Antoine Guillon1, François Darrouzain2, Nathalie Heuzé-Vourc'h3, Antoine Petitcollin2, Céline Barc4, Laurent Vecellio3, Bénédicte Cormier5, Philippe Lanotte6, Pierre Sarradin4, Pierre-François Dequin1, Gilles Paintaud2, Stephan Ehrmann7. 1. CHRU de Tours, Médecine Intensive Réanimation, INSERM CIC 1415, CRICS-Triggersep, Tours, France; Université de Tours, INSERM, Centre d'étude des pathologies respiratoires (CEPR), UMR 1100, Tours, France. 2. CHRU de Tours, Pharmacologie Médicale, Tours, France. 3. Université de Tours, INSERM, Centre d'étude des pathologies respiratoires (CEPR), UMR 1100, Tours, France. 4. INRA Val de Loire, Plateforme d'infectiologie expérimentale, UE 1277, Nouzilly, France. 5. CHRU de Tours, Anatomie et cytologie pathologiques, Tours, France. 6. CHRU de Tours, Bactériologie-Virologie, Tours, France; ISP, INRA, Université de Tours, UMR1282, F-37380, Nouzilly, France. 7. CHRU de Tours, Médecine Intensive Réanimation, INSERM CIC 1415, CRICS-Triggersep, Tours, France; Université de Tours, INSERM, Centre d'étude des pathologies respiratoires (CEPR), UMR 1100, Tours, France. Electronic address: stephan.ehrmann@univ-tours.fr.
Abstract
BACKGROUND: Nebulization during mechanical ventilation is impeded by large extra-pulmonary drug deposition and long administration durations which currently limit implementation of inhaled antibiotic therapy. Direct intra-tracheal delivery using a sprayer represents an appealing alternative investigated in small animal models, but large animal data are lacking. METHODS: Amikacin was administered through intravenous infusion (20 mg/kg), nebulization (60 mg/kg) and direct intra-tracheal spray (30 mg/kg) to 10 intubated piglets, in a randomized cross-over design. Amikacin concentrations were measured in the serum and pulmonary parenchyma. Anatomic deposition was investigated using immuno-histochemistry. RESULTS: Spray delivery resulted in higher amikacin outputs than nebulization and infusion. Pulmonary inhaled delivery techniques yielded much higher lung concentrations and much lower serum concentrations than intravenous infusion. However, unlike nebulization and infusion, intra-tracheal spray delivery was associated with more than 100- and 1000-fold variability in lung concentrations between and within animals. Amikacin specific immuno-histochemistry showed consistent bronchial and alveolar drug deposition with all modalities. CONCLUSION: Nebulization remains the most reliable and simple technique to deliver inhaled amikacin uniformly to the lung during mechanical ventilation. Further development of tracheal sprays is required to take advantage of potential benefits related to high drug output and low extra-pulmonary deposition in large animals.
BACKGROUND: Nebulization during mechanical ventilation is impeded by large extra-pulmonary drug deposition and long administration durations which currently limit implementation of inhaled antibiotic therapy. Direct intra-tracheal delivery using a sprayer represents an appealing alternative investigated in small animal models, but large animal data are lacking. METHODS:Amikacin was administered through intravenous infusion (20 mg/kg), nebulization (60 mg/kg) and direct intra-tracheal spray (30 mg/kg) to 10 intubated piglets, in a randomized cross-over design. Amikacin concentrations were measured in the serum and pulmonary parenchyma. Anatomic deposition was investigated using immuno-histochemistry. RESULTS: Spray delivery resulted in higher amikacin outputs than nebulization and infusion. Pulmonary inhaled delivery techniques yielded much higher lung concentrations and much lower serum concentrations than intravenous infusion. However, unlike nebulization and infusion, intra-tracheal spray delivery was associated with more than 100- and 1000-fold variability in lung concentrations between and within animals. Amikacin specific immuno-histochemistry showed consistent bronchial and alveolar drug deposition with all modalities. CONCLUSION: Nebulization remains the most reliable and simple technique to deliver inhaled amikacin uniformly to the lung during mechanical ventilation. Further development of tracheal sprays is required to take advantage of potential benefits related to high drug output and low extra-pulmonary deposition in large animals.