lung was measured at different times (from 10 min to 3 hr) after Exosurf inhalation. For comparison, five animals had a 99mTc-DTPA study 10 min after inhalation of the same dose of saline as Exosurf. An additional five animals inhaled a 99mTc-DTPA-Exosurf mixture to investigate the distribution of Exosurf. RESULTS Technetium-99m-DTPA distributed uniformly without significant changes in penetration indexes before and after inhalation of Exosurf and the 99mTc-DTPA-Exosurf mixture. After Exosurf inhalation, 99mTc-DTPA clearance at 10 min (T1/2; 35.6 +/- 8.7 min; n = 6) and 40 min (29.4 +/- 6.3 min; n = 4) was significantly prolonged compared with the matched baseline values (24.7 +/- 6.4 min, p < 0.0001; and 21.7 +/- 8.9 min, p = 0.01, respectively). However, later clearance times were not prolonged. By contrast, after saline inhalation, 99mTc-DTPA distributed inhomogeneously, and clearance times T1/2) were not altered from the matched baseline values. CONCLUSIONS Aerosolized Exosurf distributes homogeneously in the lungs. Exosurf initially retards 99mTc-DTPA aerosol clearance, but 99mTc-DTPA transalveolar clearance returns to baseline rates within 1-2 hr. Technetium-99m-DTPA aerosol clearance measurements can be used to monitor the effect of inhaled Exosurf on pulmonary epithelial integrity.