Advertisement
The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Evaluation of 10°C as the optimal storage temperature for aspiration-injured donor lungs in a large animal transplant model

  • Author Footnotes
    # Both authors have equal contributions.
    Etienne Abdelnour-Berchtold
    Footnotes
    # Both authors have equal contributions.
    Affiliations
    Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Author Footnotes
    # Both authors have equal contributions.
    Aadil Ali
    Footnotes
    # Both authors have equal contributions.
    Affiliations
    Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Cristina Baciu
    Affiliations
    Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Erika L. Beroncal
    Affiliations
    Departments of Pharmacology & Toxicology and Psychiatry, Mitochondrial Innovation Initiative, University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author
  • Aizhou Wang
    Affiliations
    Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Olivia Hough
    Affiliations
    Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Mitsuaki Kawashima
    Affiliations
    Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Manyin Chen
    Affiliations
    Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Yu Zhang
    Affiliations
    Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Mingyao Liu
    Affiliations
    Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Tom Waddell
    Affiliations
    Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

    Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto Lung Transplant Program, Toronto, Ontario, Canada
    Search for articles by this author
  • Ana C. Andreazza
    Affiliations
    Departments of Pharmacology & Toxicology and Psychiatry, Mitochondrial Innovation Initiative, University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author
  • Shaf Keshavjee
    Affiliations
    Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

    Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto Lung Transplant Program, Toronto, Ontario, Canada
    Search for articles by this author
  • Marcelo Cypel
    Correspondence
    Reprint requests: Marcelo Cypel, MD, MSc, FACS, FRCSC, Latner Thoracic Surgery Research Laboratories, Toronto General Hospital, 200 Elizabeth Street, 9N969, Toronto, ON M5G 2C4, Canada. Telephone: 416-340-5156, Fax: 416-340-3478.
    Affiliations
    Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

    Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto Lung Transplant Program, Toronto, Ontario, Canada
    Search for articles by this author
  • Author Footnotes
    # Both authors have equal contributions.
Published:September 08, 2022DOI:https://doi.org/10.1016/j.healun.2022.08.025

      Background

      Our recent work has challenged 4°C as an optimal lung preservation temperature by showing storage at 10°C to allow for the extension of preservation periods. Despite these findings, the impact of 10°C storage has not been evaluated in the setting of injured donor lungs.

      Methods

      Aspiration injury was created through bronchoscopic delivery of gastric juice (pH: 1.8). Injured donor lungs (n = 5/group) were then procured and blindly randomized to storage at 4°C (on ice) or at 10°C (in a thermoelectric cooler) for 12 hours. A third group included immediate transplantation. A left lung transplant was performed thereafter followed by 4 hours of graft evaluation.

      Results

      After transplantation, lungs stored at 10°C showed significantly better oxygenation when compared to 4°C group (343 ± 43 mm Hg vs 128 ± 76 mm Hg, p = 0.03). Active metabolism occurred during the 12 hours storage period at 10°C, producing cytoprotective metabolites within the graft. When compared to lungs undergoing immediate transplant, lungs preserved at 10°C tended to have lower peak airway pressures (p = 0.15) and higher dynamic lung compliances (p = 0.09). Circulating cell-free mitochondrial DNA within the recipient plasma was significantly lower for lungs stored at 10°C in comparison to those underwent immediate transplant (p = 0.048), alongside a tendency of lower levels of tissue apoptotic cell death (p = 0.075).

      Conclusions

      We demonstrate 10°C as a potentially superior storage temperature for injured donor lungs in a pig model when compared to the current clinical standard (4°C) and immediate transplantation. Continuing protective metabolism at 10°C for donor lungs may result in better transplant outcomes.

