Improved pulmonary distribution of recombinant human Cu/Zn superoxide dismutase, using a modified ultrasonic nebulizer

Prophylactic, intratracheal instillation of recombinant human Cu/Zn superoxide dismutase (rhSOD) has been shown to lessen lung injury produced by 48 h of hyperoxia and mechanical ventilation in neonatal piglets. However, instillation of small volumes of rhSOD intratracheally would not be expected to result in uniform pulmonary distribution. Aerosolization is a technique that may improve pulmonary distribution of drugs, but is limited by the poor efficiency of most nebulizers. A newly modified ultrasonic nebulizer was tested to assess pulmonary distribution of rhSOD compared to that achieved by intratracheal instillation. rhSOD was dual-labeled with technetium-99m (99mTc) and a fluorescent analog (permitting quantitative and qualitative assessments of pulmonary distribution), and administered to neonatal piglets by intratracheal instillation or by aerosolization. Intratracheal instillation of rhSOD to piglets when supine resulted in nonuniform distribution, with most of the drug being found in the right caudal lobe, and localized in airways. Placing animals in 30 degrees of Trendelenburg and administering half the dose in the left and half in the right lateral decubitus positions improved distribution, but alveolar deposition remained patchy. Aerosolization using a modified ultrasonic nebulizer uniformly delivered 45.8 +/- 3.8% of the rhSOD to the lungs that had been placed in the nebulizer. The rhSOD was still active and present in airways and alveoli in a homogeneous fashion. We conclude that intratracheal instillation of rhSOD in small volumes results in nonuniform pulmonary distribution, while aerosolization enhances rhSOD distribution and alveolar deposition. This has important implications for ongoing clinical trials of rhSOD for the prevention of acute and chronic lung injury in premature neonates.