title: Intratracheal administration of perfluorochemical-gentamicin suspension: a comparison to intravenous administration in normal and injured lungs.
abstract: Respiratory infections can lead to acute lung injury and perfusion abnormalities. We hypothesized that intratracheal (IT) administration of a perfluorochemical (PFC) gentamicin (G) suspension as compared to intravenous (IV) administration of gentamicin will result in higher lung tissue levels of gentamicin, while maintaining safe serum levels. To test this hypothesis, 21 lambs with normal and acid injured lungs were studied for 4 hr, using 2 different drug delivery methods, IT and IV. Lungs were injured with warm HCl acid in saline lavage, followed by partial liquid ventilation with perflubron (bolus FRC = 20 mL/kg). G at a dose of 5 mg/kg was delivered either IT (G-PFC; 20 mL/kg) or IV (aqueous injection with IT 20 mL/kg PFC alone). Throughout the study, serum G levels, arterial blood gases, respiratory system compliance, and mean arterial blood pressure were measured. Lung tissue G levels were measured at 4 hr and averaged across lobes. Physiologic gas exchange and pulmonary function were maintained throughout the protocol for both the normal and injured lungs. Intravenously administered G resulted in an initial 5-min serum concentration of 43 +/- 2.5 mcg/mL, followed by an exponential decline over the 4-hr protocol to a level of 2.1 +/- 0.23 mcg/mL at hr 4. The intratracheally administered G suspension resulted in a 5-min serum concentration of 1.8 +/- 0.98 mcg/mL and remained relatively constant throughout the protocol, with a 4-hr level of 1.6 +/- 0.29 mcg/mL. With respect to lung tissue G levels, IT administration was significantly more effective in delivering the drug to the normal lungs than IV (31.4 +/- 3.3 mcg/g vs. 4.0 +/- 0.7 mcg/g) 4 hr after administration. In the lung injury group, there was a small but significant difference in lung tissue G levels, with the IT-administered perfluorochemical-G suspension achieving greater levels than the IV-administered G (11.9 +/- 0.52 mcg/g vs. 10.1 +/- 0.8 mcg/g). Additionally, the drug delivered IV and IT in both the normal and injured lung models was homogeneously distributed throughout the lung. These data show that G lung tissue levels in both normal and injured lungs were higher in the IT group when compared to IV administration. The results of this study demonstrate that in normal and injured lungs, homogeneous G lung tissue levels can be more effectively achieved at lower serum levels when delivered IT in a G-PFC suspension as compared to IV administration.
authors.affiliation: Bryn Mawr Hospital, Bryn Mawr, Pennsylvania, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Cox
authors.forename: A B
authors.initials: AB
authors.lastname: Cullen
authors.forename: M R
authors.initials: MR
authors.lastname: Wolfson
authors.forename: T H
authors.initials: TH
authors.lastname: Shaffer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005466:Fluorocarbons; D005839:Gentamicins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D008168:Lung / Q000737:chemistry; D008171:Lung Diseases / Q000188:drug therapy*; D012756:Sheep; D014132:Trachea
chemical_list: D000900:Anti-Bacterial Agents; D005466:Fluorocarbons; D005839:Gentamicins