Successful 3-day lung preservation using a cyclic normothermic ex vivo lung perfusion strategy
Aadil Ali,
Antti I. Nykanen,
Erika Beroncal,
Edson Brambate,
Andrea Mariscal,
Vinicius Michaelsen,
Aizhou Wang,
Mitsuaki Kawashima,
Rafaela V.P. Ribeiro,
Yu Zhang,
Eddy Fan,
Laurent Brochard,
Jonathan Yeung,
Tom Waddell,
Mingyao Liu,
Ana C. Andreazza,
Shaf Keshavjee,
Marcelo Cypel
Affiliations
Aadil Ali
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Antti I. Nykanen
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Erika Beroncal
Departments of Pharmacology & Toxicology and Psychiatry, The Canada Mitochondrial Network, University of Toronto, Toronto, ON M5S 1A8, Canada
Edson Brambate
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Andrea Mariscal
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Vinicius Michaelsen
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Aizhou Wang
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Mitsuaki Kawashima
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Rafaela V.P. Ribeiro
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Yu Zhang
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Eddy Fan
Divisions of Respirology and Critical Care Medicine, University Health Network, University of Toronto, Toronto, ON M5B 1W8, Canada
Laurent Brochard
Divisions of Respirology and Critical Care Medicine, University Health Network, University of Toronto, Toronto, ON M5B 1W8, Canada; Keenan Research Centre, St Michael's Hospital, Unity Health Toronto and Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON M5B 1T8, Canada
Jonathan Yeung
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto Lung Transplant Program, Toronto, ON M5G 2C4, Canada
Tom Waddell
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto Lung Transplant Program, Toronto, ON M5G 2C4, Canada
Mingyao Liu
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto Lung Transplant Program, Toronto, ON M5G 2C4, Canada
Ana C. Andreazza
Departments of Pharmacology & Toxicology and Psychiatry, The Canada Mitochondrial Network, University of Toronto, Toronto, ON M5S 1A8, Canada
Shaf Keshavjee
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto Lung Transplant Program, Toronto, ON M5G 2C4, Canada
Marcelo Cypel
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto Lung Transplant Program, Toronto, ON M5G 2C4, Canada; Corresponding author at: Toronto General Hospital, 200 Elizabeth Street, 9N969, Toronto, ON M5G 2C4, Canada.
Summary: Background: Cold static preservation (CSP) at higher temperatures (10°C) has been recently shown as an optimal strategy up to 24-36h of preservation. Here, we hypothesized that alternating 10°C static storage with cycles of normothermic ex vivo lung perfusion (EVLP) would provide conditions for cellular “recharge”, allowing for multi-day lung preservation. Methods: Donor lungs from male Yorkshire pigs were preserved using 10°C CSP with two cycles of 4h EVLP. After a total of 3 days of preservation, a left lung transplant was performed followed by 4h of graft evaluation. As controls, 2 lungs were preserved solely with continuous 10°C preservation for 3 days and transplanted. Findings: For animals receiving lungs preserved using a cyclic EVLP protocol, lung function and histological structures were stable and the recipient systemic partial pressure of oxygen/fraction of inspired oxygen (P/F Ratio) after excluding the contralateral lung was 422 ± 61 mmHg. In contrast, lungs preserved solely in continuous cold static storage at 10°C for 72h developed massive lung failure, resulting in recipient death. Metabolomic analysis revealed that EVLP plays a critical role in the re-vitalization of key central carbon energy metabolites (Glucose, Succinate, N-Acetyl Aspartate) and reducing the expression of the inflammasome activation marker CASP1. Interpretation: In conclusion, we demonstrate for the first time the feasibility of 3-day lung preservation leading to excellent early post-transplant outcomes. The thoughtful combination of cold storage (10°C) and intermittent EVLP can open new opportunities in organ transplantation. Funding: This work was supported by the UHN Foundation (Grant#1013612).