      KEYWORDS

      Abbreviations:

      EVLP (ex vivo lung perfusion), ccf mtDNA (circulating cell-free mitochondrial DNA), P/F (PaO2/FiO2), ALI (acute lung injury.)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Heart and Lung Transplantation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Punch JD
        • Hayes DH
        • Laporte FB
        • McBride V
        • Seely MS.
        Organ donation and utilization in the United States, 1996-2005.
        Am J Transplant. 2007; 7: 1327-1338https://doi.org/10.1111/j.1600-6143.2007.01779.x
        • Yusen RD
        • Edwards LB
        • Dipchand AI
        • et al.
        The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Lung and Heart–Lung Transplant Report—2016; Focus Theme: Primary Diagnostic Indications for Transplant.
        J Hear Lung Transplant. 2016; 35: 1170-1184https://doi.org/10.1016/j.healun.2016.09.001
        • Bharat A
        • Narayanan K
        • Street T
        • et al.
        Early posttransplant inflammation promotes the development of alloimmunity and chronic human lung allograft rejection.
        Transplantation. 2007; 83: 150-158https://doi.org/10.1097/01.tp.0000250579.08042.b6
        • Lee JC
        • Christie JD
        • Keshavjee S.
        Primary graft dysfunction: definition, risk factors, short- and long-term outcomes.
        Semin Respir Crit Care Med. 2010; 31: 161-171https://doi.org/10.1055/s-0030-1249111
        • Antin-Ozerkis D
        • Christie J
        Evaluation of hypoxemia and respiratory failure in the early period after lung transplantation.
        Clin Pulm Med. 2007; 14: 99-105https://doi.org/10.1097/01.cpm.0000257589.07226.a2
        • V.J. SL, E. M, J.C. RA
        Primary graft dysfunction after lung transplantation.
        Med Intensiva. 2012; 36: 506-512https://doi.org/10.1016/j.medin.2012.03.017
        • Schwarz S
        • Rahimi N
        • Kifjak D
        • et al.
        Lungs from polytrauma donors with significant chest trauma can be safely used for transplantation.
        J Thorac Cardiovasc Surg. 2021; 163https://doi.org/10.1016/j.jtcvs.2020.10.150
        • Keshavjee SH
        • Yamazaki F
        • Cardoso PF
        • McRitchie DI
        • Patterson GA
        • Cooper JD.
        A method for safe twelve-hour pulmonary preservation.
        J Thorac Cardiovasc Surg. 1989; 98: 529-534
        • Ali A
        • Wang A
        • Ribeiro RVP
        • et al.
        Static lung storage at 10°C maintains mitochondrial health and preserves donor organ function.
        Sci Transl Med. 2021; 13: 1-14
        • Mariscal A
        • Caldarone L
        • Tikkanen J
        • et al.
        Pig lung transplant survival model.
        Nat Protoc. 2018; https://doi.org/10.1038/s41596-018-0019-4
        • Chong J
        • Soufan O
        • Li C
        • et al.
        MetaboAnalyst 4.0: Towards more transparent and integrative metabolomics analysis.
        Nucleic Acids Res. 2018; https://doi.org/10.1093/nar/gky310
        • Ginsberg HS
        • Lundholm-Beauchamp U
        • Horswood RL
        • et al.
        Role of early region 3 (E3) in pathogenesis of adenovirus disease.
        Proc Natl Acad Sci U S A. 1989; https://doi.org/10.1073/pnas.86.10.3823
        • Van Raemdonck D
        • Hartwig MG
        • Hertz MI
        • et al.
        Report of the ISHLT Working Group on primary lung graft dysfunction Part IV: prevention and treatment: a 2016 consensus group statement of the international society for heart and lung transplantation.
        J Hear Lung Transplant. 2017; 36: 1121-1136https://doi.org/10.1016/j.healun.2017.07.013
        • de Perrot M
        • Liu M
        • Waddell TK
        • Keshavjee S.
        Ischemia-reperfusion-induced lung injury.
        Am J Respir Crit Care Med. 2003; 167: 490-511https://doi.org/10.1164/rccm.200207-670SO
        • Sommer SP
        • Gohrbandt B
        • Fischer S
        • et al.
        Glutathione improves the function of porcine pulmonary grafts stored for 24 hours in low-potassium dextran solution.
        J Thorac Cardiovasc Surg. 2005; https://doi.org/10.1016/j.jtcvs.2005.05.021
        • Kearns SR
        • Kelly CJ
        • Barry M
        • et al.
