Study of vancomycin pharmacodynamics during ex vivo lung perfusion

• Grant number: 14/06930-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2014
• End date: August 31, 2015
• Field of knowledge: Health Sciences - Medicine - Surgery
• Principal Investigator: Marcos Naoyuki Samano
• Grantee: Paula Malvezzi Messias
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

The lack of suitable donors is one of the biggest barriers to increasing the number of lung transplants. In São Paulo, only 5% of donated lungs are suitable for transplant, in contrast to global rates, which are close to 15%. Poor lung function and infection are the main reasons for this high rejection rate. A technique currently used for lung reconditioning is the ex-vivo lung perfusion, which consists of lung ventilation and perfusion with a hypertonic solution, for prolonged periods of time and under a normothermic condition. This process enables pulmonary function recovery since it can reduce edema, the leading cause of lung deterioration in multiple organ donors. The potential of this technique to treat infected lungs has not been assessed, and since the infections are highly prevalent, this tool may be of great importance to increase the number of viable lungs for transplantation. A high incidence of positive cultures of bronchial secretions and Bronchoalveolar lavages of donors for Staphylococcus aureus was observed in lung donors, which motivated the choice for vancomycin for this study. Traditionally, vancomycin is used to treat pneumonia when there is suspicion that methicillin-resistant S. aureus (MRSA) is the etiologic agent. In general, the recommended minimum serum concentration is 10¼g/ml, but as the vancomycin's penetration in lung tissue is low, higher concentrations, of 15-20¼g/ml, are indicated. The lungs of multiple organ donors will be evaluated according to the standards adopted by InCor Lung Transplant Group, considering data provided by the Transplant Center of the Health State Secretary of São Paulo and the on-site assessment, including chest radiography, bronchoscopy, and bronchoalveolar lavage. Those who show signs of infection will be rejected for transplantation and selected to the project. Retrieval of the lungs will follow the standardized protocol for lung transplantation and the organs will be transported to the operation room. Ten perfusions will be performed. Preparation for the ex vivo perfusion will be aseptic and will include: separation of a fragment of the right lower lobe for biopsy; suture of the pulmonary artery and veins to the Xvivo® cannula set; retrograde perfusion of the Perfadex® solution; suction of tracheal secretion and tracheal connection to a conventional or tracheal tube. Every block will be placed in the perfusion chamber and connected to the Xvivo® perfusion system, which will be filled with two liters of Steen Solution®, to which will be added 500mg of methylprednisolone, 3000 IU of heparin, 500 mg of imipenem and 500mg of vancomycin, the object of this study. The lungs will undergo ex vivo perfusion for six hours. At the end of each hour, blood gases, ventilatory parameters, and pulmonary and atrial pressure will be assessed. The Steen solution® will be partially replaced and small aliquots of the perfusate will be collected for vancomycin concentration analysis. At the end of the first hour, a radiography of the lungs will be taken. After four hours of perfusion, new radiography will be performed, as well as a new biopsy of the right lower lobe. At the end of the sixth hour of ex vivo perfusion, a new bronchoalveolar lavage will be collected. Considering that vancomycin will be administered to infected lungs in order to treat the infection and recondition the organ, a concentration decrease beyond the levels predicted by the dilution of the perfuse may suggest the metabolism of the drug in the lungs. The evaluation of vancomycin concentration will also consider whether it remains at therapeutic levels, or if a complementary dose of the drug is required during the perfusion.(AU)