View Abstract

A3287 - Lung Ultrasound and Microbubbles Enhance Aminoglycoside Efficacy in the Lung in E.Coli-Induced Pneumonia and ARDS
Author Block: W. L. Lee1, M. Sugiyama2, H. Raheel3, V. Mintsopoulos3, N. Goldenberg4, J. Batt5, L. J. Brochard6, M. Kuliszewski7, M. Kolios8, W. M. Kuebler9, H. Leong-Poi10, R. Karshafian8; 1Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON, Canada, 2Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, 3Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada, 4Anesthesia, University of Toronto, Toronto, ON, Canada, 5Medicine, St Michaels Hospital, University of Toronto, Toronto,, ON, Canada, 6Critical Care Medicine Dept, St Michael's Hospital, Toronto, ON, Canada, 7Medicine, Keenan Research Centre, St. Michael's Hospital, Toronto, ON, Canada, 8Physics, Ryerson University, Toronto, ON, Canada, 9Institute of Physiology, Charite - Universitaetsmedizin, Berlin, Germany, 10Medicine, University of Toronto, Toronto, ON, Canada.
Rationale
Acute respiratory distress syndrome (ARDS) occurs due to increased permeability of the alveolar-capillary membrane; the commonest cause is pneumonia. Its hallmark is heterogeneous involvement of the lung, with densely-consolidated areas interspersed with relatively normal lung. This heterogeneity complicates management. For instance, mechanical ventilation preferentially inflates normal regions of the lung, causing over-distension. Pharmaceutical agents administered by inhalation distribute to the healthy rather than the injured lung regions while those administered systemically are delivered throughout the body. The inability to deliver therapy solely to the injured areas of the ARDS lung remains an intractable problem.
Microbubbles are used routinely as a contrast agent; when exposed to ultrasound, they undergo cavitation that induces shear stress on nearby biological membranes, causing enhanced uptake of local therapeutics. Ultrasound of the lung has traditionally been considered of limited utility since air causes scattering of ultrasound. We postulated that this limitation can be harnessed in ARDS because ultrasound waves will only penetrate damaged areas of lung (i.e. fluid-filled or atelectatic), leaving normal areas unaffected. We hypothesized that ultrasound and microbubbles (USMB) may allow delivery of drugs preferentially to the injured regions of the lung.
Methods
We wished to establish both safety and efficacy of the technique using a murine model of gram-negative pneumonia. Balb/C mice were infected intratracheally with E. coli; we measured oxygen saturation before, during and 2 hours after intravenous injection of Definity™ microbubbles and thoracic ultrasound administration using a Sonos 5500 clinical ultrasound device and S3 transducer. In a second experiment we administered gentamicin (1.5 mg/kg) by intraperitoneal injection 6 hours after infection. Microbubbles were injected intravenously and thoracic ultrasound was applied. 18 hours later, lung homogenates were plated on agar.
Results
Infected mice developed hypoxemia, lung edema and neutrophilic lung injury. Microbubbles and ultrasound were well tolerated, with no change in oxygenation. Compared to gentamicin alone, USMB caused a 5-fold reduction in bacterial growth. BAL gentamicin levels were higher in USMB-treated mice.
Conclusions
Ultrasound-induced microbubble-cavitation enhances cellular uptake of drugs; this can be harnessed in ARDS since injured regions are fluid-filled. While almost all gram-negative isolates remain sensitive to aminoglycosides, this class of antibiotics has traditionally been avoided for treating pneumonia because of poor lung penetration and nephro- and ototoxicity. Using an E. coli-pneumonia model of ARDS, we show that USMB increases the efficacy of gentamicin, causing 5-fold-increased bacterial killing. USMB may be a useful tool for precision medicine in ARDS.