        Vitamin C reduces ischaemia-reperfusion-induced acute lung injury.
        Eur J Vasc Endovasc Surg. 1999; 17: 533-536https://doi.org/10.1053/ejvs.1999.0833
        • Shimada K
        • Crother TR
        • Karlin J
        • et al.
        Oxidized mitochondrial DNA Activates the NLRP3 inflammasome during apoptosis.
        Immunity. 2012; https://doi.org/10.1016/j.immuni.2012.01.009
        • Dias I
        • Milic I
        • Heiss C
        • et al.
        Inflammation, lipid (per)oxidation and redox regulation.
        Antioxid Redox Signal. 2020; https://doi.org/10.1089/ars.2020.8022
        • Yabal M
        • Calleja DJ
        • Simpson DS
        • Lawlor KE.
        Stressing out the mitochondria: mechanistic insights into NLRP3 inflammasome activation.
        J Leukoc Biol. 2019; https://doi.org/10.1002/JLB.MR0318-124R
        • Xiong S
        • Mu T
        • Wang G
        • Jiang X.
        Mitochondria-mediated apoptosis in mammals.
        Protein Cell. 2014; https://doi.org/10.1007/s13238-014-0089-1
        • Wang LS
        • Yoshikawa K
        • Miyoshi S
        • et al.
        The effect of ischemic time and temperature on lung preservation in a simple ex vivo rabbit model used for functional assessment.
        J Thorac Cardiovasc Surg. 1989; 98: 333-342
        • Date H
        • Lima O
        • Matsumura A
        • Tsuji H
        • d'Avignon DA
        • Cooper JD.
        In a canine model, lung preservation at 10 degrees C is superior to that at 4 degrees C. A comparison of two preservation temperatures on lung function and on adenosine triphosphate level measured by phosphorus 31-nuclear magnetic resonance.
        J Thorac Cardiovasc Surg. 1992; 103: 773-780
        • Nakamoto K
        • Maeda M
        • Taniguchi K
        • Tsubota N
        • Kawashima Y.
        A study on optimal temperature for isolated lung preservation.
        Ann Thorac Surg. 1992; https://doi.org/10.1016/0003-4975(92)90766-W
        • Chambers DC
        • Cherikh WS
        • Goldfarb SB
        • et al.
        The international thoracic organ transplant registry of the international society for heart and lung transplantation: thirty-fifth adult lung and heart-lung transplant report—2018; focus theme: multiorgan transplantation.
        J Hear Lung Transplant. 2018; https://doi.org/10.1016/j.healun.2018.07.020
        • Olbertz C
        • Pizanis N
        • Bäumker H
        • et al.
        Effects of immediate vs delayed ex-vivo lung perfusion in a porcine cardiac arrest donation model.
        Int J Artif Organs. 2019; 42: 362-369https://doi.org/10.1177/0391398819841618
        • Mulloy DP
        • Stone ML
        • Crosby IK
        • et al.
        Ex vivo rehabilitation of non–heart-beating donor lungs in preclinical porcine model: Delayed perfusion results in superior lung function.
        J Thorac Cardiovasc Surg. 2012; https://doi.org/10.1016/j.jtcvs.2012.07.056
        • Trumpff C
        • Michelson J
        • Lagranha CJ
        • et al.
        Stress and circulating cell-free mitochondrial DNA: a systematic review of human studies, physiological considerations, and technical recommendations.
        Mitochondrion. 2021; https://doi.org/10.1016/j.mito.2021.04.002
        • Cypel M
        • Yeung JC
        • Liu M
        • et al.
        Normothermic ex vivo lung perfusion in clinical lung transplantation.
        N Engl J Med. 2011; 364: 1431-1440
        • Ali A
        • Watanabe Y
        • Galasso M
        • et al.
        An extracellular oxygen carrier during prolonged pulmonary preservation improves post-transplant lung function.
        J Hear Lung Transplant. 2020; https://doi.org/10.1016/j.healun.2020.03.027
        • Nakajima D
        • Liu M
        • Ohsumi A
        • et al.
        Lung lavage and surfactant replacement during ex vivo lung perfusion for treatment of gastric acid aspiration-induced donor lung injury.
        J Hear Lung Transplant. 2017; 36: 577-585
        • Inci I
        • Hillinger S
        • Arni S
        • et al.
        Surfactant improves graft function after gastric acid-induced lung damage in lung transplantation.
        Ann Thorac Surg. 2013; 95: 1013-1019https://doi.org/10.1016/j.athoracsur.2012.10.027